Bio


Clinical Focus: Cardiovascular Medicine: Atrial Fibrillation; Chronic CAD; ACS;

Research Focus:

My primary research interest is the design and conduct of multicenter clinical trials and analyses of important clinical cardiac issues using large patient databases. My research focuses on novel anticoagulation agents for the treatment of acute coronary syndromes and atrial fibrillation, the study of agents targeted to protect the myocardium during reperfusion therapy for acute myocardial infarction, and the evaluation of cardiovascular safety of diabetic therapies. I am also interested in the methodology of clinical trials. Current research activities include standardization of the definition of myocardial infarction used in clinical trials, the adjudication of suspected clinical endpoint events by Clinical Event Committees (CEC), and the efficient operational conduct of large multinational clinical trials.

Administrative Focus: Associate Dean, Clinical Research School of Medicine; Vice Chair of Clinical Research Department of Medicine; Director Stanford Center for Clinical Research; Member of the Stanford IRB

Professional Training:

1985 Stanford University, BS Chemistry
1989 University of Washington, MD
1993 University of Arizona, Internship/Residency/Chief Residency
1996 Duke University, Fellowship in Cardiology
1996 Duke University, Faculty in Cardiology
2013 Stanford University, Faculty Cardiovascular Medicine

Clinical Focus


  • Cardiovascular Disease

Academic Appointments


Administrative Appointments


  • Vice Chair of Clinical Research, Department of Medicine (2013 - Present)
  • Member, Stanford Diabetes Research Center (2017 - Present)
  • Steering Committee Member, Department of Medicine Team Science Initiative, Department of Medicine (2022 - Present)

Boards, Advisory Committees, Professional Organizations


  • Editorial Board Member, Current Cardiology Reviews (2004 - Present)
  • Associate Editor, American Heart Journal (2005 - Present)
  • Editorial Board Member, Current Cardiology Reports (2012 - Present)
  • Editorial Board Member, Cardiology & Therapy Journal (2012 - Present)

Professional Education


  • Fellowship: Duke University (1996) NC
  • Residency: University of Arizona Internal Medicine Residency (1993) AZ
  • Medical Education: University of Washington Medical Center (1989) WA
  • Board Certification: American Board of Internal Medicine, Cardiovascular Disease (1997)

Clinical Trials


  • Engaging Self-regulation Targets to Improve Mood and Weight and Understand Mechanism in Depressed and Obese Adults Recruiting

    Multimorbidity (i.e., the coexistence of 2 or more chronic conditions in an individual) is increasingly recognized as a pressing public health problem. Effective interventions targeting coexisting depression and obesity are critical given the high prevalence and worsened outcomes for patients with both conditions. ENGAGE-2 is a pilot randomized controlled trial (RCT). The objective is to investigate the outcomes and mechanisms of an integrated depression and obesity intervention that combines collaborative stepped depression treatment and evidence-based behavioral weight loss treatment. The Integrated Coaching for Better Mood and Weight-2 (I-CARE2) intervention synergistically integrates 2 proven national programs: the Program to Encourage Active and Rewarding Lives (PEARLS) for depression care and the Group Lifestyle Balance (GLB) program for weight loss and cardiometabolic risk reduction. In Phase 1 of the ENGAGE project, investigators developed a new protocol to quantify activation and connectivity of the Affective, Cognitive Control, and Default Mode brain circuits from functional magnetic resonance imaging (fMRI) among 108 depressed obese patients. Investigators implement the same fMRI protocol in this second phase of the project to examine the mechanistic role of these brain circuits as potential neural targets in treatment engagement and response in the I-CARE2 intervention. A new sample of 105 depressed obese patients are randomized in a 2:1 ratio to receive the I-CARE2 intervention (n=70) or usual care (n=35). Study assessments occur at 0 (baseline), 2 and 6 months. Investigators hypothesize that 1 or more of the neural targets under study will moderate (baseline state) and/or mediate (change at follow-up) the effect of the I-CARE2 intervention versus usual care on health behaviors (problem-solving ability, dietary intakes, physical activity) and clinical outcomes (weight loss, depression, anxiety).

    View full details

  • Project Baseline Health Study Not Recruiting

    This study is the first initiative of Project Baseline, a broader effort designed to develop a well-defined reference, or "baseline," of good health as well as a rich data platform that may be used to better understand the transition from health to disease and identify additional risk factors for disease. Project Baseline endeavors to test and develop new tools and technologies to collect, organize, and activate health information.

    Stanford is currently not accepting patients for this trial.

    View full details

Projects


All Publications


  • Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial. European heart journal Neuen, B. L., Oshima, M., Perkovic, V., Agarwal, R., Arnott, C., Bakris, G., Cannon, C. P., Charytan, D. M., Edwards, R., Gorriz, J. L., Jardine, M. J., Levin, A., Neal, B., De Nicola, L., Pollock, C., Rosenthal, N., Wheeler, D. C., Mahaffey, K. W., Heerspink, H. J. 2021

    Abstract

    AIMS: Hyperkalaemia is a common complication of type 2 diabetes mellitus (T2DM) and limits the optimal use of agents that block the renin-angiotensin-aldosterone system, particularly in patients with chronic kidney disease (CKD). In patients with CKD, sodium‒glucose cotransporter 2 (SGLT2) inhibitors provide cardiorenal protection, but whether they affect the risk of hyperkalaemia remains uncertain.METHODS AND RESULTS: The CREDENCE trial randomized 4401 participants with T2DM and CKD to the SGLT2 inhibitor canagliflozin or matching placebo. In this post hoc analysis using an intention-to-treat approach, we assessed the effect of canagliflozin on a composite outcome of time to either investigator-reported hyperkalaemia or the initiation of potassium binders. We also analysed effects on central laboratory-determined hyper- and hypokalaemia (serum potassium ≥6.0 and <3.5mmol/L, respectively) and change in serum potassium. At baseline, the mean serum potassium in canagliflozin and placebo arms was 4.5mmol/L; 4395 (99.9%) participants were receiving renin-angiotensin system blockade. The incidence of investigator-reported hyperkalaemia or initiation of potassium binders was lower with canagliflozin than with placebo [occurring in 32.7 vs. 41.9 participants per 1000 patient-years; hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.64-0.95, P=0.014]. Canagliflozin similarly reduced the incidence of laboratory-determined hyperkalaemia (HR 0.77, 95% CI 0.61-0.98, P=0.031), with no effect on the risk of hypokalaemia (HR 0.92, 95% CI 0.71-1.20, P=0.53). The mean serum potassium over time with canagliflozin was similar to that of placebo.CONCLUSION: Among patients treated with renin-angiotensin-aldosterone system inhibitors, SGLT2 inhibition with canagliflozin may reduce the risk of hyperkalaemia in people with T2DM and CKD without increasing the risk of hypokalaemia.

    View details for DOI 10.1093/eurheartj/ehab497

    View details for PubMedID 34423370

  • Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial. Diabetologia Sen, T., Li, J., Neuen, B. L., Neal, B., Arnott, C., Parikh, C. R., Coca, S. G., Perkovic, V., Mahaffey, K. W., Yavin, Y., Rosenthal, N., Hansen, M. K., Heerspink, H. J. 2021

    Abstract

    AIMS/HYPOTHESIS: Higher plasma concentrations of tumour necrosis factor receptor (TNFR)-1, TNFR-2 and kidney injury molecule-1 (KIM-1) have been found to be associated with higher risk of kidney failure in individuals with type 2 diabetes in previous studies. Whether drugs can reduce these biomarkers is not well established. We measured these biomarkers in samples of the CANVAS study and examined the effect of the sodium-glucose cotransporter 2 inhibitor canagliflozin on these biomarkers and assessed whether the early change in these biomarkers predict cardiovascular and kidney outcomes in individuals with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS).METHODS: Biomarkers were measured with immunoassays (proprietary multiplex assay performed by RenalytixAI, New York, NY, USA) at baseline and years 1, 3 and 6. Mixed-effects models for repeated measures assessed the effect of canagliflozin vs placebo on the biomarkers. Associations of baseline levels and the early change (baseline to year 1) for each biomarker with the kidney outcome were assessed using multivariable-adjusted Cox regression.RESULTS: In total, 3523/4330 (81.4%) of the CANVAS participants had available samples at baseline. Each doubling in baseline TNFR-1, TNFR-2 and KIM-1 was associated with a higher risk of kidney outcomes, with corresponding HRs of 3.7 (95% CI 2.3, 6.1; p<0.01), 2.7 (95% CI 2.0, 3.6; p<0.01) and 1.5 (95% CI 1.2, 1.8; p<0.01), respectively. Canagliflozin reduced the level of the plasma biomarkers with differences in TNFR-1, TNFR-2 and KIM-1 between canagliflozin and placebo during follow-up of 2.8% (95% CI 3.4%, 1.3%; p<0.01), 1.9% (95% CI 3.5%, 0.2%; p=0.03) and 26.7% (95% CI 30.7%, 22.7%; p<0.01), respectively. Within the canagliflozin treatment group, each 10% reduction in TNFR-1 and TNFR-2 at year 1 was associated with a lower risk of the kidney outcome (HR 0.8 [95% CI 0.7, 1.0; p=0.02] and 0.9 [95% CI 0.9, 1.0; p<0.01] respectively), independent of other patient characteristics. The baseline and 1year change in biomarkers did not associate with cardiovascular or heart failure outcomes.CONCLUSIONS/INTERPRETATION: Canagliflozin decreased KIM-1 and modestly reduced TNFR-1 and TNFR-2 compared with placebo in individuals with type 2 diabetes in CANVAS. Early decreases in TNFR-1 and TNFR-2 during canagliflozin treatment were independently associated with a lower risk of kidney disease progression, suggesting that TNFR-1 and TNFR-2 have the potential to be pharmacodynamic markers of response to canagliflozin.

    View details for DOI 10.1007/s00125-021-05512-5

    View details for PubMedID 34415356

  • Reasons for hospitalizations in patients with type 2 diabetes mellitus in the CANVAS Program: a secondary analysis. Diabetes, obesity & metabolism Feng, K. Y., Li, J., Ianus, J., de Zeeuw, D., Fulcher, G. R., Pfeifer, M., Matthews, D. R., Jardine, M. J., Perkovic, V., Neal, B., Mahaffey, K. W. 2021

    Abstract

    AIMS: To determine the reasons for hospitalizations in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program and the effects of the sodium glucose co-transporter 2 inhibitor canagliflozin on hospitalization.MATERIALS AND METHODS: A secondary analysis was performed on the CANVAS Program that included 10,142 participants with type 2 diabetes mellitus randomized to canagliflozin or placebo. The primary outcome was total (first plus all recurrent) all-cause hospitalization (ACH). Secondary outcomes were total hospitalizations categorized by the Medical Dictionary for Regulatory Activities hierarchy at the system organ class level, reported by investigators at each center. Outcomes were assessed using negative binomial models.RESULTS: Of the 7115 hospitalizations reported, the most common reasons were cardiac disorders (23.7%), infections and infestations (15.0%), and nervous system disorders (9.0%). The rate of total ACH was lower in the canagliflozin group (n=5795) compared to the placebo group (n=4347): 197.9 versus 215.8 participants per 1000 patient-years, respectively (rate ratio [RR] 0.92; 95% confidence interval [CI] 0.86, 0.98). Canagliflozin reduced the rate of total hospitalizations due to cardiac disorders (RR 0.81; 95% CI 0.75, 0.88). There was no significant difference between the canagliflozin and placebo groups in the rates of total hospitalizations due to infections and infestations (RR 0.96; 95% CI 0.86, 1.02) or nervous system disorders (RR 0.96; 95% CI 0.88, 1.05).CONCLUSIONS: In the CANVAS Program, the most common reasons for hospitalization were cardiac disorders, infections and infestations, and nervous system disorders. Canagliflozin, compared with placebo, reduced the rate of total ACH. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/dom.14525

    View details for PubMedID 34402161

  • Cost-Consequence Analysis of Using Cangrelor in High Angiographic Risk Percutaneous Coronary Intervention Patients: A US Hospital Perspective. American journal of cardiovascular drugs : drugs, devices, and other interventions Jensen, I. S., Wu, E., Cyr, P. L., Claussen, M., Winkler, T., Salahuddin, K., Prats, J., Mahaffey, K. W., Gibson, C. M., Steg, P. G., Stone, G. W., Bhatt, D. L. 2021

    Abstract

    OBJECTIVES: The objective of this study was to evaluate a US hospital's cost implications and outcomes of cangrelor use in percutaneous coronary intervention (PCI) patients with two or more angiographic high-risk features (HRFs), including avoidance of oral P2Y12 inhibitor pretreatment in patients requiring cardiac surgery. Intravenous cangrelor provides direct, immediate onset and rapid-offset P2Y12 inhibition, which may reduce the necessity for oral P2Y12 pretreatment.METHODS: A decision analytic model was developed, estimating the annual impact over 3 years of cangrelor availability. Ischemic and bleeding events (48h) from randomized clinical trial data were extrapolated to 30 days. Event costs were from the CHAMPION PHOENIX Economics substudy. Rates of coronary artery disease (CAD) presentation, PCI, oral P2Y12 pretreatment, and inpatient hospitalization costs were from published literature and clinical experts. Scenario analyses evaluated the impact of cangrelor availability on potential reduced P2Y12 pretreatment rates by 50-100%. Drug costs were 2019 wholesale acquisition costs and, where necessary, all costs were adjusted to 2019 dollars.RESULTS: In a hospital treating 1000 CAD PCI inpatients annually, increasing cangrelor use from 11 to 32% resulted in a reduction in 48-h ischemic events/year by 5.7%, while bleeding events increased by 2.9%. Total costs of $1,135,472 declined 12.8%, with a 50% reduction in P2Y12 pretreatment or 30% with no pretreatment. Savings were driven by a decrease in ischemic events, decrease in glycoprotein IIb/IIIa inhibitor use, and less need for and shorter oral P2Y12 inhibitor washout period for surgery patients.CONCLUSION: Use of cangrelor in patients with two or more angiographic HRFs may improve outcomes and lower hospital budgets, mainly from avoiding surgery delays necessitated by oral P2Y12 inhibitor pretreatment.

    View details for DOI 10.1007/s40256-021-00491-9

    View details for PubMedID 34331235

  • Ankle-Brachial Index for Risk Stratification in Patients With Symptomatic Peripheral Artery Disease With and Without Prior Lower Extremity Revascularization: Observations From the EUCLID Trial. Circulation. Cardiovascular interventions Hiatt, W. R., Hess, C. N., Bonaca, M. P., Kavanagh, S., Patel, M. R., Baumgartner, I., Berger, J. S., Blomster, J. I., Jones, W. S., Katona, B. G., Mahaffey, K. W., Norgren, L., Rockhold, F. W., Fowkes, F. G. 2021: CIRCINTERVENTIONS120009871

    Abstract

    BACKGROUND: A reduced ankle-brachial index (ABI) is a measure of atherosclerosis and is associated with ischemic risk in the general population. Whether this relationship is maintained in peripheral artery disease after lower extremity revascularization (LER), which can modify ABI, is unknown.METHODS: The EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) enrolled 13 885 patients with symptomatic peripheral artery disease; 57% with prior LER, and 43% with ABI ≤0.80. The primary major adverse cardiovascular events (MACE) outcome was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Major adverse limb events (MALE) included acute limb ischemia and major amputation. An adjusted Cox proportional hazards model demonstrated a nonlinear relationship between ABI and outcomes. A restricted cubic spline model with 4 knots was developed to identify the best fitting model to describe the relationship between ABI and MACE and MALE risk.RESULTS: Baseline ABI (mean±SD) was 0.77±0.21 in participants with prior LER and 0.63±0.14 in those without prior LER (P<0.0001). There was no statistical interaction between prior LER and ABI, meaning the shapes of the cubic spline models were similar between groups. In those with prior LER, for every 0.10 unit lower ABI below an ABI of 1.00, the hazard ratio for MACE was 1.08 (95% CI, 1.04-1.12; P<0.0001), below an ABI of 0.80 the hazard ratio for MALE was 1.32 (95% CI, 1.21-1.43; P<0.0001). In patients without prior LER, every 0.10 unit lower ABI below an ABI of 0.70 was associated with increased risk for MACE (hazard ratio, 1.14 [95% CI, 1.06-1.23]; P=0.0004) and MALE (hazard ratio, 1.27 [95% CI, 1.08-1.49]; P=0.003).CONCLUSIONS: Patients with established peripheral artery disease, particularly those with prior LER, have an increased risk of MACE and MALE. The ABI remains a strong predictor of MACE and MALE ischemic events with an inverse relationship below an ABI threshold for patients with and without prior LER.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

    View details for DOI 10.1161/CIRCINTERVENTIONS.120.009871

    View details for PubMedID 34253048

  • Assessment of North American Clinical Research Site Performance During the Start-up of Large Cardiovascular Clinical Trials. JAMA network open Goyal, A., Schibler, T., Alhanti, B., Hannan, K. L., Granger, C. B., Blazing, M. A., Lopes, R. D., Alexander, J. H., Peterson, E. D., Rao, S. V., Green, J. B., Roe, M. T., Rorick, T., Berdan, L. G., Reist, C., Mahaffey, K. W., Harrington, R. A., Califf, R. M., Patel, M. R., Hernandez, A. F., Jones, W. S. 2021; 4 (7): e2117963

    Abstract

    Importance: Randomized clinical trials (RCTs) are critical in advancing patient care, yet conducting such large-scale trials requires tremendous resources and coordination. Clinical site start-up performance metrics can provide insight into opportunities for improved trial efficiency but have not been well described.Objective: To measure the start-up time needed to reach prespecified milestones across sites in large cardiovascular RCTs in North America and to evaluate how these metrics vary by time and type of regulatory review process.Design, Setting, and Participants: This cohort study evaluated cardiovascular RCTs conducted from July 13, 2004, to February 1, 2017. The RCTs were coordinated by a single academic research organization, the Duke Clinical Research Institute. Nine consecutive trials with completed enrollment and publication of results in their target journal were studied. Data were analyzed from December 4, 2019, to January 11, 2021.Exposures: Year of trial enrollment initiation (2004-2007 vs 2008-2012) and use of a central vs local institutional review board (IRB).Main Outcomes and Measures: The primary outcome was the median start-up time (from study protocol delivery to first participant enrollment) as compared by trial year and type of IRB used. The median start-up time for the top 10% of sites was also reported. Secondary outcomes included time to site regulatory approval, time to contract execution, and time to site activation.Results: For the 9 RCTs included, the median site start-up time shortened only slightly over time from 267 days (interquartile range [IQR], 185-358 days) for 2004-2007 trials to 237 days (IQR, 162-343 days) for 2008-2012 trials (overall median, 255 days [IQR, 177-350 days]; P<.001). For the top 10% of sites, median start-up time was 107 days (IQR, 95-121 days) for 2004-2007 trials vs 104 days (IQR, 84-118 days) for 2008-2012 trials (overall median, 106 days [IQR, 90-120 days]; P=.04). The median start-up time was shorter among sites using a central IRB (199 days [IQR, 140-292 days]) than those using a local IRB (287 days [IQR, 205-390 days]; P<.001).Conclusions and Relevance: This cohort study of North American research sites in large cardiovascular RCTs found a duration of nearly 9 months from the time of study protocol delivery to the first participant enrollment; this metric was only slightly shortened during the study period but was reduced to less than 4 months for top-performing sites. These findings suggest that the use of central IRBs has the potential to improve RCT efficiency.

    View details for DOI 10.1001/jamanetworkopen.2021.17963

    View details for PubMedID 34297072

  • Canagliflozin, serum magnesium and cardiovascular outcomes-Analysis from the CANVAS Program. Endocrinology, diabetes & metabolism Wang, K. M., Li, J., Bhalla, V., Jardine, M. J., Neal, B., de Zeeuw, D., Fulcher, G., Perkovic, V., Mahaffey, K. W., Chang, T. I. 2021; 4 (3): e00247

    Abstract

    Background: Patients with type 2 diabetes (T2D) are predisposed to derangements in serum Magnesium (Mg), which may have implications for cardiometabolic events and outcomes. In clinical trials, participants with T2D randomized to sodium-glucose co-transporter 2 (SGLT2) inhibitors have shown mild to moderate increases in serum Mg from baseline levels. This post hoc analysis assesses the relation between serum Mg with cardiovascular outcomes in 10,140 participants of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program.Methods: We evaluated the association of baseline serum Mg with the primary composite end point of death from cardiovascular causes, non-fatal myocardial infarction, and non-fatal stroke, and tested whether this association is modified by baseline serum Mg. Using mediation analysis, we determined whether change in serum Mg post-randomization mediates the beneficial effect of canagliflozin on cardiovascular outcomes.Results: Mean serum Mg levels at baseline were 0.77±0.09mmol/L in both canagliflozin group and placebo groups. The canagliflozin group experienced an average increase in serum Mg by 0.07mmol/L (95% CI, 0.065-0.072mmol/L; p<.001) for the duration of the trial. We found no association between baseline serum Mg levels and the primary composite end point, and no evidence of effect modification by baseline Mg levels. Change in serum Mg post-randomization was not a mediator of the effects of canagliflozin on cardiovascular outcomes.Conclusions: In participants of the CANVAS Program, baseline and post-randomization serum Mg levels are not associated with cardiovascular outcomes.

    View details for DOI 10.1002/edm2.247

    View details for PubMedID 34277971

  • Impact of chronic kidney disease on hemoglobin among patients with peripheral artery disease treated with P2Y12 inhibitors: Insights from the EUCLID trial. Vascular medicine (London, England) Hsia, J., Kavanagh, S. T., Hopley, C. W., Baumgartner, I., Berger, J. S., Fowkes, G. R., Jones, W. S., Mahaffey, K. W., Norgren, L., Patel, M. R., Rockhold, F., Blomster, J., Katona, B. G., Hiatt, W. R., Bonaca, M. P. 2021: 1358863X211017641

    Abstract

    Patients with chronic kidney disease may develop new or more severe anemia when treated with antiplatelet agents due to blood loss in conjunction with impaired erythropoiesis. Because anemia independently predicts limb amputation and mortality among patients with peripheral artery disease (PAD), we evaluated the relationship between estimated glomerular filtration rate (eGFR) and hemoglobin (Hb) levels in the EUCLID trial in which patients with symptomatic PAD were randomized to ticagrelor or clopidogrel. At baseline, 9025, 1870, and 1000 patients had eGFR ⩾ 60, 45-59, and < 45 mL/min/1.73 m2, respectively. The mean fall in Hb during the trial was 0.46 ± 1.68 g/dL and did not differ by baseline eGFR category, although Hb fall ⩾ 10% was more frequent among patients with lower eGFR (p for trend < 0.0001). On-study treatment with iron, erythropoiesis-stimulating agents, and/or red blood cell transfusion was reported for 479 (5.3%), 165 (8.8%), and 129 (12.9%) patients in the three eGFR categories, respectively (p for trend < 0.0001). After adjustment for baseline and post-randomization effects, those not receiving anemia treatment had a smaller reduction in Hb from baseline than those receiving anemia treatment (p < 0.0001). Other determinants of Hb reduction included absence of on-study myocardial infarction, coronary or peripheral revascularization, residence outside North America, male sex, and baseline eGFR. We conclude that among patients with PAD treated with P2Y12 inhibitors, lower baseline eGFR was associated with a greater reduction in Hb. ClinicalTrials.gov Identifier: NCT01732822.

    View details for DOI 10.1177/1358863X211017641

    View details for PubMedID 34082620

  • Pharmacotherapy for diabetes and stroke risk: Results from ROCKET AF. Heart rhythm O2 Ugowe, F. E., Hellkamp, A. S., Wang, A., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Patel, M. R., Piccini, J. P., of the ROCKET AF Steering Committee and Investigators 2021; 2 (3): 215-222

    Abstract

    Background: Insulin use may be a better predictor of stroke risk and morbidity and mortality than diabetes in patients with atrial fibrillation (AF).Objectives: Determine if the increased risk of stroke observed in patients with AF and diabetes is restricted to those treated with insulin.Methods: We analyzed the association between diabetes and treatment and the occurrence of stroke/systemic embolism, myocardial infarction (MI), all-cause death, vascular death, composite outcomes, and bleeding risk in the ROCKET AF trial.Results: In a cohort of 14,264 patients, there were 40.3% (n= 5746) with diabetes, 5.9% (n = 842) on insulin, 18.9% (n = 2697) on oral medications, and 11.9% (n = 1703) diet-controlled. Compared to those without diabetes, patients with non-insulin-treated diabetes had increased risks of stroke (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.06-1.68), MI (HR 1.64, 95% CI 1.17-2.30), all-cause death (HR 1.26, 95% CI 1.08-1.46), vascular death (HR 1.33, 95% CI 1.11-1.60), and composite outcomes (HR 1.37, 95% CI 1.18-1.157). Patients with insulin-treated diabetes had a significantly higher risk of MI (HR 2.31, 95% CI 1.33-4.01) and composite outcomes (HR 1.57, 95% CI 1.19-2.08) compared to those without diabetes. There were no significant differences between insulin-treated and non-insulin-treated diabetes for any outcome.Conclusion: Among patients with AF and diabetes, there were no significant differences in outcomes in insulin-treated diabetes compared to non-insulin-treated diabetes.

    View details for DOI 10.1016/j.hroo.2021.04.001

    View details for PubMedID 34337571

  • Association of Heart Failure With Outcomes Among Patients With Peripheral Artery Disease: Insights From EUCLID. Journal of the American Heart Association Samsky, M. D., Hellkamp, A., Hiatt, W. R., Fowkes, F. G., Baumgartner, I., Berger, J. S., Katona, B. G., Mahaffey, K. W., Norgren, L., Blomster, J. I., Rockhold, F. W., DeVore, A. D., Patel, M. R., Jones, W. S. 2021: e018684

    Abstract

    Background Peripheral artery disease (PAD) and heart failure (HF) are each independently associated with poor outcomes. Risk factors associated with new-onset HF in patients with primary PAD are unknown. Furthermore, how the presence of HF is associated with outcomes in patients with PAD is unknown. Methods and Results This analysis examined risk relationships of HF on outcomes in patients with symptomatic PAD randomized to ticagrelor or clopidogrel as part of the EUCLID (Examining Use of Ticagrelor in Peripheral Arterial Disease) trial. Patients were stratified based on presence of HF at enrollment. Cox models were used to determine the association of HF with outcomes. A separate Cox model was used to identify risk factors associated with development of HF during follow-up. Patients with PAD and HF had over twice the rate of concomitant coronary artery disease as those without HF. Patients with PAD and HF had significantly increased risk of major adverse cardiovascular events (hazard ratio [HR], 1.31; 95% CI, 1.13-1.51) and all-cause mortality (HR, 1.39; 95% CI, 1.19-1.63). In patients with PAD, the presence of HF was associated with significantly less bleeding (HR, 0.65; 95% CI, 0.45-0.96). Characteristics associated with HF development included age ≥66 (HR, 1.29; 95% CI, 1.18-1.40 per 5years), diabetes mellitus (HR, 1.85; 95% CI, 1.41-2.43), and weight (bidirectionally associated, ≥76kg, HR, 0.77; 95% CI, 0.64-0.93; <76kg, HR, 1.12; 95% CI, 1.07-1.16). Conclusions Patients with PAD and HF have a high rate of coronary artery disease with a high risk for major adverse cardiovascular events and death. These data support the possible need for aggressive treatment of (recurrent) atherosclerotic disease in PAD, especially patients with HF.

    View details for DOI 10.1161/JAHA.120.018684

    View details for PubMedID 34056910

  • Effect of SGLT2 Inhibitors on Stroke and Atrial Fibrillation in Diabetic Kidney Disease: Results From the CREDENCE Trial and Meta-Analysis. Stroke Zhou, Z., Jardine, M. J., Li, Q., Neuen, B. L., Cannon, C. P., de Zeeuw, D., Edwards, R., Levin, A., Mahaffey, K. W., Perkovic, V., Neal, B., Lindley, R. I., CREDENCE Trial Investigators, Ahuad Guerrero, R. A., Aizenberg, D., Albisu, J. P., Alvarisqueta, A., Bartolacci, I., Berli, M. A., Bordonava, A., Calella, P., Cantero, M. C., Cartasegna, L. R., Cercos, E., Coloma, G. C., Colombo, H., Commendatore, V., Cuadrado, J., Cuneo, C. A., Cusumano, A. M., Douthat, W. G., Dran, R. D., Farias, E., Fernandez, M. F., Finkelstein, H., Fragale, G., Fretes, J. O., Garcia, N. H., Gastaldi, A., Gelersztein, E., Glenny, J. A., Gonzalez, J. P., Del Carmen Gonzalez Colaso, P., Goycoa, C., Greloni, G. C., Guinsburg, A., Hermida, S., Juncos, L. I., Klyver, M. I., Kraft, F., Krynski, F., Lanchiotti, P. V., Leon de la Fuente, R. A., Marchetta, N., Mele, P., Nicolai, S., Novoa, P. A., Orio, S. I., Otreras, F., Oviedo, A., Raffaele, P., Resk, J. H., Rista, L., Rodriguez Papini, N., Sala, J., Santos, J. C., Schiavi, L. B., Sessa, H., Smith Casabella, T., Ulla, M. R., Valdez, M., Vallejos, A., Villarino, A., Visco, V. E., Wassermann, A., Zaidman, C. J., Cheung, N. W., Droste, C., Fraser, I., Johnson, D., Mah, P. M., Nicholls, K., Packham, D., Proietto, J., Roberts, A., Roger, S., Tsang, V., Abrao Raduan, R., Alves da Costa, F. A., Amodeo, C., Andreotti Turatti, L. A., Bregman, R., Camelo Sanches, F. C., Canani, L. H., Chacra, A. R., Cunha Borges, J. L., Cunha Vencio, S. A., da Silva Franco, R. J., d'Avila, D., de Souza Portes, E., de Souza, P., Deboni, L. M., Fraige Filho, F., Geloneze Neto, B., Gomes, M., Keiko Kohara, S., Keitel, E., Kerr Saraiva, J. F., Kurtz Lisboa, H. R., Loss de Carvalho Contieri, F., Milagres, R., Montenegro Junior, R., Moreira de Brito, C., Nasser Hissa, M., Nazario Sabbag, A. R., Noronha, I., Panarotto, D., Pecoits Filho, R., Pereira, M. A., Saporito, W., Scafuto Scotton, A., Schuch, T., Simoes de Almeida, R., Slompo Ramos, C., Soares Felicio, J., Thome, F., Tibes Hachmann, J. C., Yamada, S., Yoiti Hayashida, C., Zanata Petry, T. B., Zanella, M. T., Andreeva, V., Angelova, A., Dimitrov, S., Genadieva, V., Genova-Hristova, G., Hristozov, K., Kamenov, Z., Koundurdjiev, A., Lozanov, L., Margaritov, V., Nonchev, B., Rangelov, R., Shinkov, A., Temelkova, M., Velichkova, E., Yakov, A., Aggarwal, N., Aronson, R., Bajaj, H., Cherney, D., Chouinard, G., Conway, J., Cournoyer, S., DaRoza, G., De Serres, S., Dube, F., Goldenberg, R., Gupta, A., Gupta, M., Henein, S., Khandwala, H., Leiter, L., Madore, F., McMahon, A., Muirhead, N., Pichette, V., Rabasa-Lhoret, R., Steele, A., Tangri, N., Torshizi, A., Woo, V., Zalunardo, N., Fernandez Montenegro, M. A., Godoy Jorquera, J. G., Medina Farina, M., Saavedra Gajardo, V., Vejar, M., Chen, N., Chen, Q., Gan, S., Kong, Y., Li, D., Li, W., Li, X., Lin, H., Liu, J., Lu, W., Mao, H., Ren, Y., Song, W., Sun, J., Sun, L., Tu, P., Wang, G., Yang, J., Yin, A., Yu, X., Zhao, M., Zheng, H., Accini Mendoza, J. L., Arcos, E., Avendano, J., Diaz Ruiz, J. E., Garcia Ortiz, L. H., Gonzalez, A., Hernandez Triana, E., Higuera, J. D., Malaver, N., Molina de Salazar, D. I., Rosero, R., Terront Lozano, M. A., Valderrama Cometa, L., Valenzuela, A., Vargas Alonso, R. D., Villegas, I., Yupanqui, H., Bartaskova, D., Barton, P., Belobradkova, J., Dohnalova, L., Drasnar, T., Ferkl, R., Halciakova, K., Klokocnikova, V., Kovar, R., Lastuvka, J., Lukac, M., Pesickova, S., Peterka, K., Pumprla, J., Rychlik, I., Saudek, F., Tesar, V., Valis, M., Weiner, P., Zemek, S., Alamartine, E., Borot, S., Cariou, B., Dussol, B., Fauvel, J., Gourdy, P., Klein, A., Le Meur, Y., Penfornis, A., Roussel, R., Saulnier, P., Thervet, E., Zaoui, P., Burst, V., Faghih, M., Faulmann, G., Haller, H., Jerwan-Keim, R., Maxeiner, S., Paschen, B., Plassmann, G., Rose, L., Gonzalez Orellana, R. A., Haase, F. P., Moreira Diaz, J. P., Ramirez Roca, L. A., Sanchez Arenales, J. A., Sanchez Polo, J. V., Turcios Juarez, E., Csecsei, G., Csiky, B., Danos, P., Deak, L., Dudas, M., Harcsa, E., Keltai, K., Keresztesi, S., Kiss, K., Konyves, L., Major, L., Mileder, M., Molnar, M., Mucsi, J., Oroszlan, T., Ory, I., Paragh, G., Peterfai, E., Petro, G., Revesz, K., Takacs, R., Vangel, S., Vasas, S., Zsom, M., Oomman, A., Raju, S. B., Dewan, D., Fernando, M. E., Gopalakrishnan, N., Gracious, N., Alva, H., Jain, D., Keshavamurthy, C. B., Khullar, D., Sahay, M., Peringat, J., Prasad, N., Rao, K. S., Reddy, S., Melemadathil, S., Sudhakar, B., Vyasam, R. C., Bonadonna, R., Castellino, P., Ceriello, A., Chiovato, L., De Cosmo, S., De Nicola, L., Derosa, G., Di Carlo, A., Di Cianni, G., Frasca, G., Fuiano, G., Gambaro, G., Garibotto, G., Giorda, C., Malberti, F., Mandreoli, M., Mannucci, E., Orsi, E., Piatti, P., Santoro, D., Sasso, F. C., Serviddio, G., Stella, A., Trevisan, R., Veronelli, A. M., Zanoli, L., Akiyama, H., Aoki, H., Asano, A., Iitsuka, T., Kajiyama, S., Kashine, S., Kawada, T., Kodera, T., Kono, H., Koyama, K., Kumeda, Y., Miyauchi, S., Mizuyama, K., Niiya, T., Oishi, H., Ota, S., Sakakibara, T., Takai, M., Tomonaga, O., Tsujimoto, M., Wada, T., Wakasugi, M., Wakida, Y., Watanabe, T., Yamada, M., Yanagida, K., Yanase, T., Yumita, W., Gaupsiene, E., Kozloviene, D., Navickas, A., Urbanaviciene, E., Abdul Ghani, R., Abdul Kadir, K., Ali, N., Che Yusof, M. D., Gan, C. L., Ismail, M., Kong, W. Y., Lam, S. W., Lee, L. Y., Lim, S. K., Loh, C. L., Manocha, A. B., Ng, K. S., Nik Ahmad, N. N., Ratnasingam, V., Shudim, S. S., Vengadasalam, P., Abraira Munoz, L. D., Alpizar Salazar, M., Baas Cruz, J., Burgos Soto, M., Chevaile Ramos, J., Chew Wong, A., Correa Rotter, J. R., Diaz Escalante, T., Enriquez Sosa, F. E., Flores Lozano, F., Flota Cervera, L. F., Frenk Baron, P., Garcia Ballesteros, C., Gomez Rangel, J. D., Herrera Jimenez, L. E., Irizar Santana, S. S., Jimenez Flores, F., Laviada Molina, H., Luna Ceballos, R. I., Martin Del Campo Blanco, B., Morales Franco, G., Moreno Loza, O. T., Mustieles Rocha, C., Obrador Vera, G., Orozco Castellanos, R., Peralta Calcaneo, J., Reyes Rosano, M. A., Rodriguez Pattzi, H., Rosas Guzman, J., Rucker Joerg, I. E., Saavedra Sanchez, S. B., Sanchez Mijangos, J. H., Serrano Sanson, P., Tamayo Y Orozco, J. A., Tellez Chavez, E., Valdes Cepeda, A., Venegas Carrillo, L., Villagordoa Mesa, J., Zamarripa Escobedo, R., Baker, J., Noonan, P., Scott, R., Walker, R., Watson, E., Williams, M., Young, S., Abejuela, Z., Agra, J., Aquitania, G., Caringal, C., Comia, R. S., Delos Santos, L., Gomez, O., Jimeno, C., Santos, F., Tan, G., Tolentino, M., Yao, C., Yap, Y. E., Ygpuara, M. D., Bijata-Bronisz, R., Hotlos, L., Januszewicz, A., Kaczmarek, B., Kaminska, A., Lazuka, L., Madej, A., Mazur, S., Mlodawska-Choluj, D., Nowicki, M., Orlowska-Kowalik, G., Popenda, G., Rewerska, B., Sowinski, D., Angelescu, L. M., Anghel, V., Avram, R., Busegeanu, M., Cif, A., Cosma, D., Crisan, C., Demian, L. D., Ferariu, I. E., Halmagyi, I., Hancu, N., Munteanu, M., Negru, D., Onaca, A. G., Petrica, L., Popa, A. R., Ranetti, A., Serafinceanu, C., Toarba, C., Agafyina, A., Barbarash, O., Barysheva, O., Chizhov, D., Dobronravov, V., Dreval, A., Glinkina, I., Grineva, E., Khirmanov, V., Kolmakova, E., Koroleva, T., Kvitkova, L., Marasaev, V., Mkrtumyan, A., Morugova, T., Nagibovich, G., Nagibovich, O., Nedogoda, S., Osipova, I., Raskina, T., Samoylova, Y., Sazonova, O., Shamkhalova, M., Shutemova, E., Shwartz, Y., Uriasyev, O., Vorobyev, S., Zateyshchikova, A., Zateyshshikov, D., Zykova, T., Antic, S., Djordjevic, M., Kendereski, A., Lalic, K., Lalic, N., Popovic-Radinovic, V., Babikova, J., Benusova, O., Buganova, I., Culak, J., Dzupina, A., Dzuponova, J., Fulop, P., Ilavska, A., Martinka, E., Ochodnicka, Z., Pella, D., Smatanova, I., Ahmed, F., Badat, A., Breedt, J., Distiller, L., Govender, V., Govender, R., Joshi, M., Jurgens, J., Latiff, G., Lombard, L., Mookadam, M., Ngcakani, N., Nortje, H., Oosthuizen, H., Pillay-Ramaya, L., Prozesky, H., Reddy, J., Rheeder, P., Seeber, M., Chae, D., Cho, Y. M., Jeong, I., Kim, S. G., Kim, Y. H., Kwon, H., Kwon, M. J., Lee, B., Lee, J., Lee, M., Nam, M., Oh, K., Park, C., Park, S., Yoon, K. H., Alvarez Garcia, P., Asmarats Mercadal, L., Barrios, C., Cereto Castro, F., Cigarran Guldris, S., Dominguez Lopez, M., Egido de Los Rios, J., Fernandez Fresnedo, G., Galan Serrano, A., Garcia, I., Gonzalez Martinez, F. J., Jodar Gimeno, J. E., Lopez Mendoza, M., Malek Marin, T., Morales Portillo, C., Munar Vila, M. A., Munoz Torres, M., Nieto Iglesias, J., Pantoja Perez, J., Perez Vera, M., Portoles Perez, J. M., Quesada Simon, M. A., Simo Canonge, R., Soto Gonzalez, A., Terns Riera, M., Tinahones Madueno, F. J., Velo Plaza, M., Chang, C., Chuang, L., Hsia, T., Hsieh, C., Hwang, S., Lin, C., Lu, Y., Sheu, W. H., Barna, O., Bilyk, S. D., Botsyurko, V., Dudar, I., Fushtey, I., Godlevska, O., Golovchenko, O., Gyrina, O., Kazmirchuk, A., Kolesnyk, M., Komisarenko, I., Korzh, O., Kravchun, N., Legun, O., Mankovskyy, B., Martynyuk, L., Mostovoy, Y., Pashkovska, N., Pererva, L., Pertseva, T., Samoylov, O., Smirnov, I., Svyshchenko, Y., Tomashkevych, H., Topchii, I., Tryshchuk, N., Tseluyko, V., Vizir, V., Vlasenko, M., Zlova, T., Zub, L., Abusnana, S., Railey, M., Abouglila, K., Ainsworth, P., Ali, Z., Arutchelvam, V., Barnard, M., Bellary, S., Davies, E., Davies, M., Davies, S., Dawson, A., El Kossi, M., English, P., Fraser, D., Gnudi, L., Gunstone, A., Hall, T., Hanif, W., Jackson, A., Johnson, A., Joseph, F., Krishnan, S., Kumwenda, M., MacDougall, I., Nixon, P., O'Hare, J., Philip, S., Ramtoola, S., Saxena, M., Sennik, D., Simon, G., Singh, B., Stephens, J., Strzelecka, A., Symonds, R., Turner, W., Wahba, M., Wakeling, J., Wheeler, D., Winocour, P., Abdallah, J., Abdullah, R., Abramowitz, M., Acosta, I., Aiello, J., Akright, L., Akyea-Djamson, A., Alappan, R., Alicic, R., Al-Karadsheh, A., Allison, D. C., Arauz-Pacheco, C., Arfeen, S., Arif, A., Arvind, M., Atray, N., Awad, A., Bakris, G., Barnhill, P., Barranco, E., Barrera, C., Beacom, M., Behara, V., Belo, D., Bentley-Lewis, R., Berenguer, R., Bermudez, L., Bernardo, M., Biscoveanu, M., Bowman-Stroud, C., Brandon, D., Brusco, O., Busch, R., Canaan, Y., Chilito, A., Christensen, T., Christiano, C., Christofides, E., Chuateco, C., Cohen, K., Cohen, R., Cohen-Stein, D., Cook, C., Coyne, D., Daboul, N., Darwish, R., Daswani, A., Deck, K., Desouza, C., Dev, D., Dhillon, M., Dua, S., Eder, F., Elosegui, A. M., El-Shahawy, M., Ervin, J., Esquenazi, A., Evans, J., Fishbane, S., Frias, J., Galindo-Ramos, E., Galphin, C., Ghazi, A., Gonzalez, E., Gorson, D., Gowda, A., Greco, B., Grubb, S., Gulati, R., Hammoud, J., Handelsman, S., Hartman, I., Hershon, K., Hiser, D., Hon, G., Jacob, R., Jaime, M., Jamal, A., Kaupke, C., Keightley, G., Kern, E., Khanna, R., Khitan, Z., Kim, S., Kopyt, N., Kovesdy, C., Krishna, G., Kropp, J. J., Kumar, A., Kumar, J., Kumar, N., Kusnir, J., Lane, W., Lawrence, M., Lehrner, L., Lentz, J., Levinson, D., Lewis, D., Liss, K., Maddux, A., Maheshwari, H., Mandayam, S., Marar, I., Mehta, B., Middleton, J., Mordujovich, J., Moreda, R., Moustafa, M., Mujica Trenche, S., Narayanan, M., Narvarte, J., Nassar, T., Newman, G., Nichol, B., Nicol, P., Nisnisan, J., Nossuli, A. K., Obialo, C., Olelewe, S., Oliver, M., O'Shaughnessy, A., Padron, J., Pankhaniya, R., Parker, R., Patel, D., Patel, G., Patel, N., Pavon, H., Perez, A., Perez, C., Perlman, A., Pettis, K., Pharr, W., Phillips, A., Purighalla, R., Quesada-Suarez, L., Ranjan, R., Rastogi, S., Reddy, J., Rendell, M., Rich, L., Robinson, M., Rodriguez, H., Rosas, S., Saba, F., Sankaram, R., Sarin, R., Schreiman, R., Scott, D., Sekkarie, M., Sensenbrenner, J., Shakeel, M., Shanik, M., Shaw, S., Smith, S., Solomon, R., Sprague, A., Spry, L., Suchinda, P., Sultan, S., Surampudi, P., Sussman, S., Tan, A., Terrelonge, A., Thompson, M., Trespalacios, F., Trippe, B., Trueba, P., Twahirwa, M., Updegrove, J., Van Buren, P., Vannorsdall, M., Varghese, F., Velasquez-Mieyer, P., Ventrapragada, S., Vukotic, G., Wadud, K., Warren, M., Watson, H., Watts, R., Weiner, D., Welker, J., Welsh, J., Williams, S., Zaniewski-Singh, M. 2021: STROKEAHA120031623

    Abstract

    BACKGROUND AND PURPOSE: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus.METHODS: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis.RESULTS: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55-1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61-1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19-1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20-1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53-1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82-1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89-1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30-0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49-1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71-0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (<45 mL/min/1.73 m2]) subgroup (HRpooled, 0.50 [95% CI, 0.31-0.79]).CONCLUSIONS: Although we found no clear effect of SGLT2i on total stroke in CREDENCE or across trials combined, there was some evidence of benefit in preventing hemorrhagic stroke and AF/AFL, as well as total stroke for those with lowest estimated glomerular filtration rate. Future research should focus on confirming these data and exploring potential mechanisms.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02065791.

    View details for DOI 10.1161/STROKEAHA.120.031623

    View details for PubMedID 33874750

  • Effects of canagliflozin on myocardial infarction: a post hoc analysis of the CANVAS Program and CREDENCE trial. Cardiovascular research Yu, J., Li, J., Leaver, P. J., Arnott, C., Huffman, M. D., Udell, J. A., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Matthews, D. R., Shaw, W., Rosenthal, N., Neal, B., Figtree, G. A. 2021

    Abstract

    AIMS: Given the benefits of sodium glucose co-transporter 2 inhibition (SGLT2i) in protecting against heart failure in diabetic patients, we sought to explore the potential impact of SGLT2i on the clinical features of patients presenting with myocardial infarction (MI) through a post-hoc analysis of CANVAS Program and CREDENCE trial.METHODS AND RESULTS: Individuals with type 2 diabetes and history or high risk of cardiovascular disease (CANVAS Program) or type 2 diabetes and chronic kidney disease (CREDENCE) were included. The intervention was Canagliflozin 100 or 300mg (combined in the analysis) or placebo. MI events were adjudicated as ST-elevation myocardial infarction (STEMI), non-STEMI as well as type 1MI or type 2MI. 421 first MI events in the CANVAS Program and 178 first MI events in the CREDENCE trial were recorded (83 fatal, 128 STEMI, 431 non-STEMI, and 40 unknown). No benefit of canagliflozin compared with placebo on time to first MI event was observed (HR 0.89; 95% CI 0.75, 1.05). Canagliflozin was associated with lower risk for non-STEMI (HR 0.78; 95% CI 0.65, 0.95) but suggested a possible increase in STEMI (HR 1.55; 95% CI 1.06, 2.27), with no difference in risk of type 1 or type 2MI. There was no change in fatal MI (HR 1.22, 95% CI 0.78, 1.93).CONCLUSIONS: Canagliflozin was not associated with a reduction in overall MI in the pooled CANVAS Program and CREDENCE trial population. The possible differential effect on STEMI and Non-STEMI observed in the CANVAS cohort warrants further investigation.

    View details for DOI 10.1093/cvr/cvab128

    View details for PubMedID 33826709

  • Dosing of Direct Oral Anticoagulants in Patients with Moderate Chronic Kidney Disease in US Clinical Practice: Results from the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF II). American journal of cardiovascular drugs : drugs, devices, and other interventions Jackson, L. R., Schrader, P., Thomas, L., Steinberg, B. A., Blanco, R., Allen, L. A., Fonarow, G. C., Freeman, J. V., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J., Singer, D. E., Peterson, E. D., Piccini, J. P., Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) II Investigators and Patients 2021

    Abstract

    INTRODUCTION: Direct oral anticoagulants (DOACs) have partial renal clearance and generally require dosage adjustments based on renal function. While current US and European guidance recommends dose adjustments in patients with moderate chronic kidney disease (CKD), it is unclear how often this is done appropriately in routine clinical practice.METHODS: We examined rates of appropriate and inappropriate dosing in patients with atrial fibrillation (AF) and moderate CKD, as determined by creatinine clearance (CrCl) of 30-50 mL/min calculated with the Cockcroft-Gault formula. Descriptive statistics were used to describe the rate of appropriate and inappropriate dosing as well as event rates.RESULTS: Among 1134 patients (8.5% of the overall ORBIT-AF II registry) with AF and CrCl 30-50 mL/min, the median age was 82 (25th, 75th percentile: 78, 86), 38% were male, and the median CHA2DS2VASC score was 4 (25th, 75th percentile: 4, 5). At baseline, more than one-third (34%) of patients with moderate CKD were inappropriately dosed with DOACs. When evaluating the specific prescribed doses in those with moderate CKD, 15% (N = 170/1134) were underdosed, 66% (743/1134) were appropriately dosed, and 20% (N = 221/1134) were overdosed. There were no significant differences in comorbid medical conditions between patients with moderate CKD who were appropriately and inappropriately dosed with a DOAC.CONCLUSION: In routine clinical practice, prescribing of DOACs in patients with AF with moderate CKD is often inconsistent with drug labeling, with up to one-third of patients being inappropriately dosed.

    View details for DOI 10.1007/s40256-021-00473-x

    View details for PubMedID 33786798

  • The Effects of Canagliflozin on Heart Failure and Cardiovascular Death by Baseline Participant Characteristics: Analysis of the CREDENCE Trial. Diabetes, obesity & metabolism Arnott, C., Li, J., Cannon, C. P., de Zeeuw, D., Neuen, B. L., Heerspink, H. J., Charytan, D. M., Agarwal, A., Huffman, M. D., Figtree, G. A., Bakris, G., Chang, T. I., Feng, K., Rosenthal, N., Zinman, B., Jardine, M. J., Perkovic, V., Neal, B., Mahaffey, K. W. 2021

    Abstract

    Heart failure is prevalent in those with type 2 diabetes and chronic kidney disease and is associated with significant mortality and morbidity. In the CREDENCE trial canagliflozin reduced the risk of hospitalization for heart failure (HHF) or cardiovascular (CV) death by 31%. In this current analysis we sought to determine whether the effect of canagliflozin on HHF/CV death differed in subgroups defined by key baseline participant characteristics. Cox regression models were used to estimate hazard ratios and 95% confidence intervals. Canagliflozin was associated with a reduction in the relative risk of HHF/CV death regardless of age, sex, history of HF or CV disease, and the use of loop diuretics or GLP1 receptor agonists (all pinteraction >0.114). The absolute benefit of canagliflozin was greater in those at highest baseline risk, such as those with CV disease (50 fewer events/1000 patients treated over 2.5years versus 20 fewer events in those without CV disease) or advanced kidney disease (eGFR 30-45 ml/min/1.73m2 : 61 events prevented/1000 patients treated over 2.5years versus 23 events in eGFR 60-90 ml/min/1.73m2 ). Canagliflozin consistently reduces the proportional risk of HHF/CV death across a broad range of subgroups with greater absolute benefits in those at highest baseline risk. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/dom.14386

    View details for PubMedID 33769679

  • Canagliflozin Reduces All-cause Hospitalization in Patients with Type 2 Diabetes Mellitus Feng, K. Y., Gogate, J., Damaraju, C. V., Li, J., Jardine, M. J., Perkovic, V., Blais, J. D., Pfeifer, M., Neal, B., Mahaffey, K. W. W B SAUNDERS CO-ELSEVIER INC. 2021: 17–18
  • Kidney, Cardiovascular, and Safety Outcomes of Canagliflozin according to Baseline Albuminuria: A CREDENCE Secondary Analysis. Clinical journal of the American Society of Nephrology : CJASN Jardine, M., Zhou, Z., Lambers Heerspink, H. J., Hockham, C., Li, Q., Agarwal, R., Bakris, G. L., Cannon, C. P., Charytan, D. M., Greene, T., Levin, A., Li, J., Neuen, B. L., Neal, B., Oh, R., Oshima, M., Pollock, C., Wheeler, D. C., de Zeeuw, D., Zhang, H., Zinman, B., Mahaffey, K. W., Perkovic, V. 2021

    Abstract

    BACKGROUND AND OBJECTIVES: The kidney protective effects of renin-angiotensin system inhibitors are greater in people with higher levels of albuminuria at treatment initiation. Whether this applies to sodium-glucose cotransporter 2 (SGLT2) inhibitors is uncertain, particularly in patients with a very high urine albumin-to-creatinine ratio (UACR; ≥3000 mg/g). We examined the association between baseline UACR and the effects of the SGLT2 inhibitor, canagliflozin, on efficacy and safety outcomes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) randomized controlled trial.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The study enrolled 4401 participants with type 2 diabetes, an eGFR of 30 to <90 ml/min per 1.73 m2, and UACR of >300 to 5000 mg/g. Using Cox proportional hazards regression, we examined the relative and absolute effects of canagliflozin on kidney, cardiovascular, and safety outcomes according to a baseline UACR of ≤1000 mg/g (n=2348), >1000 to <3000 mg/g (n=1547), and ≥3000 mg/g (n=506). In addition, we examined the effects of canagliflozin on UACR itself, eGFR slope, and the intermediate outcomes of glycated hemoglobin, body weight, and systolic BP.RESULTS: Overall, higher UACR was associated with higher rates of kidney and cardiovascular events. Canagliflozin reduced efficacy outcomes for all UACR levels, with no evidence that relative benefits varied between levels. For example, canagliflozin reduced the primary composite outcome by 24% (hazard ratio [HR], 0.76; 95% confidence interval [95% CI], 0.56 to 1.04) in the lowest UACR subgroup, 28% (HR, 0.72; 95% CI, 0.56 to 0.93) in the UACR subgroup >1000 to <3000 mg/g, and 37% (HR, 0.63; 95% CI, 0.47 to 0.84) in the highest subgroup (P heterogeneity=0.55). Absolute risk reductions for kidney outcomes were greater in participants with higher baseline albuminuria; the number of primary composite events prevented across ascending UACR categories were 17 (95% CI, 3 to 38), 45 (95% CI, 9 to 81), and 119 (95% CI, 35 to 202) per 1000 treated participants over 2.6 years (P heterogeneity=0.02). Rates of kidney-related adverse events were lower with canagliflozin, with a greater relative reduction in higher UACR categories.CONCLUSIONS: Canagliflozin safely reduces kidney and cardiovascular events in people with type 2 diabetes and severely increased albuminuria. In this population, the relative kidney benefits were consistent over a range of albuminuria levels, with greatest absolute kidney benefit in those with an UACR ≥3000 mg/g.CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov: CREDENCE, NCT02065791.PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_22_CJN15260920_final.mp3.

    View details for DOI 10.2215/CJN.15260920

    View details for PubMedID 33619120

  • Cardiovascular and renal outcomes with canagliflozin according to baseline diuretic use: a post hoc analysis from the CANVAS Program. ESC heart failure Yu, J., Arnott, C., Neuen, B. L., Heersprink, H. L., Mahaffey, K. W., Cannon, C. P., Khan, S. S., Baldridge, A. S., Shah, S. J., Huang, Y., Li, C., Figtree, G. A., Perkovic, V., Jardine, M. J., Neal, B., Huffman, M. D. 2021

    Abstract

    AIMS: The CANVAS Program identified the effect of canagliflozin on major adverse cardiovascular events (MACE) differed according to whether participants were using diuretics at study commencement. We sought to further evaluate this finding related to baseline differences, treatment effects, safety, and risk factor changes.METHODS AND RESULTS: The CANVAS Program enrolled 10142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomized to canagliflozin or placebo and followed for a mean of 188weeks. The primary outcome was major cardiovascular events, a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included multiple cardiovascular, renal, and safety events. In this post hoc subgroup analysis, participants were categorized according to baseline use of any diuretic. The effect on outcomes was compared using Cox proportional hazards models, while risk factor changes were compared using mixed-effect models. At baseline, 4490 (44.3%) participants were using a diuretic. Compared with those not using a diuretic, participants using a diuretic were more likely to be older (mean age±standard deviation, 64.3±8.0 vs. 62.5±8.3), be female (38.9% vs. 33.4%), and have heart failure (19.6% vs. 10.3%) (all Pdifference <0.0001). The effect of canagliflozin on major cardiovascular events was greater for those using diuretic at baseline than for those who were not [adjusted hazard ratio 0.65 (95% confidence interval 0.54-0.78) vs. adjusted hazard ratio 1.13 (95% confidence interval 0.93-1.36), Pheterogeneity <0.0001]. Changes in most risk factors, including blood pressure, body weight, and urine albumin-to-creatinine ratio, were similar between groups (all Pdifference >0.11), although the effect of canagliflozin on haemoglobin A1c reduction was slightly weaker in participants using compared with not using diuretics at baseline (-0.52% vs. -0.64%, Pheterogeneity =0.0007). Overall serious adverse events and key safety outcomes, including adverse renal events, were also similar (all Pheterogeneity >0.07).CONCLUSIONS: Participants on baseline diuretics derived a greater benefit for major cardiovascular events from canagliflozin, which was not fully explained by differences in participant characteristics nor risk factor changes.

    View details for DOI 10.1002/ehf2.13236

    View details for PubMedID 33595905

  • The ARREST Pneumonia (Arrest Respiratory Failure due to Pneumonia) Trial: Rationale and Design. Annals of the American Thoracic Society Levitt, J. E., Festic, E., Desai, M., Hedlin, H., Mahaffey, K. W., Rogers, A. J., Gajic, O., Matthay, M. A., ARREST Pneumonia Clinical Trial Investigators 2021

    Abstract

    Patients hospitalized for pneumonia are at high risk for mortality. Effective therapies are therefore needed. Recent randomized clinical trials suggest that systemic steroids can reduce the length of hospital stay among patients hospitalized for pneumonia. Further, preliminary findings from a feasibility study demonstrated that early treatment with a combination of an inhaled corticosteroid and a bronchodilator can improve oxygenation and reduce risk of respiratory failure in patients at risk of acute respiratory distress syndrome. Whether such a combination administered early is effective in reducing acute respiratory failure among patients hospitalized with pneumonia is unknown. Here we describe the Arrest Respiratory Failure due to Pneumonia (ARREST Pneumonia) trial designed to address this question. ARREST Pneumonia is a two-arm randomized double-blinded placebo-controlled trial designed to test the efficacy of a combination of an inhaled corticosteroid and a beta agonist compared to placebo for the prevention of acute respiratory failure in hospitalized participants with severe pneumonia. The primary outcome is acute respiratory failure within 7 days of randomization, defined as a composite endpoint of intubation and mechanical ventilation, or need for high flow nasal cannula oxygen therapy or non-invasive ventilation for > 36 hours (each alone or combined), or death within 36 hours of being placed on respiratory support. The planned enrollment is 600 adult participants at ten academic medical centers. In addition, we will measure selected plasma biomarkers to better understand mechanisms of action. The trial is funded by the National Heart Lung and Blood Institute and is registered in clinicaltrials.gov (NCT04193878).

    View details for DOI 10.1513/AnnalsATS.202009-1115SD

    View details for PubMedID 33493423

  • Rivaroxaban versus Warfarin in Patients with Atrial Fibrillation Enrolled in Latin America: Insights from ROCKET AF. American heart journal Blumer, V. n., Rivera, M. n., Corbalán, R. n., Becker, R. C., Berkowitz, S. D., Breithardt, G. n., Hacke, W. n., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Hellkamp, A. S., Singer, D. E., Fox, K. A., Patel, M. R. 2021

    Abstract

    ROCKET AF demonstrated the efficacy and safety of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). We examined baseline characteristics and outcomes in patients enrolled in Latin America compared with the rest of the world (ROW).ROCKET AF enrolled 14,264 patients from 45 countries. Of these, 1878 (13.2%) were from 7 Latin American countries. The clinical characteristics and outcomes (adjusted by baseline characteristics) of these patients were compared with 12,293 patients from the ROW. Treatment outcomes of rivaroxaban compared with warfarin were also stratified by region.The annual rate of stroke/SE was similar in those from Latin American and ROW (p=0.63), but all-cause and vascular death were significantly higher than in ROW (HR 1.40, 95% CI 1.20-1.64; HR 1.38, 95% CI 1.14-1.68; p<0.001). Rates of major or non-major clinically relevant bleeding tended to be lower in Latin America (HR 0.89, 95% CI 0.80-1.0; p=0.05). Rates of stroke/SE were similar with rivaroxaban and warfarin in patients from Latin America and ROW (HR 0.83, 95% CI 0.54-1.29 vs. HR 0.89, 95% CI 0.75-1.07; interaction p=0.77).Patients with AF in Latin America had similar rates of stroke/SE, higher rates of vascular death, and lower rates of bleeding compared with patients in the ROW. The effect of rivaroxaban compared with warfarin in Latin America was similar to the ROW. Further studies analyzing patient- and country-specific determinants of these regional differences in Latin America are warranted.

    View details for DOI 10.1016/j.ahj.2021.02.004

    View details for PubMedID 33571477

  • Efficacy of a Centralized, Blended Electronic and Human Intervention to Improve Direct Oral Anticoagulant Adherence: Smartphones to improve rivaroxaban ADHEREnce in Atrial Fibrillation (SmartADHERE) A Randomized Clinical Trial: SmartADHERE rivaroxaban adherence trial. American heart journal Turakhia, M. n., Sundaram, V. n., Smith, S. N., Ding, V. n., Michael Ho, P. n., Kowey, P. R., Piccini, J. P., Foody, J. n., Birmingham, M. n., Ianus, J. n., Rajmane, A. n., Mahaffey, K. W. 2021

    Abstract

    Improving adherence to direct oral anticoagulants (DOAC) is challenging, and simple text messaging reminders have not been effective.SmartADHERE was a randomized trial that tested a personalized digital and human direct oral anticoagulant adherence intervention compared to usual care. Eligibility required age ≥ 18, newly-prescribed (≤ 90 days) rivaroxaban for atrial fibrillation (AF), 1 of 4 at-risk criteria for nonadherence, and a smartphone. The intervention consisted of combination of a medication management smartphone app, daily app-based reminders, adaptive text messaging, and phone-based counseling for severe nonadherence. The primary outcome was the proportion of days covered by rivaroxaban (PDC) at 6 months. There were 25 U.S. sites, all cardiology and electrophysiology outpatient practices, activated for a target sample size of 378, but the study was terminated by the sponsor prior to reaching target enrollment.There were 139 participants (age 65±9.6 years, 30% female, median CHA2DS2-VASc score 3 with IQR 2-4, mean total medication burden 7.7±4.4). DOAC adherence was high in both arms with no difference in the primary outcome (PDC 0.86±0.25 intervention vs 0.88±0.25 control, p=0.62) or in secondary outcomes including PDC ≥ 0.80 and medication persistence. Per protocol analyses had similar results. Because of the high overall PDC, the likelihood to answer the primary hypothesis was only 51% even if target enrollment were achieved. There were no study-related adverse events.The use of a centralized digital and human adherence intervention was feasible across multiple sites. Overall adherence was much higher than expected despite pre-screening for at-risk individuals. SmartADHERE illustrates the challenges of trials of behavioral and technology interventions, where enrollment itself may lead to selection bias or treatment effects. Pragmatic study designs, such as cluster randomization or stepped-wedge implementation, should be considered to improve enrollment and generalizability.

    View details for DOI 10.1016/j.ahj.2021.02.023

    View details for PubMedID 33676886

  • Return of individual research results: What do participants prefer and expect? PloS one Sayeed, S., Califf, R., Green, R., Wong, C., Mahaffey, K., Gambhir, S. S., Mega, J., Patrick-Lake, B., Frazier, K., Pignone, M., Hernandez, A., Shah, S. H., Fan, A. C., Krug, S., Shaack, T., Shore, S., Spielman, S., Eckstrand, J., Wong, C. A., Project Baseline Health Study Research Group 2021; 16 (7): e0254153

    Abstract

    Newer data platforms offer increased opportunity to share multidimensional health data with research participants, but the preferences of participants for which data to receive and how is evolving. Our objective is to describe the preferences and expectations of participants for the return of individual research results within Project Baseline Health Study (PBHS). The PBHS is an ongoing, multicenter, longitudinal cohort study with data from four initial enrollment sites. PBHS participants are recruited from the general population along with groups enriched for heart disease and cancer disease risk. Cross-sectional data on return of results were collected in 2017-2018 from an (1) in-person enrollment survey (n = 1,890), (2) benchmark online survey (n = 1,059), and (3) participant interviews (n = 21). The main outcomes included (1) preferences for type of information to be added next to returned results, (2) participant plans for sharing returned results with a non-study clinician, and (3) choice to opt-out of receiving genetic results. Results were compared by sociodemographic characteristics. Enrollment and benchmark survey respondents were 57.1% and 53.5% female, and 60.0% and 66.2% white, respectively. Participants preferred the following data types be added to returned results in the future: genetics (29.9%), heart imaging, (16.4%), study watch (15.8%), and microbiome (13.3%). Older adults (OR 0.60, 95% CI: 0.41-0.87) were less likely to want their genetic results returned next. Forty percent of participants reported that they would not share all returned results with their non-study clinicians. Black (OR 0.64, 95% CI 0.43-0.95) and Asian (OR 0.47, 95% CI 0.30-0.73) participants were less likely, and older participants more likely (OR 1.45-1.61), to plan to share all results with their clinician than their counterparts. At enrollment, 5.8% of participants opted out of receiving their genetics results. The study showed that substantial heterogeneity existed in participant's preferences and expectations for return of results, and variations were related to sociodemographic characteristics.

    View details for DOI 10.1371/journal.pone.0254153

    View details for PubMedID 34324495

  • Association of Chronic Obstructive Pulmonary Disease with Morbidity and Mortality in Patients with Peripheral Artery Disease: Insights from the EUCLID Trial. International journal of chronic obstructive pulmonary disease Galani, J., Mulder, H., Rockhold, F. W., Weissler, E. H., Baumgartner, I., Berger, J. S., Blomster, J. I., Fowkes, F. G., Hiatt, W. R., Katona, B. G., Norgren, L., Mahaffey, K. W., Quint, J. K., Patel, M. R., Jones, W. S. 2021; 16: 841–51

    Abstract

    Background: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of developing lower extremity peripheral artery disease (PAD) and suffering PAD-related morbidity and mortality. However, the effect and burden of COPD on patients with PAD is less well defined. This post hoc analysis from EUCLID aimed to analyze the risk of major adverse cardiovascular events (MACE) and major adverse limb events (MALE) in patients with PAD and concomitant COPD compared with those without COPD, and to describe the adverse events specific to patients with COPD.Methods: EUCLID randomized 13,885 patients with symptomatic PAD to monotherapy with either ticagrelor or clopidogrel for the prevention of MACE. In this analysis, MACE, MALE, mortality, and adverse events were compared between groups with and without COPD using unadjusted and adjusted Cox proportional hazards model.Results: Of the 13,883 patients with COPD status available at baseline, 11% (n=1538) had COPD. Patients with COPD had a higher risk of MACE (6.02 vs 4.29 events/100 patient-years; p<0.001) due to a significantly higher risk of myocardial infarction (MI) (3.55 vs 1.85 events/100 patient-years; p<0.001) when compared with patients without COPD. These risks persisted after adjustment (MACE: adjusted hazard ratio (aHR) 1.30, 95% confidence interval [CI] 1.11-1.52; p<0.001; MI: aHR 1.45, 95% CI 1.18-1.77; p<0.001). However, patients with COPD did not have an increased risk of MALE or major bleeding. Patients with COPD were more frequently hospitalized for dyspnea and pneumonia (2.66 vs 0.9 events/100 patient-years; aHR 2.77, 95% CI 2.12-3.63; p<0.001) and more frequently discontinued study drug prematurely (19.36 vs 12.54 events/100 patient-years; p<0.001; aHR 1.34, 95% CI 1.22-1.47; p<0.001).Conclusion: In patients with comorbid PAD and COPD, the risks of MACE, respiratory-related adverse events, and premature study drug discontinuation were higher when compared with patients without COPD.Registration: ClinicalTrials.gov: NCT01732822.

    View details for DOI 10.2147/COPD.S292978

    View details for PubMedID 33824584

  • Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights from the CREDENCE Trial. Circulation Ye, N. n., Jardine, M. J., Oshima, M. n., Hockham, C. n., Heerspink, H. J., Agarwal, R. n., Bakris, G. n., Schutte, A. E., Arnott, C. n., Chang, T. I., Górriz, J. L., Cannon, C. P., Charytan, D. M., de Zeeuw, D. n., Levin, A. n., Mahaffey, K. W., Neal, B. n., Pollock, C. n., Wheeler, D. C., Di Tanna, G. L., Cheng, H. n., Perkovic, V. n., Neuen, B. L. 2021

    Abstract

    Background: People with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) experience a high burden of hypertension but the magnitude and consistency of blood pressure (BP) lowering with canagliflozin in this population is uncertain. Whether the effects of canagliflozin on kidney and cardiovascular outcomes vary by baseline BP or BP lowering therapy is also unknown. Methods: The CREDENCE trial randomized people with T2DM and CKD to canagliflozin or placebo. Post-hoc, we investigated the effect of canagliflozin on systolic BP across subgroups defined by baseline systolic BP, number of BP lowering drug classes, and history of apparent treatment-resistant hypertension (BP ≥130/80 mmHg while receiving ≥3 classes of BP lowering drugs, including a diuretic). We also assessed whether effects on clinical outcomes differed across these subgroups. Results: The trial included 4,401 participants of whom 3,361 (76.4%) had baseline systolic BP ≥130 mmHg, and 1371 (31.2%) had resistant hypertension. By week 3, canagliflozin reduced systolic BP by 3.50mmHg (95% CI, -4.27 to -2.72), an effect maintained over the duration of the trial, with similar reductions across BP and BP lowering therapy subgroups (all P-interaction ≥0.05). Canagliflozin also reduced the need for initiation of additional BP lowering agents during the trial (HR 0.68, 95% CI 0.61-0.75). The effect of canagliflozin on kidney failure, doubling of serum creatinine, or death due to kidney or cardiovascular disease (HR 0.70, 95% CI 0.59-0.82) was consistent across BP and BP lowering therapy subgroups (all P-interaction ≥0.35), as were effects on other key kidney, cardiovascular and safety outcomes. Conclusions: In people with T2DM and CKD, canagliflozin lowers systolic BP across all BP defined subgroups and reduces the need for additional BP lowering agents. These findings support use of canagliflozin for end-organ protection and as an adjunct BP lowering therapy in people with CKD. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique Identifier: NCT02065791.

    View details for DOI 10.1161/CIRCULATIONAHA.120.048740

    View details for PubMedID 33554616

  • Effects of Canagliflozin on Cardiovascular, Renal, and Safety Outcomes in Participants With Type 2 Diabetes and Chronic Kidney Disease According to History of Heart Failure: Results From the CREDENCE Trial. American heart journal Sarraju, A., Li, J., Cannon, C. P., Chang, T. I., Agarwal, R., Bakris, G., Charytan, D. M., de Zeeuw, D., Greene, T., Heerspink, H. J., Levin, A., Neal, B., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Perkovic, V., Jardine, M., Mahaffey, K. W. 2020

    Abstract

    We aimed to assess the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy according to prior history of heart failure in the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) trial. We found that participants with a prior history of heart failure at baseline (15%) were more likely to be older, female, white, have a history of atherosclerotic cardiovascular disease, and use diuretics and beta blockers (all P<0.001), and that, compared with placebo, canagliflozin safely reduced renal and cardiovascular events with consistent effects in patients with and without a prior history of heart failure (all efficacy P interaction >0.150). These results support the efficacy and safety of canagliflozin in patients with type 2 diabetes and nephropathy regardless of prior history of heart failure.

    View details for DOI 10.1016/j.ahj.2020.12.008

    View details for PubMedID 33358942

  • Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice. Kidney international Oshima, M., Jardine, M. J., Agarwal, R., Bakris, G., Cannon, C. P., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T., Levin, A., Lim, S. K., Mahaffey, K. W., Neal, B., Pollock, C., Rosenthal, N., Wheeler, D. C., Zhang, H., Zinman, B., Perkovic, V., Heerspink, H. J. 2020

    Abstract

    Canagliflozin slows the progression of chronic kidney disease in patients with type 2 diabetes and induces a reversible acute drop in estimated glomerular filtration rate (eGFR), believed to be a hemodynamic effect. Predictors of the initial drop and its association with long-term eGFR trajectories and safety outcomes are unknown. To assess this, we performed a post-hoc analysis of 4289 participants in the CREDENCE trial with type 2 diabetes and chronic kidney disease equally split into treatment and placebo groups who had eGFR measured at both baseline and week three. The eGFR was categorized at week three as greater than a 10% decline; between 0 and 10% decline; and no decline. Long-term eGFR trajectories and safety outcomes were estimated in each category of acute eGFR change by linear mixed effects models and Cox regression after adjustment for baseline characteristics and medications use. Significantly more participants in the canagliflozin (45%) compared to the placebo (21%) group experienced an acute drop in eGFR over 10%. An over 30% drop occurred infrequently (4% of participants with canagliflozin and 2% with placebo). The odds ratio for a drop in eGFR over 10% with canagliflozin compared to placebo was significant at 3.03 (95% confidence interval 2.65, 3.47). Following the initial drop in eGFR, multivariable adjusted long-term eGFR trajectories, as well as overall and kidney safety profiles, in those treated with canagliflozin were similar across eGFR decline categories. Thus, although acute drops in eGFR over 10% occurred in nearly half of all participants following initiation of canagliflozin, the clinical benefit of canagliflozin was observed regardless. Additionally, safety outcomes were similar among subgroups of acute eGFR drop.

    View details for DOI 10.1016/j.kint.2020.10.042

    View details for PubMedID 33316282

  • Cause of Death Among Patients With Peripheral Artery Disease: Insights From the EUCLID Trial. Circulation. Cardiovascular quality and outcomes Kochar, A., Mulder, H., Rockhold, F. W., Baumgartner, I., Berger, J. S., Blomster, J. I., Fowkes, F. G., Katona, B. G., Lopes, R. D., Al-Khalidi, H. R., Mahaffey, K. W., Norgren, L., Hiatt, W. R., Patel, M. R., Jones, W. S. 2020: CIRCOUTCOMES120006550

    Abstract

    BACKGROUND: Peripheral artery disease is common and associated with high mortality. There are limited data detailing causes of death among patients with peripheral artery disease.METHODS: EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) was a randomized clinical trial that assigned patients with peripheral artery disease to clopidogrel or ticagrelor. We describe the causes of death in EUCLID using mortality end points adjudicated through a clinical events classification process. The association between baseline factors and cardiovascular death was evaluated by Cox proportional hazards modeling. The competing risk of noncardiovascular death was assessed by the cumulative incidence function for cardiovascular death and the Fine and Gray method to ascertain the association between baseline characteristics and cardiovascular mortality.RESULTS: A total of 1263 out of 13 885 (9.1%) patients died (median follow-up: 30 months). There were 706 patients (55.9%) with a cardiovascular cause of death and 522 (41.3%) with a noncardiovascular cause of death. The most common cause of cardiovascular death was sudden cardiac death (20.1%); while myocardial infarction (5.2%) and ischemic stroke (3.2%) were uncommon. The most common causes of noncardiovascular death were malignancies (17.9%) and infections (11.9%). The factor most associated with a higher risk of cardiovascular death was age per 5 year increase (HR, 1.26 [95% CI, 1.20-1.32]). Female sex was associated with a lower risk of cardiovascular death (HR, 0.68 [95% CI, 0.56-0.82]). To evaluate the effect of noncardiovascular death as a competing risk, we superimposed the cumulative incidence function curve with the Kaplan-Meier curve. These curves closely approximated each other. After accounting for the competing risk of noncardiovascular death, the magnitude and direction of the factors associated with cardiovascular death were minimally changed.CONCLUSIONS: Among patients with symptomatic peripheral artery disease, noncardiovascular causes of death reflected a high proportion (40%) of deaths. Accounting for noncardiovascular deaths as a competing risk, there was not a significant change in the risk estimation for cardiovascular death.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

    View details for DOI 10.1161/CIRCOUTCOMES.120.006550

    View details for PubMedID 33176462

  • Insulin-Like Growth Factor Binding Protein 7 Predicts Renal and Cardiovascular Outcomes in the Canagliflozin Cardiovascular Assessment Study. Diabetes care Januzzi, J. L., Butler, J., Sattar, N., Xu, J., Shaw, W., Rosenthal, N., Pfeifer, M., Mahaffey, K. W., Neal, B., Hansen, M. K. 2020

    Abstract

    OBJECTIVE: To analyze the association between concentrations of plasma insulin-like growth factor binding protein 7 (IGFBP7) with renal and cardiac outcomes among participants with type 2 diabetes and high cardiovascular risk.RESEARCH DESIGN AND METHODS: Associations between IGFBP7 levels and clinical outcomes were assessed among participants in the Canagliflozin Cardiovascular Assessment Study (CANVAS) with type 2 diabetes and high cardiovascular risk.RESULTS: Among CANVAS participants, 3,577 and 2,898 had IGFBP7 measured at baseline and 1 year, respectively. Per log-unit higher concentration, baseline IGFBP7 was significantly associated with the composite renal end point of sustained 40% reduction in estimated glomerular filtration rate, need for renal replacement therapy, or renal death (hazard ratio [HR] 3.51; P < 0.001), and the composite renal end point plus cardiovascular death (HR 4.90; P < 0.001). Other outcomes, including development or progression of albuminuria, were also predicted by baseline IGFBP7. Most outcomes were improved by canagliflozin regardless of baseline IGFBP7; however, those with baseline concentrations ≥96.5 ng/mL appeared to benefit more from canagliflozin relative to the first progression of albuminuria compared with those with lower baseline IGFBP7 (HR 0.64 vs. 0.95; P interaction = 0.003). Canagliflozin did not lower IGFBP7 concentrations by 1 year; however, at 1 year, higher IGFBP7 concentrations more strongly predicted the composite renal end point (HR 15.7; P < 0.001). Patients with rising IGFBP7 between baseline and 1 year had the highest number of composite renal events.CONCLUSIONS: Plasma IGFBP7 concentrations predicted renal and cardiac events among participants with type 2 diabetes and high cardiovascular risk. More data are needed regarding circulating IGFBP7 and progression of diabetic kidney disease and its complications.

    View details for DOI 10.2337/dc20-1889

    View details for PubMedID 33158949

  • Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial. The lancet. Diabetes & endocrinology Oshima, M., Neuen, B. L., Jardine, M. J., Bakris, G., Edwards, R., Levin, A., Mahaffey, K. W., Neal, B., Pollock, C., Rosenthal, N., Wada, T., Wheeler, D. C., Perkovic, V., Heerspink, H. J. 2020; 8 (11): 903–14

    Abstract

    BACKGROUND: Sodium-glucose co-transporter 2 inhibitors might enhance erythropoiesis and increase red blood cell mass. We assessed the long-term effects of canagliflozin on anaemia-related outcomes.METHODS: In a post-hoc analysis of the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial, we included patients with type 2 diabetes and chronic kidney disease who were randomly assigned to treatment with canagliflozin or placebo at 690 sites in 34 countries. We assessed the effects of canagliflozin versus matched placebo on haemoglobin and haematocrit using linear mixed-effects models. The primary outcome of this post-hoc analysis was a composite outcome of investigator-reported anaemia or treatment for anaemia, which was assessed using Kaplan-Meier analysis and Cox regression models. All analyses were done by intention to treat.FINDINGS: Between March 24, 2014, and May 5, 2017, 4401 participants were randomly assigned to receive canagliflozin (100 mg; n=2202) or placebo (n=2199). At baseline, mean haemoglobin concentration was 132·0 g/L (SD 17·7), 1599 (36%) of 4401 participants had anaemia (defined as haemoglobin <130 g/L in men or <120 g/L in women), and 33 (<1%) of 4401 participants used erythropoiesis-stimulating agents. During a median follow-up period of 2·6 years (IQR 2·1-3·1), mean haemoglobin concentration was 7·1 g/L (95% CI 6·4-7·8) higher and haematocrit was 2·4% (2·2-2·6) higher in the canagliflozin group than the placebo group. Overall, 573 of 4401 participants had either an investigator-reported anaemia event or initiation of treatment for anaemia: 358 (8%) of 4401 participants reported anaemia events, 343 (8%) initiated iron preparations, 141 (3%) initiated erythropoiesis-stimulating agents, and 114 (2%) received blood transfusion. The risk of the composite outcome of anaemia events or initiation of treatment for anaemia was lower in the canagliflozin group than the placebo group (hazard ratio 0·65, 95% CI 0·55-0·77; p<0·0001). Compared with the placebo group, participants in the canagliflozin group also had lower risks of anaemia events alone (0·58, 0·47-0·72; p<0·0001), initiation of iron preparations (0·64, 0·52-0·80; p<0·0001), and need for erythropoiesis-stimulating agents (0·65, 0·46-0·91; p=0·012).INTERPRETATION: These data suggest that canagliflozin reduces the risk of anaemia-associated outcomes, including the need for erythropoiesis-stimulating agents, among patients with type 2 diabetes and chronic kidney disease.FUNDING: Janssen Research and Development.

    View details for DOI 10.1016/S2213-8587(20)30300-4

    View details for PubMedID 33065060

  • Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial LANCET DIABETES & ENDOCRINOLOGY Oshima, M., Neuen, B. L., Jardine, M. J., Bakris, G., Edwards, R., Levin, A., Mahaffey, K. W., Neal, B., Pollock, C., Rosenthal, N., Wada, T., Wheeler, D. C., Perkovic, V., Heerspink, H. L. 2020; 8 (11): 903–14
  • International consensus definitions of clinical trial outcomes for kidney failure: 2020. Kidney international Levin, A., Agarwal, R., Herrington, W. G., Heerspink, H. L., Mann, J. F., Shahinfar, S., Tuttle, K. R., Donner, J., Jha, V., Nangaku, M., de Zeeuw, D., Jardine, M. J., Mahaffey, K. W., Thompson, A. M., Beaucage, M., Chong, K., Roberts, G. V., Sunwold, D., Vorster, H., Warren, M., Damster, S., Malik, C., Perkovic, V., participant authors of the International Society of Nephrologys 1st International Consensus Meeting on Defining Kidney Failure in Clinical Trials, Anand, S., Argent, N., Babak, E., Banerjee, D., Barratt, J., Bello, A. K., Bernardo, A. A., Blais, J., Canovatchel, W., Caskey, F. J., Coresh, J., de Boer, I. H., Eckardt, K., Evans, R. D., Feldman, H. I., Fogo, A. B., Gudmundsdottir, H., Hamano, T., Harris, D. C., Hauske, S. J., Haynes, R., Herzog, C. A., Hiemstra, T., Idorn, T., Inker, L., Ishida, J. H., Johnson, D. W., Jones-Burton, C., Joseph, A., Koitka-Weber, A., Kretzler, M., Lawatscheck, R., Liew, A., Moist, L., Naicker, S., Nakashima, R., Patel, U., Filho, R. P., Rose, J. B., Rosenberg, N. L., Sinsakul, M., Smoyer, W. E., Sola, L., Sood, A. R., Stengel, B., Taal, M. W., Tanaka, M., Tonelli, M., Tong, A., Toto, R., Trask, M., Ulasi, I. I., Wanner, C., Wheeler, D. C., Wolthers, B. O., Wright, H. M., Yamada, Y., Zakharova, E. 2020; 98 (4): 849–59

    Abstract

    Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multi-stakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The consensus of the meeting participants was that clinical trial kidney failure outcomes should be comprised of a composite that includes receipt of a kidney transplant, initiation of maintenance dialysis, and death from kidney failure; it may also include outcomes based solely on laboratory measurements of glomerular filtration rate: a sustained low glomerular filtration rate and a sustained percent decline in glomerular filtration rate. Discussion included important considerations, such as (i) recognition of existing nomenclature for kidney failure; (ii) applicability across resource settings; (iii) ease of understanding for all stakeholders; and (iv) avoidance of inappropriate complexity so that the definitions can be used across ranges of populations and trial methodologies. The final definitions reflect the consensus for use in clinical trials.

    View details for DOI 10.1016/j.kint.2020.07.013

    View details for PubMedID 32998816

  • Appropriateness of Direct Oral Anticoagulant Dosing in Patients With Atrial Fibrillation: Insights From the Veterans Health Administration JOURNAL OF PHARMACY PRACTICE Leef, G. C., Perino, A. C., Askari, M., Fan, J., Ho, P., Olivier, C. B., Longo, L., Mahaffey, K. W., Turakhia, M. P. 2020; 33 (5): 647–53
  • Early Change in Albuminuria with Canagliflozin Predicts Kidney and Cardiovascular Outcomes: A PostHoc Analysis from the CREDENCE Trial. Journal of the American Society of Nephrology : JASN Oshima, M., Neuen, B. L., Li, J., Perkovic, V., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T., Levin, A., Mahaffey, K. W., De Nicola, L., Pollock, C., Rosenthal, N., Wheeler, D. C., Jardine, M. J., Heerspink, H. J. 2020

    Abstract

    BACKGROUND: The association between early changes in albuminuria and kidney and cardiovascular events is primarily based on trials of renin-angiotensin system blockade. It is unclear whether this association occurs with sodium-glucose cotransporter 2 inhibition.METHODS: The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial enrolled 4401 patients with type 2 diabetes and CKD (urinary albumin-creatinine ratio [UACR] >300 mg/g). This post hoc analysis assessed canagliflozin's effect on albuminuria and how early change in albuminuria (baseline to week 26) is associated with the primary kidney outcome (ESKD, doubling of serum creatinine, or kidney death), major adverse cardiovascular events, and hospitalization for heart failure or cardiovascular death.RESULTS: Complete data for early change in albuminuria and other covariates were available for 3836 (87.2%) participants in the CREDENCE trial. Compared with placebo, canagliflozin lowered UACR by 31% (95% confidence interval [95% CI], 27% to 36%) at week 26, and significantly increased the likelihood of achieving a 30% reduction in UACR (odds ratio, 2.69; 95% CI, 2.35 to 3.07). Each 30% decrease in UACR over the first 26 weeks was independently associated with a lower hazard for the primary kidney outcome (hazard ratio [HR], 0.71; 95% CI, 0.67 to 0.76; P<0.001), major adverse cardiovascular events (HR, 0.92; 95% CI, 0.88 to 0.96; P<0.001), and hospitalization for heart failure or cardiovascular death (HR, 0.86; 95% CI, 0.81 to 0.90; P<0.001). Residual albuminuria levels at week 26 remained a strong independent risk factor for kidney and cardiovascular events, overall and in each treatment arm.CONCLUSIONS: In people with type 2 diabetes and CKD, use of canagliflozin results in early, sustained reductions in albuminuria, which were independently associated with long-term kidney and cardiovascular outcomes.

    View details for DOI 10.1681/ASN.2020050723

    View details for PubMedID 32998938

  • An exploration of the heterogeneity in effects of SGLT2 inhibition on cardiovascular and all-cause mortality in the EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58, and CREDENCE trials. International journal of cardiology Yu, J., Zhou, Z., Mahaffey, K. W., Matthews, D. R., Neuen, B. L., Heerspink, H. J., Jardine, M., Li, J., Perkovic, V., Neal, B., Arnott, C. 2020

    Abstract

    BACKGROUND: Large-scale outcome trials of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have identified consistent effects on major adverse cardiovascular events, heart failure, and progression of kidney disease. However, the magnitude of effects on cardiovascular and all-cause death appeared to vary between some of the studies.METHODS: We explored the impact of differences in trial methodologies, participant characteristics, types of deaths, follow-up duration, effects on intermediate markers of risk, and drug selectivity for SGLT2 on the magnitude of the protective effect against fatal events achieved in the 4 trials.RESULTS: The trial populations differed substantively in the proportions with baseline atherosclerotic cardiovascular disease history (99.2% in EMPA-REG OUTCOME to 40.6% in DECLARE-TIMI 58), and macroalbuminuria (88.0% in CREDENCE to 7.6% in the CANVAS Program). Meta-regression analyses identified no clear effect of these (both P > 0.09) or other participant characteristics on mortality benefits (all P > 0.55). Other differences between the trials (duration, selectivity of the SGLT2 inhibitor, or effects on intermediate markers of risk) also did not explain the heterogeneity in effects on mortality observed (all P > 0.30).CONCLUSION: No clear explanation for the statistical evidence of heterogeneity in effects of SGLT2 inhibition on fatal outcomes between the trials could be identified. While the analyses had limited statistical power, these results raise the possibility that the observed variations in treatment effects on fatal outcomes between trials may be at least partly due to chance.

    View details for DOI 10.1016/j.ijcard.2020.09.050

    View details for PubMedID 32979427

  • Association of Health Status Scores With Cardiovascular and Limb Outcomes in Patients With Symptomatic Peripheral Artery Disease: Insights From the EUCLID (Examining Use of Ticagrelor in Symptomatic Peripheral Artery Disease) Trial. Journal of the American Heart Association Rymer, J. A., Mulder, H., Smolderen, K. G., Hiatt, W. R., Conte, M. S., Berger, J. S., Norgren, L., Mahaffey, K. W., Baumgartner, I., Fowkes, F. G., Katona, B. G., Rockhold, F., Jones, W. S., Patel, M. R. 2020: e016573

    Abstract

    Background There are limited data on health status instruments in patients with peripheral artery disease and cardiovascular and limb events. We evaluated the relationship between health status changes and cardiovascular and limb events. Methods and Results In an analysis of the EUCLID (Examining Use of Ticagrelor in Symptomatic Peripheral Artery Disease) trial, we examined the characteristics of 13801 patients by tertile of health status instrument scores collected in the trial (EuroQol 5-Dimensions [EQ-5D], EQ visual analog scale [VAS], and peripheral artery questionnaire). We assessed the association between the baseline health status measurements and major adverse cardiovascular events, major adverse limb events, and lower-extremity revascularization procedures during trial follow-up and the association between 12-month health status change scores and subsequent end points during follow-up. There were 13217 (95%) patients with EQ-5D scores, 13533 (98%) with VAS scores, and 4431 (32%) with peripheral artery questionnaire scores. Patients in the lowest baseline EQ-5D tertile (0 to <0.69) were more likely to be female with severe claudication compared with the highest tertile (0.79-1.0; P<0.01). Patients in the lowest VAS (0-60) and peripheral artery questionnaire (0-49) tertiles had lower ankle-brachial indices compared with the highest tertiles (80-100 and 76-108, respectively; P<0.01). There was a significant association between baseline EQ-5D, VAS, and peripheral artery questionnaire scores and adjusted major adverse cardiovascular events, major adverse limb events, and lower-extremity revascularization (P<0.05). Improved EQ-5D and VAS scores over 12months were associated with reduced risk of subsequent major adverse cardiovascular events or lower-extremity revascularization (all P<0.01). Conclusions Although health status instruments are rarely used in clinical practice, these measures are associated with outcomes, including major adverse cardiovascular events, major adverse limb events, and lower-extremity revascularization. Further research is needed to determine the relationship between changes in these instruments, revascularization, and outcomes.

    View details for DOI 10.1161/JAHA.120.016573

    View details for PubMedID 32924754

  • 2020 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants A Report of the American College of Cardiology Solution Set Oversight Committee JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tomaselli, G. F., Mahaffey, K. W., Cuker, A., Dobesh, P. P., Doherty, J. U., Eikelboom, J. W., Florido, R., Gluckman, T. J., Hucker, W. J., Mehran, R., Messe, S. R., Perino, A. C., Rodriguez, F., Sarode, R., Siegal, D. M., Wiggins, B. S., Report Amer Coll Cardiology Soluti, Solution Set Oversight Comm 2020; 76 (5): 594–622

    View details for DOI 10.1016/j.jacc.2020.04.053

    View details for Web of Science ID 000557886000001

    View details for PubMedID 32680646

  • Different eGFR Decline Thresholds and Renal Effects of Canagliflozin: Data from the CANVAS Program. Journal of the American Society of Nephrology : JASN Oshima, M., Neal, B., Toyama, T., Ohkuma, T., Li, Q., de Zeeuw, D., Heerspink, H. J., Mahaffey, K. W., Fulcher, G., Canovatchel, W., Matthews, D. R., Perkovic, V. 2020

    Abstract

    BACKGROUND: Traditionally, clinical trials evaluating effects of a new therapy with creatinine-based renal end points use doubling of serum creatinine (equivalent to a 57% eGFR reduction), requiring large sample sizes.METHODS: To assess whether eGFR declines <57% could detect canagliflozin's effects on renal outcomes, we conducted a post hoc study comparing effects of canagliflozin versus placebo on composite renal outcomes using sustained 57%, 50%, 40%, or 30% eGFR reductions in conjunction with ESKD and renal death. Because canagliflozin causes an acute reversible hemodynamic decline in eGFR, we made estimates using all eGFR values as well as estimates that excluded early measures of eGFR influenced by the acute hemodynamic effect.RESULTS: Among the 10,142 participants, 93 (0.9%), 161 (1.6%), 352 (3.5%), and 800 (7.9%) participants recorded renal outcomes on the basis of 57%, 50%, 40%, or 30% eGFR reduction, respectively, during a mean follow-up of 188 weeks. Compared with a 57% eGFR reduction (risk ratio [RR], 0.51; 95% confidence interval [95% CI], 0.34 to 0.77), the effect sizes were progressively attenuated when using 50% (RR, 0.61; 95% CI, 0.45 to 0.83), 40% (RR, 0.70; 95% CI, 0.57 to 0.86), or 30% (RR, 0.81; 95% CI, 0.71 to 0.93) eGFR reductions. In analyses that controlled for the acute hemodynamic fall in eGFR, effect sizes were comparable, regardless of whether a 57%, 50%, 40%, or 30% eGFR reduction was used. Estimated sample sizes for studies on the basis of lesser eGFR reductions were much reduced by controlling for this early hemodynamic effect.CONCLUSIONS: Declines in eGFR <57% may provide robust estimates of canagliflozin's effects on renal outcomes if the analysis controls for the drug's acute hemodynamic effect.CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: CANagliflozin cardioVascular Assessment Study (CANVAS), NCT01032629 and CANVAS-R, NCT01989754.

    View details for DOI 10.1681/ASN.2019121312

    View details for PubMedID 32694216

  • Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS Program. Diabetes, obesity & metabolism Matthews, D. R., Wysham, C., Davies, M., Slee, A., Alba, M., Lee, M., Perkovic, V., Mahaffey, K. W., Neal, B. 2020

    Abstract

    This study compared initiation of insulin and other AHAs with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs 16%), insulin (3% vs 9%;) or any non-insulin AHA (5% vs 12%; p<0.001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31,0.43; p<0.001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about two years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (p<0.001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes. Trial registration: ClinicalTrials.gov identifiers NCT01032629, NCT01989754. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/dom.14143

    View details for PubMedID 32691499

  • A Call for a New Paradigm for Diabetes Care in the Era of Sodium-Glucose Cotransporter2 Inhibitors (SGLT2i). Cardiology and therapy Kim, S. H., Chang, T. I., Mahaffey, K. W. 2020

    Abstract

    In 2013, canagliflozin was the first sodium-glucose cotransporter2 inhibitor (SGLT2i) approved by the US Food and Drug Administration for the treatment of type2 diabetes (T2DM). Today, there are four SGLT2i approved for T2DM, and some SGLT2i have been approved for indications beyond glucose control. For example, SGLT2i reduce major adverse clinical events (MACE) including nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (canagliflozin); cardiovascular death (empagliflozin, dapagliflozin); diabetic kidney disease progression (canagliflozin); and heart failure hospitalization (canagliflozin, dapagliflozin). However, despite the potential benefits of SGLT2i in reducing adverse clinical events, providers underprescribe SGLT2i for eligible patients. Thus, we propose the CKD-PCP framework which allows multiple providers to utilize the benefits of SGLT2i. CKD-PCP has dual meaning: it applies to providers who most often care for patients with T2DM (Cardiologists, Kidney specialists, Diabetologists, and Primary Care Physicians) and it refers to the benefits of SGLT2i (treatment of Cardiovascular disease, Kidney disease, Diabetes, and reduction of blood Pressure, Calories, and Plasma volume). This article is based on previously conducted studies and the authors disclosetheir roles in relevant trialsin the Acknowledgements.

    View details for DOI 10.1007/s40119-020-00190-7

    View details for PubMedID 32661684

  • Effect of Temporary Interruption of Warfarin Due to an Intervention on Downstream Time in Therapeutic Range in Patients With Atrial Fibrillation (from ORBIT AF). The American journal of cardiology Madhavan, M., Holmes, D. N., Piccini, J. P., Freeman, J. V., Fonarow, G. C., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Pieper, K., Peterson, E. D., Chan, P. S., Allen, L. A., Singer, D. E., Naccarelli, G. V., Reiffel, J. A., Steinberg, B. A., Gersh, B. J., ORBIT AF Investigators 2020

    Abstract

    The aim of this study was to quantify time in therapeutic range (TTR) before and after a temporary interruption of warfarin due to an intervention in the Outcomes Registry for Better Informed Treatment of atrial fibrillation (AF). AF patients on warfarin who had a temporary interruption followed by resumption were identified. A nonparametric method for estimating survival functions for interval censored data was used to examine the first therapeutic International Normalized Ratio (INR) after interruption. TTR was compared using Wilcoxon signed rank test. Cox proportional hazards model was used to investigate the association between TTR in the first 3 months after interruption and subsequent outcomes at 3 to 9 months. Of 9,749 AF patients, 71% were on warfarin. Over a median (IQR) follow-up of 2.6 (1.8 to 3.1) y, 33% of patients had a total of 3,022 temporary interruptions. The first therapeutic INR was recorded within 1 week in 35.0% (95% confidence interval 32.6% to 37.4%), 2 weeks in 54.6% (52.2% to 57.0%), 30 days in 70.0% (67.9% to 72.1%) and 90 days in 91.3% (90.0% to 92.5%) of patients. Compared with pre-interruption, TTR 3 months after interruption was significantly lower (61.1% [36.6% to 85.0%] vs 67.6% [50.0% to 81.3%], p <0.0001). A 10 unit increment in the TTR in the first 3 months after interruption was associated with a lower risk of major bleeding [Hazard ratio 0.91 (0.85 to 0.97), p = 0.005]. This association was noted in patients who received bridging anticoagulation, but not in those who did not. In conclusion, temporary interruption of warfarin is common, and nearly half of these patients had subtherapeutic INR after 2 weeks. Lower TTR in the first 3 months after interruption was associated with higher incidence of major bleeding in patients who received bridging anticoagulation.

    View details for DOI 10.1016/j.amjcard.2020.07.006

    View details for PubMedID 32826041

  • Patterns of oral anticoagulation use with cardioversion in clinical practice. Heart (British Cardiac Society) Geurink, K., Holmes, D., Ezekowitz, M. D., Pieper, K., Fonarow, G., Kowey, P. R., Reiffel, J. A., Singer, D. E., Freeman, J., Gersh, B. J., Mahaffey, K. W., Hylek, E. M., Naccarelli, G., Piccini, J. P., Peterson, E. D., Pokorney, S. D. 2020

    Abstract

    BACKGROUND: Cardioversion is common among patients with atrial fibrillation (AF). We hypothesised that novel oral anticoagulants (NOAC) used in clinical practice resulted in similar rates of stroke compared with vitamin K antagonists (VKA) for cardioversion.METHODS: Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, patients with AF who had a cardioversion, follow-up data and an AF diagnosis within 6 months of enrolment were identified retrospectively. Clinical outcomes were compared for patients receiving a NOAC or VKA for 1year following cardioversion.RESULTS: Among 13004 patients with AF, 2260 (17%) underwent cardioversion. 1613 met the inclusion criteria for this analysis. At the time of cardioversion, 283 (17.5%) were receiving a VKA and 1330 (82.5%) a NOAC. A transoesophageal echocardiogram (TOE) was performed in 403 (25%) cardioversions. The incidence of stroke/transient ischaemic attack (TIA) at 30 days was the same for patients having (3.04 per 100 patient-years) or not having (3.04 per 100 patient-years) a TOE (p=0.99). There were no differences in the incidence of death (HR 1.19, 95%CI 0.62 to 2.28, p=0.61), cardiovascular hospitalisation (HR 1.02, 95%CI 0.76 to 1.35, p=0.91), stroke/TIA (HR 1.18, 95%CI 0.30 to 4.74, p=0.81) or bleeding-related hospitalisation (HR 1.29, 95%CI 0.66 to 2.52, p=0.45) at 1year for patients treated with either a NOAC or VKA.CONCLUSIONS: Cardioversion was a low-risk procedure for patients treated with NOAC, and there were statistically similar rates of stroke/TIA 30 days after cardioversion as for patients treated with VKA. There were no statically significant differences in death, stroke/TIA or major bleeding at 1year among patients treated with NOAC compared with VKA after cardioversion.

    View details for DOI 10.1136/heartjnl-2019-316315

    View details for PubMedID 32591363

  • The effects of combination canagliflozin and glucagon-like peptide-1 receptor agonist therapy on intermediate markers of cardiovascular risk in the CANVAS program. International journal of cardiology Arnott, C., Neuen, B. L., Heerspink, H. J., Figtree, G. A., Kosiborod, M., Lam, C. S., Cannon, C. P., Rosenthal, N., Shaw, W., Mahaffey, K. W., Jardine, M. J., Perkovic, V., Neal, B. 2020

    Abstract

    BACKGROUND: Sodium glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) reduce cardiovascular events, and improve intermediate markers of cardiometabolic health, in those with type 2 diabetes. We investigated these effects in the CANVAS Program.METHODS AND RESULTS: The CANVAS Program comprised 2 double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-R) done in patients with type 2 diabetes and elevated cardiovascular risk. Effects were estimated using mixed-effects models for continuous measures and Cox regression models for other outcomes. Randomized treatment by subgroup interaction terms were used to compare effects of canagliflozin versus placebo across subgroups defined by baseline use of GLP1-RA. There were 10,142 participants, of whom 407 (4%) were using GLP1-RA therapy at baseline. Those using GLP1-RA at baseline were less likely to have a history of cardiovascular disease (60.4% vs 65.8%), had a longer duration of diabetes (15.2 vs 13.5 years) and a higher body mass index (BMI; 35.6 vs 31.8 kg/m2) but were otherwise similar. There were greater reductions with canagliflozin versus placebo for HbA1c (-0.75% versus -0.58%; P = .0091), SBP (-6.26 versus -3.83 mmHg; P = .0018), and body weight (-3.79 versus -2.18 kg; P < .0001) in those on baseline GLP1-RA therapy. Effects across subgroups were similar for UACR (P = .21), eGFR slope (P = .72), major adverse cardiac events (P = .94) and total serious adverse events (P = .74).CONCLUSIONS: There may be a synergistic effect of SGLT2 inhibition when used on a background of GLP1-RA for intermediate cardiometabolic markers.

    View details for DOI 10.1016/j.ijcard.2020.06.011

    View details for PubMedID 32569700

  • The Project Baseline Health Study: a step towards a broader mission to map human health NPJ DIGITAL MEDICINE Arges, K., Assimes, T., Bajaj, V., Balu, S., Bashir, M. R., Beskow, L., Blanco, R., Califf, R., Campbell, P., Carin, L., Christian, V., Cousins, S., Das, M., Dockery, M., Douglas, P. S., Dunham, A., Eckstrand, J., Fleischmann, D., Ford, E., Fraulo, E., French, J., Gambhir, S. S., Ginsburg, G. S., Green, R. C., Haddad, F., Hernandez, A., Hernandez, J., Huang, E. S., Jaffe, G., King, D., Koweek, L. H., Langlotz, C., Liao, Y. J., Mahaffey, K. W., Marcom, K., Marks, W. J., Maron, D., McCabe, R., McCall, S., McCue, R., Mega, J., Miller, D., Muhlbaier, L. H., Munshi, R., Newby, L., Pak-Harvey, E., Patrick-Lake, B., Pencina, M., Peterson, E. D., Rodriguez, F., Shore, S., Shah, S., Shipes, S., Sledge, G., Spielman, S., Spitler, R., Schaack, T., Swamy, G., Willemink, M. J., Wong, C. A. 2020; 3 (1): 84

    Abstract

    The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

    View details for DOI 10.1038/s41746-020-0290-y

    View details for Web of Science ID 000538242900001

    View details for PubMedID 32550652

    View details for PubMedCentralID PMC7275087

  • The Project Baseline Health Study: a step towards a broader mission to map human health. NPJ digital medicine Arges, K., Assimes, T., Bajaj, V., Balu, S., Bashir, M. R., Beskow, L., Blanco, R., Califf, R., Campbell, P., Carin, L., Christian, V., Cousins, S., Das, M., Dockery, M., Douglas, P. S., Dunham, A., Eckstrand, J., Fleischmann, D., Ford, E., Fraulo, E., French, J., Gambhir, S. S., Ginsburg, G. S., Green, R. C., Haddad, F., Hernandez, A., Hernandez, J., Huang, E. S., Jaffe, G., King, D., Koweek, L. H., Langlotz, C., Liao, Y. J., Mahaffey, K. W., Marcom, K., Marks, W. J., Maron, D., McCabe, R., McCall, S., McCue, R., Mega, J., Miller, D., Muhlbaier, L. H., Munshi, R., Newby, L. K., Pak-Harvey, E., Patrick-Lake, B., Pencina, M., Peterson, E. D., Rodriguez, F., Shore, S., Shah, S., Shipes, S., Sledge, G., Spielman, S., Spitler, R., Schaack, T., Swamy, G., Willemink, M. J., Wong, C. A. 2020; 3 (1): 84

    Abstract

    The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.

    View details for DOI 10.1038/s41746-020-0290-y

    View details for PubMedID 33597683

  • CANAGLIFLOZIN AND RISK OF GENITAL INFECTIONS AND URINARY TRACT INFECTIONS IN PEOPLE WITH DIABETES MELLITUS AND KIDNEY DISEASE- A POST-HOC ANALYSIS OF THE CREDENCE TRIAL Kang, A., Neuen, B., Heerspink, H., Di Tanna, G., Neal, B., Zhang, H., Hockham, C., Agarwal, R., Bakris, G., Charytan, D. M., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D., Zinman, B., Mahaffey, K. W., Perkovic, V., Jardine, M. OXFORD UNIV PRESS. 2020: 1336
  • EFFECTS OF CANAGLIFLOZIN ON MAJOR ADVERSE CARDIOVASCULAR OUTCOMES IN PATIENTS WITH DIFFERENT BASELINE LEVELS OF TYPE 2 DIABETES MELLITUS DISEASE SEVERITY: RESULTS FROM THE CANVAS PROGRAM Young, T., Li, J., Kang, A., Heerspink, H., Hockham, C., Arnott, C., Neuen, B., Zoungas, S., Mahaffey, K. W., Perkovic, V., De Zeeuw, D., Fulcher, G., Neal, B., Jardine, M. OXFORD UNIV PRESS. 2020: 1351
  • CANAGLIFLOZIN AND RISK OF SKIN AND SOFT TISSUE INFECTIONS IN PEOPLE WITH DIABETES MELLITUS AND KIDNEY DISEASE - A POST-HOC ANALYSIS OF THE CREDENCE TRIAL Kang, A., Smyth, B., Neuen, B., Heerspink, H., Di Tanna, G., Neal, B., Zhang, H., Hockham, C., Agarwal, R., Bakris, G., Charytan, D. M., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D., Zinman, B., Mahaffey, K. W., Perkovic, V., Jardine, M. OXFORD UNIV PRESS. 2020: 1342
  • The effect of canagliflozin on amputation risk in the CANVAS Program and the CREDENCE trial. Diabetes, obesity & metabolism Arnott, C., Huang, Y., Neuen, B., Di Tanna, G. L., Cannon, C. P., Oh, R., Edwards, R., Kavalam, M., Rosenthal, N., Perkovic, V., Jardine, M., Mahaffey, K., Neal, B. 2020

    Abstract

    AIMS: The SGLT2 inhibitor canagliflozin was associated with increased amputation risk in the CANVAS Program but not in CREDENCE. We explored possible explanations for these differences in amputation risk.METHODS: We performed a pooled analysis of patient-level data from the CANVAS Program and CREDENCE trial. Patient characteristics associated with amputation risk were assessed in univariable and multivariable regression models and compared between studies. Effects of canagliflozin on amputation risk were determined from Cox proportional hazards models and compared between studies, subgroups, and for a range of amputation outcomes. Effects over time were explored by cumulative event curves.RESULTS: In the CANVAS Program (n=10,142; median follow-up 2·4y) and CREDENCE trial (n=4401; median follow-up 2·5y), 2·3% and 5·3% of participants, respectively, reported baseline amputation history. Key differences at baseline were the proportions with nephropathy (CREDENCE higher, 100% vs 17·5%) and cardiovascular disease (CANVAS Program higher, 66% vs 50%). There were 133 amputations in CREDENCE (3·0% annual event rate) and 187 amputations in CANVAS (1·8% annual event rate), with prior amputation being the strongest predictor of future amputation in both groups. Effects of canagliflozin on amputation risk were significantly different between trials (pheterogeneity 0·02, I2 =82%), but this was not explained by participant or trial differences. There was no evidence that foot disease management protocols instituted during CREDENCE ameliorated amputation risk.CONCLUSIONS: We identified no explanation for the difference in amputation risk between CREDENCE and the CANVAS Program. In the context of null effects of SGLT2 inhibition on amputation in CREDENCE and all other large trials, there is a possibility that the finding in CANVAS was the result of chance. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/dom.14091

    View details for PubMedID 32436638

  • Shared Decision Making in Atrial Fibrillation: Patient-Reported Involvement in Treatment Decisions. European heart journal. Quality of care & clinical outcomes Ali-Ahmed, F., Pieper, K., North, R., Allen, L. A., Chan, P. S., Ezekowitz, M. D., Fonarow, G. C., Freeman, J. V., Go, A. S., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Naccarelli, G. V., Pokorney, S. D., Reiffel, J. A., Singer, D. E., Steinberg, B. A., Peterson, E. D., Piccini, J. P., O'Brien, E. C. 2020

    Abstract

    AIMS: To determine the extent of shared decision-making (SDM), during selection of oral anticoagulant (OAC) and rhythm control treatments, in patients with newly diagnosed AF.METHODS AND RESULTS: We evaluated survey data from 1,006 patients with new-onset AF enrolled at 56U.S. sites participating in the SATELLITE substudy of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT II). Patients completed surveys at enrollment and at 6-month follow-up. Patients were asked about who made their AF treatment decisions. SDM was classified as one that the patient felt was an autonomous decision or a shared decision with their healthcare provider (HCP). Approximately half of patients reported that their OAC treatment decisions were made entirely by their HCP. Compared with those reporting no SDM, patients reporting SDM for OAC were more often female (47.2% vs 38.4%), while patients reporting SDM for rhythm control were more often male (62.2% vs 57.6%). The most important factors cited by patients during decision-making for OAC were reducing stroke and bleeding risk, and their HCP's recommendations. After adjustment, patients with self-reported understanding of OAC, and rhythm control options, had higher odds of having participated in SDM (OR 2.54, CI: 1.75-3.68 and OR 2.36, CI: 1.50-3.71, both p=<0.001, respectively).CONCLUSION: SDM is not widely implemented in contemporary AF practice. Patient understanding about available therapeutic options is associated with a more than a 2-fold higher likelihood of SDM, and may be a potential target for future interventions.

    View details for DOI 10.1093/ehjqcco/qcaa040

    View details for PubMedID 32392287

  • Outpatient Inhaled Nitric Oxide in a Patient with Vasoreactive IPAH and COVID-19 Infection. American journal of respiratory and critical care medicine Zamanian, R. T., Pollack, C. V., Gentile, M. A., Rashid, M., Fox, J. C., Mahaffey, K. W., de Jesus Perez, V. 2020

    View details for DOI 10.1164/rccm.202004-0937LE

    View details for PubMedID 32369396

  • Renal, Cardiovascular, and Safety Outcomes of Canagliflozin by Baseline Kidney Function: A Secondary Analysis of the CREDENCE Randomized Trial. Journal of the American Society of Nephrology : JASN Jardine, M. J., Zhou, Z., Mahaffey, K. W., Oshima, M., Agarwal, R., Bakris, G., Bajaj, H. S., Bull, S., Cannon, C. P., Charytan, D. M., de Zeeuw, D., Di Tanna, G. L., Greene, T., Heerspink, H. J., Levin, A., Neal, B., Pollock, C., Qiu, R., Sun, T., Wheeler, D. C., Zhang, H., Zinman, B., Rosenthal, N., Perkovic, V., CREDENCE Study Investigators, Jardine, M. J., Zhou, Z., Mahaffey, K. W., Oshima, M., Agarwal, R., Bakris, G., Bajaj, H. S., Bull, S., Cannon, C. P., Charytan, D. M., de Zeeuw, D., Luca di Tanna, G., Greene, T., Heerspink, H. J., Levin, A., Neal, B., Pollock, C., Qiu, R., Sun, T., Wheeler, D. C., Zhang, H., Zinman, B., Rosenthal, N., Perkovic, V. 2020; 31 (5): 1128–39

    Abstract

    BACKGROUND: Canagliflozin reduced renal and cardiovascular events in people with type 2 diabetes in the CREDENCE trial. We assessed efficacy and safety of canagliflozin by initial estimated glomerular filtration rate (eGFR).METHODS: CREDENCE randomly assigned 4401 participants with an eGFR of 30 to <90 ml/min per 1.73 m2 and substantial albuminuria to canagliflozin 100 mg or placebo. We used Cox proportional hazards regression to analyze effects on renal and cardiovascular efficacy and safety outcomes within screening eGFR subgroups (30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2) and linear mixed effects models to analyze the effects on eGFR slope.RESULTS: At screening, 1313 (30%), 1279 (29%), and 1809 (41%) participants had an eGFR of 30 to <45, 45 to <60, and 60 to <90 ml/min per 1.73 m2, respectively. The relative benefits of canagliflozin for renal and cardiovascular outcomes appeared consistent among eGFR subgroups (all P interaction >0.11). Subgroups with lower eGFRs, who were at greater risk, exhibited larger absolute benefits for renal outcomes. Canagliflozin's lack of effect on serious adverse events, amputations, and fractures appeared consistent among eGFR subgroups. In all subgroups, canagliflozin use led to an acute eGFR drop followed by relative stabilization of eGFR loss. Among those with an eGFR of 30 to <45 ml/min per 1.73 m2, canagliflozin led to an initial drop of 2.03 ml/min per 1.73 m2. Thereafter, decline in eGFR was slower in the canagliflozin versus placebo group (-1.72 versus -4.33 ml/min per 1.73 m2; between-group difference 2.61 ml/min per 1.73 m2).CONCLUSIONS: Canagliflozin safely reduced the risk of renal and cardiovascular events, with consistent results across eGFR subgroups, including the subgroup initiating treatment with an eGFR of 30 to <45 ml/min per 1.73 m2. Absolute benefits for renal outcomes were greatest in subgroups with lower eGFR.CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants With Diabetic Nephropathy (CREDENCE), NCT02065791.

    View details for DOI 10.1681/ASN.2019111168

    View details for PubMedID 32354987

  • Outcomes of Cardiac Catheterization in Patients With Atrial Fibrillation on Anticoagulation in Contemporary in Practice: An Analysis of the ORBIT II Registry. Circulation. Cardiovascular interventions Sherwood, M. W., Piccini, J. P., Holmes, D. N., Pieper, K. S., Steinberg, B. A., Fonarow, G. C., Allen, L. A., Naccarelli, G. V., Kowey, P. R., Gersh, B. J., Mahaffey, K. W., Singer, D. E., Ansell, J. E., Freeman, J. V., Chan, P. S., Reiffel, J. A., Blanco, R., Peterson, E. D., Rao, S. V. 2020; 13 (5): e008274

    Abstract

    BACKGROUND: Patients with atrial fibrillation on oral anticoagulation (OAC) undergoing cardiac catheterization face risks for embolic and bleeding events, yet information on strategies to mitigate these risks in contemporary practice is lacking.METHODS: We aimed to describe the clinical/procedural characteristics of a contemporary cohort of patients with atrial fibrillation on OAC who underwent cardiac catheterization. Use of bleeding avoidance strategies and bridging therapy were described and outcomes including death, stroke, and major bleeding at 30 days and 1 year were compared by OAC type.RESULTS: Of 13404 patients in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II Registry from 2013 to 2016, 741 underwent cardiac catheterization (139 with percutaneous coronary intervention) in the setting of OAC. The patients' median age was 71, 61.8% were male, white (87.2%), had hypertension (83.7%), hyperlipidemia (72.1%), diabetes mellitus (31.6%), and chronic kidney disease (28.2%); 20.2% received warfarin while 79.8% received direct acting oral anticoagulant. One third of patients underwent radial artery access, and bivalirudin was used in 4.6%. Bridging therapy was used more often in patients on warfarin versus direct acting oral anticoagulant (16.7% versus10.0%). OAC was interrupted in 93.8% of patients. Patients on warfarin versus direct acting oral anticoagulant were equally likely to restart OAC (58.0% versus 60.7%), had similar use of antiplatelet therapy (44.0% versus 41.3%) after catheterization, and had similar rates of myocardial infarction and death at 1 year, but higher rates of major bleeding (43.3 versus 12.9 events/100 patient years) and stroke (4.9 versus 1.9 events/100 patient years).CONCLUSIONS: In a real-world registry of patients with atrial fibrillation undergoing cardiac catheterization, most cases are elective, performed by femoral access, with interruption of OAC. Bleeding avoidance strategies such as radial artery access and bivalirudin were used infrequently and use of bridging therapy was uncommon. Nearly 40% of patients did not restart OAC postprocedure, exposing patients to risk for stroke. Further research is necessary to optimize the management of patients with atrial fibrillation undergoing cardiac catheterization.

    View details for DOI 10.1161/CIRCINTERVENTIONS.119.008274

    View details for PubMedID 32408815

  • Preventing Atrial Fibrillation With Treatments for Diabetes Mellitus. Circulation Granger, C. B., Mahaffey, K. W. 2020; 141 (15): 1235–37

    View details for DOI 10.1161/CIRCULATIONAHA.120.045864

    View details for PubMedID 32282249

  • Methods for safety and endpoint ascertainment: identification of adverse events through scrutiny of negatively adjudicated events. Trials Fanaroff, A. C., Haque, G., Thomas, B., Stone, A. E., Perkins, L. M., Wilson, M., Jones, W. S., Melloni, C., Mahaffey, K. W., Alexander, K. P., Lopes, R. D. 2020; 21 (1): 323

    Abstract

    BACKGROUND: The primary goal of phase 2 and 3 clinical trials is to evaluate the safety and effectiveness of therapeutic interventions, and efficient and reproducible ascertainment of important clinical events, either as clinical outcome events (COEs) or adverse events (AEs), is critical. Clinical outcomes require consistency and clinical judgment, so these events are often adjudicated centrally by clinical events classification (CEC) physician reviewers using standardized definitions. In contrast, AEs are reported by sites to the trial coordinating center based on common reporting criteria set by regulatory authorities and trial sponsors. These different requirements have led to the development of separate tracks for COE and AE review.MAIN BODY: Potential COEs that fail to meet standardized definitions for CEC adjudication - i.e. negatively adjudicated events (NAE) - may meet criteria for AEs. Trial oversight practices require the sponsor to process AEs regardless of how the AEs are submitted; therefore, review of NAEs may be necessary to ensure that important AEs do not go unreported. The Duke Clinical Research Institute (DCRI) developed and implemented a process for scrutinizing NAEs to detect potential missed serious AEs. Initial experience with this process across two trials suggests that approximately 0.2% of NAEs are serious unexpected AEs that were not otherwise reported and another 1.5% are serious expected AEs.CONCLUSIONS: Given their infrequent concealment of serious AEs in two large trials assessing cardiovascular outcomes, routine scrutiny of NAEs to identify AEs is not recommended at this time, though it may be useful in some trials and should be carefully considered by the trial team. Closer integration of data across safety surveillance and endpoint adjudication systems may enable scrutiny of NAEs when indicated while limiting complexity associated with this process.

    View details for DOI 10.1186/s13063-020-04254-w

    View details for PubMedID 32272961

  • CANAGLIFLOZIN (CANA) REDUCES CARDIOVASCULAR (CV) AND RENAL EVENTS INDEPENDENT OF BASELINE HEART FAILURE (HF): A CREDENCE SECONDARY ANALYSIS Sarraju, A., Li, J., Cannon, C. P., Chang, T. I., Agarwal, R., Bakris, G. L., Charytan, D. M., de Zeeuw, D., Greene, T., Heerspink, H. L., Levin, A., Neal, B., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Perkovic, V., Jardine, M., Mahaffey, K. W. ELSEVIER SCIENCE INC. 2020: 1018
  • Cangrelor in clinical use. Future cardiology Feng, K. Y., Mahaffey, K. W. 2020

    Abstract

    Inadequate antiplatelet effects can result in substantial morbidity and mortality in patients with acute coronary syndrome and percutaneous coronary intervention (PCI). Cangrelor is a rapid onset and potent intravenous P2Y12 inhibitor that has been shown in large randomized controlled trials to reduce periprocedural complications for PCI compared with clopidogrel, the most commonly used P2Y12 inhibitor. Cangrelor should be considered in the setting of PCI to reduce the risk of periprocedural complications such as myocardial infarction, repeat coronary revascularization and stent thrombosis in patients not yet treated with another P2Y12 inhibitor or glycoprotein IIb/IIIa inhibitor. In this review, the importance of adequate P2Y12 inhibition, cangrelor's pharmacology and clinical profiles, and future directions for the cangrelor are discussed.

    View details for DOI 10.2217/fca-2019-0095

    View details for PubMedID 32067479

  • Risk of major cardiovascular and neurologic events with obstructive sleep apnea among patients with atrial fibrillation. American heart journal Dalgaard, F., North, R., Pieper, K., Fonarow, G. C., Kowey, P. R., Gersh, B. J., Mahaffey, K. W., Pokorney, S., Steinberg, B. A., Naccarrelli, G., Allen, L. A., Reiffel, J. A., Ezekowitz, M., Singer, D. E., Chan, P. S., Peterson, E. D., Piccini, J. P. 2020; 223: 65–71

    Abstract

    BACKGROUND: Obstructive sleep apnea (OSA) is a known risk factor for atrial fibrillation (AF). However, it remains unclear whether OSA is independently associated with worse cardiovascular and neurological outcomes in patients with AF.METHODS: We used the ORBIT-AF I and ORBIT-AF II to conduct a retrospective cohort study of 22,760 patients with AF with and without OSA. Adjusted multivariable Cox proportional hazards models was used to determine whether OSA was associated with increased risk for major adverse cardiac and neurologic events (MACNEs) (cardiovascular death, myocardial infarction, stroke/transient ischemic attack/non-central nervous system embolism (stroke/SE), and new-onset heart failure], combined and individually.RESULTS: A total of 4,045 (17.8%) patients had OSA at baseline. Median follow-up time was 1.5 (interquartile range: 1-2.2) years, and 1,895 patients experienced a MACNE. OSA patients were younger (median [interquartile range] 68 [61-75] years vs 74 [66-81] years), were more likely male (70.7% vs 55.3%), and had increased body mass index (median 34.6 kg/m2 [29.8-40.2] vs 28.7 kg/m2 [25.2-33.0]). Those with OSA had a higher prevalence of concomitant comorbidities such as diabetes, chronic obstructive pulmonary disease, and heart failure. OSA patients had higher use of antithrombotic therapy. After adjustment, the presence of OSA was significantly associated with MACNE (hazard ratio: 1.16 [95% CI: 1.03-1.31], P = .011). OSA was also an independent risk factor for stroke/SE beyond the CHA2DS2-VASc risk factors (HR: 1.38 [95% CI 1.12-1.70], P = .003) but not cardiovascular death, myocardial infarction, new-onset heart failure, or major bleeding.CONCLUSIONS: Among patients with AF, OSA is an independent risk factor for MACNE and, more specifically, stroke/SE.

    View details for DOI 10.1016/j.ahj.2020.01.001

    View details for PubMedID 32179257

  • Decline in renal function and oral anticoagulation dose reduction among patients with atrial fibrillation. Heart (British Cardiac Society) Inohara, T., Holmes, D. N., Pieper, K., Blanco, R. G., Allen, L. A., Fonarow, G. C., Gersh, B. J., Hylek, E. M., Ezekowitz, M. D., Kowey, P. R., Reiffel, J. A., Naccarelli, G. V., Chan, P. S., Mahaffey, K. W., Singer, D. E., Freeman, J. V., Steinberg, B. A., Peterson, E. D., Piccini, J. P., ORBIT AF Patients and Investigators 2020

    Abstract

    OBJECTIVE: Non-vitamin K oral anticoagulants (NOACs) require dose adjustment for renal function. We sought to investigate change in renal function over time in patients with atrial fibrillation (AF) and whether those on NOACs have appropriate dose adjustments according to its decline.METHODS: We included patients with AF enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry treated with oral anticoagulation. Worsening renal function (WRF) was defined as a decrease of >20% in creatinine clearance (CrCl) from baseline. The US Food and Drug Administration (FDA)-approved package inserts were used to define the reduction criteria of NOACs dosing.RESULTS: Among 6682 patients with AF from 220 sites (median age (25th, 75th): 72.0 years (65.0, 79.0); 57.1% male; median CrCl at baseline: 80.1mL/min (57.4, 108.5)), 1543 patients (23.1%) experienced WRF with mean decline in CrCl during 2year follow-up of -6.63mL/min for NOACs and -6.16mL/min for warfarin. Among 4120 patients on NOACs, 154 (3.7%) patients had a CrCl decline sufficient to warrant FDA-recommended dose reductions. Of these, NOACs dosing was appropriately reduced in only 31 (20.1%) patients. Compared with patients with appropriately reduced NOACs, those without were more likely to experience bleeding complications (major bleeding: 1.7% vs 0%; bleeding hospitalisation: 2.6% vs 0%) at 1year.CONCLUSIONS: In the US practice, about one-fourth of patients with AF had >20% decline in CrCl over time during 2year follow-up. As a result, about 3.7% of those treated with NOACs met guideline criteria for dose reduction, but of these, only 20.1% actually had a reduction.

    View details for DOI 10.1136/heartjnl-2019-315792

    View details for PubMedID 31911503

  • Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes. Kidney international Li, J. n., Neal, B. n., Perkovic, V. n., de Zeeuw, D. n., Neuen, B. L., Arnott, C. n., Simpson, R. n., Oh, R. n., Mahaffey, K. W., Heerspink, H. J. 2020

    Abstract

    Canagliflozin reduced kidney disease progression in participants with type 2 diabetes in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program that explored potential mediators of the effects of canagliflozin on kidney outcomes. The percent mediating effect of 18 biomarkers indicative of disease was determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the average post-randomization level of each biomarker. Multivariable analyses assessed the joint effects of biomarkers that mediated most strongly in univariable analyses. The kidney outcome was defined as a composite of 40% estimated glomerular filtration rate decline, end-stage kidney disease, or death due to kidney disease. Nine biomarkers (systolic blood pressure [8.9% of effect explained], urinary albumin:creatinine ratio [UACR; 23.9%], gamma glutamyltransferase [4.1%], hematocrit [51.1%], hemoglobin [41.3%], serum albumin [19.5%], erythrocytes [56.7%], serum urate [35.4%], and urine pH [7.5%]) individually mediated the effect of canagliflozin on the kidney outcome. In a parsimonious multivariable model, erythrocyte concentration, serum urate, and systolic blood pressure maximized cumulative mediation (115%). Mediating effects of UACR, but not other mediators, were highly dependent upon the baseline level of UACR: UACR mediated 42% and 7% of the effect in those with baseline UACR 30 mg/g or more and under 30 mg/g, respectively. The identified mediators support existing hypothesized mechanisms for the prevention of kidney outcomes with sodium glucose co-transporter 2 inhibitors. Thus, the disparity in mediating effects across baseline UACR subgroups suggests that the mechanism for kidney protection with canagliflozin may vary across patient subgroups.

    View details for DOI 10.1016/j.kint.2020.04.051

    View details for PubMedID 32470492

  • Factors Associated with Large Improvements in Health-Related Quality of Life in Patients with Atrial Fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation. Arrhythmia and electrophysiology Steinberg, B. A., Holmes, D. N., Pieper, K. n., Allen, L. A., Chan, P. S., Ezekowitz, M. D., Freeman, J. V., Fonarow, G. C., Gersh, B. J., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Naccarelli, G. n., Reiffel, J. n., Singer, D. E., Peterson, E. D., Piccini, J. P. 2020

    Abstract

    Background - Atrial fibrillation (AF) adversely impacts health-related quality of life (hrQoL). While some patients demonstrate improvements in hrQoL, the factors associated with large improvements in hrQoL are not well described. Methods - We assessed factors associated with a 1-year increase in AFEQT of 1 standard deviation (≥18 points; 3x clinically important difference), among outpatients in the ORBIT-AF I registry. Results - Overall, 28% (181/636) of patients had such a hrQoL improvement. Compared with patients not showing large hrQoL improvement, they were of similar age (median 73 vs. 74, p=0.3), equally likely to be female (44% vs. 48%, p=0.3), but more likely to have newly-diagnosed AF at baseline (18% vs. 8%; p=0.0004), prior antiarrhythmic drug use (52% vs. 40%, 0.005), baseline antiarrhythmic drug use (34.8% vs, 26.8%, p=0.045), and more likely to undergo AF-related procedures during follow-up (AF ablation: 6.6% vs. 2.0%, p=0.003; cardioversion:12.2% vs. 5.9% p=0.008). In multivariable analysis, a history of alcohol abuse (adjusted OR 2.41, p=0.01) and increased baseline diastolic BP (adjusted OR 1.23 per 10-point increase and >65 mm Hg, p=0.04) were associated with large improvements in hrQoL at 1 year, whereas patients with prior stroke/TIA, COPD, and PAD were less likely to improve (p<0.05 for each). Conclusions - In this national registry of AF patients, potentially treatable AF risk factors are associated with large hrQoL improvement, whereas less reversible conditions appeared negatively associated with hrQoL improvement. Understanding which patients are most likely to have large hrQoL improvement may facilitate targeting interventions for high-value care that optimizes patient reported outcomes in AF. Clinical Trial Registration - clinicaltrials.gov.; Unique Identifier: NCT01165710.

    View details for DOI 10.1161/CIRCEP.119.007775

    View details for PubMedID 32298144

  • Dedicated kidney disease-focused outcome trials with sodium-glucose cotransporter-2 inhibitors: Lessons from CREDENCE and expectations from DAPA-HF, DAPA-CKD, and EMPA-KIDNEY. Diabetes, obesity & metabolism Rhee, J. J., Jardine, M. J., Chertow, G. M., Mahaffey, K. W. 2020; 22 Suppl 1: 46–54

    Abstract

    In the past decade, many cardiovascular outcome trials (CVOT) on the efficacy and safety of glucose-lowering agents have been completed. Amongst newer agents available for treatment of type 2 diabetes mellitus (T2DM), sodium-glucose cotransporter-2 (SGLT2) inhibitors have garnered much attention in contemporary clinical practice due to observed benefits on cardiovascular and kidney outcomes among patients with T2DM, as reported in large randomized controlled trials (RCT). These findings are reflected in the updated clinical guidelines of several major professional societies. Herein, we briefly review the mechanism of action of SGLT2 inhibitors and their pleiotropic effects, summarize key findings and limitations of initial CVOTs, then discuss three major kidney disease-focused outcome trials, including the Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical Evaluation (CREDENCE) trial as well as two ongoing RCTs: Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure-chronic kidney disease and EMPA-KIDNEY.

    View details for DOI 10.1111/dom.13987

    View details for PubMedID 32267076

  • Incremental value of diastolic stress test in identifying subclinical heart failure in patients with diabetes mellitus. European heart journal cardiovascular Imaging Nishi, T. n., Kobayashi, Y. n., Christle, J. W., Cauwenberghs, N. n., Boralkar, K. n., Moneghetti, K. n., Amsallem, M. n., Hedman, K. n., Contrepois, K. n., Myers, J. n., Mahaffey, K. W., Schnittger, I. n., Kuznetsova, T. n., Palaniappan, L. n., Haddad, F. n. 2020

    Abstract

    Resting echocardiography is a valuable method for detecting subclinical heart failure (HF) in patients with diabetes mellitus (DM). However, few studies have assessed the incremental value of diastolic stress for detecting subclinical HF in this population.Asymptomatic patients with Type 2 DM were prospectively enrolled. Subclinical HF was assessed using systolic dysfunction (left ventricular longitudinal strain <16% at rest and <19% after exercise in absolute value), abnormal cardiac morphology, or diastolic dysfunction (E/e' > 10). Metabolic equivalents (METs) were calculated using treadmill speed and grade, and functional capacity was assessed by percent-predicted METs (ppMETs). Among 161 patients studied (mean age of 59 ± 11 years and 57% male sex), subclinical HF was observed in 68% at rest and in 79% with exercise. Among characteristics, diastolic stress had the highest yield in improving detection of HF with 57% of abnormal cases after exercise and 45% at rest. Patients with revealed diastolic dysfunction during stress had significantly lower exercise capacity than patients with normal diastolic stress (7.3 ± 2.1 vs. 8.8 ± 2.5, P < 0.001 for peak METs and 91 ± 30% vs. 105 ± 30%, P = 0.04 for ppMETs). On multivariable modelling found that age (beta = -0.33), male sex (beta = 0.21), body mass index (beta = -0.49), and exercise E/e' >10 (beta = -0.17) were independently associated with peak METs (combined R2 = 0.46). A network correlation map revealed the connectivity of peak METs and diastolic properties as central features in patients with DM.Diastolic stress test improves the detection of subclinical HF in patients with diabetes mellitus.

    View details for DOI 10.1093/ehjci/jeaa070

    View details for PubMedID 32386203

  • Canagliflozin and cardiovascular outcomes in Type 2 diabetes. Future cardiology Sarraju, A. n., Spencer-Bonilla, G. n., Rodriguez, F. n., Mahaffey, K. W. 2020

    Abstract

    SGLT2 inhibitors have risen to prominence in recent years as Type 2 diabetes mellitus medications with favorable effects on cardiovascular (CV) and renal outcomes. Canagliflozin is a US FDA-approved SGLT2 inhibitor that has demonstrated CV and renal outcome benefits in large scale placebo-controlled randomized trials of patients with Type 2 diabetes mellitus and elevated CV risk. Canagliflozin use may also be associated with serious and nonserious adverse effects requiring ongoing monitoring in patients initiated on this medication. This paper provides a detailed overview of canagliflozin including its pharmacologic profile, clinical efficacy and safety data, with discussion of both clinical trial results, as well as real-world evidence.

    View details for DOI 10.2217/fca-2020-0029

    View details for PubMedID 32748638

  • Association of Hypertension and Arterial Blood Pressure on Limb and Cardiovascular Outcomes in Symptomatic Peripheral Artery Disease: The EUCLID Trial. Circulation. Cardiovascular quality and outcomes Fudim, M. n., Hopley, C. W., Huang, Z. n., Kavanagh, S. n., Rockhold, F. W., Baumgartner, I. n., Berger, J. S., Blomster, J. I., Fowkes, F. G., Katona, B. G., Mahaffey, K. W., Norgren, L. n., Ostrom, C. n., Patel, M. R., Jones, W. S., Hiatt, W. R. 2020: CIRCOUTCOMES120006512

    Abstract

    Background Current guidelines recommend aggressive management of hypertension. Recent evidence suggested potential harm with low blood pressure targets in patients with peripheral artery disease. We investigated the association of a history of hypertension and office systolic blood pressure (SBP) with major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs). Methods and Results The EUCLID trial (Examining the Use of Ticagrelor in Peripheral Artery Disease) included 13 885 participants with symptomatic peripheral artery disease; median follow-up was 30 months. Cox proportional hazards regression was used to calculate hazard ratios (HRs) for any MACE, MALE, and MALE including lower extremity revascularization. A clinical history of arterial hypertension was present in 10 857 (78%) participants, and these participants were older and more likely to be female when compared with the 3026 (22%) patients without hypertension. In patients with a history of hypertension, the adjusted hazard ratio for MACE was 0.94, 95% CI, 0.82-1.08; P=0.39, and the adjusted hazard ratio for MALE was 1.08, 95% CI, 0.96-1.23; P=0.21. During follow-up, average SBP was 135 mm Hg (125-145). Every 10 mmHg increase in SBP>125 mmHg was associated with an increased risk of MACE (HR, 1.10 [95% CI, 1.06-1.14]; P<0.001), a marginally increased risk of MALE (HR, 1.07 [95% CI, 1.00-1.15]; P=0.062), and an increased risk of MALE/lower extremity revascularization (HR, 1.08 [95% CI, 1.04-1.11]; P<0.001). Every decrease in 10 mmHg SBP ≤125 mmHg was associated with an increased risk of MACE (HR, 1.19 [95% CI, 1.09-1.31]; P<0.001) but not MALE or MALE/lower extremity revascularization (HR, 1.02 [95% CI, 0.84-1.23], P=0.824; HR, 1.04 [95% CI, 0.95-1.13], P=0.392, respectively). Conclusions History of hypertension was not associated with higher hazard for MACE or MALE in patients with peripheral artery disease. In contrast, there was a higher hazard of MACE in patients with out-of-target low and high SBP. High but not low SBP was associated with an increased risk of ischemic limb events. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

    View details for DOI 10.1161/CIRCOUTCOMES.120.006512

    View details for PubMedID 32862697

  • CYP2C19 status and risk of major adverse cardiovascular events in peripheral artery disease: Insights from the EUCLID Trial. American heart journal Gutierrez, J. A., Heizer, G. M., Jones, W. S., Rockhold, F. W., Mahaffey, K. W., Fowkes, F. G., Berger, J. S., Baumgartner, I. n., Held, P. n., Katona, B. G., Norgren, L. n., Blomster, J. I., Hiatt, W. R., Patel, M. R. 2020; 229: 118–20

    View details for DOI 10.1016/j.ahj.2020.07.017

    View details for PubMedID 32950849

  • Association of Disease Progression With Cardiovascular and Limb Outcomes in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial. Circulation. Cardiovascular interventions Rymer, J. A., Mulder, H. n., Narcisse, D. I., Rockhold, F. n., Hiatt, W. R., Fowkes, F. G., Baumgartner, I. n., Berger, J. S., Katona, B. G., Mahaffey, K. n., Norgren, L. n., Blomster, J. I., Jones, W. S., Patel, M. R. 2020: CIRCINTERVENTIONS120009326

    Abstract

    Patients with peripheral artery disease have a high risk of future cardiovascular disease events and mortality. Little is known about the changes in symptom classification over time in patients with peripheral artery disease and the association of changes in symptom classification with subsequent cardiovascular disease events.In this analysis of the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease), we examined the changes in Rutherford classification (RC) of patients over 12 months. We examined the baseline characteristics of patients by change in symptom classification at 12 months (improved=decreased RC, no change, or worsened=increased RC), and the association between changes in symptom classification (RC) at 12 months and subsequent cardiovascular disease events.Among 12 759 patients, 3240 (25%) were classified as improved by RC at 12 months, 8132 (64%) as no change, and 1387 (11%) as worsened. At 12 months, many patients who were asymptomatic or had mild/moderate claudication at enrollment had no change in symptom classification over 12 months (73.7% and 70.9%). Patients who worsened over 12 months were more likely to have comorbidities (diabetes mellitus and prior myocardial infarction) and more events (myocardial infarction, amputation, and major bleeding) by 12 months postrandomization, all P<0.001. Worsened symptom classification over 12 months was associated with increased risk of all-cause death (adjusted hazard ratio, 1.29 [95% CI, 1.03-1.62]), major amputation (adjusted hazard ratio, 4.12 [95% CI, 2.46-6.88]), and a composite of cardiovascular death, myocardial infarction, or stroke (adjusted hazard ratio, 1.30 [95% CI, 1.05-1.62]), all P<0.05 after 12 months postrandomization.Patients with comorbidities and prior history of cardiovascular disease events at baseline and within the first 12 months of the trial were more likely to have worsened symptom classification at 12 months. Worsening symptom classification over 12 months was associated subsequently with an increased risk of all-cause death, amputation, and a composite of cardiovascular death, myocardial infarction, or stroke.

    View details for DOI 10.1161/CIRCINTERVENTIONS.120.009326

    View details for PubMedID 33040584

  • SGLT2 inhibitors with and without metformin: a meta-analysis of cardiovascular, kidney and mortality outcomes. Diabetes, obesity & metabolism Neuen, B. L., Arnott, C. n., Perkovic, V. n., Figtree, G. n., de Zeeuw, D. n., Fulcher, G. n., Jun, M. n., Jardine, M. J., Zoungas, S. n., Pollock, C. n., Mahaffey, K. W., Neal, B. n., Heerspink, H. J. 2020

    Abstract

    Almost all clinical practice guidelines recommend that SGLT2 inhibitors are used as second-line pharmacotherapy in people with type 2 diabetes and chronic kidney disease or heart failure if they do not achieve sufficient glucose control with metformin. We sought to assess whether the effects of SGLT2 inhibitors on cardiovascular, kidney and mortality outcomes are consistent with and without concomitant metformin use.We conducted a meta-analysis of event-driven, randomized, placebo-controlled SGLT2 inhibitor trials that reported cardiovascular, kidney or mortality outcomes by baseline metformin use. Treatment effects reported as hazards ratios (HR) and 95% confidence intervals (CI) were pooled using random effects meta-analysis. The main outcomes in this analysis were (1) major adverse cardiovascular events (MACE) and (2) hospitalized heart failure (HHF) or cardiovascular death.We included six trials of four SGLT2 inhibitors that enrolled 51,743 participants. Baseline metformin use varied from 21% in DAPA-HF to 82% in DECLARE-TIMI 58. SGLT2 inhibitors reduced the risk of MACE, with and without concomitant metformin use (HR 0.93, 95% CI 0.87-1.00 and HR 0.82, 95% CI 0.71-0.86 respectively; P-heterogeneity=0.14). There were also clear and separate reductions in HHF or cardiovascular death with SGLT2 inhibitors irrespective of metformin use (HR 0.79, 95% CI 0.73-0.86 and HR 0.74, 95% CI 0.63-0.87 respectively; P-heterogeneity=0.48), as well as for major kidney outcomes and all-cause mortality (all P-heterogeneity>0.40).Treatment with SGLT2 inhibitors results in clear and consistent reductions in cardiovascular, kidney and mortality outcomes regardless of whether patients are receiving or not receiving metformin. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/dom.14226

    View details for PubMedID 33043620

  • Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial. Journal of the American College of Cardiology Bhatt, D. L., Briggs, A. H., Reed, S. D., Annemans, L. n., Szarek, M. n., Bittner, V. A., Diaz, R. n., Goodman, S. G., Harrington, R. A., Higuchi, K. n., Joulain, F. n., Jukema, J. W., Li, Q. H., Mahaffey, K. W., Sanchez, R. J., Roe, M. T., Lopes, R. D., White, H. D., Zeiher, A. M., Schwartz, G. G., Gabriel Steg, P. n. 2020; 75 (18): 2297–2308

    Abstract

    Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain.This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy.A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl.Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses.In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402).

    View details for DOI 10.1016/j.jacc.2020.03.029

    View details for PubMedID 32381160

  • Discontinuation rates of warfarin versus direct acting oral anticoagulants in US clinical practice: Results from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II). American heart journal Jackson, L. R., Kim, S. n., Blanco, R. n., Thomas, L. n., Ansell, J. n., Fonarow, G. C., Gersh, B. J., Go, A. S., Kowey, P. R., Mahaffey, K. W., Hylek, E. M., Peterson, E. D., Piccini, J. P. 2020; 226: 85–93

    Abstract

    While oral anticoagulation is a cornerstone of stroke prevention therapy in atrial fibrillation (AF), few studies have evaluated comparative discontinuation rates in clinical practice. The objective of this study is to evaluate discontinuation rates among patients on warfarin and direct oral anticoagulants (DOACs) in clinical practice.The ORBIT-AF II Registry enrolled 10,005 total AF patients with a CHA2DS2VASc score of ≥2 on warfarin or DOACs from 235 clinical practices across the US from February 13, 2013 and July 12, 2017. Descriptive statistics and multivariable Cox regression modeling were used to describe baseline characteristics and predictors of discontinuation. Unadjusted and adjusted discontinuation rates and 95% confidence intervals (CI) were calculated using Cox proportional hazards models and propensity score adjustment, respectively.At baseline, 16.4% (N = 1642/10,005) were treated with warfarin, 83.6% (N = 8363/10,005) with DOACs and 1498/10,005 patients (15.0%) discontinued therapy [warfarin = 236/1642 (14.4%) vs DOACs = 1262/8363 (15.1%)]. At 6 and 12 months respectively, among 7049 patients with a new diagnosis of AF within 6 months, adjusted discontinuation rates for warfarin versus DOACs were as follows: [6 months: 7.9%, 95%CI (6.8%-9.0%) vs 9.6% (8.4%-10.7%), P = .16]; [12 months: 12.7% (11.0%-14.3%) vs 15.3% (13.6%-16.9%), P = .02)]. Patients who discontinued therapy with warfarin or DOACs had higher risk of adverse clinical outcomes including: all-cause mortality and cardiovascular death (CV) than those who continued treatment.In a community based AF cohort, adjusted rates of discontinuation at 12-months were higher in DOAC-treated versus VKA-treated patients. Discontinuation of oral anticoagulation was associated with increased absolute risk of all-cause mortality and CV death.URL:https://clinicaltrials.gov. Unique Identifier: NCT01701817.

    View details for DOI 10.1016/j.ahj.2020.04.016

    View details for PubMedID 32526533

  • Sex-Specific Risks of Major Cardiovascular and Limb Events in Patients With Symptomatic Peripheral Artery Disease. Journal of the American College of Cardiology Haine, A. n., Kavanagh, S. n., Berger, J. S., Hess, C. N., Norgren, L. n., Fowkes, F. G., Katona, B. G., Mahaffey, K. W., Blomster, J. I., Patel, M. R., Jones, W. S., Rockhold, F. W., Hiatt, W. R., Baumgartner, I. n. 2020; 75 (6): 608–17

    Abstract

    Patients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD.The aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial.Cox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection.EUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex.Although women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

    View details for DOI 10.1016/j.jacc.2019.11.057

    View details for PubMedID 32057375

  • Effects of Canagliflozin on Amino-Terminal Pro-B-Type Natriuretic Peptide: Implications for Cardiovascular Risk Reduction. Journal of the American College of Cardiology Januzzi, J. L., Xu, J. n., Li, J. n., Shaw, W. n., Oh, R. n., Pfeifer, M. n., Butler, J. n., Sattar, N. n., Mahaffey, K. W., Neal, B. n., Hansen, M. K. 2020; 76 (18): 2076–85

    Abstract

    Canagliflozin reduces cardiovascular events including hospitalization for heart failure (HHF) in patients with type 2 diabetes and cardiovascular risk. Elevated amino-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations are associated with HF diagnosis and predict cardiovascular risk.The purpose of this study was to measure NT-proBNP in CANVAS (Canagliflozin Cardiovascular Assessment Study) participants.Associations between baseline NT-proBNP and cardiovascular, renal, and mortality outcomes and intervention-associated changes were determined.Of the 4,330 participants in the CANVAS trial, NT-proBNP was measured in 3,587, 2,918, and 995 participants at baseline, 1 year, and 6 years, respectively. The median baseline NT-proBNP concentration was 91 pg/ml, and 39.3% had NT-proBNP ≥125 pg/ml. NT-proBNP was higher in those with investigator-reported HF (13% of participants at baseline) versus those without (187 pg/ml vs. 81 pg/ml), with substantial overlap between groups. By 1 year, NT-proBNP increased with placebo, whereas canagliflozin reduced NT-proBNP by 11% (geometric mean ratio for canagliflozin vs. placebo = 0.89 [95% confidence interval (CI): 0.84 to 0.94]; p < 0.001). Lower NT-proBNP with canagliflozin was also observed at 6 years (p = 0.004). In adjusted models, baseline NT-proBNP ≥125 pg/ml was prognostic for incident HHF (hazard ratio [HR]: 5.40; 95% CI: 2.67 to 10.9), HHF/cardiovascular death (HR: 3.52; 95% CI: 2.38 to 5.20), and all-cause death (HR: 2.53; 95% CI: 1.78 to 3.61). Mediation analyses suggested that 10.4% of the effects of canagliflozin on HHF were reflected in NT-proBNP lowering.A substantial percentage of patients in the CANVAS trial had elevated NT-proBNP values. Canagliflozin reduced NT-proBNP concentrations versus placebo; however, reduction in NT-proBNP explained only a small proportion of the benefit of canagliflozin on HF events. (CANVAS [CANagliflozin cardioVascular Assessment Study]; NCT01032629).

    View details for DOI 10.1016/j.jacc.2020.09.004

    View details for PubMedID 33121714

  • Incidence and Factors Associated With Major Amputation in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial. Circulation. Cardiovascular quality and outcomes Long, C. A., Mulder, H. n., Fowkes, F. G., Baumgartner, I. n., Berger, J. S., Katona, B. G., Mahaffey, K. W., Norgren, L. n., Blomster, J. I., Rockhold, F. W., Hiatt, W. R., Patel, M. R., Jones, W. S., Nehler, M. R. 2020: CIRCOUTCOMES119006399

    Abstract

    Background Peripheral artery disease (PAD) is associated with increased risk of mortality, cardiovascular morbidity, and major amputation. Data on major amputation from a large randomized trial that included a substantial cohort of patients without critical limb ischemia (CLI) have not been described. The objective was to describe the incidence and types of amputations in the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) population, subcategorize amputations in the CLI versus no CLI cohorts, and describe the events surrounding major amputation. Methods and Results Postrandomization major amputation was analyzed in the EUCLID trial. Patients were stratified by baseline CLI status. The occurrence of major amputation was ascertained and defined as the highest level. Perioperative events surrounding major amputation were obtained including acute limb ischemia, revascularization, and all-cause mortality. All variables were assessed for significance in univariable and multivariable models. The rate of major amputation during the course of the trial was 1.6% overall, 8.4% in the CLI at baseline group, and 1.2% in the no CLI at baseline group. The annualized rate of major amputation was 0.6% in PAD overall, 3.9% in the CLI at baseline group, and 0.5% in the no CLI at baseline group. Several factors were associated with increased risk of major amputation, including history of amputation, the presence of diabetes mellitus, baseline Rutherford category 4 to 6, and an ankle-brachial index <0.8. Factors associated with a lower risk for major amputation included prior statin use. The 30-day mortality rate after major amputation was 6.5% overall, 5.6% in the CLI at baseline group, and 6.8% in the no CLI at baseline group. The annual mortality rate following major amputation was 22.8% in the CLI at baseline group and 16.0% in the no CLI at baseline group. Conclusions The risk factors for major amputation in EUCLID patients are similar to previous large registries' reports except for diabetes mellitus in patients with CLI. The mortality following major amputation is lower in the Examining Use of Ticagrelor in Peripheral Artery Disease trial compared with registry data. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01732822.

    View details for DOI 10.1161/CIRCOUTCOMES.119.006399

    View details for PubMedID 32615798

  • Effects of Canagliflozin in Patients with Baseline eGFR <30 ml/min per 1.73 m2: Subgroup Analysis of the Randomized CREDENCE Trial. Clinical journal of the American Society of Nephrology : CJASN Bakris, G. n., Oshima, M. n., Mahaffey, K. W., Agarwal, R. n., Cannon, C. P., Capuano, G. n., Charytan, D. M., de Zeeuw, D. n., Edwards, R. n., Greene, T. n., Heerspink, H. J., Levin, A. n., Neal, B. n., Oh, R. n., Pollock, C. n., Rosenthal, N. n., Wheeler, D. C., Zhang, H. n., Zinman, B. n., Jardine, M. J., Perkovic, V. n. 2020

    Abstract

    The Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial demonstrated that the sodium glucose cotransporter 2 (SGLT2) inhibitor canagliflozin reduced the risk of kidney failure and cardiovascular events in participants with type 2 diabetes mellitus and CKD. Little is known about the use of SGLT2 inhibitors in patients with eGFR <30 ml/min per 1.73 m2. The participants in the CREDENCE study had type 2 diabetes mellitus, a urinary albumin-creatinine ratio >300-5000 mg/g, and an eGFR of 30 to <90 ml/min per 1.73 m2 at screening. This post hoc analysis evaluated participants with eGFR <30 ml/min per 1.73 m2 at randomization.Effects of eGFR slope through week 130 were analyzed using a piecewise, linear, mixed-effects model. Efficacy was analyzed in the intention-to-treat population, on the basis of Cox proportional hazard models, and safety was analyzed in the on-treatment population. At randomization (an average of 29 days after screening), 174 of 4401 (4%) participants had an eGFR <30 ml/min per 1.73 m2 (mean [SD] eGFR, 26 [3] ml/min per 1.73 m2).From weeks 3 to 130, there was a 66% difference in the mean rate of eGFR decline with canagliflozin versus placebo (mean slopes, -1.30 versus -3.83 ml/min per 1.73 m2 per year; difference, -2.54 ml/min per 1.73 m2 per year; 95% confidence interval [CI], 0.90 to 4.17). Effects of canagliflozin on kidney, cardiovascular, and mortality outcomes were consistent for those with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.20). The estimate for kidney failure in participants with eGFR <30 ml/min per 1.73 m2 (hazard ratio, 0.67; 95% CI, 0.35 to 1.27) was similar to those with eGFR ≥30 ml/min per 1.73 m2 (hazard ratio, 0.70; 95% CI, 0.54 to 0.91; P interaction=0.80). There was no imbalance in the rate of kidney-related adverse events or AKI associated with canagliflozin between participants with eGFR <30 and ≥30 ml/min per 1.73 m2 (all P interaction >0.12).This post hoc analysis suggests canagliflozin slowed progression of kidney disease, without increasing AKI, even in participants with eGFR <30 ml/min per 1.73 m2.

    View details for DOI 10.2215/CJN.10140620

    View details for PubMedID 33214158

  • Relative and Absolute Risk Reductions in Cardiovascular and Kidney Outcomes With Canagliflozin Across KDIGO Risk Categories: Findings From the CANVAS Program. American journal of kidney diseases : the official journal of the National Kidney Foundation Neuen, B. L., Ohkuma, T. n., Neal, B. n., Matthews, D. R., de Zeeuw, D. n., Mahaffey, K. W., Fulcher, G. n., Blais, J. n., Li MBiostat, Q. n., Jardine, M. J., Perkovic, V. n., Wheeler, D. C. 2020

    Abstract

    Canagliflozin reduces the risk of cardiovascular and kidney outcomes in type 2 diabetes. This study aimed to assess the relative and absolute effects of canagliflozin on clinical outcomes across different Kidney Disease: Improving Global Outcomes (KDIGO) risk categories based on estimated glomerular filtration rate (eGFR) and urinary albumin:creatinine ratio (UACR.Post-hoc analysis of the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program.& Participants: The CANVAS Program randomized 10,142 participants with type 2 diabetes at high cardiovascular risk and an eGFR of ≥30 mL/min/1.73 m2 to canagliflozin or placebo.Canagliflozin or matching placebo.The primary outcome was a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death, with a set of other cardiovascular and kidney pre-specified outcomes.Of 10,142 participants, 10,031 (98.9%) had available baseline eGFR and UACR data. The proportions of participants in low-, moderate-, high-, and very high-risk categories were 58.6%, 25.8%, 10.6%, and 5.0%, respectively. The relative effect of canagliflozin on the primary outcome (HR 0.86, 95% CI 0.75-0.97) was consistent across KDIGO risk categories (P-trend=0.21), with similar results for other cardiovascular and kidney outcomes. Absolute reductions in the primary outcome were greater within higher KDIGO risk categories (P-trend=0.03) with a similar pattern of effect for the composite of cardiovascular death or hospitalization for heart failure (P-trend=0.06) and for chronic eGFR slope (P-trend=0.04).Predominantly a low kidney risk population, relatively few participants in higher KDIGO risk categories, and exclusion of individuals with eGFR <30 mL/min/1.73 m2.While the relative effects of canagliflozin are similar across KDIGO risk categories, absolute risk reductions are likely greater for individuals at higher KDIGO risk. The KDIGO classification system may be able to identify individuals who might derive greater benefits for end-organ protection from treatment with canagliflozin.

    View details for DOI 10.1053/j.ajkd.2020.06.018

    View details for PubMedID 32971190

  • Diabetes and heart failure post-acute myocardial infarction: Important associations and need for evidence-based interventions. European journal of preventive cardiology Parizo, J. n., Mahaffey, K. W. 2020: 2047487320904232

    View details for DOI 10.1177/2047487320904232

    View details for PubMedID 32090588

  • Post-Discharge Bleeding and Mortality Following Acute Coronary Syndromes With or Without PCI. Journal of the American College of Cardiology Marquis-Gravel, G. n., Dalgaard, F. n., Jones, A. D., Lokhnygina, Y. n., James, S. K., Harrington, R. A., Wallentin, L. n., Steg, P. G., Lopes, R. D., Storey, R. F., Goodman, S. G., Mahaffey, K. W., Tricoci, P. n., White, H. D., Armstrong, P. W., Ohman, E. M., Alexander, J. H., Roe, M. T. 2020; 76 (2): 162–71

    Abstract

    The long-term prognostic impact of post-discharge bleeding in the unique population of patients with acute coronary syndrome (ACS) treated without percutaneous coronary intervention (PCI) remains unexplored.The aim of this study was to assess the association between post-discharge bleeding and subsequent mortality after ACS according to index strategy (PCI or no PCI) and to contrast with the association between post-discharge myocardial infarction (MI) and subsequent mortality.In a harmonized dataset of 4 multicenter randomized trials (APPRAISE-2 [Apixaban for Prevention of Acute Ischemic Events-2], PLATO [Study of Platelet Inhibition and Patient Outcomes], TRACER [Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome], and TRILOGY ACS [Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes]), the association between post-discharge noncoronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate, severe, or life-threatening bleeding (landmark 7 days post-ACS) and subsequent all-cause mortality was evaluated in a time-updated Cox proportional hazards analysis. Interaction with index treatment strategy was assessed. Results were contrasted with risk for mortality following post-discharge MI.Among 45,011 participants, 1,133 experienced post-discharge bleeding events (2.6 per 100 patient-years), and 2,149 died during follow-up. The risk for mortality was significantly higher <30 days (adjusted hazard ratio: 15.7; 95% confidence interval: 12.3 to 20.0) and 30 days to 12 months (adjusted hazard ratio: 2.7; 95% confidence interval: 2.1 to 3.4) after bleeding, and this association was consistent in participants treated with or without PCI for their index ACS (p for interaction = 0.240). The time-related association between post-discharge bleeding and mortality was similar to the association between MI and subsequent mortality in participants treated with and without PCI (p for interaction = 0.696).Post-discharge bleeding after ACS is associated with a similar increase in subsequent all-cause mortality in participants treated with or without PCI and has an equivalent prognostic impact as post-discharge MI.

    View details for DOI 10.1016/j.jacc.2020.05.031

    View details for PubMedID 32646565

  • Sodium-Glucose Cotransporter 2 Inhibition for the Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. Journal of the American Heart Association Arnott, C. n., Li, Q. n., Kang, A. n., Neuen, B. L., Bompoint, S. n., Lam, C. S., Rodgers, A. n., Mahaffey, K. W., Cannon, C. P., Perkovic, V. n., Jardine, M. J., Neal, B. n. 2020; 9 (3): e014908

    Abstract

    Background Several trials have demonstrated protective effects from inhibition of sodium-glucose cotransporter 2 among patients with type 2 diabetes mellitus. There is uncertainty about the consistency of the cardiovascular benefits achieved across patient subsets. Methods and Results We included 4 large-scale trials of sodium-glucose cotransporter 2 inhibition compared with placebo in patients with diabetes mellitus that reported effects on cardiovascular outcomes overall and for participant subgroups defined at baseline by cardiovascular disease, reduced kidney function, and heart failure. Fixed effects models with inverse variance weighting were used to estimate summary hazard ratios and 95% CIs. There were 38 723 patients from 4 trials, with a mean 2.9 years of follow-up. Of the patients, 22 870 (59%) had cardiovascular disease, 7754 (20%) had reduced kidney function, and 4543 (12%) had heart failure. There were 3828 major adverse cardiac events. There was overall benefit for major adverse cardiac events (0.88; 95% CI, 0.82-0.94; P<0.001) and no evidence that the effects of sodium-glucose cotransporter 2 inhibition varied across patient subgroups, defined by the presence of cardiovascular disease or heart failure at baseline (all P interaction >0.252; I2<25%). All patient subgroups benefited with respect to hospitalization for heart failure (all P interaction>0.302; I2<10%), cardiovascular death (all P interaction>0.167; I2<50%), and death from any cause (all P interaction>0.354; I2=0%). The only difference in effects across subgroups was for stroke, with protection observed among those with reduced kidney function but not those with preserved kidney function (P interaction=0.020; I2=81%). Conclusions Sodium-glucose cotransporter 2 inhibitors protect against cardiovascular disease and death in diverse subsets of patients with type 2 diabetes mellitus regardless of cardiovascular disease history.

    View details for DOI 10.1161/JAHA.119.014908

    View details for PubMedID 31992158

  • Apixaban versus Warfarin for Stroke Prevention in Patients With End Stage Renal Disease on Hemodialysis and Atrial Fibrillation: Results of a Randomized Clinical Trial Assessing Safety Pokorney, S. D., Chertow, G. M., Al-Khalidi, H., Gallup, D., Dignacco, P., Mussina, K., Bansal, N., Gadegbeku, C. A., Garcia, D., Jones-Burton, C., Lopes, R. D., Mahaffey, K. W., Middleton, J., Mills, D., Rymer, J. A., Thadhani, R., Thomas, K. L., Winkelmayer, W. C., Granger, C. B. LIPPINCOTT WILLIAMS & WILKINS. 2019: E988–E989
  • Amino-Terminal Pro-B Type Natriuretic Peptide in the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program Januzzi, J. L., Xu, J., Shaw, W., Oh, R., Ranadive, G., Butler, J., Sattar, N., Mahaffey, K., Neal, B., Hansen, M. K. LIPPINCOTT WILLIAMS & WILKINS. 2019: E996
  • Apple Watch App Identifies Clinically Important Arrhythmias Other Than Atrial Fibrillation: Results From the Apple Heart Study Perez, M. V., Mahaffey, K., Hedlin, H., Rumsfeld, J. S., Garcia, A., Ferris, T., Balasubramanian, V., Russo, A. M., Rajmane, A., Cheung, L., Hung, G., Lee, J., Kowey, P. R., Talati, N., Nag, D., Gummidipundi, S., Beatty, A. L., Hills, M. T., Desai, S., Granger, C. B., Desai, M., Turakhia, M. LIPPINCOTT WILLIAMS & WILKINS. 2019: E988
  • The effects of canagliflozin on gout in type 2 diabetes: a post-hoc analysis of the CANVAS Program LANCET RHEUMATOLOGY Li, J., Badve, S., Zhou, Z., Rodgers, A., Day, R., Oh, R., Lee, M., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Futcher, G., Matthews, D. R., Neal, B. 2019; 1 (4): E220–E228
  • Outcomes and Anticoagulation Use After Catheter Ablation for Atrial Fibrillation. Circulation. Arrhythmia and electrophysiology Freeman, J. V., Shrader, P., Pieper, K. S., Allen, L. A., Chan, P. S., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J. A., Singer, D. E., Go, A. S., Hylek, E. M., Steinberg, B. A., Peterson, E. D., Piccini, J. P. 2019; 12 (12): e007612

    Abstract

    BACKGROUND: Studies evaluating the effects of atrial fibrillation (AF) catheter ablation versus antiarrhythmic therapy on outcomes have shown mixed results. In addition, guidelines recommend continuing oral anticoagulation (OAC) after ablation for those at risk of stroke, but real-world data are lacking.METHODS: We evaluated outcomes including death, myocardial infarction, stroke or systemic embolism, intracranial bleeding, major bleeding, and hospitalization in patients undergoing AF ablation compared with a propensity score matched cohort of patients treated with anti-arrhythmic medications only in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation registries. Cox proportional hazards regression was performed to evaluate the association between AF ablation and outcomes. We then evaluated patterns of treatment with OAC among AF ablation patients.RESULTS: Among 21595 patients, 1190 (6%) underwent de novo AF ablation. Our propensity score-matched cohort included 1087 patients who underwent AF ablation matched 1:1 with 1087 patients treated with antiarrhythmic medications only. There were no significant differences in the risk of all-cause and cardiovascular death, and most other major adverse cardiovascular and neurological events. AF catheter ablation was associated with an increased risk of all-cause hospitalization during follow-up (hazard ratio, 1.24 [95% CI, 1.05-1.46]), particularly in the first 3 months (the standard blanking period) after the procedure. Among those who underwent AF ablation with a CHA2DS2 VASc score ≥2 for men and ≥3 for women, 23% had OAC discontinued after ablation. Among those who discontinued OAC, the median time to discontinuation was 6.2 months.CONCLUSIONS: In this large US national registry, we found no difference in adjusted rates of cardiovascular or all-cause death between patients treated with AF catheter ablation and antiarrhythmic medications only. Notably, discontinuation of OAC after ablation remains relatively common despite guideline recommendations for continued stroke prevention therapy in patients at risk of stroke.

    View details for DOI 10.1161/CIRCEP.119.007612

    View details for PubMedID 31830822

  • A double-blind, randomized, placebo-controlled pilot trial to evaluate safety and efficacy of vorapaxar on arteriovenous fistula maturation. The journal of vascular access Olivier, C. B., Sundaram, V., Chertow, G. M., Shashidhar, S., McDonnell, L. K., Ding, V. Y., Desai, M., Mahaffey, K. W., Mell, M. 2019: 1129729819887269

    Abstract

    BACKGROUND: Protease-activated receptor-1 antagonism by vorapaxar could facilitate arteriovenous fistula maturation but may increase bleeding risk.OBJECTIVE: The primary objective of the Vorapaxar Study for Maturation of arteriovenous fistula for Hemodialysis Access (VorapAccess) was to determine if vorapaxar improves arteriovenous fistula functional maturation in patients with end-stage renal disease.METHODS: VorapAccess was a randomized, placebo-controlled, double-blind pilot trial comparing 2.5mg vorapaxar per day with placebo for twelve weeks starting on day two after arteriovenous fistula creation. The primary outcome was time to functional maturation defined as successful cannulation for six hemodialysis sessions within three weeks. The planned sample size was 50 participants. The study was terminated early after withdrawal of planned financial support. Given the small number of randomized patients, we performed descriptive analyses without inference testing.RESULTS: A total of 13 participants were randomly allocated study drug (six vorapaxar and seven placebo). The median age was 56years and seven participants (54%) were female. The median (minimum-maximum) days to functional maturation were 169 (77-287)days in the vorapaxar group and 145 (48-198)days in the placebo group. Six of the 13 (46%) participants had arteriovenous fistula functional maturation within 180days; two of six (33%) in the vorapaxar group and four of seven (57%) in the placebo group. There was one bleeding event in the placebo group.CONCLUSION: Fewer than half of participants had functional maturation within 180days after surgery, suggesting a major need for agents or strategies that enhance arteriovenous fistula maturation.

    View details for DOI 10.1177/1129729819887269

    View details for PubMedID 31774037

  • Evaluating the Effects of Canagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Chronic Kidney Disease According to Baseline HbA1c, Including Those with HbA1c <7%: Results From the CREDENCE Trial. Circulation Cannon, C. P., Perkovic, V., Agarwal, R., Baldassarre, J., Bakris, G., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T., Heerspink, H. J., Jardine, M. J., Levin, A., Li, J., Neal, B., Pollock, C., Wheeler, D. C., Zhang, H., Zinman, B., Mahaffey, K. W. 2019

    Abstract

    Traditional management of diabetes mellitus has focused on glycemic control, beginning with lifestyle changes, followed by metformin, and then other classes of antiglycemic agents.1 Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) events, including CV death, myocardial infarction (MI) and heart failure, and slow progression of renal dysfunction, including prevention of end-stage kidney disease (ESKD).2-3 Because initial clinical trials included mostly patients with baseline HbA1c >7%, current guidelines have recommended this class as add-on therapy for patients whose HbA1c is not at goal, typically ≥7%.1 We hypothesized that there would be similar benefits on CV and renal endpoints regardless of baseline HbA1c, including those with HbA1c <7%.

    View details for DOI 10.1161/CIRCULATIONAHA.119.044359

    View details for PubMedID 31707795

  • Guideline-directed therapies for comorbidities and clinical outcomes among individuals with atrial fibrillation. American heart journal Loring, Z., Shrader, P., Allen, L. A., Blanco, R., Chan, P. S., Ezekowitz, M. D., Fonarow, G. C., Freeman, J. V., Gersh, B. J., Mahaffey, K. W., Naccarelli, G. V., Pieper, K., Reiffel, J. A., Singer, D. E., Steinberg, B. A., Thomas, L. E., Peterson, E. D., Piccini, J. P. 2019; 219: 21–30

    Abstract

    BACKGROUND: Comorbidities are common in patients with atrial fibrillation (AF) and affect prognosis, yet are often undertreated. However, contemporary rates of use of guideline-directed therapies (GDT) for non-AF comorbidities and their association with outcomes are not well described.METHODS: We used the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) to test the association between GDT for non-AF comorbidities and major adverse cardiac or neurovascular events (MACNE; cardiovascular death, myocardial infarction, stroke/thromboembolism, or new-onset heart failure), all-cause mortality, new-onset heart failure, and AF progression. Adjustment was performed using Cox proportional hazards models and logistic regression.RESULTS: Only 6,782 (33%) of the 20,434 patients eligible for 1 or more GDT for non-AF comorbidities received all indicated therapies. Use of all comorbidity-specific GDT was highest for patients with hyperlipidemia (75.6%) and lowest for those with diabetes mellitus (43.1%). Use of "all eligible" GDT was associated with a nonsignificant trend toward lower rates of MACNE (HR 0.90 [0.79-1.02]) and all-cause mortality (HR 0.90 [0.80-1.01]). Use of GDT for heart failure was associated with a lower risk of all-cause mortality (HR 0.77 [0.67-0.89]), and treatment of obstructive sleep apnea was associated with a lower risk of AF progression (OR 0.75 [0.62-0.90]).CONCLUSIONS: In AF patients, there is underuse of GDT for non-AF comorbidities. The association between GDT use and outcomes was strongest in heart failure and obstructive sleep apnea patients where use of GDT was associated with lower mortality and less AF progression.

    View details for DOI 10.1016/j.ahj.2019.10.008

    View details for PubMedID 31710841

  • Mediators of the Effects of Canagliflozin on HeartFailure in Patients With Type 2 Diabetes. JACC. Heart failure Li, J., Woodward, M., Perkovic, V., Figtree, G. A., Heerspink, H. J., Mahaffey, K. W., de Zeeuw, D., Vercruysse, F., Shaw, W., Matthews, D. R., Neal, B. 2019

    Abstract

    OBJECTIVES: The purpose of this study was to explore potential mediators of the effects of canagliflozin on heart failure in the CANVAS Program (CANagliflozin cardioVascular Assessment Study; NCT01032629 and CANagliflozin cardioVascular Assessment Study-Renal; NCT01989754).BACKGROUND: Canagliflozin reduced the risk of heart failure among patients with type 2 diabetes in the CANVAS Program. The mechanism of protection is uncertain.METHODS: The percentages of mediating effects of 19 biomarkers were determined by comparing the hazard ratios for the effect of randomized treatment from an unadjusted model and from a model adjusting for the biomarker of interest. Multivariable analyses were used to assess the joint effects of biomarkers that mediated most strongly in univariable analyses.RESULTS: Early changes after randomization in levels of 3 biomarkers (urinary albumin:creatinine ratio, serum bicarbonate, and serum urate) were identified as mediating the effect of canagliflozin on heart failure. Average post-randomization levels of 14 biomarkers (systolic blood pressure, low-density lipoprotein and high-density lipoprotein cholesterol,total cholesterol, urinary albumin:creatinine ratio, weight, body mass index, gamma glutamyltransferase, hematocrit, hemoglobin concentration, serum albumin, erythrocyte concentration, serum bicarbonate, and serum urate) were identified as significant mediators. Individually, the 3 biomarkers with the largest mediating effect were erythrocyte concentration (45%), hemoglobin concentration (43%), and serum urate (40%). In a parsimonious multivariable model, erythrocyte concentration, serum urate, and urinary albumin:creatinine ratio were the 3 biomarkers that maximized cumulative mediation (102%).CONCLUSIONS: A diverse set of potential mediators of the effect of canagliflozin on heart failure were identified. Some mediating effects were anticipated, whereas others were not. The mediators that were identified support existing and novel hypothesized mechanisms for the prevention of heart failure with sodium glucose cotransporter 2 inhibitors.

    View details for DOI 10.1016/j.jchf.2019.08.004

    View details for PubMedID 31676303

  • Patterns of amiodarone use and outcomes in clinical practice for atrial fibrillation. American heart journal Pokorney, S. D., Holmes, D. N., Shrader, P., Thomas, L., Fonarow, G. C., Mahaffey, K. W., Gersh, B. J., Kowey, P. R., Naccarelli, G. V., Freeman, J. V., Singer, D. E., Washam, J. B., Peterson, E. D., Piccini, J. P., Reiffel, J. A. 2019; 220: 145–54

    Abstract

    BACKGROUND: Amiodarone is the most effective antiarrhythmic drug (AAD) for atrial fibrillation (AF), but it has a high incidence of adverse effects.METHODS: Using the ORBIT AF registry, patients with AF on amiodarone at enrollment, prescribed amiodarone during follow-up, or never on amiodarone were analyzed for the proportion treated with a guideline-based indication for amiodarone, the variability in amiodarone use across sites, and the outcomes (mortality, hospitalization, and stroke) among patients treated with amiodarone. Hierarchical logistic regression modeling with site-specific random intercepts compared rates of amiodarone use across 170 sites. A logistic regression model for propensity to receive amiodarone created a propensity-matched cohort. Cox proportional hazards modeling, stratified by matched pairs evaluated the association between amiodarone and outcomes.RESULTS: Among 6,987 AF patients, 867 (12%) were on amiodarone at baseline and 451 (6%) started on incident amiodarone during the 3-year follow-up. Use of amiodarone varied among sites from 3% in the lowest tertile to 21% in the highest (p<0.0001). Among those treated, 32% had documented contraindications to other AADs or had failed another AAD in the past. Mortality, cardiovascular hospitalization, and stroke were similar among matched patients on and not on amiodarone at baseline, while incident amiodarone use in matched patients was associated with higher all-cause mortality (adjusted HR 2.06, 95% CI 1.35-3.16).CONCLUSIONS: Use of amiodarone among AF patients in community practice is highly variable. More than 2 out of 3 patients treated with amiodarone appeared to be eligible for a different AAD.

    View details for DOI 10.1016/j.ahj.2019.09.017

    View details for PubMedID 31812756

  • The Association of Health-Related Quality-of-Life Scores With Cardiovascular and Limb Outcomes in Patients With Symptomatic Peripheral Artery Disease: Insights From the EUCLID Trial Rymer, J., Mulder, H., Smolderen, K., Hiatt, W., Conte, M., Berger, J., Katona, B., Norgren, L., Mahaffey, K., Rockhold, F., Fowkes, F., Jones, S., Patel, M. ELSEVIER SCIENCE INC. 2019: B547
  • Effect of Canagliflozin on Renal and Cardiovascular Outcomes across Different Levels of Albuminuria: Data from the CANVAS Program. Journal of the American Society of Nephrology : JASN Neuen, B. L., Ohkuma, T., Neal, B., Matthews, D. R., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Li, Q., Jardine, M., Oh, R., Heerspink, H. L., Perkovic, V. 2019

    Abstract

    BACKGROUND: If SGLT2 inhibitors protect the kidneys by reducing albuminuria as hypothesized, people with type 2 diabetes mellitus (T2DM) with higher albuminuria should benefit more.METHODS: We conducted a post-hoc analysis of data from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, which randomized 10,142 participants with T2DM and high cardiovascular risk to canagliflozin or placebo. We assessed effects of canagliflozin on renal, cardiovascular, and safety outcomes by baseline albuminuria. The trial included 2266 participants (22.3%) with moderately increased albuminuria (urinary albumin/creatinine ratio [UACR] 30-300 mg/g) and 760 (7.5%) with severely increased albuminuria (UACR >300 mg/g) at baseline.RESULTS: Canagliflozin lowered albuminuria with greater proportional reductions in those with moderately and severely increased albuminuria (P heterogeneity<0.001). After week 13, canagliflozin slowed the annual loss of kidney function across albuminuria subgroups, with greater absolute reductions in participants with severely increased albuminuria (placebo-subtracted difference 3.01 ml/min per 1.73 m2 per year; P heterogeneity<0.001). Heterogeneity for the renal composite outcome of 40% reduction in eGFR, ESKD, or renal-related death was driven by lesser effects in participants with moderately increased albuminuria (P heterogeneity=0.03), but no effect modification was observed when albuminuria was fitted as a continuous variable (P heterogeneity=0.94). Cardiovascular and safety outcomes were mostly consistent across albuminuria levels including increased risks for amputation across albuminuria subgroups (P heterogeneity=0.66). Greater absolute risk reductions in the renal composite outcome were observed in participants with severely increased albuminuria (P heterogeneity=0.004).CONCLUSIONS: The proportional effects of canagliflozin on renal and cardiovascular outcomes are mostly consistent across patients with different levels of albuminuria, but absolute benefits are greatest among those with severely increased albuminuria.

    View details for DOI 10.1681/ASN.2019010064

    View details for PubMedID 31530577

  • Open versus Endovascular Repair of Abdominal Aortic Aneurysm REPLY NEW ENGLAND JOURNAL OF MEDICINE Jardine, M. J., Mahaffey, K. W., Perkovic, V. 2019; 381 (11): 1089–90
  • SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. The lancet. Diabetes & endocrinology Neuen, B. L., Young, T., Heerspink, H. J., Neal, B., Perkovic, V., Billot, L., Mahaffey, K. W., Charytan, D. M., Wheeler, D. C., Arnott, C., Bompoint, S., Levin, A., Jardine, M. J. 2019

    Abstract

    BACKGROUND: The effects of sodium-glucose co-transporter-2 (SGLT2) inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain. Additionally, previous studies have been underpowered to robustly assess heterogeneity of effects on kidney outcomes by different levels of estimated glomerular filtration rate (eGFR) and albuminuria. We aimed to do a systematic review and meta-analysis to assess the effects of SGLT2 inhibitors on major kidney outcomes in patients with type 2 diabetes and to determine the consistency of effect size across trials and different levels of eGFR and albuminuria.METHODS: We did a systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes. We searched MEDLINE and Embase from database inception to June 14, 2019, to identify eligible trials. The primary outcome was a composite of dialysis, transplantation, or death due to kidney disease. We used random-effects models to obtain summary relative risks (RRs) with 95% CIs and random-effects meta-regression to explore effect modification by subgroups of baseline eGFR, albuminuria, and use of renin-angiotensin system (RAS) blockade. This review is registered with PROSPERO (CRD42019131774).FINDINGS: From 2085 records identified, four studies met our inclusion criteria, assessing three SGLT2 inhibitors: empagliflozin (EMPA-REG OUTCOME), canagliflozin (CANVAS Program and CREDENCE), and dapagliflozin (DECLARE-TIMI 58). From a total of 38 723 participants, 252 required dialysis or transplantation or died of kidney disease, 335 developed end-stage kidney disease, and 943 had acute kidney injury. SGLT2 inhibitors substantially reduced the risk of dialysis, transplantation, or death due to kidney disease (RR 0·67, 95% CI 0·52-0·86, p=0·0019), an effect consistent across studies (I2=0%, pheterogeneity=0·53). SGLT2 inhibitors also reduced end-stage kidney disease (0·65, 0·53-0·81, p<0·0001), and acute kidney injury (0·75, 0·66-0·85, p<0·0001), with consistent benefits across studies. Although we identified some evidence that the proportional effect of SGLT2 inhibitors might attenuate with declining kidney function (ptrend=0·073), there was clear, separate evidence of benefit for all eGFR subgroups, including for participants with a baseline eGFR 30-45 mL/min per 1·73 m2 (RR 0·70, 95% CI 0·54-0·91, p=0·0080). Renoprotection was also consistent across studies irrespective of baseline albuminuria (ptrend=0·66) and use of RAS blockade (pheterogeneity=0·31).INTERPRETATION: SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against acute kidney injury. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with type 2 diabetes.FUNDING: None.

    View details for DOI 10.1016/S2213-8587(19)30256-6

    View details for PubMedID 31495651

  • Alirocumab in Patients With Polyvascular Disease and Recent Acute Coronary Syndrome ODYSSEY OUTCOMES Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Jukema, J., Szarek, M., Zijlstra, L. E., de Silva, H., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Karpov, Y., Moryusef, A., Pordy, R., Prieto, J. C., Roe, M. T., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, P., ODYSSEY OUTCOMES Comm Investigator 2019; 74 (9): 1167–76
  • Risk Categorization Using New American College of Cardiology/American Heart Association Guidelines for Cholesterol Management and Its Relation to Alirocumab Treatment Following Acute Coronary Syndromes. Circulation Roe, M. T., Li, Q. H., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Lopez-Jaramillo, P., Lopes, R. D., Louie, M. J., Moriarty, P. M., Szarek, M., Vogel, R., White, H. D., Zeiher, A. M., Baccara-Dinet, M. T., Steg, P. G., Schwartz, G. G., ODYSSEY OUTCOMES Investigators 2019

    View details for DOI 10.1161/CIRCULATIONAHA.119.042551

    View details for PubMedID 31475572

  • Cardiovascular Risk Factors and Secondary Events Among Acute and Chronic Stable Myocardial Infarction Patients: Findings from a Managed Care Database. Cardiology and therapy Bash, L. D., White, K., Patel, M. D., Liu, J., Mavros, P., Mahaffey, K. W. 2019

    Abstract

    INTRODUCTION: Long-term risk for recurrent cardiovascular events among myocardial infarction (MI) patients in the acute versus chronic stable phase is not well characterized. This study was conducted to evaluate risk factors associated with all-cause mortality and cardiovascular (CVD) morbidity and to determine the transition period from the acute to chronic stable phase of disease.METHODS: Administrative claims data from a managed care database (2007-2012) were linked to the Social Security Death Index. Kaplan-Meier curves were generated over a 3-year period. The association between risk factors and clinical endpoints was assessed using Cox proportional hazard models. Poisson models estimated the 'transition time' from acute to chronic phase of disease.RESULTS: On average, recurrent cardiovascular event rates were higher among acute MI patients in comparison to the chronic MI patients during the first 3months of follow-up. Over the 3-year follow-up period, survival curves became parallel and for some outcomes (i.e., acute myocardial infarction and bleeding events), were not statistically significantly different between the two groups. In both the acute and chronic MI cohorts, diabetes, heart failure, and renal disease were consistently statistically significant and positively associated with greater risk of death and ischemic events. PAD was consistently associated with increased risk among the chronic cohort and composite endpoints among the acute patients.CONCLUSIONS: Greater understanding of differences in the CVD risk profiles and the transition from acute to chronic stable phase may help identify high-risk patients and inform clinical risk stratification and long-term disease management in MI patients.FUNDING: Merck & Co., Inc., Kenilworth, NJ, USA.

    View details for DOI 10.1007/s40119-019-00147-5

    View details for PubMedID 31432429

  • Canagliflozin and fracture risk in individuals with type 2 diabetes: results from the CANVAS Program. Diabetologia Zhou, Z., Jardine, M., Perkovic, V., Matthews, D. R., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Desai, M., Oh, R., Simpson, R., Watts, N. B., Neal, B. 2019

    Abstract

    AIMS/HYPOTHESIS: An increased risk of fracture with canagliflozin vs placebo was reported from the CANagliflozin cardioVascular Assessment Study (CANVAS) Program, with heterogeneity of findings identified between the two trials that comprise the CANVAS Program, CANVAS and CANVAS-R. The objective of these analyses was to identify reasons for the possibly different effects on fracture observed between CANVAS and CANVAS-R.METHODS: This study was an analysis of two highly similar trials, CANVAS and CANVAS-R, conducted in 10,142 individuals with type 2 diabetes and history or high risk of cardiovascular disease who received canagliflozin (pooled 100/300mg once daily) or placebo. Outcomes assessed in this analysis were effects on adjudicated fractures overall and by type, location, association with a fall, dose and follow-up time.RESULTS: A total of 496 participants recorded ≥1 fracture event during follow-up (15.40 vs 11.93 per 1000 patient-years with canagliflozin vs placebo; HR 1.26 [95% CI 1.04, 1.52]). There was significant heterogeneity in the effects on fracture (p=0.005) between CANVAS (n=4330: HR 1.55 [95% CI 1.21, 1.97]) and CANVAS-R (n=5812: HR 0.86 [95% CI 0.62, 1.19]). The between-study heterogeneity in fracture risk was not clearly explained by differences in baseline characteristics, interactions of randomised treatment with participant characteristics, dose effects, duration of follow-up, metabolic effects, adverse events related to falls or adverse events possibly causing falls.CONCLUSIONS/INTERPRETATION: There was no evidence to explain clearly the fracture risk observed in the CANVAS Program or the heterogeneity in fracture risk between the two studies. The recently reported null result for fracture in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial suggests that the observed association in CANVAS is likely to be a chance finding, although an unidentified fall-related mechanism remains a possibility.TRIAL REGISTRATION: ClinicalTrials.gov NCT01032629, NCT01989754.

    View details for DOI 10.1007/s00125-019-4955-5

    View details for PubMedID 31399845

  • Canagliflozin and Cardiovascular and Renal Outcomes in Type 2 Diabetes and Chronic Kidney Disease in Primary and Secondary Cardiovascular Prevention Groups: Results from the Randomized CREDENCE Trial. Circulation Mahaffey, K. W., Jardine, M. J., Bompoint, S., Cannon, C. P., Neal, B., Heerspink, H. J., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Capuano, G., de Zeeuw, D., Greene, T., Levin, A., Pollock, C., Sun, T., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Rosenthal, N., Brenner, B. M., Perkovic, V., CREDENCE study investigators 2019

    Abstract

    BACKGROUND: Canagliflozin reduces the risk of kidney failure in patients with type 2 diabetes and chronic kidney disease, but effects on specific cardiovascular outcomes are uncertain, as are effects in people without prior cardiovascular disease (primary prevention).METHODS: In CREDENCE, 4401 participants with type 2 diabetes and chronic kidney disease were randomly assigned to canagliflozin or placebo on a background of optimized standard of care.RESULTS: Primary prevention participants (N=2181; 49.6%) were younger (61 vs 65 years), more often female (37% vs 31%), and had shorter diabetes duration (15 vs 16 years) compared to secondary prevention participants (N=2220; 50.4%). Canagliflozin reduced the risk of major cardiovascular events overall (hazard ratio [HR], 0.80; 95% confidence interval [CI] 0.67-0.95; P=0.01), with consistent reductions in both the primary (HR, 0.68; 95% CI, 0.49-0.94) and secondary (HR, 0.85; 95% CI, 0.69-1.06) prevention groups (P-interaction 0.25). Effects were also similar for the components of the composite including cardiovascular death (HR, 0.78; 95% CI, 0.61-1.00), nonfatal myocardial infarction (HR, 0.81; 95% CI, 0.59-1.10), and nonfatal stroke (HR, 0.80; 95% CI, 0.56-1.15). The risk of the primary composite renal outcome and the composite of cardiovascular death or hospitalization for heart failure were also consistently reduced in both the primary and secondary prevention groups (P-interaction >0.5 for each outcome).CONCLUSIONS: Canagliflozin significantly reduced major cardiovascular events, as well as kidney failure, in patients with type 2 diabetes and chronic kidney disease, including in participants who did not have prior cardiovascular disease.CLINICAL TRIAL REGISTRATION: URL: https://ClinicalTrials.gov Unique identifier: NCT02065791.

    View details for DOI 10.1161/CIRCULATIONAHA.119.042007

    View details for PubMedID 31291786

  • Association Between Warfarin Control Metrics and Atrial Fibrillation Outcomes in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation. JAMA cardiology Pokorney, S. D., Holmes, D. N., Thomas, L., Fonarow, G. C., Kowey, P. R., Reiffel, J. A., Singer, D. E., Freeman, J. V., Gersh, B. J., Mahaffey, K. W., Hylek, E. M., Naccarelli, G. V., Ezekowitz, M. D., Piccini, J. P., Peterson, E. D., Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Investigators 2019

    Abstract

    Importance: Bleeding and thrombotic events (eg, stroke and systemic embolism) are common in patients with atrial fibrillation (AF) taking warfarin sodium despite a well-established therapeutic range.Objective: To evaluate whether history of therapeutic warfarin control in patients with AF is independently associated with subsequent bleeding or thrombotic events.Design, Setting, and Participants: In this multicenter cohort study of 176 primary care, cardiology, and electrophysiology clinics in the United States, data were obtained during 51 830 visits among 10 137 patients with AF in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry; 5545 patients treated with warfarin were included in the bleeding analysis, and 5635 patients were included in the thrombotic event analysis. Patient follow-up was performed from June 29, 2010, to November 30, 2014. Data analysis was performed from August 4, 2016, to February 15, 2019.Exposures: Multiple measures of warfarin control within the preceding 6 months were analyzed: time in therapeutic range of 2.0 to 3.0, most recent international normalized ratio (INR), percentage of time that a patient had interpolated INR values less than 2.0 or greater than 3.0, INR variance, INR range, and percentage of INR values in therapeutic range.Main Outcomes and Measures: Association of INR measures, alone or in combination, with clinical factors and risk for thrombotic events and bleeding during the subsequent 6 months was assessed post hoc using logistic regression models.Results: A total of 5545 patients (mean [SD] age, 74.5 [9.8] years; 3184 [57.4%] male) with AF were included in the major bleeding analysis and 5635 patients (mean [SD] age, 74.5 [9.8] years; 3236 [57.4%] male) in the thrombotic event analysis. During a median follow-up of 1.5 years (interquartile range, 1.0-2.5 years), there were 339 major bleeds (6.1%) and 51 strokes (0.9%). Multiple metrics of warfarin control were individually associated with subsequent bleeding. After adjustment for clinical bleeding risk, 3 measures-time in therapeutic range (per 1-SD increase ≤55: adjusted odds ratio [aOR], 1.16; 95% CI, 1.02-1.32), variation in INR values (aOR, 1.32; 95% CI, 1.19-1.47), and maximum INR (aOR, 1.20; 95% CI, 1.10-1.31)-remained associated with bleeding risk. Adding INR variance to a clinical risk model slightly increased the C statistic from 0.68 to 0.69 and had a net reclassification improvement index of 0.028 (95% CI, -0.029 to 0.067). No INR measures were associated with subsequent stroke risk.Conclusions and Relevance: Three metrics of prior warfarin control were associated with bleeding risk but only marginally more so than traditional clinical factors. This study did not identify any measures of INR control that were significantly associated with stroke risk.

    View details for DOI 10.1001/jamacardio.2019.1960

    View details for PubMedID 31268487

  • Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. The lancet. Diabetes & endocrinology Ray, K. K., Colhoun, H. M., Szarek, M., Baccara-Dinet, M., Bhatt, D. L., Bittner, V. A., Budaj, A. J., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Loizeau, V., Lopes, R. D., Moryusef, A., Murin, J., Pordy, R., Ristic, A. D., Roe, M. T., Tunon, J., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, P. G., ODYSSEY OUTCOMES Committees and Investigators, Schwartz, G. G., Steg, P. G., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Szarek, M., White, H. D., Zeiher, A. M., Tricoci, P., Roe, M. T., Mahaffey, K. W., Edelberg, J. M., Hanotin, C., Lecorps, G., Moryusef, A., Pordy, R., Sasiela, W. J., Tamby, J., Aylward, P. E., Drexel, H., Sinnaeve, P., Dilic, M., Lopes, R. D., Gotcheva, N. N., Prieto, J., Yong, H., Lopez-Jaramillo, P., Pecin, I., Reiner, Z., Ostadal, P., Viigimaa, M., Nieminen, M. S., Chumburidze, V., Marx, N., Danchin, N., Liberopoulos, E., Montenegro Valdovinos, P. C., Tse, H., Kiss, R. G., Xavier, D., Zahger, D., Valgimigli, M., Kimura, T., Kim, H. S., Kim, S., Erglis, A., Laucevicius, A., Kedev, S., Yusoff, K., Ramos Lopez, G. A., Alings, M., Halvorsen, S., Correa Flores, R. M., Budaj, A., Morais, J., Dorobantu, M., Karpov, Y., Ristic, A. D., Chua, T., Murin, J., Fras, Z., Dalby, A. J., Tunon, J., de Silva, H. A., Hagstrom, E., Landmesser, U., Chiang, C., Sritara, P., Guneri, S., Parkhomenko, A., Ray, K. K., Moriarty, P. M., Vogel, R., Chaitman, B., Kelsey, S. F., Olsson, A. G., Rouleau, J., Simoons, M. L., Alexander, K., Meloni, C., Rosenson, R., Sijbrands, E. J., Tricoci, P., Alexander, J. H., Armaganijan, L., Bagai, A., Bahit, M. C., Brennan, J. M., Clifton, S., DeVore, A. D., Deloatch, S., Dickey, S., Dombrowski, K., Ducrocq, G., Eapen, Z., Endsley, P., Eppinger, A., Harrison, R. W., Hess, C. N., Hlatky, M. A., Jordan, J. D., Knowles, J. W., Kolls, B. J., Kong, D. F., Leonardi, S., Lillis, L., Maron, D. J., Marcus, J., Mathews, R., Mehta, R. H., Mentz, R. J., Moreira, H. G., Patel, C. B., Bernardez-Pereira, S., Perkins, L., Povsic, T. J., Puymirat, E., Schuyler Jones, W., Shah, B. R., Sherwood, M. W., Stringfellow, K., Sujjavanich, D., Toma, M., Trotter, C., Van Diepen, S., Wilson, M. D., Yan, A. T., Schiavi, L. B., Garrido, M., Alvarisqueta, A. F., Sassone, S. A., Bordonava, A. P., Alves De Lima, A. E., Schmidberg, J. M., Duronto, E. A., Caruso, O. C., Novaretto, L. P., Hominal, M. A., Montana, O. R., Caccavo, A., Gomez Vilamajo, O. A., Lorenzatti, A. J., Cartasegna, L. R., Paterlini, G. A., Mackinnon, I. J., Caime, G. D., Amuchastegui, M., Salomone, O., Codutti, O. R., Jure, H. O., Bono, J. O., Hrabar, A. D., Vallejos, J. A., Ahuad Guerrero, R. A., Novoa, F., Patocchi, C. A., Zaidman, C. J., Giuliano, M. E., Dran, R. D., Vico, M. L., Carnero, G. S., Guzman, P. N., Medrano Allende, J. C., Garcia Brasca, D. F., Bustamante Labarta, M. H., Nani, S., Blumberg, E. D., Colombo, H. R., Liberman, A., Fuentealba, V., Luciardi, H. L., Waisman, G. D., Berli, M. A., Garcia Duran, R. O., Cestari, H. G., Luquez, H. A., Giordano, J. A., Saavedra, S. S., Zapata, G., Costamagna, O., Llois, S., Waites, J. H., Collins, N., Soward, A., Hii, C. L., Shaw, J., Arstall, M. A., Horowitz, J., Ninio, D., Rogers, J. F., Colquhoun, D., Oqueli Flores, R. E., Roberts-Thomson, P., Raffel, O., Lehman, S. J., Aroney, C., Coverdale, S. G., Garrahy, P. J., Starmer, G., Sader, M., Carroll, P. A., Dick, R., Zweiker, R., Hoppe, U., Huber, K., Berger, R., Delle-Karth, G., Frey, B., Weidinger, F., Faes, D., Hermans, K., Pirenne, B., Leone, A., Hoffer, E., Vrolix, M. C., De Wolf, L., Wollaert, B., Castadot, M., Dujardin, K., Beauloye, C., Vervoort, G., Striekwold, H., Convens, C., Roosen, J., Barbato, E., Claeys, M., Cools, F., Terzic, I., Barakovic, F., Midzic, Z., Pojskic, B., Fazlibegovic, E., Kulic, M., Durak-Nalbantic, A., Vulic, D., Muslibegovic, A., Goronja, B., Reis, G., Sousa, L., Nicolau, J. C., Giorgeto, F. E., Silva, R. P., Nigro Maia, L., Rech, R., Rossi, P. R., Cerqueira, M. J., Duda, N., Kalil, R., Kormann, A., Abrantes, J. A., Pimentel Filho, P., Soggia, A. P., de Santos, M. O., Neuenschwander, F., Bodanese, L. C., Michalaros, Y. L., Eliaschewitz, F. G., Vidotti, M. H., Leaes, P. E., Botelho, R. V., Kaiser, S., Manenti, E. R., Precoma, D. B., Moura Jorge, J. C., de B Silva, P. G., Silveira, J. A., Saporito, W., Marin-Neto, J. A., Feitosa, G. S., Ritt, L. E., de Souza, J. A., Costa, F., Souza, W. K., Reis, H. J., Machado, L., Ayoub, J. C., Todorov, G. V., Nikolov, F. P., Velcheva, E. S., Tzekova, M. L., Benov, H. O., Petranov, S. L., Tumbev, H. S., Shehova-Yankova, N. S., Markov, D. T., Raev, D. H., Mollov, M. N., Kichukov, K. N., Ilieva-Pandeva, K. A., Ivanova, R., Gospodinov, M., Mincheva, V. M., Lazov, P. V., Dimov, B. I., Senaratne, M., Stone, J., Kornder, J., Pearce, S., Dion, D., Savard, D., Pesant, Y., Pandey, A., Robinson, S., Gosselin, G., Vizel, S., Hoag, G., Bourgeois, R., Morisset, A., Sabbah, E., Sussex, B., Kouz, S., MacDonald, P., Diaz, A., Michaud, N., Fell, D., Leung, R., Vuurmans, T., Lai, C., Nigro, F., Davies, R., Nogareda, G., Vijayaraghavan, R., Ducas, J., Lepage, S., Mehta, S., Cha, J., Dupuis, R., Fong, P., Lutchmedial, S., Rodes-Cabau, J., Fadlallah, H., Cleveland, D., Huynh, T., Bata, I., Hameed, A., Pincetti, C., Potthoff, S., Prieto, J. C., Acevedo, M., Aguirre, A., Vejar, M., Yanez, M., Araneda, G., Fernandez, M., Perez, L., Varleta, P., Florenzano, F., Huidobro, L., Raffo, C. A., Olivares, C., Nahuelpan, L., Montecinos, H., Chen, J., Dong, Y., Huang, W., Wang, J., Huang, S., Yao, Z., Li, X., Cui, L., Lin, W., Sun, Y., Wang, J., Li, J., Zhang, X., Zhu, H., Chen, D., Huang, L., Dong, S., Su, G., Xu, B., Su, X., Cheng, X., Lin, J., Zong, W., Li, H., Feng, Y., Xu, D., Yang, X., Ke, Y., Lin, X., Zhang, Z., Zheng, Z., Luo, Z., Chen, Y., Ding, C., Zhong, Y., Zheng, Y., Li, X., Peng, D., Zhao, S., Li, Y., Liu, X., Wei, M., Liu, S., Yu, Y., Qu, B., Jiang, W., Zhou, Y., Zhao, X., Yuan, Z., Guo, Y., Xu, X., Shi, X., Ge, J., Fu, G., Bai, F., Fang, W., Shou, X., Yang, X., Wang, J., Xiang, M., Sun, Y., Lu, Q., Zhang, R., Zhu, J., Xu, Y., Fan, Z., Li, T., Wu, C., Jaramillo, N., Sanchez Vallejo, G., Luna Botia, D. C., Botero Lopez, R., Molina De Salazar, D. I., Cadena Bonfanti, A. J., Cotes Aroca, C., Diego Higuera, J., Blanquicett, M., Barrera Silva, S. I., Garcia Lozada, H. J., Coronel Arroyo, J. A., Accini Mendoza, J. L., Fernandez Ruiz, R. L., Quintero Ossa, A. M., Manzur Jatin, F. G., Sotomayor Herazo, A., Castellanos Parada, J., Suarez Arambula, R., Urina Triana, M. A., Fernandez Trujillo, A. M., Strozzi, M., Car, S., Jeric, M., Milicic, D., Bencic, M. L., Pintaric, H., Prvulovic, D., Sikic, J., Persic, V., Mileta, D., Stambuk, K., Babic, Z., Tomulic, V., Lukenda, J., Mejic-Krstulovic, S., Starcevic, B., Spinar, J., Horak, D., Velicka, Z., Stasek, J., Alan, D., Machova, V., Linhart, A., Novotny, V., Kaucak, V., Rokyta, R., Naplava, R., Coufal, Z., Adamkova, V., Podpera, I., Zizka, J., Motovska, Z., Marusincova, I., Svab, P., Heinc, P., Kuchar, J., Povolny, P., Matuska, J., Poulsen, S. H., Raungaard, B., Clemmensen, P., Bang, L. E., May, O., Bottcher, M., Hove, J. D., Frost, L., Gislason, G., Larsen, J., Betton Johansen, P., Hald, F., Johansen, P., Jeppesen, J., Nielsen, T., Kristensen, K. S., Walichiewicz, P. M., Lomholdt, J. D., Klausen, I. C., Nielsen, P. K., Davidsen, F., Videbaek, L., Soots, M., Vahula, V., Hedman, A., Soopold, U., Martsin, K., Jurgenson, T., Kristjan, A., Helsinki, J. K., Vikman, S., Huikuri, H., Airaksinen, J., Coste, P., Ferrari, E., Morel, O., Montalescot, G., Machecourt, J., Barone-Rochette, G., Mansourati, J., Cottin, Y., Leclercq, F., Belhassane, A., Delarche, N., Boccara, F., Paganelli, F., Clerc, J., Schiele, F., Aboyans, V., Probst, V., Berland, J., Lefevre, T., Citron, B., Khintibidze, I., Shaburishvili, T., Pagava, Z., Ghlonti, R., Lominadze, Z., Khabeishvili, G., Hemetsberger, R., Edward, K., Rauch-Krohnert, U., Stratmann, M., Appel, K., Schmidt, E., Omran, H., Stellbrink, C., Dorsel, T., Lianopoulos, E., Vohringer, H. F., Marx, R., Zirlik, A., Schellenberg, D., Heitzer, T., Laufs, U., Werner, C., Marx, N., Gielen, S., Nuding, S., Winkelmann, B., Behrens, S., Sydow, K., Karakas, M., Simonis, G., Muenzel, T., Werner, N., Leggewie, S., Bocker, D., Braun-Dullaeus, R., Toursarkissian, N., Jeserich, M., WeiSSbrodt, M., Schaeufele, T., Weil, J., Voller, H., Waltenberger, J., Natour, M., Schmitt, S., Muller-Wieland, D., Steiner, S., Heidenreich, L., Offers, E., Gremmler, U., Killat, H., Rieker, W., Patsilinakos, S., Kartalis, A., Manolis, A., Sionis, D., Chachalis, G., Skoumas, I., Athyros, V., Vardas, P., Parthenakis, F., Alexopoulos, D., Hahalis, G., Lekakis, J., Hatzitolios, A., Fausto Ovando, S. R., Arango Benecke, J. L., Rodriguez De Leon, E. R., Yan, B. P., Siu, D. C., Turi, T., Merkely, B., Ungi, I., Lupkovics, G., Nagy, L., Katona, A., Edes, I., Muller, G., Horvath, I., Kapin, T., Szigeti, Z., Falukozy, J., Kumbla, M., Sandhu, M., Annam, S., Proddutur, N. R., Regella, R., Premchand, R. K., Mahajan, A., Pawar, S., Abhyanakar, A. D., Kerkar, P., Govinda, R. A., Oomman, A., Sinha, D., Patil, S. N., Kahali, D., Sawhney, J., Joshi, A. B., Chaudhary, S., Harkut, P., Guha, S., Porwal, S., Jujjuru, S., Pothineni, R. B., Monteiro, M. R., Khan, A., Iyengar, S. S., Grewal, J. S., Chopda, M., Fulwani, M. C., Patange, A., Sachin, P., Chopra, V. K., Goyal, N. K., Shinde, R., Manakshe, G. V., Patki, N., Sethi, S., Munusamy, V., Karna, S., Thanvi, S., Adhyapak, S., Patil, C., Pandurangi, U., Mathur, R., Gupta, J., Kalashetti, S., Bhagwat, A., Raghuraman, B., Yerra, S. K., Bhansali, P., Borse, R., Rahul, P., Das, S., Kumar, V., Abdullakutty, J., Saathe, S., Palimkar, P., Sathe, S., Atar, S., Shechter, M., Mosseri, M., Arbel, Y., Ehud, C., Ofer, H., Lotan, C., Rosenschein, U., Katz, A., Henkin, Y., Francis, A., Klutstein, M., Nikolsky, E., Zukermann, R., Turgeman, Y., Halabi, M., Marmor, A., Kornowski, R., Jonas, M., Amir, O., Hasin, Y., Rozenman, Y., Fuchs, S., Zvi, V., Hussein, O., Gavish, D., Vered, Z., Caraco, Y., Elias, M., Tov, N., Wolfovitz, E., Lishner, M., Elias, N., Piovaccari, G., De Pellegrin, A., Garbelotto, R., Guardigli, G., Marco, V., Licciardello, G., Auguadro, C., Scalise, F., Cuccia, C., Salvioni, A., Musumeci, G., Senni, M., Calabro, P., Novo, S., Faggiano, P., Metra, M., De Cesare, N. B., Berti, S., Cavallini, C., Puccioni, E., Galvani, M., Tespili, M., Piatti, P., Palvarini, M., De Luca, G., Violini, R., De Leo, A., Olivari, Z., Perrone Filardi, P., Ferratini, M., Racca, V., Dai, K., Shimatani, Y., Kamiya, H., Ando, K., Takeda, Y., Morino, Y., Hata, Y., Kimura, K., Kishi, K., Michishita, I., Uehara, H., Higashikata, T., Hirayama, A., Hirooka, K., Doi, Y., Sakagami, S., Taguchi, S., Koike, A., Fujinaga, H., Koba, S., Kozuma, K., Kawasaki, T., Ono, Y., Shimizu, M., Katsuda, Y., Wada, A., Shinke, T., Kimura, T., Ako, J., Fujii, K., Takahashi, T., Sakamoto, T., Nakao, K., Furukawa, Y., Sugino, H., Tamura, R., Mano, T., Uematsu, M., Utsu, N., Ito, K., Haraguchi, T., Sato, K., Ueda, Y., Nishibe, A., Fujimoto, K., Masutani, M., Yoon, J. H., Kim, H., Park, H. S., Chae, I., Kim, M. H., Jeong, M. H., Rha, S., Kim, C., Kim, H., Kim, H. Y., Hong, T., Tahk, S., Kim, Y., Busmane, A., Pontaga, N., Strelnieks, A., Mintale, I., Sime, I., Petrulioniene, Z., Kavaliauskiene, R., Jurgaitiene, R., Sakalyte, G., Slapikas, R., Norkiene, S., Misonis, N., Kibarskis, A., Kubilius, R., Bojovski, S., Lozance, N., Kjovkaroski, A., Doncovska, S., Ong, T. K., Kasim, S., Maskon, O., Kandasamy, B., Liew, H. B., Wan Mohamed, W. M., Garcia Castillo, A., Carrillo Calvillo, J., Fajardo Campos, P., Nunez Fragoso, J. C., Bayram Llamas, E. A., Alcocer Gamba, M. A., Carranza Madrigal, J., Gonzalez Salas, L. G., Lopez Rosas, E., Gonzalez Diaz, B., Salcido Vazquez, E., Nacoud Ackar, A., Llamas Esperon, G. A., Martinez Sanchez, C. R., Guerrero De Leon, M., Suarez Otero, R., Fanghanel Salmon, G., Perez Rios, J. A., Garza Ruiz, J. A., Breedveld, R. W., Feenema-Aardema, M., Borger-Van Der Burg, A., Hoogslag, P. A., Suryapranata, H., Oomen, A., Van Haelst, P., Wiersma, J. J., Basart, D., Van Der Wal, R. M., Zwart, P., Monraats, P., Van Kesteren, H., Karalis, I., Jukema, J., Verdel, G. J., Brueren, B. R., Troquay, R. P., Viergever, E. P., Al-Windy, N. Y., Bartels, G. L., Cornel, J. H., Hermans, W. R., Herrman, J. P., Bos, R. J., Groutars, R. G., Van Der Zwaan, C. C., Kaplan, R., Lionarons, R., Ronner, E., Groenemeijer, B. E., Bronzwaer, P. N., Liem, A. A., Rensing, B. J., Bokern, M. J., Nijmeijer, R., Hersbach, F. M., Willems, F. F., Gosselink, A. T., Rasoul, S., Elliott, J., Wilkins, G., Fisher, R., Scott, D., Hart, H., Stewart, R., Harding, S., Ternouth, I., Fisher, N., Wilson, S., Aitken, D., Anscombe, R., Davidson, L., Tomala, T., Nygard, O., Sparby, J. A., Andersen, K., Gullestad, L., Jortveit, J., Munk, P. S., Singsaas, E. G., Hurtig, U., Calderon Ticona, J. R., Durand Velasquez, J. R., Negron Miguel, S. A., Sanabria Perez, E. S., Carrion Chambilla, J. M., Chavez Ayala, C. A., Castillo Leon, R. P., Vargas Gonzales, R. J., Hernandez Zuniga, J. D., Camacho Cosavalente, L. A., Bravo Mannucci, J. E., Heredia Landeo, J., Llerena Navarro, N. C., Roldan Concha, Y. M., Rodriguez Chavez, V. E., Anchante Hernandez, H. A., Zea Nunez, C. A., Mogrovejo Ramos, W., Ferrolino, A., Sy, R. A., Tirador, L., Sy, R. G., Matiga, G., Coching, R. M., Bernan, A., Rogelio, G., Morales, D. D., Tan, E., Sulit, D. J., Wlodarczak, A., Jaworska, K., Skonieczny, G., Pawlowicz, L., Wojewoda, P., Busz-Papiez, B., Bednarski, J., Goch, A., Staneta, P., Dulak, E., Saminski, K., Krasowski, W., Sudnik, W., Zurakowski, A., Skorski, M., Miklaszewicz, B., Kubica, J., Andrzej Lipko, J., Kostarska-Srokosz, E., Piepiorka, M., Drzewiecka, A., Stasiewski, A., Blicharski, T., Bystryk, L., Szpajer, M., Korol, M., Czerski, T., Mirek-Bryniarska, E., Gniot, J., Lubinski, A., Gorny, J., Franek, E., Raczak, G., Szwed, H., Monteiro, P., Mesquita Bastos, J., Pereira, H. H., Martins, D., Seixo, F., Mendonca, C., Botelho, A., Caetano, F., Minescu, B., Istratoaie, O., Tesloianu, D. N., Cristian, G., Dumitrescu, S., Podoleanu, C. G., Constantinescu, M. C., Bengus, C. M., Militaru, C., Rosu, D., Parepa, I. R., Matei, A. V., Alexandru, T. M., Malis, M., Coman, I., Stanescu-Cioranu, R., Dimulescu, D., Shvarts, Y., Orlikova, O., Kobalava, Z., Barbarash, O. L., Markov, V., Lyamina, N., Gordienko, A., Zrazhevsky, K., Vishnevsky, A. Y., Gurevich, V., Stryuk, R., Lomakin, N. V., Bokarev, I., Khlevchuk, T., Shalaev, S., Khaisheva, L., Chizhov, P., Viktorova, I., Osokina, N., Shchekotov, V., Akatova, E., Chumakova, G., Libov, I., Voevoda, M. I., Tretyakova, T. V., Baranov, E., Shustov, S., Yakushin, S., Gordeev, I., Khasanov, N., Reshetko, O., Sotnikova, T., Molchanova, O., Nikolaev, K., Gapon, L., Baranova, E., Shogenov, Z., Kosmachova, E., Karpov, Y., Povzun, A., Egorova, L., Tyrenko, V. V., Ivanov, I. G., Ilya, M., Kanorsky, S., Simic, D., Ivanovic, N., Davidovic, G., Tasic, N., Asanin, M. R., Stojic, S., Apostolovic, S. R., Ilic, S., Putnikovic Tosic, B., Stankovic, A., Arandjelovic, A., Radovanovic, S., Todic, B., Balinovac, J., Dincic, D. V., Seferovic, P., Karadzic, A., Dodic, S., Dimkovic, S., Jakimov, T., Poh, K., Ong, H. Y., Tang I-Shing, J., Micko, K., Nociar, J., Pella, D., Fulop, P., Hranai, M., Palka, J., Mazur, J., Majercak, I., Dzupina, A., Fazekas, F., Gonsorcik, J., Bugan, V., Selecky, J., Kamensky, G., Strbova, J., Smik, R., Dukat, A., Zuran, I., Poklukar, J., Cernic Suligoj, N., Cevc, M., Cyster, H. P., Ranjith, N., Corbett, C., Bayat, J., Makotoko, E. M., du Toit Theron, H., Kapp, I. E., de V Basson, M. M., Lottering, H., Van Aswegen, D., Van Zyl, L. J., Sebastian, P. J., Pillay, T., Saaiman, J. A., Commerford, P. J., Cassimjee, S., Riaz, G., Ebrahim, I. O., Sarvan, M., Mynhardt, J. H., Reuter, H., Moodley, R., Vida, M., Cequier Fillat, A. R., Bodi Peris, V., Fuentes Jimenez, F., Marin, F., Cruz Fernandez, J. M., Hidalgo Urbano, R. J., Gil-Extremera, B., Toledo, P., Worner Diz, F., Garcia-Dorado, D., Iniguez, A., Tunon Fernandez, J., Gonzalez-Juanatey, J. R., Fernandez Portales, J., Civeira Murillo, F., Matas Pericas, L., Zamorano, J. L., De Mora Martin, M., Bruguera Cortada, J., Alonso Martin, J. J., Serrano Antolin, J. M., De Berrazueta Fernandez, J. R., Vazquez de Prada, J. A., Diaz Fernandez, J. F., Garcia Lledo, J. A., Cosin Sales, J., Botas Rodriguez, J., Gusi Tragant, G., Benedicto, A., Gonzalez-Juanatey, C., Camprubi Potau, M., Plaza Perez, I., De La Tassa, C. M., Loma-Osorio Rincon, P., Balaguer Recena, J., Escudier, J. M., Payeras, A. C., Alonso Orcajo, N., Valdivielso, P., Constantine, G., Haniffa, R., Tissera, N., Amarasekera, S., Ponnamperuma, C., Fernando, N., Fernando, K., Jayawardena, J., Wijeyasingam, S., Ranasinghe, G., Ekanayaka, R., Mendis, S., Senaratne, V., Mayurathan, G., Sirisena, T., Rajapaksha, A., Herath, J. I., Amarasena, N., Berglund, S., Rasmanis, G., Vedin, O., Witt, N., Mourtzinis, G., Nicol, P., Hansen, O., Romeo, S., Agergaard Jensen, S., Torstensson, I., Ahremark, U., Sundelin, T., Moccetti, T., Muller, C., Mach, F., Binde, R., Tsai, W., Ueng, K., Lai, W., Liu, M., Hwang, J., Yin, W., Hsieh, I., Hsieh, M., Lin, W. H., Kuo, J., Huang, T., Fang, C., Kaewsuwanna, P., Soonfuang, W., Jintapakorn, W., Sukonthasarn, A., Wongpraparut, N., Sastravaha, K., Sansanayudh, N., Kehasukcharoen, W., Piyayotai, D., Chotnoparatpat, P., Camsari, A., Kultursay, H., Mutlu, B., Ersanli, M., Demirtas, M., Kirma, C., Ural, E., Koldas, L., Karpenko, O., Prokhorov, A., Vakaluyk, I., Myshanych, H., Reshotko, D., Batushkin, V., Rudenko, L., Kovalskyi, I., Kushnir, M., Tseluyko, V., Mostovoy, Y., Stanislavchuk, M., Kyiak, Y., Karpenko, Y., Malynovsky, Y., Klantsa, A., Kutniy, O., Amosova, E., Tashchuk, V., Leshchuk, O., Rishko, M., Kopytsya, M., Yagensky, A., Vatutin, M., Bagriy, A., Barna, O. M., Ushakov, O., Dzyak, G., Goloborodko, B., Rudenko, A., Zheleznyy, V., Trevelyan, J., Zaman, A., Lee, K., Moriarty, A., Aggarwal, R. K., Clifford, P., Wong, Y., Iqbal, S. M., Subkovas, E., Braganza, D., Sarkar, D., Storey, R., Griffiths, H., McClure, S., Muthusamy, R., Smith, S., Kurian, J., Levy, T., Barr, C., Kadr, H., Gerber, R., Simaitis, A., Soran, H., Mathur, A., Brodison, A., Ayaz, M., Cheema, M., Oliver, R., Thackray, S., Mudawi, T., Rahman, G., Sultan, A., Sharman, D., Sprigings, D., Butler, R., Wilkinson, P., Lip, G. Y., Halcox, J., Gallagher, S., Ossei-Gerning, N., Vardi, G., Baldari, D., Brabham, D., Treasure Ii, C., Dahl, C., Palmer, B., Wiseman, A., Khan, A., Puri, S., Mohart, A. E., Ince, C., Flores, E., Wright, S., Cheng, S., Rosenberg, M., Rogers, W. J., Kosinski, E., Forgosh, L., Waltman, J., Khan, M., Shoukfeh, M., Dagher, G., Cambier, P., Lieber, I., Kumar, P., East, C., Krichmar, P., Hasan, M., White, L., Knickelbine, T., Haldis, T., Gillespie, E., Amidon, T., Suh, D., Arif, I., Abdallah, M., Akhter, F., Carlson, E., D'Urso, M., El-Ahdab, F., Nelson, W., Moriarty, K., Harris, B., Cohen, S., Carter, L., Doty, D., Sabatino, K., Haddad, T., Malik, A., Rao, S., Mulkay, A., Jovin, I., Klancke, K., Malhotra, V., Devarapalli, S. K., Koren, M., Chandna, H., Dodds Iii, G., Goraya, T., Bengston, J., Janik, M., Moran, J., Sumner, A., Kobayashi, J., Davis, W., Yazdani, S., Pasquini, J., Thakkar, M., Vedere, A., Leimbach, W., Rider, J., Fenton, S., Singh, N., Shah, A. V., Janosik, D., Pepine, C., Berman, B., Gelormini, J., Daniels, C., Richard, K., Keating, F., Kondo, N. I., Shetty, S., Levite, H., Waider, W., Takata, T., Abu-Fadel, M., Shah, V., Aggarwal, R., Izzo, M., Kumar, A., Hattler, B., Do, R., Link, C., Bortnick, A., Kinzfogl Iii, G., Ghitis, A., Larry, J., Teufel, E., Kuhlman, P., Mclaurin, B., Zhang, W., Thew, S., Abbas, J., White, M., Islam, O., Subherwal, S., Ranadive, N., Vakili, B., Gring, C., Henderson, D., Schuchard, T., Farhat, N., Kline, G., Mahal, S., Whitaker, J., Speirs, S., Andersen, R., Daboul, N., Horwitz, P., Zahr, F., Ponce, G., Jafar, Z., Mcgarvey, J. J., Panchal, V., Voyce, S., Blok, T., Sheldon, W., Azizad, M. M., Schmalfuss, C., Picone, M., Pederson, R., Herzog, W. J., Friedman, K., Lindsey, J., Nowins, R., Timothy, E., Leonard, P., Lepor, N., El Shahawy, M., Weintraub, H., Irimpen, A., Alonso, A., May, W., Christopher, D., Galski, T., Chu, A., Mody, F., Ramin, E., Hodes, Z., Rossi, J., Rose, G., Fairlamb, J., Lambert, C. J., Raisinghani, A., Abbate, A., Vetrovec, G., King, M., Carey, C., Gerber, J., Younis, L., Park, H. T., Vidovich, M., Knutson, T., Friedman, D., Chaleff, F., Loussararian, A., Rozeman, P., Kimmelstiel, C., Kuvin, J., Silver, K., Foster, M., Tonnessen, G., Espinoza, A., Amlani, M., Wali, A., Malozzi, C., Jong, G. T., Massey, C., Wattanakit, K., O'Donnell, P. J., Singal, D., Jaffrani, N., Banuru, S., Fisher, D., Xenakis, M., Perlmutter, N., Bhagwat, R., Strader, J. J., Blonder, R., Akyea-Djamson, A., Labroo, A., Lee, K., Marais, H. J., Claxton, E. J., Weiss, R., Kathryn, R., Berk, M., Rossi, P., Joshi, P., Khera, A., Khaira, A. S., Kumkumian, G., Lupovitch, S., Purow, J., Welka, S., Hoffman, D., Fischer, S., Soroka, E., Eagerton, D., Pancholy, S., Ray, M., Erenrich, N., Farrar, M., Pollock, S., French, W. J., Diamantis, S., Guy, D., Gimple, L., Neustel, M., Schwartz, S., Pereira, E., Albert, S., Spriggs, D., Strain, J., Mittal, S., Vo, A., Chane, M., Hall, J., Vijay, N., Lotun, K., Lester, F. M., Nahhas, A., Pope, T., Nager, P., Vohra, R., Sharma, M., Bashir, R., Ahmed, H., Berlowitz, M., Fishberg, R., Barrucco, R., Yang, E., Radin, M., Sporn, D., Stapleton, D., Eisenberg, S., Landzberg, J., Mcgough, M., Turk, S., Schwartz, M., Sundram, P. S., Jain, D., Zainea, M., Bayron, C., Karlsberg, R., Dohad, S., Lui, H., Keen, W., Westerhausen, D. J., Khurana, S., Agarwal, H., Birchem, J., Penny, W. J., Chang, M., Murphy, S., Henry, J., Schifferdecker, B., Gilbert, J. M., Chalavarya, G., Eaton, C., Schmedtje, J. F., Christenson, S., Dotani, I., Denham, D., Macdonell, A., Gibson, P., Rahman, A., Al Joundi, T., Assi, N., Conrad, G., Kotha, P., Love, M., Giesler, G., Rubenstein, H., Gamil, D., Akright, L., Krawczyk, J., Cobler, J., Wells, T., Welker, J., Foster, R., Gilmore, R., Anderson, J., Jacoby, D., Harris, B., Gardner, G., Dandillaya, R., Vora, K., Kostis, J., Hunter, J., Laxson, D., Ball, E., Wells, T., Vora, K., Ball, E., Welker, J., Lopes, R., Egydio, F., Kawakami, A., Oliveira, J., Wozniak, J., Matthews, A., Ratky, C., Valiris, J., Berdan, L., Hepditch, A., Quintero, K., Rorick, T., Westbrook, M., Pascual, A., Rovito, C., Bezault, M., Drouet, E., Simon, T., White, H. D., Alsweiler, C., Luyten, A., Butters, J., Griffith, L., Shaw, M., Grunberg, L., Islam, S., Bregeault, M., Bougon, N., Faustino, D., Fontecave, S., Murphy, J., Verrier, M., Agnetti, V., Andersen, D., Badreddine, E., Bekkouche, M., Bouancheau, C., Brigui, I., Brocklehurst, M., Cianciarulo, J., Devaul, D., Domokos, S., Gache, C., Gobillot, C., Guillou, S., Healy, J., Heath, M., Jaiwal, G., Javierre, C., Labeirie, J., Monier, M., Morales, U., Mrabti, A., Mthombeni, B., Okan, B., Smith, L., Sheller, J., Sopena, S., Pellan, V., Benbernou, F., Bengrait, N., Lamoureux, M., Kralova, K., Scemama, M., Bejuit, R., Coulange, A., Berthou, C., Repincay, J., Lorenzato, C., Etienne, A., Gouet, V., Lecorps, G., Loizeau, V., Normand, M., Ourliac, A., Rondel, C., Adamo, A., Beltran, P., Barraud, P., Dubois-Gache, H., Halle, B., Metwally, L., Mourgues, M., Sotty, M., Vincendet, M., Cotruta, R., Chengyue, Z., Fournie-Lloret, D., Morrello, C., Perthuis, A., Picault, P., Zobouyan, I., Colhoun, H. M., Dempsey, M. A., McClanahan, M. A. 2019

    Abstract

    BACKGROUND: After acute coronary syndrome, diabetes conveys an excess risk of ischaemic cardiovascular events. A reduction in mean LDL cholesterol to 1·4-1·8 mmol/L with ezetimibe or statins reduces cardiovascular events in patients with an acute coronary syndrome and diabetes. However, the efficacy and safety of further reduction in LDL cholesterol with an inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) after acute coronary syndrome is unknown. We aimed to explore this issue in a prespecified analysis of the ODYSSEY OUTCOMES trial of the PCSK9 inhibitor alirocumab, assessing its effects on cardiovascular outcomes by baseline glycaemic status, while also assessing its effects on glycaemic measures including risk of new-onset diabetes.METHODS: ODYSSEY OUTCOMES was a randomised, double-blind, placebo-controlled trial, done at 1315 sites in 57 countries, that compared alirocumab with placebo in patients who had been admitted to hospital with an acute coronary syndrome (myocardial infarction or unstable angina) 1-12 months before randomisation and who had raised concentrations of atherogenic lipoproteins despite use of high-intensity statins. Patients were randomly assigned (1:1) to receive alirocumab or placebo every 2 weeks; randomisation was stratified by country and was done centrally with an interactive voice-response or web-response system. Alirocumab was titrated to target LDL cholesterol concentrations of 0·65-1·30 mmol/L. In this prespecified analysis, we investigated the effect of alirocumab on cardiovascular events by glycaemic status at baseline (diabetes, prediabetes, or normoglycaemia)-defined on the basis of patient history, review of medical records, or baseline HbA1c or fasting serum glucose-and risk of new-onset diabetes among those without diabetes at baseline. The primary endpoint was a composite of death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402.FINDINGS: At study baseline, 5444 patients (28·8%) had diabetes, 8246 (43·6%) had prediabetes, and 5234 (27·7%) had normoglycaemia. There were no significant differences across glycaemic categories in median LDL cholesterol at baseline (2·20-2·28 mmol/L), after 4 months' treatment with alirocumab (0·80 mmol/L), or after 4 months' treatment with placebo (2·25-2·28 mmol/L). In the placebo group, the incidence of the primary endpoint over a median of 2·8 years was greater in patients with diabetes (16·4%) than in those with prediabetes (9·2%) or normoglycaemia (8·5%); hazard ratio (HR) for diabetes versus normoglycaemia 2·09 (95% CI 1·78-2·46, p<0·0001) and for diabetes versus prediabetes 1·90 (1·65-2·17, p<0·0001). Alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycaemic category, but a greater absolute reduction in the incidence of the primary endpoint in patients with diabetes (2·3%, 95% CI 0·4 to 4·2) than in those with prediabetes (1·2%, 0·0 to 2·4) or normoglycaemia (1·2%, -0·3 to 2·7; absolute risk reduction pinteraction=0·0019). Among patients without diabetes at baseline, 676 (10·1%) developed diabetes in the placebo group, compared with 648 (9·6%) in the alirocumab group; alirocumab did not increase the risk of new-onset diabetes (HR 1·00, 95% CI 0·89-1·11). HRs were 0·97 (95% CI 0·87-1·09) for patients with prediabetes and 1·30 (95% CI 0·93-1·81) for those with normoglycaemia (pinteraction=0·11).INTERPRETATION: After a recent acute coronary syndrome, alirocumab treatment targeting an LDL cholesterol concentration of 0·65-1·30 mmol/L produced about twice the absolute reduction in cardiovascular events among patients with diabetes as in those without diabetes. Alirocumab treatment did not increase the risk of new-onset diabetes.FUNDING: Sanofi and Regeneron Pharmaceuticals.

    View details for DOI 10.1016/S2213-8587(19)30158-5

    View details for PubMedID 31272931

  • Acute Limb Ischemia in Peripheral Artery Disease: Insights from EUCLID. Circulation Hess, C. N., Huang, Z., Patel, M. R., Baumgartner, I., Berger, J. S., Blomster, J. I., Fowkes, F. G., Held, P., Jones, W. S., Katona, B., Mahaffey, K. W., Norgren, L., Rockhold, F. W., Hiatt, W. R. 2019

    Abstract

    BACKGROUND: Acute limb ischemia (ALI) is an important clinical event and an emerging cardiovascular clinical trial outcome. Risk factors for and outcomes after ALI have not been fully evaluated.METHODS: EUCLID randomized patients with peripheral artery disease (PAD) to ticagrelor versus clopidogrel. Enrollment criteria included an ankle-brachial index (ABI) ≤0.80 or prior lower extremity revascularization. Patients were grouped according to the primary outcome, post-randomization ALI hospitalization. Baseline factors associated with ALI were identified using Cox proportional hazards modeling. Models with ALI hospitalization as a time-dependent covariate were developed for secondary outcomes of major adverse cardiovascular events (MACE: myocardial infarction, cardiovascular death, ischemic stroke), all-cause mortality, and major amputation.RESULTS: Among 13,885 patients, 1.7% (n=232) had 293 ALI hospitalizations (0.8 per 100 patient-years). Patients with versus without ALI were younger and more often had prior peripheral revascularization and lower baseline ABI. Treatment during ALI hospitalization included endovascular revascularization (39.2%, n=115), surgical bypass (24.6%, n=72), and major amputation (13.0%, n=38). After multivariable adjustment, any prior peripheral revascularization (HR 4.7, 95% CI 3.3-6.8, p<0.01), baseline atrial fibrillation (HR 1.8, 95% CI 1.1-3.2, p=0.03), and baseline ABI ≤0.60 (HR 1.3 per 0.10 decrease, 95% CI 1.1-1.5, p<0.01) were associated with higher ALI risk. Older age (HR 0.8 per 10-year increase, 95% CI 0.7-1.0, p=0.02) and baseline statin use (HR 0.7, 95% CI 0.5-0.9, p<0.01) were associated with lower risk for ALI. There was no relationship between randomized treatment to ticagrelor or clopidogrel and ALI. Among patients with prior revascularization, surgical versus endovascular procedures performed more than 6 months prior were associated with ALI (adjusted HR 2.63, 95% CI 1.75-3.96). In the overall population, ALI hospitalization was associated with subsequent MACE (adjusted HR 1.4, 95% CI 1.0-2.1, p=0.04), all-cause mortality (adjusted HR 3.3, 95% CI 2.4-4.6, p<0.01), and major amputation (adjusted HR 34.2, 95% CI 9.7-20.8, p<0.01).CONCLUSIONS: Prior peripheral revascularization, baseline atrial fibrillation, and lower ABI identify PAD patients at heightened risk for ALI, an event associated with subsequent cardiovascular and limb-related morbidity and mortality.CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov Unique Identifier: NCT01732822.

    View details for DOI 10.1161/CIRCULATIONAHA.119.039773

    View details for PubMedID 31238713

  • Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy NEW ENGLAND JOURNAL OF MEDICINE Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. L., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P., De Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Meininger, G., Brenner, B. M., Mahaffey, K. W., CREDENCE Trial Investigators 2019; 380 (24): 2295–2306
  • EGFR LOSS WITH GLUCAGON-LIKE PEPTIDE-1 (GLP-1) ANALOGUE TREATMENT: DATA FROM SUSTAIN 6 AND LEADER Perkovic, V., Bain, S., Bakris, G., Buse, J., Gondolf, T., Idorn, T., Lausvig, N., Mahaffey, K., Marso, S., Nauck, M., Pratley, R., Rossing, P., Zinman, B., Mann, J. OXFORD UNIV PRESS. 2019
  • Characteristics of Digital Health Studies Registered in ClinicalTrials.gov JAMA INTERNAL MEDICINE Chen, C. E., Harrington, R. A., Desai, S. A., Mahaffey, K. W., Turakhia, M. P. 2019; 179 (6): 838–40
  • Stroke in Patients With Peripheral Artery Disease: Insights From the EUCLID Study STROKE Kolls, B. J., Sapp, S., Rockhold, F. W., Jordan, J., Dombrowski, K. E., Fowkes, F. R., Mahaffey, K. W., Berger, J. S., Katona, B. G., Blomster, J. I., Norgren, L., Abramson, B. L., Leiva-Pons, J. L., Carlos Prieto, J., Sokurenko, G., Hiatt, W. R., Jones, W., Patel, M. R. 2019; 50 (6): 1356–63
  • Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program DIABETOLOGIA Matthews, D. R., Li, Q., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Desai, M., Hiatt, W. R., Nehler, M., Fabbrini, E., Kavalam, M., Lee, M., Neal, B. 2019; 62 (6): 926–38
  • DIFFERENT EGFR THRESHOLDS AND THE RENAL EFFECTS OF CANAGLIFLOZIN: DATA FROM THE CANVAS PROGRAM Oshima, M., Ohkuma, T., Neal, B., Li, Q., De Zeeuw, D., Mahaffey, K. W., Fulcher, G., Canovatchel, W., Matthews, D. R., Perkovic, V. OXFORD UNIV PRESS. 2019: 206
  • EFFECTS OF SEMAGLUTIDE AND LIRAGLUTIDE ON URINARY ALBUMIN-TO-CREATININE RATIO (UACR) - A POOLED ANALYSIS OF SUSTAIN 6 AND LEADER Perkovic, V., Bain, S., Bakris, G., Buse, J., Idorn, T., Mahaffey, K., Marso, S., Nauck, M., Pratley, R., Rasmussen, S., Rossing, P., Tornoe, K., Zinman, B., Mann, J. OXFORD UNIV PRESS. 2019: 205–U715
  • EFFECTS OF THE GLUCAGON-LIKE PEPTIDE-1 (GLP-1) ANALOGUES SEMAGLUTIDE AND LIRAGLUTIDE ON RENAL OUTCOMES - A POOLED ANALYSIS OF THE SUSTAIN 6 AND LEADER TRIALS Perkovic, V., Bain, S., Bakris, G., Buse, J., Idorn, T., Mahaffey, K., Marso, S., Nauck, M., Pratley, R., Rasmussen, S., Rossing, P., Tornoe, K., Zinman, B., Mann, J. OXFORD UNIV PRESS. 2019: 338
  • Effects of Canagliflozin on Heart Failure Outcomes Associated With Preserved and Reduced Ejection Fraction in Type 2 Diabetes Mellitus Results From the CANVAS Program CIRCULATION Figtree, G. A., Radholm, K., Barrett, T. D., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Matthews, D. R., Shaw, W., Neal, B. 2019; 139 (22): 2591–93
  • Stroke in Patients With Peripheral Artery Disease. Stroke Kolls, B. J., Sapp, S., Rockhold, F. W., Jordan, J. D., Dombrowski, K. E., Fowkes, F. G., Mahaffey, K. W., Berger, J. S., Katona, B. G., Blomster, J. I., Norgren, L., Abramson, B. L., Leiva-Pons, J. L., Prieto, J. C., Sokurenko, G., Hiatt, W. R., Jones, W. S., Patel, M. R. 2019: STROKEAHA118023534

    Abstract

    Background and Purpose- Predictors of stroke and transient ischemic attack (TIA) in patients with peripheral artery disease (PAD) are poorly understood. The primary aims of this analysis were to (1) determine the incidence of ischemic/hemorrhagic stroke and TIA in patients with symptomatic PAD, (2) identify predictors of stroke in patients with PAD, and (3) compare the rate of stroke in ticagrelor- and clopidogrel-treated patients. Methods- EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) randomized 13 885 patients with symptomatic PAD to receive monotherapy with ticagrelor or clopidogrel for the prevention of major adverse cardiovascular events (cardiovascular death, myocardial infarction, or ischemic stroke). Ischemic/hemorrhagic stroke and TIA were adjudicated and measured as incidence rates postrandomization and cumulative incidence (per patient-years). Post hoc multivariable competing risk hazards analyses were performed using baseline characteristics to determine factors associated with all-cause stroke in patients with PAD. Results- A total of 458 cerebrovascular events in 424 patients (317 ischemic strokes, 39 hemorrhagic strokes, and 102 TIAs) occurred over a median follow-up of 30 months, for a cumulative incidence of 0.87, 0.11, and 0.27 per 100 patient-years, respectively. Age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, geographic region, ankle-brachial index <0.60, prior amputation, and systolic blood pressure were independent baseline factors associated with the occurrence of all-cause stroke. After adjustment for baseline factors, the rates of ischemic stroke and all-cause stroke remained lower in patients treated with ticagrelor as compared with those receiving clopidogrel. There was no significant difference in the incidence of hemorrhagic stroke or TIA between the 2 treatment groups. Conclusions- In patients with symptomatic PAD, ischemic stroke and TIA occur frequently over time. Comorbidities such as age, prior stroke, prior atrial fibrillation/flutter, diabetes mellitus, higher blood pressure, prior amputation, lower ankle-brachial index, and geographic region were each independently associated with the occurrence of all-cause stroke. Use of ticagrelor, as compared with clopidogrel, was associated with a lower adjusted rate of ischemic and all-cause stroke. Further study is needed to optimize medical management and risk reduction of all-cause stroke in patients with PAD. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT01732822.

    View details for PubMedID 31092165

  • Blood Pressure Control and Cardiovascular Outcomes in Patients With Atrial Fibrillation (From the ORBIT-AF Registry) AMERICAN JOURNAL OF CARDIOLOGY Vemulapalli, S., Inohara, T., Kim, S., Thomas, L., Piccini, J. P., Patel, M. R., Chang, P., Fonarow, G. C., Ezekowitz, M. D., Hylek, E., Go, A. S., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Peterson, E. D. 2019; 123 (10): 1628–36
  • Comparison of Patient-Reported Care Satisfaction, Quality of Warfarin Therapy, and Outcomes of Atrial Fibrillation: Findings From the ORBIT-AF Registry JOURNAL OF THE AMERICAN HEART ASSOCIATION Perino, A. C., Shrader, P., Turakhia, M. P., Ansell, J. E., Gersh, B. J., Fonarow, G. C., Go, A. S., Kaiser, D. W., Hylek, E. M., Kowey, P. R., Singer, D. E., Thomas, L., Steinberg, B. A., Peterson, E. D., Piccini, J. P., Mahaffey, K. W. 2019; 8 (9)
  • Association of frailty and cognitive impairment with benefits of oral anticoagulation in patients with atrial fibrillation AMERICAN HEART JOURNAL Madhavan, M., Holmes, D. N., Piccini, J. P., Ansell, J. E., Fonarow, G. C., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Peterson, E. D., Chan, P., Allen, L. A., Gersh, B. J., ORBIT AF Investigators 2019; 211: 77–89
  • Treatment of atrial fibrillation with concomitant coronary or peripheral artery disease: Results from the outcomes registry for better informed treatment of atrial fibrillation II. American heart journal Inohara, T., Shrader, P., Pieper, K., Blanco, R. G., Allen, L. A., Fonarow, G. C., Gersh, B. J., Go, A. S., Ezekowitz, M. D., Kowey, P. R., Reiffel, J. A., Naccarelli, G. V., Chan, P. S., Mahaffey, K. W., Singer, D. E., Freeman, J. V., Steinberg, B. A., Peterson, E. D., Piccini, J. P., ORBIT AF Patients and Investigators 2019; 213: 81–90

    Abstract

    BACKGROUND: Treatment patterns and outcomes of individuals with vascular disease who have new-onset atrial fibrillation (AF) are not well characterized.METHODS: Among patients with new-onset AF, we analyzed treatment and outcomes in those with or without vascular disease in the ORBIT-AF II registry. Vascular disease was defined as coronary disease with or without myocardial infarction (MI) or revascularization, or peripheral artery disease. The primary outcomes included major adverse cardiovascular or neurological events (MACNE) and major bleeding. Cox proportional hazard models were used to adjust the difference in patient characteristics.RESULTS: Overall 1920 of 6203 (31.0%) of new-onset AF had vascular disease. In patients with vascular disease, 62.2% of those were treated with direct oral anticoagulants (DOACs) and 23.4% with warfarin. Dual therapy and triple therapy were used in 36.9% and 4.9%, respectively. Vascular disease patients had increased risk of MACNE (adjusted hazard ratio [aHR] 1.83 [95%CIs 1.32-2.55]), but not major bleeding (aHR 1.24 [0.95-1.63]). Among patients with vascular disease, relative to those on warfarin, those treated with DOACs had similar risk for MACNE (aHR 1.20 [0.77-1.87]) but lower risks for bleeding, although it did not reach statistical significance (aHR 0.70 [0.43-1.15]). Concomitant antiplatelet therapy was associated with higher bleeding (aHR 2.27 [1.38-3.73]) with no apparent reduction in MACNE (aHR 1.50 [1.00-2.25]).CONCLUSIONS: Most patients with AF and vascular disease were managed with oral anticoagulation. About half of them were also treated with concomitant antiplatelet therapy, which was associated with increased risk of bleeding, without evidence of improved cardiovascular outcomes.

    View details for DOI 10.1016/j.ahj.2019.04.007

    View details for PubMedID 31129441

  • Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. The New England journal of medicine Perkovic, V., Jardine, M. J., Neal, B., Bompoint, S., Heerspink, H. J., Charytan, D. M., Edwards, R., Agarwal, R., Bakris, G., Bull, S., Cannon, C. P., Capuano, G., Chu, P., de Zeeuw, D., Greene, T., Levin, A., Pollock, C., Wheeler, D. C., Yavin, Y., Zhang, H., Zinman, B., Meininger, G., Brenner, B. M., Mahaffey, K. W., CREDENCE Trial Investigators 2019

    Abstract

    BACKGROUND: Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium-glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes.METHODS: In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically.RESULTS: The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture.CONCLUSIONS: In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. (Funded by Janssen Research and Development; CREDENCE ClinicalTrials.gov number, NCT02065791.).

    View details for PubMedID 30990260

  • Efficacy and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and a history of cancer: observations from ROCKETAF EUROPEAN HEART JOURNAL-QUALITY OF CARE AND CLINICAL OUTCOMES Chen, S. T., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R., Melloni, C. 2019; 5 (2): 145–52
  • Effects of Canagliflozin on Heart Failure Outcomes Associated with Preserved and Reduced Ejection Fraction in Type 2 Diabetes: Results from the CANVAS Program. Circulation Figtree, G. A., Radholm, K., Barrett, T. D., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Matthews, D. R., Shaw, W., Neal, B. 2019

    Abstract

    Patients with type 2 diabetes mellitus are at high risk of developing heart failure (HF).1 Sodium glucose co-transporter 2 (SGLT2) inhibitors have been demonstrated, in large scale trials, to reduce the risk of HF events in patients with type 2 diabetes deemed to be at high risk based on established cardiovascular disease or multiple risk factors.2-4 However, it is unclear whether benefits are experienced across the broad spectrum of HF patients that includes those with preserved (HFpEF) as well as reduced ejection fraction (HFrEF).

    View details for PubMedID 30882240

  • EFFICACY OF A CENTRALIZED, BLENDED ELECTRONIC, AND HUMAN INTERVENTION TO IMPROVE DOAC ADHERENCE: THE SMARTADHERE TRIAL Turakhia, M. P., Sundaram, V., Smith, S., Ding, V., Ho, P., Kowey, P. R., Piccini, J., Foody, J., Birmingham, M., Ianus, J., Rajmane, A., Mahaffey, K. ELSEVIER SCIENCE INC. 2019: 510
  • Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia Matthews, D. R., Li, Q., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Desai, M., Hiatt, W. R., Nehler, M., Fabbrini, E., Kavalam, M., Lee, M., Neal, B. 2019

    Abstract

    AIMS/HYPOTHESIS: The primary analysis of the Canagliflozin cardioVascular Assessment Study (CANVAS) Program showed canagliflozin to have a beneficial effect on cardiovascular and renal outcomes in people with type 2 diabetes at high cardiovascular risk, but also an unexpected increased risk of major or minor lower extremity amputation. These secondary analyses explore this finding in more detail.METHODS: The effect of canagliflozin on amputation risk in the CANVAS Program was calculated for amputations of different types and proximate aetiologies and different canagliflozin doses. Univariate and multivariate associations of baseline characteristics with amputation risk were determined and proportional and absolute effects of canagliflozin were compared across subgroups.RESULTS: There were 187 (1.8%) participants with atraumatic lower extremity amputations (minor 71%, major 29%); as previously published, rates were 6.30 vs 3.37 per 1000 participant-years with canagliflozin vs placebo (HR 1.97 [95% CI 1.41, 2.75]). Risk was similar for ischaemic and infective aetiologies and for 100mg and 300mg doses. Overall amputation risk was strongly associated with baseline history of prior amputation (major or minor) (HR 21.31 [95% CI 15.40, 29.49]) and other established risk factors. No interactions between randomised treatment and participant characteristics explained the effect of canagliflozin on amputation risk. For every clinical subgroup studied, numbers of amputation events projected were smaller than numbers of major adverse cardiovascular events averted.CONCLUSIONS/INTERPRETATION: The CANVAS Program demonstrated that canagliflozin increased the risk of amputation (mainly minor) in this study population. Anticipated risk factors for amputation were identified, such as prior history of amputation, peripheral vascular disease and neuropathy, but no specific aetiological mechanism or at-risk subgroup for canagliflozin was identified.

    View details for PubMedID 30868176

  • B-type natriuretic peptide, disease progression and clinical outcomes in atrial fibrillation HEART Inohara, T., Kim, S., Pieper, K., Blanco, R. G., Allen, L. A., Fonarow, G. C., Gersh, B. J., Ezekowitz, M. D., Kowey, P. R., Reiffel, J. A., Naccarelli, G. V., Chan, P. S., Mahaffey, K. W., Singer, D. E., Freeman, J. V., Steinberg, B. A., Peterson, E. D., Piccini, J. P., ORBIT AF Patients & Investigators 2019; 105 (5): 370–77
  • Periprocedural Outcomes According to Timing of Clopidogrel Loading Dose in Patients Who Did Not Receive P2Y12 Inhibitor Pretreatment. Circulation. Cardiovascular interventions Abtan, J., Ducrocq, G., Steg, P. G., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., White, H. D., Harrington, R. A., Bhatt, D. L. 2019; 12 (3): e007445

    Abstract

    BACKGROUND: In patients undergoing percutaneous coronary intervention (PCI), who did not receive P2Y12 inhibitor pretreatment, the optimal timing of P2Y12 inhibitor loading dose remains debated. We sought to examine whether the choice of administration of the clopidogrel loading dose before or after the start of PCI had an impact on periprocedural complications, including bleeding.METHODS AND RESULTS: The CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) double-blind randomized trial compared cangrelor with clopidogrel loading dose at the time of PCI. Pretreatment with clopidogrel before randomization was not permitted per protocol. In the clopidogrel-only group (n=5438), a loading dose was given before (early load [EL]) or after the start of PCI (late load [LL]) according to physician choice. Overall, 3442 (63.3%) patients had EL and 1997 LL (36.7%). Median times were 5 minutes before and 20 minutes after the start of PCI, respectively. EL was more frequently used among patients with ST-segment-elevation myocardial infarction (84.4%) and non-ST-segment-elevation acute coronary syndromes (71.5%) than in stable patients (53.7%). At 48 hours, rates of the primary outcome of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis were similar (6.0% versus 5.4%) for EL versus LL, respectively (odds ratio [OR], 1.11 [95% CI, 0.87-1.41]; P=0.41), and remained so after adjustment for potential confounders, including clinical presentation (OR [95% CI], 1.39 [0.90-2.15]; P=0.14). Compared with clopidogrel, cangrelor consistently reduced the primary outcome in both EL (4.8% versus 6.0%; OR [95% CI], 0.80 [0.64-0.98]) and LL (4.3% versus 5.4%; OR [95% CI], 0.79 [0.59-1.06]; interaction P=0.99). Global Use of Strategies to Open Occluded Coronary Arteries severe/moderate bleeding rates were similar between treatment arms for both EL (OR [95% CI], 1.24 [0.58-2.66]) and LL (OR [95% CI], 2.53 [0.98-6.54]; interaction P=0.25).CONCLUSIONS: In a nonrandomized comparison of patients with clopidogrel loading before or after the start of PCI, the rates of periprocedural PCI complications, including bleeding, were similar, as were the benefits of cangrelor, regardless of the timing.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCINTERVENTIONS.118.007445

    View details for PubMedID 30871355

  • Characteristics of Digital Health Studies Registered in ClinicalTrials.gov. JAMA internal medicine Chen, C. E., Harrington, R. A., Desai, S. A., Mahaffey, K. W., Turakhia, M. P. 2019

    View details for PubMedID 30801617

  • Blood Pressure Control and Cardiovascular Outcomes in Patients With Atrial Fibrillation (From the ORBIT-AF Registry). The American journal of cardiology Vemulapalli, S., Inohara, T., Kim, S., Thomas, L., Piccini, J. P., Patel, M. R., Chang, P., Fonarow, G. C., Ezekowitz, M. D., Hylek, E., Go, A. S., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Peterson, E. D. 2019

    Abstract

    Systolic blood pressure (SBP) and its association with clinical outcomes in atrial fibrillation (AF) patients in community practice are poorly characterized. In patients with AF, we sought to (1) examine the prevalence of baseline uncontrolled hypertension and the overall change in SBP control, (2) identify predictors of uncontrolled SBP over 2 years of follow-up, and (3) determine the relation between SBP and clinical outcomes. We analyzed 10,132 patients with AF at 176 clinics in the ORBIT-AF registry between 2010 and 2014, classified as: (1) no history of hypertension; (2) controlled hypertension (baseline SBP <140 mm Hg); (3) and uncontrolled hypertension (baseline SBP >140 mm Hg). Predictors of SBP >140 mm Hg at baseline or in follow-up were identified with pooled logistic regression. Random effects Cox regression models were used to compare cardiovascular outcomes and major bleeding as a function of continuous, time-dependent SBP. Overall 8,383 (83%) of patients with AF had hypertension. Of these, 24.2% (n = 2032) had uncontrolled baseline SBP, with little change over 2 years. Predictors of elevated follow-up SBP included uncontrolled baseline SBP, females, previous percutaneous coronary intervention, and diabetes. For every 5 mm Hg increase in follow-up SBP, the adjusted risk of stroke or systemic embolism or transient ischemic attack (adjusted hazard ratio [aHR] 1.05, 95% confidence interval [CI] 1.01 to 1.08, p = 0.01), myocardial infarction (aHR 1.05, 95% CI 1.00 to 1.11, p = 0.04), and major bleeding (aHR 1.03, 95% CI 1.00 to 1.06, p = 0.04) increased modestly. In conclusion, in patients with AF, higher SBP was associated with increasing adverse events; therefore, more rigorous blood pressure control should be emphasized.

    View details for PubMedID 30846214

  • Appropriateness of Direct Oral Anticoagulant Dosing in Patients With Atrial Fibrillation: Insights From the Veterans Health Administration. Journal of pharmacy practice Leef, G. C., Perino, A. C., Askari, M., Fan, J., Ho, P. M., Olivier, C. B., Longo, L., Mahaffey, K. W., Turakhia, M. P. 2019: 897190019828270

    Abstract

    BACKGROUND:: Direct oral anticoagulants (DOACs) have strict dosing guidelines, but recent studies indicate that inappropriate dosing is common, particularly in chronic kidney disease (CKD), for which it has been reported to be as high as 43%. Since 2011, the Veterans Health Administration (VA) has implemented anticoagulation management programs for DOACs, generally led by pharmacists, which has previously been shown to improve medication adherence.OBJECTIVE:: We investigated the prevalence of overdosing and underdosing of DOACs in the VA.METHODS:: Using data from the TREAT-AF cohort study (The Retrospective Evaluation and Assessment of Therapies in AF), we identified VA patients with newly diagnosed atrial fibrillation (AF) and receipt of a DOAC between 2003 and 2015. We classified dosing as correct, overdosed, or underdosed based on the Food and Drug Administration-approved dosing criteria.RESULTS:: Of 230 762 patients, 5060 received dabigatran (77.3%) or rivaroxaban (22.7%) within 90 days of AF diagnosis (age 69 [10[ years; CHA2DS2-VASc 1.6 [1.4]), of which 1312 (25.9%) had CKD based on estimated glomerular filtration rate <60. Overall, 93.6% of patients, 83.2% with CKD, received appropriate DOAC dosing. Incorrect dosing increased with worsening renal function.CONCLUSION:: Compared to recent studies of commercial payers and health-care systems, incorrect dosing of DOACs is less common across the VA. Pharmacist-led DOAC management or similar anticoagulation management interventions may reduce the risk of incorrect dosing across health-care systems.

    View details for PubMedID 30791808

  • Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9259 Deaths in 9 Trials CIRCULATION Fanaroff, A. C., Clare, R., Pieper, K. S., Mahaffey, K. W., Melloni, C., Green, J. B., Alexander, J. H., Jones, W., Harrison, R. W., Mehta, R. H., Povsic, T. J., Moreira, H. G., Ai-Khatib, S. M., Roe, M. T., Kong, D. F., Mathews, R., Tricoci, P., Holman, R. R., Wallentin, L., Held, C., Califf, R. M., Alexander, K. P., Lopes, R. D. 2019; 139 (7): 863–73
  • Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events The ODYSSEY OUTCOMES Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Szarek, M., White, H. D., Schwartz, G. G., Alings, M., Bhatt, D. L., Bittner, V. A., Chiang, C., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J., Kimura, T., Kiss, R., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Tricoci, P., Xavier, D., Zeiher, A. M., Steg, G., Schwartz, G. G., Steg, P., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J., Szarek, M., White, H. D., Zeiher, A. M., Tricoci, P., Roe, M. T., Mahaffey, K. W., Edelberg, J. M., Hanotin, C., Lecorps, G., Moryusef, A., Pordy, R., Sasiela, W. J., Tamby, J., Aylward, P. E., Drexel, H., Sinnaeve, P., Dilic, M., Gotcheva, N. N., Goodman, S. G., Prieto, J., Yong, H., Lopez-Jaramillo, P., Pecin, I., Reiner, Z., Ostadal, P., Poulsen, S., Viigimaa, M., Nieminen, M. S., Danchin, N., Chumburidze, V., Marx, N., Liberopoulos, E., Valdovinos, P., Tse, H., Kiss, R., Xavier, D., Zahger, D., Valgimigli, M., Kimura, T., Kim, H., Kim, S., Kedev, S., Erglis, A., Laucevicius, A., Yusoff, K., Lopez, R., Arturo, G., Alings, M., White, H. D., Halvorsen, S., Correa Flores, R. M., Sy, R. G., Budaj, A., Morais, J., Dorobantu, M., Karpov, Y., Ristic, A. D., Chua, T., Murin, J., Fras, Z., Dalby, A. J., Tunon, J., de Silva, H., Hagstrom, E., Muller, C., Chiang, C., Sritara, P., Guneri, S., Parkhomenko, A., Ray, K. K., Moriarty, P. M., Roe, M. T., Chaitman, B., Kelsey, S. F., Olsson, A. G., Rouleau, J., Simoons, M. L., Alexander, K., Meloni, C., Rosenson, R., Sijbrands, E. G., Alexander, J. H., Armaganijan, L., Bagai, A., Bahit, M., Brennan, J., Clifton, S., DeVore, A. D., Deloatch, S., Dickey, S., Dombrowski, K., Ducrocq, G., Eapen, Z., Endsley, P., Eppinger, A., Harrison, R. W., Hess, C., Hlatky, M. A., Jordan, J., Knowles, J. W., Kolls, B. J., Kong, D. F., Leonardi, S., Lillis, L., Maron, D. J., Marcus, J., Mathews, R., Mehta, R. H., Mentz, R. J., Moreira, H., Patel, C. B., Pereira, S., Perkins, L., Povsic, T. J., Puymirat, E., Jones, W., Shah, B. R., Sherwood, M. W., Stringfellow, K., Sujjavanich, D., Toma, M., Van Diepen, S. P., Wilson, M. D., Yan, A., Lopes, R. D., Trotter, C., Schiavi, L. B., Garrido, M., Alvarisqueta, A. F., Sassone, S. A., Bordonava, A. P., Alves De Lima, A. E., Schmidberg, J. M., Duronto, E. A., Caruso, O. C., Novaretto, L. P., Angel Hominal, M., Montana, O. R., Caccavo, A., Gomez Vilamajo, O. A., Lorenzatti, A. J., Cartasegna, L. R., Paterlini, G. A., Mackinnon, I. J., Caime, G. D., Amuchastegui, M., Salomone, R., Codutti, O. R., Jure, H. O., Bono, J. E., Hrabar, A. D., Vallejos, J. A., Ahuad Guerrero, R. A., Novoa, F., Patocchi, C. A., Zaidman, C. J., Giuliano, M. E., Dran, R. D., Vico, M. L., Carnero, G. S., Guzman, P. N., Medrano Allende, J. C., Garcia Brasca, D. F., Bustamante Labarta, M. H., Nani, S., Blumberg, E. S., Colombo, H. R., Liberman, A., Luciardi, H. L., Waisman, G. D., Berli, M. A., Duran, R., Cestari, H. G., Luquez, H. A., Giordano, J. A., Saavedra, S. S., Zapata, G., Costamagna, O., Llois, S., Waites, J. H., Collins, N., Soward, A., Aylward, P. E., Hii, C. S., Shaw, J., Arstall, M. A., Horowitz, J., Rogers, J. F., Colquhoun, D., Oqueli Flores, R. E., Roberts-Thomson, P., Raffel, O., Lehman, S. J., Aroney, C., Coverdale, S. M., Garrahy, P. J., Starmer, G., Sader, M., Carroll, P. A., Dick, R., Zweiker, R., Hoppe, U., Huber, K., Berger, R., Weidinger, F., Faes, D., Hermans, K., Pirenne, B., Leone, A., Hoffer, E., Vrolix, M. M., De Wolf, L., Wollaert, B., Castadot, M., Dujardin, K., Beauloye, C., Vervoort, G., Striekwold, H., Convens, C., Roosen, J., Barbato, E., Claeys, M., Cools, F., Terzic, I., Barakovic, F., Midzic, Z., Pojskic, B., Fazlibegovic, E., Durak-Nalbantic, A., Vulic, D., Muslibegovic, A., Goronja, B., Reis, G., Sousa, L., Nicolau, J. C., Giorgeto, F. E., Silva, R. P., Maia, L., Rech, R., Rossi, P. F., Cerqueira, M. G., Duda, N., Kalil, R., Kormann, A., Abrantes, J. M., Pimentel Filho, P., Soggia, A., de Santos, M. N., Neuenschwander, F., Bodanese, L. C., Michalaros, Y. L., Eliaschewitz, F. G., Vidotti, M. H., Leaes, P. E., Botelho, R. V., Kaiser, S., Fernandes Manenti, E. F., Precoma, D. B., Moura Jorge, J. C., Silva, P. B., Silveira, J. A., Saporito, W., Marin Neto, J. A., Feitosa, G. S., Ritt, L. F., de Souza, J. A., Costa, F., Souza, W. B., Reis, H. L., Machado, L., Aidar Ayoub, J., Todorov, G. V., Nikolov, F. P., Velcheva, E. S., Tzekova, M. L., Benov, H. O., Petranov, S. L., Tumbev, H. S., Shehova-Yankova, N. S., Markov, D. T., Raev, D. H., Mollov, M. N., Kichukov, K. N., Ilieva-Pandeva, K. A., Ivanova, R., Mincheva, V. M., Lazov, P. V., Dimov, B. I., Senaratne, M., Stone, J., Kornder, J., Pearce, S., Dion, D., Savard, D., Pesant, Y., Pandey, A., Robinson, S., Gosselin, G., Vizel, S., Hoag, G., Bourgeois, R., Morisset, A., Sabbah, E., Sussex, B., Kouz, S., MacDonald, P., Diaz, A., Michaud, N., Fell, D., Leung, R., Vuurmans, T., Lai, C., Nigro, F., Davies, R., Nogareda, G., Vijayaraghavan, R., Ducas, J., Lepage, S., Mehta, S., Cha, J., Dupuis, R., Fong, P., Rodes-Cabau, J., Fadlallah, H., Cleveland, D., Thao Huynh, Bata, I., Hameed, A., Pincetti, C., Potthoff, S., Prieto, J. C., Acevedo, M., Aguirre, A., Vejar, M., Yanez, M., Araneda, G., Fernandez, M., Perez, L., Varleta, P., Florenzano, F., Huidobro, L., Raffo, C. A., Olivares, C., Nahuelpan, L., Montecinos, H., Chen, J., Dong, Y., Huang, W., Wang, J., Huang, S., Yao, Z., Li, X., Cui, L., Lin, W., Sun, Y., Wang, J., Li, J., Zhang, X., Zhu, H., Chen, D., Huang, L., Dong, S., Su, G., Xu, B., Su, X., Cheng, X., Lin, J., Zong, W., Li, H., Feng, Y., Xu, D., Yang, X., Ke, Y., Lin, X., Zhang, Z., Zheng, Z., Luo, Z., Chen, Y., Ding, C., Zheng, Y., Li, X., Peng, D., Li, Y., Wei, M., Liu, S., Yu, Y., Qu, B., Jiang, W., Zhou, Y., Zhao, X., Yuan, Z., Guo, Y., Xu, X., Shi, X., Ge, J., Fu, G., Bai, F., Fang, W., Shou, X., Yang, X., Wang, J., Sun, Y., Lu, Q., Zhang, R., Zhu, J., Xu, Y., Fan, Z., Li, T., Wu, C., Jaramillo, N., Vallejo, G., Botia, D., Lopez, R., De Salazar, D., Bonfanti, A., Higuera, J., Silva, S., Lozada, H., Arroyo, J., Mendoza, J., Ruiz, R., Jatin, F., Herazo, A., Parada, J., Triana, M., Strozzi, M., Car, S., Milicic, D., Bencic, M., Pintaric, H., Prvulovic, D., Sikic, J., Persic, V., Mileta, D., Stambuk, K., Zdravko, B., Tomulic, V., Krstulovic, S., Starcevic, B., Spinar, J., Horak, D., Stasek, J., Alan, D., Machova, V., Linhart, A., Novotny, V., Kaucak, V., Rokyta, R., Naplava, R., Coufal, Z., Adamkova, V., Podpera, I., Zizka, J., Motovska, Z., Marusincova, I., Svab, P., Ostadal, P., Heinc, P., Kuchar, J., Povolny, P., Matuska, J., Raungaard, B., Clemmensen, P., Bang, L. E., May, O., Bottcher, M., Hove, J. D., Frost, L., Gislason, G., Larsen, J., Johansen, P., Hald, F., Jeppesen, J., Nielsen, T., Kristensen, K. S., Walichiewicz, P., Lomholdt, J. D., Klausen, I. C., Nielsen, P., Davidsen, F., Videbaek, L., Soots, M., Vahula, V., Hedman, A., Soopold, U., Martsin, K., Kristjan, A., Taskinen, M., Porthan, K., Airaksinen, J. K., Juonala, M., Kiviniemi, T., Vikman, S., Posio, P., Taurio, J., Huikuri, H., Kaikkonen, K., Coste, P., Ferrari, E., Morel, O., Montalescot, G., Barone-Rochette, G., Mansourati, J., Cottin, Y., Leclercq, F., Belhassane, A., Delarche, N., Boccara, F., Paganelli, F., Clerc, J., Schiele, F., Aboyans, V., Probst, V., Berland, J., Lefevre, T., Citron, B., Khintibidze, I., Shaburishvili, T., Pagava, Z., Ghlonti, R., Lominadze, Z., Khabeishvili, G., Hemetsberger, R., Rauch-Kroehnert, U., Stratmann, M., Appel, K., Schmidt, E., Omran, H., Stellbrink, C., Dorsel, T., Lianopoulos, E., Marx, R., Zirlik, A., Schellenberg, D., Heitzer, T., Laufs, U., Marx, N., Gielen, S., Winkelmann, B., Behrens, S., Sydow, K., Simonis, G., Muenzel, T., Werner, N., Leggewie, S., Boecker, D., Braun-Dullaeus, R., Toursarkissian, N., Jeserich, M., Weissbrodt, M., Schaeufele, T., Weil, J., Voeller, H., Waltenberger, J., Natour, M., Schmitt, S., Steiner, S., Heidenreich, L., Gremmler, U., Killat, H., Rieker, W., Patsilinakos, S., Kartalis, A., Manolis, A., Sionis, D., Liberopoulos, E., Skoumas, I., Athyros, V., Vardas, P., Parthenakis, F., Alexopoulos, D., Hahalis, G., Lekakis, J., Hatzitolios, A., Ovando, S., Valdovinos, P., Benecke, J., De Leon, E., Yan, B. Y., Siu, D. W., Turi, T., Merkely, B., Kiss, R., Ungi, I., Lupkovics, G., Nagy, L., Katona, A., Edes, I., Muller, G., Horvath, I., Kapin, T., Falukozy, J., Kumbla, M., Sandhu, M., Annam, S., Proddutur, N., Premchand, R. K., Mahajan, A., Abhyanakar, A. D., Kerkar, P., Govinda, R. A., Oomman, A., Sinha, D., Patil, S. N., Kahali, D., Sawhney, J., Joshi, A. B., Chaudhary, S., Harkut, P., Guha, S., Porwal, S., Jujjuru, S., Pothineni, R. B., Monteiro, M. R., Khan, A., Iyengar, S. S., Grewal, J., Chopda, M., Fulwani, M. C., Patange, A., Chopra, V. K., Goyal, N. K., Shinde, R., Manakshe, G. V., Patki, N., Sethi, S., Munusamy, V., Karna, S., Adhyapak, S., Pandurangi, U., Mathur, R., Kalashetti, S., Bhagwat, A., Raghuraman, B., Yerra, S., Bhansali, P., Borse, R., Das, S., Abdullakutty, J., Saathe, S., Palimkar, P., Abdullkutty, J., Sathe, S., Palimkar, P., Atar, S., Shechter, M., Mosseri, M., Arbel, Y., Lotan, C., Rosenschein, U., Katz, A., Henkin, Y., Francis, A., Klutstein, M., Nikolsky, E., Turgeman, Y., Halabi, M., Kornowski, R., Jonas, M., Amir, O., Rozenman, Y., Fuchs, S., Hussein, O., Gavish, D., Vered, Z., Caraco, Y., Elias, M., Tov, N., Lishner, M., Elias, N., Piovaccari, G., De Pellegrin, A., Guardigli, G., Licciardello, G., Auguadro, C., Cuccia, C., Salvioni, A., Musumeci, G., Calabro, P., Novo, S., Faggiano, P., De Cesare, N. B., Berti, S., Cavallini, C., Puccioni, E., Galvani, M., Tespili, M., Piatti, P., Palvarini, M., De Luca, G., Violini, R., De Leo, A., Filardi, P., Ferratini, M., Ricca, V., Dai, K., Kamiya, H., Ando, K., Takeda, Y., Morino, Y., Hata, Y., Kimura, K., Kishi, K., Michishita, I., Uehara, H., Higashikata, T., Hirayama, A., Hirooka, K., Sakagami, S., Taguchi, S., Koike, A., Fujinaga, H., Koba, S., Kozuma, K., Kawasaki, T., Ono, Y., Shimizu, M., Katsuda, Y., Wada, A., Shinke, T., Kimura, T., Ako, J., Fujii, K., Takahashi, T., Sakamoto, T., Furukawa, Y., Sugino, H., Mano, T., Utsu, N., Ito, K., Haraguchi, T., Ueda, Y., Nishibe, A., Fujimoto, K., Masutani, M., Fujimoto, K., Yoon, J., Kim, S., Park, H., Chae, I., Kim, M., Jeong, M., Rha, S., Kim, C., Kim, H., Hong, T., Tahk, S., Kim, Y., Busmane, A., Pontaga, N., Strelnieks, A., Mintale, I., Sime, I., Petrulioniene, Z., Kavaliauskiene, R., Jurgaitiene, R., Sakalyte, G., Slapikas, R., Norkiene, S., Misonis, N., Kibarskis, A., Kubilius, R., Bojovski, S., Kedev, S., Lozance, N., Kjovkaroski, A., Doncovska, S., Ong, T., Kasim, S., Maskon, O., Kandasamy, B., Yusoff, K., Liew, H. B., Mohamed, W., ODYSSEY OUTCOMES Comm Investigator 2019; 73 (4): 387–96
  • Canagliflozin and Stroke in Type 2 Diabetes Mellitus Results From the Randomized CANVAS Program Trials STROKE Zhou, Z., Lindley, R. I., Radholm, K., Jenkins, B., Watson, J., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Shaw, W., Oh, R., Desai, M., Matthews, D. R., Neal, B. 2019; 50 (2): 396–404
  • Factors Associated With Patient-Reported Shared Decision-Making for Stroke Prevention in Atrial Fibrillation O'Brien, E. C., Pieper, K., Thiem, R., Fonarow, G. C., Kowey, P. R., Chan, P. S., Freeman, J., Naccarelli, G., Mahaffey, K. W., Ezekowitz, M. D., Go, A. S., Gersh, B. J., Singer, D. E., Reiffel, J. A., Piccini, J. P. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial AMERICAN HEART JOURNAL Held, C., White, H. D., Stewart, R. H., Davies, R., Sampson, S., Chiswell, K., Silverstein, A., Lopes, R. D., Heldestad, U., Budaj, A., Mahaffey, K. W., Wallentin, L., STABILITY Investigators 2019; 208: 65–73
  • Canagliflozin review - safety and efficacy profile in patients with T2DM. Diabetes, metabolic syndrome and obesity : targets and therapy Jakher, H., Chang, T. I., Tan, M., Mahaffey, K. W. 2019; 12: 209-215

    Abstract

    Canagliflozin is a sodium glucose-cotransporter (SGLT) receptor inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM). This article reviews the mechanism of action of SGLT-2 receptor inhibitors and the efficacy of canagliflozin as an antidiabetic agent, its cardiovascular and renal benefits, and safety profile. During the development of canagliflozin, Phase II trials showed an improvement in cardiac and renal biomarkers such as blood pressure, body weight, and albuminuria. The large CANVAS program showed that canagliflozin reduced the composite cardiovascular outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The CANVAS program also showed a possible benefit of canagliflozin on a renal composite of sustained 40% reduction in estimated glomerular filtration rate, the need for renal replacement therapy, or death from renal causes. The safety profile of canagliflozin has been well characterized, and known side effects such as mycotic genital infections were confirmed in CANVAS. However, an increased risk of amputations was observed in CANVAS that requires further study. Overall, canagliflozin is an effective antidiabetic medication with cardiovascular and likely renal benefits, and with a generally well-tolerated safety profile. Results from the CREDENCE trial will further evaluate the safety and potential renal benefits of canagliflozin in patients with established diabetic nephropathy.

    View details for DOI 10.2147/DMSO.S184437

    View details for PubMedID 30787627

    View details for PubMedCentralID PMC6363491

  • Association of frailty and cognitive impairment with benefits of oral anticoagulation in patients with atrial fibrillation. American heart journal Madhavan, M., Holmes, D. N., Piccini, J. P., Ansell, J. E., Fonarow, G. C., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Peterson, E. D., Chan, P., Allen, L. A., Gersh, B. J., ORBIT AF Investigators 2019; 211: 77–89

    Abstract

    BACKGROUND: The incidence of cognitive impairment and frailty increase with age and may impact both therapy and outcomes in atrial fibrillation (AF).METHODS: We examined the prevalence of clinically recognized cognitive impairment and frailty (as defined by the American Geriatric Society Criteria) in the Outcomes Registry for Better Informed Care in AF (ORBIT AF) and associated adjusted outcomes via multivariable Cox regression. The interaction between cognitive impairment and frailty and oral anticoagulation (OAC) in determining outcomes was examined.RESULTS: Among 9749 patients with AF [median (IQR) age 75 (67-82) y, 57% male], cognitive impairment and frailty was identified in 293 (3.0%) and 575 (5.9%) patients respectively. Frail patients (68 vs 77%, P < .001) and those with cognitive impairment (70 vs 77%, P = .006) were both less likely to receive an OAC. Both cognitive impairment [HR (95% CI) 1.34 (1.05-1.72), P = .0198] and frailty [HR 1.29 (1.08-1.55), P = .0060] were associated with increased risk of death. Cognitive impairment and frailty were not associated with stroke/transient ischemic attack (TIA) or major bleeding. In multivariable analysis, there was no interaction between OAC use and cognitive impairment or frailty in their associations with mortality, major bleeding and a composite end point of stroke, non-central nervous system systemic embolism, TIA, myocardial infarction or cardiovascular death.CONCLUSION: Those with cognitive impairment or frailty in AF had higher predicted risk for stroke and higher observed mortality, yet were less likely to be treated with OAC. Despite this, the benefits of OAC were similar in patients with and without cognitive impairment or frailty.

    View details for PubMedID 30901602

  • Cohort profile: patient characteristics and quality-of-life measurements for newly-referred patients with atrial fibrillation-Keio interhospital Cardiovascular Studies-atrial fibrillation (KiCS-AF). BMJ open Ikemura, N. n., Spertus, J. A., Kimura, T. n., Mahaffey, K. n., Piccini, J. P., Inohara, T. n., Ueda, I. n., Tanimoto, K. n., Suzuki, M. n., Nakamura, I. n., Akaishi, M. n., Mitamura, H. n., Fukuda, K. n., Takatsuki, S. n., Kohsaka, S. n. 2019; 9 (12): e032746

    Abstract

    Besides the high rates of morbidity and mortality, atrial fibrillation (AF) is also associated with impairment of quality-of-life (QOL). However, reports covering non-selected AF population within Asian countries remain scarce. The objective of the Keio interhospital Cardiovascular Studies-atrial fibrillation (KiCS-AF) registry is to clarify the baseline and QOL profiles of the AF patients at the time of initial referral to identify areas for improvement and country-specific gaps.The KiCS-AF registry is a multicentre, prospective cohort study designed to specifically recruit AF patients newly referred to the 11 network hospitals within the Kanto area of Japan. The registry completed its enrolment in June 2018. All patients were requested to answer the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire both at baseline and 1 year, with planned clinical follow-up for 5 years. The registry also assessed individual treatment strategies including rate and rhythm control, stroke prophylaxis, and their impacts on patient-reported QOL.As of December 2016, 2464 AF patients were registered; their mean age was 67.1 years (SD, 11.7), majority (69.7%; n=1717) were men and 49.2% presented with paroxysmal AF. The mean CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age ≥75 years, diabetes, stroke including vascular disease, age 65-74 years, and sex category [female]) score was 2.3 (SD, 1.6) and oral anticoagulant therapy was used for 88.6% of patients with CHA2DS2-VASc scores ≥2. The median AFEQT-overall summary score was 79.1 (IQR, 66.6-89.1). Roughly 50% had significantly impaired QOL (ie, AFEQT <80) at baseline. Currently, 2307 eligible patients (93.6%) have completed the 1-year follow-up, of which 2072 patients (89.8%) answered the second AFEQT questionnaire.The KiCS-AF allowed for extensive investigation of AF-related QOL in a non-selected population with long-term follow-up using a rigorously validated QOL assessment tool. Almost half of patients had impaired QOL at baseline. Further investigations aimed at providing care and improving patient-reported QOL are required.

    View details for DOI 10.1136/bmjopen-2019-032746

    View details for PubMedID 31857312

  • Site Variation and Outcomes for Antithrombotic Therapy in Atrial Fibrillation Patients After Percutaneous Coronary Intervention. Circulation. Cardiovascular interventions Olivier, C. B., Fan, J. n., Askari, M. n., Mahaffey, K. W., Heidenreich, P. A., Perino, A. C., Leef, G. C., Ho, P. M., Harrington, R. A., Turakhia, M. P. 2019; 12 (8): e007604

    Abstract

    Patients with atrial fibrillation (AF) treated with percutaneous coronary intervention (PCI) require multiple antithrombotic therapies. The optimal strategy is debated suggesting increased treatment variation. This study sought to characterize site-level variation in antithrombotic therapies in AF patients after PCI and determine the association with outcomes.Using the retrospective TREAT-AF study (The Retrospective Evaluation and Assessment of Therapies in AF) from the Veterans Health Administration, patients with newly diagnosed, nonvalvular AF between 2004 and 2015 followed by a PCI with a P2Y12-antagonist prescription were identified. Patients were grouped according to the therapy dispensed 7 days before until 30 days after the PCI: oral anticoagulation plus platelet inhibition (OAC+PI) or platelet inhibition only. A combined outcome of death, myocardial infarction, stroke, or major bleeding was assessed 1 year after PCI and Cox regression was performed to estimate hazard ratios.Of 230 762 patients with newly diagnosed AF, 4042 (1.8%) underwent PCI and received a P2Y12-antagonist during the observation period (age, 67±9 years; CHA2DS2-VASc, 2.7±1.7; HAS-BLED, 2.6±1.2). Among these, 47% were prescribed OAC+PI, and 53% platelet inhibition only 7 days before until 30 days after the PCI. Across 63 sites, the use of OAC+PI ranged from 19% to 66%. Prescription of OAC+PI was independently associated with a reduction in the combined outcome of death, myocardial infarction, stroke, or major bleeding compared with platelet inhibition only (adjusted hazard ratio, 0.85; 95% CI, 0.73-0.99; P=0.033).In patients with established AF undergoing PCI, the use of OAC+PI varied substantially across sites in the 30 days post-PCI. Anticoagulation appeared to be underutilized but was associated with improved outcomes. Strategies to promote OAC+PI and minimize site variation may be useful, particularly in light of recent randomized trials.

    View details for DOI 10.1161/CIRCINTERVENTIONS.118.007604

    View details for PubMedID 31416357

  • Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study AMERICAN HEART JOURNAL Turakhia, M. P., Desai, M., Hedlin, H., Rajmane, A., Talati, N., Ferris, T., Desai, S., Nag, D., Patel, M., Kowey, P., Rumsfeld, J. S., Russo, A. M., Hills, M., Granger, C. B., Mahaffey, K. W., Perez, M. V. 2019; 207: 66–75
  • Comparison of Patient-Reported Care Satisfaction, Quality of Warfarin Therapy, and Outcomes of Atrial Fibrillation: Findings From the ORBIT - AF Registry. Journal of the American Heart Association Perino, A. C., Shrader, P. n., Turakhia, M. P., Ansell, J. E., Gersh, B. J., Fonarow, G. C., Go, A. S., Kaiser, D. W., Hylek, E. M., Kowey, P. R., Singer, D. E., Thomas, L. n., Steinberg, B. A., Peterson, E. D., Piccini, J. P., Mahaffey, K. W. 2019; 8 (9): e011205

    Abstract

    Background Patient satisfaction with therapy is an important metric of care quality and has been associated with greater medication persistence. We evaluated the association of patient satisfaction with warfarin therapy to other metrics of anticoagulation care quality and clinical outcomes among patients with atrial fibrillation ( AF ). Methods and Results Using data from the ORBIT - AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, patients were identified with AF who were taking warfarin and had completed an Anti-Clot Treatment Scale ( ACTS ) questionnaire, a validated metric of patient-reported burden and benefit of oral anticoagulation. Multivariate regressions were used to determine association of ACTS burden and benefit scores with time in therapeutic international normalized ratio range ( TTR ; both ≥75% and ≥60%), warfarin discontinuation, and clinical outcomes (death, stroke, major bleed, and all-cause hospitalization). Among 1514 patients with AF on warfarin therapy (75±10 years; 42% women; CHA 2 DS 2- VAS c 3.9±1.7), those most burdened with warfarin therapy were younger and more likely to be women, have paroxysmal AF , and to be treated with antiarrhythmic drugs. After adjustment for covariates, ACTS burden scores were independent of TTR ( TTR ≥75%: odds ratio, 1.01 [95% CI , 0.99-1.03]; TTR ≥60%: odds ratio, 1.01 [95% CI , 0.98-1.05]), warfarin discontinuation (odds ratio, 0.99; 95% CI , 0.97-1.01), or clinical outcomes. ACTS benefit scores were also not associated with TTR , warfarin discontinuation, or clinical outcomes. Conclusions In a large registry of patients with AF taking warfarin, ACTS scores provided independent information beyond other traditional metrics of oral anticoagulation care quality and identified patient groups at high risk for dissatisfaction with warfarin therapy.

    View details for PubMedID 31023126

  • Canagliflozin and Renal Outcomes in Diabetic Nephropathy. Reply. The New England journal of medicine Jardine, M. J., Mahaffey, K. W., Perkovic, V. 2019; 381 (11): 1089–90

    View details for DOI 10.1056/NEJMc1909687

    View details for PubMedID 31509685

  • Incidence, Characteristics, and Outcomes of Myocardial Infarction in Patients With Peripheral Artery Disease Insights From the EUCLID Trial JAMA CARDIOLOGY Olivier, C. B., Mulder, H., Hiatt, W. R., Jones, W., Fowkes, F. R., Rockhold, F. W., Berger, J. S., Baumgartner, I., Held, P., Katona, B. G., Norgren, L., Blomster, J., Patel, M. R., Mahaffey, K. W. 2019; 4 (1): 7–15
  • Eligibility of sodium-glucose co-transporter-2 inhibitors among patients with diabetes mellitus admitted for heart failure. ESC heart failure Sharma, A. n., Wu, J. n., Ezekowitz, J. A., Felker, G. M., Udell, J. A., Heidenreich, P. A., Fonarow, G. C., Mahaffey, K. W., Hernandez, A. F., DeVore, A. D. 2019

    Abstract

    Sodium-glucose co-transporter (SGLT)-2 inhibitors have been shown to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with type 2 diabetes mellitus (DM) and high cardiovascular risk in two large clinical outcome trials: empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS. The scope of eligibility for SGLT-2 inhibitors (empagliflozin and canagliflozin) among patients with type 2 DM and HF, based on clinical trial criteria and current US Food and Drug Administration (FDA) labelling criteria, remains unknown.Using data from the US Get With The Guidelines (GWTG)-Heart Failure registry, we evaluated the proportion of patients with DM and HF eligible for SGLT-2 inhibitor therapy based on the clinical trial criteria and the US FDA labelling criteria. The GWTG-HF registry is a quality improvement registry of patients admitted in hospital with HF in the USA. We included GWTG-HF registry participants meeting eligibility criteria hospitalized between August 2014 and 30 June 2017 from sites fully participating in the registry. The initial inclusion time point reflects when both drugs had FDA approval. Among the 139 317 patients (out of 407 317) with DM hospitalized with HF (in 460 hospitals; 2014 to 2017), the median age was 71 years, 47% (n = 65 685) were female, and 43% (n = 59 973) had HF with reduced ejection fraction. Overall, 43% (n = 59 943) were eligible for the EMPA-REG OUTCOME trial, 45% (n = 62 818) were eligible for the CANVAS trial, and 34% (n = 47 747) of patients were eligible for either SGLT-2 inhibitors based on the FDA labelling criteria. Among the FDA-eligible patients, 91.5% (n = 43 708) were eligible for either the EMPA-REG OUTCOME trial or the CANVAS trial. Patients who were FDA eligible, compared with those who were not, were younger (70.0 vs. 72.0 years of age), more likely to be male (57.7 vs. 50.3%), and had less burden of co-morbidities.The majority of patients with DM who are hospitalized with HF are not eligible for SGLT-2 inhibitor therapies. Ongoing studies evaluating the safety and efficacy of SGLT-2 inhibitors among patients with HF may potentially broaden the population that may benefit from these therapies.

    View details for DOI 10.1002/ehf2.12528

    View details for PubMedID 31747132

  • Clinical outcomes with canagliflozin according to baseline body mass index: results from post hoc analyses of the CANVAS Program. Diabetes, obesity & metabolism Ohkuma, T. n., Van Gaal, L. n., Shaw, W. n., Mahaffey, K. W., de Zeeuw, D. n., Matthews, D. R., Perkovic, V. n., Neal, B. n. 2019

    Abstract

    Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce several cardiovascular risk factors including plasma glucose, blood pressure, albuminuria and body weight. Long-term treatment lowers risks of cardiovascular and renal events. The objective of this post hoc analysis was to determine the effects of canagliflozin treatment versus placebo on clinical outcomes in relation to body mass index (BMI).The CANVAS Program randomized 10,142 participants with type 2 diabetes to canagliflozin or placebo. These analyses tested the consistency of canagliflozin treatment effects across BMI levels for cardiovascular, renal, safety, and body weight outcomes in 3 groups defined by baseline BMI: <25, 25-<30, and ≥30 kg/m2 .A total of 10,128 participants with baseline BMI measurements were included. There were 966 participants with BMI <25 kg/m2 , 3153 with BMI 25-<30 kg/m2 , and 6009 with BMI ≥30 kg/m2 . Mean body weight reduction with canagliflozin compared to placebo was greater at 12 months (-2.47 kg [95% CI: -2.64, -2.30]) than at 3 months (-1.53 kg [95% CI: -1.63, -1.44]). The HRs (95% CI) for canagliflozin compared with placebo control for the composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke were HR 1.03 (95% CI: 0.66, 1.59) in participants with BMI <25 kg/m2 , 0.97 (0.76, 1.23) with BMI 25-<30 kg/m2 , and 0.79 (0.67, 0.93) with BMI ≥30 kg/m2 (P for heterogeneity = 0.55). The effects of canagliflozin on each component of the composite were also similar across BMI subgroups, as were effects on heart failure, renal, and safety outcomes (all P for heterogeneity ≥0.15).Canagliflozin improved cardiovascular and renal outcomes consistently across patients with a broad range of BMI levels. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1111/dom.13920

    View details for PubMedID 31729107

  • Claims-based cardiovascular outcome identification for clinical research: Results from 7 large randomized cardiovascular clinical trials. American heart journal Brennan, J. M., Wruck, L. n., Pencina, M. J., Clare, R. M., Lopes, R. D., Alexander, J. H., O'Brien, S. n., Krucoff, M. n., Rao, S. V., Wang, T. Y., Curtis, L. H., Newby, L. K., Granger, C. B., Patel, M. n., Mahaffey, K. n., Ross, J. S., Normand, S. L., Eloff, B. C., Caños, D. A., Lokhnygina, Y. V., Roe, M. T., Califf, R. M., Marinac-Dabic, D. n., Peterson, E. D. 2019; 218: 110–22

    Abstract

    Medicare insurance claims may provide an efficient means to ascertain follow-up of older participants in clinical research. We sought to determine the accuracy and completeness of claims- versus site-based follow-up with clinical event committee (+CEC) adjudication of cardiovascular outcomes.We performed a retrospective study using linked Medicare and Duke Database of Clinical Trials data. Medicare claims were linked to clinical data from 7 randomized cardiovascular clinical trials. Of 52,476 trial participants, linking resulted in 5,839 (of 10,497 linkage-eligible) Medicare-linked trial participants with fee-for-service A and B coverage. Death, myocardial infarction (MI), stroke, and revascularization incidences were compared using Medicare inpatient claims only, site-reported events (+CEC) only, or a combination of the 2. Randomized treatment effects were compared as a function of whether claims-based, site-based (+CEC), or a combined system was used for event detection.Among the 5,839 study participants, the annual event rates were similar between claims- and site-based (+CEC) follow-up: death (overall rate 5.2% vs 5.2%; adjusted κ 0.99), MI (2.2% vs 2.3%; adjusted κ 0.96), stroke (0.7% vs 0.7%; adjusted κ 0.99), and any revascularization (7.4% vs 7.9%; adjusted κ 0.95). Of events detected by claims yet not reported by CEC, a minority were reported by sites but negatively adjudicated by CEC (39% of MIs and 18% of strokes). Differences in individual case concordance led to higher event rates when claims- and site-based (+CEC) systems were combined. Randomized treatment effects were similar among the 3 approaches for each outcome of interest.Claims- versus site-based (+CEC) follow-up identified similar overall cardiovascular event rates despite meaningful differences in the events detected. Randomized treatment effects were similar using the 2 methods, suggesting claims data could be used to support clinical research leveraging routinely collected data. This approach may lead to more effective evidence generation, synthesis, and appraisal of medical products and inform the strategic approaches toward the National Evaluation System for Health Technology.

    View details for DOI 10.1016/j.ahj.2019.09.002

    View details for PubMedID 31726314

  • Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation. The New England journal of medicine Perez, M. V., Mahaffey, K. W., Hedlin, H., Rumsfeld, J. S., Garcia, A., Ferris, T., Balasubramanian, V., Russo, A. M., Rajmane, A., Cheung, L., Hung, G., Lee, J., Kowey, P., Talati, N., Nag, D., Gummidipundi, S. E., Beatty, A., Hills, M. T., Desai, S., Granger, C. B., Desai, M., Turakhia, M. P., Apple Heart Study Investigators, Perez, M. V., Turakhia, M. P., Lhamo, K., Smith, S., Berdichesky, M., Sharma, B., Mahaffey, K., Parizo, J., Olivier, C., Nguyen, M., Tallapalli, S., Kaur, R., Gardner, R., Hung, G., Mitchell, D., Olson, G., Datta, S., Gerenrot, D., Wang, X., McCoy, P., Satpathy, B., Jacobsen, H., Makovey, D., Martin, A., Perino, A., O'Brien, C., Gupta, A., Toruno, C., Waydo, S., Brouse, C., Dorfman, D., Stein, J., Huang, J., Patel, M., Fleischer, S., Doll, E., O'Reilly, M., Dedoshka, K., Chou, M., Daniel, H., Crowley, M., Martin, C., Kirby, T., Brumand, M., McCrystale, K., Haggerty, M., Newberger, J., Keen, D., Antall, P., Holbrook, K., Braly, A., Noone, G., Leathers, B., Montrose, A., Kosowsky, J., Lewis, D., Finkelmeier, J. R., Bemis, K., Mahaffey, K. W., Desai, M., Talati, N., Nag, D., Rajmane, A., Desai, S., Caldbeck, D., Cheung, L., Granger, C., Rumsfeld, J., Kowey, P. R., Hills, M. T., Russo, A., Rockhold, F., Albert, C., Alonso, A., Wruck, L., Friday, K., Wheeler, M., Brodt, C., Park, S., Rogers, A., Jones, R., Ouyang, D., Chang, L., Yen, A., Dong, J., Mamic, P., Cheng, P., Shah, R., Lorvidhaya, P. 2019; 381 (20): 1909–17

    Abstract

    BACKGROUND: Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown.METHODS: Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10.RESULTS: We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events.CONCLUSIONS: The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.).

    View details for DOI 10.1056/NEJMoa1901183

    View details for PubMedID 31722151

  • Canagliflozin review - safety and efficacy profile in patients with T2DM DIABETES METABOLIC SYNDROME AND OBESITY-TARGETS AND THERAPY Jakher, H., Chang, T. I., Tan, M., Mahaffey, K. W. 2019; 12: 209–15
  • Impact of Procedural Bleeding in Peripheral Artery Disease: An Analysis From EUCLID Trial. Circulation. Cardiovascular interventions Kansal, A. n., Huang, Z. n., Rockhold, F. W., Baumgartner, I. n., Berger, J. S., Blomster, J. I., Fowkes, F. G., Katona, B. n., Mahaffey, K. W., Norgren, L. n., Hiatt, W. R., Patel, M. R., Jones, W. S. 2019; 12 (10): e008069

    Abstract

    The relationship between invasive vascular procedures and bleeding in patients with peripheral artery disease has not been well described in the literature. This post hoc analysis from the EUCLID trial (Examining Use of Ticagrelor in Peripheral Artery Disease) aimed to describe the incidence of major and minor postprocedural bleeding and characterize the timing and severity of bleeding events relative to the procedure.EUCLID was a multicenter, randomized controlled trial of 13 885 patients with symptomatic peripheral artery disease that tested the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events. A total of 2661 patients underwent 3062 coronary revascularization, peripheral revascularization, and amputation during the study. The primary safety end point was Thrombolysis in Myocardial Infarction major or minor bleeding. All bleeding events were formally adjudicated by a clinical end point classification group.Major bleeding events most often occurred ≤7 days following the procedure. The incidence of Thrombolysis in Myocardial Infarction major or minor bleeding ≤7 days following peripheral revascularization (3.3%; 95% CI, 2.5%-4.1%) was similar to rates after coronary revascularization (4.0%; 95% CI, 2.6%-5.4%) and lower extremity amputation (2.3%; 95% CI, 0.8%-3.8%). The severity of bleeding events (as graded by drop in hemoglobin, need for transfusion, bleeding in a critical location, and fatal bleeding) was also similar following peripheral, coronary revascularization, and lower extremity amputation.The incidence of Thrombolysis in Myocardial Infarction major/minor bleeding following peripheral revascularization is comparable to rates after coronary revascularization and lower extremity amputation, and the majority of bleeding events occur within 7 days following the procedure. The severity of periprocedural bleeding is also similar after procedures, with the most frequently adjudicated reason being a drop in hemoglobin ≥2 g/dL. Future studies should be performed to enhance our understanding of bleeding risk related to revascularization and amputation procedures in peripheral artery disease patients.

    View details for DOI 10.1161/CIRCINTERVENTIONS.119.008069

    View details for PubMedID 31581789

  • Effect of Alirocumab on Mortality After Acute Coronary Syndromes: An Analysis of the ODYSSEY OUTCOMES Randomized Clinical Trial. Circulation Steg, P. G., Szarek, M. n., Bhatt, D. L., Bittner, V. A., Brégeault, M. F., Dalby, A. J., Diaz, R. n., Edelberg, J. M., Goodman, S. G., Hanotin, C. n., Harrington, R. A., Jukema, J. W., Lecorps, G. n., Mahaffey, K. W., Moryusef, A. n., Ostadal, P. n., Parkhomenko, A. n., Pordy, R. n., Roe, M. T., Tricoci, P. n., Vogel, R. n., White, H. D., Zeiher, A. M., Schwartz, G. G. 2019

    Abstract

    Trials of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome (ACS).ODYSSEY OUTCOMES was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1-12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death.Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years' follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths ( P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events ( P<0.001) and thereby may have attenuated the number of noncardiovascular deaths. A post-hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend).Alirocumab added to intensive statin therapy has the potential to reduce death after ACS, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low.URL: https://www.clinicaltrials.gov. Unique Identifier: NCT01663402.

    View details for DOI 10.1161/CIRCULATIONAHA.118.038840

    View details for PubMedID 31117810

  • Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial. European heart journal White, H. D., Steg, P. G., Szarek, M. n., Bhatt, D. L., Bittner, V. A., Diaz, R. n., Edelberg, J. M., Erglis, A. n., Goodman, S. G., Hanotin, C. n., Harrington, R. A., Jukema, J. W., Lopes, R. D., Mahaffey, K. W., Moryusef, A. n., Pordy, R. n., Roe, M. T., Sritara, P. n., Tricoci, P. n., Zeiher, A. M., Schwartz, G. G. 2019

    Abstract

    The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin-kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI.Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77-0.99; P = 0.032) and Type 2 (0.77, 0.61-0.97; P = 0.025), but not Type 4 MI.After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.

    View details for DOI 10.1093/eurheartj/ehz299

    View details for PubMedID 31121022

  • Incremental prognostic value of renal function for stroke prediction in atrial fibrillation INTERNATIONAL JOURNAL OF CARDIOLOGY O'Brien, E. C., Holmes, D. N., Thomas, L., Singer, D. E., Fonarow, G. C., Mahaffey, K. W., Kowey, P. R., Hylek, E. M., Pokorney, S. D., Ansell, J. E., Pencina, M. J., Peterson, E. D., Piccini, J. P., ORBIT-AF Patients & Investigators 2019; 274: 152–57

    Abstract

    Renal function has been associated with an increased stroke risk in patients with atrial fibrillation (AF). However, whether renal function incrementally adds to risk prediction in both anticoagulated and non-anticoagulated patients with AF is unclear.We used data from the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF)-a national, prospective, outpatient AF registry in patients aged >18 years (2010-2011). The association between baseline renal function and risk of stroke/systemic embolism (SSE) was evaluated in proportional hazards models adjusting for stroke risk score components. We compared discrimination of 2-year outcomes using C-indices and evaluated calibration by comparing event rates in ORBIT-AF to published rates from an external clinical trial population (ROCKET AF) and an observational cohort (ATRIA).Among 9743 patients included in the analysis, the median age was 75 years (interquartile range [IQR] 67-82), 89.5% were white, 43% were female, and 76% were taking oral anticoagulation (OAC). Over a median follow-up of 2.3 years, 214 SSE events occurred (1.00 per 100 patient-years). Continuous creatinine clearance (CrCl) was not associated with SSE risk after adjusting for other clinical factors (components of CHADS2 or CHA2DS2-VASc). Discrimination for predicting stroke (C-index; 95% CI) was similar for R2CHADS2 (0.65; 0.61-0.69), CHADS2 (0.65; 0.61-0.69), and CHA2DS2-VASc (0.66; 0.62-0.70).In a community patient population with AF, renal dysfunction was not independently associated with embolic risk beyond other established risk factors in either OAC-treated or untreated patients. Additional study is needed to identify clinical factors that incrementally add to stroke risk prediction.

    View details for PubMedID 30144994

  • Major bleeding in patients with peripheral artery disease: Insights from the EUCLID trial. American heart journal Ward, R. n., Huang, Z. n., Rockhold, F. W., Baumgartner, I. n., Berger, J. S., Blomster, J. I., Fowkes, F. G., Katona, B. G., Mahaffey, K. W., Norgren, L. n., Vemulapalli, S. n., Povsic, T. J., Mehta, R. n., Hiatt, W. R., Patel, M. R., Jones, W. S. 2019; 220: 51–58

    Abstract

    Rates and predictors of major bleeding in patients with peripheral artery disease (PAD) treated with antiplatelets have not been well studied. This post hoc analysis of EUCLID aimed to determine the incidence of major/minor bleeding, predictors of major bleeding, and risk of major adverse cardiovascular events (MACE) following major bleeding events.EUCLID, a multicenter randomized controlled trial of 13,885 patients with symptomatic PAD, compared ticagrelor with clopidogrel for the prevention of MACE. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. Baseline characteristics were used to develop a multivariable model to determine factors associated with TIMI major bleeding. The occurrence and timing of MACE relative to a first major bleeding event were determined.TIMI major bleeding occurred in 2.3% of participants overall (0.94 event/100 patient-years). There was no significant difference in major bleeding rates by treatment assignment. Factors associated with TIMI major bleeding included older age, geographic region, Rutherford class, and β-blocker use. Patients with TIMI major bleeding postrandomization had an increased risk of MACE (hazard ratio [HR] 4.46; 95% CI 3.40-5.84; P < .0001) compared with those without major bleeding; the association was strongest within 30 days after a bleeding event.In patients with symptomatic PAD, 0.94 major bleeding event/100 patient-years was observed and associated with older age, residing in North America, disease severity, and β-blocker use. Patients who had a major bleeding event were significantly more likely to experience MACE, especially within the first 30 days, when compared with patients who did not have major bleeding.

    View details for DOI 10.1016/j.ahj.2019.11.007

    View details for PubMedID 31783279

  • A Cluster Analysis of the Japanese Multicenter Outpatient Registry of Patients With Atrial Fibrillation. The American journal of cardiology Inohara, T. n., Piccini, J. P., Mahaffey, K. W., Kimura, T. n., Katsumata, Y. n., Tanimoto, K. n., Inagawa, K. n., Ikemura, N. n., Ueda, I. n., Fukuda, K. n., Takatsuki, S. n., Kohsaka, S. n. 2019

    Abstract

    Recently, cluster analysis was used to identify unique clinically relevant phenotypes of atrial fibrillation (AF) in a cohort from the United States (US) and classified clusters according to the presence of comorbid behavioral disorders, those with conduction disorders, or atherosclerotic comorbidities. Whether these phenotypes are consistent in AF cohorts outside the US remains unknown. Thus, we sought to conduct a cluster analysis in a cohort of Japanese AF patients. We conducted a cluster analysis of phenotypic data (46 variables) in an AF patient cohort recruited from 11 Japanese sites participating in the KiCS-AF Registry. Overall, 2,458 AF patients (median [IQR] age, 68.0 [60.0 to 76.0]; 30.3% female; median [IQR] CHA2DS2-Vasc, 2 [1, 3]) were analyzed. Similar to the US cohort, atherosclerotic comorbidities were identified as distinguishing factors to characterize clusters. Distribution of AF type and left atrial (LA) size substantially varied and was the key feature for cluster formation. CHA2DS2-Vasc score also contributed to cluster formation, although behavioral disorders and/or conduction disorders did not readily characterize clusters. Subsequently, the cohort was classified into 3 clusters: (1) Younger paroxysmal AF (n = 1,190); (2) Persistent/permanent AF with LA enlargement (n = 1,143); and (3) Atherosclerotic comorbid AF in elderly patients (N = 125). In conclusion, conventional classifications, such as atherosclerotic risk factors and CHA2DS2-Vasc score contributed to cluster formation in mutually, whereas in nonatherosclerotic clusters, AF type or LA size rather than the presence or absence of behavior risk factors or sinus node dysfunction (tachy-brady syndrome) seemed to contribute to cluster formation in the Japanese cohort.

    View details for DOI 10.1016/j.amjcard.2019.05.071

    View details for PubMedID 31350002

  • Chronic kidney disease and risk for cardiovascular and limb outcomes in patients with symptomatic peripheral artery disease: The EUCLID trial. Vascular medicine (London, England) Hopley, C. W., Kavanagh, S. n., Patel, M. R., Ostrom, C. n., Baumgartner, I. n., Berger, J. S., Blomster, J. I., Fowkes, F. G., Jones, W. S., Katona, B. G., Mahaffey, K. W., Norgren, L. n., Rockhold, F. W., Hiatt, W. R. 2019: 1358863X19864172

    Abstract

    In patients with symptomatic peripheral artery disease (PAD), the impact of chronic kidney disease (CKD) on major adverse cardiovascular events has not been fully evaluated. The Examining Use of Ticagrelor In PAD (EUCLID) trial randomized 13,885 patients with PAD to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. This post hoc analysis compared the incidence of the primary composite endpoint (cardiovascular death, myocardial infarction (MI), or ischemic stroke) in patients with CKD (eGFR < 60 mL/min/1.73 m2) with those without CKD (eGFR ⩾ 60 mL/min/1.73 m2). The primary safety endpoint was thrombolysis in MI (TIMI) major bleeding. A total of 13,483 patients were included; 3332 (25%) had CKD, of whom 237 had stage 4/5 disease. Median follow-up was approximately 30 months. After statistical adjustment, patients with CKD had a higher rate of the primary endpoint compared with those without CKD (6.75 vs 3.72 events/100 patient-years; adjusted hazard ratio (HR) 1.45, 95% CI 1.30-1.63). CKD was not associated with increased risk of hospitalization for acute limb ischemia (ALI) (adjusted HR 0.96, 95% CI 0.69-1.34) or major amputation (adjusted HR 0.92, 95% CI 0.66-1.28). CKD was not associated with a significantly increased risk of major bleeding (adjusted HR 1.21, 95% CI 0.89-1.64), but minor bleeding was significantly increased (adjusted HR 1.51, 95% CI 1.07-2.15). In conclusion, patients with PAD and CKD had higher rates of cardiovascular death, MI, and ischemic stroke, but similar rates of ALI, major amputation, and TIMI major bleeding when compared with patients without CKD. ClinicalTrials.gov Identifier: NCT01732822.

    View details for DOI 10.1177/1358863X19864172

    View details for PubMedID 31339474

  • Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF. Cardiology and therapy Ungar, L. n., Rodriguez, F. n., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G. n., Fox, K. A., Hacke, W. n., Halperin, J. L., Hankey, G. J., Nessel, C. C., Singer, D. E., Patel, M. R., Piccini, J. P., Mahaffey, K. W. 2019

    Abstract

    Patient-reported outcomes (PROs) and satisfaction endpoints are increasingly important in clinical trials and may be associated with treatment adherence. In this post hoc substudy from ROCKET AF, we examined whether patient-reported satisfaction was associated with study drug discontinuation.ROCKET AF (n = 14,264) compared rivaroxaban with warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation. We analyzed treatment satisfaction scores: the Anti-Clot Treatment Scale (ACTS) and Treatment Satisfaction Questionnaire for Medication version II (TSQM II). We compared satisfaction with study drug between the two treatment arms, and examined the association between satisfaction and patient-driven study drug discontinuation (stopping study drug due to withdrawal of consent, noncompliance, or loss to follow-up).A total of 1577 (11%) patients participated in the Patient Satisfaction substudy; 1181 (8.3%) completed both the ACTS and TSQM II 4 weeks after starting study drug. Patients receiving rivaroxaban did not experience significant differences in satisfaction compared with those receiving warfarin. During a median follow-up of 1.6 years, 448 premature study drug discontinuations occurred (213 rivaroxaban group; 235 warfarin group), of which 116 (26%) were patient-driven (52 [24%] rivaroxaban group; 64 [27%] warfarin group). No significant differences were observed between satisfaction level and rates of patient-driven study drug discontinuation.Study drug satisfaction did not predict rate of study drug discontinuation. No significant difference was observed between satisfaction with warfarin and rivaroxaban, as expected given the double-blind trial design. Although these results are negative, the importance of PRO data will only increase, and these analyses may inform future studies that explore the relationship between drug-satisfaction PROs, adherence, and clinical outcomes. CLINICALTRIALS.GOV: NCT00403767.The ROCKET AF trial was funded by Johnson & Johnson and Bayer.

    View details for DOI 10.1007/s40119-019-00146-6

    View details for PubMedID 31376090

  • The efficacy and safety of cangrelor in single vessel vs multi vessel percutaneous coronary intervention: Insights from CHAMPION PHOENIX. Clinical cardiology Yong, C. M., Sundaram, V. n., Abnousi, F. n., Olivier, C. B., Yang, J. n., Stone, G. W., Steg, P. G., Michael Gibson, C. n., Hamm, C. W., Price, M. J., Deliargyris, E. N., Prats, J. n., White, H. D., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. 2019

    Abstract

    The intravenous, rapidly acting P2Y12 inhibitor cangrelor reduces the rate of ischemic events during PCI with no significant increase in severe bleeding. However, the efficacy and safety of cangrelor compared with clopidogrel in patients treated with single vessel (SV)-percutaneous coronary intervention (PCI) or multi vessel (MV)-PCI remains unexplored.We studied the modified intention-to-treat population of patients from the CHAMPION PHOENIX trial who were randomized to either cangrelor or clopidogrel. We used logistic regression and propensity score matching to evaluate the effect of cangrelor compared with clopidogrel on the primary efficacy outcome (composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) at 48 hours. The safety outcome was moderate or severe Global Utilization of Streptokinase and tPA for Occluded Arteries bleeding at 48 hours.Cangrelor isas efficacious and safe as clopidogrel in both SVand MV PCI.Among 10 854 patients, 9204 (85%) underwent SV- and 1650 (15%) MV-PCI. After adjustment, cangrelor was associated with similar reductions vs clopidogrel in the primary efficacy outcome in patients undergoing SV-PCI (4.5% vs 5.2%; odds ratio [OR] 0.81 [0.66-0.98]) or MV-PCI (6.1% vs 9.8%, OR 0.59 [0.41-0.85]; Pint 0.14). Similar results were observed after propensity score matching (SV-PCI: 5.5% vs 5.9%, OR 0.93 [0.74-1.18]; MV-PCI: 6.2% vs 8.9%, OR 0.67 [0.44-1.01]; Pint 0.17). There was no evidence of heterogeneity in the treatment effect of cangrelor compared with clopidogrel for the safety outcome.In patients undergoing SV- or MV-PCI, cangrelor was associated with similar relative risk reductions in ischemic complications and no increased risk of significant bleeding compared with clopidogrel, which highlights the expanding repertoire of options for use in complex PCI.

    View details for DOI 10.1002/clc.23221

    View details for PubMedID 31254472

  • Central Adjudication Identified Additional and Prognostically Important Myocardial Infarctions in Patients Undergoing Percutaneous Coronary Intervention. Circulation. Cardiovascular interventions Olivier, C. B., Bhatt, D. L., Leonardi, S. n., Stone, G. W., Gibson, C. M., Steg, P. G., Hamm, C. W., Wilson, M. D., Mangum, S. n., Price, M. J., Prats, J. n., White, H. D., Lopes, R. D., Harrington, R. A., Mahaffey, K. W. 2019; 12 (7): e007342

    Abstract

    In the CHAMPION PHOENIX trial, cangrelor reduced the primary composite end point of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis at 48 hours. This study aimed to explore the impact of event adjudication and the prognostic importance of MI reported by a clinical events committee (CEC) or site investigators (SIs).Data from the CHAMPION PHOENIX trial of patients undergoing elective or nonelective percutaneous coronary intervention were analyzed. A CEC systematically identified and adjudicated MI using predefined criteria, a computer algorithm to identify suspected events, and semilogarithmic plots to review biomarker changes. Thirty-day death was modeled using baseline characteristics. Of 10 942 patients, 462 (4.2%) patients had at least 1 MI by 48 hours identified by the CEC (207 [3.8%] cangrelor; 255 [4.7%] clopidogrel; odds ratio [OR] 0.80; 95% CI, 0.67-0.97; P=0.022), and 143 patients had at least 1 MI by 48 hours reported by the SI (60 [1.1%] cangrelor; 83 [1.5%] clopidogrel; OR, 0.72; 95% CI, 0.52-1.01; P=0.053). Of the 462 MIs identified by the CEC, 92 (20%) were reported by SI, and 370 (80%) were not. Of the 143 MI reported by the SI, 51 (36%) were not confirmed by CEC. All categories were associated with an increased adjusted risk for 30-day death (CEC: OR, 5.35; 95% CI, 2.56-11.2; P<0.001; SI: 9.08 [4.01-20.5]; P<0.001; CEC and SI: 10.9 [3.23-36.6]; P<0.001; CEC but not SI: 4.69 [1.94-11.3]; P<0.001; SI but not CEC: 15.4 [5.26-44.9]; P<0.001).In patients undergoing percutaneous coronary intervention, CEC procedures identified 3 times as many MIs as the SI reported. Compared with clopidogrel, cangrelor significantly reduced MIs identified by the CEC with a qualitatively similar relative risk reduction in MIs reported by the SI. MIs identified by CEC or reported by SI were independently associated with worse 30-day death. Central adjudication identified additional, prognostically important events.URL: https://www.clinicaltrials.gov . Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCINTERVENTIONS.118.007342

    View details for PubMedID 31296081

  • Canagliflozin and Stroke in Type 2 Diabetes Mellitus. Stroke Zhou, Z., Lindley, R. I., Radholm, K., Jenkins, B., Watson, J., Perkovic, V., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Shaw, W., Oh, R., Desai, M., Matthews, D. R., Neal, B. 2018: STROKEAHA118023009

    Abstract

    Background and Purpose- This study reports the detailed effects of canagliflozin on stroke, stroke subtypes, and vascular outcomes in participants with and without cerebrovascular disease (stroke or transient ischemic attack) at baseline from the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program. Methods- The CANVAS Program, comprising 2 similarly designed and conducted clinical trials, randomly assigned 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk to canagliflozin or placebo. Its primary outcome was a composite of major adverse cardiovascular events. The main outcome of interest for this report was fatal or nonfatal stroke. Additional exploratory outcomes were stroke subtypes and other vascular outcomes defined according to standard criteria. Results- There were 1 958 (19%) participants with prior stroke or transient ischemic attack at baseline. These individuals were older, more frequently women, and had higher rates of heart failure, atrial fibrillation, and microvascular disease (all P<0.001) compared with those without such a history. There were 309 participants with stroke events during follow-up (123 had prior stroke or transient ischemic attack at baseline and 186 did not), at a rate of 7.93/1000 patient-years among those assigned canagliflozin and 9.62/1000 patient-years among placebo (hazard ratio, 0.87; 95% CI, 0.69-1.09). Analysis of stroke subtypes found no effect on ischemic stroke (n=253, hazard ratio, 0.95; 95% CI, 0.74-1.22), a significant reduction for hemorrhagic stroke (n=30, hazard ratio, 0.43; 95% CI, 0.20-0.89) and no effect on undetermined stroke (n=29, hazard ratio, 1.04; 95% CI, 0.48-2.22). Effects on other cardiovascular outcomes were comparable among participants with and without stroke or transient ischemic attack at baseline. Conclusions- There were too few events in the CANVAS Program to separately define the effects of canagliflozin on stroke, but benefit is more likely than harm. The observed possible protective effect for hemorrhagic stroke was based on small numbers but warrants further investigation. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01032629 and NCT01989754.

    View details for PubMedID 30591006

  • Cardiovascular and Limb Outcomes in Patients With Diabetes and PeripheralArtery Disease: The EUCLID Trial. Journal of the American College of Cardiology Low Wang, C. C., Blomster, J. I., Heizer, G., Berger, J. S., Baumgartner, I., Fowkes, F. G., Held, P., Katona, B. G., Norgren, L., Jones, W. S., Lopes, R. D., Olin, J. W., Rockhold, F. W., Mahaffey, K. W., Patel, M. R., Hiatt, W. R., EUCLID Trial Executive Committee and Investigators 2018; 72 (25): 3274–84

    Abstract

    BACKGROUND: Diabetes confers an increased risk for atherosclerotic cardiovascular disease, but less is known about the independent risk diabetes confers on major cardiovascular and limb events in patients with symptomatic peripheral artery disease (PAD) on contemporary management.OBJECTIVES: The authors sought to assess the risk of cardiovascular and limb events in patients with PAD and diabetes as compared with those with PAD alone.METHODS: In the EUCLID (Examining Use of Ticagrelor in Peripheral Artery Disease) trial, 13,885 patients with symptomatic PAD were evaluated with a primary endpoint of an adjudicated composite of major adverse cardiovascular events (MACE) (cardiovascular death, myocardial infarction, ischemic stroke) followed over a median of 30months. The diabetes subgroup was analyzed compared with the subgroup without diabetes, and further examined for diabetes-specific factors such as glycosylated hemoglobin (HbA1c) that might affect risk for major cardiovascular and limb outcomes.RESULTS: A total of 5,345 patients (38.5%) had diabetes; the majority (n=5,134 [96.1%]) had type 2 diabetes. The primary endpoint occurred in 15.9% of patients with PAD and diabetes as compared with 10.4% of those without diabetes (absolute risk difference 5.5%; adjusted hazard ratio: 1.56; 95% confidence interval [CI]: 1.41 to 1.72; p< 0.001). Every 1% increase in HbA1c was associated with a 14.2% increased relative risk for MACE (95% CI: 1.09 to 1.20; p<0.0001).CONCLUSIONS: Patients with PAD and diabetes are at high risk for cardiovascular and limb ischemic events, even on contemporary therapies. Every 1% increase in HbA1c was associated with a 14.2% increased relative risk for MACE (95%CI: 1.09 to 1.20; p< 0.0001). (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in PatientsWith Peripheral Artery Disease [EUCLID]; NCT01732822).

    View details for PubMedID 30573030

  • Cardiovascular and Limb Outcomes in Patients With Diabetes and Peripheral Artery Disease The EUCLID Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Wang, C., Blomster, J. I., Heizer, G., Berger, J. S., Baumgartner, I., Fowkes, F. R., Held, P., Katona, B. G., Norgren, L., Jones, W., Lopes, R. D., Olin, J. W., Rockhold, F. W., Mahaffey, K. W., Patel, M. R., Hiatt, W. R., EUCLID Trial Executive Comm Invest 2018; 72 (25): 3274–84
  • Stroke Outcomes With Vorapaxar Versus Placebo in Patients With Acute Coronary Syndromes: Insights From the TRACER Trial. Journal of the American Heart Association Ungar, L., Clare, R. M., Rodriguez, F., Kolls, B. J., Armstrong, P. W., Aylward, P., Held, C., Moliterno, D. J., Strony, J., Van de Werf, F., Wallentin, L., White, H. D., Tricoci, P., Harrington, R. A., Mahaffey, K. W., Melloni, C. 2018; 7 (24): e009609

    Abstract

    Background Vorapaxar, a protease-activated receptor-1 antagonist, is approved for secondary prevention of cardiovascular events but is associated with increased intracranial hemorrhage. Methods and Results TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) was a trial of vorapaxar versus placebo among patients with acute coronary syndrome. Strokes were adjudicated by a central events committee. Of 12944 patients, 199 (1.5%) had ≥1 stroke during the study period (median follow-up, 477days). Four patients had a single stroke of unknown type; 195 patients had ≥1 stroke classified as hemorrhagic or nonhemorrhagic (165 nonhemorrhagic, 28 hemorrhagic, and 2 both). Strokes occurred in 96 of 6473 patients (1.5%) assigned vorapaxar and 103 of 6471 patients (1.6%) assigned placebo. Kaplan-Meier incidence of stroke for vorapaxar versus placebo was higher for hemorrhagic stroke (0.45% versus 0.14% [hazard ratio, 2.74; 95% confidence interval, 1.22-6.15]), lower but not significantly different for nonhemorrhagic stroke (1.53% versus 1.98% at 2years [hazard ratio, 0.79; 95% confidence interval, 0.58-1.07]), and similar for stroke overall (1.93% versus 2.13% at 2years [hazard ratio, 0.94; 95% confidence interval, 0.71-1.24]). Conclusions Stroke occurred in <2% of patients. Vorapaxar-assigned patients had increased hemorrhagic stroke but a nonsignificant trend toward lower nonhemorrhagic stroke. Overall stroke frequency was similar with vorapaxar versus placebo.

    View details for PubMedID 30526198

  • Stroke Outcomes With Vorapaxar Versus Placebo in Patients With Acute Coronary Syndromes: Insights From the TRACER Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Ungar, L., Clare, R. M., Rodriguez, F., Kolls, B. J., Armstrong, P. W., Aylward, P., Held, C., Moliterno, D. J., Strony, J., Van de Werf, F., Wallentin, L., White, H. D., Tricoci, P., Harrington, R. A., Mahaffey, K. W., Melloni, C. 2018; 7 (24)
  • Cost-Effectiveness of Alirocumab Based on Evidence From a Large Multinational Outcome Trial: The ODYSSEY OUTCOMES Economics Study Bhatt, D. L., Briggs, A., Reed, S. D., Annemans, L., Szarek, M., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Sanchez, R., Higuchi, K., White, H. D., Zeiher, A. M., Schwartz, G. G., Steg, G., ODYSSEY OUTCOMES Investigators LIPPINCOTT WILLIAMS & WILKINS. 2018: E753–E754
  • Alirocumab Reduces Risk of Death after Acute Coronary Syndrome in Patients with Persistently Elevated Atherogenic Lipoproteins on Intensive Statin Treatment Schwartz, G. G., Szarek, M. M., Bhatt, D. L., Bittner, V. A., Bregeault, M., Dalby, A. J., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Ostadal, P., Parkhomenko, A., Pordy, R., Roe, M. T., Tricoci, P., Vogel, R., White, H. D., Zeiher, A. M., Steg, P. G. LIPPINCOTT WILLIAMS & WILKINS. 2018: E772–E773
  • Incidence, Characteristics, and Outcomes of Myocardial Infarction in Patients With Peripheral Artery Disease: Insights From the EUCLID Trial. JAMA cardiology Olivier, C. B., Mulder, H., Hiatt, W. R., Jones, W. S., Fowkes, F. G., Rockhold, F. W., Berger, J. S., Baumgartner, I., Held, P., Katona, B. G., Norgren, L., Blomster, J., Patel, M. R., Mahaffey, K. W. 2018

    Abstract

    Importance: Patients with peripheral artery disease (PAD) are at high risk for myocardial infarction (MI).Objective: To characterize the incidence and types of MI in a PAD population, identify factors associated with MI, and determine the association of MI with cardiovascular mortality and acute limb ischemia.Design, Setting, and Participants: The Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease (EUCLID) was a double-blind randomized clinical trial conducted at 811 sites in 28 countries that randomized 13 885 patients with symptomatic PAD to monotherapy with ticagrelor or clopidogrel. Participants had an ankle-brachial index (ABI) of 0.80 or less or previous lower extremity revascularization. Median follow-up was 30 months. For these analyses, patients were evaluated for MI occurrence during follow-up irrespective of treatment. Data were analyzed from June 2017 to September 2018.Main Outcomes and Measures: An adjudication clinical events committee classified MI as type 1 (spontaneous), type 2 (secondary), type 3 (sudden cardiac death), type 4a (less than 48 hours after percutaneous coronary intervention), type 4b (definite stent thrombosis), or type 5 (less than 72 hours after coronary artery bypass graft). A multivariate regression model was developed by stepwise selection to identify factors associated with MI, and a time-dependent multivariate Cox regression analysis was performed to determine the association of MI with cardiovascular death and acute limb ischemia requiring hospitalization.Results: Of the 13 885 patients included in this analysis, 9997 (72.0%) were male, and the median (interquartile range) age was 66 (60-73) years. Myocardial infarction occurred in 683 patients (4.9%; 2.4 events per 100 patient-years) during a median follow-up of 30 months. Patients experiencing MI were older (median [interquartile range] age, 69 [62-75] vs 66 [60-72] years), more likely to have diabetes (349 of 683 [51.1%] vs 4996 of 13 202 [37.8%]) or a previous lower extremity revascularization (466 of 683 [68.2%] vs 7409 of 13 202 [56.1%]), and had a lower ABI (if included by ABI) compared with censored patients. Of the 683 patients with MI during follow-up, the most common MI type was type 1 (405 [59.3%]), followed by type 2 (236 [34.6%]), type 4a (14 [2.0%]), type 3 (12 [1.8%]), type 4b (11 [1.6%]), and type 5 (5 [0.7%]). Postrandomization MI was independently associated with cardiovascular death (adjusted hazard ratio, 9.0; 95% CI, 7.3-11.2; P<.001) and acute limb ischemia requiring hospitalization (adjusted hazard ratio, 2.5; 95% CI, 1.3-5.0; P=.008).Conclusions and Relevance: Approximately 5% of patients with symptomatic PAD had an MI during a median follow-up of 30 months. Type 1 MI (spontaneous) was the most common MI type; however, one-third of MIs were type 2 MI (secondary). More research is needed to identify therapies to reduce the risk of MI in patients with PAD and to improve management of type 2 MI.Trial Registration: ClinicalTrials.gov Identifier: NCT01732822.

    View details for PubMedID 30540355

  • Impact of lesion complexity on peri-procedural adverse events and the benefit of potent intravenous platelet adenosine diphosphate receptor inhibition after percutaneous coronary intervention: core laboratory analysis from 10854 patients from the CHAMPION PHOENIX trial. European heart journal Stone, G. W., Genereux, P., Harrington, R. A., White, H. D., Gibson, C. M., Steg, P. G., Hamm, C. W., Mahaffey, K. W., Price, M. J., Prats, J., Deliargyris, E. N., Bhatt, D. L. 2018; 39 (46): 4112–21

    Abstract

    Aims: In the CHAMPION PHOENIX trial, the potent, rapidly acting, intravenous platelet adenosine diphosphate receptor antagonist cangrelor reduced the 48-h incidence of major adverse cardiac events (MACE; death, myocardial infarction, stent thrombosis, or ischaemia-driven revascularization) compared with a loading dose of clopidogrel in patients undergoing percutaneous coronary intervention (PCI). We sought to determine whether the efficacy of cangrelor during PCI varies in patients with simple vs. complex target lesion coronary anatomy.Methods and results: Blinded angiographic core laboratory analysis was completed in 10854 of 10942 (99.2%) randomized patients in CHAMPION PHOENIX (13418 target lesions). Outcomes were analysed according to the number of angiographic PCI target lesion high-risk features (HRF) present (bifurcation, left main, thrombus, angulated, tortuous, eccentric, calcified, long, or multi-lesion treatment). The number of patients with 0, 1, 2, and ≥3 HRFs was 1817 (16.7%), 3442 (31.7%), 2901 (26.7%), and 2694 (24.8%), respectively. The 48-h MACE rate in clopidogrel-treated patients increased progressively with lesion complexity (from 3.3% to 4.4% to 6.9% to 8.7%, respectively, P<0.0001). Cangrelor reduced the 48-h rate of MACE by 21% {4.7% vs. 5.9%, odds ratio (OR) [95% confidence interval (95% CI)] 0.79 (0.67, 0.93), P=0.006} compared with clopidogrel, an effect which was consistent regardless of PCI lesion complexity (Pinteraction=0.66) and presentation with stable ischaemic heart disease (SIHD) or an acute coronary syndrome (ACS). By multivariable analysis, the number of high-risk PCI characteristics [OR (95% CI) 1.68 (1.20, 2.36), 2.78 (2.00, 3.87), and 3.23 (2.33, 4.48) for 1, 2, and 3 HRFs compared with 0 HRFs, all P<0.0001] and treatment with cangrelor vs. clopidogrel [OR (95% CI) 0.78 (0.66, 0.92), P=0.004] were independent predictors of the primary 48-h MACE endpoint. Major bleeding rates were unrelated to lesion complexity and were not increased by cangrelor.Conclusion: Peri-procedural MACE after PCI is strongly dependent on the number of treated high-risk target lesion features. Compared with a loading dose of clopidogrel, cangrelor reduced MACE occurring within 48h after PCI in patients with SIHD and ACS regardless of baseline lesion complexity. The absolute benefit:risk profile for cangrelor will therefore be greatest during PCI in patients with complex coronary anatomy.Clinicaltrials.gov identifier: NCT01156571.

    View details for PubMedID 30203006

  • Impact of lesion complexity on peri-procedural adverse events and the benefit of potent intravenous platelet adenosine diphosphate receptor inhibition after percutaneous coronary intervention: core laboratory analysis from 10 854 patients from the CHAMPIONPHOENIX trial EUROPEAN HEART JOURNAL Stone, G. W., Genereux, P., Harrington, R. A., White, H. D., Gibson, C., Steg, P., Hamm, C. W., Mahaffey, K. W., Price, M. J., Prats, J., Deliargyris, E. N., Bhatt, D. L. 2018; 39 (46): 4112–21
  • Reviewing the role of healthy volunteer studies in drug development. Journal of translational medicine Karakunnel, J. J., Bui, N., Palaniappan, L., Schmidt, K. T., Mahaffey, K. W., Morrison, B., Figg, W. D., Kummar, S. 2018; 16 (1): 336

    Abstract

    BACKGROUND: With the exception of genotoxic oncology drugs, first-in-human, Phase 1 clinical studies of investigational drugs have traditionally been conducted in healthy volunteers (HVs). The primary goal of these studies is to investigate the pharmacokinetics and pharmacodynamics of a novel drug candidate, determine appropriate dosing, and document safety and tolerability.MAIN BODY: When tailored to specific study objectives, HV studies are beneficial to manufacturers and patients alike and can be applied to both non-oncology and oncology drug development. Enrollment of HVs not only increases study accrual rates for dose-escalation studies but also alleviates the ethical concern of enrolling patients with disease in a short-term study at subtherapeutic doses when other studies (e.g. Phase 2 or Phase 3 studies) may be more appropriate for the patient. The use of HVs in non-oncology Phase 1 clinical trials is relatively safe but nonetheless poses ethical challenges because of the potential risks to which HVs are exposed. In general, most adverse events associated with non-oncology drugs are mild in severity, and serious adverse events are rare, but examples of severe toxicity have been reported. The use of HVs in the clinical development of oncology drugs is more limited but is nonetheless useful for evaluating clinical pharmacology and establishing an appropriate starting dose for studies in cancer patients. During the development of oncology drugs, clinical pharmacology studies in HVs have been used to assess pharmacokinetics, drug metabolism, food effects, potential drug-drug interactions, effects of hepatic and renal impairment, and other pharmacologic parameters vital for clinical decision-making in oncology. Studies in HVs are also being used to evaluate biosimilars versus established anticancer biologic agents.CONCLUSION: A thorough assessment of toxicity and pharmacology throughout the drug development process is critical to ensure the safety of HVs. With the appropriate safeguards, HVs will continue to play an important role in future drug development.

    View details for PubMedID 30509294

  • Reviewing the role of healthy volunteer studies in drug development JOURNAL OF TRANSLATIONAL MEDICINE Karakunnel, J. J., Bui, N., Palaniappan, L., Schmidt, K. T., Mahaffey, K. W., Morrison, B., Figg, W. D., Kummar, S. 2018; 16
  • Ticagrelor versus clopidogrel in patients with symptomatic peripheral artery disease and prior coronary artery disease: Insights from the EUCLID trial VASCULAR MEDICINE Berger, J. S., Abramson, B. L., Lopes, R. D., Heizer, G., Rockhold, F. W., Baumgartner, I., Fowkes, F. R., Held, P., Katona, B. G., Norgren, L., Jones, W., Millegard, M., Blomster, J., Reist, C., Hiatt, W. R., Patel, M. R., Mahaffey, K. W., EUCLID Trial Steering Comm Inve 2018; 23 (6): 523–30

    Abstract

    Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular morbidity and mortality. We sought to evaluate the risk of concomitant coronary artery disease (CAD) in patients with symptomatic PAD versus PAD without diagnosed CAD, and whether ticagrelor was superior to clopidogrel in reducing that risk. The EUCLID trial randomized 13,885 patients with PAD to antithrombotic monotherapy with ticagrelor or clopidogrel. CAD was defined as prior myocardial infarction (MI), percutaneous coronary intervention (PCI), or coronary artery bypass graft (CABG) surgery. Median follow-up was 30 months. Among 4032 (29%) patients with PAD and CAD, 63% had prior MI, 54% prior PCI, and 38% prior CABG. After adjustment for baseline characteristics, patients with PAD and CAD had significantly higher rates of the primary endpoint (cardiovascular death/MI/stroke, 15.3% vs 8.9%, hazard ratio (HR) 1.50, 95% CI: 1.13-1.99; p=0.005), but no statistically significant increase in acute limb ischemia (HR 1.28, 95% CI: 0.57-2.85; p=0.55) or major bleeding (HR 1.10, 95% CI: 0.49-2.48; p=0.81) versus PAD without CAD. Among patients with PAD and CAD, there was no differential treatment effect between ticagrelor versus clopidogrel for the primary efficacy endpoint (HR 1.02, 95% CI: 0.87-1.19; p=0.84), acute limb ischemia (HR 1.03, 95% CI: 0.63-1.69; p=0.89), or major bleeding (HR 1.06, 95% CI: 0.66-1.69; p=0.81). There was a statistically significant interaction between prior coronary stent placement and study treatment ( p=0.03) with a numerical reduction in the primary efficacy endpoint with ticagrelor versus clopidogrel (13.8% vs 16.8%, HR 0.82, 95% CI: 0.65-1.03; p=0.09). Patients with PAD and prior CAD had higher composite rates of cardiovascular death, MI, and ischemic stroke versus PAD without diagnosed CAD. There were no significant differences between ticagrelor and clopidogrel in cardiovascular events or major bleeding. ClinicalTrials.gov Identifier: NCT01732822.

    View details for PubMedID 29992857

  • Association of Race/Ethnicity With Oral Anticoagulant Use in Patients With Atrial Fibrillation Findings From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II JAMA CARDIOLOGY Essien, U. R., Holmes, D. N., Jackson, L. R., Fonarow, G. C., Mahaffey, K. W., Reiffel, J. A., Steinberg, B. A., Allen, L. A., Chan, P. S., Freeman, J., Blanco, R. G., Pieper, K. S., Piccini, J. P., Peterson, E. D., Singer, D. E. 2018; 3 (12): 1174–82
  • Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome NEW ENGLAND JOURNAL OF MEDICINE Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Quintero, K., Roe, M. T., Sasiela, W. J., Tamby, J., Tricoci, P., White, H. D., Zeiher, A. M., ODYSSEY OUTCOMES Comm Inv 2018; 379 (22): 2097–2107
  • Association of Race/Ethnicity With Oral Anticoagulant Use in Patients With Atrial Fibrillation: Findings From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II. JAMA cardiology Essien, U. R., Holmes, D. N., Jackson, L. R., Fonarow, G. C., Mahaffey, K. W., Reiffel, J. A., Steinberg, B. A., Allen, L. A., Chan, P. S., Freeman, J. V., Blanco, R. G., Pieper, K. S., Piccini, J. P., Peterson, E. D., Singer, D. E. 2018

    Abstract

    Importance: Black and Hispanic patients are less likely than white patients to use oral anticoagulants for atrial fibrillation. Little is known about racial/ethnic differences in use of direct-acting oral anticoagulants (DOACs) for atrial fibrillation.Objective: To assess racial/ethnic differences in the use of oral anticoagulants, particularly DOACs, in patients with atrial fibrillation.Design, Setting, and Participants: This cohort study used data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II, a prospective, US-based registry of outpatients with nontransient atrial fibrillation 21 years and older who were followed up from February 2013 to July 2016. Data were analyzed from February 2017 to February 2018.Exposures: Self-reported race/ethnicity as white, black, or Hispanic.Main Outcomes and Measures: The primary outcome was use of any oral anticoagulant, particularly DOACs. Secondary outcomes included the quality of anticoagulation received and oral anticoagulant discontinuation at 1 year.Results: Of 12 417 patients, 11 100 were white individuals (88.6%), 646 were black individuals (5.2%), and 671 were Hispanic individuals (5.4%) with atrial fibrillation. After adjusting for clinical features, black individuals were less likely to receive any oral anticoagulant than white individuals (adjusted odds ratio [aOR], 0.75 [95% CI, 0.56, 0.99]) and less likely to receive DOACs if an anticoagulant was prescribed (aOR, 0.63 [95% CI, 0.49-0.83]). After further controlling for socioeconomic factors, oral anticoagulant use was no longer significantly different in black individuals (aOR, 0.78 [95% CI, 0.59-1.04]); among patients using oral anticoagulants, DOAC use remained significantly lower in black individuals (aOR, 0.73 [95% CI, 0.55-0.95]). There was no significant difference between white and Hispanic groups in use of oral anticoagulants. Among patients receiving warfarin, the median time in therapeutic range was lower in black individuals (57.1% [IQR, 39.9%-72.5%]) and Hispanic individuals (51.7% [interquartile range {IQR}, 39.1%-66.7%]) than white individuals (67.1% [IQR, 51.8%-80.6%]; P<.001). Black and Hispanic individuals treated with DOACs were more likely to receive inappropriate dosing than white individuals (black patients, 61 of 394 [15.5%]; Hispanic patients, 74 of 409 [18.1%]; white patients, 1003 of 7988 [12.6%]; P=.01). One-year persistence on oral anticoagulants was the same across groups.Conclusions and Relevance: After controlling for clinical and socioeconomic factors, black individuals were less likely than white individuals to receive DOACs for atrial fibrillation, with no difference between white and Hispanic groups. When atrial fibrillation was treated, the quality of anticoagulant use was lower in black and Hispanic individuals. Identifying modifiable causes of these disparities could improve the quality of care in atrial fibrillation.

    View details for PubMedID 30484833

  • Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials: A Pooled Analysis of 9,259 Deaths in 9 Trials. Circulation Fanaroff, A. C., Clare, R., Pieper, K. S., Mahaffey, K. W., Melloni, C., Green, J., Alexander, J. H., Jones, W. S., Harrison, R. W., Mehta, R. H., Povsic, T. J., Moreira, H. G., Al-Khatib, S. M., Roe, M. T., Kong, D. F., Mathews, R., Tricoci, P., Holman, R. R., Wallentin, L., Held, C., Califf, R. M., Alexander, K. P., Lopes, R. D. 2018

    Abstract

    BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The U.S. Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed.METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to CV, non-CV, or undetermined causes by therapeutic area (diabetes mellitus [DM]/pre-DM, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient- and trial-level variables associated with undetermined cause of death were identified using a logistic model.RESULTS: Across 127,049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) due to CV causes, 2800 (30.2%) due to non-CV causes, and 1447 (15.6%) due to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or DM/pre-DM), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause.CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term follow-up, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.

    View details for PubMedID 30586739

  • Characteristics and outcomes of patients requiring bailout use of glycoprotein IIb/IIIa inhibitors for thrombotic complications of percutaneous coronary intervention: An analysis from the CHAMPION PHOENIX trial. International journal of cardiology Abtan, J., Ducrocq, G., Steg, P. G., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Hamm, C., Price, M. J., Prats, J., Elkin, S., Deliargyris, E. N., White, H. D., Menozzi, A., Harrington, R. A., Bhatt, D. L., MPH on Behalf of the CHAMPION PHOENIX Investigators 2018

    Abstract

    AIMS: To describe the characteristics and outcomes of patients receiving bailout glycoprotein IIb/IIIa inhibitors (GPI) for thrombotic complications of percutaneous coronary intervention (PCI) in a large, contemporary trial.METHODS AND RESULTS: In the CHAMPION PHOENIX trial, the use of GPI was restricted to bailout for thrombotic complications. We describe the characteristics and outcomes of patients requiring bailout GPI compared to patients not receiving GPIs, with adjustment through propensity-score. A multivariable model was constructed to identify independent correlates associated with bailout GPI use. A total of 380 out of 10,942 patients received GPI (3.5%); GPI patients were younger, more frequently male, more likely to present with ST segment elevation myocardial infarction and less frequently treated with cangrelor. At 48 h, GPI patients experienced higher rates of the primary composite outcome of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) (19.2% vs 4.8%; adjusted OR: 5.65(4.08, 7.82), p < 0.0001) and a higher rate of GUSTO severe or moderate bleeding (2.6% vs 0.4% adjusted OR: 4.90 (1.98, 12.18), p = 0.0006) compared with non GPI patients. Independent correlates of GPI use were STEMI, use of unfractionated heparin, drug-eluting stents and longer procedure duration.CONCLUSIONS: In a large contemporary trial, patients receiving bailout GPI for thrombotic complications of PCI experienced very high risks of both ischemic and bleeding complications, suggesting that prevention of periprocedural complications rather than bailout GPI may be preferable.CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov identifier: NCT01156571.

    View details for DOI 10.1016/j.ijcard.2018.11.114

    View details for PubMedID 30563770

  • Embolic and Other Adverse Outcomes in Symptomatic Versus Asymptomatic Patients With Atrial Fibrillation (from the ORBIT-AF Registry) AMERICAN JOURNAL OF CARDIOLOGY Thind, M., Holmes, D. N., Badri, M., Pieper, K. S., Singh, A., Blanco, R. G., Steinberg, B. A., Fonarow, G. C., Gersh, B. J., Mahaffey, K. W., Peterson, E. D., Reiffel, J. A., Piccini, J. P., Kowey, P. R., ORBIT-AF Investigators Patients 2018; 122 (10): 1677–83

    Abstract

    Asymptomatic atrial fibrillation (AF) is being increasingly diagnosed via implantable devices, screening, and inpatient telemetry. Management of asymptomatic AF is controversial, in part, because the associated risks have not been well described. We examined the incidence of major adverse outcomes in patients with asymptomatic versus symptomatic AF using Outcomes Registry for Better Informed Treatment of Atrial, a nationwide US registry of AF patients. We compared stroke and/or non-central nervous system (CNS) embolism, major adverse cardiovascular and neurologic events, bleeding, and death in 9,319 asymptomatic (defined by European Heart Rhythm Association score = 1 or "no symptoms") versus symptomatic patients. Overall, median (interquartile) age was 75 (67 to 82) years, 3,944 (42%) were women, and 38% versus 37% were asymptomatic based on physician versus patient-reported symptoms. Compared with those with symptoms, physician-defined asymptomatic patients were less likely to be woman (35%/47%) or be on an antiarrhythmic agent (22%/33%), but were more likely to have permanent and/or persistent AF (51%/40%). CHA2DS2-VASc scores did not vary by symptom status. After adjustment, risk of first stroke and/or non-CNS embolism (hazard ratio [HR] 0.85 [95% confidence interval {CI} 0.63 to 1.16], p = 0.32), major adverse cardiovascular and neurologic events (HR 0.88 [95% CI 0.76 to 1.03], p = 0.11), bleeding (HR 0.85 [95% CI 0.72 to 1.00], p = 0.05), and death (HR 0.99 [95% CI 0.87 to 1.13], p = 0.88) were similar in asymptomatic (European Heart Rhythm Association = 1) and symptomatic AF, respectively. Prospective, randomized studies are needed to further define associated adverse events and delineate optimal prophylactic therapies in patients with asymptomatic AF.

    View details for PubMedID 30227964

  • Association of Multiple Biomarkers With Risk of All-Cause and Cause-Specific Mortality After Acute Coronary Syndromes: A Secondary Analysis of the PLATO Biomarker Study. JAMA cardiology Lindholm, D., James, S. K., Gabrysch, K., Storey, R. F., Himmelmann, A., Cannon, C. P., Mahaffey, K. W., Steg, P. G., Held, C., Siegbahn, A., Wallentin, L. 2018

    Abstract

    Importance: Mortality remains at about 5% within a year after an acute coronary syndrome event. Prior studies have assessed biomarkers in relation to all-cause or cardiovascular deaths but not across multiple causes.Objective: To assess if different biomarkers provide information about the risk for all-cause and cause-specific mortality.Design, Setting, and Participants: The Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18 624 patients with acute coronary syndrome to ticagrelor or clopidogrel from October 2006 through July 2008. In this secondary analysis biomarker substudy, 17 095 patients participated.Main Outcomes and Measures: Death due to myocardial infarction, heart failure, sudden cardiac death/arrhythmia, bleeding, procedures, other vascular causes, and nonvascular causes, as well as all-cause death.Exposures: At baseline, levels of cystatin-C, growth differentiation factor-15 (GDF-15), high-sensitivity C-reactive protein, high-sensitivity troponin I and T, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were determined.Results: The median (interquartile range) age of patients was 62.0 (54.0-71.0) years. Of 17 095 patients, 782 (4.6%) died during follow-up. The continuous associations between biomarkers and all-cause and cause-specific mortality were modeled using Cox models and presented as hazard ratio (HR) comparing the upper vs lower quartile. For all-cause mortality, NT-proBNP and GDF-15 were the strongest markers with adjusted HRs of 2.96 (95% CI, 2.33-3.76) and 2.65 (95% CI, 2.17-3.24), respectively. Concerning death due to heart failure, NT-proBNP was associated with an 8-fold and C-reactive protein, GDF-15, and cystatin-C, with a 3-fold increase in risk. Regarding sudden cardiac death/arrhythmia, NT-proBNP was associated with a 4-fold increased risk and GDF-15 with a doubling in risk. Growth differentiation factor-15 had the strongest associations with other vascular and nonvascular deaths and was possibly associated with death due to major bleeding (HR, 4.91; 95% CI, 1.39-17.43).Conclusions and Relevance: In patients with acute coronary syndrome, baseline levels of NT-proBNP and GDF-15 were strong markers associated with all-cause death based on their associations with death due to heart failure as well as due to arrhythmia and sudden cardiac death. Growth differentiation factor-15 had the strongest associations with death due to other vascular or nonvascular causes and possibly with death due to bleeding.Trial Registration: ClinicalTrials.gov Identifier: NCT00391872.

    View details for DOI 10.1001/jamacardio.2018.3811

    View details for PubMedID 30427997

  • Characterization of cardiovascular clinical events and impact of event adjudication on the treatment effect of darapladib versus placebo in patients with stable coronary heart disease: Insights from the STABILITY trial. American heart journal Held, C., White, H. D., Stewart, R. A., Davies, R., Sampson, S., Chiswell, K., Silverstein, A., Lopes, R. D., Heldestad, U., Budaj, A., Mahaffey, K. W., Wallentin, L., STABILITY Investigators 2018; 208: 65–73

    Abstract

    BACKGROUND: Clinical Endpoint Classification (CEC) in clinical trials allows FOR standardized, systematic, blinded, and unbiased adjudication of investigator-reported events. We quantified the agreement rates in the STABILITY trial on 15,828 patients with stable coronary heart disease.METHODS: Investigators were instructed to report all potential events. Each reported event was reviewed independently by 2 reviewers according to prespecified processes and prespecified end point definitions. Concordance between reported and adjudicated cardiovascular (CV) events was evaluated, as well as event classification influence on final study results.RESULTS: In total, CEC reviewed 7,096 events: 1,064 deaths (696 CV deaths), 958 myocardial infarctions (MI), 433 strokes, 182 transient ischemic attacks, 2,052 coronary revascularizations, 1,407 hospitalizations for unstable angina, and 967 hospitalizations for heart failure. In total, 71.8% events were confirmed by CEC. Concordance was high (>80%) for cause of death and nonfatal MI and lower for hospitalization for unstable angina (25%) and heart failure (50%). For the primary outcome (composite of CV death, MI, and stroke), investigators reported 2,086 events with 82.5% confirmed by CEC. The STABILITY trial treatment effect of darapladib versus placebo on the primary outcome was consistent using investigator-reported events (hazard ratio 0.96 [95% CI 0.87-1.06]) or adjudicated events (hazard ratio 0.94 [95% CI 0.85-1.03]).CONCLUSIONS: The primary outcome results of the STABILITY trial were consistent whether using investigator-reported or CEC-adjudicated events. The proportion of investigator-reported events confirmed by CEC varied by type of event. These results should help improve event identification in clinical trials to optimize ascertainment and adjudication.

    View details for PubMedID 30572273

  • Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. The New England journal of medicine Schwartz, G. G., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Quintero, K., Roe, M. T., Sasiela, W. J., Tamby, J., Tricoci, P., White, H. D., Zeiher, A. M., ODYSSEY OUTCOMES Committees and Investigators 2018

    Abstract

    BACKGROUND: Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy.METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization.RESULTS: The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group).CONCLUSIONS: Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402 .).

    View details for PubMedID 30403574

  • Estimation of Stroke Outcomes in Atrial Fibrillation Using Continuous Clinical and Implantable Device Data From the Treat-AF Study: A Comparison With CHA2DS2-VASc Score Bentley, J. P., Askari, M., Fan Jun, Heidenreich, P. A., Mahaffey, K. W., Desai, M., Scheinker, D., Turakhia, M. P. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Comparison of Patient Reported Care Satisfaction, Quality of Warfarin Therapy, and Outcomes of Atrial Fibrillation: Findings From the ORBIT-AF Registry Perino, A. C., Shrader, P., Turakhia, M. P., Ansell, J. E., Gersh, B. J., Fonarow, G. C., Go, A. S., Kaiser, D. W., Hylek, E. M., Kowey, P. R., Singer, D. E., Thomas, L., Steinberg, B. A., Peterson, E. D., Piccini, J. P., Mahaffey, K. W. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events in the ODYSSEY OUTCOMES Trial Szarek, M., White, H. D., Schwartz, G. G., Alings, M., Bhatt, D. L., Bittner, V. A., Chiang, C., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J., Kimura, T., Kiss, R., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Tricoci, P., Xavier, D., Zeiher, A. M., Steg, P., ODYSSEY Outcomes Investigators LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Acute Limb Ischemia in Peripheral Artery Disease: Insights From EUCLID Hess, C. N., Huang, Z., Patel, M. R., Baumgartner, I., Berger, J. S., Blomster, J., Fowkes, F. R., Held, P., Jones, W., Katona, B. G., Mahaffey, K. W., Norgren, L., Rockhold, F. W., Hiatt, W. R. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • The TIMI Risk Score for Secondary Prevention for Myocardial Infarction Applied to Patients With Peripheral Artery Disease: A Collaborative Analysis for the Chronic Kidney Disease Prognosis Consortium and the Risk Validation Scientific Committee Mok, Y., Ballew, S. H., Bash, L. D., Bhatt, D. L., Bonaca, M. P., Carrero, J., Coresh, J., D'Agostino, R. B., Fowkes, F. R., Jee, S., Kenealy, T., Kovesdy, C. P., Mahaffey, K. W., Sang, Y., Matsushita, K. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Stroke Outcomes With Vorapaxar versus Placebo in Patients With Acute Coronary Syndromes: Insights From the TRACER Trial Ungar, L., Clare, R., Rodriguez, F., Kolls, B., Armstrong, P., Aylward, P., Held, C., Moliterno, D., Strony, J., Van de Werf, F., Wallentin, L., White, H., Tricoci, P., Harrington, R., Mahaffey, K., Melloni, C. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Treatment Patterns and Clinical Outcomes in Adults With Concomitant Atrial Fibrillation and Vascular Disease Inohara, T., Shrader, P., Pieper, K., Blanco, R. G., Fonarow, G. C., Mahaffey, K. W., Gersh, B. J., Go, A. S., Kowey, P. R., Peterson, E., Piccini, J. P. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Comparing Treatments and Outcomes Across the Spectrum of Stroke and Bleeding Risks in Non-Valvular Atrial Fibrillation: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Marzec, L. N., Piccini, J. P., Shrader, P., Pieper, K., Blanco, R. G., Fonarow, G. C., Gersh, B. J., Ho, P., Hylek, E., Kowey, P. R., Mahaffey, K. W., Steinberg, B. A., Peterson, E. D., Allen, L. A. LIPPINCOTT WILLIAMS & WILKINS. 2018
  • Polyvascular Disease and Risk of Major Adverse Cardiovascular Events in Peripheral Artery Disease: A Secondary Analysis of the EUCLID Trial. JAMA network open Gutierrez, J. A., Mulder, H., Jones, W. S., Rockhold, F. W., Baumgartner, I., Berger, J. S., Blomster, J. I., Fowkes, F. G., Held, P., Katona, B. G., Mahaffey, K. W., Norgren, L., Hiatt, W. R., Patel, M. R. 2018; 1 (7): e185239

    Abstract

    The effect of polyvascular disease on cardiovascular outcomes in the background of peripheral artery disease (PAD) is unclear.To determine the risk of ischemic events (both cardiac and limb) among patients with PAD and polyvascular disease.In this post hoc secondary analysis of the international Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, outcomes were compared among 13 885 enrolled patients with PAD alone, PAD + coronary artery disease (CAD), PAD + cerebrovascular disease (CVD), and PAD + CAD + CVD. Adjusted Cox proportional hazards regression models were implemented to determine the risk associated with polyvascular disease and outcomes, and intention-to-treat analysis was performed. The EUCLID trial was conducted from December 31, 2012, to March 7, 2014; the present post hoc analysis was performed from June 1, 2017, to February 5, 2018.EUCLID evaluated ticagrelor vs clopidogrel in preventing major adverse cardiac events (cardiovascular death, myocardial infarction [MI], or ischemic stroke) and major bleeding in patients with PAD.The primary end point was a composite of cardiovascular death, MI, or ischemic stroke. Key secondary end points included the individual components of the primary end point and acute limb ischemia leading to hospitalization, major amputation, and lower-extremity revascularization. The primary end point of Thrombolysis in Myocardial Infarction (TIMI) major bleeding was also evaluated.The EUCLID trial randomized 13 885 patients with a median age of 66 years (interquartile range, 60-73 years), of whom 3888 (28.0%) were women. At baseline, 7804 patients (56.2%) had PAD alone; 2639 (19.0%) had PAD + CAD; 2049 (14.8%) had PAD + CVD; and 1393 (10.0%) had PAD + CAD + CVD. Compared with patients with isolated PAD, the adjusted hazard ratios (aHRs) for major adverse cardiac events were 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CVD, 1.65 (95% CI, 1.43-1.91; P < .001) for PAD + CAD, and 1.99 (95% CI, 1.69-2.34; P < .001) for PAD + CAD + CVD. The aHRs for lower-extremity revascularization were 1.17 (95% CI, 1.03-1.34; P = .01) for PAD + CAD, 1.17 (95% CI, 1.02-1.35; P = .02) for PAD + CVD, and 1.34 (95% CI, 1.15-1.57; P < .001) for PAD + CAD + CVD. Polyvascular disease was not associated with an increased risk of acute limb ischemia (aHR for PAD + CVD, 0.91; 95% CI, 0.62-1.34, P = .63; PAD + CAD, 0.93; 95% CI, 0.64-1.34, P = .69; and PAD + CAD + CVD, 0.98; 95% CI, 0.63-1.53, P = .93), major amputation (aHR for PAD + CVD, 0.83; 95% CI, 0.54-1.27, P = .40; PAD + CAD, 0.74; 95% CI, 0.47-1.16, P = .19; and PAD + CAD + CVD, 1.12; 95% CI, 0.69-1.80, P = .65), or TIMI major bleeding (PAD + CVD, 0.98; 0.66-1.44, P = .91; PAD + CAD, 1.04; 0.74-1.48, P = .81; and PAD + CAD + CVD, 0.96; 95% CI, 0.62-1.51, P = .88).Compared with patients with PAD alone, the risk of major adverse cardiac events and lower-extremity revascularization increased with multiple vascular bed involvement. There was no clear increased risk of bleeding associated with polyvascular disease.

    View details for DOI 10.1001/jamanetworkopen.2018.5239

    View details for PubMedID 30646395

    View details for PubMedCentralID PMC6324381

  • Characteristics and outcomes of adults with chronic obstructive pulmonary disease and atrial fibrillation HEART Durheim, M. T., Holmes, D. N., Blanco, R. G., Allen, L. A., Chan, P. S., Freeman, J. V., Fonarow, G. C., Go, A. S., Hylek, E. M., Mahaffey, K. W., Pokorney, S. D., Reiffel, J. A., Singer, D. E., Peterson, E. D., Piccini, J. P. 2018; 104 (22): 1850–58

    Abstract

    Chronic obstructive pulmonary disease (COPD) is associated with the development of atrial fibrillation (AF), and may complicate treatment of AF. We examined the association between COPD and symptoms, quality of life (QoL), treatment and outcomes among patients with AF.We compared patients with and without a diagnosis of COPD in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, a prospective registry that enrolled outpatients with AF not secondary to reversible causes, from both academic and community settings.Among 9749 patients with AF, 1605 (16%) had COPD. Relative to patients without COPD, those with COPD were more likely to be older, current/former smokers (73% vs 43%), have heart failure (54% vs 29%) and coronary artery disease (49% vs 34%). Oral anticoagulant and beta blocker use were similar, whereas digoxin use was more common among patients with COPD. Symptom burden was generally higher, and QoL worse, among patients with COPD (median Atrial Fibrillation Effect on QualiTy-of-Life score 76 vs 83). Patients with COPD had higher risk of all-cause mortality (adjusted HR 1.52 (95% CI 1.32 to 1.74)), cardiovascular mortality (adjusted HR 1.51 (95% CI 1.24 to 1.84)) and cardiovascular hospitalisation (adjusted HR 1.15 (95% CI 1.05 to 1.26)). Patients with COPD also had higher risk of major bleeding events (adjusted HR 1.25 (95% CI 1.05 to 1.50)). There did not appear to be associations between COPD and AF progression, ischaemic events or new-onset heart failure.Among patients with AF, COPD is associated with higher symptom burden, worse QoL, and worse cardiovascular and bleeding outcomes. These associations were not fully explained by cardiovascular risk factors, AF treatment or smoking history.NCT01165710.

    View details for PubMedID 29875139

  • Definitions of peri-procedural myocardial infarction and the association with one-year mortality: Insights from CHAMPION trials INTERNATIONAL JOURNAL OF CARDIOLOGY Olivier, C. B., Sundaram, V., Bhatt, D. L., Leonardi, S., Lopes, R. D., Ding, V. Y., Yang, L., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., White, H. D., Desai, M., Lynch, D. R., Harrington, R. A., Mahaffey, K. W., CHAMPION PLATFORM & CHAM 2018; 270: 96–101
  • Early therapeutic persistence on dabigatran versus warfarin therapy in patients with atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry JOURNAL OF THROMBOSIS AND THROMBOLYSIS Jackson, L. R., Kim, S., Shrader, P., Blanco, R., Thomas, L., Ezekowitz, M. D., Ansell, J., Fonarow, G. C., Gersh, B. J., Go, A. S., Kowey, P. R., Mahaffey, K. W., Hylek, E. M., Peterson, E. D., Piccini, J. P. 2018; 46 (4): 435–39

    Abstract

    Anticoagulation is highly effective for the prevention of stroke in patients with atrial fibrillation (AF) but it is dependent on patients continuing therapy. While studies have demonstrated suboptimal therapeutic persistence on warfarin, few have studied persistence rates with non vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran. We examined rates of continued use of dabigatran versus warfarin over 1 year among AF patients in the ORBIT-AF registry between June 29, 2010 and August 09, 2011. Multivariable logistic regression analysis was used to identify characteristics associated with 1-year persistent use of dabigatran therapy or warfarin. At baseline, 6.4 and 93.6% of 7150 AF patients were on dabigatran and warfarin, respectively. At 12 months, dabigatran-treated patients were less likely to have continued their therapy than warfarin-treated patients [Adjusted persistence rates: 66% (95% CI 60-72) vs. 82% (95% CI 80-84), p < .0001]. Predictors of dabigatran persistence included: CHA2DS2-VASc risk scores ≥ 2 OR 5.69, (95% CI 1.50-21.6) and BMI greater than 25 mg/m2 but less than 38 kg/m2 1.05 (1.01-1.09). Predictors of persistence on warfarin included: African American race (vs. White) 1.53 (1.07-2.19), Hispanic ethnicity (vs. White) 1.66 (1.06-2.60), paroxysmal and persistent AF (vs. new-onset) 1.68 (1.21-2.33) and 1.91 (1.35-2.69) respectively, LVH 1.40 (1.08-1.81), and CHA2DS2-VASc risk scores ≥ 2 1.94 (1.18-3.19). While 1-year persistence rates for dabigatran were lower than warfarin, persistence rates for both agents were not ideal. Future studies evaluating contemporary persistence are needed in order to assist in better targeting interventions aimed to improve anticoagulation persistence.

    View details for PubMedID 30051164

  • Alirocumab Reduces Total Nonfatal Cardiovascular and Fatal Events in the ODYSSEY OUTCOMES Trial. Journal of the American College of Cardiology Szarek, M., White, H. D., Schwartz, G. G., Alings, M., Bhatt, D. L., Bittner, V. A., Chiang, C., Diaz, R., Edelberg, J. M., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Kimura, T., Kiss, R. G., Lecorps, G., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Tricoci, P., Xavier, D., Zeiher, A. M., Steg, P. G., ODYSSEY OUTCOMES Committees and Investigators 2018

    Abstract

    BACKGROUND: The ODYSSEY OUTCOMES trial compared alirocumab with placebo, added to high-intensity or maximum tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths.OBJECTIVES: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES.METHODS: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death.RESULTS: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio 0.87, 95% confidence interval 0.82 to 0.93) and death (hazard ratio 0.83, 95% confidence interval 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk.CONCLUSIONS: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.

    View details for PubMedID 30428396

  • Cardiovascular and Renal Outcomes With Canagliflozin According to Baseline Kidney Function: Data From the CANVAS Program CIRCULATION Neuen, B. L., Ohkuma, T., Neal, B., Matthews, D. R., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Desai, M., Li, Q., Deng, H., Rosenthal, N., Jardine, M. J., Bakris, G., Perkovic, V. 2018; 138 (15): 1537–50

    Abstract

    Background : Canagliflozin is approved for glucose lowering in type 2 diabetes and confers cardiovascular and renal benefits. We sought to assess whether it had benefits in people with chronic kidney disease (CKD), including those with an estimated glomerular filtration rate (eGFR) between 30 and 45 mL/min/1.73 m2 in whom the drug is not currently approved for use. Methods : The CANagliflozin cardioVascular Assessment Study Program (CANVAS) randomized 10,142 participants with type 2 diabetes and eGFR greater than 30 mL/min/1.73 m2 to canagliflozin or placebo. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, with other cardiovascular, renal, and safety outcomes. This secondary analysis describes outcomes in participants with and without CKD, defined as eGFR <60 and ≥60 mL/min/1.73 m2, and according to baseline kidney function (eGFR <45, 45-<60, 60-<90, and ≥90 mL/min/1.73 m2). Results : At baseline, 2039 (20.1%) participants had an eGFR <60 mL/min/1.73 m2, of whom 71.6% had a history of cardiovascular disease. The effect of canagliflozin on the primary outcome was similar in people with CKD (HR 0.70, 95% CI 0.55-0.90) and those with preserved kidney function (HR 0.92, 95% CI 0.79-1.07, P heterogeneity = 0.08). Relative effects on most cardiovascular and renal outcomes were similar across eGFR subgroups, with possible heterogeneity suggested only for the outcome of fatal/nonfatal stroke (P heterogeneity = 0.01), as were results for almost all safety outcomes. Conclusions : The effect of canagliflozin on cardiovascular and renal outcomes was not modified by baseline level of kidney function in people with type 2 diabetes and a history or high risk of cardiovascular disease down to eGFR levels of 30 mL/min/1.73 m2 Reassessing current limitations on the use of canagliflozin in CKD may allow additional individuals to benefit from this therapy. Clinical Trial Registration : URL: https://clinicaltrials.gov. Unique identifiers: NCT01032629, NCT01989754.

    View details for PubMedID 29941478

  • Cardiovascular Outcomes After Lower Extremity Endovascular or Surgical Revascularization JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Baumgartner, I., Norgren, L., Fowkes, F. R., Mulder, H., Patel, M. R., Berger, J. S., Jones, W., Rockhold, F. W., Katona, B. G., Mahaffey, K., Hiatt, W. R., Executive Comm Investigators EUCLI 2018; 72 (14): 1563–72

    Abstract

    Lower extremity revascularization (LER) is a common treatment in patients with peripheral artery disease (PAD), but long-term outcomes are poorly defined.The aim was to analyze LER in the EUCLID (Examining Use of tiCagreLor In paD) trial to determine predictors and cardiovascular outcomes.Patients were grouped according to whether they received a post-randomization LER (n = 1,738) or not (n = 12,147). All variables were assessed for significance in univariable and parsimonious multivariable models. The primary endpoint was myocardial infarction, ischemic stroke, or cardiovascular death; major adverse limb events (MALE) included acute limb ischemia or major amputation.A post-randomization LER occurred in 12.5% of patients and was an endovascular LER in 74.7%. Endovascular LERs were performed more often in North America, whereas surgical procedures occurred more frequently in Europe. Independent factors predicting LER were prior and type of prior LER, geographic region, limb symptoms, diabetes, and smoking. A post-randomization LER was associated with an increased risk for the primary endpoint (hazard ratio: 1.60; 95% confidence interval: 1.35 to 1.90; p < 0.0001) and MALE (hazard ratio: 12.0; 95% confidence interval: 9.47 to 15.30; p < 0.0001). Event rates for the primary endpoint after LER were numerically higher in the surgical subgroup, but MALE were similar between surgical and endovascular LER.In the EUCLID trial, LER was most often endovascular. Following LER, there was an increased hazard for the primary endpoint (with higher event rates in the surgical group) and a markedly increased risk for MALE events (with similar event rates between surgical and endovascular LER procedures). (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

    View details for PubMedID 30261955

  • Academic health centers: integration of clinical research with healthcare and education. Comments on a workshop. Clinics (Sao Paulo, Brazil) Arai, R. J., Noronha, I. d., Nicolau, J. C., Schmidt, C., de Albuquerque, G. M., Mahaffey, K. W., Krieger, E. M., Auler Junior, J. O. 2018; 73 (suppl 1): e515s

    View details for PubMedID 30281697

  • B-type natriuretic peptide, disease progression and clinical outcomes in atrial fibrillation. Heart (British Cardiac Society) Inohara, T., Kim, S., Pieper, K., Blanco, R. G., Allen, L. A., Fonarow, G. C., Gersh, B. J., Ezekowitz, M. D., Kowey, P. R., Reiffel, J. A., Naccarelli, G. V., Chan, P. S., Mahaffey, K. W., Singer, D. E., Freeman, J. V., Steinberg, B. A., Peterson, E. D., Piccini, J. P., ORBIT AF Patients and Investigators 2018

    Abstract

    OBJECTIVE: The association with B-type natriuretic peptide (BNP), disease progression and outcomes in patients with atrial fibrillation (AF) has not been thoroughly investigated.METHODS: We evaluated the association between BNP levels and outcomes, including AF progression, composite outcome of major adverse cardiovascular or neurological events (MACNE) and major bleeding, via pooled logistic regression and Cox frailty models in Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry. AF progression was defined as either paroxysmal becoming persistent or permanent, or persistent becoming permanent at any follow-up.RESULTS: Among 13375 patients with AF, 2797 with BNP values at baseline (median age (IQR), 72.0 (63.0-80.0) years; 43.0% women; median BNP, 238 (102-502) ng/L; 42.3% prior heart failure) were included in the models evaluating the association between BNP levels and MACNE or major bleeding. Of these, 1282 patients with paroxysmal or persistent AF at baseline were analysed in AF progression model. The likelihood of AF progression (adjusted OR, 1.11 for every 100ng/mL; 95% CI 1.03 to 1.19) and MACNE (adjusted HR, 1.11 for every doubling in BNP values; 95%CI 1.01 to 1.22) increased with BNP concentration, while the elevated BNP values were not associated with increased risks of major bleeding. BNP values improved the risk prediction of AF progression and MACNE when added to conventional risk estimates.CONCLUSIONS: BNP levels are associated with increased risk of AF progression and cardiovascular outcomes in patients with AF. Further studies are required to assess whether biomarker-based risk stratification improves patient outcomes.CLINICAL TRIAL REGISTRATION: NCT01701817.

    View details for PubMedID 30228248

  • Pharmacotherapy for Atrial Fibrillation in Patients With Chronic Kidney Disease: Insights From ORBIT-AF JOURNAL OF THE AMERICAN HEART ASSOCIATION Washam, J. B., Holmes, D. N., Thomas, L. E., Pokorney, S. D., Hylek, E. M., Fonarow, G. C., Mahaffey, K. W., Gersh, B. J., Kowey, P. R., Ansell, J. E., Go, A. S., Reiffel, J. A., Freeman, J. V., Singer, D. E., Naccarelli, G., Blanco, R., Peterson, E. D., Piccini, J. P. 2018; 7 (18)
  • Pharmacotherapy for Atrial Fibrillation in Patients With Chronic Kidney Disease: Insights From ORBIT-AF. Journal of the American Heart Association Washam, J. B., Holmes, D. N., Thomas, L. E., Pokorney, S. D., Hylek, E. M., Fonarow, G. C., Mahaffey, K. W., Gersh, B. J., Kowey, P. R., Ansell, J. E., Go, A. S., Reiffel, J. A., Freeman, J. V., Singer, D. E., Naccarelli, G., Blanco, R., Peterson, E. D., Piccini, J. P. 2018; 7 (18): e008928

    Abstract

    Background Chronic kidney disease ( CKD ) is a common comorbidity in patients with atrial fibrillation. The presence of CKD complicates drug selection for stroke prevention and rhythm control. Methods and Results Patients enrolled in ORBIT AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) with baseline renal function and follow-up data were included (N=9019). CKD was defined as an estimated creatinine clearance <60 mL /min. Patient characteristics were compared by CKD status, and Cox proportional hazards modeling was used to examine the association between oral anticoagulant ( OAC ) use and outcomes and antiarrhythmic drug use and outcomes stratified by CKD stages. At enrollment, 3490 (39%) patients had an estimated creatinine clearance <60 mL /min. Patients with CKD were older and had higher CHA 2 DS 2 VAS c and Anticoagulant and Risk Factors in Atrial Fibrillation (ATRIA) scores. A rhythm control strategy was selected less frequently in patients with CKD , while OAC use was lower among Stage IV and V CKD patients. After adjustment, no significant interaction was noted for OAC and CKD on all-cause mortality ( P=0.5442) or cardiovascular death ( P=0.1233), although a trend for increased major bleeding ( P=0.0608) and stroke, systemic embolism or transient ischemic attack ( P=0.0671) was observed. No interaction was noted for antiarrhythmic drug use and CKD status on all-cause mortality ( P=0.9706), or stroke, systemic embolism or transient ischemic attack ( P=0.4218). Conclusions Patients with atrial fibrillation and CKD are less likely to be treated with rhythm control. Patients with advanced CKD are less likely to receive OAC . Finally, outcomes with OAC in patients with advanced CKD may be materially different with higher rates of both bleeding and stroke.

    View details for PubMedID 30371218

  • Efficacy and Safety of Rivaroxaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation and a History of Cancer: Observations from ROCKET AF. European heart journal. Quality of care & clinical outcomes Chen, S. T., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R., Melloni, C. 2018

    Abstract

    Aims: The management of anticoagulation therapy in patients with atrial fibrillation (AF) and cancer is challenging due to increased thrombotic and bleeding risks. We sought to determine the safety and efficacy of rivaroxaban in patients with AF and a history of cancer.Methods and Results: ROCKET AF randomized 14,264 patients with AF to rivaroxaban or warfarin with a median follow-up of 1.9 years. Cox regression models were used to assess the association between cancer history and clinical outcomes, and the relative treatment effect of rivaroxaban versus warfarin in these patients. A total of 640 patients enrolled in ROCKET AF had a history of cancer, with the most common types being prostate (28.6%), colorectal (16.1%), and breast (14.7%) cancer. Patients with a history of cancer were older, more frequently male, more likely to have prior VKA use, and had higher rates of overall bleeding (HR 1.30 95% CI 1.16-1.47; p<0.0001) and non-cardiovascular death (HR 1.47 95% CI 1.04-2.07; p=0.031) compared with those with no cancer history. There were no significant associations between cancer history and stroke, venous thromboembolism, or myocardial infarction. The relative efficacy of rivaroxaban versus warfarin for prevention of stroke/systemic embolism was similar in those with and without a history of cancer (interaction p-value=0.21).Conclusion: In ROCKET AF, a history of cancer was associated with a higher risk of bleeding and non-cardiovascular death, but not ischemic events. The relative efficacy and safety of rivaroxaban compared with warfarin were not significantly different in patients with and without a history of cancer. The results of this study are exploratory and should be taken in context of the study population, which may not be generalizable to those with advanced malignancy. Further investigation is needed to understand optimal anticoagulation strategies in patients with AF and cancer.

    View details for PubMedID 30219887

  • Rationale and design of a large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple Heart Study. American heart journal Turakhia, M. P., Desai, M., Hedlin, H., Rajmane, A., Talati, N., Ferris, T., Desai, S., Nag, D., Patel, M., Kowey, P., Rumsfeld, J. S., Russo, A. M., Hills, M. T., Granger, C. B., Mahaffey, K. W., Perez, M. V. 2018

    Abstract

    BACKGROUND: Smartwatch and fitness band wearable consumer electronics can passively measure pulse rate from the wrist using photoplethysmography (PPG). Identification of pulse irregularity or variability from these data has the potential to identify atrial fibrillation or atrial flutter (AF, collectively). The rapidly expanding consumer base of these devices allows for detection of undiagnosed AF at scale.METHODS: The Apple Heart Study is a prospective, single arm pragmatic study that has enrolled 419,093 participants (NCT03335800). The primary objective is to measure the proportion of participants with an irregular pulse detected by the Apple Watch (Apple Inc, Cupertino, CA) with AF on subsequent ambulatory ECG patch monitoring. The secondary objectives are to: 1) characterize the concordance of pulse irregularity notification episodes from the Apple Watch with simultaneously recorded ambulatory ECGs; 2) estimate the rate of initial contact with a health care provider within 3 months after notification of pulse irregularity. The study is conducted virtually, with screening, consent and data collection performed electronically from within an accompanying smartphone app. Study visits are performed by telehealth study physicians via video chat through the app, and ambulatory ECG patches are mailed to the participants.CONCLUSIONS: The results of this trial will provide initial evidence for the ability of a smartwatch algorithm to identify pulse irregularity and variability which may reflect previously unknown AF. The Apple Heart Study will help provide a foundation for how wearable technology can inform the clinical approach to AF identification and screening.

    View details for PubMedID 30392584

  • Effects of genetic variation in protease activated receptor 4 after an acute coronary syndrome: Analysis from the TRACER trial BLOOD CELLS MOLECULES AND DISEASES Tricoci, P., Neely, M., Whitley, M. J., Edelstein, L. C., Simon, L. M., Shaw, C., Fortina, P., Moliterno, D. J., Armstrong, P. W., Aylward, P., White, H., Van de Werf, F., Jennings, L. K., Wallentin, L., Held, C., Harrington, R. A., Mahaffey, K. W., Bray, P. F. 2018; 72: 37–43

    Abstract

    Variation in platelet response to thrombin may affect the safety and efficacy of PAR antagonism. The Thr120 variant of the common single nucleotide polymorphism (SNP) rs773902 in the protease-activated receptor (PAR) 4 gene is associated with higher platelet aggregation compared to the Ala120 variant. We investigated the relationship between the rs773902 SNP with major bleeding and ischemic events, safety, and efficacy of PAR1 inhibition in 6177 NSTE ACS patients in the TRACER trial. There was a lower rate of GUSTO moderate/severe bleeding in patients with the Thr120 variant. The difference was driven by a lower rate in the smaller homozygous group (recessive model, HR 0.13 [0.02-0.92] P = 0.042). No significant differences were observed in the ischemic outcomes. The excess in bleeding observed with PAR1 inhibition was attenuated in patients with the Thr120 variant, but the interactions were not statistically significant. In summary, lower major bleeding rates were observed in the overall TRACER cohort with the hyperreactive PAR4 Thr120 variant. The increase in bleeding with vorapaxar was attenuated with the Thr120 variant, but we could not demonstrate an interaction with PAR1 inhibition. These findings warrant further exploration, including those of African ancestry where the A allele (Thr120) frequency is ~65%.

    View details for PubMedID 30055940

    View details for PubMedCentralID PMC6097632

  • Association of Healthcare Plan with atrial fibrillation prescription patterns CLINICAL CARDIOLOGY Chang, A., Askari, M., Fan, J., Heidenreich, P. A., Ho, P., Mahaffey, K. W., Ullal, A., Perino, A., Turakhia, M. P. 2018; 41 (9): 1136–43

    View details for DOI 10.1002/clc.23042

    View details for Web of Science ID 000446429700004

  • Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials LANCET DIABETES & ENDOCRINOLOGY Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Erondu, N., Shaw, W., Barrett, T. D., Weidner-Wells, M., Deng, H., Matthews, D. R., Neal, B. 2018; 6 (9): 691–704

    Abstract

    In the Canagliflozin Cardiovascular Assessment Study (CANVAS) Program, canagliflozin reduced the rates of major adverse cardiovascular events and the results suggested a renal benefit in patients with type 2 diabetes who were at high risk for cardiovascular events, compared with those treated with placebo. Here we report the results of a prespecified exploratory analysis of the long-term effects of canagliflozin on a range of sustained and adjudicated renal outcomes.The CANVAS Program consists of two double-blind, randomised trials that assessed canagliflozin versus placebo in participants with type 2 diabetes who were at high risk of cardiovascular events, done at 667 centres in 30 countries. People with type 2 diabetes and an HbA1c of 7·0-10·5% (53-91 mmol/mol) who were aged at least 30 years and had a history of symptomatic atherosclerotic vascular disease, or who were aged at least 50 years and had at least two cardiovascular risk factors were eligible to participate. Participants in CANVAS were randomly assigned (1:1:1) to receive 300 mg canagliflozin, 100 mg canagliflozin, or matching placebo once daily. Participants in CANVAS-R were randomly assigned (1:1) to receive canagliflozin or matching placebo, at an initial dose of 100 mg daily, with optional uptitration to 300 mg from week 13 or matching placebo. Participants and all study staff were masked to treatment allocations until study completion. Prespecified outcomes reported here include a composite of sustained and adjudicated doubling in serum creatinine, end-stage kidney disease, or death from renal causes; the individual components of this composite outcome; annual reductions in estimated glomerular filtration rate (eGFR); and changes in urinary albumin-to-creatinine ratio (UACR). The trials are registered with ClinicalTrials.gov, numbers NCT01032629 (CANVAS) and NCT01989754 (CANVAS-R).Between Nov 17, 2009, and March 7, 2011 (CANVAS), and Jan 17, 2014, and May 29, 2015 (CANVAS-R), 15 494 people were screened, of whom 10 142 participants (with a baseline mean eGFR 76·5 mL/min per 1·73 m2, median UACR 12·3 mg/g, and 80% of whom were receiving renin-angiotensin system blockade) were randomly allocated to receive either canagliflozin or placebo. The composite outcome of sustained doubling of serum creatinine, end-stage kidney disease, and death from renal causes occurred less frequently in the canagliflozin group compared with the placebo group (1·5 per 1000 patient-years in the canagliflozin group vs 2·8 per 1000 patient-years in the placebo group; hazard ratio 0·53, 95% CI 0·33-0·84), with consistent findings across prespecified patient subgroups. Annual eGFR decline was slower (slope difference between groups 1·2 mL/min per 1·73 m2 per year, 95% CI 1·0-1·4) and mean UACR was 18% lower (95% CI 16-20) in participants treated with canagliflozin than in those treated with placebo. Total serious renal-related adverse events were similar between the canagliflozin and placebo groups (2·5 vs 3·3 per 1000 patient-years; HR 0·76, 95% CI 0·49-1·19).In a prespecified exploratory analysis, canagliflozin treatment was associated with a reduced risk of sustained loss of kidney function, attenuated eGFR decline, and a reduction in albuminuria, which supports a possible renoprotective effect of this drug in people with type 2 diabetes.Janssen Research & Development.

    View details for PubMedID 29937267

  • Prognostic Significance of Nuisance Bleeding in Anticoagulated Patients With Atrial Fibrillation CIRCULATION O'Brien, E. C., Holmes, D. N., Thomas, L. E., Fonarow, G. C., Allen, L. A., Gersh, B. J., Kowey, P. R., Singer, D. E., Ezekowitz, M. D., Naccarelli, G. V., Ansell, J. E., Chan, P. S., Mahaffey, K. W., Go, A. S., Freeman, J. V., Reiffel, J. A., Peterson, E. D., Piccini, J. P., Hylek, E. M. 2018; 138 (9): 889–97

    Abstract

    Background -Bleeding is commonly cited as a reason for stopping oral anticoagulants (OAC). Whether minor bleeding events ("nuisance bleeding", NB) in patients with atrial fibrillation (AF) on OAC are associated with OAC discontinuation, major bleeding and stroke/systemic embolism (SSE), is unknown. Methods -Within the ORBIT-AF prospective, outpatient registry, we identified 6771 patients ≥18 years of age at 172 sites with AF and eligible followup visits. NB was ascertained from the medical record and was defined as minor bleeding that did not require medical attention (e.g. bruising, hemorrhoidal bleeding). We used multivariable pooled logistic regression modeling to evaluate the associations between NB and major bleeding and SSE in the 180 days after documentation of NB. Our unit of analysis was the patient visit, occurring at approximately 6 month intervals for a median of 1.5 years following enrollment. Changes in anticoagulation treatment satisfaction after NB were examined descriptively in a subset of patients. Results -The median age of the overall population was 75.0 (IQR 67.0 - 81.0); 90.0% were white and 42.5% were female. Among 6771 patients (18,560 visits), n=1357 (20.0%) had documented NB, for an incidence rate of 14.8 events per 100 person-years. Over 96.4% of patients remained on OAC therapy after the NB event. Overall, 287 (4.3%) patients experienced major bleeding and 64 (0.96%) had a SSE event during follow-up. NB was not associated with a significant increased risk of major bleeding over 6 months models adjusting for the ATRIA bleeding score (OR 1.04; 95% CI 0.68-1.60; p=0.86). NB was also not associated with increased SSE risk over 6 months in or models adjusting for CHA2DS2-VASc risk score (OR 1.24; 95% CI 0.53-2.91; p=0.62). Conclusions -Nuisance bleeding is common among AF patients on OAC. However, NB was not associated with a higher risk of major bleeding or SSE over the next 6 months, suggesting its occurrence should not lead to changes in anticoagulation treatment strategies in OAC-treated patients. Clinical Trial Registration -URL: https://clinicaltrials.gov Unique Identifier: NCT01165710.

    View details for PubMedID 29678813

  • Stroke Risk and Treatment in Patients with Atrial Fibrillation and Low CHA2DS2-VASc Scores: Findings From the ORBIT-AF I and II Registries. Journal of the American Heart Association Jackson, L. R., Kim, S., Fonarow, G. C., Freeman, J. V., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Singer, D., Thomas, L., Blanco, R., Peterson, E. D., Piccini, J. P., Outcomes Registry for Better Informed Treatment of Atrial Fibrillation Patients and Investigators 2018; 7 (16): e008764

    Abstract

    Background Current American College of Cardiology/American Heart Association guidelines suggest that for patients with atrial fibrillation who are at low risk for stroke (CHA2DS2VASc=1) (or women with CHA2DS2VASc=2) a variety of treatment strategies may be considered. However, in clinical practice, patterns of treatment in these "low-risk" patients are not well described. The objective of this analysis is to define thromboembolic event rates and to describe treatment patterns in patients with low-risk CHA2DS2VASc scores. Methods and Results We compared characteristics, treatment strategies, and outcomes among patients with a CHA2DS2VASc=0, CHA2DS2VASc=1, females with a CHA2DS2VASc=2, and CHA2DS2VASc ≥2 in ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) I & II. Compared with CHA2DS2VASc ≥2 patients (84.2%), those with a CHA2DS2VASc=0 (60.3%), 1 (69.9%), and females with a CHA2DS2VASc score=2 (72.4%) were significantly less often treated with oral anticoagulation ( P<0.0001). Stroke rates were low overall and ranged from 0 per 100 patient-years in those with CHA2DS2VASc=0, 0.8 (95% confidence interval [CI] [0.5-1.2]) in those with CHA2DS2VASc=1, 0.8 (95% CI [0.4-1.6]) in females with a CHA2DS2VASc score=2, and 1.7 (95% CI [1.6-1.9]) in CHA2DS2VASc ≥2. All-cause mortality (per 100 patient-years) was highest in females with a CHA2DS2VASc score=2 (1.4) (95% CI [0.8-2.3]), compared with patients with a CHA2DS2VASc=0 (0.2) (95% CI [0.1-1.0]), and CHA2DS2VASc=1 (1.0) (95% CI [0.7-1.4]), but lower than patients with a CHA2DS2VASc ≥2 (5.7) (95% CI [5.4-6.0]). Conclusion The majority of CHA2DS2VASc=0-1 patients are treated with oral anticoagulation. In addition, the absolute risks of death and stroke/transient ischemic attack were low among both male and females CHA2DS2VASc=0-1 as well as among females with a CHA2DS2VASc score=2. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01701817.

    View details for PubMedID 30369317

  • Initiating anticoagulation with the intention of cardioverting: does drug choice matter? EUROPEAN HEART JOURNAL Mahaffey, K. W., Turakhia, M. P. 2018; 39 (32): 2972–74
  • Stroke Risk and Treatment in Patients with Atrial Fibrillation and Low CHA(2)DS(2)-VASc Scores: Findings From the ORBIT-AF I and II Registries JOURNAL OF THE AMERICAN HEART ASSOCIATION Jackson, L. R., Kim, S., Fonarow, G. C., Freeman, J. V., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Singer, D., Thomas, L., Blanco, R., Peterson, E. D., Piccini, J. P., Outcomes Registry Better Informed 2018; 7 (16)
  • Letter by Matthews et al Regarding Article, "Class Effect for Sodium Glucose-Cotransporter-2 Inhibitors in Cardiovascular Outcomes: Implications for the Cardiovascular Disease Specialist" CIRCULATION Matthews, D. R., Perkovic, V., Mahaffey, K. W. 2018; 138 (6): 660–61
  • Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Quinn, G. R., Hellkamp, A. S., Hankey, G. J., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fava, M., Fox, K. A., Halperin, J. L., Mahaffey, K. W., Nessel, C. C., Patel, M. R., Piccini, J. P., Singer, D. E. 2018; 7 (15)
  • Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial. Journal of the American Heart Association Quinn, G. R., Hellkamp, A. S., Hankey, G. J., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fava, M., Fox, K. A., Halperin, J. L., Mahaffey, K. W., Nessel, C. C., Patel, M. R., Piccini, J. P., Singer, D. E. 2018; 7 (15): e008755

    Abstract

    Background There is concern that selective serotonin reuptake inhibitors ( SSRI s) substantially increase bleeding risk in patients taking anticoagulants. Methods and Results We studied 737 patients taking SSRI s in the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Embolism and Stroke Trial in Atrial Fibrillation) trial of rivaroxaban compared with warfarin for the prevention of stroke/systemic embolism in patients with atrial fibrillation. These patients were propensity score matched 1:1 to 737 patients not taking SSRI s. The primary outcome measure was major and nonmajor clinically relevant bleeding events, the principal safety outcome in ROCKET AF . Over a mean 1.6years of follow-up, the rate of major/ nonmajor clinically relevant bleeding was 18.57 events/100 patient-years for SSRI users versus 16.84 events/100 patient-years for matched comparators, adjusted hazard ratio ( aHR ) of 1.16 (95% confidence interval [CI], 0.95-1.43). The aHR s were similar in patients taking rivaroxaban ( aHR 1.11 [95% CI, 0.82-1.51]) and those taking warfarin ( aHR 1.21 [95% CI, 0.91-1.60]). For the rarer outcome of major bleeding, the aHR for SSRI users versus those not taking SSRI s was 1.13 (95% CI, 0.62-2.06) for rivaroxaban; for warfarin, the aHR was higher, at 1.58 (95% CI , 0.96-2.60) but not statistically significantly elevated. Conclusions We found no significant increase in bleeding risk when SSRI s were combined with anticoagulant therapy, although there was a suggestion of increased bleeding risk with SSRI s added to warfarin. While physicians should be vigilant regarding bleeding risk, our results provide reassurance that SSRI s can be safely added to anticoagulants in patients with atrial fibrillation . Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00403767.

    View details for PubMedID 30371223

  • Letter by Matthews et al Regarding Article, "Class Effect for Sodium Glucose-Cotransporter-2 Inhibitors in Cardiovascular Outcomes: Implications for the Cardiovascular Disease Specialist". Circulation Matthews, D. R., Perkovic, V., Mahaffey, K. W. 2018; 138 (6): 660-661

    View details for DOI 10.1161/CIRCULATIONAHA.118.035717

    View details for PubMedID 30354619

  • Safety of ticagrelor in patients with baseline conduction abnormalities: A PLATO (Study of Platelet Inhibition and Patient Outcomes) analysis AMERICAN HEART JOURNAL Scirica, B. M., Bansilal, S., Davoudi, F., Armstrong, P. W., Clare, R. M., Schulte, P. J., Pieper, K. S., Becker, R. C., James, S. K., Storey, R. F., Steg, P., Held, C., Himmelmann, A., Mahaffey, K. W., Wallentin, L., Cannon, C. P., PLATO Steering Comm & Investigato 2018; 202: 54–60

    Abstract

    Although bradyarrhythmias have been observed with ticagrelor and its use with advanced atrioventricular block is not recommended, questions arise regarding its use in patients with mild conduction abnormalities. The objectives were to compare rates of clinically relevant arrhythmias in relation to any mild baseline conduction abnormality in patients with acute coronary syndrome randomized to ticagrelor versus clopidogrel.We included all subjects in the electrocardiographic (ECG) substudy of the Platelet Inhibition and Patient Outcomes trial, excluding those with missing baseline ECG or with a pacemaker at baseline (N = 15,460). Conduction abnormality was defined as sinus bradycardia, first-degree atrioventricular block, hemiblock, or bundle-branch block. The primary arrhythmic outcome was the composite of any symptomatic brady- or tachyarrhythmia, permanent pacemaker placement, or cardiac arrest through 12 months.Patients with baseline conduction abnormalities (n = 4,256, 27.5%) were older and more likely to experience the primary arrhythmic outcome. There were no differences by ticagrelor versus clopidogrel in the composite arrhythmic end point in those with baseline conduction disease (1-year cumulative incidence rate: 17% for both study arms; hazard ratio: 0.99 [0.86-1.15]) or without baseline conduction disease (1-year cumulative incidence rate: clopidogrel 12.8% vs ticagrelor 12.4%; hazard ratio: 0.98 (0.88-1.09). There were also no statistically significant differences between ticagrelor and clopidogrel in the rates of bradycardic (or any individual arrhythmic) events in patients with baseline conduction abnormalities.Ticagrelor compared to clopidogrel did not increase arrhythmic events even in subjects with acute coronary syndrome who present with mild conduction abnormalities on their baseline ECG.

    View details for PubMedID 29859968

  • Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program CIRCULATION Radholm, K., Figtree, G., Perkovic, V., Solomon, S. D., Mahaffey, K. W., de Zeeuw, D., Fulcher, G., Barrett, T. D., Shaw, W., Desai, M., Matthews, D. R., Neal, B. 2018; 138 (5): 458–68

    Abstract

    BACKGROUND : Canagliflozin is a sodium glucose cotransporter 2 inhibitor that reduces the risk of cardiovascular events. We report the effects on heart failure and cardiovascular death overall, in those with and without a baseline history of heart failure, and in other participant subgroups. METHODS : The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) enrolled 10 142 participants with type 2 diabetes mellitus and high cardiovascular risk. Participants were randomly assigned to canagliflozin or placebo and followed for a mean of 188 weeks. The primary end point for these analyses was adjudicated cardiovascular death or hospitalized heart failure. RESULTS : Participants with a history of heart failure at baseline (14.4%) were more frequently women, white, and hypertensive and had a history of prior cardiovascular disease (all P<0.001). Greater proportions of these patients were using therapies such as blockers of the renin angiotensin aldosterone system, diuretics, and β-blockers at baseline (all P<0.001). Overall, cardiovascular death or hospitalized heart failure was reduced in those treated with canagliflozin compared with placebo (16.3 versus 20.8 per 1000 patient-years; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.67-0.91), as was fatal or hospitalized heart failure (HR, 0.70; 95% CI, 0.55-0.89) and hospitalized heart failure alone (HR, 0.67; 95% CI, 0.52-0.87). The benefit on cardiovascular death or hospitalized heart failure may be greater in patients with a prior history of heart failure (HR, 0.61; 95% CI, 0.46-0.80) compared with those without heart failure at baseline (HR, 0.87; 95% CI, 0.72-1.06; P interaction =0.021). The effects of canagliflozin compared with placebo on other cardiovascular outcomes and key safety outcomes were similar in participants with and without heart failure at baseline (all interaction P values >0.130), except for a possibly reduced absolute rate of events attributable to osmotic diuresis among those with a prior history of heart failure (P=0.03). CONCLUSIONS : In patients with type 2 diabetes mellitus and an elevated risk of cardiovascular disease, canagliflozin reduced the risk of cardiovascular death or hospitalized heart failure across a broad range of different patient subgroups. Benefits may be greater in those with a history of heart failure at baseline. CLINICAL TRIAL REGISTRATION : URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.

    View details for PubMedID 29526832

  • International Validation of the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention in Post-MI Patients: A Collaborative Analysis of the Chronic Kidney Disease Prognosis Consortium and the Risk Validation Scientific Committee JOURNAL OF THE AMERICAN HEART ASSOCIATION Mok, Y., Ballew, S. H., Bash, L. D., Bhatt, D. L., Boden, W. E., Bonaca, M. P., Carrero, J., Coresh, J., D'Agostino, R. B., Elley, C., Fowkes, F. R., Jee, S., Kovesdy, C. P., Mahaffey, K. W., Nadkarni, G., Peterson, E. D., Sang, Y., Matsushita, K. 2018; 7 (14)

    Abstract

    The Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention (TRS2°P), a 0-to-9-point system based on the presence/absence of 9 clinical factors, was developed to classify the risk of major adverse cardiovascular events (MACE) (a composite of cardiovascular death, recurrent myocardial infarction, or ischemic stroke) among patients with a recent myocardial infarction. Its performance has not been examined internationally outside of a clinical trial setting.We evaluated the performance of TRS2°P for predicting MACE in 53 599 patients with recent myocardial infarction in 5 international cohorts from New Zealand, South Korea, Sweden, and the United States participating in the Chronic Kidney Disease Prognosis Consortium. Overall, there were 19 444 cases of MACE across 5 cohorts over a mean follow-up of 5 years, and the overall MACE rate ranged from 5.0 to 18.4 (per 100 person-years). The TRS2°P showed modest calibration (Brier score ranged from 0.144 to 0.173) and discrimination (C-statistics >0.61 in all studies except 1 from Korea with 0.55) across cohorts relative to its original Brier score of 0.098 and C-statistic of 0.67 in the derived data set. Although there was some heterogeneity across cohorts, the 9 predictors in the TRS2°P were generally associated with higher MACE risk, with strongest associations observed (meta-analyzed adjusted hazard ratio 1.6-1.7) for history of heart failure, age ≥75 years, and prior stroke, followed by peripheral artery disease, kidney dysfunction, diabetes mellitus, and hypertension (hazard ratio 1.3-1.4). Prior coronary bypass graft surgery and smoking did not reach statistical significance (hazard ratio ≈1.1).TRS2°P, a simple scoring system with 9 routine clinical factors, was modestly predictive of secondary events when applied in patients with recent myocardial infarction from diverse clinical and geographic settings.

    View details for DOI 10.1161/JAHA.117.008426

    View details for Web of Science ID 000452803800010

    View details for PubMedID 29982232

    View details for PubMedCentralID PMC6064832

  • Discharge timing and outcomes after uncomplicated non-ST-segment elevation acute myocardial infarction AMERICAN HEART JOURNAL Rymer, J. A., Tempelhof, M. W., Clare, R. M., Pieper, K. S., Granger, C. B., Van de Werf, F., Moliterno, D. J., Harrington, R. A., White, H. D., Armstrong, P. W., Lopes, R. D., Mahaffey, K. W., Newby, L. 2018; 201: 103–10

    Abstract

    Length of stay after non-ST-segment elevation myocardial infarction (NSTEMI) continues to decrease, but information to guide duration of hospitalization is limited.We used landmark analyses, in which the landmark defined potential days of discharge, to estimate complication rates on the first day the patient would have been out of the hospital, and estimated associations between timing of discharge and 30-day and 1-year event-free survival after discharge among NSTEMI patients.Among 20,410 NSTEMI patients, median length of stay was 7 (4, 12) days; 3,209 (15.7%) experienced a cardiac complication on days 0 to 2 and 1,322 (6.5%) were discharged without complications during hospital days 0 to 2. At the start of day 3, 15,879 patients (77.8%) were still hospitalized without complications. Of these, 1,689 (10.6%) were discharged event-free on day 3. Adjusted event-free survival rates of death or myocardial infarction from day 4 to 30 days after among the 1,689 patients was 99.1% compared with 93.1% for the 14,190 who remained hospitalized at the end of day 3. For 1-year mortality, these rates were 98.1% and 96.4%, respectively. Among 13,334 patients hospitalized without complications at the start of day 4, 1,706 were discharged event-free that day. Adjusted survival rates among these patients, compared with those still hospitalized at the end of day 4, were 98.0% versus 93.7% for 30-day death or myocardial infarction and 97.8% versus 96.1% for 1-year mortality.Patients with NSTEMI who had no serious complications during the first 2 hospital days were at low risk of subsequent short- and intermediate-term death or ischemic events.

    View details for PubMedID 29910048

  • Incidence, timing, and type of first and recurrent ischemic events in patients with and without peripheral artery disease after an acute coronary syndrome AMERICAN HEART JOURNAL Inohara, T., Pieper, K., Wojdyla, D. M., Patel, M. R., Jones, W., Tricoci, P., Mahaffey, K. W., James, S. K., Alexander, J. H., Lopes, R. D., Wallentin, L., Oilman, E., Roe, M. T., Vemulapalli, S. 2018; 201: 25–32

    Abstract

    Patients with peripheral artery disease (PAD) are known to have an increased risk of ischemic cardiovascular events. However, the influence of concomitant PAD on first and subsequent recurrent ischemic events after an acute coronary syndrome (ACS) remains poorly characterized.We analyzed the combined data set from 4 randomized trials (PLATO, APPRAISE-2, TRA-CER, and TRILOGY ACS) in ACS for a follow-up length of 1 year. Using multivariable regression, we examined the association between PAD and major adverse cardiovascular events, a composite of cardiovascular death, myocardial infarction, and stroke. Among patients with a nonfatal first event, we evaluated the incidence and type of a second recurrent event.A total of 4,098 of 48,094 (8.5%) post-ACS patients had a history of PAD. The unadjusted frequency of major adverse cardiovascular events was 2-fold higher in patients with PAD (14.3% vs 7.5%) over a median (25th-75th) follow-up of 353 (223-365) days with an adjusted hazard ratio of 1.63 (95% CI: 1.48-1.78; P < .001). The frequency of recurrent ischemic events among those patients with a first, nonfatal event was higher among those with PAD (40.0% vs 27.7%). The relative frequency of each event type (cardiovascular death, noncardiovascular death, myocardial infarction, or stroke) within first and subsequent ischemic events was similar regardless of PAD status at baseline.Patients with PAD have a significantly higher risk of first and recurrent ischemic events in the post-ACS setting. These findings highlight the opportunity for improved treatments in patients with PAD who experience an ACS.

    View details for PubMedID 29910052

  • Therapeutic Strategies Following Major, Clinically Relevant Nonmajor, and Nuisance Bleeding in Atrial Fibrillation: Findings From ORBIT-AF JOURNAL OF THE AMERICAN HEART ASSOCIATION O'Brien, E. C., Holmes, D. N., Thomas, L., Fonarow, G. C., Kowey, P. R., Ansell, J. E., Mahaffey, K. W., Gersh, B. J., Peterson, E. D., Piccini, J. P., Hylek, E. M. 2018; 7 (12)

    Abstract

    Oral anticoagulation (OAC) reduces stroke risk in atrial fibrillation, but bleeding is a frequent side effect. The decision to discontinue or modify medication regimens in response to a bleeding event may differ according to bleeding site and severity.We used data from a large, national outpatient registry, ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation; 2010-2011), to evaluate event characteristics and OAC management following the first bleeding event occurring during follow-up. Bleeding events were classified into 3 categories: (1) International Society of Thrombosis and Hemostasis major bleeding, (2) clinically relevant nonmajor bleeding requiring medical attention, and (3) nuisance bleeding not requiring medical attention (eg, bruising, hemorrhoidal bleeding). Of 9743 patients enrolled in ORBIT-AF with follow-up data, 510 (3.23/100 subject-years) experienced a major bleed, 615 (3.90/100 subject-years), experienced a clinically relevant nonmajor bleed, and 1558 (9.87/100 subject-years) experienced a nuisance bleed, among first bleeds over 2 years. Nearly one third of patients (31.6%) discontinued OAC therapy following a major bleeding event, 12.7% following a clinically relevant nonmajor bleed, and 4.5% following a nuisance bleed. Compared with those who experienced a clinically relevant nonmajor or nuisance bleed, patients who experienced a major bleed were more likely to be black and female and to have a history of heart failure and stroke. Those who discontinued were more likely to have central nervous system or gastrointestinal bleeding than those who persisted on OAC therapy.Overall, 1 in 3 patients who experienced a major bleed was no longer anticoagulated after the event. Those who discontinued OAC were more likely to have central nervous system or gastrointestinal bleeding than those who persisted on OAC.

    View details for PubMedID 29886422

  • Definitions of peri-procedural myocardial infarction and the association with one-year mortality: Insights from CHAMPION trials. International journal of cardiology Olivier, C. B., Sundaram, V., Bhatt, D. L., Leonardi, S., Lopes, R. D., Ding, V. Y., Yang, L., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., White, H. D., Desai, M., Lynch, D. R., Harrington, R. A., Mahaffey, K. W., CHAMPION PLATFORM and CHAMPION PCI Investigators 2018

    Abstract

    BACKGROUND: Controversies exist over the appropriate definition for peri-procedural myocardial infarction (PPMI) and its association with mortality. This study aims to evaluate one-year survival following percutaneous coronary intervention (PCI) and the association of different definitions of PPMI with survival among patients with stable angina (SA) or acute coronary syndrome (ACS) in the contemporary era.METHODS: We used data from the CHAMPION PLATFORM and CHAMPION PCI trials of patients undergoing PCI and conducted univariable and multivariable Cox proportional hazard regression models to evaluate mortality risk during the first year after PCI. A blinded events committee adjudicated suspected PPMI defined by biomarker elevations ≥3* the upper limit of normal (ULN) or new Q-waves. We further analyzed PPMI by the magnitude of CK-MB elevation ([a] 3 to <5* ULN, [b] 5 to <10* ULN, [c] ≥10* ULN) or by the 2nd universal definition of myocardial infarction (UDMICK-MB) excluding patients with evidence of myocardial infarction (MI) prior to PCI.RESULTS: Of 13,968 patients, 11% initially presented with SA, and 89% with ACS. One-year mortality was 3.4% (SA: 1.5%; ACS: 3.6%). PPMI occurred in 6.3% of the patients (3 to <5* ULN: 2.5%; 5 to <10* ULN: 2.1%; ≥10* ULN: 1.6%; UDMICK-MB: 2.7%). After multivariable adjustment, a significantly higher risk of one-year mortality was observed for patients with PPMI compared with patients without PPMI (HR 2.35 [1.74-3.18], p < 0.001; 3 to <5* ULN: 1.55 [0.92-2.62], p = 0.10; 5 to <10* ULN: 1.22 [0.67-2.20], p = 0.52; ≥10* ULN: 4.78 [3.06-7.47], p < 0.001; UDMICK-MB: 2.19 [1.29-3.73], p = 0.004).CONCLUSION: PPMI occurred in 6.3% of the patients and was associated with increased risk of death within one year. Survival was not significantly impacted by PPMI if defined by periprocedural CK-MB elevations <10* ULN alone and without additional evaluation of symptoms or evidence of ischemia. These findings highlight the importance of PPMI for long-term outcome in the contemporary era and of its definition in the planning and interpretation of clinical trials.

    View details for PubMedID 29937301

  • Initiating anticoagulation with the intention of cardioverting: does drug choice matter? European heart journal Mahaffey, K. W., Turakhia, M. P. 2018

    View details for PubMedID 29873723

  • Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes - A systematic review DIABETES RESEARCH AND CLINICAL PRACTICE Radholm, K., Wu, J. Y., Wong, M., Foote, C., Fulcher, G., Mahaffey, K. W., Perkovic, V., Neal, B. 2018; 140: 118–28

    Abstract

    Sodium glucose co-transporter 2 (SGLT2) inhibitors appear to protect against increased risks of cardiovascular and kidney disease in patients with type 2 diabetes but also cause some harms. Whether effects are comparable across drug class or specific to individual compounds is unclear. This meta-analysis assessed the class and individual compound effects of SGLT2 inhibition versus control on cardiovascular events, death, kidney disease and safety outcomes in patients with type 2 diabetes.MEDLINE, EMBASE, the Cochrane Library and regulatory databases were systematically searched for data from randomized clinical trials that included reporting of cardiovascular events, deaths or safety outcomes. We used fixed effects models and inverse variance weighting to calculate relative risks with the 95% confidence intervals.The analyses included data from 82 trials, four overviews and six regulatory reports and there were 1,968 major cardiovascular events identified for analysis. Patients randomly assigned to SGLT2 had lower risks of major cardiovascular events (RR 0.85, 95%CI 0.77-0.93), heart failure (RR 0.67, 95%CI 0.55-0.80), all-cause death (RR 0.79, 95%CI 0.70-0.88) and serious decline in kidney function (RR 0.59, 0.49-0.71). Significant adverse effects were observed for genital infections (RR 3.06, 95%CI 2.73-4.43), volume depletion events (RR 1.24, 95%CI 1.07-1.43) and amputation (RR 1.44 95%CI 1.13-1.83). There was a high likelihood of differences in the associations of the individual compounds with cardiovascular death, hypoglycaemia and amputation (all I2 > 80%) and a moderate likelihood of differences in the associations with non-fatal stroke, all-cause death, urinary tract infection and fracture (all I2 > 30%).There are strong overall associations of SGLT2 inhibition with protection against major cardiovascular events, heart failure, serious decline in kidney function and all-cause death. SGLT2 inhibitors were also associated with infections, volume depletion effects and amputation. Some associations appear to differ between compounds.

    View details for PubMedID 29604389

  • Impact of polyvascular disease on patients with atrial fibrillation: Insights from ROCKET AF AMERICAN HEART JOURNAL Chen, S. T., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R. 2018; 200: 102–9

    Abstract

    We investigated the impact of polyvascular disease in patients enrolled in ROCKET AF.Cox regression models were used to assess clinical outcomes and treatment effects of rivaroxaban compared with warfarin in patients with atrial fibrillation and coronary, peripheral, or carotid artery disease, or any combination of the 3.A total of 655 (4.6%) patients had polyvascular disease (≥2 disease locations), and 3,391 (23.8%) had single-arterial bed disease. Patients with polyvascular disease had similar rates of stroke/systemic embolism but higher rates of cardiovascular and bleeding events when compared with those without vascular disease. Use of rivaroxaban compared with warfarin was associated with higher rates of stroke in patients with polyvascular disease (hazard ratio [HR] 2.41, 95% CI 1.05-5.54); however, this was not seen in patients with single-bed (HR 0.90, 95% CI 0.64-1.28) or no vascular disease (HR 0.85, 95% CI 0.69-1.04; interaction P = .058). There was a significant interaction for major or nonmajor clinically relevant bleeding in patients with polyvascular (HR 1.23, 95% CI 0.91-1.65) and single-bed vascular disease (HR 1.30, 95% CI 1.13-1.49) treated with rivaroxaban compared with warfarin when compared with those without vascular disease (HR 0.95, 95% CI 0.87-1.04; interaction P = .0006). Additional antiplatelet therapy in this population did not improve stroke or cardiovascular outcomes.The use of rivaroxaban compared with warfarin was associated with a higher risk of stroke and bleeding in patients with polyvascular disease enrolled in ROCKET AF. Further studies are needed to understand the optimal management of this high-risk population.

    View details for PubMedID 29898836

  • Prognostic and Practical Validation of Current Definitions of Myocardial Infarction Associated With Percutaneous Coronary Intervention JACC-CARDIOVASCULAR INTERVENTIONS Tricoci, P., Newby, L., Clare, R. M., Leonardi, S., Gibson, C., Giugliano, R. P., Armstrong, P. W., Van de Werf, F., Montalescot, G., Moliterno, D. J., Held, C., Aylward, P. E., Wallentin, L., Harrington, R. A., Braunwald, E., Mahaffey, K. W., White, H. D. 2018; 11 (9): 856-+

    Abstract

    In 13,038 patients with non-ST-segment elevation acute coronary syndrome undergoing index percutaneous coronary intervention (PCI) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) and TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trials, the relationship between PCI-related myocardial infarction (MI) and 1-year mortality was assessed.The definition of PCI-related MI is controversial. The third universal definition of PCI-related MI requires cardiac troponin >5 times the 99th percentile of the normal reference limit from a stable or falling baseline and PCI-related clinical or angiographic complications. The definition from the Society for Cardiovascular Angiography and Interventions (SCAI) requires creatine kinase-MB elevation >10 times the upper limit of normal (or 5 times if new electrocardiographic Q waves are present). Implications of these definitions on prognosis, prevalence, and implementation are not established.In our cohort of patients undergoing PCI, PCI-related MIs were classified using the third universal type 4a MI definition and SCAI criteria. In the subgroup of patients included in the angiographic core laboratory (ACL) substudy of EARLY ACS (n = 1,401) local investigator- versus ACL-reported angiographic complications were compared.Altogether, 2.0% of patients met third universal definition of PCI-related MI criteria, and 1.2% met SCAI criteria. One-year mortality was 3.3% with the third universal definition (hazard ratio: 1.96; 95% confidence interval: 1.24 to 3.10) and 5.3% with SCAI criteria (hazard ratio: 2.79; 95% confidence interval: 1.69 to 4.58; p < 0.001). Agreement between ACL and local investigators in detecting angiographic complications during PCI was overall moderate (κ = 0.53).The third universal definition of MI and the SCAI definition were both associated with significant risk for mortality at 1 year. Suboptimal concordance was observed between ACL and local investigators in identifying patients with PCI complications detected on angiography. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRA·CER] [Study P04736]; NCT00527943; EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome [Study P03684AM2]; NCT00089895).

    View details for PubMedID 29747915

  • External validation of the TIMI risk score for secondary cardiovascular events among patients with recent myocardial infarction ATHEROSCLEROSIS Williams, B. A., Chagin, K. M., Bash, L. D., Boden, W. E., Duval, S., Fowkes, F. R., Mahaffey, K. W., Patel, M. D., D'Agostino, R. B., Peterson, E. D., Kattan, M. W., Bhatt, D. L., Bonaca, M. P. 2018; 272: 80–86

    Abstract

    Risk stratification of patients with recent myocardial infarction (MI) for subsequent cardiovascular (CV) events helps identify patients most likely to benefit from secondary prevention therapies. This study externally validated a new risk score (TRS2˚P) for secondary events derived from the TRA2°P-TIMI 50 trial among post-MI patients from two large health care systems.This retrospective cohort study included 9618 patients treated for acute MI at either the Cleveland Clinic (CC) or Geisinger Health System (GHS) between 2008 and 2013. Patients with a clinic visit within 2-52 weeks of MI were included and followed for CV death, repeat MI, and ischemic stroke through electronic medical records (EMR). The TRS2˚P is based on nine factors determined through EMR documentation. Discrimination and calibration of the TRS2˚P were quantified in both patient populations.MI patients at CC and GHS were older, had more comorbidities, received fewer medications, and had higher 3-year event rates compared to subjects in the TRA2°P trial: 31% (CC), 33% (GHS), and 10% (TRA2°P-TIMI 50). The proposed risk score had similar discrimination across the three cohorts with c-statistics of 0.66 (CC), 0.66 (GHS), and 0.67 (TRA2°P-TIMI 50). A strong graded relationship between the risk score and event rates was observed in all cohorts, though 3-year event rates were consistently higher within TRS2°P strata in the CC and GHS cohorts relative to TRA2˚P-TIMI 50.The TRS2˚P demonstrated consistent risk discrimination across trial and non-trial patients with recent MI, but event rates were consistently higher in the non-trial cohorts.

    View details for PubMedID 29579671

  • Mineralocorticoid Receptor Antagonism in Patients With Atrial Fibrillation: Findings From the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) Registry JOURNAL OF THE AMERICAN HEART ASSOCIATION Fudim, M., Liu, P. R., Shrader, P., Blanco, R. G., Allen, L. A., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Hylek, E., Go, A. S., Thomas, L., Peterson, E. D., Piccini, J. P. 2018; 7 (8)

    Abstract

    Mineralocorticoid receptor antagonist (MRA) therapy may be beneficial to patients with atrial fibrillation (AF), but little is known about their use in patients with AF and subsequent outcomes.In order to better understand MRA use and subsequent outcomes, we performed a retrospective cohort study of the contemporary ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry. AF progression and cardiovascular outcomes were compared using propensity-matched Cox proportional hazards modeling according to MRA use at baseline and new MRA use at follow-up versus patients with no MRA use. Among 7012 patients with nonpermanent AF, 320 patients were taking MRA at enrollment, and 416 patients initiated MRA use during follow-up. The mean patient age was 72.5 years, 56.3% were men, and 70.4% had paroxysmal AF. Among all patients taking MRAs, 434 (59.0%) had heart failure, 655 (89.0%) had hypertension, and 380 (51.6%) had both. After adjustment, new MRA use was not associated with reduced AF progression (hazard ratio, 1.18; 95% confidence interval, 0.88-1.58; P=0.27) but showed a trend towards lower risk of stroke, transient ischemic attack, or systemic embolism (hazard ratio, 0.17; 95% confidence interval, 0.02-1.23; P=0.08). Results were similar for a comparison of new MRA users and baseline MRA users compared with nonusers.In community-based outpatients with AF, the majority of MRA use was for heart failure and hypertension. MRA use also trended towards lower adjusted stroke risk. Future studies should test the hypothesis that MRA use may decrease the risk of stroke in patients with AF.

    View details for PubMedID 29654203

  • Net clinical benefit of rivaroxaban compared with warfarin in atrial fibrillation: Results from ROCKET AF INTERNATIONAL JOURNAL OF CARDIOLOGY Barnett, A. S., Cyr, D. D., Goodman, S. G., Levitan, B. S., Yuan, Z., Hankey, G. J., Singer, D. E., Becker, R. C., Breithardt, G., Berkowitz, S. D., Halperin, J. L., Hacke, W., Mahaffey, K. W., Nessel, C. C., Fox, K. A., Patel, M. R., Piccini, J. P. 2018; 257: 78–83

    Abstract

    The aim of this study was to determine the net clinical benefit (NCB) of rivaroxaban compared with warfarin in patients with atrial fibrillation.This was a retrospective analysis of 14,236 patients included in ROCKET AF who received at least one dose of study drug. We analyzed NCB using four different methods: (1) composite of death, stroke, systemic embolism, myocardial infarction, and major bleeding; (2) method 1 with fatal or critical organ bleeding substituted for major bleeding; (3) difference between the rate of ischemic stroke or systemic embolism minus 1.5 times the difference between the rate of intracranial hemorrhage; and (4) weighted sum of differences between rates of death, ischemic stroke or systemic embolism, intracranial hemorrhage, and major bleeding.Rivaroxaban was associated with a lower risk of the composite outcome of death, myocardial infarction, stroke, or systemic embolism (rate difference per 10,000 patient-years [RD]=-86.8 [95% CI -143.6 to -30.0]) and fatal or critical organ bleeding (-41.3 [-68 to -14.7]). However, rivaroxaban was associated with a higher risk of major bleeding other than fatal or critical organ bleeding (55.9 [14.7 to 97.2]). Method 1 showed no difference between treatments (-35.5 [-108.4 to 37.3]). Methods 2-4 favored treatment with rivaroxaban (2: -96.8 [-157.0 to -36.8]; 3: -65.2 [-112.3 to -17.8]; 4: -54.8 [-96.0 to -10.2]).Rivaroxaban was associated with favorable NCB compared with warfarin. The NCB was attributable to lower rates of ischemic events and fatal or critical organ bleeding.

    View details for PubMedID 29506743

  • Incidence, Predictors, and Outcomes of Acquired Thrombocytopenia After Percutaneous Coronary Intervention: A Pooled, Patient-Level Analysis of the CHAMPION Trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). Circulation. Cardiovascular interventions Groves, E. M., Bhatt, D. L., Steg, P. G., Deliargyris, E. N., Stone, G. W., Gibson, C. M., Hamm, C. W., Mahaffey, K. W., White, H. D., Angiolillo, D., Prats, J., Harrington, R. A., Price, M. J. 2018; 11 (4): e005635

    Abstract

    BACKGROUND: The influence of cangrelor on the incidence and outcomes of post-percutaneous coronary intervention (PCI) thrombocytopenia is not defined. We aimed to explore the incidence, predictors, and clinical impact of thrombocytopenia after PCI in cangrelor-treated patients.METHODS AND RESULTS: This was a pooled, patient-level analysis of the CHAMPION trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), which compared cangrelor with clopidogrel for prevention of thrombotic complications during and after PCI. Acquired thrombocytopenia was defined as either a drop in platelet count to <100 000 after PCI or a drop of >50% between baseline and a follow-up. The main efficacy outcome was major adverse cardiac events. The primary safety outcome was noncoronary artery bypass grafting-related Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries-defined severe bleeding at 48 hours. Patients (23 783) were enrolled, and 3009 (12.7%) received a GPI (glycoprotein IIb/IIIa inhibitor). Acquired thrombocytopenia occurred in 200 patients (0.8%). The adjusted rate of major adverse cardiovascular events at 48 hours was significantly higher in patients who developed thrombocytopenia compared with those who did not (odds ratio, 3.00; 95% confidence interval, 1.89-4.69; P<0.001), as was major bleeding (odds ratio, 14.71; 95% confidence interval, 5.96-36.30; P<0.001). GPI use was the strongest independent predictor of acquired thrombocytopenia (odds ratio, 2.93; 95% confidence interval, 2.15-3.97; P<0.0001). There was no difference in the rate of acquired thrombocytopenia in patients randomized to cangrelor or clopidogrel.CONCLUSIONS: Acquired thrombocytopenia after PCI is strongly associated with substantial early morbidity and mortality, as well as major bleeding. GPI use is a significant predictor of thrombocytopenia. Cangrelor is not associated with acquired thrombocytopenia, and its clinical efficacy and safety is consistent irrespective of thrombocytopenia occurrence.CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00305162, NCT00385138, and NCT01156571.

    View details for PubMedID 29632238

  • Incidence, Predictors, and Outcomes of Acquired Thrombocytopenia After Percutaneous Coronary Intervention A Pooled, Patient-Level Analysis of the CHAMPION Trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) CIRCULATION-CARDIOVASCULAR INTERVENTIONS Groves, E. M., Bhatt, D. L., Steg, P., Deliargyris, E. N., Stone, G. W., Gibson, C., Hamm, C. W., Mahaffey, K. W., White, H. D., Angiolillo, D., Prats, J., Harrington, R. A., Price, M. J., CHAMPION Investigators 2018; 11 (4)
  • Optimised care of elderly patients with acute coronary syndrome EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE Leonardi, S., Bueno, H., Ahrens, I., Hassager, C., Bonnefoy, E., Lettino, M. 2018; 7 (3): 287–95
  • THE EFFICACY AND SAFETY OF CANGRELOR FOR PATIENTS UNDERGOING SINGLE VESSEL VERSUS MULTI VESSEL PERCUTANEOUS CORONARY INTERVENTION: INSIGHTS FROM THE CHAMPION PHOENIX TRIAL Olivier, C., Abnousi, F., Sundaram, V., Yang, J., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., Deliargyris, E., Prats, J., White, H., Harrington, R., Bhatt, D., Mahaffey, K., Yong, C., CHAMPION PHOENIX Investigators ELSEVIER SCIENCE INC. 2018: 29
  • 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hicks, K. A., Mahaffey, K. W., Mehran, R., Nissen, S. E., Wiviott, S. D., Dunn, B., Solomon, S. D., Marler, J. R., Teerlink, J. R., Farb, A., Morrow, D. A., Targum, S. L., Sila, C. A., Hai, M., Jaff, M. R., Joffe, H. V., Cutlip, D. E., Desai, A. S., Lewis, E. F., Gibson, C., Landray, M. J., Lincoff, A., White, C. J., Brooks, S. S., Rosenfield, K., Domanski, M. J., Lansky, A. J., McMurray, J. V., Tcheng, J. E., Steinhubl, S. R., Burton, P., Mauri, L., O'Connor, C. M., Pfeffer, M. A., Hung, H., Stockbridge, N. L., Chaitman, B. R., Temple, R. J., Standardized Data Collection 2018; 71 (9): 1021–34

    Abstract

    This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the U.S. Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

    View details for PubMedID 29495982

  • Disease understanding in patients newly diagnosed with atrial fibrillation HEART Kaufman, B. G., Kim, S., Pieper, K., Allen, L. A., Gersh, B. J., Naccarelli, G. V., Ezekowitz, M. D., Fonarow, G. C., Mahaffey, K. W., Singer, D. E., Chan, P. S., Freeman, J. V., Ansell, J., Kowey, P. R., Rieffel, J. A., Piccini, J., Peterson, E., O'Brien, E. C. 2018; 104 (6): 494–501

    Abstract

    To describe self-reported disease understanding for newly diagnosed patients with atrial fibrillation (AF) and assess (1) how disease understanding changes over the first 6 months after diagnosis and (2) the relationship between patient understanding of therapies at baseline and treatment receipt at 6 months among treatment-naïve patients.We analysed survey data from SATELLITE (Survey of Patient Knowledge and Personal Priorities for Treatment), a substudy of patients with new-onset AF enrolled in the national Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) II registry across 56 US sites. Patients were surveyed at the baseline and 6-month follow-up clinic visits using Likert scales.Among 1004 baseline survey responses, patients' confidence in their understanding of rhythm control, ablation, anticoagulation and cardioversion was suboptimal, with 'high' understanding ranging from 8.5% for left atrial appendage closure to 71.3% for rhythm therapy. Of medical history and demographic factors, education level was the strongest predictor of reporting 'high' disease understanding. Among the 786 patients with 6-month survey data, significant increases in the proportion reporting high understanding were observed (p<0.05) only for warfarin and direct oral anticoagulants (DOACs). With the exception of ablation, high understanding for a given therapeutic option was not associated with increased use of that therapy at 6 months.About half of patients with new-onset AF understood the benefits of oral anticoagulant at the time of diagnosis and understanding improved over the first 6 months. However, understanding of AF treatment remains suboptimal at 6 months. Our results suggest a need for ongoing patient education.Clinicaltrials.gov. Identifier: NCT01701817.

    View details for DOI 10.1136/heartjnl-2017-311800

    View details for Web of Science ID 000428906600011

    View details for PubMedID 28790169

    View details for PubMedCentralID PMC5861387

  • 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials CIRCULATION Hicks, K. A., Mahaffey, K. W., Mehran, R., Nissen, S. E., Wiviott, S. D., Dunn, B., Solomon, S. D., Mar-Ler, J. R., Teerlink, J. R., Farb, A., Morrow, D. A., Targum, S. L., Sila, C. A., Hai, M., Jaff, M. R., Joffe, H. V., Cutlip, D. E., Desai, A. S., Lewis, E. F., Gibson, C., Landray, M. J., Lincoff, A., White, C. J., Brooks, S. S., Rosenfield, K., Domanski, M. J., Lansky, A. J., McMurray, J. V., Tcheng, J. E., Steinhubl, S. R., Burton, P., Mauri, L., O'Connor, C. M., Pfeffer, M. A., Hung, H., Stockbridge, N. L., Chaitman, B. R., Temple, R. J., Standardized Data Collection 2018; 137 (9): 961–72

    Abstract

    This publication describes uniform definitions for cardiovascular and stroke outcomes developed by the Standardized Data Collection for Cardiovascular Trials Initiative and the US Food and Drug Administration (FDA). The FDA established the Standardized Data Collection for Cardiovascular Trials Initiative in 2009 to simplify the design and conduct of clinical trials intended to support marketing applications. The writing committee recognizes that these definitions may be used in other types of clinical trials and clinical care processes where appropriate. Use of these definitions at the FDA has enhanced the ability to aggregate data within and across medical product development programs, conduct meta-analyses to evaluate cardiovascular safety, integrate data from multiple trials, and compare effectiveness of drugs and devices. Further study is needed to determine whether prospective data collection using these common definitions improves the design, conduct, and interpretability of the results of clinical trials.

    View details for PubMedID 29483172

  • Frequency and Outcomes of Reduced Dose Non-Vitamin K Antagonist Anticoagulants: Results From ORBIT-AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) JOURNAL OF THE AMERICAN HEART ASSOCIATION Steinberg, B. A., Shrader, P., Pieper, K., Thomas, L., Allen, L. A., Ansell, J., Chan, P. S., Ezekowitz, M. D., Fonarow, G. C., Freeman, J. V., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Naccarelli, G. V., Reiffel, J. A., Singer, D. E., Peterson, E. D., Piccini, J. P., Outcomes Registry Better Informed 2018; 7 (4)

    Abstract

    Non-vitamin K antagonist oral anticoagulants (NOACs) are indicated for stroke prevention in atrial fibrillation (AF) but require lower doses in certain patients. We sought to describe the frequency, appropriateness (according to Food and Drug Administration labeling), and outcomes of patients prescribed reduced doses of NOACs in community practice.We analyzed data from the ORBIT-AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) registry, a prospective, national, observational registry of AF patients. Among 7925 AF patients receiving NOACs, we assessed patterns of use of reduced NOAC doses and associated cardiovascular and bleeding outcomes at median follow-up of 1 year. Overall, 6636 patients (84%) received a NOAC at standard dose, which was consistent with US Food and Drug Administration labeling in 6376 (96%). Reduced NOAC dose was prescribed to 1289 (16% overall), which was consistent with Food and Drug Administration labeling in only 555 patients (43%). Compared with those whose NOAC dose was appropriately reduced, patients receiving inappropriate dose reductions were younger (median age 79 versus 84, P<0.0001) and had lower ORBIT bleeding risk scores (26% ≥4 versus 45%, P<0.0001). Compared with those appropriately receiving standard dosing, patients receiving inappropriately reduced-dose NOACs had higher unadjusted rates of thromboembolic events (2.11 versus 1.35 events per 100 patient years, hazard ratio 1.56, 95% confidence interval 0.92-2.67) and death (6.77 versus 2.60, hazard ratio 2.61, 95% confidence interval 1.86-3.67). After adjustment, outcomes were not significantly different but tended to favor patients dosed appropriately.The majority of dose reductions of NOACs in AF are inconsistent with US Food and Drug Administration recommendations. There appear to be opportunities to improve current NOAC dosing in community practice.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701817.

    View details for PubMedID 29453305

  • Short- and long-term mortality following bleeding events in patients undergoing percutaneous coronary intervention: insights from four validated bleeding scales in the CHAMPION trials EUROINTERVENTION Vaduganathan, M., Harrington, R. A., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., Lopes, R. D., Leonardi, S., Deliargyris, E. N., Prats, J., Mahaffey, K. W., White, H. D., Bhatt, D. L., CHAMPION Investigators 2018; 13 (15): 1841–49

    Abstract

    The aim of this study was to determine the prognostic significance of periprocedural bleeding based on various definitions on 30-day and one-year all-cause mortality in patients undergoing routine or urgent percutaneous coronary intervention (PCI).In this exploratory analysis of 25,107 patients enrolled in the three phase-3 CHAMPION trials, we assessed the prognostic impact of four bleeding scales (GUSTO, TIMI, ACUITY, and BARC) at 48 hrs. Follow-up all-cause mortality data were available at 30 days in all three trials, and at one year in CHAMPION PCI and CHAMPION PLATFORM. Bleeding rates within 48 hrs of PCI were variably identified by each clinical definition (range: <0.5% to >3.5%). Severe/major bleeding, measured by all bleeding scales, and blood transfusion requirement were independently associated with increased mortality at 30 days and one year after PCI (p<0.001 for all associations). Mild/minor bleeding was not independently predictive of one-year mortality (p>0.07 for all associations). Each bleeding definition demonstrated only modest ability to discriminate 30-day and one-year mortality (adjusted C-statistics range: 0.49 to 0.67).Commonly employed clinical definitions variably identify rates of bleeding after PCI. Severe or major, but not mild or minor, bleeding is independently associated with increased 30-day and one-year mortality. These data may aid in selection of appropriate bleeding metrics in future clinical trials.

    View details for DOI 10.4244/EIJ-D-17-00723

    View details for Web of Science ID 000424328100020

    View details for PubMedID 28988157

  • Ischaemic Events and Stent Thrombosis following Planned Discontinuation of Study Treatment with Ticagrelor or Clopidogrel in the PLATO Study THROMBOSIS AND HAEMOSTASIS Storey, R. F., Ardissino, D., Vignali, L., Cairns, R., Becker, R. C., Cannon, C. P., Mahaffey, K. W., Himmelmann, A., Katus, H. A., James, S. K., Wallentin, L., PLATO Investigators 2018; 118 (2): 427–29

    View details for PubMedID 29443375

  • Clinical features and outcomes of patients with type 2 myocardial infarction: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial AMERICAN HEART JOURNAL Guimaraes, P. O., Leonardi, S., Huang, Z., Wallentin, L., Van de Werf, F., Aylward, P. E., Held, C., Harrington, R. A., Moliterno, D. J., Armstrong, P. W., White, H. D., Alexander, K. P., Lopes, R. D., Mahaffey, K. W., Tricoci, P. 2018; 196: 28–35

    Abstract

    Type 2 myocardial infarction (MI) is characterized by an imbalance between myocardial blood supply and demand, leading to myocardial ischemia without coronary plaque rupture, but its diagnosis is challenging.In the TRACER trial, patients with non-ST-segment elevation acute coronary syndromes were included. We aimed to describe provoking factors, cardiac biomarker profiles, treatment patterns, and clinical outcomes of patients with type 2 MIs. MI events during trial follow-up were adjudicated by an independent clinical events classification committee (CEC) and were classified according to the Third Universal Definition of MI. Using available source documents retrieved as part of the CEC process, we performed a retrospective chart abstraction to collect details on the type 2 MIs. Cox regression models were used to explore the association between MI type (type 1 or type 2) and cardiovascular death.Overall, 10.3% (n=1327) of TRACER participants had a total of 1579 adjudicated MIs during a median follow-up of 502 days (25th and 75th percentiles [IQR] 349-667). Of all MIs, 5.2% (n=82) were CEC-adjudicated type 2 MIs, occurring in 76 patients. The incidence of type 2 MI was higher in the first month following randomization, after which the distribution became more scattered. The most frequent potential provoking factors for type 2 MIs were tachyarrhythmias (38.2%), anemia/bleeding (21.1%), hypotension/shock (14.5%), and hypertensive emergencies (11.8%). Overall, 36.3% had a troponin increase >10× the upper limit of normal. Coronary angiography was performed in 22.4% (n=17) of patients during hospitalizations due to type 2 MIs. The hazard of cardiovascular death was numerically higher following type 2 MI (vs. no MI, adj. HR 11.82, 95% CI 5.71-24.46; P<.0001) than that of type 1 MI (vs. no MI, adj. HR 8.90, 95% CI 6.93-11.43; P<.0001).Type 2 MIs were more prevalent in the first month after ACS, were characterized by the presence of triggers and infrequent use of an invasive strategy, and were associated with a high risk of death. Further efforts are needed to better define the role and implications of type 2 MI in both clinical practice and research.

    View details for PubMedID 29421012

  • Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study) CIRCULATION Mahaffey, K. W., Neal, B., Perkovic, V., de Zeeuw, D., Fulcher, G., Erondu, N., Shaw, W., Fabbrini, E., Sun, T., Li, Q., Desai, M., Matthews, D. R., CANVAS Program Collaborative Grp 2018; 137 (4): 323–34

    Abstract

    Canagliflozin is a sodium glucose cotransporter 2 inhibitor that significantly reduces the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes mellitus and elevated cardiovascular risk. The comparative effects among participants with and without a history of cardiovascular disease (secondary versus primary prevention) were prespecified for evaluation.The CANVAS Program (Canagliflozin Cardiovascular Assessment Study) randomly assigned 10 142 participants with type 2 diabetes mellitus to canagliflozin or placebo. The primary prevention cohort comprised individuals ≥50 years of age with ≥2 risk factors for cardiovascular events but with no prior cardiovascular event, and the secondary prevention cohort comprised individuals ≥30 years of age with a prior cardiovascular event. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included heart failure hospitalization and a renal composite (40% reduction in estimated glomerular filtration rate, renal replacement therapy, or renal death).Primary prevention participants (N=3486; 34%) were younger (63 versus 64 years of age), were more often female (45% versus 31%), and had a longer duration of diabetes mellitus (14 versus 13 years) compared with secondary prevention participants (N=6656; 66%). The primary end point event rate was higher in the secondary prevention group compared with the primary prevention group (36.9 versus 15.7/1000 patient-years, P<0.001). In the total cohort, the primary end point was reduced with canagliflozin compared with placebo (26.9 versus 31.5/1000 patient-years; hazard ratio [HR], 0.86; 95% confidence interval [CI], 0.75-0.97; P<0.001 for noninferiority, P=0.02 for superiority) with no statistical evidence of heterogeneity (interaction P value=0.18) between the primary (HR, 0.98; 95% CI, 0.74-1.30) and secondary prevention (HR, 0.82; 95% CI, 0.72-0.95) cohorts. Renal outcomes (HR, 0.59; 95% CI, 0.44-0.79 versus HR, 0.63; 95% CI, 0.39-1.02; interaction P value=0.73) and heart failure hospitalization (HR, 0.68; 95% CI, 0.51-0.90 versus HR, 0.64; 95% CI, 0.35-1.15; interaction P value=0.91) were similarly reduced in the secondary and primary prevention cohorts, respectively. Lower extremity amputations were similarly increased in the secondary and primary prevention cohorts (HR, 2.07; 95% CI, 1.43-3.00 versus HR, 1.52; 95% CI, 0.70-3.29; interaction P value=0.63).Patients with type 2 diabetes mellitus and prior cardiovascular events had higher rates of cardiovascular outcomes compared with the primary prevention patients. Canagliflozin reduced cardiovascular and renal outcomes with no statistical evidence of heterogeneity of the treatment effect across the primary and secondary prevention groups. Additional studies will provide further insights into the effects of canagliflozin in these patient populations.URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.

    View details for PubMedID 29133604

    View details for PubMedCentralID PMC5777572

  • Cangrelor compared with clopidogrel in patients with prior myocardial infarction - Insights from the CHAMPION trials INTERNATIONAL JOURNAL OF CARDIOLOGY Eisen, A., Harrington, R. A., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L., CHAMPION Investigators 2018; 250: 49–55

    Abstract

    Patients who have had a prior myocardial infarction (MI) are at increased risk for adverse outcomes after subsequent percutaneous coronary intervention (PCI).The objective of this study is to examine the efficacy and safety of cangrelor, a potent intravenous P2Y12 inhibitor, in patients with prior MI.Pooled data from the CHAMPION trials were examined. Prior MI was defined as a history of MI, excluding MI events at baseline. The primary endpoint was a composite of death, MI, ischemia-driven revascularization, or stent thrombosis at 48-h post-randomization. The primary safety endpoint was GUSTO-defined severe bleeding at 48h.Out of 24,691 patients, 5699 (23%) had a prior MI. The primary endpoint was higher in patients with vs. without prior MI (4.9% vs. 4.0%, p=0.002). The primary endpoint was 4.2% with cangrelor vs. 5.7% with clopidogrel (absolute risk reduction=1.5%; OR 0.72 [95%CI 0.57-0.92]) in patients with prior MI and 3.7% with cangrelor vs. 4.3% with clopidogrel (absolute risk reduction=0.6%; OR 0.85 [95%CI 0.74-0.99]) in patients without prior MI (P-interaction=0.25). The rate of GUSTO-defined severe bleeding was 0.1% with cangrelor vs. 0.1% with clopidogrel (OR 1.39 [95%CI 0.31-6.24]) in patients with prior MI, and 0.2% with cangrelor vs. 0.2% with clopidogrel (OR 1.18 [95%CI 0.65-2.14]) in patients without prior MI (P-interaction=0.84).In the CHAMPION trials, patients with prior MI had higher rates of ischemic outcomes within 48h after PCI. Cangrelor reduced ischemic events with no significant increase in GUSTO-defined severe bleeding in patients with or without prior MI.

    View details for PubMedID 29030140

  • Association of Healthcare Plan with Atrial Fibrillation Prescription Patterns. Clinical cardiology Chang, A. Y., Askari, M. n., Fan, J. n., Heidenreich, P. A., Ho, P. M., Mahaffey, K. W., Ullal, A. J., Perino, A. C., Turakhia, M. P. 2018

    Abstract

    Atrial fibrillation (AF) is treated by many types of physician specialists, including primary care physicians (PCPs). Health plans have different policies for how patients encounter these providers, and these may affect selection of AF treatment strategy.We hypothesized that healthcare plans with PCP-gatekeeping to specialist access may be associated with different pharmacologic treatments for AF.We performed a retrospective cohort study using a commercial pharmaceutical claims database. We utilized logistic regression models to compare odds of prescription of oral anticoagulant (OAC), non-vitamin K-dependent oral anticoagulant (NOAC), rate control, and rhythm control medications used to treat AF between patients with PCP-gated healthcare plans (e.g. HMO, EPO, POS) and patients with non-PCP-gated healthcare plans (e.g. PPO, CHDP, HDHP, Comprehensive) between 2007 and 2012. We also calculated median time to receipt of therapy within 90 days of index AF diagnosis.We found similar odds of OAC prescription at 90 days following new AF diagnosis in patients with PCP-gated plans compared to those with non-PCP-gated plans (OR: OAC 1.01, p=0.84; warfarin 1.05, p=0.08). Relative odds were similar for rate control (1.17, p<0.01) and rhythm control agents (0.93, p=0.03). However, PCP-gated plan patients had slightly lower likelihood of being prescribed NOACs (0.82, p=0.001) than non-gated plan patients. Elapsed time until receipt of medication was similar between PCP-gated and non-gated groups across drug classes.Pharmaceutical claims data do not suggest that PCP-gatekeeping by healthcare plans is a structural barrier to AF therapy, although it was associated with lower use of NOACs.

    View details for PubMedID 30098034

  • Academic health centers: integration of clinical research with healthcare and education. Comments on a workshop CLINICS Arai, R., Noronha, I., Nicolau, J., Schmidt, C., de Albuquerque, G., Mahaffey, K. W., Krieger, E., Costa Auler Junior, J. 2018; 73
  • Outcomes of Patients with Critical Limb Ischaemia in the EUCLID Trial EUROPEAN JOURNAL OF VASCULAR AND ENDOVASCULAR SURGERY Norgren, L., Patel, M. R., Hiatt, W. R., Wojdyla, D. M., Fowkes, F. R., Baumgartner, I., Mahaffey, K. W., Berger, J. S., Jones, W., Katona, B. G., Held, P., Blomster, J. I., Rockhold, F. W., Bjoerck, M., EUCLID Steering Comm & Investiga 2018; 55 (1): 109–17

    Abstract

    Critical limb ischaemia (CLI) implies an increased risk of cardiovascular morbidity and mortality, and the optimal antithrombotic treatment is not established.The EUCLID trial investigated the effect of monotherapy with ticagrelor versus clopidogrel in 13,885 patients with peripheral artery disease (PAD); the primary endpoint was cardiovascular death, myocardial infarction, or ischaemic stroke. Patients planned for revascularisation or amputation within 3 months, were excluded. This analysis focuses on the subgroup with CLI, defined by rest pain (58.8%), major (9.0%) or minor (32.2%) tissue loss.In EUCLID, 643 patients (4.6%) had CLI at baseline. Diabetes mellitus was more common in the CLI group, while coronary disease, carotid disease, and hypertension were more common in the non-CLI group. A majority of CLI patients (62.1%) had only lower extremity PAD. In patients enrolled on the ankle brachial index (ABI) criteria, ABI was 0.55 ± 0.21 (mean ± SD) for those with CLI versus 0.63 ± 0.15 for those without CLI. The primary efficacy endpoint significantly increased among patients with CLI compared with those without CLI with a rate of 8.85 versus 4.28/100 patient years (adjusted for baseline characteristics hazard ratio [HR] 1.43 [95% CI 1.16-1.76]; p = 0.0009). When acute limb ischaemia requiring hospitalisation was added to the model, significant differences remained (adjusted HR 1.38, [95% CI 1.13-1.69]; p = 0.0016). The 1 year mortality was 8.9%. A trend towards increased lower limb revascularisation among those with CLI was observed. Bleeding (TIMI major, fatal, intracranial) did not differ between those with and without CLI.Nearly 5% of patients enrolled in EUCLID had CLI at baseline. Milder forms of CLI dominated, a result of the trial design. Patients with CLI had a significantly higher rate of cardiovascular mortality and morbidity versus those without CLI. Further efforts are required to reduce the risk of cardiovascular events in PAD, especially in patients with CLI. CLINICALTRIALS.GOV: NCT01732822.

    View details for PubMedID 29273390

  • Efficacy and safety of rivaroxaban compared with warfarin in patients with carotid artery disease and nonvalvular atrial fibrillation: Insights from the ROCKET AF trial CLINICAL CARDIOLOGY Kochar, A., Hellkamp, A. S., Lokhnygina, Y., Jones, W., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Piccini, J. P., Patel, M. R. 2018; 41 (1): 39–45

    Abstract

    Atrial fibrillation (AF) increases risk of stroke 5-fold. Carotid artery disease (CD) also augments the risk of stroke, yet there are limited data about the interplay of these 2 diseases and clinical outcomes in patients with comorbid AF and CD.Among patients with both AF and CD, use of rivaroxaban when compared with warfarin is associated with a lower risk of stroke.This post hoc analysis from ROCKET AF aimed to determine absolute rates of stroke/systemic embolism (SE) and bleeding, and the efficacy and safety of rivaroxaban compared with warfarin in patients with AF and CD (defined as history of carotid occlusive disease or carotid revascularization [endarterectomy and/or stenting]).A total of 593 (4.2%) patients had CD at enrollment. Patients with and without CD had similar rates of stroke or SE (adjusted hazard ratio [HR]: 0.99, 95% confidence interval [CI]: 0.66-1.48, P = 0.96), and there was no difference in major or nonmajor clinically relevant bleeding (adjusted HR: 1.04, 95% CI: 0.88-1.24, P = 0.62). The efficacy of rivaroxaban compared with warfarin for the prevention of stroke/SE was not statistically significant in patients with vs those without CD (interaction P = 0.25). The safety of rivaroxaban vs warfarin for major or nonmajor clinically relevant bleeding was similar in patients with and without CD (interaction P = 0.64).Patients with CD in ROCKET AF had similar risk of stroke/SE compared with patients without CD. Additionally, there was no interaction between CD and the treatment effect of rivaroxaban or warfarin for stroke prevention or safety endpoints.

    View details for PubMedID 29389037

  • Anticoagulant and antiplatelet therapy choices for patients with atrial fibrillation one year after coronary stenting or acute coronary syndrome EXPERT OPINION ON DRUG SAFETY Olivier, C. B., Turakhia, M. P., Mahaffey, K. W. 2018; 17 (3): 251–58

    Abstract

    Guidelines recommend a combined anticoagulant and antiplatelet approach for patients with atrial fibrillation (AF) after coronary stenting (CS) or acute coronary syndrome (ACS). Finding the optimal balance of reducing ischemic risk and minimizing bleeding risk is challenging. Recent trials have evaluated a variety of regimens for up to one year for AF patients after CS/ACS. Little empiric evidence exists about the best antithrombotic strategy beyond one year. Areas covered: In this review two key areas are covered. First, a summary of the overall risk and benefits of anticoagulant and antiplatelet therapy in patients with AF and CS or ACS is provided. Second, despite limited empiric evidence to guide therapeutic decisions for combined anticoagulant and antiplatelet therapy in patients with AF one year after CS/ACS we provide guidance for shared patient-physician decision making. Expert opinion: The evidence is limited. For all patients with AF and stable CAD (≥1 year after CS or ACS) the risk for thromboembolism, cardiovascular events and bleeding should be assessed individually. For patients with low bleeding risk and high risk for cardiovascular events, antiplatelet therapy might be added to anticoagulant therapy.

    View details for PubMedID 29363352

  • Prevalence, Characteristics, and Outcomes of Valvular Heart Disease in Patients With Atrial Fibrillation: Insights From the ORBIT-AF (Outcomes Registry for Better Informed Treatment for Atrial Fibrillation). Journal of the American Heart Association Thomas, K. L., Jackson, L. R., Shrader, P., Ansell, J., Fonarow, G. C., Gersh, B., Kowey, P. R., Mahaffey, K. W., Singer, D. E., Thomas, L., Piccini, J. P., Peterson, E. D. 2017; 6 (12)

    Abstract

    The presence of valvular heart disease (VHD) may affect the risk of stroke and mortality in patients with atrial fibrillation (AF). Community-based estimates of prevalence and outcomes of specific forms of VHD in patients with AF are lacking.We examined the prevalence of VHD, anticoagulation use, mortality, stroke/transient ischemic attack, and bleeding among a community cohort of patients with AF. Significant VHD was defined as follows: (1) moderate/severe mitral stenosis or mechanical valve; (2) bioprosthetic valve, surgical repair, or balloon valvuloplasty; and (3) moderate/severe aortic regurgitation or stenosis, mitral regurgitation, or tricuspid regurgitation. Proportional hazards models were performed to test the association between VHD groups and outcomes. Among 9748 patients with AF, 2705 (27.7%) had significant VHD. Anticoagulation use was highest among patients with mitral stenosis/mechanical valve (91.8%). Compared with individuals with no significant VHD, individuals with aortic regurgitation/aortic stenosis, mitral regurgitation, or tricuspid regurgitation (hazard ratio, 1.23; 95% confidence interval, 1.07-1.42) had the highest risk of death. There were no differences in stroke or transient ischemic attack and major bleeding among individuals with and without significant VHD. Patients with AF and aortic stenosis had the highest risk of death (hazard ratio, 1.32; 95% confidence interval, 1.08-1.62).Significant VHD is common among patients with AF in community practice. In a community cohort of patients with AF and CHA2DS2-VASc score ≥2, most were anticoagulated. Individuals with AF and moderate-to-severe biological VHD have more comorbidities and a higher mortality risk; however, stroke and major bleeding are similar among those with and without significant VHD.

    View details for DOI 10.1161/JAHA.117.006475

    View details for PubMedID 29273635

    View details for PubMedCentralID PMC5778999

  • Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events in Type 2 Diabetes: Results From the CANVAS Program Mahaffey, K. W., Neal, B., Perkovic, V., de Zeeuw, D., Fulcher, G., Erondu, N., Shaw, W., Sun, T., Desai, M., Matthews, D. R., CANVAS Program Collaborative Grp LIPPINCOTT WILLIAMS & WILKINS. 2017: E454–E455
  • International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries AMERICAN HEART JOURNAL Steinberg, B. A., Gao, H., Shrader, P., Pieper, K., Thomas, L., Camm, A., Ezekowitz, M. D., Fonarow, G. C., Gersh, B. J., Goldhaber, S., Haas, S., Hacke, W., Kowey, P. R., Ansell, J., Mahaffey, K. W., Naccarelli, G., Reiffel, J. A., Turpie, A., Verheugt, F., Piccini, J. P., Kakkar, A., Peterson, E. D., Fox, K. A., GARFIELD-AF ORBIT-AF Investigators 2017; 194: 132–40
  • International trends in clinical characteristics and oral anticoagulation treatment for patients with atrial fibrillation: Results from the GARFIELD-AF, ORBIT-AF I, and ORBIT-AF II registries. American heart journal Steinberg, B. A., Gao, H., Shrader, P., Pieper, K., Thomas, L., Camm, A. J., Ezekowitz, M. D., Fonarow, G. C., Gersh, B. J., Goldhaber, S., Haas, S., Hacke, W., Kowey, P. R., Ansell, J., Mahaffey, K. W., Naccarelli, G., Reiffel, J. A., Turpie, A., Verheugt, F., Piccini, J. P., Kakkar, A., Peterson, E. D., Fox, K. A. 2017; 194: 132-140

    Abstract

    Atrial fibrillation (AF) is the most common cardiac arrhythmia in the world. We aimed to provide comprehensive data on international patterns of AF stroke prevention treatment.Demographics, comorbidities, and stroke risk of the patients in the GARFIELD-AF (n=51,270), ORBIT-AF I (n=10,132), and ORBIT-AF II (n=11,602) registries were compared (overall N=73,004 from 35 countries). Stroke prevention therapies were assessed among patients with new-onset AF (≤6 weeks).Patients from GARFIELD-AF were less likely to be white (63% vs 89% for ORBIT-AF I and 86% for ORBIT-AF II) or have coronary artery disease (19% vs 36% and 27%), but had similar stroke risk (85% CHA2DS2-VASc ≥2 vs 91% and 85%) and lower bleeding risk (11% with HAS-BLED ≥3 vs 24% and 15%). Oral anticoagulant use was 46% and 57% for patients with a CHA2DS2-VASc=0 and 69% and 87% for CHA2DS2-VASc ≥2 in GARFIELD-AF and ORBIT-AF II, respectively, but with substantial geographic heterogeneity in use of oral anticoagulant (range: 31%-93% [GARFIELD-AF] and 66%-100% [ORBIT-AF II]). Among patients with new-onset AF, non-vitamin K antagonist oral anticoagulant use increased over time to 43% in 2016 for GARFIELD-AF and 71% for ORBIT-AF II, whereas use of antiplatelet monotherapy decreased from 36% to 17% (GARFIELD-AF) and 18% to 8% (ORBIT-AF I and II).Among new-onset AF patients, non-vitamin K antagonist oral anticoagulant use has increased and antiplatelet monotherapy has decreased. However, anticoagulation is used frequently in low-risk patients and inconsistently in those at high risk of stroke. Significant geographic variability in anticoagulation persists and represents an opportunity for improvement.

    View details for DOI 10.1016/j.ahj.2017.08.011

    View details for PubMedID 29223431

  • Prevalence, Characteristics, and Outcomes of Valvular Heart Disease in Patients With Atrial Fibrillation: Insights From the ORBIT-AF (Outcomes Registry for Better Informed Treatment for Atrial Fibrillation) JOURNAL OF THE AMERICAN HEART ASSOCIATION Thomas, K. L., Jackson, L. R., Shrader, P., Ansell, J., Fonarow, G. C., Gersh, B., Kowey, P. R., Mahaffey, K. W., Singer, D. E., Thomas, L., Piccini, J. P., Peterson, E. D. 2017; 6 (12)
  • Outcome of Patients Receiving Thrombolytic Therapy While on Rivaroxaban for Nonvalvular Atrial Fibrillation (from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) AMERICAN JOURNAL OF CARDIOLOGY Chen, S. T., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R. 2017; 120 (10): 1837–40

    Abstract

    The safety of intravenous thrombolysis in patients taking rivaroxaban has not been well established. We retrospectively analyzed the outcomes of all patients who received thrombolytic therapy in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). A review of medical and adverse event records for patients receiving thrombolytic therapy while enrolled in ROCKET AF was performed to determine their baseline characteristics, indications for thrombolysis, and type of agent used. Safety end points were 30-day post-thrombolytic rates of stroke, bleeding, and mortality. A total of 28 patients in ROCKET AF received thrombolytic therapy, with 19 patients on rivaroxaban and 9 patients on warfarin. Ischemic stroke was the most common indication for thrombolysis (n = 10), and alteplase was the most commonly used fibrinolytic agent (n = 14). Of the 19 patients in the rivaroxaban group, there were 2 nonfatal bleeding events and 2 deaths, mostly occurring when thrombolytic therapy was administered within 48 hours of the last rivaroxaban dose. Of the 9 patients in the warfarin group, there was 1 nonfatal bleeding event and 3 deaths, most occurring when thrombolytic therapy was administered outside of 48 hours from the last warfarin dose. In conclusion, these observations suggest that careful assessment of the time since the last dose may be of clinical significance in patients on novel oral anticoagulants who require emergent thrombolysis.

    View details for PubMedID 28886856

  • Treatment of Atrial Fibrillation and Concordance With the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines: Findings From ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation). Circulation. Arrhythmia and electrophysiology Barnett, A. S., Kim, S., Fonarow, G. C., Thomas, L. E., Reiffel, J. A., Allen, L. A., Freeman, J. V., Naccarelli, G., Mahaffey, K. W., Go, A. S., Kowey, P. R., Ansell, J. E., Gersh, B. J., Hylek, E. M., Peterson, E. D., Piccini, J. P. 2017; 10 (11)

    Abstract

    BACKGROUND: It is unclear how frequently patients with atrial fibrillation receive guideline-concordant (GC) care and whether guideline concordance is associated with improved outcomes.METHODS AND RESULTS: Using data from ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation), we determined how frequently patients received care that was concordant with 11 recommendations from the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society atrial fibrillation guidelines pertaining to antithrombotic therapy, rate control, and antiarrhythmic medications. We also analyzed the association between GC care and clinical outcomes at both the patient level and center level. A total of 9570 patients were included. The median age was 75 years (interquartile range, 67-82), and the median CHA2DS2-VASc score was 4 (interquartile range, 3-5). A total of 5977 patients (62.5%) received care that was concordant with all guideline recommendations for which they were eligible. Rates of GC care were higher in patients treated by providers with greater specialization in arrhythmias (60.0%, 62.4%, and 67.0% for primary care physicians, cardiologists, and electrophysiologists, respectively; P<0.001). During a median of 30 months of follow-up, patients treated with GC care had a higher risk of bleeding hospitalization (hazard ratio=1.21; P=0.021) but a similar risk of death, stroke, major bleeding, and all-cause hospitalization.CONCLUSIONS: Over a third of patients with atrial fibrillation in this large outpatient registry received care that differed in some respect from guideline recommendations. There was no apparent association between GC care and improved risk-adjusted outcomes.

    View details for PubMedID 29141842

  • Treatment of Atrial Fibrillation and Concordance With the American Heart Association/American College of Cardiology/Heart Rhythm Society Guidelines Findings From ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY Barnett, A. S., Kim, S., Fonarow, G. C., Thomas, L. E., Reiffel, J. A., Allen, L. A., Freeman, J. V., Naccarelli, G., Mahaffey, K. W., Go, A. S., Kowey, P. R., Ansell, J. E., Gersh, B. J., Hylek, E. M., Peterson, E. D., Piccini, J. P. 2017; 10 (11)
  • Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort. Clinical cardiology Kittle, J., Lopes, R. D., Huang, M., Marquess, M. L., Wilson, M. D., Ascher, J., Krishen, A., Hasselblad, V., Kolls, B. J., Roe, M. T., McGuire, D. K., Russell, S. D., Mahaffey, K. W. 2017; 40 (10): 899-906

    Abstract

    In 2011, the US Food and Drug Administration requested that GlaxoSmithKline perform retrospective adjudication of cardiovascular (CV) events reported in the bupropion drug-development trials for smoking cessation.Retrospective adjudication of clinical trial data will not increase the identification of adverse events.We performed a comprehensive retrospective analysis of adverse events in 19 previously completed controlled US clinical trials of bupropion marketed for the treatment of smoking cessation, yielding 9479 subjects (5290 bupropion, 2927 placebo, 1018 active control [ACT], and 244 treated concurrently with bupropion and ACT). All adverse events were sent to the Duke Clinical Research Institute for adjudication by Clinical Events Classification (CEC) physician reviewers. The primary endpoint was a composite of major adverse CV events: CV death, nonfatal myocardial infarction (MI), and nonfatal stroke.Overall, 416 nonfatal CV events in 366 subjects, and 22 deaths, were identified and processed for adjudication. Of these, 7 nonfatal MIs (4 bupropion, 3 placebo, 0 ACT), 5 nonfatal strokes (1 bupropion, 3 placebo, 1 ACT), and 9 CV deaths (4 bupropion, 4 placebo, 1 ACT) were confirmed by the CEC Committee. The primary endpoint occurred in 3/4297 (0.07%) subjects in the bupropion group and in 4/2927 (0.14%) subjects in the placebo group (log-rank P value: 0.613).CV events in bupropion clinical trials for smoking cessation were uncommon, with no observed increase among subjects assigned to bupropion vs placebo. However, this effort was limited by a paucity of quality data.

    View details for DOI 10.1002/clc.22744

    View details for PubMedID 28605035

  • Cangrelor Versus Clopidogrel on a Background of Unfractionated Heparin (from CHAMPION PHOENIX) AMERICAN JOURNAL OF CARDIOLOGY Vaduganathan, M., Harrington, R. A., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., Deliargyris, E. N., Prats, J., Mahaffey, K. W., White, H. D., Bhatt, D. L., CHAMPION PHOENIX Investigators 2017; 120 (7): 1043–48

    Abstract

    Cangrelor is approved for use during percutaneous coronary intervention (PCI) and is administered with different parenteral anticoagulants. We examined the efficacy and safety of cangrelor in the subgroup of patients who received unfractionated heparin (UFH) during PCI in the modified intention-to-treat population of the randomized CHAMPION PHOENIX trial (cangrelor vs clopidogrel; n = 10,939). The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis (ST) at 48 hours. The key secondary efficacy end point was ST. UFH was used in 69.2% (7,569/10,939) of patients. In the UFH subgroup, cangrelor reduced the primary composite efficacy end point at 48 hours compared with clopidogrel (4.8% vs 5.9%; odds ratio [OR] 0.80 [0.65 to 0.98]; p = 0.03). Cangrelor consistently reduced ST at 2 hours (0.7% vs 1.3%; OR 0.56 [0.35 to 0.90]; p = 0.01) and 48 hours (0.9% vs 1.4%; OR 0.70 [0.45 to 1.07]; p = 0.10). There was no difference in GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries)-defined severe or life-threatening bleeding (0.1% vs 0.1%; OR 1.24 [0.33 to 4.61]; p = 0.75) or blood transfusion requirement at 48 hours (0.4% vs 0.2%; OR 1.87 [0.83 to 4.21]; p = 0.12). In conclusion, cangrelor reduces early ischemic periprocedural complications without increasing severe bleeding compared with clopidogrel in patients undergoing PCI with UFH.

    View details for PubMedID 28802512

  • Care Patterns and Outcomes in Atrial Fibrillation Patients With and Without Diabetes ORBIT-AF Registry JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Echouffo-Tcheugui, J. B., Shrader, P., Thomas, L., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Singer, D. E., Hylek, E. M., Go, A. S., Peterson, E. D., Piccini, J. P., Fonarow, G. C. 2017; 70 (11): 1325–35

    Abstract

    Diabetes is a well-established risk factor for thromboembolism in patients with atrial fibrillation (AF), but less is known about how diabetes influences outcomes among AF patients.This study assessed whether symptoms, health status, care, and outcomes differ between AF patients with and without diabetes.The cohort study included 9,749 patients from the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry, a prospective, nationwide, outpatient registry of patients with incident and prevalent AF. Outcomes included symptoms, health status, and AF treatment, as well as 2-year risk of death, hospitalization, thromboembolic events, heart failure (HF), and AF progression.Patients with diabetes (29.5%) were younger, more likely to have hypertension, chronic kidney disease, HF, coronary heart disease, and stroke. Compared to patients without diabetes, patients with diabetes also had a lower Atrial Fibrillation Effects on Quality of Life score of 80 (interquartile range [IQR]: 62.5 to 92.6) versus 82.4 (IQR: 67.6 to 93.5; p = 0.025) and were more likely to receive anticoagulation (p < 0.001). Diabetes was associated with higher mortality risk, including overall (adjusted hazard ratio [aHR]: 1.63; 95% confidence interval [CI]: 1.04 to 2.56, for age <70 years vs. aHR: 1.25; 95% CI: 1.09 to 1.44, for age ≥70 years) and cardiovascular (CV) mortality (aHR: 2.20; 95% CI: 1.22 to 3.98, for age <70 years vs. 1.24; 95% CI: 1.02 to 1.51 for age ≥70 years). Diabetes conferred a higher risk of non-CV death, sudden cardiac death, hospitalization, CV hospitalization, and non-CV and nonbleeding-related hospitalization, but no increase in risks of thromboembolic events, bleeding-related hospitalization, new-onset HF, and AF progression.Among AF patients, diabetes was associated with worse AF symptoms and lower quality of life, and increased risk of death and hospitalizations, but not thromboembolic or bleeding events.

    View details for PubMedID 28882229

  • Efficacy and Safety of Rivaroxaban Versus Warfarin in Patients Taking Nondihydropyridine Calcium Channel Blockers for Atrial Fibrillation (from the ROCKET AF Trial) AMERICAN JOURNAL OF CARDIOLOGY Washam, J. B., Hellkamp, A. S., Lokhnygina, Y., Piccini, J. P., Berkowitz, S. D., Nessel, C. C., Becker, R. C., Breithardt, G., Fox, K. A., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Singer, D. E., Patel, M. R., ROCKET AF Steering Comm & Investig 2017; 120 (4): 588–94

    Abstract

    Non-dihydropyridine calcium channel blockers (non-DHP CCBs) possess combined P-glycoprotein and moderate CYP3A4 inhibition, which may lead to increased exposure of medications that are substrates for these metabolic pathways, such as rivaroxaban. We evaluated the use and outcomes of non-DHP CCBs in patients with atrial fibrillation (AF) in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). We assessed clinical outcomes in patients who received non-DHP CCBs and the impact on the efficacy and safety of rivaroxaban compared with warfarin. Stroke or noncentral nervous system (CNS) systemic embolism (SE), major or nonmajor clinically relevant (NMCR) bleeding, all-cause death, and major bleeding were compared according to non-DHP CCB use. At randomization, 1,308 patients (9.2%) were taking a non-DHP CCB. They were more likely to be women, have diabetes and COPD, and less likely to have heart failure and had a lower mean CHADS2 score (3.3 vs 3.5). Non-DHP CCB use was not associated with an increased risk of stroke/non-CNS SE (p = 0.11) or the composite outcome of NMCR or major bleeding (p = 0.087). Non-DHP CCB use was associated with an increased risk of major bleeding (adjusted hazard ratio 1.50, 95% CI 1.11 to 2.04) and intracranial hemorrhage (adjusted hazard ratio 2.84, 95% CI 1.53 to 5.29). No significant difference was observed in the primary efficacy (stroke or non-CNS SE; adjusted interaction p value = 0.38) or safety outcome (NMCR or major bleeding; adjusted interaction p value = 0.14) between rivaroxaban and warfarin with non-DHP CCB use. In conclusion, although the overall use of non-DHP CCBs was associated with an increased risk of major bleeding and intracranial hemorrhage, the use was not associated with a significant change in the safety or efficacy of rivaroxaban compared with warfarin observed in ROCKET AF.

    View details for PubMedID 28645473

  • Cangrelor in Older Patients Undergoing Percutaneous Coronary Intervention Findings From CHAMPION PHOENIX CIRCULATION-CARDIOVASCULAR INTERVENTIONS Cavender, M. A., Bhatt, D. L., Stone, G. W., Steg, P., Gibson, C., Hamm, C. W., Price, M. J., Prats, J., Elkin, S., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Harrington, R. A. 2017; 10 (8)

    Abstract

    Older patients treated with percutaneous coronary intervention are at increased risk of periprocedural events.CHAMPION (cangrelor versus standard therapy to achieve optimal management of platelet inhibition) PHOENIX randomized 11 145 patients to cangrelor or clopidogrel. We sought to determine the outcomes in the prespecified subgroup of patients ≥75 years old (n=2010; 18%). Cangrelor resulted in directionally consistent effects on the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis) in patients ≥75 years old (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.50-1.02) and in those <75 years old (OR, 0.81; 95% CI, 0.67-0.98; P [interaction]=0.55). Age ≥75 years was an independent predictor of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate/severe bleeding (1.0% versus 0.3%; adjusted OR, 2.94; 95% CI, 1.28-6.77; P=0.01) when compared with patients <75 years old. There was no significant difference in GUSTO moderate/severe bleeding with cangrelor versus clopidogrel (1.1% versus 1.0%; OR, 1.07; 95% CI 0.45-2.53) in patients ≥75 years old or in those <75 years old (0.4% versus 0.2%; OR, 2.24; 95% CI, 1.02-4.93; P [interaction]=0.21). For the net composite end point of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis plus GUSTO moderate/severe bleeding, the OR for cangrelor in those ≥75 years old was 0.75 (6.4% versus 8.3%; 95% CI, 0.54-1.05; P=0.09). The effects were similar in those <75 years old (4.9% versus 5.8%; OR, 0.85; 95% CI, 0.70-1.02; P=0.08; P [interaction]=0.53).Patients ≥75 years old have an overall ≈3-fold increased odds of moderate/severe bleeding. Cangrelor, when compared with clopidogrel, provides similar efficacy and in patients ≥75 years old as in those <75 years old but does not increase the risk of major bleeding.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for PubMedID 28801539

  • Use of troponin assay 99th percentile as the decision level for myocardial infarction diagnosis AMERICAN HEART JOURNAL Bagai, A., Alexander, K. P., Berger, J. S., Senior, R., Sajeev, C., Pracon, R., Mavromatis, K., Luis Lopez-Sendon, J., Gosselin, G., Diaz, A., Perna, G., Drozdz, J., Humen, D., Petrauskiene, B., Cheema, A. N., Phaneuf, D., Banerjee, S., Miller, T. D., Kedev, S., Schuchlenz, H., Stone, G. W., Goodman, S. G., Mahaffey, K. W., Jaffe, A. S., Rosenberg, Y. D., Bangalore, S., Newby, L., Maron, D. J., Hochman, J. S., Chaitman, B. R. 2017; 190: 135–39

    Abstract

    The Universal Definition of Myocardial Infarction recommends the 99th percentile concentration of cardiac troponin in a normal reference population as part of the decision threshold to diagnose type 1 spontaneous myocardial infarction. Adoption of this recommendation in contemporary worldwide practice is not well known.We performed a cohort study of 276 hospital laboratories in 31 countries participating in the National Heart, Lung, and Blood Institute-sponsored International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial. Each hospital laboratory's troponin assay manufacturer and model, the recommended assay's 99th percentile upper reference limit (URL) from the manufacturer's package insert, and the troponin concentration used locally as the decision level to diagnose myocardial infarction were ascertained.Twenty-one unique troponin assays from 9 manufacturers were used by the surveyed hospital laboratories. The ratio of the troponin concentration used locally to diagnose myocardial infarction to the assay manufacturer-determined 99th percentile URL was <1 at 19 (6.6%) laboratories, equal to 1 at 91 (31.6%) laboratories, >1 to ≤5 at 101 (35.1%) laboratories, >5 to ≤10 at 34 (11.8%) laboratories, and >10 at 43 (14.9%) laboratories. The variability in troponin decision level for myocardial infarction relative to the assay 99th percentile URL was present for laboratories in and outside of the United States, as well as for high- and standard-sensitivity assays.There is substantial hospital-level variation in the troponin threshold used to diagnose myocardial infarction; only one-third of hospital laboratories currently follow the Universal Definition of Myocardial Infarction consensus recommendation for use of troponin concentration at the 99th percentile of a normal reference population as the decision level to diagnose myocardial infarction. This variability across laboratories has important implications for both the diagnosis of myocardial infarction in clinical practice as well as adjudication of myocardial infarction in clinical trials.

    View details for PubMedID 28760208

  • Management and outcomes of patients with atrial fibrillation and a history of cancer: the ORBIT-AF registry EUROPEAN HEART JOURNAL-QUALITY OF CARE AND CLINICAL OUTCOMES Melloni, C., Shrader, P., Carver, J., Piccini, J. P., Thomas, L., Fonarow, G. C., Ansell, J., Gersh, B., Go, A. S., Hylek, E., Herling, I. M., Mahaffey, K. W., Yu, A. F., Peterson, E. D., Kowey, P. R., ORBIT-AF Steering Comm 2017; 3 (3): 192–97

    Abstract

    The presence of cancer can complicate treatment choices for patients with atrial fibrillation (AF) increasing both the risk of thrombotic and bleeding events.Using data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we aimed to characterize AF patients with cancer, to describe their management and to assess the association between cancer and cardiovascular (CV) outcomes. Among 9749 patients, 23.8% had history of cancer (57% solid malignancy, 1.3% leukaemia, 3.3% lymphoma, 40% other type, and 2.2% metastatic cancer). Patients with history of cancer were older, more likely to have CV disease, CV risk factors, and prior gastrointestinal bleeding. No difference in antiarrhythmic and antithrombotic therapy was observed between those with and without cancer. Patients with history of cancer had a significantly higher risk of death (7.8 vs. 4.9 deaths per 100 patient-years follow-up, P = 0.0003) mainly driven by non-CV death (4.2 vs. 2.4 per 100 patient-years follow-up; P = 0.0004) and higher risk of major bleeding (5.1 vs. 3.5 per 100 patient-years follow-up; P = 0.02) compared with non-cancer patients; no differences were observed in risks of strokes/non-central nervous system embolism (1.96 vs. 1.48, P = 0.74) and CV death (2.89 vs. 2.07, P = 0.35) between the two groups.A history of cancer is common among AF patients with up to one in four patients having both. Antithrombotic therapy, rates of cerebrovascular accident, other thrombotic events and cardiac death were similar in AF patients with or without a history of cancer. Patients with cancer, however, were at higher risk of major bleeding and non-CV death.

    View details for PubMedID 28838088

  • Factors associated with non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with new-onset atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II) AMERICAN HEART JOURNAL Steinberg, B. A., Shrader, P., Thomas, L., Ansell, J., Fonarow, G. C., Gersh, B. J., Hylek, E., Kowey, P. R., Mahaffey, K. W., O'Brien, E. C., Singer, D. E., Peterson, E. D., Piccini, J. P., Outcomes Registry Better Informed 2017; 189: 40–47

    Abstract

    Several non-vitamin K antagonist oral anticoagulant (NOAC) alternatives to warfarin are available for stroke prevention in atrial fibrillation (AF). We aimed to describe the factors associated with selection of NOACs versus warfarin in patients with new onset AF.The ORBIT-AF II study is a national, US, prospective, observational, cohort study of anticoagulation treatment in patients with AF receiving NOACs or warfarin in the United States from 2013 to 2016. We measured factors associated with oral anticoagulant selection in 4,670 patients recently diagnosed with AF.At baseline, 1,169 (25%) patients were started on warfarin and 3,501 (75%) on NOACs: of these latter, 259 (6%) were started on dabigatran, 1858 (40%) on rivaroxaban, and 1384 (30%) on apixaban. Those receiving NOACs were slightly younger patients (median age 71 vs 72, P<.0001); were less likely to have prior stroke (5.3% vs 8.6%; P<.0001) or prior bleeding (2.7% vs 4.4%; P=.005); had better kidney function (mean estimated glomerular filtration rate 91 mL/min vs 80 mL/min, P<.0001); and had fewer patients at high stroke risk (CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age ≥75years, Diabetes mellitus, Prior stroke, transient ischemic attack {TIA}, or thromboembolism,Vascular disease, Age 65-74years, Sex category {female}] ≥2 in 86% vs 93%; P<.0001). In multivariable analysis, factors associated with NOAC selection versus warfarin included renal function, prior stroke or valve replacement, rhythm control AF management strategy, treatment by a cardiologist, and higher patient education level.In contemporary clinical practice, up to three-fourths of patients with new-onset AF are now initially treated with a NOAC for stroke prevention. Those selected for NOAC treatment had lower stroke and bleeding risk profiles, were more likely treated by cardiologists, and had higher socioeconomic status.clinicaltrials.gov Identifier: NCT01701817.

    View details for PubMedID 28625380

  • Relation of Risk of Stroke in Patients With Atrial Fibrillation to Body Mass Index (from Patients Treated With Rivaroxaban and Warfarin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation Trial). American journal of cardiology Balla, S. R., Cyr, D. D., Lokhnygina, Y., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Patel, M. R. 2017; 119 (12): 1989-1996

    Abstract

    We investigated stroke outcomes in normal weight (body mass index [BMI] 18.50 to 24.99 kg/m(2)), overweight (BMI 25.00 to 29.99 kg/m(2)), and obese (BMI ≥30 kg/m(2)) patients with atrial fibrillation treated with rivaroxaban and warfarin. We compared the incidence of stroke and systemic embolic events as well as bleeding events in normal weight (n = 3,289), overweight (n = 5,535), and obese (n = 5,206) patients in a post hoc analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial. Stroke and systemic embolic event rates per 100 patient-years were 2.93 in the normal weight group (reference group), 2.28 in the overweight group (adjusted hazard ratio [HR] 0.81, 95% CI 0.66 to 0.99, p = 0.04) and 1.88 in the obese group (adjusted HR 0.69, 95% CI 0.55 to 0.86, p <0.001). The risk of stroke was statistically significantly lower for obese patients with BMI ≥35 than that for normal weight patients in both the rivaroxaban and warfarin groups (rivaroxaban: HR 0.62, 95% CI 0.40 to 0.96, p = 0.033; warfarin: HR 0.48, 95% CI 0.31 to 0.74, p <0.001). In conclusion, in patients with atrial fibrillation treated with anticoagulant therapy, increased BMI was associated with decreased stroke risk. Warfarin and the novel anticoagulant rivaroxaban are effective in stroke prevention in all subgroups of obese patients.

    View details for DOI 10.1016/j.amjcard.2017.03.028

    View details for PubMedID 28477860

  • Cangrelor reduces the risk of ischemic complications in patients with single-vessel and multi-vessel disease undergoing percutaneous coronary intervention: Insights from the CHAMPION PHOENIX trial. American heart journal Abnousi, F., Sundaram, V., Yong, C. M., Prats, J., Deliargyris, E. N., Stone, G. W., Hamm, C. W., Steg, P. G., Gibson, C. M., White, H. D., Price, M. J., Généreux, P., Desai, M., Yang, L., Ding, V. Y., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. 2017; 188: 147-155

    Abstract

    To examine the safety and efficacy of cangrelor in patients with single-vessel disease (SVD) and multi-vessel disease (MVD).Cangrelor, an intravenous, rapidly acting P2Y12 inhibitor, is superior to clopidogrel in reducing ischemic events among patients receiving percutaneous coronary intervention (PCI).We studied a modified intention to treat population of patients with SVD and MVD from the CHAMPION PHOENIX trial. The primary efficacy outcome was the composite of death, myocardial infarction (MI), ischemia-driven revascularization (IDR), and stent thrombosis (ST) at 48hours. The key safety outcome was non-coronary artery bypass grafting GUSTO severe bleeding at 48hours.Among 10,921 patients, 5,220 (48%) had SVD and 5,701 (52%) had MVD. MVD patients were older and more often had diabetes, hyperlipidemia, hypertension, prior stroke, and prior MI. After adjustment, MVD patients had similar rates of 48-hour death/MI/IDR/ST (6.3% vs 4.2%, adjusted odds ratio [OR] 1.6 [95% CI 0.42-6.06]) and GUSTO severe bleeding (0.1% vs 0.2%, P=.67) compared with SVD patients. Consistent with overall trial findings, cangrelor use reduced ischemic complications in patients with both SVD (3.9% vs 4.5%; OR 0.86, 95% CI 0.65-1.12) and MVD (5.5% vs 7.2%; OR 0.74, 95% CI 0.6-0.92, P-interaction=.43). GUSTO severe bleeding outcomes were not significantly increased with cangrelor or clopidogrel in either SVD or MVD patients.In the CHAMPION PHOENIX trial, MVD and SVD patients had similar ischemic outcomes at 48hours and 30days. Cangrelor consistently reduced ischemic complications in both SVD and MVD patients without a significant increase in GUSTO severe bleeding. CLINICAL PERSPECTIVES.

    View details for DOI 10.1016/j.ahj.2017.02.031

    View details for PubMedID 28577670

  • Characteristics of dyspnoea and associated clinical outcomes in the CHAMPION PHOENIX study THROMBOSIS AND HAEMOSTASIS Parker, W. A., Bhatt, D. L., Prats, J., Day, J. S., Steg, P., Stone, G. W., Hamm, C. W., Mahaffey, K. W., Price, M. J., Gibson, C., White, H. D., Storey, R. F., CHAMPION PHOENIX Investigators 2017; 117 (6): 1093–1100

    Abstract

    Dyspnoea may be induced by some reversibly-binding P2Y12 inhibitors, including cangrelor and ticagrelor. Dyspnoea was not associated with any compromise to the efficacy of ticagrelor in the PLATO study. The CHAMPION PHOENIX study (NCT01156571) compared initial treatment with cangrelor versus initial treatment with clopidogrel in patients undergoing PCI. We investigated the incidence, characteristics, and associated clinical outcomes in patients with dyspnoea in CHAMPION PHOENIX. Adverse events (AEs) of dyspnoea to 48 hours were recorded in patients randomised to cangrelor or clopidogrel in CHAMPION PHOENIX. The composite primary endpoint of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis as well its individual components were assessed in patients who did or did not report dyspnoea. A total of 68 (1.2 %) cangrelor-treated patients and 18 (0.3 %) clopidogrel-treated patients reported dyspnoea (p<0.001). Most dyspnoea events in cangrelor-treated patients were considered mild (71 %) or moderate (28 %) and only one event was considered severe and led to discontinuation of cangrelor. The dyspnoea events in the clopidogrel-treated patients were mild (78 %) or moderate (22 %). Characteristics of dyspnoea were consistent with those seen in the CHAMPION programme as a whole. In the modified intention-to-treat population, rates of the composite primary outcome and its individual components were not affected by the presence of dyspnoea in cangrelor-treated patients. Cangrelor-related dyspnoea is transient, usually mild or moderate, and unlikely to lead to discontinuation of therapy. The occurrence of dyspnoea does not seem to be associated with any reduction in the efficacy of cangrelor compared with clopidogrel as initial therapy in PCI patients.

    View details for DOI 10.1160/TH16-12-0958

    View details for Web of Science ID 000402591300009

    View details for PubMedID 28382371

  • Safety and Efficacy of Rivaroxaban in Patients With Cardiac Implantable Electronic Devices: Observations From the ROCKET AF Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Leef, G. C., Hellkamp, A. S., Patel, M. R., Becker, R. C., Berkowitz, S. D., Breithardt, G., Halperin, J. L., Hankey, G. J., Hacke, W., Nessel, C. C., Singer, D. E., Fox, K. A., Mahaffey, K. W., Piccini, J. P. 2017; 6 (6)

    Abstract

    Although implantation of cardiac implantable electronic devices (CIEDs) in patients receiving warfarin is well studied, limited data are available on the use of oral factor Xa inhibitors in this setting.Using data from Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) (n=14 264), we compared baseline characteristics and clinical outcomes in patients with atrial fibrillation randomized to rivaroxaban versus warfarin who did and did not undergo CIED implantation or revision. In this post-hoc, postrandomization, on-treatment analysis, only the first intervention per patient was analyzed. During a median follow-up of 2.2 years, 453 patients (242 rivaroxaban group; 211 warfarin group) underwent de novo CIED implantation (64.2%) or revision procedures (35.8%). Patients who received CIEDs were older, more likely to be male, and more likely to have past myocardial infarction, but had similar stroke risk compared to patients who did not receive CIEDs. Most patients who received a device had study drug interrupted for the procedure and did not receive bridging anticoagulation. During the 30-day postprocedural period, 11 patients (4.55%) in the rivaroxaban group experienced bleeding complications compared with 15 (7.13%) in the warfarin group. Thromboembolic complications occurred in 3 patients (1.26%) in the rivaroxaban group and 1 (0.48%) in the warfarin group. Event rates were too low for formal hypothesis testing.Bleeding and thromboembolic events were low in both rivaroxaban- and warfarin-treated patients. Periprocedural use of oral factor Xa inhibitors in CIED implantation requires further study in prospective, randomized trials.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for PubMedID 28615214

  • Effect of Atrial Fibrillation on Mortality, Stroke Risk, and Quality-of-Life Scores in Patients With Heart Failure (from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF]). American journal of cardiology Cherian, T. S., Shrader, P., Fonarow, G. C., Allen, L. A., Piccini, J. P., Peterson, E. D., Thomas, L., Kowey, P. R., Gersh, B. J., Mahaffey, K. W. 2017; 119 (11): 1763-1769

    Abstract

    The degree to which clinical outcomes are worsened in patients with atrial fibrillation (AF) with heart failure (HF) compared with those without HF is not well described. This study aimed to determine the impact of HF on clinical outcomes in patients with AF. We analyzed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, a national registry of 10,135 patients with AF to determine associations between HF and left ventricular ejection fraction (LVEF) and outcomes, including stroke, mortality, and hospitalization using Cox multivariable modeling. Atrial Fibrillation Effect on Quality-of-Life Questionnaire (AFEQT) scores between groups were also compared. Overall, 33% (n = 3,203) of patients had HF; of these 33% (n = 985) had LVEF ≤40%. Oral anticoagulation was prescribed more commonly in patients with HF (81% vs 74%). Compared with patients without HF, those with HF had similar rate of stroke (1.28 vs 0.88 per 100-patient years, hazard ratio [HR] 1.11, confidence interval [CI] 0.83 to 1.48, p = 0.47) but higher mortality (HR 1.69, CI 1.49 to 1.92, p <0.001) and hospitalization (HR 1.31, CI 1.23 to 1.39, p <0.0001). Patients with LVEF ≤40% had similar stroke risk (HR 1.06, CI 0.67 to 1.67) but higher mortality (HR 2.06, CI 1.74 to 2.44) and hospitalization (HR 1.38, CI 1.25 to 1.51). AFEQT overall score was significantly lower (76.9 vs 83.3, p <0.0001) in patients with HF. In conclusion, HF was associated with increased risk of death and hospitalization and worse quality of life, but similar rates of thromboembolism regardless of LVEF among patients with AF. These findings highlight the need to develop therapeutic strategies targeting functional status and survival for patients with HF and AF.

    View details for DOI 10.1016/j.amjcard.2017.02.050

    View details for PubMedID 28416199

  • Levosimendan in Patients with Left Ventricular Dysfunction Undergoing Cardiac Surgery NEW ENGLAND JOURNAL OF MEDICINE Mehta, R. H., Leimberger, J. D., van Diepen, S., Meza, J., Wang, A., Jankowich, R., Harrison, R. W., Hay, D., Fremes, S., Duncan, A., Soltesz, E. G., Luber, J., Park, S., Argenziano, M., Murphy, E., Marcel, R., Kalavrouziotis, D., Nagpal, D., Bozinovski, J., Toller, W., Heringlake, M., Goodman, S. G., Levy, J. H., Harrington, R. A., Anstrom, K. J., Alexander, J. H., LEVO-CTS Investigators 2017; 376 (21): 2032–42

    Abstract

    Levosimendan is an inotropic agent that has been shown in small studies to prevent or treat the low cardiac output syndrome after cardiac surgery.In a multicenter, randomized, placebo-controlled, phase 3 trial, we evaluated the efficacy and safety of levosimendan in patients with a left ventricular ejection fraction of 35% or less who were undergoing cardiac surgery with the use of cardiopulmonary bypass. Patients were randomly assigned to receive either intravenous levosimendan (at a dose of 0.2 μg per kilogram of body weight per minute for 1 hour, followed by a dose of 0.1 μg per kilogram per minute for 23 hours) or placebo, with the infusion started before surgery. The two primary end points were a four-component composite of death through day 30, renal-replacement therapy through day 30, perioperative myocardial infarction through day 5, or use of a mechanical cardiac assist device through day 5; and a two-component composite of death through day 30 or use of a mechanical cardiac assist device through day 5.A total of 882 patients underwent randomization, 849 of whom received levosimendan or placebo and were included in the modified intention-to-treat population. The four-component primary end point occurred in 105 of 428 patients (24.5%) assigned to receive levosimendan and in 103 of 421 (24.5%) assigned to receive placebo (adjusted odds ratio, 1.00; 99% confidence interval [CI], 0.66 to 1.54; P=0.98). The two-component primary end point occurred in 56 patients (13.1%) assigned to receive levosimendan and in 48 (11.4%) assigned to receive placebo (adjusted odds ratio, 1.18; 96% CI, 0.76 to 1.82; P=0.45). The rate of adverse events did not differ significantly between the two groups.Prophylactic levosimendan did not result in a rate of the short-term composite end point of death, renal-replacement therapy, perioperative myocardial infarction, or use of a mechanical cardiac assist device that was lower than the rate with placebo among patients with a reduced left ventricular ejection fraction who were undergoing cardiac surgery with the use of cardiopulmonary bypass. (Funded by Tenax Therapeutics; LEVO-CTS ClinicalTrials.gov number, NCT02025621 .).

    View details for PubMedID 28316276

  • Oral anticoagulation management in patients with atrial fibrillation undergoing cardiac implantable electronic device implantation. Clinical cardiology Black-Maier, E., Kim, S., Steinberg, B. A., Fonarow, G. C., Freeman, J. V., Kowey, P. R., Ansell, J., Gersh, B. J., Mahaffey, K. W., Naccarelli, G., Hylek, E. M., Go, A. S., Peterson, E. D., Piccini, J. P. 2017

    Abstract

    Oral anticoagulation (OAC) therapy is associated with increased periprocedural risks after cardiac implantable electronic device (CIED) implantation. Patterns of anticoagulation management involving non-vitamin K antagonist oral anticoagulants (NOACs) have not been characterized.Anticoagulation strategies and outcomes differ by anticoagulant type in patients undergoing CIED implantation.Using the nationwide Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we assessed how atrial fibrillation (AF) patients undergoing CIED implantation were cared for and their subsequent outcomes. Outcomes were compared by oral anticoagulant therapy (none, warfarin, or NOAC) as well as by anticoagulation interruption status.Among 9129 AF patients, 416 (5%) underwent CIED implantation during a median follow-up of 30 months (interquartile range, 24-36). Of these, 60 (14%) had implantation on a NOAC. Relative to warfarin therapy, those on a NOAC were younger (70.5 years [range, 65-77.5 years] vs 77 years [range, 70-82 years]), had less valvular heart disease (15.0% vs 31.3%), higher creatinine clearance (67.3 [range, 59.7-99.0] vs 65.8 [range, 50.0-91.6]), were more likely to have persistent AF (26.7% vs 22.9%), and use concomitant aspirin (51.7% vs 35.2%). OAC therapy was commonly interrupted for CIED in 64% (n = 183 of 284) of warfarin patients and 65% (n = 39 of 60) of NOAC patients. Many interrupted patients received intravenous bridging anticoagulation: 33/183 (18%) interrupted warfarin and 4/39 (10%) interrupted NOAC patients. Thirty-day periprocedure bleeding and stroke adverse events were infrequent.Management of anticoagulation among AF patients undergoing CIED implantation is highly variable, with OAC being interrupted in more than half of both warfarin- and NOAC-treated patients. Bleeding and stroke events were infrequent in both warfarin and NOAC-treated patients.

    View details for DOI 10.1002/clc.22726

    View details for PubMedID 28543401

  • Management of Major Bleeding in Patients With Atrial Fibrillation Treated With Non-Vitamin K Antagonist Oral Anticoagulants Compared With Warfarin in Clinical Practice (from Phase II of the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation [ORBIT-AF II]). American journal of cardiology Steinberg, B. A., Simon, D. N., Thomas, L., Ansell, J., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Peterson, E. D., Piccini, J. P. 2017; 119 (10): 1590-1595

    Abstract

    Non-vitamin K antagonist oral anticoagulants (NOACs) are effective at preventing stroke in patients with atrial fibrillation (AF). However, little is known about the management of bleeding in contemporary, clinical use of NOACs. We aimed to assess the frequency, management, and outcomes of major bleeding in the setting of community use of NOACs. Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II registry, we analyzed rates of International Society on Thrombosis and Haemostasis major bleeding and subsequent outcomes in patients treated with NOACs versus warfarin. Outcomes of interest included acute and chronic bleeding management, recurrent bleeding, thromboembolic events, and death. In total, 344 patients with atrial fibrillation experienced major bleeding events over a median follow-up of 360 days follow-up: n = 273 on NOAC (3.3 per 100 patient-years) and n = 71 on warfarin (3.5 per 100 patient-years). Intracranial bleeding was uncommon but similar (0.34 per 100 patient-years for NOAC vs 0.44 for warfarin, p = 0.5), as was gastrointestinal bleeding (1.8 for NOAC vs 1.3 for warfarin, p = 0.1). Blood products and correction agents were less commonly used in NOAC patients with major bleeds compared with warfarin-treated patients (53% vs 76%, p = 0.0004 for blood products; 0% vs 1.5% for recombinant factor; p = 0.0499); no patients received pharmacologic hemostatic agents (aminocaproic acid, tranexamic acid, desmopressin, aprotinin). Within 30 days, 23 NOAC-treated patients (8.4%) died versus 5 (7.0%) on warfarin (p = 0.7). At follow-up, 126 NOAC-treated (46%) and 29 warfarin-treated patients (41%) were not receiving any anticoagulation. In conclusion, rates of major bleeding are similar in warfarin and NOAC-treated patients in clinical practice. However, NOAC-related bleeds require less blood product administration and rarely require factor replacement.

    View details for DOI 10.1016/j.amjcard.2017.02.015

    View details for PubMedID 28363354

  • Adjuvant Antithrombotic Therapy in TAVR CURRENT CARDIOLOGY REPORTS O'Malley, R. G., Mahaffey, K. W., Fearon, W. F. 2017; 19 (5)

    Abstract

    Transcatheter aortic valve replacement (TAVR) has developed into an important alternative to surgical aortic valve replacement (SAVR) for patients with severe aortic stenosis (AS). Adjuvant antithrombotic therapies are commonly used during and after TAVR to decrease the risk of valve thrombosis and thromboembolic cerebrovascular events (CVEs) but consequently increase the risk of bleeding. This article reviews the past and current clinical data regarding adjuvant antithrombotic therapies in TAVR.Cerebrovascular and bleeding events during and after TAVR are associated with substantial morbidity and mortality. Bivalirudin, a direct thrombin inhibitor, has been shown to be safe alternative to unfractionated heparin (UFH) as procedural anticoagulation during TAVR; however, sparse evidence exists to guide use of antiplatelet and anticoagulant therapies in patients after TAVR. Multiple studies comparing different antithrombotic regimens in the post-TAVR setting are currently underway. Current guidelines recommend intra-procedural anticoagulation with UFH for during TAVR and with dual antiplatelet therapy (DAPT) after TAVR. There is a need to better understand the role of adjuvant antithrombotic therapies in TAVR. The results of ongoing studies are needed to develop evidence-based guidance for the use of adjuvant antithrombotic therapies after TAVR.

    View details for DOI 10.1007/s11886-017-0850-1

    View details for PubMedID 28391560

  • Noncentral Nervous System Systemic Embolism in Patients With Atrial Fibrillation Results From ROCKET AF (Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Orgel, R., Wojdyla, D., Huberman, D., Halperin, J. L., Breithardt, G., Singer, D. E., Fox, K. A., Hankey, G. J., Mahaffey, K. W., Jones, W. S., Patel, M. R. 2017; 10 (5)
  • An examination of the relationship between serum uric acid level, a clinical history of gout, and cardiovascular outcomes among patients with acute coronary syndrome. American heart journal Pagidipati, N. J., Hess, C. N., Clare, R. M., Akerblom, A., Tricoci, P., Wojdyla, D., Keenan, R. T., James, S., Held, C., Mahaffey, K. W., Klein, A. B., Wallentin, L., Roe, M. T. 2017; 187: 53-61

    Abstract

    Studies have suggested a relationship between higher baseline serum uric acid (sUA) levels and an elevated risk of subsequent ischemic cardiovascular outcomes among acute coronary syndrome (ACS) patients; this relationship may be modified by a clinical history of gout and has not been studied in large patient cohorts. We sought to understand the effect of sUA and gout on ACS outcomes.Using PLATO and TRACER data on 27,959 ACS patients, we evaluated baseline sUA levels in relation to a composite of cardiovascular death, myocardial infarction (MI), or stroke. We assessed interaction terms to determine if a baseline clinical diagnosis of gout modified this putative relationship; 46% (n=12,882) had sUA levels elevated >6.0 mg/dL.Patients with elevated levels were more often male with a history of prior MI, diabetes, and heart failure compared with those with sUA <6.0 mg/dL. The unadjusted risk of the composite endpoint increased with corresponding elevations in sUA levels (per 1 mg/dL increase) (HR=1.23 [95% CI: 1.20-1.26]) above the statistical inflection point of 5.0 mg/dL. After adjustment, the association between sUA level and the composite outcome remained significant (HR=1.07 [95% CI: 1.04-1.10]), and baseline gout did not modify this relationship.In patients with ACS, increasing levels of sUA are associated with an elevated risk of cardiovascular events, regardless of a clinical diagnosis of gout. Further investigation is warranted to determine the mechanism behind this relationship and to delineate whether sUA is an appropriate therapeutic target to reduce cardiovascular risk.

    View details for DOI 10.1016/j.ahj.2017.02.023

    View details for PubMedID 28454808

  • Differential occurrence, profile, and impact of first recurrent cardiovascular events after an acute coronary syndrome. American heart journal Hess, C. N., Clare, R. M., Neely, M. L., Tricoci, P., Mahaffey, K. W., James, S. K., Alexander, J. H., Held, C., Lopes, R. D., Fox, K. A., White, H. D., Wallentin, L., Armstrong, P. W., Harrington, R. A., Ohman, E. M., Roe, M. T. 2017; 187: 194-203

    Abstract

    Acute coronary syndrome (ACS) trials typically use a composite primary outcome (myocardial infarction [MI], stroke, or cardiovascular death), but differential patient characteristics, timing, and consequences associated with individual component end points as first events have not been well studied. We compared patient characteristics and prognostic significance associated with first cardiovascular events in the post-ACS setting for initially stabilized patients.We combined patient-level data from 4 trials of post-ACS antithrombotic therapies (PLATO, APPRAISE-2, TRACER, and TRILOGY ACS) to characterize the timing of and characteristics associated with first cardiovascular events (MI, stroke, or cardiovascular death). Landmark analysis at 7 days after index ACS presentation was used to focus on spontaneous, postdischarge events that were not confounded by in-hospital procedural complications. Using a competing risk framework, we tested for differential associations between prespecified covariates and the occurrence of nonfatal stroke vs MI as the first event, and we examined subsequent events after the first nonfatal event.Among 46,694 patients with a median follow-up of 358 (25th, 75th percentiles 262, 486) days, a first ischemic event occurred in 4,307 patients (9.2%) as follows: MI in 5.8% (n = 2,690), stroke in 1.0% (n = 477), and cardiovascular death in 2.4% (n = 1,140). Older age, prior stroke/transient ischemic attack, prior atrial fibrillation, and higher diastolic blood pressure were associated with a significantly greater risk of stroke vs MI, whereas prior percutaneous coronary intervention was associated with a greater risk of MI vs stroke. Second events occurred in 32% of those with a first nonfatal stroke at a median of 13 (3, 59) days after the first event and in 32% of those with a first nonfatal MI at a median of 35 (5, 137) days after the first event. The most common second event was a recurrent MI among those with MI as the first event and cardiovascular death among those with stroke as the first event.Approximately 9% of patients experienced a first cardiovascular event in the post-ACS setting during a median follow-up of 1 year. Although the profile and prognostic implications of stroke vs MI as the first nonfatal event differ substantially, approximately one-third of these patients experienced a second event, typically soon after the first event. These findings have implications for improving post-ACS care and influencing the design of future cardiovascular trials.

    View details for DOI 10.1016/j.ahj.2017.01.016

    View details for PubMedID 28454804

  • Efficacy and safety of rivaroxaban versus warfarin in patients from mainland China with nonvalvular atrial fibrillation: A subgroup analysis from the ROCKET AF trial. Thrombosis research Sun, Y., Hu, D., Stevens, S., Lokhnygina, Y., Becker, R. C., Berkowitz, S. D., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Piccini, J. P., Singer, D. E., Fox, K. A., Patel, M. R. 2017

    Abstract

    The ROCKET AF study evaluated once-daily rivaroxaban versus dose-adjusted warfarin for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). In this analysis, we compared rivaroxaban with warfarin in patients with AF from China, East Asia, and the rest of the world (ROW).We assessed baseline demographics and interaction of treatment effects of rivaroxaban versus warfarin among patients from mainland China, other East Asian countries, and ROW. Of the 14,236 patients enrolled in the per-protocol population, 495 were from mainland China, 433 from other East-Asian regions, and 13,308 from the rest of the world (ROW). At baseline, patients from China had significantly higher rates of previous stroke/transient ischemic attack (TIA) compared with patients from other East Asian regions and ROW (79.6%, 44.6%, 51.6% respectively; p<0.0001) and lower rates of VKA use (33.7%, 66.7%, 63.4%, respectively; p<0.0001). The rates of stroke or systemic embolism among those on warfarin while on treatment was 5.23% in patients from China, 1.82% in those from other East Asian regions, and 2.07% from ROW; on rivaroxaban, the rates were 2.29% in patients from China, 1.86% in those from other east Asian regions, and 1.67% from ROW. There were no significant treatment-by-region interactions for any efficacy or safety outcome (all p>0.12). Numerically higher rates of intracranial bleeding were seen in patients from China receiving warfarin versus rivaroxaban.In patients from China, rates of intracranial hemorrhage were numerically lower among those receiving rivaroxaban and consistent with the overall trial.URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

    View details for DOI 10.1016/j.thromres.2017.04.010

    View details for PubMedID 28433206

  • Obesity, Diabetes, and Acute Coronary Syndrome: Differences Between Asians and Whites. The American journal of medicine Koshizaka, M., Lopes, R. D., Newby, L. K., Clare, R. M., Schulte, P. J., Tricoci, P., Mahaffey, K. W., Ogawa, H., Moliterno, D. J., Giugliano, R. P., Huber, K., James, S., Harrington, R. A., Alexander, J. H. 2017

    Abstract

    Most diabetes and cardiovascular studies have been conducted in white patients, with data being extrapolated to other population groups.For this analysis, patient-level data were extracted from 5 randomized clinical trials in patients with acute coronary syndrome; we compared obesity levels between Asian and white populations, stratified by diabetes status. By using an adjusted Cox proportional hazards model, hazard ratios (HRs) for cardiovascular outcomes after an acute coronary syndrome were determined.We identified 49,224 patient records from the 5 trials, with 3176 Asians and 46,048 whites. Whites with diabetes had higher body mass index values than those without diabetes (median 29.3 vs 27.2 kg/m(2); P < .0001), whereas Asians with diabetes and without diabetes had similar body mass index (24.7 vs 24.2 kg/m(2)). Asians with diabetes (HR, 1.63; 95% confidence interval [CI], 1.32-2.02), whites with diabetes (HR, 1.15; 95% CI, 1.06-1.25), and Asians without diabetes (HR, 1.36; 95% CI, 1.14-1.64) had higher rates of the composite of death, myocardial infarction, or stroke at 30 days than whites without diabetes. Asians with diabetes (HR, 1.84; 95% CI, 1.47-2.31), whites with diabetes (HR, 1.47; 95% CI, 1.33-1.62), and Asians without diabetes (HR, 1.38; 95% CI, 1.11-1.73) had higher rates of death at 1 year compared with whites without diabetes. There were no significant interactions between race and diabetes for ischemic outcomes.Although Asians with diabetes and acute coronary syndrome are less likely to be obese than their white counterparts, their risk for death or recurrent ischemic events was not lower.

    View details for DOI 10.1016/j.amjmed.2017.03.030

    View details for PubMedID 28396226

  • Predicting the risk of bleeding during dual antiplatelet therapy after acute coronary syndromes. Heart (British Cardiac Society) Alfredsson, J., Neely, B., Neely, M. L., Bhatt, D. L., Goodman, S. G., Tricoci, P., Mahaffey, K. W., Cornel, J. H., White, H. D., Fox, K. A., Prabhakaran, D., Winters, K. J., Armstrong, P. W., Ohman, E. M., Roe, M. T. 2017

    Abstract

    Dual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patient's bleeding risk during DAPT treatment in the post-ACS setting.To develop a longitudinal bleeding risk prediction model, we analysed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revascularisation and treated with DAPT for a median of 14.8 months.We identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomisation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomisation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneau's C-indices: 0.78 (SE=0.024) for the GUSTO model and 0.67 (SE=0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68).Longitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform risk-benefit considerations regarding the duration of DAPT following ACS.ClinicalTrials.gov identifier: https://clinicaltrials.gov/ct2/show/NCT00699998.

    View details for DOI 10.1136/heartjnl-2016-310090

    View details for PubMedID 28381584

  • Data monitoring committees: Promoting best practices to address emerging challenges CLINICAL TRIALS Fleming, T. R., DeMets, D. L., Roe, M. T., Wittes, J., Calis, K. A., Vora, A. N., Meisel, A., Bain, R. P., Konstam, M. A., Pencina, M. J., Gordon, D. J., Mahaffey, K. W., Hennekens, C. H., Neaton, J. D., Pearson, G. D., Andersson, T. L., Pfeffer, M. A., Ellenberg, S. S. 2017; 14 (2): 115-123

    Abstract

    Data monitoring committees are responsible for safeguarding the interests of study participants and assuring the integrity and credibility of clinical trials. The independence of data monitoring committees from sponsors and investigators is essential in achieving this mission. Creative approaches are needed to address ongoing and emerging challenges that potentially threaten data monitoring committees' independence and effectiveness.An expert panel of representatives from academia, industry and government sponsors, and regulatory agencies discussed these challenges and proposed best practices and operating principles for effective functioning of contemporary data monitoring committees.Prospective data monitoring committee members need better training. Options could include didactic instruction as well as apprenticeships to provide real-world experience. Data monitoring committee members should be protected against legal liability arising from their service. While avoiding breaches in confidentiality of interim data remains a high priority, data monitoring committees should have access to unblinded efficacy and safety data throughout the trial to enable informed judgments about risks and benefits. Because overly rigid procedures can compromise their independence, data monitoring committees should have the flexibility necessary to best fulfill their responsibilities. Data monitoring committee charters should articulate principles that guide the data monitoring committee process rather than list a rigid set of requirements. Data monitoring committees should develop their recommendations by consensus rather than through voting processes. The format for the meetings of the data monitoring committee should maintain the committee's independence and clearly establish the leadership of the data monitoring committee chair. The independent statistical group at the Statistical Data Analysis Center should have sufficient depth of knowledge about the study at hand and experience with trials in general to ensure that the data monitoring committee has access to timely, reliable, and readily interpretable insights about emerging evidence in the clinical trial. Contracts engaging data monitoring committee members for industry-sponsored trials should have language customized to the unique responsibilities of data monitoring committee members rather than use language appropriate to consultants for product development. Regulatory scientists would benefit from experiencing data monitoring committee service that does not conflict with their regulatory responsibilities.

    View details for DOI 10.1177/1740774516688915

    View details for Web of Science ID 000397934800001

    View details for PubMedID 28359194

  • Absence of Oral Anticoagulation and Subsequent Outcomes Among Outpatients with Atrial Fibrillation AMERICAN JOURNAL OF MEDICINE Hess, P. L., Kim, S., Fonarow, G. C., Thomas, L., Singer, D. E., Freeman, J. V., Gersh, B. J., Ansell, J., Kowey, P. R., Mahaffey, K. W., Chan, P. S., Steinberg, B. A., Peterson, E. D., Piccini, J. P. 2017; 130 (4): 449-456

    Abstract

    Prior studies have shown a treatment gap in oral anticoagulation (OAC) use among patients with atrial fibrillation yet have incompletely characterized factors associated with failure to treat and subsequent outcomes in contemporary practice.Using data collected between June 2010 and August 2011 from 174 ambulatory care sites in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we identified factors associated with absence of OAC via stratified logistic regression. Using weighted Cox regression, we assessed the association between OAC non-use and subsequent outcomes over 2.5 years.Among 9553 patients, 2202 (23.0%) were not on OAC. Among OAC nonrecipients, 1846 (83.8%) had a CHA2DS2-VASc score ≥2. Factors independently associated with OAC non-use included atrial fibrillation type (paroxysmal odds ratio [OR] 0.73, 95% confidence interval [CI] 0.54-0.99; persistent OR 0.14, 95% CI 0.10-0.21; permanent OR 0.35, 95% CI 0.25-0.49; reference = new-onset), left atrial diameter enlargement (mild OR 0.80, 95% CI 0.66-0.97; moderate 0.58, 95% CI 0.47-0.73; severe 0.53, 95% CI 0.42-0.68; reference = normal diameter), and age >80 years (OR 1.04, 95% CI 1.02-1.08). Untreated patients had a higher risk of death (adjusted hazard ratio [HR] 1.22, 95% CI 1.05-1.41), a lower bleeding risk (adjusted HR 0.35, 95% CI 0.15-0.81), and a nonsignificant trend toward higher risk of stroke/non-central nervous system embolism/transient ischemic attack than those treated (adjusted HR 1.18, 95% CI 0.91-1.54).A majority of atrial fibrillation patients not treated with an OAC in current community practice meet guideline indications for treatment. Atrial fibrillation burden, chronicity, and comorbidity are associated with nontreatment. Untreated patients are at increased risk for adverse outcomes.

    View details for DOI 10.1016/j.amjmed.2016.11.001

    View details for Web of Science ID 000400462300035

  • CANGRELOR VERSUS CLOPIDOGREL ON A BACKGROUND OF UNFRACTIONATED HEPARIN INSIGHTS FROM CHAMPION PHOENIX Vaduganathan, M., Harrington, R., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., Deliargyris, E., Prats, J., Mahaffey, K., White, H., Bhatt, D. ELSEVIER SCIENCE INC. 2017: 1345
  • ONE-YEAR MORTALITY INCREASED IN PATIENTS WITH PERI-PROCEDURAL MYOCARDIAL INFARCTION: INSIGHTS FROM THE CHAMPION TRIALS Olivier, C., Sundaram, V., Ding, V., Yang, L., Leonardi, S., Lopes, R., Bhatt, D., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., White, H., Desai, M., Harrington, R., Lynch, D. R., Mahaffey, K., CHAMPION Investigators ELSEVIER SCIENCE INC. 2017: 7
  • IMPACT OF PERIPROCEDURAL MYOCARDIAL INFARCTION IN CONTEMPORARY PCI: POOLED PATIENT-LEVEL DATA FROM THE CHAMPION TRIALS Vaduganathan, M., Harrington, R., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., Deliargyris, E., Prats, J., Mahaffey, K., White, H., Bhatt, D. ELSEVIER SCIENCE INC. 2017: 112
  • Trade-off of myocardial infarction vs. bleeding types on mortality after acute coronary syndrome: lessons from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) randomized trial EUROPEAN HEART JOURNAL Valgimigli, M., Costa, F., Lokhnygina, Y., Clare, R. M., Wallentin, L., Moliterno, D. J., Armstrong, P. W., White, H. D., Held, C., Aylward, P. E., Van de Werf, F., Harrington, R. A., Mahaffey, K. W., Tricoci, P. 2017; 38 (11): 804-?

    Abstract

    Dual antiplatelet therapy reduces non-fatal ischaemic events after acute coronary syndrome (ACS) but increases bleeding to a similar extent. We sought to determine the prognostic impact of myocardial infarction (MI) vs. bleeding during an extended follow-up period to gain insight into the trade-off between efficacy and safety among patients after ACS.In 12 944 patients with non-ST-segment elevation ACS from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial, we investigated the relative impact of MI and bleeding occurring >30 days post-ACS and subsequent all-cause mortality. Bleeding was graded according to Bleeding Academic Research Consortium (BARC) criteria. MI was associated with a five-fold increase in mortality. BARC type 2 and 3, but not type 1, bleeding had a significant impact on mortality. MI was associated with a greater risk of mortality compared with BARC 2 [relative risk (RR) 3.5; 95% confidence interval (CI) 2.08-4.77; P < 0.001] and BARC 3a bleeding (RR 2.23; 95% CI 1.36-3.64; P = 0.001), and a risk similar to BARC 3b bleeding (RR 1.37; 95% CI 0.81-2.30; P = 0.242). Risk of death after MI was significantly lower than after BARC 3c bleeding (RR 0.22; 95% CI 0.13-0.36; P < 0.001). MI and bleeding had similar time-associations with mortality, which remained significant for several months, still being higher early after the event.In patients treated with antiplatelet therapy after ACS, both MI and bleeding significantly impacted mortality with similar time-dependency. Although BARC 2 and 3a bleeding were less prognostic for death than MI, the risk of mortality was equivalent between BARC 3b bleeding and MI, and was higher following BARC 3c bleeding.

    View details for DOI 10.1093/eurheartj/ehw525

    View details for Web of Science ID 000396777300005

    View details for PubMedID 28363222

  • Treatment Consistency Across Levels of Baseline Renal Function With Rivaroxaban or Warfarin A ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) Analysis CIRCULATION Lindner, S. M., Fordyce, C. B., Hellkamp, A. S., Lokhnygina, Y., Piccini, J. P., Breithardt, G., Mahaffey, K. W., Singer, D. E., Hacke, W., Halperin, J. L., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Becker, R. C., Fox, K. A., Patel, M. R., ROCKET AF Steering Comm 2017; 135 (10): 1001–3

    View details for PubMedID 28264892

  • Results of a curtailed randomized controlled trial, evaluating the efficacy and safety of azimilide in patients with implantable cardioverter-defibrillators: The SHIELD-2 trial. American heart journal Robinson, V. M., Bharucha, D. B., Mahaffey, K. W., Dorian, P., Kowey, P. R. 2017; 185: 43-51

    Abstract

    Frequent hospital attendances in patients with implantable cardioverter-defibrillators (ICDs) result in significant morbidity and health care costs. Current drugs to reduce ICD shocks and hospital visits have limited efficacy and considerable toxicity. We evaluated the efficacy and safety of azimilide, a novel oral class III antiarrhythmic, for use in ICD patients.A total of 240 patients were enrolled in a prospective, randomized, double-blind, placebo-controlled trial to evaluate the effect of oral azimilide 75 mg daily in ICD patients with previously documented ventricular tachycardia or ventricular fibrillation, and a left ventricular ejection fraction ≤40%. The primary outcome metric was the adjudicated time-to-first unplanned cardiovascular (CV) hospitalization, or CV emergency department (ED) visit, or CV death. The trial was prematurely discontinued due to withdrawal of study sponsorship.Azimilide demonstrated numerical but statistically nonsignificant reductions in the primary composite outcome (odds ratio [OR] 0.79, 95% CI 0.44-1.44), unplanned CV hospitalizations (OR 0.75, 95% CI 0.41-1.38), ED visits (OR 0.68, 95% CI 0.35-1.31), and all-cause shocks (OR 0.58, 95% CI 0.32-1.05). The incidence of adverse events was lower in the azimilide group. Neutropenia was not observed (absolute neutrophil count <1000 μ/L), and there was one possible torsade de pointes case that led to a successful ICD discharge.The SHIELD-2 trial was statistically underpowered due to early trial termination and did not meet its primary objective. Despite this limitation, azimilide showed promise as a safe and effective drug in reducing all-cause shocks, unplanned hospitalizations, and ED visits in ICD patients.

    View details for DOI 10.1016/j.ahj.2016.10.025

    View details for PubMedID 28267474

  • Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): A randomized, placebo-controlled trial. Diabetes, obesity & metabolism Neal, B., Perkovic, V., Matthews, D. R., Mahaffey, K. W., Fulcher, G., Meininger, G., Erondu, N., Desai, M., Shaw, W., Vercruysse, F., Yee, J., Deng, H., de Zeeuw, D. 2017; 19 (3): 387-393

    Abstract

    The primary aim of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R) is to determine whether the favourable effects of inhibition of the sodium glucose co-transporter 2 (SGLT2) on blood glucose, blood pressure and body weight are accompanied by protection against adverse renal outcomes.CANVAS-R is a prospective, randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes with a history or high risk of cardiovascular events. Patients were randomly assigned to once-daily placebo or canagliflozin 100 mg (with optional uptitration to 300 mg) for a planned average of 2.5 years of follow-up. The primary outcome is kidney disease progression, defined by class change in albuminuria. The two secondary outcomes are the composite of hospitalized heart failure or cardiovascular death, and cardiovascular death alone. Effects on end-stage renal disease and a range of other outcomes will also be explored.A total of 5812 participants were recruited at 422 sites in 24 countries between January 2014 and May 2015. The mean baseline age was 64 years, mean duration of diabetes was 14 years, mean glycated haemoglobin level was 8.3% and mean body mass index was 32 kg/m(2) . Of these participants, 37% were women, 71% had a history of cardiovascular disease, 22.3% had microalbuminuria and 8.7% had macroalbuminuria. The mean baseline estimated glomerular filtration rate was 76 mL/min/1.73 m(2) . The study will have at least 90% power ( P = .05) to detect a 22% or greater reduction in the risk of progression of albuminuria.The trial should define the potential renoprotective effect of canagliflozin and will provide additional important new data about its effects on vascular outcomes, death and kidney failure.

    View details for DOI 10.1111/dom.12829

    View details for PubMedID 28120497

    View details for PubMedCentralID PMC5348724

  • Cardioversion and subsequent quality of life and natural history of atrial fibrillation. American heart journal Pokorney, S. D., Kim, S., Thomas, L., Fonarow, G. C., Kowey, P. R., Gersh, B. J., Mahaffey, K. W., Peterson, E. D., Piccini, J. P. 2017; 185: 59-66

    Abstract

    Cardioversion is a class I procedure for patients with symptomatic atrial fibrillation (AF) pursuing rhythm control. There are few contemporary reports on quality of life and outcomes after cardioversion.Using the nationwide prospective ORBIT-AF registry, cardioversion patients were propensity matched 3:1 to noncardioverted patients and Cox proportional hazards modeling evaluated hospitalization at 1 year in those with and without cardioversion. Cardiovascular outcomes, AF progression, and quality of life were evaluated for the matched cohorts with and without cardioversion.Among 9,642 patients, 817 patients (8%) underwent 906 cardioversions during a median follow-up of 12 (interquartile range 6-18) months. Among matched cardioverted and noncardioverted patients, 1-year cardiovascular hospitalization rates were 43% vs 21% (adjusted hazard ratio 2.2, 95% CI 1.8-2.8, P<.001), and sinus rhythm at both first and second follow-ups was 36% vs 27% (P=.042), respectively. Findings were similar among first-time cardioversion patients. Matched cardioversion patients did not exhibit greater symptom improvement (34% vs 42%) or less symptomatic progression (15% vs 4%) by European Heart Rhythm Association scores. Cardioversion was associated with AF progression with an odds ratio of 1.6 (95% CI 1.2-2.2, P=.001) after cardioversion and 2.7 (P<.001) after first cardioversion vs matched noncardioversion patients. After cardioversion, only 18% of patients not previously on an antiarrhythmic started one, less than 5% underwent ablation, and 22% stopped their antiarrhythmic.Cardioversion was not associated with improved AF-related quality of life or less progression. Many patients who undergo cardioversion do not receive adjunctive rhythm control therapies. These findings may help to better inform therapeutic decision making.

    View details for DOI 10.1016/j.ahj.2016.10.018

    View details for PubMedID 28267476

  • Optimising the analysis strategy for the CANVAS Program - a pre-specified plan for the integrated analyses of the CANVAS and CANVAS-R trials. Diabetes, obesity & metabolism Neal, B., Perkovic, V., Mahaffey, K. W., Fulcher, G., Erondu, N., Desai, M., Shaw, W., Law, G., Walton, M. K., Rosenthal, N., Zeeuw, D. d., Matthews, D. R. 2017

    Abstract

    Two large cardiovascular outcome trials of canagliflozin, comprising the CANVAS Program, will complete in early 2017: the CANagliflozin cardioVascular Assessment Study (CANVAS) and the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R). Accruing data for the sodium glucose co-transporter 2 (SGLT2) inhibitor class has identified questions and opportunities that were not apparent when the trials were designed. Accordingly, a series of modifications have been made to the planned analyses. These updates will ensure that the data from the CANVAS Program will maximize advances in scientific knowledge and patient care. The specification of the analysis strategy prior to knowledge of the trial results, their design by the independent scientific trial Steering Committee, the detailed a priori definition of the analysis plans, and the external review provided by the US Food and Drug Administration all provide maximally efficient and robust utilization of the data. The CANVAS Program should significantly advance our understanding of the effects of canagliflozin, and the broader SGLT2 inhibitor class, on a range of important efficacy and safety outcomes.

    View details for DOI 10.1111/dom.12924

    View details for PubMedID 28244644

  • Evaluation of Ischemic and Bleeding Risks Associated With 2 Parenteral Antiplatelet Strategies Comparing Cangrelor With Glycoprotein IIb/IIIa Inhibitors: An Exploratory Analysis From the CHAMPION Trials. JAMA cardiology Vaduganathan, M., Harrington, R. A., Stone, G. W., Deliargyris, E. N., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Menozzi, A., Prats, J., Elkin, S., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2017; 2 (2): 127-135

    Abstract

    In the context of contemporary pharmacotherapy, optimal antiplatelet management with percutaneous coronary intervention (PCI) has not been well established.To compare the ischemic and bleeding risks associated with glycoprotein IIb/IIIa inhibitors (GPIs) and a potent P2Y12 antagonist, cangrelor, in patients undergoing PCI.An exploratory analysis of pooled patient-level data from the 3 phase 3 Cangrelor vs Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PCI, CHAMPION PLATFORM, and CHAMPION PHOENIX) trials of patients undergoing elective or nonelective PCI. The participants included 10 929 patients assigned to cangrelor but not receiving GPIs (cangrelor alone) and 1211 patients assigned to clopidogrel (or placebo) and receiving routine GPIs (clopidogrel-GPI). Patients requiring bailout or rescue GPI therapy were excluded. To account for risk imbalances, 1:1 propensity score matching based on 16 baseline clinical variables yielded 1021 unique matched pairs. The present study's data analysis was conducted from October 28, 2015, to August 6, 2016.The primary efficacy end point was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours. Safety was assessed by 3 validated bleeding scales (Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO], Thrombolysis in Myocardial Infarction [TIMI], and Acute Catheterization and Urgent Intervention Triage) and requirement for blood transfusions.Of the 12 140 patients included in the analysis, 8779 were men (72.3%), and the mean (SD) age was 63.2 (11.3) years. Patients in the clopidogrel-GPI group were more likely to be male (75.6% vs 71.9%), younger (median, 60 [range, 23-91] years vs 64 [range, 26-95] years), enrolled from the United States (77.9% vs 40.0%), and present with an acute coronary syndrome, but they had lower comorbid disease burden and were less likely to receive bivalirudin (8.8% vs 27.3%). In the matched cohorts, the rates of the primary efficacy end point were not significantly different between the cangrelor alone and clopidogrel-GPI groups (2.6% vs 3.3%; odds ratio [OR], 0.79; 95% CI, 0.48-1.32). There was a nonsignificant trend toward lower rates of GUSTO-defined severe/life-threatening bleeding with cangrelor alone compared with clopidogrel-GPI (0.3% vs 0.7%; OR, 0.43; 95% CI, 0.11-1.66). Rates of TIMI-defined major or minor bleeding were significantly lower in patients treated with cangrelor alone (0.7% vs 2.4%; OR, 0.29; 95% CI, 0.13-0.68).Based on a pooled analysis from the 3 phase 3 CHAMPION trials, cangrelor alone was associated with similar ischemic risk and lower risk-adjusted bleeding risk compared with clopidogrel-GPIs.clinicaltrials.gov Identifiers: NCT00305162, NCT00385138, and NCT01156571.

    View details for DOI 10.1001/jamacardio.2016.4556

    View details for PubMedID 27902833

  • Cangrelor With and Without Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vaduganathan, M., Harrington, R. A., Stone, G. W., Deliargyris, E. N., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Menozzi, A., Prats, J., Elkin, S., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2017; 69 (2): 176-185

    Abstract

    Cangrelor, an intravenous, reversible P2Y12 antagonist, is approved for use in patients undergoing percutaneous coronary intervention (PCI).This study sought to evaluate the efficacy and safety of cangrelor compared with clopidogrel in subgroups that did and did not receive glycoprotein IIb/IIIa inhibitors (GPIs).This pooled, patient-level analysis of the 3 CHAMPION (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) trials analyzed all randomized patients who underwent PCI and received the study drug (n = 24,902). Only bailout/rescue GPI use was permitted, except in CHAMPION PCI, in which routine or bailout/rescue GPI use was at the site investigator's discretion. The primary efficacy endpoint was the composite of all-cause mortality, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h after randomization.Overall, 3,173 patients (12.7%) received a GPI, most commonly eptifibatide (69.4%). Despite variation in indications for GPIs, baseline characteristics were well balanced between the cangrelor and clopidogrel arms in subsets receiving and not receiving GPIs. Rates of the primary composite endpoint were lower with cangrelor compared with clopidogrel in patients who did (4.9% vs. 6.5%; odds ratio [OR]: 0.74; 95% confidence interval [CI]: 0.55 to 1.01) or did not receive a GPI (3.6% vs. 4.4%; OR: 0.82; 95% CI: 0.72 to 0.94; Pint = 0.55). Cangrelor did not increase the primary safety endpoint, GUSTO-defined severe/life-threatening bleeding, in patients who did (0.4% vs. 0.5%; OR: 0.71; 95% CI: 0.25 to 1.99) or did not receive GPIs (0.2% vs. 0.1%; OR: 1.56; 95% CI: 0.80 to 3.04; Pint = 0.21). GPI use was associated with increased risk of bleeding in both treatment arms.Cangrelor's efficacy in reducing ischemic complications in patients undergoing PCI was maintained irrespective of GPI administration. GPI use was associated with substantially higher bleeding rates, regardless of the randomization to cangrelor or clopidogrel. (A Clinical Trial to Demonstrate the Efficacy of Cangrelor [PCI]: NCT00305162; Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition [PLATFORM]: NCT00385138; A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]: NCT01156571).

    View details for DOI 10.1016/j.jacc.2016.10.055

    View details for Web of Science ID 000392993100009

    View details for PubMedID 28081827

  • Ticagrelor Compared With Clopidogrel in Patients With Prior Lower Extremity Revascularization for Peripheral Artery Disease CIRCULATION Jones, W. S., Baumgartner, I., Hiatt, W. R., Heizer, G., Conte, M. S., White, C. J., Berger, J. S., Held, P., Katona, B. G., Mahaffey, K. W., Norgren, L., Blomster, J., Millegard, M., Reist, C., Patel, M. R., Fowkes, F. G. 2017; 135 (3): 241-?

    Abstract

    In patients with symptomatic peripheral artery disease with a history of limb revascularization, the optimal antithrombotic regimen for long-term management is unknown.The EUCLID trial (Examining Use of Ticagrelor In PAD) randomized 13 885 patients with peripheral artery disease to treatment with ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. Patients were enrolled based on an abnormal ankle-brachial index ≤0.80 or a previous lower extremity revascularization. This analysis focuses on the 7875 (57%) patients enrolled based on the previous lower extremity revascularization criterion. Patients could not be enrolled within 30 days of most recent revascularization, and patients with an indication for dual antiplatelet therapy were excluded. The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding.Patients with a previous revascularization had a mean age of 66 years, 73% were male, and the median baseline ankle-brachial index was 0.78. After adjustment for baseline characteristics, patients enrolled based on previous revascularization had similar rates of the primary composite end point (hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.98-1.23, P=0.12) and statistically significantly higher rates of myocardial infarction (HR 1.29, 95% CI 1.08-1.55, P=0.005) and acute limb ischemia (HR 4.23, 95% CI 2.86-6.25, P<0.001) when compared with patients enrolled based on ankle-brachial index criteria. No differences in ticagrelor- versus clopidogrel-treated patients were found for the primary efficacy end point (11.4% vs 11.3%; HR 1.01, 95% CI 0.88-1.15; P=0.90), all-cause mortality (9.2% vs 9.2%; HR 0.99, 95% CI 0.86-1.15; P=0.93), acute limb ischemia (2.5% vs 2.5%; HR 1.03, 95% CI 0.78-1.36; P=0.84), or major bleeding (1.9% vs 1.8%; HR 1.15, 95% CI 0.83-1.59; P=0.41). The median duration of follow-up was ≈30 months.After adjustment for baseline characteristics, patients enrolled based on previous revascularization for peripheral artery disease had higher rates of myocardial infarction and acute limb ischemia, with similar composite rates of cardiovascular death, myocardial infarction, and stroke when compared with patients enrolled based on the ankle-brachial index criterion. No significant differences were found between ticagrelor and clopidogrel for reduction of cardiovascular or acute limb events.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01732822.

    View details for DOI 10.1161/CIRCULATIONAHA.116.025880

    View details for Web of Science ID 000392291000009

    View details for PubMedID 27840336

  • Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease NEW ENGLAND JOURNAL OF MEDICINE Hiatt, W. R., Fowkes, F. G., Heizer, G., Berger, J. S., Baumgartner, I., Held, P., Katona, B. G., Mahaffey, K. W., Norgren, L., Jones, W. S., Blomster, J., Millegard, M., Reist, C., Patel, M. R. 2017; 376 (1): 32-40

    Abstract

    Peripheral artery disease is considered to be a manifestation of systemic atherosclerosis with associated adverse cardiovascular and limb events. Data from previous trials have suggested that patients receiving clopidogrel monotherapy had a lower risk of cardiovascular events than those receiving aspirin. We wanted to compare clopidogrel with ticagrelor, a potent antiplatelet agent, in patients with peripheral artery disease.In this double-blind, event-driven trial, we randomly assigned 13,885 patients with symptomatic peripheral artery disease to receive monotherapy with ticagrelor (90 mg twice daily) or clopidogrel (75 mg once daily). Patients were eligible if they had an ankle-brachial index (ABI) of 0.80 or less or had undergone previous revascularization of the lower limbs. The primary efficacy end point was a composite of adjudicated cardiovascular death, myocardial infarction, or ischemic stroke. The primary safety end point was major bleeding. The median follow-up was 30 months.The median age of the patients was 66 years, and 72% were men; 43% were enrolled on the basis of the ABI and 57% on the basis of previous revascularization. The mean baseline ABI in all patients was 0.71, 76.6% of the patients had claudication, and 4.6% had critical limb ischemia. The primary efficacy end point occurred in 751 of 6930 patients (10.8%) receiving ticagrelor and in 740 of 6955 (10.6%) receiving clopidogrel (hazard ratio, 1.02; 95% confidence interval [CI], 0.92 to 1.13; P=0.65). In each group, acute limb ischemia occurred in 1.7% of the patients (hazard ratio, 1.03; 95% CI, 0.79 to 1.33; P=0.85) and major bleeding in 1.6% (hazard ratio, 1.10; 95% CI, 0.84 to 1.43; P=0.49).In patients with symptomatic peripheral artery disease, ticagrelor was not shown to be superior to clopidogrel for the reduction of cardiovascular events. Major bleeding occurred at similar rates among the patients in the two trial groups. (Funded by AstraZeneca; EUCLID ClinicalTrials.gov number, NCT01732822 .).

    View details for DOI 10.1056/NEJMoa1611688

    View details for PubMedID 27959717

  • Impact of Cerebrovascular Events Older Than One Year on Ischemic and Bleeding Outcomes With Cangrelor in Percutaneous Coronary Intervention CIRCULATION-CARDIOVASCULAR INTERVENTIONS Sawlani, N. N., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2017; 10 (1)

    Abstract

    Cangrelor is a potent intravenous adenosine diphosphate-receptor antagonist that in the CHAMPION trials reduced the 48-hour and 30-day rates of ischemic events during percutaneous coronary intervention without an increase in severe bleeding.CHAMPION PCI (A Clinical Trial to Demonstrate the Efficacy of Cangrelor), CHAMPION PLATFORM (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), and CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) were 3 randomized, double-blind, double-dummy trials in which cangrelor was compared with clopidogrel during percutaneous coronary intervention. The effect of cangrelor on ischemic events and bleeding was analyzed in the subgroup of patients with a history of cerebrovascular events at least 1 year prior to randomization; the Breslow-Day test was used to test for interaction of treatment effect in subgroups with and without such a history. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours. Among 24 910 randomized patients, 1270 patients (5.1%) had a cerebrovascular event >1 year old, including 650 assigned to cangrelor and 620 assigned to clopidogrel. Consistent with the overall trial results, the rate of the primary efficacy end point was 4.3% in the cangrelor group versus 5.3% in the clopidogrel group (odds ratio 0.80; 95% confidence interval 0.48-1.34; P=0.40; P for interaction =0.97), and the rate of GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe bleeding was 0.3% in both groups (P=0.97; P for interaction =0.81).Among patients in the CHAMPION trials with a prior cerebrovascular event at least 1 year before the percutaneous coronary intervention, the efficacy and bleeding profile of cangrelor compared with clopidogrel was similar to that in the overall trial.

    View details for DOI 10.1161/CIRCINTERVENTIONS.116.004380

    View details for Web of Science ID 000393178000006

    View details for PubMedID 28039321

  • Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference. Cardiovascular drugs and therapy Povsic, T. J., Scott, R. n., Mahaffey, K. W., Blaustein, R. n., Edelberg, J. M., Lefkowitz, M. P., Solomon, S. D., Fox, J. C., Healy, K. E., Khakoo, A. Y., Losordo, D. W., Malik, F. I., Monia, B. P., Montgomery, R. L., Riesmeyer, J. n., Schwartz, G. G., Zelenkofske, S. L., Wu, J. C., Wasserman, S. M., Roe, M. T. 2017; 31 (4): 445–58

    Abstract

    The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease.The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe.We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development.The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.

    View details for PubMedID 28735360

  • Cardiovascular adverse events in the drug-development program of bupropion for smoking cessation: A systematic retrospective adjudication effort. Clin Cardiol. 2017 Jun 12. Kittle, J., et al 2017: 899–906

    Abstract

    In 2011, the US Food and Drug Administration requested that GlaxoSmithKline perform retrospective adjudication of cardiovascular (CV) events reported in the bupropion drug-development trials for smoking cessation.Retrospective adjudication of clinical trial data will not increase the identification of adverse events.We performed a comprehensive retrospective analysis of adverse events in 19 previously completed controlled US clinical trials of bupropion marketed for the treatment of smoking cessation, yielding 9479 subjects (5290 bupropion, 2927 placebo, 1018 active control [ACT], and 244 treated concurrently with bupropion and ACT). All adverse events were sent to the Duke Clinical Research Institute for adjudication by Clinical Events Classification (CEC) physician reviewers. The primary endpoint was a composite of major adverse CV events: CV death, nonfatal myocardial infarction (MI), and nonfatal stroke.Overall, 416 nonfatal CV events in 366 subjects, and 22 deaths, were identified and processed for adjudication. Of these, 7 nonfatal MIs (4 bupropion, 3 placebo, 0 ACT), 5 nonfatal strokes (1 bupropion, 3 placebo, 1 ACT), and 9 CV deaths (4 bupropion, 4 placebo, 1 ACT) were confirmed by the CEC Committee. The primary endpoint occurred in 3/4297 (0.07%) subjects in the bupropion group and in 4/2927 (0.14%) subjects in the placebo group (log-rank P value: 0.613).CV events in bupropion clinical trials for smoking cessation were uncommon, with no observed increase among subjects assigned to bupropion vs placebo. However, this effort was limited by a paucity of quality data.

    View details for DOI 10.1002/clc.22744

  • The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) Study Rationale, Design, and Baseline Characteristics AMERICAN JOURNAL OF NEPHROLOGY Jardine, M. J., Mahaffey, K. W., Neal, B., Agarwal, R., Bakris, G. L., Brenner, B. M., Bull, S., Cannon, C. P., Charytan, D. M., de Zeeuw, D., Edwards, R., Greene, T., Heerspink, H. L., Levin, A., Pollock, C., Wheeler, D. C., Xie, J., Zhang, H., Zinman, B., Desai, M., Perkovic, V., CREDENCE Study Investigators 2017; 46 (6): 462–72

    Abstract

    People with diabetes and kidney disease have a high risk of cardiovascular events and progression of kidney disease. Sodium glucose co-transporter 2 inhibitors lower plasma glucose by reducing the uptake of filtered glucose in the kidney tubule, leading to increased urinary glucose excretion. They have been repeatedly shown to induce modest natriuresis and reduce HbA1c, blood pressure, weight, and albuminuria in patients with type 2 diabetes. However, the effects of these agents on kidney and cardiovascular events have not been extensively studied in patients with type 2 diabetes and established kidney disease.The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial aims to compare the efficacy and safety of canagliflozin -versus placebo at preventing clinically important kidney and cardiovascular outcomes in patients with diabetes and established kidney disease. CREDENCE is a randomized, double-blind, event-driven, placebo-controlled trial set in in 34 countries with a projected duration of ∼5.5 years and enrolling 4,401 adults with type 2 diabetes, estimated glomerular filtration rate ≥30 to <90 mL/min/1.73 m2, and albuminuria (urinary albumin:creatinine ratio >300 to ≤5,000 mg/g). The study has 90% power to detect a 20% reduction in the risk of the primary outcome (α = 0.05), the composite of end-stage kidney disease, doubling of serum creatinine, and renal or cardiovascular death.CREDENCE will provide definitive evidence about the effects of canagliflozin on renal (and cardiovascular) outcomes in patients with type 2 diabetes and established kidney disease.EudraCT number: 2013-004494-28; ClinicalTrials.gov identifier: NCT02065791.

    View details for PubMedID 29253846

    View details for PubMedCentralID PMC5804835

  • Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. The New England journal of medicine Neal, B. n., Perkovic, V. n., Mahaffey, K. W., de Zeeuw, D. n., Fulcher, G. n., Erondu, N. n., Shaw, W. n., Law, G. n., Desai, M. n., Matthews, D. R. 2017; 377 (7): 644–57

    Abstract

    Background Canagliflozin is a sodium-glucose cotransporter 2 inhibitor that reduces glycemia as well as blood pressure, body weight, and albuminuria in people with diabetes. We report the effects of treatment with canagliflozin on cardiovascular, renal, and safety outcomes. Methods The CANVAS Program integrated data from two trials involving a total of 10,142 participants with type 2 diabetes and high cardiovascular risk. Participants in each trial were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks. The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Results The mean age of the participants was 63.3 years, 35.8% were women, the mean duration of diabetes was 13.5 years, and 65.6% had a history of cardiovascular disease. The rate of the primary outcome was lower with canagliflozin than with placebo (occurring in 26.9 vs. 31.5 participants per 1000 patient-years; hazard ratio, 0.86; 95% confidence interval [CI], 0.75 to 0.97; P<0.001 for noninferiority; P=0.02 for superiority). Although on the basis of the prespecified hypothesis testing sequence the renal outcomes are not viewed as statistically significant, the results showed a possible benefit of canagliflozin with respect to the progression of albuminuria (hazard ratio, 0.73; 95% CI, 0.67 to 0.79) and the composite outcome of a sustained 40% reduction in the estimated glomerular filtration rate, the need for renal-replacement therapy, or death from renal causes (hazard ratio, 0.60; 95% CI, 0.47 to 0.77). Adverse reactions were consistent with the previously reported risks associated with canagliflozin except for an increased risk of amputation (6.3 vs. 3.4 participants per 1000 patient-years; hazard ratio, 1.97; 95% CI, 1.41 to 2.75); amputations were primarily at the level of the toe or metatarsal. Conclusions In two trials involving patients with type 2 diabetes and an elevated risk of cardiovascular disease, patients treated with canagliflozin had a lower risk of cardiovascular events than those who received placebo but a greater risk of amputation, primarily at the level of the toe or metatarsal. (Funded by Janssen Research and Development; CANVAS and CANVAS-R ClinicalTrials.gov numbers, NCT01032629 and NCT01989754 , respectively.).

    View details for PubMedID 28605608

  • A 15-year review of the Stanford Internal Medicine Residency Program: predictors of resident satisfaction and dissatisfaction ADVANCES IN MEDICAL EDUCATION AND PRACTICE Kahn, J. S., Witteles, R. M., Mahaffey, K. W., Desai, S. A., Ozdalga, E., Heidenreich, P. A. 2017; 8: 559–66

    Abstract

    Satisfaction with training and with educational experiences represents important internal medicine (IM) programmatic goals. Graduates from IM residency programs are uniquely poised to provide insights into their educational and training experiences and to assess whether these experiences were satisfactory and relevant to their current employment.We surveyed former IM residents from the training program held during the years 2000-2015 at the Department of Medicine, Stanford University. The first part of the survey reviewed the IM residency program and the second part sought identifying data regarding gender, race, ethnicity, work, relationships, and financial matters. The primary outcome was satisfaction with the residency experience.Of the 405 individuals who completed the Stanford IM residency program in the study period, we identified 384 (95%) former residents with a known email address. Two hundred and one (52%) former residents responded to the first part and 185 (48%) answered both the parts of the survey. The mean age of the respondents was 36.9 years; 44% were female and the mean time from IM residency was 6.1 (±4.3) years. Fifty-eight percent reported extreme satisfaction with their IM residency experience. Predictors associated with being less than extremely satisfied included insufficient outpatient experience, insufficient international experience, insufficient clinical research experience, and insufficient time spent with family and peers.The residents expressed an overall high satisfaction rate with their IM training. The survey results provided insights for improving satisfaction with IM residency training that includes diversifying and broadening IM training experiences.

    View details for PubMedID 28814910

  • Rejoinder. Clinical trials Fleming, T. R., DeMets, D. L., Roe, M. T., Wittes, J., Calis, K. A., Vora, A. N., Meisel, A., Bain, R. P., Konstam, M. A., Pencina, M. J., Gordon, D. J., Mahaffey, K. W., Hennekens, C. H., Neaton, J. D., Pearson, G. D., Andersson, T. L., Pfeffer, M. A., Ellenberg, S. S. 2017: 1740774516688917-?

    View details for DOI 10.1177/1740774516688917

    View details for PubMedID 28135837

    View details for PubMedCentralID PMC5376229

  • Predictors and Prognostic Implications of Incident Heart Failure in Patients With Prevalent Atrial Fibrillation JACC-HEART FAILURE Pandey, A., Kim, S., Moore, C., Thomas, L., Gersh, B., Allen, L. A., Kowey, P. R., Mahaffey, K. W., Hylek, E., Peterson, E. D., Piccini, J. P., Fonarow, G. C. 2017; 5 (1): 44-52

    Abstract

    The purpose of this study was to determine the significant clinical predictors of incident heart failure (HF) and its prognostic effect on long-term outcomes among community-based patients with established atrial fibrillation (AF).AF is associated with an increased risk of HF. However, in this population, little focus is placed on risk stratification for and the prevention of HF.Patients with AF but without HF at baseline enrolled in the ORBIT-AF (Outcomes Registry for Informed Treatment of Atrial Fibrillation) registry were included. Separate multivariable-adjusted Cox frailty regression models were used to identify significant predictors of HF incidence and determine the associated risk of adverse clinical events.The study included 6,545 participants with AF from 173 participating sites. Incident HF developed in 236 participants (3.6%) over the 2-year follow-up period; ejection fraction was preserved (>40%) in 64%, reduced (≤40%) in 13.5%, and missing in 22.5%. In multivariable analysis, traditional HF risk factors (age, coronary artery disease, renal dysfunction, and valvular disease), presence of permanent AF (hazard ratio [HR]: 1.60 [95% confidence interval (CI): 1.18 to 2.16]; reference group: paroxysmal AF), and elevated baseline heart rate (HR: 1.07 [95% CI: 1.02 to 1.13] per 5 beats/min higher heart rate) were independently associated with incident HF risk. Incident HF among patients with AF was independently associated with higher risk of mortality, all-cause hospitalization, and bleeding events.Incident HF among patients with AF is common, is more likely to be HF with preserved ejection fraction, and is associated with poor long-term outcomes. Traditional HF risk factors, AF type, and baseline heart rate are independent clinical predictors of incident HF.

    View details for DOI 10.1016/j.jchf.2016.09.016

    View details for Web of Science ID 000391520500007

    View details for PubMedID 28034376

  • Off-Label Dosing of Non-Vitamin K Antagonist Oral Anticoagulants and Adverse Outcomes The ORBIT-AF II Registry JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Steinberg, B. A., Shrader, P., Thomas, L., Ansell, J., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J., Singer, D. E., Peterson, E. D., Piccini, J. P. 2016; 68 (24): 2597-2604

    Abstract

    Although non-vitamin K antagonist oral anticoagulants (NOACs) do not require frequent laboratory monitoring, each compound requires dose adjustments on the basis of certain clinical criteria.This study assessed the frequency of off-label NOAC doses among AF patients and the associations between off-label dose therapy and clinical outcomes in community practice.We evaluated 5,738 patients treated with a NOAC at 242 ORBIT-AF II (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation phase II) sites. NOAC doses were classified as either underdosed or overdosed, consistent with Food and Drug Administration labeling. Longitudinal outcomes (median follow-up: 0.99 years) included stroke or systemic embolism, myocardial infarction, major bleeding (International Society of Thrombosis and Haemostasis criteria), cause-specific hospitalization, and all-cause mortality.Overall, 541 NOAC-treated patients (9.4%) were underdosed, 197 were overdosed (3.4%), and 5,000 were dosed according to U.S. labeling (87%). Compared with patients receiving the recommended dose, those who were receiving off-label doses were older (median: 79 and 80 years of age vs. 70 years of age, respectively; p < 0.0001), more likely female (48% and 67% vs. 40%, respectively; p < 0.0001), less likely to be treated by an electrophysiologist (18% and 19% vs. 27%, respectively; p < 0.0001), and had higher CHA2DS2-VASc scores (96% and 97% ≥2 vs. 86%, respectively; p < 0.0001) and higher ORBIT bleeding scores (25% and 31% >4 vs. 11%, respectively; p < 0.0001). After dose adjustment, NOAC overdosing was associated with increased all-cause mortality compared with recommended doses (adjusted hazard ratio: 1.91; 95% confidence interval [CI]: 1.02 to 3.60; p = 0.04). Underdosing was associated with increased cardiovascular hospitalization (adjusted hazard ratio: 1.26; 95% CI: 1.07 to 1.50; p = 0.007).A significant minority (almost 1 in 8) of U.S. patients in the community received NOAC doses inconsistent with labeling. NOAC over- and underdosing are associated with increased risk for adverse events. (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II [ORBIT-AF II]; NCT01701817).

    View details for DOI 10.1016/j.jacc.2016.09.966

    View details for Web of Science ID 000389593000001

    View details for PubMedID 27978942

  • Effects of Ticagrelor Compared With Clopidogrel in Patients With Peripheral Artery Disease (EUCLID) Patel, M. R., Fowkes, F. R., Berger, J. S., Norgren, L., Heizer, G., Baumgartner, I., Mahaffey, K. W., Katona, B. G., Held, P., Blomster, J., Jones, W., Reisr, C., Millegard, M., Hiatt, W. R. LIPPINCOTT WILLIAMS & WILKINS. 2016: E703
  • Relation of Post Coronary Artery Bypass Graft Creatine Kinase-MB Elevations and New Q Waves With Long-Term Cardiovascular Death in Patients With Diabetes Mellitus and Multivessel Coronary Artery Disease AMERICAN JOURNAL OF CARDIOLOGY Domanski, M., Farkouh, M. E., Zak, V., French, J., Alexander, J. H., Bochenek, A., Hamon, M., Mahaffey, K., Puskas, J., Smith, P., Shrader, P., Fuster, V. 2016; 118 (11): 1655-1660

    Abstract

    Associations of early creatine phosphokinase-MB (CK-MB) elevation and new Q waves and their association with cardiovascular death (CVD) after coronary artery bypass grafting (CABG) have been reported, but this association has not been studied in a large population of patients with diabetes mellitus. In this study, we examine the association of periprocedural CK-MB elevations and new Q waves with CVD in the Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease trial. Cox proportional hazards regression was used to assess the relation of CK-MB elevations and new Q waves in the first 24 hours after procedure and their relation to CVD; logistic regression was used to assess odds ratios of these variables. Hazard ratios, 95% confidence intervals, and p values associated with Wald chi-square test are reported. CK-MB elevation in first 24 hours after procedure was independently associated with CVD. CVD hazard increased by 6% (p <0.001) with each multiple of CK-MB above the upper reference limit (URL); odds of new post-CABG Q waves increased by a factor of 1.08 (p <0.001); at 7× CK-MB URL, HR was >2. CK-MB URL multiples of 7, 12, and 15 were associated with new Q-wave odds ratios of 9, 16, and 27 times, respectively (p ≤0.001, C-statistic >0.70). New Q waves were independently associated with survival in the multivariate model only when CK-MB was excluded (p = 0.01). In conclusion, independent associations included (1) CVD and early post-CABG CK-MB elevation; (2) new Q waves with early post-CABG CK-MB elevation; (3) CVD with new Q waves only when CK-MB elevation is excluded from analysis.

    View details for DOI 10.1016/j.amjcard.2016.08.041

    View details for Web of Science ID 000389686100008

    View details for PubMedID 27816118

  • Absence of Oral Anticoagulation and Subsequent Outcomes Among Outpatients with Atrial Fibrillation. American journal of medicine Hess, P. L., Kim, S., Fonarow, G. C., Thomas, L., Singer, D. E., Freeman, J. V., Gersh, B. J., Ansell, J., Kowey, P. R., Mahaffey, K. W., Chan, P. S., Steinberg, B. A., Peterson, E. D., Piccini, J. P. 2016

    Abstract

    Prior studies have shown a treatment gap in oral anticoagulation (OAC) use among patients with atrial fibrillation yet have incompletely characterized factors associated with failure to treat and subsequent outcomes in contemporary practice.Using data collected between June 2010 and August 2011 from 174 ambulatory care sites in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we identified factors associated with absence of OAC via stratified logistic regression. Using weighted Cox regression, we assessed the association between OAC non-use and subsequent outcomes over 2.5 years.Among 9553 patients, 2202 (23.0%) were not on OAC. Among OAC nonrecipients, 1846 (83.8%) had a CHA2DS2-VASc score ≥2. Factors independently associated with OAC non-use included atrial fibrillation type (paroxysmal odds ratio [OR] 0.73, 95% confidence interval [CI] 0.54-0.99; persistent OR 0.14, 95% CI 0.10-0.21; permanent OR 0.35, 95% CI 0.25-0.49; reference = new-onset), left atrial diameter enlargement (mild OR 0.80, 95% CI 0.66-0.97; moderate 0.58, 95% CI 0.47-0.73; severe 0.53, 95% CI 0.42-0.68; reference = normal diameter), and age >80 years (OR 1.04, 95% CI 1.02-1.08). Untreated patients had a higher risk of death (adjusted hazard ratio [HR] 1.22, 95% CI 1.05-1.41), a lower bleeding risk (adjusted HR 0.35, 95% CI 0.15-0.81), and a nonsignificant trend toward higher risk of stroke/non-central nervous system embolism/transient ischemic attack than those treated (adjusted HR 1.18, 95% CI 0.91-1.54).A majority of atrial fibrillation patients not treated with an OAC in current community practice meet guideline indications for treatment. Atrial fibrillation burden, chronicity, and comorbidity are associated with nontreatment. Untreated patients are at increased risk for adverse outcomes.

    View details for DOI 10.1016/j.amjmed.2016.11.001

    View details for PubMedID 27888051

  • Vorapaxar: emerging evidence and clinical questions in a new era of PAR-1 inhibition. Coronary artery disease Ungar, L., Rodriguez, F., Mahaffey, K. W. 2016; 27 (7): 604-615

    Abstract

    Despite the use of therapies recommended in practice guidelines for secondary prevention in patients with atherosclerotic coronary artery disease, the residual risk for cardiovascular events remains high. Some of the residual risk is believed to result from incomplete platelet inhibition with current therapy. Vorapaxar is a first-in-class, novel antiplatelet agent that acts by antagonizing the PAR-1 receptor, inhibiting thrombin-mediated platelet activation. Vorapaxar was recently approved by the Food and Drug Administration for secondary prevention of cardiovascular events in patients with a history of myocardial infarction or peripheral artery disease who do not have a history of transient ischemic attack or stroke. We review the data from two key phase III cardiovascular outcome trials with vorapaxar: TRACER and TRA 2P-TIMI 50. We will focus on identifying the key patient populations that should be identified for treatment, highlight practical clinical issues when prescribing vorapaxar, and review unanswered questions. Vorapaxar should be considered in patients at high risk for recurrent ischemic events and low risk of bleeding.

    View details for DOI 10.1097/MCA.0000000000000409

    View details for PubMedID 27398626

  • How well does physician risk assessment predict stroke and bleeding in atrial fibrillation? Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). American heart journal Steinberg, B. A., Shrader, P., Kim, S., Thomas, L., Fonarow, G. C., Ansell, J., Kowey, P. R., Singer, D. E., Gersh, B. J., Mahaffey, K. W., Peterson, E. D., Piccini, J. P. 2016; 181: 145-152

    Abstract

    Assessments of stroke and bleeding risks are essential to selecting oral anticoagulation in patients with atrial fibrillation (AF). We aimed to assess outcomes according to physician assessed risk, with comparison to empirical risk scores.This was a prospective, observational study of 9,715 outpatients with AF enrolled in ORBIT-AF, a US national registry. Stroke and bleeding risks were quantified by physician assignment, CHADS2 and CHA2DS2-VASc stroke scores, and ATRIA and HAS-BLED bleeding scores. Outcomes were stroke or systemic embolism and major bleeding during a median follow-up of 28 months.Physician-assigned risk was associated with thromboembolic events: low risk (0.71 per 100 patient-years [95% CI 0.56-0.91], n=3,991), intermediate risk (0.98 [95% CI 0.79-1.20], n=4,148), and high risk (1.84 [95% CI 1.43-2.37], n=1,576, P<.0001), and major bleeding: low (3.43 [95% CI 3.07-3.82], n=4,250), intermediate (4.55 [95% CI 4.03-5.15], n=2,702), and high (5.76 [95% CI 4.42-7.50], n=468; P<.0001). Discrimination of stroke risk was similar with CHADS2 (c=0.59, 95% CI 0.57-0.61) vs physician assessment (c=0.58, 95% CI 0.55-0.62). Among patients on oral anticoagulation, bleeding risk discrimination was higher with ATRIA (c=0.63, 95% CI 0.61-0.65) and HAS-BLED (c=0.60, 95% CI 0.59-0.62) than with physician assessment (0.55, 95% CI 0.53-0.57). Physician-assessed risk categories did not add significantly to empirical risk scores, in Cox models for outcomes (Padjusted>.05 for all physician assessments vs Padjusted<.05 for empirical scores).Physician-assigned risk showed a graded relationship with outcomes, and both physician-based and empirical scores yielded only moderate discrimination. Although empirical scores provided valuable risk stratification information (with or without physician judgment), physician assessment added little to existing scores. These data support the use of empirical scores for stroke and bleeding risk stratification, and the need for novel approaches to risk stratification in this population.

    View details for DOI 10.1016/j.ahj.2016.07.026

    View details for PubMedID 27823686

  • Influence of Kidney Function Estimation Methods on Eligibility for Edoxaban Population Impact of the US Food and Drug Administration's Approach for Its Product Labeling CIRCULATION Pokorney, S. D., Shrader, P., Thomas, L., Fonarow, G. C., Kowey, P. R., Singer, D. E., Ansell, J., Gersh, B. J., Mahaffey, K. W., Hylek, E. M., Go, A. S., Piccini, J. P., Peterson, E. D., Outcomes Registry Better Informed 2016; 134 (15): 1122–24

    View details for PubMedID 27753615

  • Temporal changes in biomarkers and their relationships to reperfusion and to clinical outcomes among patients with ST segment elevation myocardial infarction. Journal of thrombosis and thrombolysis van Diepen, S., Alemayehu, W. G., Zheng, Y., Theroux, P., Newby, L. K., Mahaffey, K. W., Granger, C. B., Armstrong, P. W. 2016; 42 (3): 376-385

    Abstract

    Coronary plaque rupture mediating acute ST segment elevation myocardial infarction (STEMI) is associated with a systemic inflammatory response. Whether early temporal changes in inflammatory biomarkers are associated with angiographic and electrocardiographic markers of reperfusion and subsequent clinical outcomes is unclear. In the APEX-AMI biomarker substudy, 376 patients with STEMI had inflammatory biomarkers measured at the time of hospital presentation and 24 h later. The primary outcome was the 90-day composite of death, shock, or heart failure. Secondary reperfusion outcomes were (1) worst least residual ST segment elevation (ST-E: <1 mm, 1 to <2 mm, ≥2 mm) and (2) post-percutaneous coronary intervention (PCI) TIMI flow grade (0/1/2 vs 3) and TIMI myocardial perfusion grade (TMPG 0/1 vs 2/3). The 90-day incidence of death, shock or heart failure was 21.3 % in this cohort. Electrocardiographic reperfusion (worst residual ST-E <1 mm, 1 to <2 mm, ≥2 mm) was associated with differences in 24 h change in N-terminal proB-type natriuretic peptide (NT-proBNP) (1192.8, 1332.5, 1859.0 ng/mL; p = 0.043) and the pro-inflammatory cytokines Interleukin (IL)-6 (14.0, 13.6, 22.1 pg/mL; p = 0.016), IL-12 (-0.5, -0.9, -0.1 pg/mL; p = 0.013), and tumor necrosis factor α (TNFα) (1.0, 0.6, 3.6 pg/mL; p = 0.023). Angiographic reperfusion (TMPG 0/1 vs 2/3) was associated with changes in median NT-proBNP (2649.3, 1382.7 ng/mL; p = 0.002) and IL-6 (28.7, 15.1; p = 0.040). After adjustment for baseline covariates, the 24 h change in the pro-inflammatory cytokine TNFα [hazard ratio (HR) 0.49; 95 % CI 0.26-0.95; p = 0.035] and the anti-inflammatory cytokine IL 10 (HR 1.41; 95 % CI 1.06-1.87; p = 0.018) were independently associated with the primary composite outcome. Successful coronary reperfusion was associated with less systemic inflammatory response and greater temporal inflammatory changes were independently associated with higher 90-day composite of death, shock, or heart failure. These findings provide support for an association between success of reperfusion, an acute STEMI inflammatory response and subsequent clinical outcomes.

    View details for DOI 10.1007/s11239-016-1390-z

    View details for PubMedID 27324144

  • Efficacy and Safety of Cangrelor in Preventing Periprocedural Complications in Patients With Stable Angina and Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention The CHAMPION PHOENIX Trial JACC-CARDIOVASCULAR INTERVENTIONS Abtan, J., Steg, P. G., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Hamm, C. W., Price, M. J., Abnousi, F., Prats, J., Deliargyris, E. N., White, H. D., Harrington, R. A., Bhatt, D. L. 2016; 9 (18): 1905-1913

    Abstract

    The purpose of this study was to examine the safety and efficacy of cangrelor in patients with stable angina (SA) or acute coronary syndrome (ACS).The CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial demonstrated that cangrelor significantly reduced periprocedural ischemic events in all-comer percutaneous coronary intervention with a modest increase in mild and moderate bleeding. Whether this benefit is consistent across SA and ACS has not been explored fully.The CHAMPION PHOENIX trial compared periprocedural administration of cangrelor or clopidogrel, with either a 300- or 600-mg loading dose for the prevention of periprocedural complications in patients undergoing percutaneous coronary intervention. Among the 10,942 patients in the modified intention to treat population, 6,358 patients were classified as having SA, and 4,584 patients had ACS (including unstable angina, non ST-segment elevation myocardial infarction and ST-segment elevation myocardial infarction) at randomization. The primary composite endpoint was death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 h. A key secondary endpoint was stent thrombosis, and the primary safety endpoint was GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) severe bleeding.Cangrelor consistently reduced the primary endpoint in SA and ACS (odds ratio [OR]: 0.83 [95% confidence interval (CI): 0.67 to 1.01] and OR: 0.71 [95% CI: 0.52 to 0.96], respectively; interaction p = 0.41). Cangrelor also consistently reduced stent thrombosis in SA and ACS (OR: 0.55 [95% CI: 0.30 to 1.01] and OR: 0.67 [95% CI: 0.42 to 1.06], respectively; interaction p = 0.62). The impact of cangrelor on GUSTO severe/moderate bleeding was also similar for SA and ACS (OR: 1.49 [95% CI: 0.67 to 3.33] and OR: 1.79 [95% CI: 0.79 to 4.07], respectively; interaction p = 0.75).The benefits and risks of cangrelor were consistent in patients with SA and ACS. (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX] [CHAMPION]; NCT01156571).

    View details for DOI 10.1016/j.jcin.2016.06.046

    View details for Web of Science ID 000385713800010

    View details for PubMedID 27659566

  • Consistent Reduction in Periprocedural Myocardial Infarction With Cangrelor as Assessed by Multiple Definitions: Findings From CHAMPION PHOENIX (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). Circulation Cavender, M. A., Bhatt, D. L., Stone, G. W., White, H. D., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Leonardi, S., Prats, J., Deliargyris, E. N., Mahaffey, K. W., Harrington, R. A. 2016; 134 (10): 723-733

    Abstract

    Cangrelor is an intravenous P2Y12 inhibitor approved to reduce periprocedural ischemic events in patients undergoing percutaneous coronary intervention not pretreated with a P2Y12 inhibitor.A total of 11 145 patients were randomized to cangrelor or clopidogrel in the CHAMPION PHOENIX trial (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). We explored the effects of cangrelor on myocardial infarction (MI) using different definitions and performed sensitivity analyses on the primary end point of the trial.A total of 462 patients (4.2%) undergoing percutaneous coronary intervention had an MI as defined by the second universal definition. The majority of these MIs (n=433, 93.7%) were type 4a. Treatment with cangrelor reduced the incidence of MI at 48 hours (3.8% versus 4.7%; odds ratio [OR], 0.80; 95% confidence interval [CI], 0.67-0.97; P=0.02). When the Society of Coronary Angiography and Intervention definition of periprocedural MI was applied to potential ischemic events, there were fewer total MIs (n=134); however, the effects of cangrelor on MI remained significant (OR, 0.65; 95% CI, 0.46-0.92; P=0.01). Similar effects were seen in the evaluation of the effects of cangrelor on MIs with peak creatinine kinase-MB ≥10 times the upper limit of normal (OR, 0.64; 95% CI, 0.45-0.91) and those with peak creatinine kinase-MB ≥10 times the upper limit of normal, ischemic symptoms, or ECG changes (OR, 0.63; 95% CI, 0.48-0.84). MIs defined by any of these definitions were associated with increased risk of death at 30 days. Treatment with cangrelor reduced the composite end point of death, MI (Society of Coronary Angiography and Intervention definition), ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis (1.4% versus 2.1%; OR, 0.69; 95% CI, 0.51-0.92).MI in patients undergoing percutaneous coronary intervention, regardless of definition, remains associated with increased risk of death in the current era. Cangrelor compared with clopidogrel significantly reduces MI regardless of the definition.URL: http://clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCULATIONAHA.115.020829

    View details for PubMedID 27482008

    View details for PubMedCentralID PMC5006794

  • Use of concomitant aspirin in patients with atrial fibrillation: Findings from the ROCKET AF trial AMERICAN HEART JOURNAL Shah, R., Hellkamp, A., Lokhnygina, Y., Becker, R. C., Berkowitz, S. D., Breithardt, G., Backe, W., Halperin, J. L., Hankey, G. J., Fox, K. A., Nessel, C. C., Mahaffey, K. W., Piccini, J. P., Singer, D. E., Patel, M. R. 2016; 179: 77-86

    Abstract

    We aimed to investigate the relationship between aspirin use and clinical outcomes in patients enrolled in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), in particular, those with known coronary artery disease (CAD).Patients in ROCKET AF, comparing rivaroxaban and warfarin, were analyzed. Aspirin use was assessed at baseline. Stroke and systemic embolism, myocardial infarction, death, and major or nonmajor clinically relevant (NMCR) bleeding were compared between groups. Multivariable modeling was done adjusting for baseline risk factors.A total of 5,205 (36.5%) patients were receiving aspirin at baseline (mean dose 99.2mg); 30.6% of those had known CAD. Patients receiving aspirin were more likely to have prior myocardial infarction (22% vs 14%; P<.001) and heart failure (68% vs 59%; P<.001). Relative efficacy of rivaroxaban versus warfarin was similar with and without aspirin use for both stroke/systemic embolism (P=.95 for interaction), and major or NMCR bleeding (P=.76 for interaction). After adjustment, aspirin use was associated with similar rates of stroke/systemic embolism (hazard ratio [HR] 1.16, 95% CI 0.98-1.37; P=.094) but higher rates of all-cause death (HR 1.27, 95% CI 1.13-1.42; P<.0001) and major or NMCR bleeding (HR 1.32, 95% CI 1.21-1.43; P<.0001). There was a significant interaction between no CAD at baseline and aspirin for all-cause death (P=.009).Aspirin use at baseline was associated with an increased risk for bleeding and all-cause death in ROCKET AF, a risk most pronounced in patients without known CAD. Although these findings may reflect unmeasured clinical factors, further investigation is warranted to determine optimal aspirin use in patients with AF.

    View details for DOI 10.1016/j.ahj.2016.05.019

    View details for Web of Science ID 000383112100009

  • Use of concomitant aspirin in patients with atrial fibrillation: Findings from the ROCKET AF trial. American heart journal Shah, R., Hellkamp, A., Lokhnygina, Y., Becker, R. C., Berkowitz, S. D., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Fox, K. A., Nessel, C. C., Mahaffey, K. W., Piccini, J. P., Singer, D. E., Patel, M. R. 2016; 179: 77-86

    Abstract

    We aimed to investigate the relationship between aspirin use and clinical outcomes in patients enrolled in Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), in particular, those with known coronary artery disease (CAD).Patients in ROCKET AF, comparing rivaroxaban and warfarin, were analyzed. Aspirin use was assessed at baseline. Stroke and systemic embolism, myocardial infarction, death, and major or nonmajor clinically relevant (NMCR) bleeding were compared between groups. Multivariable modeling was done adjusting for baseline risk factors.A total of 5,205 (36.5%) patients were receiving aspirin at baseline (mean dose 99.2mg); 30.6% of those had known CAD. Patients receiving aspirin were more likely to have prior myocardial infarction (22% vs 14%; P<.001) and heart failure (68% vs 59%; P<.001). Relative efficacy of rivaroxaban versus warfarin was similar with and without aspirin use for both stroke/systemic embolism (P=.95 for interaction), and major or NMCR bleeding (P=.76 for interaction). After adjustment, aspirin use was associated with similar rates of stroke/systemic embolism (hazard ratio [HR] 1.16, 95% CI 0.98-1.37; P=.094) but higher rates of all-cause death (HR 1.27, 95% CI 1.13-1.42; P<.0001) and major or NMCR bleeding (HR 1.32, 95% CI 1.21-1.43; P<.0001). There was a significant interaction between no CAD at baseline and aspirin for all-cause death (P=.009).Aspirin use at baseline was associated with an increased risk for bleeding and all-cause death in ROCKET AF, a risk most pronounced in patients without known CAD. Although these findings may reflect unmeasured clinical factors, further investigation is warranted to determine optimal aspirin use in patients with AF.

    View details for DOI 10.1016/j.ahj.2016.05.019

    View details for PubMedID 27595682

  • Use of Dual Antiplatelet Therapy and Patient Outcomes in Those Undergoing Percutaneous Coronary Intervention: The ROCKET AF Trial. JACC. Cardiovascular interventions Sherwood, M. W., Cyr, D. D., Jones, W. S., Becker, R. C., Berkowitz, S. D., Washam, J. B., Breithardt, G., Fox, K. A., Halperin, J. L., Hankey, G. J., Singer, D. E., Piccini, J. P., Nessel, C. C., Mahaffey, K. W., Patel, M. R. 2016; 9 (16): 1694-1702

    Abstract

    The authors assessed the use of dual antiplatelet therapy (DAPT) and outcomes in patients undergoing percutaneous coronary intervention (PCI) during the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).The frequency, patterns, and outcomes when adding DAPT to non-vitamin K antagonist oral anticoagulants in the setting of PCI in patients with AF are largely unknown.The study population included all patients in the treatment group of the ROCKET AF trial divided by the receipt of PCI during follow-up. Clinical characteristics, PCI frequency, and rates of DAPT were reported. Clinical outcomes were adjudicated independently as part of the trial.Among 14,171 patients, 153 (1.1%) underwent PCI during a median 806 days of follow-up. Patients treated with rivaroxaban were significantly less likely to undergo PCI compared with warfarin-treated patients (61 vs. 92; p = 0.01). Study drug was continued during PCI in 81% of patients. Long-term DAPT (≥30 days) was used in 37% and single antiplatelet therapy in 34%. A small number switched from DAPT to monotherapy within 30 days of PCI (n = 19 [12.3%]) and 15% of patients received no antiplatelet therapy after PCI. Rates of stroke/systemic embolism and major bleeding events were high in post-PCI patients (4.5/100 patient-years and 10.2/100 patient-years) in both treatment groups.In patients with AF at moderate to high risk for stroke, PCI occurred in <1% per year. DAPT was used in a variable manner, with the majority of patients remaining on study drug after PCI. Rates of both thrombotic and bleeding events were high after PCI, highlighting the need for studies to determine the optimal antithrombotic therapy.

    View details for DOI 10.1016/j.jcin.2016.05.039

    View details for PubMedID 27539689

  • Implications of different criteria for percutaneous coronary intervention-related myocardial infarction on study results of three large phase III clinical trials: The CHAMPION experience. European heart journal. Acute cardiovascular care Leonardi, S., Lopes, R. D., Steg, P. G., Abnousi, F., Menozzi, A., Prats, J., Mangum, S., Wilson, M., Todd, M., Stone, G. W., Gibson, C. M., Hamm, C. W., Price, M. J., White, H. D., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. 2016

    Abstract

    The purpose of this study was to test whether different results between Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON (CHAMPION) PCI/PLATFORM and PHOENIX trials are due in part to different definitions of percutaneous coronary intervention (PCI)-related myocardial infarction (MI).In patients with acute coronary syndrome (ACS), the definition of MI was identical in CHAMPION PCI and PLATFORM and did not require an assessment of baseline cardiac biomarker status, while in PHOENIX specific MI criteria were associated with different patient presentations. The same MI criteria were used in PCI, PLATFORM, and PHOENIX for patients with stable angina. Logistic regression assessed the effect of cangrelor on MI (PCI- and non-PCI related) in the combined PCI/PLATFORM population and in PHOENIX. Consistency of cangrelor's effect in PCI/PLATFORM and in PHOENIX in patients with stable angina and in those with an ACS (with or without ST elevation) was evaluated. Overall, the incidence of PCI-related MI at 48 h was 6.3% in PCI/PLATFORM and 4.0% in PHOENIX. In patients with ACS, MI incidence was 6.4% in PCI/PLATFORM and 1.7% in PHOENIX, and 6.3% and 5.6%, respectively in stable angina patients. Cangrelor's effect on PCI-related MI differed between PCI/PLATFORM (odds ratio (OR) 1.03, 95% confidence interval (CI) 0.90-1.17) and PHOENIX (OR 0.80, 95% CI 0.66-0.98) with pINT=0.04. This difference was mostly evident in patients with ACS (pINT= 0.06) while the effect was consistent in patients with stable angina (pINT=0.81). Results were similar when all MIs were analyzed.The definition of PCI-related MI has important implications for event rates, treatment effect, and study results. This illustrates the importance of a rigorous assessment of PCI-related MI in clinical trials of patients with an ACS.

    View details for PubMedID 27485140

  • Blood pressure control and stroke or bleeding risk in anticoagulated patients with atrial fibrillation: Results from the ROCKET AF Trial. American heart journal Vemulapalli, S., Hellkamp, A. S., Jones, W. S., Piccini, J. P., Mahaffey, K. W., Becker, R. C., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Breithardt, G., Singer, D. E., Fox, K. A., Patel, M. R. 2016; 178: 74-84

    Abstract

    We conducted a retrospective analysis examining the association between systolic blood pressure (SBP) or hypertension bracket and stroke risk in patients with atrial fibrillation (AF).The study included 14,256 anticoagulated patients in the ROCKET AF trial. Cox proportional hazards models were used to compare the risk of adverse outcomes by European Society of Cardiology hypertension bracket and screening SBP.In total, 90.5% of patients had hypertension (55.8% controlled, 34.6% uncontrolled). The adjusted risk of stroke or systemic embolism (SE) increased significantly for every 10-mm Hg increase in screening SBP (hazard ratio [HR] 1.07, 95% CI 1.02-1.13). There was a trend toward an increased adjusted risk of stroke or SE in patients with controlled (HR 1.22, 95% CI 0.89-1.66) and uncontrolled hypertension (HR 1.42, 95% CI 1.03-1.95) (P = .06). In contrast, the adjusted risk of major bleeding was similar between hypertensive brackets and did not vary significantly by screening SBP. The benefit of rivaroxaban versus warfarin in preventing stroke or SE was consistent among patients regardless of SBP (P interaction = .69).In a trial of anticoagulated patients with AF, increasing screening SBP was independently associated with stroke and SE, and one-third of patients had uncontrolled hypertension. The relative effectiveness and safety of rivaroxaban versus warfarin were consistent across all levels of screening SBP. A single SBP may be an important factor in reducing the overall risk of stroke and SE in anticoagulated patients with AF.

    View details for DOI 10.1016/j.ahj.2016.05.001

    View details for PubMedID 27502854

  • Arterial access site and outcomes in patients undergoing percutaneous coronary intervention with and without vorapaxar. Catheterization and cardiovascular interventions Déry, J., Mahaffey, K. W., Tricoci, P., White, H. D., Podder, M., Westerhout, C. M., Moliterno, D. J., Harrington, R. A., Chen, E., Strony, J., Van de Werf, F., Ziada, K. M., Held, C., Aylward, P. E., Armstrong, P. W., Rao, S. V. 2016; 88 (2): 163-173

    Abstract

    We evaluated outcomes associated with transradial vs. transfemoral approaches and vorapaxar in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) in the TRACER trial.Vorapaxar reduces ischemic events but increases the risk of major bleeding.We compared 30-day and 2-year major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization) and noncoronary artery bypass graft (CABG)-related bleedings in 2,192 transradial and 4,880 transfemoral patients undergoing PCI after adjusting for confounding variables, including propensity for transradial access.Overall, 30-day GUSTO moderate/severe and non-CABG TIMI major/minor bleeding occurred less frequently in transradial (0.9% vs. 2.0%, P = 0.001) vs. transfemoral (1.1% vs. 2.5%, P = 0.005) patients. A similar reduction was seen at 2 years (3.3% vs. 4.7%, P = 0.008; 3.3% vs. 4.9%, P < 0.001, respectively). Transradial was associated with an increased risk of ischemic events at 30 days (OR 1.38, 95% CI 1.11-1.72; P = 0.004), driven primarily by increased periprocedural myocardial infarctions. At 2 years, rates of MACE were comparable (HR 1.14, 95% CI 0.98-1.33; P = 0.096). Although bleeding rates were higher with vorapaxar in transfemoral vs. transradial patients, there was no significant treatment interaction. Also, the access site did not modulate the association between vorapaxar and MACE.Transradial access was associated with lower bleeding rates and similar long-term ischemic outcomes, suggesting transradial access is safer than transfemoral access among ACS patients receiving potent antiplatelet therapies. Because of the nonrandomized allocation of arterial access, these results should be considered exploratory. © 2015 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ccd.26335

    View details for PubMedID 26698636

  • Albuminuria and cardiovascular events in patients with acute coronary syndromes: Results from the TRACER trial. American heart journal Åkerblom, A., Clare, R. M., Lokhnygina, Y., Wallentin, L., Held, C., Van de Werf, F., Moliterno, D. J., Patel, U. D., Leonardi, S., Armstrong, P. W., Harrington, R. A., White, H. D., Aylward, P. E., Mahaffey, K. W., Tricoci, P. 2016; 178: 1-8

    Abstract

    Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of mortality and CV morbidity in 12,944 patients with non-ST-segment elevation acute coronary syndromes.Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (≥30 but <300 mg/dL), or macroalbuminuria (≥300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury, identified by adverse event reporting and creatinine increase (absolute ≥0.3 mg/dL or relative ≥50%), was descriptively reported.Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs 27%) or hypertension (86% vs 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria); 5.8% and 9.0% (microalbuminuria); and 7.7% and 12.6% (macroalbuminuria) at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed acute kidney injury rates were 0.6%, 1.2%, and 2.9% (n = 79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15-2.37), and after adjustment with eGFR, 1.37 (95% CI 0.93-2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37-2.42) and 1.47 (95% CI 1.08-1.98).High-risk patients with non-ST-segment elevation acute coronary syndromes and albuminuria have increased morbidity and increased overall mortality independent of eGFR.

    View details for DOI 10.1016/j.ahj.2016.04.013

    View details for PubMedID 27502846

  • Effect of age on efficacy and safety of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome: Insights from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial. American heart journal Armaganijan, L. V., Alexander, K. P., Huang, Z., Tricoci, P., Held, C., Van de Werf, F., Armstrong, P. W., Aylward, P. E., White, H. D., Moliterno, D. J., Wallentin, L., Chen, E., Harrington, R. A., Strony, J., Mahaffey, K. W., Lopes, R. D. 2016; 178: 176-184

    Abstract

    Antithrombotic therapy plays an important role in the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS) but is associated with bleeding risk. Advanced age may modify the relationship between efficacy and safety.Efficacy and safety of vorapaxar (a protease-activated receptor 1 antagonist) was analyzed across ages as a continuous and a categorical variable in the 12,944 patients with NSTE ACS enrolled in the TRACER trial. To evaluate the effect of age, Cox regression models were developed to estimate hazard ratios (HRs) with the adjustment of other baseline characteristics and randomized treatment for the primary efficacy composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization, and the primary safety composite of moderate or severe Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding.The median age of the population was 64years (25th, 75th percentiles = 58, 71). Also, 1,791 patients (13.8%) were ≤54years of age, 4,968 (38.4%) were between 55 and 64 years, 3,979 (30.7%) were between 65 and 74 years, and 2,206 (17.1%) were 75years or older. Older patients had higher rates of hypertension, renal insufficiency, and previous stroke and worse Killip class. The oldest age group (≥75years) had substantially higher 2-year rates of the composite ischemic end point and moderate or severe GUSTO bleeding compared with the youngest age group (≤54years). The relationships between treatment assignment (vorapaxar vs placebo) and efficacy outcomes did not vary by age. For the primary efficacy end point, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were as follows: 1.12 (0.88-1.43), 0.88 (0.76-1.02), 0.89 (0.76-1.04), and 0.88 (0.74-1.06), respectively (P value for interaction = .435). Similar to what was observed for efficacy outcomes, we did not observe any interaction between vorapaxar and age on bleeding outcomes. For the composite of moderate or severe bleeding according to the GUSTO classification, the HRs (95% CIs) comparing vorapaxar and placebo in the 4 age groups were 1.73 (0.89-3.34), 1.39 (1.04-1.86), 1.10 (0.85-1.42), and 1.73 (1.29-2.33), respectively (P value for interaction = .574).Older patients had a greater risk for ischemic and bleeding events; however, the efficacy and safety of vorapaxar in NSTE ACS were not significantly influenced by age.

    View details for DOI 10.1016/j.ahj.2016.05.012

    View details for PubMedID 27502866

  • Hospitalizations in patients with atrial fibrillation: an analysis from ROCKET AF. Europace DeVore, A. D., Hellkamp, A. S., Becker, R. C., Berkowitz, S. D., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Fox, K. A., Patel, M. R., Piccini, J. P. 2016; 18 (8): 1135-1142

    Abstract

    The high costs associated with treatment for atrial fibrillation (AF) are primarily due to hospital care, but there are limited data to understand the reasons for and predictors of hospitalization in patients with AF.The ROCKET AF trial compared rivaroxaban with warfarin for stroke prophylaxis in AF. We described the frequency of and reasons for hospitalization during study follow-up and utilized Cox proportional hazards models to assess for baseline characteristics associated with all-cause hospitalization. Of 14 171 patients, 14% were hospitalized at least once. Of 2614 total hospitalizations, 41% were cardiovascular including 4% for AF; of the remaining, 12% were for bleeding. Compared with patients not hospitalized, hospitalized patients were older (74 vs. 72 years), and more frequently had diabetes (46 vs. 39%), prior MI (23 vs. 16%), and paroxysmal AF (19 vs. 17%), but less frequently had prior transient ischaemic attack/stroke (49 vs. 56%). After multivariable adjustment, lung disease [hazard ratio (HR) 1.46, 95% confidence interval (CI) 1.29-1.66], diabetes [1.22, (1.11-1.34)], prior MI [1.27, (1.13-1.42)], and renal dysfunction [HR 1.07 per 5 unit GFR < 65 mL/min, (1.04-1.10)] were associated with increased hospitalization risk. Treatment assignment was not associated with differential rates of hospitalization.Nearly 1 in 7 of the moderate-to-high-risk patients with AF enrolled in this trial was hospitalized within 2 years, and both AF and bleeding were rare causes of hospitalization. Further research is needed to determine whether care pathways directed at comorbid conditions among AF patients could reduce the need for and costs associated with hospitalization.

    View details for DOI 10.1093/europace/euv404

    View details for PubMedID 27174904

    View details for PubMedCentralID PMC4974633

  • Management of Patients With NSTE-ACS A Comparison of the Recent AHA/ACC and ESC Guidelines JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rodriguez, F., Mahaffey, K. W. 2016; 68 (3): 313-321

    Abstract

    Non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are the leading cause of morbidity and mortality from cardiovascular disease worldwide. The American Heart Association/American College of Cardiology and the European Society of Cardiology periodically release practice guidelines to guide clinicians in the management of NSTE-ACS, most recently in in 2014 and 2015, respectively. The present review compares and contrasts the 2 guidelines, with a focus on the strength of recommendation and level of evidence in the approach to initial presentation and diagnosis of NSTE-ACS, risk assessment, treatments, and systems of care. Important differences include the use of a rapid rule-out protocol with high-sensitivity troponin assays, a preference for prasugrel/ticagrelor and fondaparinux for anticoagulation therapy, and a preference for radial arterial access in the European Society of Cardiology guidelines compared with the American Heart Association/American College of Cardiology guidelines. We also highlight the similarities and differences in the guidelines for special patient populations and suggest areas of further study.

    View details for DOI 10.1016/j.jacc.2016.03.599

    View details for Web of Science ID 000379518600012

    View details for PubMedID 27417010

  • Response by Piccini et al to Letters Regarding Article, "Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation" CIRCULATION Piccini, J. P., Hellkamp, A. S., Washam, J. B., Becker, R. C., Breithardt, G., Berkowitz, S. D., Halperin, J. L., Hankey, G. J., Hacke, W., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Fox, K. A., Patel, M. R. 2016; 134 (2): E7–E8

    View details for PubMedID 27400902

  • On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin Insights From ROCKET AF CIRCULATION Fordyce, C. B., Hellkamp, A. S., Lokhnygina, Y., Lindner, S. M., Piccini, J. P., Becker, R. C., Berkowitz, S. D., Breithardt, G., Fox, K. A., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Patel, M. R. 2016; 134 (1): 37-?

    Abstract

    Despite rapid clinical adoption of novel anticoagulants, it is unknown whether outcomes differ among patients with worsening renal function (WRF) taking these new drugs compared with warfarin. We aimed to determine whether the primary efficacy (stroke or systemic embolism) and safety (major bleeding and nonmajor clinically relevant bleeding) end points from the ROCKET AF trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial) differed among participants with WRF taking rivaroxaban and those taking warfarin.After excluding patients without at least 1 follow-up creatinine measurement (n=1624), we included all remaining patients (n=12 612) randomly assigned to either rivaroxaban or dose-adjusted warfarin. On-treatment WRF (a decrease of >20% from screening creatinine clearance measurement at any time point during the study) was evaluated as a time-dependent covariate in Cox proportional hazards models.Baseline characteristics were generally similar between patients with stable renal function (n=9292) and WRF (n=3320). Rates of stroke or systemic embolism, myocardial infarction, and bleeding were also similar, but WRF patients experienced a higher incidence of vascular death versus stable renal function (2.21 versus 1.41 events per 100 patient-years; P=0.026). WRF patients who were randomized to receive rivaroxaban had a reduction in stroke or systemic embolism compared with those taking warfarin (1.54 versus 3.25 events per 100 patient-years) that was not seen in patients with stable renal function who were randomized to receive rivaroxaban (P=0.050 for interaction). There was no difference in major or nonmajor clinically relevant bleeding among WRF patients randomized to warfarin versus rivaroxaban.Among patients with on-treatment WRF, rivaroxaban was associated with lower rates of stroke and systemic embolism compared with warfarin, without an increase in the composite bleeding end point.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.116.021890

    View details for Web of Science ID 000378900300008

    View details for PubMedID 27358435

  • Cinacalcet, dialysate calcium concentration, and cardiovascular events in the EVOLVE trial HEMODIALYSIS INTERNATIONAL Pun, P. H., Abdalla, S., Block, G. A., Chertow, G. M., Correa-Rotter, R., Dehmel, B., Drueke, T. B., Floege, J., Goodman, W. G., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Parfrey, P. S., Wheeler, D. C., Middleton, J. P. 2016; 20 (3): 421-431

    Abstract

    Among patients receiving hemodialysis, abnormalities in calcium regulation have been linked to an increased risk of cardiovascular events. Cinacalcet lowers serum calcium concentrations through its effect on parathyroid hormone secretion and has been hypothesized to reduce the risk of cardiovascular events. In observational cohort studies, prescriptions of low dialysate calcium concentration and larger observed serum-dialysate calcium gradients have been associated with higher risks of in-dialysis facility or peri-dialytic sudden cardiac arrest. We performed this study to examine the risks associated with dialysate calcium and serum-dialysate gradients among participants in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial. In EVOLVE, 3883 hemodialysis patients were randomized 1:1 to cinacalcet or placebo. Dialysate calcium was administered at the discretion of treating physicians. We examined whether baseline dialysate calcium concentration or the serum-dialysate calcium gradient modified the effect of cinacalcet on the following adjudicated endpoints: (1) primary composite endpoint (death or first non-fatal myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular event); (2) cardiovascular death; and (3) sudden death. In EVOLVE, use of higher dialysate calcium concentrations was more prevalent in Europe and Latin America compared with North America. There was a significant fall in serum calcium concentration in the cinacalcet group; dialysate calcium concentrations were changed infrequently in both groups. There was no association between baseline dialysate calcium concentration or serum-dialysate calcium gradient and the endpoints examined. Neither the baseline dialysate calcium nor the serum-dialysate calcium gradient significantly modified the effects of cinacalcet on the outcomes examined. The effects of cinacalcet on cardiovascular death and major cardiovascular events are not altered by the dialysate calcium prescription and serum-dialysate calcium gradient.

    View details for DOI 10.1111/hdi.12382

    View details for PubMedID 26564024

  • Native valve disease in patients with non-valvular atrial fibrillation on warfarin or rivaroxaban HEART Breithardt, G., Baumgartner, H., Berkowitz, S. D., Hellkamp, A. S., Piccini, J. P., Lokhnygina, Y., Halperin, J. L., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Mahaffey, K. W., Califf, R. M., Fox, K. A., Patel, M. R. 2016; 102 (13): 1036-1043

    Abstract

    To compare the characteristics and outcomes of patients with atrial fibrillation (AF) and aortic stenosis (AS) with patients with AF with mitral regurgitation (MR) or aortic regurgitation (AR) and patients without significant valve disease (no SVD).Using Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) data, we analysed efficacy and safety outcomes, adjusting hazard ratios (HRs) for potential confounders using Cox regression analysis.Among 14 119 intention-to-treat ROCKET AF trial patients, a trial that excluded patients with mitral stenosis or artificial valve prosthesis, 214 had AS with or without other valve abnormalities, 1726 had MR or AR and 12 179 had no SVD. After adjusting for prognostic factors, the composite of stroke, systemic embolism or vascular death increased approximately twofold in patients with AS (AS 10.84, MR or AR 4.54 and no SVD 4.31 events per 100 patient-years, p=0.0001). All-cause death also significantly increased (AS 11.22, MR or AR 4.90 and no SVD 4.39 events per 100 patient-years, p=0.0003). Major bleeding occurred more frequently in AS (adjusted HR 1.61, confidence intervals (CI) 1.03 to 2.49, p<0.05) and MR or AR (HR 1.30, 1.07 to 1.57, p<0.01) than in no SVD, but there was no difference between AS and MR or AR (HR 1.24, 0.78 to 1.97). The relative efficacy of rivaroxaban versus warfarin was consistent among patients with and without valvular disease. Rivaroxaban was associated with higher rates of major bleeding than warfarin in patients with MR or AR (HR 1.63, 1.15 to 2.31).We found that patients with AF and AS on oral anticoagulants may have distinctly different efficacy and safety outcomes than patients with MR or AR or no SVD.NCT00403767; Post-results.

    View details for DOI 10.1136/heartjnl-2015-308120

    View details for PubMedID 26888572

    View details for PubMedCentralID PMC4941167

  • Variation in Patient Profiles and Outcomes in US and Non-US Subgroups of the Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX Trial CIRCULATION-CARDIOVASCULAR INTERVENTIONS Vaduganathan, M., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2016; 9 (6)

    Abstract

    The Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION) PHOENIX trial demonstrated superiority of cangrelor in reducing ischemic events at 48 hours in patients undergoing percutaneous coronary intervention compared with clopidogrel.We analyzed all patients included in the modified intention-to-treat analysis in US (n=4097; 37.4%) and non-US subgroups (n=6845; 62.6%). The US cohort was older, had a higher burden of cardiovascular risk factors, and had more frequently undergone prior cardiovascular procedures. US patients more frequently underwent percutaneous coronary intervention for stable angina (77.9% versus 46.2%). Almost all US patients (99.1%) received clopidogrel loading doses of 600 mg, whereas 40.5% of non-US patients received 300 mg. Bivalirudin was more frequently used in US patients (56.7% versus 2.9%). At 48 hours, rates of the primary composite end point were comparable in the US and non-US cohorts (5.5% versus 5.2%; P=0.53). Cangrelor reduced rates of the primary composite end point compared with clopidogrel in US (4.5% versus 6.4%; odds ratio 0.70 [95% confidence interval 0.53-0.92]) and in non-US patients (4.8% versus 5.6%; odds ratio 0.85 [95% confidence interval 0.69-1.05]; interaction P=0.26). Similarly, rates of the key secondary end point, stent thrombosis, were reduced by cangrelor in both regions. Rates of Global Use of Strategies to Open Occluded Arteries (GUSTO)-defined severe bleeding were low and not significantly increased by cangrelor in either region.Despite broad differences in clinical profiles and indications for percutaneous coronary intervention by region in a large global cardiovascular clinical trial, cangrelor consistently reduced rates of ischemic end points compared with clopidogrel without an excess in severe bleeding in both the US and non-US subgroups.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCINTERVENTIONS.116.003612

    View details for Web of Science ID 000378134200013

    View details for PubMedID 27313282

    View details for PubMedCentralID PMC4920208

  • Association of Body Mass Index WithCareand Outcomes in Patients WithAtrialFibrillation: Results From the ORBIT-AF Registry. JACC. Clinical electrophysiology Pandey, A., Gersh, B. J., McGuire, D. K., Shrader, P., Thomas, L., Kowey, P. R., Mahaffey, K. W., Hylek, E., Sun, S., Burton, P., Piccini, J., Peterson, E., Fonarow, G. C. 2016; 2 (3): 355–63

    Abstract

    OBJECTIVES: This study sought to determine the association between body mass index (BMI) and clinical outcomes among patients with prevalent atrial fibrillation (AF).BACKGROUND: Higher BMI is an independent risk factor for incident AF. However, its impact on management strategies and clinical outcomes among patients with prevalent AF is unclear.METHODS: Patients with AF enrolled in the ORBIT-AF (Outcomes Registry for Better Informed Treatment of Atrial Fibrillation) registry from June 2010 through August 2011 were stratified into BMI-based categories as normal weight, overweight, class I obese, class II obese, and class III obese. Unadjusted and adjusted Cox frailty models were constructed to assess the association of BMI with clinical outcomes over a 2-year follow-up.RESULTS: We evaluated 9,606 patients with AF (42% women; 78% overweight/obese) from 174 ORBIT participating practices in the United States. Higher BMI patients were younger and had a greater prevalence of diabetes, hypertension, and obstructive sleep apnea (OSA). Use of anticoagulation and rhythm control strategies was significantly greater among higher BMI patients. Rates for all-cause mortality and thromboembolic events decreased in a near linear fashion across increasing BMI categories (p< 0.001). After multivariable adjustment, higher BMI was associated with lower risk for all-cause mortality with lowest risk among class I obese patients (hazard ratio [HR]: 0.65; 95% CI: 0.54 to 0.78); reference: normal weight). For every 5-kg/m2 increase in BMI, the odds of risk-adjusted mortality were 7% lower. Incontrast, BMI was not associated with adjusted risk for thromboembolic events and AF progression.CONCLUSIONS: Although AF patients with higher BMI were significantly younger, higher BMI in AF patients was associated with similar or better clinical outcomes.

    View details for PubMedID 29766895

  • Triple vs Dual Antithrombotic Therapy in Patients with Atrial Fibrillation and Coronary Artery Disease AMERICAN JOURNAL OF MEDICINE Lopes, R. D., Rao, M., Simon, D. N., Thomas, L., Ansell, J., Fonarow, G. C., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P., Piccini, J. P., Singer, D. E., Chang, P., Peterson, E. D., Mahaffey, K. W. 2016; 129 (6): 592-U197

    Abstract

    The role of triple antithrombotic therapy vs dual antithrombotic therapy in patients with both atrial fibrillation and coronary artery disease remains unclear. This study explores the differences in treatment practices and outcomes between triple antithrombotic therapy and dual antithrombotic therapy in patients with atrial fibrillation and coronary artery disease.Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (n = 10,135), we analyzed outcomes in patients with coronary artery disease (n = 1827) according to treatment with triple antithrombotic therapy (defined as concurrent therapy with an oral anticoagulant, a thienopyridine, and aspirin) or dual antithrombotic therapy (comprising either an oral anticoagulant and one antiplatelet agent [OAC plus AA] or 2 antiplatelet drugs and no anticoagulant [DAP]).The use of triple antithrombotic therapy, OAC plus AA, and DAP at baseline was 8.5% (n = 155), 80.4% (n = 1468), and 11.2% (n = 204), respectively. Among patients treated with OAC plus AA, aspirin was the most common antiplatelet agent used (90%), followed by clopidogrel (10%) and prasugrel (0.1%). The use of triple antithrombotic therapy was not affected by patient risk of either stroke or bleeding. Patients treated with triple antithrombotic therapy at baseline were hospitalized for all causes (including cardiovascular) more often than patients on OAC plus AA (adjusted hazard ratio 1.75; 95% confidence interval, 1.35-2.26; P <.0001) or DAP (hazard ratio 1.82; 95% confidence interval, 1.25-2.65; P = .0018). Rates of major bleeding or a combined cardiovascular outcome were not significantly different by treatment group.Choice of antithrombotic therapy in patients with atrial fibrillation and coronary artery disease was not affected by patient stroke or bleeding risks. Triple antithrombotic therapy-treated patients were more likely to be hospitalized for all causes than those on OAC plus AA or on DAP.

    View details for DOI 10.1016/j.amjmed.2015.12.026

    View details for Web of Science ID 000376499100030

    View details for PubMedID 26797080

  • Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes The TRACER Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Vranckx, P., White, H. D., Huang, Z., Mahaffey, K. W., Armstrong, P. W., Van de Werf, F., Moliterno, D. J., Wallentin, L., Held, C., Aylward, P. E., Cornel, J. H., Bode, C., Huber, K., Nicolau, J. C., Ruzyllo, W., Harrington, R. A., Tricoci, P. 2016; 67 (18): 2135-2144

    Abstract

    The Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed.This study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries).We analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death.During follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1); the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35; 95% confidence interval: 5.59 to 9.68; p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05; 95% confidence interval: 5.41 to 18.69; p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding.In patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736]; NCT00527943).

    View details for DOI 10.1016/j.jacc.2016.02.056

    View details for Web of Science ID 000375406100007

    View details for PubMedID 27151345

  • Lack of Concordance Between Local Investigators, Angiographic Core Laboratory, and Clinical Event Committee in the Assessment of Stent Thrombosis Results From the TRACER Angiographic Substudy CIRCULATION-CARDIOVASCULAR INTERVENTIONS Popma, C. J., Sheng, S., Korjian, S., Daaboul, Y., Chi, G., Tricoci, P., Huang, Z., Moliterno, D. J., White, H. D., Van de Werf, F., Harrington, R. A., Wallentin, L., Held, C., Armstrong, P. W., Aylward, P. E., Strony, J., Mahaffey, K. W., Gibson, C. M. 2016; 9 (5)

    Abstract

    Stent thrombosis (ST) is an important end point in cardiovascular clinical trials. Adjudication is traditionally based on clinical event committee (CEC) review of case report forms and source documentation rather than angiograms. However, the degree to which this method of adjudication is concordant with the review of independent angiographic core laboratories (ACLs) has not been studied. This report represents the first assessment of variability between local investigators (LIs), a CEC, and an ACL.Serial angiograms of 329 patients with acute coronary syndrome without ST-segment-elevation who underwent percutaneous coronary intervention at entry in the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Particpants With Acute Coronary Syndrome (TRACER) and who met criteria for possible ST subsequent to the index event were reviewed by an ACL. The ACL was blinded to the assessment by both LIs and the CEC regarding the presence or absence of ST. CEC adjudication was based on Academic Research Consortium definitions of ST, using case report form data and source documents, including catheterization laboratory reports. The ACL, CEC, and LIs agreed on the presence or absence of ST in 52.9% events (κ=0.32; 95% confidence interval, 0.26-0.39). The ACL and CEC agreed on 82.7% of events (κ=0.57; 95% confidence interval, 0.47-0.67); the ACL and LIs agreed on 61.1% of events (κ=0.25; 95% confidence interval, 0.16-0.34); and the CEC and LIs agreed on 62% of events (κ=0.28; 95% confidence interval, 0.21-0.36).ST reporting by an ACL, a CEC, and LIs is discordant. The assessment of ST is more often detected by direct review of angiograms by an ACL.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00527943.

    View details for DOI 10.1161/CIRCINTERVENTIONS.115.003114

    View details for Web of Science ID 000376742000002

    View details for PubMedID 27162212

  • Clinical Characteristics, Oral Anticoagulation Patterns, and Outcomes of Medicaid Patients With Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF I) Registry. Journal of the American Heart Association O'Brien, E. C., Kim, S., Thomas, L., Fonarow, G. C., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Piccini, J. P., Peterson, E. D. 2016; 5 (5)

    Abstract

    Whereas insurance status has been previously associated with care patterns, little is currently known about the association between Medicaid insurance and the clinical characteristics, treatment, or outcomes of patients with atrial fibrillation (AF).We used data from adults with AF enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), a national outpatient registry conducted at 176 community, multispecialty sites. The primary outcome of interest was the proportion of patients prescribed any oral anticoagulation (OAC; warfarin or novel oral anticoagulants [NOAC]). Secondary outcomes of interest included the proportion of patients prescribed NOACs (dabigatran or rivaroxaban); time in therapeutic range (TTR) for warfarin users, all-cause mortality, stroke/systemic embolism, and major bleed. Of 10 133 patients, N=470 (4.6%) had Medicaid insurance. Medicaid patients were similarly likely to receive OAC at baseline (72.8% vs 76.3%; unadjusted P=0.079), but less likely to receive NOAC at baseline or follow-up (12.1% vs 16.3%; unadjusted P=0.019). After risk adjustment, Medicaid status was associated with lower use of OAC at baseline among patients with high stroke risk (odds ratio [OR]=0.68; 95% CI=0.49, 0.94), but was not associated with OAC use overall (OR=0.82; 95% CI=0.61, 1.09). Among warfarin users, median TTR was lower among Medicaid patients (60% vs 68%; P<0.0001; adjusted TTR difference, -2.9; 95% CI=-5.7, -0.2; P=0.04). Use of an NOAC over 2 years of follow-up was not statistically different by insurance. Compared with non-Medicaid patients, Medicaid patients had higher unadjusted rates of mortality, stroke/systemic embolism, and major bleeding; however, these differences were attenuated following adjustment for clinical characteristics.In a contemporary AF cohort, use of OAC overall and use of NOACs were not significantly lower among Medicaid patients relative to others. However, among warfarin users, Medicaid patients spent less time in therapeutic range compared with those with other forms of insurance.

    View details for DOI 10.1161/JAHA.115.002721

    View details for PubMedID 27146448

    View details for PubMedCentralID PMC4889165

  • North American Thrombosis Forum, AF Action Initiative Consensus Document AMERICAN JOURNAL OF MEDICINE Ruff, C. T., Ansell, J. E., Becker, R. C., Benjamin, E. J., Deicicchi, D. J., Estes, N. A., Ezekowitz, M. D., Fanikos, J., Fareed, J., Garcia, D., Giugliano, R. P., Goldhaber, S. Z., Granger, C., Healey, J. S., Hull, R., Hylek, E. M., Libby, P., Lopes, R. D., Mahaffey, K. W., Mega, J., Piazza, G., Sasahara, A. A., Sorond, F. A., Spyropoulos, A. C., Walenga, J. M., Weitz, J. I. 2016; 129 (5): S1-S29

    Abstract

    The North American Thrombosis Forum Atrial Fibrillation Action Initiative consensus document is a comprehensive yet practical briefing document focusing on stroke and bleeding risk assessment in patients with atrial fibrillation, as well as recommendations regarding anticoagulation options and management. Despite the breadth of clinical trial data and guideline recommendation updates, many clinicians continue to struggle to synthesize the disparate information available. This problem slows the uptake and utilization of updated risk prediction tools and adoption of new oral anticoagulants. This document serves as a practical and educational reference for the entire medical community involved in the care of patients with atrial fibrillation.

    View details for DOI 10.1016/j.amjmed.2016.02.001

    View details for PubMedID 27126598

  • Design and rationale for the Effects of Ticagrelor and Clopidogrel in Patients with Peripheral Artery Disease (EUCLID) trial AMERICAN HEART JOURNAL Berger, J. S., Katona, B. G., Jones, W. S., Patel, M. R., Norgren, L., Baumgartner, I., Blomster, J., Mahaffey, K. W., Held, P., Millegard, M., Heizer, G., Reist, C., Fowkes, F. G., Hiatt, W. R. 2016; 175: 86-93

    Abstract

    Despite overwhelming data demonstrating the efficacy of antiplatelet therapy in heart disease and stroke, data in peripheral artery disease (PAD) are less compelling. Aspirin has modest evidence supporting a reduction in cardiovascular events in patients with PAD, whereas clopidogrel monotherapy may be more effective in PAD. Ticagrelor, a potent, reversibly binding P2Y12 receptor antagonist, is beneficial in patients with acute coronary syndrome and prior myocardial infarction. The EUCLID trial is designed to address the need for effective antiplatelet therapy in PAD to decrease the risk of cardiovascular events.EUCLID is a randomized, double-blind, parallel-group, multinational clinical trial designed to evaluate the efficacy and safety of ticagrelor compared with clopidogrel for the prevention of major adverse cardiovascular events in subjects with symptomatic PAD. Subjects with established PAD will be randomized in a 1:1 fashion to ticagrelor 90 mg twice daily or clopidogrel 75 mg daily. The primary end point is a composite of cardiovascular death, myocardial infarction, or ischemic stroke. Other end points address limb events including acute leg ischemia, need for revascularization, disease progression by ankle-brachial index, and quality of life. The primary safety objective is Thrombolysis in Myocardial Infarction-defined major bleeding. Recruitment began in December 2012 and was completed in March 2014; 13,887 patients were randomized. The trial will continue until at least 1,364 adjudicated primary end points occur.The EUCLID study is investigating whether treatment with ticagrelor versus clopidogrel, given as antiplatelet monotherapy, will reduce the incidence of cardiovascular and limb-specific events in patients with symptomatic PAD.

    View details for DOI 10.1016/j.ahj.2016.01.018

    View details for Web of Science ID 000375655200011

    View details for PubMedID 27179727

  • Family history of atrial fibrillation is associated with earlier-onset and more symptomatic atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry AMERICAN HEART JOURNAL Gundlund, A., Fosbol, E. L., Kim, S., Fonarow, G. C., Gersh, B. J., Kowey, P. R., Hylek, E., Mahaffey, K. W., Thomas, L., Piccini, J. P., Peterson, E. D. 2016; 175: 28-35

    Abstract

    We addressed whether patients with a family history of atrial fibrillation (AF) were diagnosed as having AF earlier in life, were more symptomatic, and had worse outcomes compared with those without a family history of AF.Using the ORBIT-AF, we compared symptoms and disease characteristics in those with and without a family history of AF. A family history of AF was defined as AF in a first-degree family member and obtained by patient self-reporting. Multivariable Cox proportional hazard analyses were performed to compare the incidence of cardiovascular outcomes, AF progression, all-cause hospitalization, and all-cause death.Among 9,999 patients with AF from 176 US outpatient clinics, 1,481 (14.8%) had a family history of AF. Relative to those without, those with a family history of AF developed AF 5 years earlier on average (median age 65 vs 70 years, P < .01), with less comorbidity, and had more severe AF-related symptoms. No differences were found between the 2 groups in the risk of AF progression (adjusted hazard ratio [HR] 0.98, 95% CI 0.85-1.14), stroke, non-central nervous system embolism, or transient ischemic attack (adjusted HR 0.95, 95% CI 0.67-1.34), all-cause hospitalization (adjusted HR 1.03, 95% CI 0.94-1.12), and all-cause death (adjusted HR 1.05, 95% CI 0.86-1.27).Patients with a family history of AF developed AF at a younger age, had less comorbidity, and were more symptomatic. Once AF developed, no significantly increased risks of AF progression and thromboembolism were associated with a family history of AF compared with no family history.

    View details for DOI 10.1016/j.ahj.2016.01.020

    View details for Web of Science ID 000375655200005

    View details for PubMedID 27179721

  • Trends in Enrollment, Clinical Characteristics, Treatment, and Outcomes According to Age in Non-ST-Segment-Elevation Acute Coronary Syndromes Clinical Trials CIRCULATION Kragholm, K., Goldstein, S. A., Yang, Q., Lopes, R. D., Schulte, P. J., Bernacki, G. M., White, H. D., Mahaffey, K. W., Giugliano, R. P., Armstrong, P. W., Harrington, R. A., Tricoci, P., Van de Werf, F., Alexander, J. H., Alexander, K. P., Newby, L. K. 2016; 133 (16): 1560-?

    Abstract

    Representation by age ensures appropriate translation of clinical trial results to practice, but, historically, older patients have been underrepresented in clinical trial populations. As the general population has aged, it is unknown whether clinical trial enrollment has changed in parallel.We studied time trends in enrollment, clinical characteristics, treatment, and outcomes by age among 76 141 patients with non-ST-segment-elevation acute coronary syndrome enrolled in 11 phase III clinical trials over 17 years (1994-2010). Overall, 19.7% of patients were ≥75 years; this proportion increased from 16% during 1994 to 1997 to 21% during 1998 to 2001 and 23.2% during 2002 to 2005, but declined to 20.2% in 2006 to 2010. The number of comorbidities increased with successive time periods irrespective of age. There were substantial increases in the use of evidence-based medication in-hospital and at discharge regardless of age. Although predicted 6-month mortality increased slightly over time, observed 6-month mortality declined significantly in all age strata (1994-1997 versus 2006-2010: <65 years: 3.0% versus 1.9%; 65-74 years: 7.5% versus 3.4%; 75-79 years: 13.0% versus 6.5%; 80-84 years: 17.6% versus 8.2%; and ≥85 years: 24.8% versus 12.6%).The distribution of enrollment by age in phase III non-ST-segment-elevation acute coronary syndrome trials was unchanged over time. Irrespective of age, post-myocardial infarction mortality decreased significantly over time, concurrent with increased evidence-based care and despite increasing comorbidities.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00089895.

    View details for DOI 10.1161/CIRCULATIONAHA.115.017299

    View details for Web of Science ID 000374553400011

    View details for PubMedID 26957532

    View details for PubMedCentralID PMC4856566

  • The effect of cangrelor and access site on ischaemic and bleeding events: insights from CHAMPION PHOENIX EUROPEAN HEART JOURNAL Gutierrez, J. A., Harrington, R. A., Blankenship, J. C., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Genereux, P., Prats, J., Deliargyris, E. N., Mahaffey, K., White, H. D., Bhatt, D. L. 2016; 37 (14): 1122-1130

    Abstract

    To assess whether the use of the femoral or radial approach for percutaneous coronary intervention (PCI) interacted with the efficacy and safety of cangrelor, an intravenous P2Y12 inhibitor, in CHAMPION PHOENIX.A total of 11 145 patients were randomly assigned in a double-dummy, double-blind manner either to a cangrelor bolus and 2-h infusion or to clopidogrel at the time of PCI. The primary endpoint, a composite of death, myocardial infarction, ischaemia-driven revascularization, or stent thrombosis, and the primary safety endpoint, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) defined severe bleeding, were evaluated at 48 h. Of the patients undergoing PCI and receiving study drug treatment, a total of 8064 (74%) and 2855 (26%) patients underwent femoral or radial PCI, respectively. Among the femoral cohort, the primary endpoint rate was 4.8% with cangrelor vs. 6.0% with clopidogrel (odds ratio, OR [95% confidence interval, CI] = 0.79 [0.65-0.96]); among the radial cohort, the primary endpoint was 4.4% with cangrelor vs. 5.7% with clopidogrel (OR [95% CI] = 0.76 [0.54-1.06]), P-interaction 0.83. The rate of GUSTO severe bleeding in the femoral cohort was 0.2% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.73 [0.51-5.93]). Among the radial cohort, the rate of GUSTO severe bleeding was 0.1% with cangrelor vs. 0.1% with clopidogrel (OR [95% CI] = 1.02 [0.14-7.28]), P-interaction 0.65. The evaluation of safety endpoints with the more sensitive ACUITY-defined bleeding found major bleeding in the femoral cohort to be 5.2% with cangrelor vs. 3.1% with clopidogrel (OR [95% CI] = 1.69 [1.35-2.12]); among the radial cohort the rate of ACUITY major bleeding was 1.5% with cangrelor vs. 0.7% with clopidogrel (OR [95% CI] = 2.17 [1.02-4.62], P-interaction 0.54).In CHAMPION PHOENIX, cangrelor reduced ischaemic events with no significant increase in GUSTO-defined severe bleeding. The absolute rates of bleeding, regardless of the definition, tended to be lower when PCI was performed via the radial artery.http://www.clinicaltrials.gov identifier: NCT01156571.

    View details for DOI 10.1093/eurheartj/ehv498

    View details for Web of Science ID 000373558500011

    View details for PubMedID 26400827

    View details for PubMedCentralID PMC4823635

  • THE EFFICACY AND SAFETY OF CANGRELOR WITH AND WITHOUT GLYCOPROTEIN IIB/IIIA INHIBITORS IN PATIENTS UNDERGOING PERCUTANEOUS CORONARY INTERVENTION: A POOLED ANALYSIS OF THE CHAMPION TRIALS Vaduganathan, M., Harrington, R., Stone, G., Steg, P., Gibson, C., Hamm, C., Price, M., Menozzi, A., Prats, J., Deliargyris, E., Mahaffey, K., White, H., Bhatt, D. ELSEVIER SCIENCE INC. 2016: 452
  • Racial/ethnic differences in atrial fibrillation symptoms, treatment patterns, and outcomes: Insights from Outcomes Registry for Better Informed Treatment for Atrial Fibrillation Registry AMERICAN HEART JOURNAL Golwala, H., Jackson, L. R., Simon, D. N., Piccini, J. P., Gersh, B., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Fonarow, G. C., Peterson, E. D., Thomas, K. L. 2016; 174: 29-36

    Abstract

    Significant racial/ethnic differences exist in the incidence of atrial fibrillation (AF). However, less is known about racial/ethnic differences in quality of life (QoL), treatment, and outcomes associated with AF.Using data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we compared clinical characteristics, QoL, management strategies, and long-term outcomes associated with AF among various racial/ethnic groups.We analyzed 9,542 participants with AF (mean age 74 ± 11 years, 43% women, 91% white, 5% black, 4% Hispanic) from 174 centers. Compared with AF patients identified as white race, patients identified as Hispanic ethnicity and those identified as black race were younger, were more often women, and had more cardiac and noncardiac comorbidities. Black patients were more symptomatic with worse QoL and were less likely to be treated with a rhythm control strategy than other racial/ethnic groups. There were no significant racial/ethnic differences in CHA2DS2-VASc stroke or ATRIA bleeding risk scores and rates of oral anticoagulation use were similar. However, racial and ethnic minority populations treated with warfarin spent a lower median time in therapeutic range of international normalized ratio (59% blacks vs 68% whites vs 62% Hispanics, P < .0001). There was no difference in long-term outcomes associated with AF between the 3 groups at a median follow-up of 2.1 years.Relative to white and Hispanic patients, black patients with AF had more symptoms, were less likely to receive rhythm control interventions, and had lower quality of warfarin management. Despite these differences, clinical events at 2 years were similar by race and ethnicity.

    View details for DOI 10.1016/j.ahj.2015.10.028

    View details for Web of Science ID 000372538500007

  • Rhythm Control Versus Rate Control andClinical Outcomes in Patients WithAtrial Fibrillation: Results From the ORBIT-AF Registry. JACC. Clinical electrophysiology Noheria, A., Shrader, P., Piccini, J. P., Fonarow, G. C., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Noseworthy, P. A., Reiffel, J. A., Steinberg, B. A., Thomas, L. E., Peterson, E. D., Gersh, B. J., ORBIT-AF Investigators and Patients 2016; 2 (2): 221–29

    Abstract

    OBJECTIVES: The study sought to evaluate clinical outcomes in clinical practice with rhythm control versus rate control strategy for management of atrial fibrillation (AF).BACKGROUND: Randomized trials have not demonstrated significant differences in stroke, heart failure, or mortality between rhythm and rate control strategies. The comparative outcomes in contemporary clinical practice are not well described.METHODS: Patients managed with a rhythm control strategy targeting maintenance of sinus rhythm were retrospectively compared with a strategy of rate control alone in a AF registry across various U.S. practice settings. Unadjusted and adjusted (inverse-propensity weighted) outcomes were estimated.RESULTS: The overall study population (N= 6,988) had a median of 74 (65 to 81) years of age, 56% were males, 77% had first detected or paroxysmal AF, and 68% had CHADS2 score≥2. In unadjusted analyses, rhythm control was associated with lower all-cause death, cardiovascular death, first stroke/non-central nervous system systemic embolization/transient ischemic attack, or first major bleeding event (all p< 0.05); no difference in new onset heart failure (p=0.28); and more frequent cardiovascular hospitalizations (p= 0.0006). There was no difference in the incidence of pacemaker, defibrillator, or cardiac resynchronization device implantations (p= 0.99). In adjusted analyses, there were no statistical differences in clinical outcomes between rhythm control and rate control treated patients (all p > 0.05); however, rhythm control was associated with more cardiovascular hospitalizations (hazard ratio: 1.24; 95% confidence interval: 1.10 to 1.39; p= 0.0003).CONCLUSIONS: Among patients with AF, rhythm control was not superior to rate control strategy for outcomes of stroke, heart failure, or mortality, but was associated with more cardiovascular hospitalizations.

    View details for PubMedID 29766874

  • Sudden Cardiac Death After Non-ST-Segment Elevation Acute Coronary Syndrome. JAMA cardiology Hess, P. L., Wojdyla, D. M., Al-Khatib, S. M., Lokhnygina, Y., Wallentin, L., Armstrong, P. W., Roe, M. T., Ohman, E. M., Harrington, R. A., Alexander, J. H., White, H. D., Van de Werf, F., Piccini, J. P., Held, C., Aylward, P. E., Moliterno, D. J., Mahaffey, K. W., Tricoci, P. 2016; 1 (1): 73-79

    Abstract

    In the current therapeutic era, the risk for sudden cardiac death (SCD) after non-ST-segment elevation acute coronary syndrome (NSTE ACS) has not been characterized completely.To determine the cumulative incidence of SCD during long-term follow-up after NSTE ACS, to develop a risk model and risk score for SCD after NSTE ACS, and to assess the association between recurrent events after the initial ACS presentation and the risk for SCD.This pooled cohort analysis merged individual data from 48 286 participants in 4 trials: the Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2), Study of Platelet Inhibition and Patient Outcomes (PLATO), Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER), and Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trials. The cumulative incidence of SCD and cardiovascular death was examined according to time after NSTE ACS. Using competing risk and Cox proportional hazards models, clinical factors at baseline and after the index event that were associated with SCD after NSTE ACS were identified. Baseline factors were used to develop a risk model. Data were analyzed from January 2, 2014, to December 11, 2015.Sudden cardiac death.Of the initial 48 286 patients, 37 555 patients were enrolled after NSTE ACS (67.4% men; 32.6% women; median [interquartile range] age, 65 [57-72] years). Among these, 2109 deaths occurred after a median follow-up of 12.1 months. Of 1640 cardiovascular deaths, 513 (31.3%) were SCD. At 6, 18, and 30 months, the cumulative incidence estimates of SCD were 0.79%, 1.65%, and 2.37%, respectively. Reduced left ventricular ejection fraction, older age, diabetes mellitus, lower estimated glomerular filtration rate, higher heart rate, prior myocardial infarction, peripheral artery disease, Asian race, male sex, and high Killip class were significantly associated with SCD. A model developed to calculate the risk for SCD in trials with systematic collection of left ventricular ejection fraction had a C index of 0.77. An integer-based score was developed from this model and yielded a calculated SCD probability ranging from 0.1% to 56.7% (C statistic, 0.75). In a multivariable model that included time-dependent clinical events occurring after the index hospitalization for ACS, SCD was associated with recurrent myocardial infarction (hazard ratio [HR], 2.95; 95% CI, 2.29-3.80; P < .001) and any hospitalization (HR, 2.45; 95% CI, 1.98-3.03; P < .001), whereas coronary revascularization had a negative relationship with SCD (HR, 0.75; 95% CI, 0.58-0.98; P = .03).In the current therapeutic era, SCD accounts for about one-third of cardiovascular deaths after NSTE ACS. Risk stratification can be performed with good accuracy using commonly collected clinical variables. Clinical events occurring after the index hospitalization are underappreciated but important risk factors.

    View details for DOI 10.1001/jamacardio.2015.0359

    View details for PubMedID 27437658

  • Racial/ethnic differences in atrial fibrillation symptoms, treatment patterns, and outcomes: Insights from Outcomes Registry for Better Informed Treatment for Atrial Fibrillation Registry. American heart journal Golwala, H., Jackson, L. R., Simon, D. N., Piccini, J. P., Gersh, B., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L., Fonarow, G. C., Peterson, E. D., Thomas, K. L. 2016; 174: 29-36

    Abstract

    Significant racial/ethnic differences exist in the incidence of atrial fibrillation (AF). However, less is known about racial/ethnic differences in quality of life (QoL), treatment, and outcomes associated with AF.Using data from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation, we compared clinical characteristics, QoL, management strategies, and long-term outcomes associated with AF among various racial/ethnic groups.We analyzed 9,542 participants with AF (mean age 74 ± 11 years, 43% women, 91% white, 5% black, 4% Hispanic) from 174 centers. Compared with AF patients identified as white race, patients identified as Hispanic ethnicity and those identified as black race were younger, were more often women, and had more cardiac and noncardiac comorbidities. Black patients were more symptomatic with worse QoL and were less likely to be treated with a rhythm control strategy than other racial/ethnic groups. There were no significant racial/ethnic differences in CHA2DS2-VASc stroke or ATRIA bleeding risk scores and rates of oral anticoagulation use were similar. However, racial and ethnic minority populations treated with warfarin spent a lower median time in therapeutic range of international normalized ratio (59% blacks vs 68% whites vs 62% Hispanics, P < .0001). There was no difference in long-term outcomes associated with AF between the 3 groups at a median follow-up of 2.1 years.Relative to white and Hispanic patients, black patients with AF had more symptoms, were less likely to receive rhythm control interventions, and had lower quality of warfarin management. Despite these differences, clinical events at 2 years were similar by race and ethnicity.

    View details for DOI 10.1016/j.ahj.2015.10.028

    View details for PubMedID 26995367

  • Pooled analysis of adverse event collection from 4 acute coronary syndrome trials. American heart journal Zimerman, A., Lopes, R. D., Stebbins, A. L., Guimarães, P. O., Haque, G., Melloni, C., Trollinger, K., James, S. K., Alexander, J. H., Tricoci, P., Roe, M. T., Ohman, E. M., Mahaffey, K. W., Held, C., Tinga, B., Pieper, K. S., Alexander, K. P. 2016; 174: 60-67

    Abstract

    Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied.Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded.In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs.Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.

    View details for DOI 10.1016/j.ahj.2016.01.003

    View details for PubMedID 26995371

  • Pooled analysis of adverse event collection from 4 acute coronary syndrome trials AMERICAN HEART JOURNAL Zimerman, A., Lopes, R. D., Stebbins, A. L., Guimaraes, P. O., Haque, G., Melloni, C., Trollinger, K., James, S. K., Alexander, J. H., Tricoci, P., Roe, M. T., Ohman, E. M., Mahaffey, K. W., Held, C., Tinga, B., Pieper, K. S., Alexander, K. P. 2016; 174: 60-67

    Abstract

    Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied.Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded.In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs.Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.

    View details for DOI 10.1016/j.ahj.2016.01.003

    View details for Web of Science ID 000372538500011

  • Lessons Learned from EVOLVE for Planning of Future Randomized Trials in Patients on Dialysis CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Parfrey, P. S., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Chertow, G. M. 2016; 11 (3): 539-546

    Abstract

    The effect of the calcimimetic cinacalcet on cardiovascular disease in patients undergoing hemodialysis with secondary hyperparathyroidism was assessed in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events trial. This was the largest (in size) and longest (in duration) randomized controlled clinical trial undertaken in this population. During planning, execution, analysis, and reporting of the trial, many lessons were learned, including those related to the use of a composite cardiovascular primary endpoint, definition of endpoints (particularly heart failure and severe unremitting hyperparathyroidism), importance of age for optimal stratification at randomization, use of unadjusted and adjusted intention-to-treat analysis for the primary outcome, how to respond to a lower-than-predicted event rate during the trial, development of a prespecified analytic plan that accounted for nonadherence and for cointerventions that diminished the power of the trial to observe a treatment effect, determination of the credibility of a subgroup effect, use of adverse effects database to investigate rare diseases, collection of blood for biomarker measurement not designated before trial initiation, and interpretation of the benefits-to-harms ratio for individual patients. It is likely that many of these issues will arise in the planning of future trials in CKD.

    View details for DOI 10.2215/CJN.06370615

    View details for Web of Science ID 000371453100023

    View details for PubMedID 26614406

    View details for PubMedCentralID PMC4791832

  • The effects of cinacalcet on blood pressure, mortality and cardiovascular endpoints in the EVOLVE trial JOURNAL OF HUMAN HYPERTENSION Chang, T. I., AbdAlla, S., London, G. M., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Herzog, C. A., Mahaffey, K. W., Moe, S. M., Parfrey, P. S., Wheeler, D. C., Dehmel, B., Goodman, W. G., Chertow, G. M. 2016; 30 (3): 204-209

    Abstract

    Patients with end-stage renal disease often have derangements in calcium and phosphorus homeostasis and resultant secondary hyperparathyroidism (sHPT), which may contribute to the high prevalence of arterial stiffness and hypertension. We conducted a secondary analysis of the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events (EVOLVE) trial, in which patients receiving hemodialysis with sHPT were randomly assigned to receive cinacalcet or placebo. We sought to examine whether the effect of cinacalcet on death and major cardiovascular events was modified by baseline pulse pressure as a marker of arterial stiffness, and whether cinacalcet yielded any effects on blood pressure. As reported previously, an unadjusted intention-to-treat analysis failed to conclude that randomization to cinacalcet reduces the risk of the primary composite end point (all-cause mortality or non-fatal myocardial infarction, heart failure, hospitalization for unstable angina or peripheral vascular event). However, after prespecified adjustment for baseline characteristics, patients randomized to cinacalcet experienced a nominally significant 13% lower adjusted risk (95% confidence limit 4-20%) of the primary composite end point. The effect of cinacalcet was not modified by baseline pulse pressure (Pinteraction=0.44). In adjusted models, at 20 weeks cinacalcet resulted in a 2.2 mm Hg larger average decrease in systolic blood pressure (P=0.002) and a 1.3 mm Hg larger average decrease in diastolic blood pressure (P=0.002) compared with placebo. In summary, in the EVOLVE trial, the effect of cinacalcet on death and major cardiovascular events was independent of baseline pulse pressure.

    View details for DOI 10.1038/jhh.2015.56

    View details for PubMedID 26040438

  • Use of thienopyridine prior to presentation with non-ST-segment elevation acute coronary syndrome and association with safety and efficacy of vorapaxar: insights from the TRACER trial. European heart journal. Acute cardiovascular care Harskamp, R. E., Clare, R. M., Ambrosio, G., Held, C., Lokhnygina, Y., Moliterno, D. J., White, H. D., Aylward, P. E., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Van de Werf, F., Wallentin, L., Strony, J., Tricoci, P. 2016

    Abstract

    Vorapaxar is effective in the prevention of secondary atherothrombotic events, although the efficacy/safety balance appears less favorable in the treatment of patients with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS). We hypothesized that patients with NSTE ACS already receiving thienopyridine prior to the ACS event may show differential efficacy/safety effects with vorapaxar vs. placebo added to their standard care.We studied 12,944 patients from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial with respect to thienopyridine use before admission for the index NSTE ACS event. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, rehospitalization for ischemia, and urgent revascularization. The key secondary endpoint was a composite of cardiovascular death, myocardial infarction, and stroke. Safety endpoints were bleeding complications.Only 1513 patients (11.7%) were receiving thienopyridine before admission for the index NSTE ACS event. In these patients, Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) moderate/severe bleeding occurred in 5.7% treated with vorapaxar and 5.3% treated with a placebo (hazards ratio (HR) 1.10, 95% confidence interval (CI) 0.70-1.71); in thienopyridine-naïve patients, the rates were 5.7% and 4.1%, respectively (HR 1.32, 95% CI 1.11-1.57; Pint=0.45). GUSTO severe bleeding in the prior thienopyridine group occurred in 0.5% of patients treated with vorapaxar and 1.3% of patients treated with placebo (HR 0.34, 95% CI 0.09-1.30); in thienopyridine-naïve patients, the rates were 2.0% and 1.0%, respectively (HR 1.89, 95% CI 1.36-2.62; Pint=0.01). No interaction was observed between vorapaxar efficacy and prior thienopyridine use on the primary (adjusted Pint=0.53) or key secondary endpoints ( Pint=0.61).TRACER was largely conducted in thienopyridine-naïve patients with unknown tolerance to multiple antiplatelet treatments. Patients receiving thienopyridine before the index event may have had an attenuated increase in bleeding when adding vorapaxar, whereas concomitantly adding vorapaxar and thienopyridine in naïve patients may have uncovered a latent susceptibility to bleeding.

    View details for PubMedID 26895973

  • Sinus Node Dysfunction Is Associated With Higher Symptom Burden and Increased Comorbid Illness: Results From the ORBIT-AF Registry CLINICAL CARDIOLOGY Jackson, L. R., Kim, S. H., Piccini, J. P., Gersh, B. J., Naccarelli, G. V., Reiffel, J. A., Freeman, J., Thomas, L., Chang, P., Fonarow, G. C., Go, A. S., Mahaffey, K. W., Peterson, E. D., Kowey, P. R. 2016; 39 (2): 119-125

    Abstract

    Patients with sinus node dysfunction (SND) have increased risk of atrial tachyarrhythmias, including atrial fibrillation (AF). To date, treatment patterns and outcomes of patients with SND and AF have not been well described.Patients with SND and AF have higher risk of adverse cardiovascular outcomes.Sinus node dysfunction was defined clinically, based on treating physician. Treatment patterns were described and logistic regression analysis performed to assess outcomes.Overall, 1710 (17.7%) out of 9631 patients had SND at enrollment. Patients with SND and AF had increased comorbid medical illnesses, more severe symptoms (European Heart Rhythm Association class IV: 17.5% vs 13.9%; P = 0.0007), and poorer quality of life (median 12-month Atrial Fibrillation Effect on Quality of Life score: 79.6 vs 85.2; P = 0.0008). There were no differences in AF management strategy between patients with SND and those without (rate control, 69.7% vs 67.7%; rhythm control, 30.0% vs 32.0%; P = 0.11). After adjustment, patients with SND were more likely than those without SND to progress from paroxysmal AF at baseline to persistent or permanent AF at any follow-up, or persistent AF at baseline to permanent AF at any follow-up (odds ratio: 1.23, 95% confidence interval: 1.01-1.49, P = 0.035). However, there was no association between SND and major risk-adjusted outcomes.Sinus node dysfunction is present in 1 of 6 patients with AF and is associated with increased comorbidities and higher symptom burden. However, SND is not associated with an increase in major risk-adjusted outcomes.

    View details for DOI 10.1002/clc.22504

    View details for Web of Science ID 000371415400008

    View details for PubMedID 26720750

    View details for PubMedCentralID PMC4784163

  • Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation. Circulation Piccini, J. P., Hellkamp, A. S., Washam, J. B., Becker, R. C., Breithardt, G., Berkowitz, S. D., Halperin, J. L., Hankey, G. J., Hacke, W., Mahaffey, K. W., Nessel, C. C., Singer, D. E., Fox, K. A., Patel, M. R. 2016; 133 (4): 352-360

    Abstract

    Patients with atrial fibrillation (AF) often take multiple medications.We examined characteristics and compared adjusted outcomes between rivaroxaban and warfarin according to number of concomitant baseline medications and the presence of combined cytochrome P450 3A4 and P-glycoprotein inhibitors in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study. At baseline, 5101 patients (36%) were on 0 to 4 medications, 7298 (51%) were on 5 to 9, and 1865 (13%) were on ≥ 10. Although polypharmacy was not associated with higher risk of stroke or non-central nervous system embolism (adjusted hazard ratio, 1.02 for ≥ 10 versus 0-4 medications; 95% confidence interval, 0.76-1.38), it was associated with higher risks of the combined end point of stroke, non-central nervous system embolism, vascular death, or myocardial infarction (adjusted hazard ratio, 1.41 for ≥ 10 versus 0-4 medications; 95% confidence interval, 1.18-1.68) and nonmajor clinically relevant or major bleeding (adjusted hazard ratio, 1.47 for ≥ 10 versus 0-4 medications; 95% confidence interval, 1.31-1.65). There was no significant difference in primary efficacy (adjusted interaction P=0.99) or safety outcomes (adjusted interaction P=0.87) between treatment groups by number of medications. Patients treated with 0 to 4 medications had lower rates of major bleeding with rivaroxaban (adjusted hazard ratio, 0.71; 95% confidence interval, 0.52-0.95; interaction P=0.0074). There was no evidence of differential outcomes in those treated with ≥ 1 combined cytochrome P450 3A4 and P-glycoprotein inhibitors.In a population of patients with atrial fibrillation, two thirds were on ≥ 5 medications. Increasing medication use was associated with higher risk of bleeding but not stroke. Rivaroxaban was tolerated across complex patients on multiple medications.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.115.018544

    View details for PubMedID 26673560

  • Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention Insights From the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) Trial CIRCULATION O'Donoghue, M. L., Bhatt, D. L., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Liu, T., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Harrington, R. A. 2016; 133 (3): 248-255

    Abstract

    Cangrelor is an intravenous ADP receptor antagonist that leads to potent and reversible inhibition of platelet aggregation. The relative safety and efficacy of some antiplatelet drugs in women has been disputed.The Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial randomized 11,145 patients undergoing elective or urgent percutaneous coronary intervention to cangrelor or clopidogrel. The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was GUSTO severe bleeding at 48 hours. Of subjects analyzed, 3051 (28%) were female. Cangrelor reduced the odds of the primary end point by 35% in women (adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.48-0.89) and by 14% in men (OR, 0.86; 95% CI, 0.70-1.05; P interaction=0.23) compared with clopidogrel. Cangrelor reduced the odds of stent thrombosis by 61% in women (OR, 0.39; 95% CI, 0.20-0.77) and 16% in men (OR, 0.84; 95% CI, 0.53-1.33; P interaction=0.11). The odds of severe bleeding were similar in both women and men treated with cangrelor (0.3% versus 0.2%, P=0.30 [women]; 0.1% versus 0.1%, P=0.41 [men]; P interaction=0.88) versus clopidogrel. Cangrelor increased the odds of moderate bleeding in women (0.9% versus 0.3%, P=0.02), but not in men (0.2% versus 0.2%, P=0.68; P interaction=0.040). The net clinical benefit (primary efficacy and safety end point) favored cangrelor in both women (OR, 0.68; 95% CI, 0.50-0.92) and men (OR, 0.87; 95% CI, 0.71-1.06; P interaction=0.26).In CHAMPION PHOENIX, cangrelor reduced the odds of major adverse cardiovascular events and stent thrombosis in women and men and appeared to offer greater net clinical benefit than clopidogrel.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCULATIONAHA.115.017300

    View details for Web of Science ID 000368540900004

    View details for PubMedCentralID PMC4894784

  • Efficacy and Safety of Cangrelor in Women Versus Men During Percutaneous Coronary Intervention: Insights From the Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) Trial. Circulation O'Donoghue, M. L., Bhatt, D. L., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Liu, T., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Harrington, R. A. 2016; 133 (3): 248-55

    Abstract

    Cangrelor is an intravenous ADP receptor antagonist that leads to potent and reversible inhibition of platelet aggregation. The relative safety and efficacy of some antiplatelet drugs in women has been disputed.The Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition (CHAMPION PHOENIX) trial randomized 11,145 patients undergoing elective or urgent percutaneous coronary intervention to cangrelor or clopidogrel. The primary efficacy end point was the composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was GUSTO severe bleeding at 48 hours. Of subjects analyzed, 3051 (28%) were female. Cangrelor reduced the odds of the primary end point by 35% in women (adjusted odds ratio [OR], 0.65; 95% confidence interval [CI], 0.48-0.89) and by 14% in men (OR, 0.86; 95% CI, 0.70-1.05; P interaction=0.23) compared with clopidogrel. Cangrelor reduced the odds of stent thrombosis by 61% in women (OR, 0.39; 95% CI, 0.20-0.77) and 16% in men (OR, 0.84; 95% CI, 0.53-1.33; P interaction=0.11). The odds of severe bleeding were similar in both women and men treated with cangrelor (0.3% versus 0.2%, P=0.30 [women]; 0.1% versus 0.1%, P=0.41 [men]; P interaction=0.88) versus clopidogrel. Cangrelor increased the odds of moderate bleeding in women (0.9% versus 0.3%, P=0.02), but not in men (0.2% versus 0.2%, P=0.68; P interaction=0.040). The net clinical benefit (primary efficacy and safety end point) favored cangrelor in both women (OR, 0.68; 95% CI, 0.50-0.92) and men (OR, 0.87; 95% CI, 0.71-1.06; P interaction=0.26).In CHAMPION PHOENIX, cangrelor reduced the odds of major adverse cardiovascular events and stent thrombosis in women and men and appeared to offer greater net clinical benefit than clopidogrel.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01156571.

    View details for DOI 10.1161/CIRCULATIONAHA.115.017300

    View details for PubMedID 26762525

    View details for PubMedCentralID PMC4894784

  • Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes DIABETES OBESITY & METABOLISM Fulcher, G., Matthews, D. R., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Mathieu, C., Woo, V., Wysham, C., Capuano, G., Desai, M., Shaw, W., Vercruysse, F., Meininger, G., Neal, B. 2016; 18 (1): 82-91

    Abstract

    To assess the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes enrolled in the CANagliflozin cardioVascular Assessment Study (CANVAS) who were on an incretin mimetic [dipeptidyl peptidase-4 (DPP-4) inhibitor or glucagon-like peptide-1 (GLP-1) receptor agonist].CANVAS is a double-blind, placebo-controlled study that randomized participants to canagliflozin 100 or 300 mg or placebo added to routine therapy. The present post hoc analysis assessed the efficacy and safety of canagliflozin 100 and 300 mg compared with placebo in subsets of patients from CANVAS who were taking background DPP-4 inhibitors or GLP-1 receptor agonists with or without other antihyperglycaemic agents at week 18.Of the 4330 patients in CANVAS, 316 were taking DPP-4 inhibitors and 95 were taking GLP-1 receptor agonists. At 18 weeks, canagliflozin 100 and 300 mg provided larger placebo-subtracted reductions in glycated haemoglobin (HbA1c) in patients taking DPP-4 inhibitors [-0.56% (95% confidence interval [CI]: -0.77, -0.35), and -0.75% (95% CI: -0.95, -0.54), respectively] and GLP-1 receptor agonists [-1.00% (95% CI: -1.35, -0.65), and -1.06% (95% CI: -1.43, -0.69), respectively]. Body weight and blood pressure (BP) reductions were seen with canagliflozin versus placebo in both subsets. Higher incidences of genital mycotic infections and osmotic diuresis-related adverse events (AEs) were seen with canagliflozin compared with placebo. The incidence of hypoglycaemia was numerically higher with canagliflozin versus placebo; nearly all events occurred in patients on background insulin or insulin secretagogues.In patients on background incretin mimetics, canagliflozin improved HbA1c, body weight and BP, with an increased incidence of AEs related to SGLT2 inhibition.

    View details for DOI 10.1111/dom.12589

    View details for Web of Science ID 000367233900011

  • Racial Differences in Quality of Anticoagulation Therapy for Atrial Fibrillation (from the TREAT-AF Study). The American journal of cardiology Yong, C., Azarbal, F., Abnousi, F., Heidenreich, P. A., Schmitt, S., Fan, J., Than, C. T., Ullal, A. J., Yang, F., Phibbs, C. S., Frayne, S. M., Ho, P. M., Shore, S., Mahaffey, K. W., Turakhia, M. P. 2016; 117 (1): 61-8

    Abstract

    The influence of race on quality of anticoagulation control is not well described. We examined the association between race, international normalized ratio (INR) monitoring intensity, and INR control in warfarin-treated patients with atrial fibrillation (AF). Using data from the Veterans Health Administration (VHA), we performed a retrospective cohort study of 184,161 patients with a new diagnosis of AF/flutter from 2004 to 2012 who received any VHA prescription within 90 days of diagnosis. The primary predictor was race, ascertained from multiple VHA and linked Medicare demographic files. The primary outcome was first-year and long-term time in therapeutic range (TTR) of INR 2.0 to 3.0. Secondary outcomes were INR monitoring intensity and warfarin persistence. Of the 116,021 patients who received warfarin in the cohort, INR monitoring intensity was similar across racial groups. However, TTR was lowest in blacks and highest in whites (first year 0.49 ± 0.23 vs 0.57 ± 0.21, p <0.001; long term 0.52 ± 0.20 vs 0.59 ± 0.18, p <0.001); 64% of whites and 49% of blacks had long-term TTR >55% (p <0.001). After adjusting for site and patient-level covariates, black race was associated with lower first-year and long-term TTRs (4.2% and 4.1% below the conditional mean, relative to whites; p <0.0001 for both). One-year warfarin persistence was slightly lower in blacks compared to whites (58% vs 60%, p <0.0001). In conclusion, in patients with AF anticoagulated with warfarin, differences in INR control are most evident among blacks, underscoring the need to determine if other types of intensive management or warfarin alternatives may be necessary to improve anticoagulation among vulnerable AF populations.

    View details for DOI 10.1016/j.amjcard.2015.09.047

    View details for PubMedID 26552504

  • High-degree atrioventricular block, asystole, and electro-mechanical dissociation complicating non-ST-segment elevation myocardial infarction AMERICAN HEART JOURNAL Pokorney, S. D., Radder, C., Schulte, P. J., Al-Khatib, S. M., Tricocci, P., Van de Werf, F., James, S. K., Cannon, C. P., Armstrong, P. W., White, H. D., Califf, R. M., Gibson, C. M., Giugliano, R. P., Wallentin, L., Mahaffey, K. W., Harrington, R. A., Newby, L. K., Piccini, J. P. 2016; 171 (1): 25-32

    Abstract

    Non-ST-segment myocardial infarction (NSTEMI) can be complicated by high-degree atrioventricular (AV) block, asystole, or electromechanical dissociation (EMD), but these events are not well characterized in the contemporary era. This analysis assesses the incidence of and factors associated with these dysrhythmias in acute NSTEMIs.Patients with NSTEMI in the EARLY ACS, PLATO, and TRACER trials were included in the pooled cohort (N = 29,677). Logistic regression was used to identify factors associated with in-hospital high-degree AV block and asystole or EMD, and Kaplan-Meier methods were used to assess mortality.High-degree AV block occurred in 112 (0.4%) patients, asystole in 157 (0.5%), and EMD in 38 (0.1%). Pacemakers were inserted in 241 patients (0.8%) during the index hospitalization: 30 (12%) for AV block. Among patients with high-degree AV block, we observed more frequent right coronary artery lesions (47% vs 29%). Age, diabetes, lower heart rate, and lower blood pressure were associated with high-degree AV block. Higher Killip class, ST-segment depression, prior myocardial infarction, and peripheral vascular disease were most strongly associated with asystole or EMD. Ten-day unadjusted survival was 90% for patients with high-degree AV block and 43% for those with asystole or EMD.Although high-degree AV block, asystole, and EMD were infrequent complications of NSTEMI, they were associated with substantial short-term mortality. Only 1 in 8 pacemakers placed in NSTEMI patients during the acute hospitalization was for high-degree AV block.

    View details for DOI 10.1016/j.ahj.2015.09.004

    View details for Web of Science ID 000367126200004

    View details for PubMedID 26699597

    View details for PubMedCentralID PMC4692180

  • Racial Differences in Quality of Anticoagulation Therapy for Atrial Fibrillation (from the TREAT-AF Study) AMERICAN JOURNAL OF CARDIOLOGY Yong, C., Azarbal, F., Abnousi, F., Heidenreich, P. A., Schmitt, S., Fan, J., Than, C. T., Ullal, A. J., Yang, F., Phibbs, C. S., Frayne, S. M., Ho, P. M., Shore, S., Mahaffey, K. W., Turakhia, M. P. 2016; 117 (1): 61-68

    Abstract

    The influence of race on quality of anticoagulation control is not well described. We examined the association between race, international normalized ratio (INR) monitoring intensity, and INR control in warfarin-treated patients with atrial fibrillation (AF). Using data from the Veterans Health Administration (VHA), we performed a retrospective cohort study of 184,161 patients with a new diagnosis of AF/flutter from 2004 to 2012 who received any VHA prescription within 90 days of diagnosis. The primary predictor was race, ascertained from multiple VHA and linked Medicare demographic files. The primary outcome was first-year and long-term time in therapeutic range (TTR) of INR 2.0 to 3.0. Secondary outcomes were INR monitoring intensity and warfarin persistence. Of the 116,021 patients who received warfarin in the cohort, INR monitoring intensity was similar across racial groups. However, TTR was lowest in blacks and highest in whites (first year 0.49 ± 0.23 vs 0.57 ± 0.21, p <0.001; long term 0.52 ± 0.20 vs 0.59 ± 0.18, p <0.001); 64% of whites and 49% of blacks had long-term TTR >55% (p <0.001). After adjusting for site and patient-level covariates, black race was associated with lower first-year and long-term TTRs (4.2% and 4.1% below the conditional mean, relative to whites; p <0.0001 for both). One-year warfarin persistence was slightly lower in blacks compared to whites (58% vs 60%, p <0.0001). In conclusion, in patients with AF anticoagulated with warfarin, differences in INR control are most evident among blacks, underscoring the need to determine if other types of intensive management or warfarin alternatives may be necessary to improve anticoagulation among vulnerable AF populations.

    View details for DOI 10.1016/j.amjcard.2015.09.047

    View details for Web of Science ID 000368048900010

  • Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF. Journal of the American Heart Association Pokorney, S. D., Piccini, J. P., Stevens, S. R., Patel, M. R., Pieper, K. S., Halperin, J. L., Breithardt, G., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Berkowitz, S. D., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2016; 5 (3)

    Abstract

    Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions.In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS2 score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P<0.0001) and age ≥75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P<0.0001) were associated with higher all-cause mortality. Multiple additional characteristics were independently associated with higher mortality, with decreasing creatinine clearance, chronic obstructive pulmonary disease, male sex, peripheral vascular disease, and diabetes being among the most strongly associated (model C-index 0.677).In a large population of patients anticoagulated for nonvalvular atrial fibrillation, ≈7 in 10 deaths were cardiovascular, whereas <1 in 10 deaths were caused by nonhemorrhagic stroke or systemic embolism. Optimal prevention and treatment of heart failure, renal impairment, chronic obstructive pulmonary disease, and diabetes may improve survival.URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00403767.

    View details for DOI 10.1161/JAHA.115.002197

    View details for PubMedID 26955859

  • The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. European heart journal O'Brien, E. C., Simon, D. N., Thomas, L. E., Hylek, E. M., Gersh, B. J., Ansell, J. E., Kowey, P. R., Mahaffey, K. W., Chang, P., Fonarow, G. C., Pencina, M. J., Piccini, J. P., Peterson, E. D. 2015; 36 (46): 3258-3264

    Abstract

    Therapeutic decisions in atrial fibrillation (AF) are often influenced by assessment of bleeding risk. However, existing bleeding risk scores have limitations.We sought to develop and validate a novel bleeding risk score using routinely available clinical information to predict major bleeding in a large, community-based AF population.We analysed data from Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), a prospective registry that enrolled incident and prevalent AF patients at 176 US sites. Using Cox proportional hazards regression, we identified factors independently associated with major bleeding among patients taking oral anticoagulation (OAC) over a median follow-up of 2 years (interquartile range = 1.6-2.5). We also created a numerical bedside risk score that included the five most predictive risk factors weighted according to their strength of association with major bleeding. The predictive performance of the full model, the simple five-item score, and two existing risk scores (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly, HAS-BLED, and anticoagulation and risk factors in atrial fibrillation, ATRIA) were then assessed in both the ORBIT-AF cohort and a separate clinical trial population, Rivaroxaban Once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET-AF).Among 7411 ORBIT-AF patients taking OAC, the rate of major bleeding was 4.0/100 person-years. The full continuous model (12 variables) and five-factor ORBIT risk score (older age [75+ years], reduced haemoglobin/haematocrit/history of anaemia, bleeding history, insufficient kidney function, and treatment with antiplatelet) both had good ability to identify those who bled vs. not (C-index 0.69 and 0.67, respectively). These scores both had similar discrimination, but markedly better calibration when compared with the HAS-BLED and ATRIA scores in an external validation population from the ROCKET-AF trial.The five-element ORBIT bleeding risk score had better ability to predict major bleeding in AF patients when compared with HAS-BLED and ATRIA risk scores. The ORBIT risk score can provide a simple, easily remembered tool to support clinical decision making.

    View details for DOI 10.1093/eurheartj/ehv476

    View details for PubMedID 26424865

    View details for PubMedCentralID PMC4670965

  • Lost to Follow-up and Withdrawal of Consent in Contemporary Global Cardiovascular Randomized Clinical Trials. Critical pathways in cardiology Rodriguez, F., Harrison, R. W., Wojdyla, D., Mahaffey, K. W. 2015; 14 (4): 150-153

    Abstract

    High rates of lost to follow-up (LTFU) and withdrawal of consent (WDC) may introduce uncertainty around the validity of the results of clinical trials. We sought to better understand published proportions of LTFU and WDC in large contemporary cardiovascular clinical trials.Large (>5000 randomized subjects) cardiovascular clinical trials published between 2007 and 2012 in N Engl J Med were systematically reviewed. Data regarding LTFU and WDC were extracted from the primary manuscripts and supplementary online material.Twenty-five published randomized trials were identified. Trials ranged in size from 5518 to 26449 subjects. All trials reported LTFU with 15 separately reporting WDC. The duration of follow-up ranged from 30 days to 6.2 years. The number of subjects LTFU ranged from 8 to 905, and the median proportion of subjects LTFU was 0.23% (interquartile range: 0.12%-0.58%). Individual LTFU proportions varied 300-fold, from 0.03% to 9.7%. Proportions of WDC ranged from 0.02% to 8.3%-a 400-fold difference-with a median of 1.1% (interquartile range: 0.2%-2.6%). WDC occurred more frequently than LTFU in all but 2 studies.Contemporary cardiovascular clinical trials typically have low proportions of LTFU or WDC, but some trials have approximately 10% of subjects with LTFU or WDC. WDC occurred more frequently than LTFU but was only reported in 60% of the trials. These results emphasize the need to standardize reporting of LTFU and WDC as important trial metrics of quality and to develop strategies to minimize their occurrence.

    View details for DOI 10.1097/HPC.0000000000000055

    View details for PubMedID 26569655

  • Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction. Journal of the American Society of Hypertension Kuznetsova, T., Haddad, F., Knez, J., Rosenberg-Hasson, Y., Sung, J., Cauwenberghs, N., Thijs, L., Karakikes, I., Maecker, H., Mahaffey, K. W., Wu, J. C., Staessen, J. A. 2015; 9 (12): 975-984 e3

    Abstract

    There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

    View details for DOI 10.1016/j.jash.2015.10.003

    View details for PubMedID 26565110

  • Cytokines profile in hypertensive patients with left ventricular remodeling and dysfunction JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION Kuznetsova, T., Haddad, F., Knez, J., Rosenberg-Hasson, Y., Sung, J., Cauwenberghs, N., Thijs, L., Karakikes, I., Maecker, H., Mahaffey, K. W., Wu, J. C., Staessen, J. A. 2015; 9 (12): 975-984

    Abstract

    There is strong evidence that inflammatory mediators play a key role in the progression to heart failure in patients with systemic hypertension (HTN). The present study aimed to identify a set of cytokines that are associated with early left ventricular (LV) remodeling and dysfunction as captured by echocardiography in patients with HTN in a cross-sectional case-control study nested within the FLEMish study on ENvironment, Genes and Health Outcome. We identified three groups of participants from the cohort: normotensive subjects (normotension; n = 30), HTN with normal LV structure and function (HTN [LV-]; n = 30), and HTN with evidence of adverse LV remodeling (HTN [LV+]; n = 50). We measured cytokines using a 63-plex Luminex platform. Using partial least squares-discriminant analysis, we constructed three latent variables from the measured cytokines that explained 35%-45% of the variance between groups. We identified five common cytokines (interleukin 18, monokine induced by gamma interferon, hepatocyte growth factor, epithelial neutrophil-activating peptide 78, and vascular endothelial growth factor D) with a stable signal which had a major impact on the construction of the latent variables. Among these cytokines, after adjustment for confounders, interleukin 18 remained significantly different between HTN participants with and without LV involvement (P = .02). Moreover, granulocyte-macrophage colony-stimulating factor and leptin showed a consistent upward trend in all HTN patients compared with normotensive subjects. In conclusion, in HTN patients with LV remodeling or/and dysfunction, we identified a set of cytokines strongly associated with LV maladaptation. We also found a distinct profile of inflammatory biomarkers that characterize HTN.

    View details for DOI 10.1016/j.jash.2015.10.003

    View details for Web of Science ID 000367214500014

    View details for PubMedID 26565110

  • Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin ROCKET AF Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Sherwood, M. W., Nessel, C. C., Hellkamp, A. S., Mahaffey, K. W., Piccini, J. P., Suh, E., Becker, R. C., Singer, D. E., Halperin, J. L., Hankey, G. J., Berkowitz, S. D., Fox, K. A., Patel, M. R. 2015; 66 (21): 2271-2281

    Abstract

    Gastrointestinal (GI) bleeding is a common complication of oral anticoagulation.This study evaluated GI bleeding in patients who received at least 1 dose of the study drug in the on-treatment arm of the ROCKET AF (Rivaroxaban Once-daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial.The primary outcome was adjudicated GI bleeding reported from first to last drug dose + 2 days. Multivariable modeling was performed with pre-specified candidate predictors.Of 14,236 patients, 684 experienced GI bleeding during follow-up. These patients were older (median age 75 years vs. 73 years) and less often female. GI bleeding events occurred in the upper GI tract (48%), lower GI tract (23%), and rectum (29%) without differences between treatment arms. There was a significantly higher rate of major or nonmajor clinical GI bleeding in rivaroxaban- versus warfarin-treated patients (3.61 events/100 patient-years vs. 2.60 events/100 patient-years; hazard ratio: 1.42; 95% confidence interval: 1.22 to 1.66). Severe GI bleeding rates were similar between treatment arms (0.47 events/100 patient-years vs. 0.41 events/100 patient-years; p = 0.39; 0.01 events/100 patient-years vs. 0.04 events/100 patient-years; p = 0.15, respectively), and fatal GI bleeding events were rare (0.01 events/100 patient-years vs. 0.04 events/100 patient-years; 1 fatal events vs. 5 fatal events total). Independent clinical factors most strongly associated with GI bleeding were baseline anemia, history of GI bleeding, and long-term aspirin use.In the ROCKET AF trial, rivaroxaban increased GI bleeding compared with warfarin. The absolute fatality rate from GI bleeding was low and similar in both treatment arms. Our results further illustrate the need for minimizing modifiable risk factors for GI bleeding in patients on oral anticoagulation.

    View details for DOI 10.1016/j.jacc.2015.09.024

    View details for Web of Science ID 000365099600001

    View details for PubMedID 26610874

  • Efficacy of Cangrelor in Lesions with High-Risk and Low-Risk Angiographic Characteristics: The CHAMPION PHOENIX trial Stone, G. W., Genereux, P., White, H. D., Gibson, C., Hamm, C., Mahaffey, K., Price, M. J., Prats, J., Harrington, R., Bhatt, D. L. ELSEVIER SCIENCE INC. 2015: B36–B37
  • Cangrelor Improves Ischemic Outcomes In Patients With Multivessel Disease And Single Vessel Disease Undergoing PCI: Insights From The CHAMPION PHOENIX Trial Abnousi, F., Sundaram, V., Prats, J., Deliargyris, E. N., Stone, G. W., Hamm, C., Steg, P. G., Gibson, C., White, H. D., Price, M. J., Yong, C., Desai, M., Harrington, R., Bhatt, D. L., Mahaffey, K. ELSEVIER SCIENCE INC. 2015: B35
  • Impact of cangrelor overdosing on bleeding complications in patients undergoing percutaneous coronary intervention: insights from the CHAMPION trials JOURNAL OF THROMBOSIS AND THROMBOLYSIS Angiolillo, D. J., Bhatt, D. L., Steg, P. G., Stone, G. W., White, H. D., Gibson, C. M., Hamm, C. W., Price, M. J., Prats, J., Liu, T., Mahaffey, K. W., Harrington, R. A. 2015; 40 (3): 317-322

    Abstract

    Overdosing of parenteral antithrombotic therapies can increase the risk of bleeding. Cangrelor is a potent intravenous platelet P2Y12 receptor antagonist with rapid onset and offset of action. In patients undergoing percutaneous coronary interventions (PCI), compared with control, cangrelor (30 µg/kg bolus, followed immediately by a 4 µg/kg per minute infusion for 2-4 h or until the conclusion of the index PCI, whichever was longer) reduces periprocedural thrombotic complications without an increase in major bleeding complications, although minor bleeding is increased. The impact of cangrelor overdosing on bleeding is unknown and represented the aim of this analysis. Patients with cangrelor overdosing were identified among safety population patients enrolled in the CHAMPION program (n = 25,107). Overdose was defined as administration of an excess >20 % of the bolus dose (30 μg/kg) and/or infusion rate (4 μg/kg per min). Bleeding complications were assessed. Among the safety analysis population in the CHAMPION program, 12,565 patients received cangrelor. A total of 36 overdosed cangrelor patients (0.29 %) were identified in this pooled analysis (20 with both bolus and infusion, 5 with bolus only, and 11 with infusion only). In the majority of patients, the dose did not exceed 2.5 times the recommended dose. Bleeding events were balanced between treatment arms and were consistent with those in the overall CHAMPION program. Only one overdosed patient experienced a serious bleed. There was no correlation between bleeding and magnitude of cangrelor overdose. In a large clinical trial program of patients undergoing PCI, cangrelor overdosing was rare and not associated with an increase in bleeding complications, an observation that may be attributed to its very short-half life and rapid offset of action.

    View details for DOI 10.1007/s11239-015-1233-3

    View details for Web of Science ID 000360193200010

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Journal of nuclear cardiology Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L. 2015; 22 (5): 1041-1144

    View details for DOI 10.1007/s12350-015-0209-1

    View details for PubMedID 26204990

  • Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: The Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). American heart journal Bansilal, S., Bloomgarden, Z., Halperin, J. L., Hellkamp, A. S., Lokhnygina, Y., Patel, M. R., Becker, R. C., Breithardt, G., Hacke, W., Hankey, G. J., Nessel, C. C., Singer, D. E., Berkowitz, S. D., Piccini, J. P., Mahaffey, K. W., Fox, K. A. 2015; 170 (4): 675-682 e8

    Abstract

    The prevalence of both atrial fibrillation (AF) and diabetes mellitus (DM) are rising, and these conditions often occur together. Also, DM is an independent risk factor for stroke in patients with AF. We aimed to examine the safety and efficacy of rivaroxaban vs warfarin in patients with nonvalvular AF and DM in a prespecified secondary analysis of the ROCKET AF trial.We stratified the ROCKET AF population by DM status, assessed associations with risk of outcomes by DM status and randomized treatment using Cox proportional hazards models, and tested for interactions between randomized treatments. For efficacy, primary outcomes were stroke (ischemic or hemorrhagic) or non-central nervous system embolism. For safety, the primary outcome was major or nonmajor clinically relevant bleeding.The 5,695 patients with DM (40%) in ROCKET AF were younger, were more obese, and had more persistent AF, but fewer had previous stroke (the CHADS2 score includes DM and stroke). The relative efficacy of rivaroxaban and warfarin for prevention of stroke and systemic embolism was similar in patients with (1.74 vs 2.14/100 patient-years, hazard ratio [HR] 0.82) and without (2.12 vs 2.32/100 patient-years, HR 0.92) DM (interaction P = .53). The safety of rivaroxaban vs warfarin regarding major bleeding (HRs 1.00 and 1.12 for patients with and without DM, respectively; interaction P = .43), major or nonmajor clinically relevant bleeding (HRs 0.98 and 1.09; interaction P = .17), and intracerebral hemorrhage (HRs 0.62 and 0.72; interaction P = .67) was independent of DM status. Adjusted exploratory analyses suggested 1.3-, 1.5-, and 1.9-fold higher 2-year rates of stroke, vascular mortality, and myocardial infarction in DM patients.The relative efficacy and safety of rivaroxaban vs warfarin was similar in patients with and without DM, supporting use of rivaroxaban as an alternative to warfarin in diabetic patients with AF.

    View details for DOI 10.1016/j.ahj.2015.07.006

    View details for PubMedID 26386791

  • Increased Heart Rate Is Associated With Higher Mortality in Patients With Atrial Fibrillation (AF): Results From the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) JOURNAL OF THE AMERICAN HEART ASSOCIATION Steinberg, B. A., Kim, S., Thomas, L., Fonarow, G. C., Gersh, B. J., Holmqvist, F., Hylek, E., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J. A., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 4 (9)

    Abstract

    Most patients with atrial fibrillation (AF) require rate control; however, the optimal target heart rate remains under debate. We aimed to assess rate control and subsequent outcomes among patients with permanent AF.We studied 2812 US outpatients with permanent AF in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation. Resting heart rate was measured longitudinally and used as a time-dependent covariate in multivariable Cox models of all-cause and cause-specific mortality during a median follow-up of 24 months. At baseline, 7.4% (n=207) had resting heart rate <60 beats per minute (bpm), 62% (n=1755) 60 to 79 bpm, 29% (n=817) 80 to 109 bpm, and 1.2% (n=33) ≥110 bpm. Groups did not differ by age, previous cerebrovascular disease, heart failure status, CHA2DS2-VASc scores, renal function, or left ventricular function. There were significant differences in race (P=0.001), sinus node dysfunction (P=0.004), and treatment with calcium-channel blockers (P=0.006) and anticoagulation (P=0.009). In analyses of continuous heart rates, lower heart rate ≤65 bpm was associated with higher all-cause mortality (adjusted hazard ratio [HR], 1.15 per 5-bpm decrease; 95% CI, 1.01 to 1.32; P=0.04). Similarly, increasing heart rate >65 bpm was associated with higher all-cause mortality (adjusted HR, 1.10 per 5-bpm increase; 95% CI, 1.05 to 1.15; P<0.0001). This relationship was consistent across endpoints and in a broader sensitivity analysis of permanent and nonpermanent AF patients.Among patients with permanent AF, there is a J-shaped relationship between heart rate and mortality. These data support current guideline recommendations, and clinical trials are warranted to determine optimal rate control.URL: http://clinicaltrials.gov/. Unique identifier: NCT01165710.

    View details for DOI 10.1161/JAHA.115.002031

    View details for Web of Science ID 000364152100007

    View details for PubMedID 26370445

  • Efficacy and Safety of Canagliflozin Used in Conjunction with Sulfonylurea in Patients with Type 2 Diabetes Mellitus: A Randomized, Controlled Trial. Diabetes therapy : research, treatment and education of diabetes and related disorders Fulcher, G., Matthews, D. R., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Weiss, R., Rosenstock, J., Capuano, G., Desai, M., Shaw, W., Vercruysse, F., Meininger, G., Neal, B. 2015; 6 (3): 289-302

    Abstract

    The efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, was evaluated in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on sulfonylurea monotherapy.The CANagliflozin cardioVascular Assessment Study (CANVAS) is a double-blind, placebo-controlled cardiovascular outcomes study that randomized participants to placebo or canagliflozin 100 or 300 mg once daily in addition to routine therapy. Participants in the CANVAS trial are men and women aged ≥30 years with T2DM and a history or high risk of cardiovascular disease, and inadequate glycemic control (glycated hemoglobin [HbA1c] ≥7.0% and ≤10.5%) on current antihyperglycemic therapies. The primary objective of this prespecified substudy was to assess change from baseline to 18 weeks in HbA1c among patients on sulfonylurea monotherapy.Of the 4330 patients enrolled in CANVAS, 127 met the entry criteria for the sulfonylurea monotherapy substudy (placebo, n = 45; canagliflozin 100 mg, n = 42; canagliflozin 300 mg, n = 40). At 18 weeks, placebo-subtracted changes (95% confidence interval) in HbA1c were -0.74% (-1.15, -0.33; P < 0.001) and -0.83% (-1.24, -0.42; P < 0.001) with canagliflozin 100 and 300 mg, respectively. Relative to placebo, canagliflozin 100 and 300 mg also decreased fasting plasma glucose (FPG; -2.1 mmol/L [-3.0, -1.2] and -2.7 mmol/L [-3.6, -1.7], respectively). Body weight was lower with canagliflozin 300 mg (-1.8% [-3.2, -0.4]; P = 0.014) but unchanged with canagliflozin 100 mg (-0.4% [-1.8, 1.0]; P = 0.557). Canagliflozin 300 mg increased hypoglycemia episodes compared to canagliflozin 100 mg and placebo (15%, 0%, and 4.4%, respectively). Adverse events (AEs) of male and female genital mycotic infections, pollakiuria, and thirst were more common with canagliflozin.Canagliflozin added to ongoing sulfonylurea monotherapy produced improvements in HbA1c, FPG, and body weight, with an increased incidence of AEs consistent with the mechanism of action of SGLT2 inhibition.Janssen Research & Development, LLC.ClinicalTrials.gov NCT01032629.

    View details for DOI 10.1007/s13300-015-0117-z

    View details for PubMedID 26081793

    View details for PubMedCentralID PMC4575303

  • Heart Failure is Associated With Worse Quality of Life and Survival But Similar Stroke Risk in Atrial Fibrillation Cherian, T. S., Shrader, P., Fonarow, G. C., Allen, L. A., Peterson, E. D., Piccini, J., Thomas, L., Kowey, P. R., Burton, P., Gersh, B. J., Mahaffey, K. W. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2015: S115–S116
  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L., Weintraub, W. S., Bozkurt, B., Fonarow, G. C., Hendel, R. C., Jacobs, J. P., Jneid, H. H., Kutcher, M. A., Lichtman, J. H., Smith, E. E., Tcheng, J. E., Wang, T. Y. 2015; 66 (4): 403-469
  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Circulation Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L. 2015; 132 (4): 302-361

    View details for DOI 10.1161/CIR.0000000000000156

    View details for PubMedID 25547519

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Cardiovascular Endpoints Data Standards). Journal of the American College of Cardiology Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L. 2015; 66 (4): 403-469

    View details for DOI 10.1016/j.jacc.2014.12.018

    View details for PubMedID 25553722

  • 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint Events in Clinical Trials A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Data Standards ( Writing Committee to Develop Cardiovascular Endpoints Data Standards) CIRCULATION Hicks, K. A., Tcheng, J. E., Bozkurt, B., Chaitman, B. R., Cutlip, D. E., Farb, A., Fonarow, G. C., Jacobs, J. P., Jaff, M. R., Lichtman, J. H., Limacher, M. C., Mahaffey, K. W., Mehran, R., Nissen, S. E., Smith, E. E., Targum, S. L., Weintraub, W. S., Bozkurt, B., Fonarow, G. C., Hendel, R. C., Jacobs, J. P., Jneid, H. H., Kutcher, M. A., Lichtman, J. H., Smith, E. E., Tcheng, J. E., Wang, T. Y. 2015; 132 (4): 302-361
  • Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial CIRCULATION Moe, S. M., Chertow, G. M., Parfrey, P. S., Kubo, Y., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Stolina, M., Dehmel, B., Goodman, W. G., Floege, J. 2015; 132 (1): 27-39

    Abstract

    Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events.This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99).Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

    View details for DOI 10.1161/CIRCULATIONAHA.114.013876

    View details for Web of Science ID 000357498100005

  • Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Circulation Moe, S. M., Chertow, G. M., Parfrey, P. S., Kubo, Y., Block, G. A., Correa-Rotter, R., Drüeke, T. B., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Stolina, M., Dehmel, B., Goodman, W. G., Floege, J. 2015; 132 (1): 27-39

    Abstract

    Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events.This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99).Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

    View details for DOI 10.1161/CIRCULATIONAHA.114.013876

    View details for PubMedID 26059012

  • Sex-Stratified Trends in Enrollment, Patient Characteristics, Treatment, and Outcomes Among Non-ST-Segment Elevation Acute Coronary Syndrome Patients Insights From Clinical Trials Over 17 Years CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Kragholm, K., Halim, S. A., Yang, Q., Schulte, P. J., Hochman, J. S., Melloni, C., Mahaffey, K. W., Moliterno, D. J., Harrington, R. A., White, H. D., Armstrong, P. W., Ohman, E. M., Van de Werf, F., Tricoci, P., Alexander, J. H., Giugliano, R. P., Newby, L. K. 2015; 8 (4): 357-367

    Abstract

    Adequate representation by sex in trials allows generalizability of results. We examined representation of women in clinical trials during a 17-year period in which inclusion criteria were broadened and federal mandates for representativeness were launched.Using mixed models, we studied sex-stratified temporal trends in enrollment, clinical characteristics, treatment, and outcomes among 76 148 non-ST-segment elevation acute coronary syndrome patients using patient-level data merged from 11 phase III trials conducted from 1994 to 2010. Overall, 33.3% of patients were women, which changed minimally over time. Women were consistently 4 to 5 years older than men (median age 68 [interquartile range 61-75] versus 64 [interquartile range 56-72] years) and more frequently had diabetes mellitus, hypertension, and heart failure; men more frequently had prior myocardial infarction and revascularization. GRACE risk scores increased over time for both sexes with the inclusion of older patients with more comorbidities. Use of percutaneous coronary intervention, in-hospital and discharge angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, β-blockers, and lipid-lowering drugs also increased among both sexes. Kaplan-Meier estimates of 6-month mortality declined from 7.0% [95% confidence interval 6.5%-7.6%] to 4.5% [95% confidence interval 4.0%-5.0%] among women and 6.3% [95% confidence interval 6.0%-6.7%] to 3.1% [95% confidence interval 2.9%-3.4%] among men during the 17-year period.The relative proportion of women in non-ST-segment elevation acute coronary syndrome trials changed minimally over time. Nevertheless, in parallel with men, use of evidence-based care and outcomes improved significantly over time among women.

    View details for DOI 10.1161/CIRCOUTCOMES.114.001615

    View details for Web of Science ID 000358214000007

    View details for PubMedCentralID PMC4512844

  • Cardiac Safety Research Consortium (CSRC): Cardiovascular Safety and Adverse Event Case Report Forms THERAPEUTIC INNOVATION & REGULATORY SCIENCE Sabol, M., Finkle, J., Krucoff, M., Stockbridge, N., Parkhill, N., Shinagawa, K., Mahaffey, K., Tcheng, J., Lenihan, D., Melloni, C., Todaro, T., Michelson, E., Munley, J., Zander, J., Oh, R. 2015; 49 (4): 511–13

    Abstract

    Detection of off-target cardiovascular (CV) effects remains a significant challenge to drug development. Documentation of CV events in non-CV trials is often inadequate to interpret imbalances between treatment arms, which may lead to concerns about potential CV safety "signals." The Cardiac Safety Research Consortium (CSRC) public-private partnership has developed CV case report forms (CRFs) for adverse CV events, including death. These CRFs are intended to encourage collection, as near to the occurrence of an event as possible, of the minimum information necessary to assess, or possibly adjudicate, the event. A broad range of stakeholders (representing industry, academia, and regulatory authorities) developed these forms with the goal of balancing the collection of key information with the resources likely to be available. Use of these forms is optional, and sponsors may modify them. These forms have not undergone any type of "validation" process. The CSRC will continue to sponsor a working group to invite public comment and feedback on these forms.

    View details for PubMedID 30222439

  • Association Between Atrial Fibrillation Symptoms, Quality of Life, and Patient Outcomes: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation. Cardiovascular quality and outcomes Freeman, J. V., Simon, D. N., Go, A. S., Spertus, J., Fonarow, G. C., Gersh, B. J., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L. E., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 8 (4): 393-402

    Abstract

    Instruments to assess symptom burden and quality of life among patients with atrial fibrillation (AF) have not been well evaluated in community practice or associated with patient outcomes.Using data from 10 087 AF patients in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), symptom severity was evaluated using the European Heart Rhythm Association (EHRA) classification system, and quality of life was assessed using the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire. The association between AF-related symptoms, quality of life, and outcomes was assessed using Cox regression. The majority of AF patients (61.8%) were symptomatic (EHRA >2) and 16.5% had severe or disabling symptoms (EHRA 3-4). EHRA symptom class was well correlated with the AFEQT score (Spearman correlation coefficient -0.39). Over 1.8 years of follow-up, AF symptoms were associated with a higher risk of hospitalization (adjusted hazard ratio for EHRA ≥2 versus EHRA 1 1.23, 95% confidence interval, 1.15-1.31) and a borderline higher risk of major bleeding. Lower quality of life was associated with a higher risk of hospitalization (adjusted hazard ratio for lowest quartile of AFEQT versus highest 1.49, 95% confidence interval, 1.2-1.84), but not other major adverse events, including death.In a community-based study, most patients with AF were symptomatic and had impaired quality of life. Quality of life measured by the AFEQT correlated closely with symptom severity measured by the EHRA class. AF symptoms and lower quality of life were associated with higher risk of hospitalization but not mortality during follow-up.

    View details for DOI 10.1161/CIRCOUTCOMES.114.001303

    View details for PubMedID 26058720

  • Sex-Stratified Trends in Enrollment, Patient Characteristics, Treatment, and Outcomes Among Non-ST-Segment Elevation Acute Coronary Syndrome Patients: Insights From Clinical Trials Over 17 Years. Circulation. Cardiovascular quality and outcomes Kragholm, K., Halim, S. A., Yang, Q., Schulte, P. J., Hochman, J. S., Melloni, C., Mahaffey, K. W., Moliterno, D. J., Harrington, R. A., White, H. D., Armstrong, P. W., Ohman, E. M., Van de Werf, F., Tricoci, P., Alexander, J. H., Giugliano, R. P., Newby, L. K. 2015; 8 (4): 357-367

    Abstract

    Adequate representation by sex in trials allows generalizability of results. We examined representation of women in clinical trials during a 17-year period in which inclusion criteria were broadened and federal mandates for representativeness were launched.Using mixed models, we studied sex-stratified temporal trends in enrollment, clinical characteristics, treatment, and outcomes among 76 148 non-ST-segment elevation acute coronary syndrome patients using patient-level data merged from 11 phase III trials conducted from 1994 to 2010. Overall, 33.3% of patients were women, which changed minimally over time. Women were consistently 4 to 5 years older than men (median age 68 [interquartile range 61-75] versus 64 [interquartile range 56-72] years) and more frequently had diabetes mellitus, hypertension, and heart failure; men more frequently had prior myocardial infarction and revascularization. GRACE risk scores increased over time for both sexes with the inclusion of older patients with more comorbidities. Use of percutaneous coronary intervention, in-hospital and discharge angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers, β-blockers, and lipid-lowering drugs also increased among both sexes. Kaplan-Meier estimates of 6-month mortality declined from 7.0% [95% confidence interval 6.5%-7.6%] to 4.5% [95% confidence interval 4.0%-5.0%] among women and 6.3% [95% confidence interval 6.0%-6.7%] to 3.1% [95% confidence interval 2.9%-3.4%] among men during the 17-year period.The relative proportion of women in non-ST-segment elevation acute coronary syndrome trials changed minimally over time. Nevertheless, in parallel with men, use of evidence-based care and outcomes improved significantly over time among women.

    View details for DOI 10.1161/CIRCOUTCOMES.114.001615

    View details for PubMedID 26152683

    View details for PubMedCentralID PMC4512844

  • Patients' time in therapeutic range on warfarin among US patients with atrial fibrillation: Results from ORBIT-AF registry AMERICAN HEART JOURNAL Pokorney, S. D., Simon, D. N., Thomas, L., Fonarow, G. C., Kowey, P. R., Chang, P., Singer, D. E., Ansell, J., Blanco, R. G., Gersh, B., Mahaffey, K. W., Hylek, E. M., Go, A. S., Piccini, J. P., Peterson, E. D. 2015; 170 (1): 141-U194

    Abstract

    Time in therapeutic range (TTR) of international normalized ratio (INR) of 2.0 to 3.0 is important for the safety and effectiveness of warfarin anticoagulation. There are few data on TTR among patients with atrial fibrillation (AF) in community-based clinical practice.Using the US Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF), we examined TTR (using a modified Rosendaal method) among 5,210 patients with AF on warfarin and treated at 155 sites. Patients were grouped into quartiles based on TTR data. Multivariable logistic regression modeling with generalized estimating equations was used to determine patient and provider factors associated with the lowest (worst) TTR.Overall, 59% of the measured INR values were between 2.0 and 3.0, with an overall mean and median TTR of 65% ± 20% and 68% (interquartile range [IQR] 53%-79%). The median times below and above the therapeutic range were 17% (IQR 8%-29%) and 10% (IQR 3%-19%), respectively. Patients with renal dysfunction, advanced heart failure, frailty, prior valve surgery, and higher risk for bleeding (ATRIA score) or stroke (CHA2DS2-VASc score) had significantly lower TTR (P < .0001 for all). Patients treated at anticoagulation clinics had only slightly higher median TTR (69%) than those not (66%) (P < .0001).Among patients with AF in US clinical practices, TTR on warfarin is suboptimal, and those at highest predicted risks for stroke and bleeding were least likely to be in therapeutic range.

    View details for DOI 10.1016/j.ahj.2015.03.017

    View details for Web of Science ID 000356452700018

    View details for PubMedID 26093875

  • Association Between Atrial Fibrillation Symptoms, Quality of Life, and Patient Outcomes Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Freeman, J. V., Simon, D. N., Go, A. S., Spertus, J., Fonarow, G. C., Gersh, B. J., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L. E., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 8 (4): 393-402

    Abstract

    Instruments to assess symptom burden and quality of life among patients with atrial fibrillation (AF) have not been well evaluated in community practice or associated with patient outcomes.Using data from 10 087 AF patients in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), symptom severity was evaluated using the European Heart Rhythm Association (EHRA) classification system, and quality of life was assessed using the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire. The association between AF-related symptoms, quality of life, and outcomes was assessed using Cox regression. The majority of AF patients (61.8%) were symptomatic (EHRA >2) and 16.5% had severe or disabling symptoms (EHRA 3-4). EHRA symptom class was well correlated with the AFEQT score (Spearman correlation coefficient -0.39). Over 1.8 years of follow-up, AF symptoms were associated with a higher risk of hospitalization (adjusted hazard ratio for EHRA ≥2 versus EHRA 1 1.23, 95% confidence interval, 1.15-1.31) and a borderline higher risk of major bleeding. Lower quality of life was associated with a higher risk of hospitalization (adjusted hazard ratio for lowest quartile of AFEQT versus highest 1.49, 95% confidence interval, 1.2-1.84), but not other major adverse events, including death.In a community-based study, most patients with AF were symptomatic and had impaired quality of life. Quality of life measured by the AFEQT correlated closely with symptom severity measured by the EHRA class. AF symptoms and lower quality of life were associated with higher risk of hospitalization but not mortality during follow-up.

    View details for DOI 10.1161/CIRCOUTCOMES.114.001303

    View details for Web of Science ID 000358214000011

  • Digoxin Use and Subsequent Outcomes Among Patients in a Contemporary Atrial Fibrillation Cohort JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Allen, L. A., Fonarow, G. C., Simon, D. N., Thomas, L. E., Marzec, L. N., Pokorney, S. D., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Chang, P., Peterson, E. D., Piccini, J. P. 2015; 65 (25): 2691-2698

    Abstract

    Although digoxin has long been used to treat atrial fibrillation (AF) and heart failure (HF), its safety remains controversial.This study sought to describe digoxin use over time in patients with AF who were stratified by the presence or absence of HF, to characterize the predictors of digoxin use and initiation, and to correlate digoxin use with outcomes.Longitudinal patterns of digoxin use and its association with a variety of outcomes were assessed in a prospective outpatient registry conducted at 174 U.S. sites with enrollment from June 2010 to August 2011.Among 9,619 patients with AF and serial follow-up every 6 months for up to 3 years, 2,267 (23.6%) received digoxin at study enrollment, 681 (7.1%) were initiated on digoxin during follow-up, and 6,671 (69.4%) were never prescribed digoxin. After adjusting for other medications, heart rate was 72.9 beats/min among digoxin users and 71.5 beats/min among nonusers (p < 0.0001). Prevalent digoxin use at registry enrollment was not associated with subsequent onset of symptoms, hospitalization, or mortality (in patients with HF, adjusted hazard ratio [HR] for death: 1.04; without HF, HR: 1.22). Incident digoxin use during follow-up was not associated with subsequent death in patients with HF (propensity adjusted HR: 1.05), but was associated with subsequent death in those without HF (propensity adjusted HR: 1.99).After adjustment for detailed clinical factors, digoxin use in registry patients with AF had a neutral association with outcomes under most circumstances. Because of the multiple conflicting observational reports about digoxin's safety and possible concerns in specific clinical situations, a large pragmatic trial of digoxin therapy in AF is needed.

    View details for DOI 10.1016/j.jacc.2015.04.045

    View details for Web of Science ID 000356775100003

    View details for PubMedID 26112191

    View details for PubMedCentralID PMC4483195

  • Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) LANCET Washam, J. B., Stevens, S. R., Lokhnygina, Y., Halperin, J. L., Breithardt, G., Singer, D. E., Mahaffey, K. W., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Fox, K. A., Califf, R. M., Piccini, J. P., Patel, M. R. 2015; 385 (9985): 2363-2370

    Abstract

    Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767.In 14,171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04-1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03-1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08-1·70, p=0·0076).Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed.Janssen Research & Development and Bayer HealthCare AG.

    View details for DOI 10.1016/S0140-6736(14)61836-5

    View details for Web of Science ID 000356003700029

    View details for PubMedID 25749644

  • Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial. Journal of the American Society of Nephrology Moe, S. M., Abdalla, S., Chertow, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Dehmel, B., Goodman, W. G., Drüeke, T. B. 2015; 26 (6): 1466-1475

    Abstract

    Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.

    View details for DOI 10.1681/ASN.2014040414

    View details for PubMedID 25505257

    View details for PubMedCentralID PMC4446874

  • The future of cardiovascular clinical research in North America and beyond-addressing challenges and leveraging opportunities through unique academic and grassroots collaborations. American heart journal Roe, M. T., Mahaffey, K. W., Ezekowitz, J. A., Alexander, J. H., Goodman, S. G., Hernandez, A., Temple, T., Berdan, L., Califf, R. M., Harrington, R. A., Peterson, E. D., Armstrong, P. W. 2015; 169 (6): 743-750

    Abstract

    Recent developments have highlighted the challenges facing cardiovascular clinical research in global contemporary practice, particularly in North America, including shifting priorities for drug development targets, increasing regulatory requirements, and expensive operational approaches for conducting randomized clinical trials. Nonetheless, emerging trends such as the consolidation of practices and hospitals into integrated health systems, the integration of electronic health records from thousands of practices into large data repositories to support prospective research studies, and streamlined operational approaches such as registry-based trials and risk-based monitoring have created numerous opportunities to disrupt the clinical research paradigm. Within this context, academic research organizations around the globe, particularly a strengthened collaboration of 3 established academic research organizations in North America, are uniquely positioned to promote and develop grassroots collaborations across all types of clinical practices, to delineate successful solutions to obstacles that limit clinical research initiatives, and to guide the future of cardiovascular research in the global research environment.

    View details for DOI 10.1016/j.ahj.2015.03.002

    View details for PubMedID 26027610

  • Effects of Cinacalcet on Fracture Events in Patients Receiving Hemodialysis: The EVOLVE Trial JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Moe, S. M., Abdalla, S., Chertow, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Wheeler, D. C., Dehmel, B., Goodman, W. G., Drueeke, T. B. 2015; 26 (6): 1466-1475

    Abstract

    Fractures are frequent in patients receiving hemodialysis. We tested the hypothesis that cinacalcet would reduce the rate of clinical fractures in patients receiving hemodialysis using data from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial, a placebo-controlled trial that randomized 3883 hemodialysis patients with secondary hyperparathyroidism to receive cinacalcet or placebo for ≤64 months. This study was a prespecified secondary analysis of the trial whose primary end point was all-cause mortality and non-fatal cardiovascular events, and one of the secondary end points was first clinical fracture event. Clinical fractures were observed in 255 of 1935 (13.2%) patients randomized to placebo and 238 of 1948 (12.2%) patients randomized to cinacalcet. In an unadjusted intention-to-treat analysis, the relative hazard for fracture (cinacalcet versus placebo) was 0.89 (95% confidence interval [95% CI], 0.75 to 1.07). After adjustment for baseline characteristics and multiple fractures, the relative hazard was 0.83 (95% CI, 0.72 to 0.98). Using a prespecified lag-censoring analysis (a measure of actual drug exposure), the relative hazard for fracture was 0.72 (95% CI, 0.58 to 0.90). When participants were censored at the time of cointerventions (parathyroidectomy, transplant, or provision of commercial cinacalcet), the relative hazard was 0.71 (95% CI, 0.58 to 0.87). Fracture rates were higher in older compared with younger patients and the effect of cinacalcet appeared more pronounced in older patients. In conclusion, using an unadjusted intention-to-treat analysis, cinacalcet did not reduce the rate of clinical fracture. However, when accounting for differences in baseline characteristics, multiple fractures, and/or events prompting discontinuation of study drug, cinacalcet reduced the rate of clinical fracture by 16%-29%.

    View details for DOI 10.1681/ASN.2014040414

    View details for Web of Science ID 000355386100024

    View details for PubMedCentralID PMC4446874

  • Magnitude of troponin elevation and long-term clinical outcomes in acute coronary syndrome patients treated with and without revascularization. Circulation. Cardiovascular interventions Bagai, A., Huang, Z., Lokhnygina, Y., Harrington, R. A., Armstrong, P. W., Strony, J., White, H. D., Leonardi, S., Held, C., Van de Werf, F., Wallentin, L., Tricoci, P., Mahaffey, K. W. 2015; 8 (6)

    Abstract

    In patients with non-ST-segment-elevation acute coronary syndrome (NSTE ACS), elevated troponin levels identify patients at high risk for adverse outcomes; however, it is unknown whether the magnitude of troponin elevation during hospitalization remains predictive of subsequent events in patients undergoing coronary revascularization.We studied 12 635 patients with NSTE ACS in the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) study with at least 1 troponin measurement during index hospitalization. Cox proportional hazards regression was used to examine the relationship between peak troponin level (standardized as the ratio of peak troponin value measured during hospitalization and local laboratory upper reference limit [URL]) and revascularization on all-cause mortality at 2 years. Revascularization (percutaneous coronary intervention or coronary artery bypass graft) was performed during index hospitalization in 8586 patients (68.0%); revascularized patients had higher peak troponin ratios (median, 23 versus 9.5× URL). Among patients that did not undergo revascularization, the mortality rate at 2 years increased in a curvilinear fashion with increasing levels of peak troponin. In contrast, the mortality rate at 2 years remained constant irrespective of peak troponin levels among revascularized patients (P for interaction=0.004). This relationship was unchanged after multivariable adjustment.There is a differential relationship between the magnitude of troponin elevation and long-term mortality in ACS patients treated with and without revascularization. Although prognostically important in patients treated without revascularization, the prognostic implications of peak troponin level seem to be minimal in revascularized patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00527943.

    View details for DOI 10.1161/CIRCINTERVENTIONS.115.002314

    View details for PubMedID 26025218

  • Meta-Analysis of Intracranial Hemorrhage in Acute Coronary Syndromes: Incidence, Predictors, and Clinical Outcomes JOURNAL OF THE AMERICAN HEART ASSOCIATION Mahaffey, K. W., Hager, R., Wojdyla, D., White, H. D., Armstrong, P. W., Alexander, J. H., Tricoci, P., Lopes, R. D., Ohman, E. M., Roe, M. T., Harrington, R. A., Wallentin, L. 2015; 4 (6)

    Abstract

    Little is known about the incidence, predictors, or outcomes of intracranial hemorrhage (ICH) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). We aimed to determine the incidence and timing of ICH, characterize the location of ICH, and identify independent baseline predictors of ICH in NSTE ACS patients.We pooled patient-level data from 4 contemporary antithrombotic therapy trials. Multivariable modeling identified independent predictors of ICH. ICHs were adjudicated by a clinical events committee. Of 37 815 patients, 135 (0.4%) had an ICH. The median (25th, 75th percentiles) follow-up was 332 (184, 434) days but differed across trials. Locations of ICH were intracerebral (50%), subdural (31%), subarachnoid (18.5%), and intraventricular (11%). Independent predictors of ICH were older age (HR per 10 years, 1.61; 95% CI, 1.35 to 1.91); prior stroke/transient ischemic attack; HR, 1.95; 95% CI, 1.14 to 3.35), higher systolic blood pressure; HR per 10 mm Hg increase, 1.09; 95% CI, 1.01 to 1.18), and larger number of antithrombotic agents (HR per each additional agent, 2.06; 95% CI, 1.49 to 2.84). Of all ICHs, 45 (33%) were fatal.In patients with NSTE ACS enrolled in recent clinical trials of antithrombotic therapies, ICH was uncommon. Patients with older age, prior transient ischemic attack/stroke, higher systolic blood pressure, or larger number of antithrombotic agents were at increased risk. One-third of patients with ICH died. These data may be useful to trialists and data and safety monitoring committees for trial conduct and monitoring.URL: https://www.clinicaltrials.gov/. Unique identifiers: TRACER: NCT00527943, PLATO: NCT00391872, APPRAISE-2: NCT00831441, TRILOGY ACS: NCT00699998.

    View details for DOI 10.1161/JAHA.114.001512

    View details for Web of Science ID 000357025100007

    View details for PubMedID 26089177

  • Heart rate is associated with progression of atrial fibrillation, independent of rhythm HEART Holmqvist, F., Kim, S., Steinberg, B. A., Reiffel, J. A., Mahaffey, K. W., Gersh, B. J., Fonarow, G. C., Naccarelli, G. V., Chang, P., Freeman, J. V., Kowey, P. R., Thomas, L., Peterson, E. D., Piccini, J. P. 2015; 101 (11): 894-899

    Abstract

    Atrial fibrillation (AF) often progresses from paroxysmal or persistent to more sustained forms, but the rate and predictors of AF progression in clinical practice are not well described.Using the Outcomes Registry for Better Informed Treatment of AF, we analysed the incidence and predictors of progression and tested the discrimination and calibration of the HATCH (hypertension, age, TIA/stroke, chronic obstructive pulmonary disease, heart failure) and CHA₂DS₂VASc scores for identifying AF progression.Among 6235 patients with paroxysmal or persistent AF at baseline, 1479 progressed, during follow-up (median 18 (IQR 12-24) months). These patients were older and had more comorbidities than patients who did not progress (CHADS₂ 2.3±1.3 vs 2.1±1.3, p<0.0001). At baseline, patients with AF progression were more often on a rate control as opposed to a rhythm control strategy (66 vs 56%, p<0.0001) and had higher heart rate (72(64-80) vs 68(60-76) bpm, p<0.0001). The strongest predictors of AF progression were AF on the baseline ECG (OR 2.30, 95% CI 1.95 to 2.73, p<0.0001) and increasing age (OR 1.16, 95% CI1.09 to 1.24, p<0.0001, per 10 increase), while patients with lower heart rate (OR 0.84, 95% CI 0.79 to 0.89, p<0.0001, per 10 decrease ≤80) were less likely to progress. There was no significant interaction between rhythm on baseline ECG and heart rate (p=0.71). The HATCH and CHA₂DS₂VASc scores had modest discriminatory power for AF progression (C-indices 0.55 (95% CI 0.53 to 0.58) and 0.55 (95% CI 0.52 to 0.57)).Within 1.5 years, almost a quarter of the patients with paroxysmal or persistent AF progress to a more sustained form. Progression is strongly associated with heart rate, and age.

    View details for DOI 10.1136/heartjnl-2014-307043

    View details for Web of Science ID 000354277600014

    View details for PubMedID 25732748

    View details for PubMedCentralID PMC4453487

  • Cardiovascular events in acute coronary syndrome patients with peripheral arterial disease treated with ticagrelor compared with clopidogrel: Data from the PLATO Trial EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY Patel, M. R., Becker, R. C., Wojdyla, D. M., Emanuelsson, H., Hiatt, W. R., Horrow, J., Husted, S., Mahaffey, K. W., Steg, P. G., Storey, R. F., Wallentin, L., James, S. K. 2015; 22 (6): 734-742

    Abstract

    To determine the effect of ticagrelor compared to clopidogrel in patients with peripheral artery disease (PAD) and acute coronary syndromes (ACS).PLATO (n = 18,624) was a multicentre, double-blind, randomized trial in ACS, that showed a 16% reduction in cardiovascular death (CV-death), myocardial infarction (MI) and stroke with ticagrelor compared with clopidogrel, without significant increase in overall major bleeding. We performed a post-hoc analysis of cardiovascular and bleeding outcomes in PLATO according to reported PAD status at baseline. At one year, CV death, MI or stroke occurred in 19.3% of patients with PAD (n = 1144) compared to 10.2% in patients without PAD (p < 0.001). The Kaplan-Meier one year event rate for the primary endpoint of CV death, MI or stroke in PAD patients treated with ticagrelor as compared with clopidogrel, was 18% vs 20.6% (HR: 0.85 95% CI 0.64-1.11; for PAD status by treatment interaction, p = 0.99) and for death from any cause 8.7% vs 11.9%, (HR: 0.74 95% CI 0.50-1.08; interaction p = 0.73). PLATO-defined major bleeding event rates at one year were 14.8% for ticagrelor compared to 17.9% for clopidogrel, (HR: 0.81 95% CI 0.59-1.10; interaction p = 0.09).PAD patients have a high rate of ischaemic and bleeding events post ACS. The reduction of CV death, MI or stroke with ticagrelor compared with clopidogrel in PAD patients was consistent with the overall trial result although it did not reach statistical significance. Overall major bleeding was similar between the therapies.

    View details for DOI 10.1177/2047487314533215

    View details for Web of Science ID 000354129500006

    View details for PubMedID 24830710

  • The future of cardiovascular clinical research in North America and beyond-addressing challenges and leveraging opportunities through unique academic and grassroots collaborations AMERICAN HEART JOURNAL Roe, M. T., Mahaffey, K. W., Ezekowitz, J. A., Alexander, J. H., Goodman, S. G., Hernandez, A., Temple, T., Berdan, L., Califf, R. M., Harrington, R. A., Peterson, E. D., Armstrong, P. W. 2015; 169 (6): 743-750

    Abstract

    Recent developments have highlighted the challenges facing cardiovascular clinical research in global contemporary practice, particularly in North America, including shifting priorities for drug development targets, increasing regulatory requirements, and expensive operational approaches for conducting randomized clinical trials. Nonetheless, emerging trends such as the consolidation of practices and hospitals into integrated health systems, the integration of electronic health records from thousands of practices into large data repositories to support prospective research studies, and streamlined operational approaches such as registry-based trials and risk-based monitoring have created numerous opportunities to disrupt the clinical research paradigm. Within this context, academic research organizations around the globe, particularly a strengthened collaboration of 3 established academic research organizations in North America, are uniquely positioned to promote and develop grassroots collaborations across all types of clinical practices, to delineate successful solutions to obstacles that limit clinical research initiatives, and to guide the future of cardiovascular research in the global research environment.

    View details for DOI 10.1016/j.ahj.2015.03.002

    View details for Web of Science ID 000355213300001

  • Glycoprotein IIb/IIIa Receptor Inhibitors in Combination With Vorapaxar, a Platelet Thrombin Receptor Antagonist, Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes (from the TRACER Trial) AMERICAN JOURNAL OF CARDIOLOGY Cornel, J. H., Tricoci, P., Lokhnygina, Y., Moliterno, D. J., Wallentin, L., Armstrong, P. W., Aylward, P. E., Clare, R. M., Chen, E., Leonardi, S., de Werf, F. V., White, H. D., Held, C., Strony, J., Mahaffey, K. W., Harrington, R. A. 2015; 115 (10): 1325-1332

    Abstract

    We evaluated the interaction between protease-activated receptor-1 antagonist vorapaxar and concomitant glycoprotein (GP) IIb/IIIa receptor inhibitors in patients with non-ST-segment elevation acute coronary syndromes who underwent PCI. In Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial, 12,944 patients with non-ST-segment elevation acute coronary syndromes were randomized to vorapaxar or placebo. Administration of GP IIb/IIIa receptor inhibitors was allowed at the treating physician's discretion. We investigated whether use of GP IIb/IIIa receptor inhibitors modified vorapaxar's effect on non-coronary artery bypass grafting (CABG)-related bleeding at 7 days and ischemic events at 30 days. In total, 7,455 patients underwent PCI during index hospitalization. Of these, 2,023 patients (27.1%) received inhibitors and 5,432 (72.9%) did not. Vorapaxar was associated with a numerically higher rate of non-CABG-related moderate/severe Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding at 7 days compared with placebo in those who did (1.3% vs 1.0%) and did not (0.6% vs 0.4%) receive GP IIb/IIIa receptor inhibitors. Ischemic end point rates at 30 days were not significantly lower with vorapaxar versus placebo. Increased rates of non-CABG GUSTO moderate/severe bleeding were observed in patients who received GP IIb/IIIa receptor inhibitors versus those who did not (adjusted hazard ratio [HR] 1.77, 95% confidence interval [CI] 0.43 to 7.35 in placebo arm; adjusted HR 2.02, 95% CI 0.62 to 6.61 in vorapaxar arm) and in those who received vorapaxar versus placebo (adjusted HR 1.54, 95% CI 0.36 to 6.56 in the GP IIb/IIIa group; adjusted HR 1.34, 95% CI 0.44 to 4.07 in the no-GP IIb/IIIa group). No interaction was found between vorapaxar and inhibitor use up to 7 days (P interaction = 0.89) nor at the end of the treatment (P interaction = 0.74); however, the event rate was low. Also, no interaction was observed for efficacy end points after PCI at 30 days or at the end of the treatment. In conclusion, GP IIb/IIIa receptor inhibitor use plus dual antiplatelet therapy in a population with non-ST-segment elevation myocardial infarction planned for PCI was frequent but did not interact with vorapaxar's efficacy or safety. Nonetheless, GP IIb/IIIa receptor inhibitors and vorapaxar were associated with increased bleeding risk, and their combined use may result in additive effects on bleeding rates.

    View details for DOI 10.1016/j.amjcard.2015.02.043

    View details for Web of Science ID 000354422500001

  • Glycoprotein IIb/IIIa Receptor Inhibitors in Combination With Vorapaxar, a Platelet Thrombin Receptor Antagonist, Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes (from the TRACER Trial). American journal of cardiology Cornel, J. H., Tricoci, P., Lokhnygina, Y., Moliterno, D. J., Wallentin, L., Armstrong, P. W., Aylward, P. E., Clare, R. M., Chen, E., Leonardi, S., Van de Werf, F., White, H. D., Held, C., Strony, J., Mahaffey, K. W., Harrington, R. A. 2015; 115 (10): 1325-1332

    Abstract

    We evaluated the interaction between protease-activated receptor-1 antagonist vorapaxar and concomitant glycoprotein (GP) IIb/IIIa receptor inhibitors in patients with non-ST-segment elevation acute coronary syndromes who underwent PCI. In Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial, 12,944 patients with non-ST-segment elevation acute coronary syndromes were randomized to vorapaxar or placebo. Administration of GP IIb/IIIa receptor inhibitors was allowed at the treating physician's discretion. We investigated whether use of GP IIb/IIIa receptor inhibitors modified vorapaxar's effect on non-coronary artery bypass grafting (CABG)-related bleeding at 7 days and ischemic events at 30 days. In total, 7,455 patients underwent PCI during index hospitalization. Of these, 2,023 patients (27.1%) received inhibitors and 5,432 (72.9%) did not. Vorapaxar was associated with a numerically higher rate of non-CABG-related moderate/severe Global Use of Strategies to Open Occluded Arteries (GUSTO) bleeding at 7 days compared with placebo in those who did (1.3% vs 1.0%) and did not (0.6% vs 0.4%) receive GP IIb/IIIa receptor inhibitors. Ischemic end point rates at 30 days were not significantly lower with vorapaxar versus placebo. Increased rates of non-CABG GUSTO moderate/severe bleeding were observed in patients who received GP IIb/IIIa receptor inhibitors versus those who did not (adjusted hazard ratio [HR] 1.77, 95% confidence interval [CI] 0.43 to 7.35 in placebo arm; adjusted HR 2.02, 95% CI 0.62 to 6.61 in vorapaxar arm) and in those who received vorapaxar versus placebo (adjusted HR 1.54, 95% CI 0.36 to 6.56 in the GP IIb/IIIa group; adjusted HR 1.34, 95% CI 0.44 to 4.07 in the no-GP IIb/IIIa group). No interaction was found between vorapaxar and inhibitor use up to 7 days (P interaction = 0.89) nor at the end of the treatment (P interaction = 0.74); however, the event rate was low. Also, no interaction was observed for efficacy end points after PCI at 30 days or at the end of the treatment. In conclusion, GP IIb/IIIa receptor inhibitor use plus dual antiplatelet therapy in a population with non-ST-segment elevation myocardial infarction planned for PCI was frequent but did not interact with vorapaxar's efficacy or safety. Nonetheless, GP IIb/IIIa receptor inhibitors and vorapaxar were associated with increased bleeding risk, and their combined use may result in additive effects on bleeding rates.

    View details for DOI 10.1016/j.amjcard.2015.02.043

    View details for PubMedID 25776457

  • The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial. Clinical journal of the American Society of Nephrology Parfrey, P. S., Drüeke, T. B., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Kubo, Y., Dehmel, B., Goodman, W. G., Chertow, G. M. 2015; 10 (5): 791-799

    Abstract

    The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients.Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups.In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

    View details for DOI 10.2215/CJN.07730814

    View details for PubMedID 25710802

  • Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation-Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) AMERICAN HEART JOURNAL Holmqvist, F., Guan, N., Zhu, Z., Kowey, P. R., Allen, L. A., Fonarow, G. C., Hylek, E. M., Mahaffey, K. W., Freeman, J. V., Chang, P., Holmes, D. N., Peterson, E. D., Piccini, J. P., Gersh, B. J. 2015; 169 (5): 647-U93

    Abstract

    Obstructive sleep apnea (OSA) is common in patients with atrial fibrillation (AF). Little is known about the impact of OSA on AF treatment and long-term outcomes. We studied whether patients with OSA have a greater likelihood of progressing to more persistent forms of AF or require more hospitalizations and/or worse outcomes compared with patients without OSA.A total of 10,132 patients were enrolled between June 2010 and August 2011 in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) and followed for up to 2 years. The prevalence of OSA and continuous positive airway pressure (CPAP) treatment was captured at baseline. The association between OSA and major cardiovascular outcomes was analyzed using multivariable hierarchical logistic regression modeling and Cox frailty regression model.Of the 10,132 patients with AF, 1,841 had OSA. Patients with OSA were more symptomatic (22% vs 16% severe/disabling symptoms; P < .0001) and more often on rhythm control therapy (35% vs 31%; P = .0037). In adjusted analyses, patients with OSA had higher risk of hospitalization (hazard ratio [HR], 1.12; 95% CI, 1.03-1.22; P = .0078), but no difference in the risks of death (HR, 0.94; 95% CI, 0.77-1.15; P = .54); the composite of CV death, myocardial infarction, and stroke/transient ischemic attack (HR, 1.07; 95% CI, 0.85-1.34; P = .57); major bleeding (HR, 1.18; 95% CI, 0.96-1.46; P = .11); or AF progression (HR, 1.06; 95% CI, 0.89-1.28; P = .51). Patients with OSA on CPAP treatment were less likely to progress to more permanent forms of AF compared with patients without CPAP (HR, 0.66; 95% CI, 0.46-0.94; P = .021).Compared with those without, AF patients with OSA have worse symptoms and higher risks of hospitalization, but similar mortality, major adverse cardiovascular outcome, and AF progression rates.NCT01165710 (http://www.clinicaltrials.gov).

    View details for DOI 10.1016/j.ahj.2014.12.024

    View details for Web of Science ID 000354172400011

    View details for PubMedID 25965712

  • Assessing the treatment effect in a randomized controlled trial with extensive non-adherence: the EVOLVE trial PHARMACEUTICAL STATISTICS Kubo, Y., Sterling, L. R., Parfrey, P. S., Gill, K., Mahaffey, K. W., Gioni, I., Trotman, M., Dehmel, B., Chertow, G. M. 2015; 14 (3): 242-251

    Abstract

    Intention-to-treat (ITT) analysis is widely used to establish efficacy in randomized clinical trials. However, in a long-term outcomes study where non-adherence to study drug is substantial, the on-treatment effect of the study drug may be underestimated using the ITT analysis. The analyses presented herein are from the EVOLVE trial, a double-blind, placebo-controlled, event-driven cardiovascular outcomes study conducted to assess whether a treatment regimen including cinacalcet compared with placebo in addition to other conventional therapies reduces the risk of mortality and major cardiovascular events in patients receiving hemodialysis with secondary hyperparathyroidism. Pre-specified sensitivity analyses were performed to assess the impact of non-adherence on the estimated effect of cinacalcet. These analyses included lag-censoring, inverse probability of censoring weights (IPCW), rank preserving structural failure time model (RPSFTM) and iterative parameter estimation (IPE). The relative hazard (cinacalcet versus placebo) of mortality and major cardiovascular events was 0.93 (95% confidence interval 0.85, 1.02) using the ITT analysis; 0.85 (0.76, 0.95) using lag-censoring analysis; 0.81 (0.70, 0.92) using IPCW; 0.85 (0.66, 1.04) using RPSFTM and 0.85 (0.75, 0.96) using IPE. These analyses, while not providing definitive evidence, suggest that the intervention may have an effect while subjects are receiving treatment. The ITT method remains the established method to evaluate efficacy of a new treatment; however, additional analyses should be considered to assess the on-treatment effect when substantial non-adherence to study drug is expected or observed.

    View details for DOI 10.1002/pst.1680

    View details for PubMedID 25851955

  • The Effects of Cinacalcet in Older and Younger Patients on Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Parfrey, P. S., Drueeke, T. B., Block, G. A., Correa-Rotter, R., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Kubo, Y., Dehmel, B., Goodman, W. G., Chertow, G. M. 2015; 10 (5): 791-799

    Abstract

    The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older (≥65 years, n=1005) and younger (<65 years, n=2878) patients.Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were >3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups.In the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

    View details for DOI 10.2215/CJN.07730814

    View details for Web of Science ID 000354144900011

    View details for PubMedCentralID PMC4422239

  • Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes care Neal, B., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Ways, K., Desai, M., Shaw, W., Capuano, G., Alba, M., Jiang, J., Vercruysse, F., Meininger, G., Matthews, D. 2015; 38 (3): 403-411

    Abstract

    There are limited data about the effects of sodium-glucose cotransporter 2 inhibitors when used with insulin. We report the efficacy and safety of canagliflozin in patients with type 2 diabetes using insulin.The CANagliflozin CardioVascular Assessment Study is a double-blind, placebo-controlled study that randomized participants to placebo, canagliflozin 100 mg, or canagliflozin 300 mg once daily, added to a range of therapies. The primary end point of this substudy was the change in HbA1c from baseline at 18 weeks among patients using insulin; 52-week effects were also examined.Individuals receiving insulin at baseline were randomized to receive placebo (n = 690), canagliflozin 100 mg (n = 692), or canagliflozin 300 mg (n = 690). These individuals were 66% male and had a median age of 63 years, mean HbA1c of 8.3% (67 mmol/mol), BMI of 33.1 kg/m(2), estimated glomerular filtration rate of 75 mL/min/1.73 m(2), fasting plasma glucose of 9.2 mmol/L, and a median daily insulin dose of 60 IU. Most individuals were using basal/bolus insulin. Reductions in HbA1c with canagliflozin 100 and 300 mg versus placebo were -0.62% (95% CI -0.69, -0.54; -6.8 mmol/mol [95% CI -7.5, -5.9]; P < 0.001) and -0.73% (95% CI -0.81, -0.65; -8.0 mmol/mol [95% CI -8.9, -7.1]; P < 0.001) at 18 weeks and -0.58% (95% CI -0.68, -0.48; -6.3 mmol/mol [95% CI -7.4, -5.2]) and -0.73% (95% CI -0.83, -0.63; -8.0 mmol/mol [95% CI -9.1, -6.9]) at 52 weeks. There were significant falls in fasting plasma glucose, body weight, and blood pressure at both time points and there was a greater incidence of hypoglycemia, genital mycotic infections, and hypovolemia with both canagliflozin doses.Canagliflozin added to insulin therapy improved glycemic control and decreased body weight. There was a greater frequency of several anticipated side effects, although few led to discontinuation of treatment.

    View details for DOI 10.2337/dc14-1237

    View details for PubMedID 25468945

  • Outcomes With Cangrelor Versus Clopidogrel on a Background of Bivalirudin Insights From the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) JACC-CARDIOVASCULAR INTERVENTIONS White, H. D., Bhatt, D. L., Gibson, C. M., Hamm, C. W., Mahaffey, K. W., Price, M. J., Steg, P. G., Stone, G. W., Cortese, B., Wilensky, M., Deliargyris, E. N., Liu, T., Prats, J., Harrington, R. A. 2015; 8 (3): 424-433

    Abstract

    The aim of this study was to examine the efficacy and bleeding outcomes of cangrelor in patients in the CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI]) who underwent percutaneous coronary intervention with bivalirudin.Cangrelor is a potent intravenous P2Y12 inhibitor with rapid onset and offset. In the CHAMPION PHOENIX, cangrelor compared with clopidogrel significantly reduced 48-h ischemic events including stent thrombosis, without increasing major bleeding. Bivalirudin has demonstrated ischemic outcomes similar to those with heparin plus glycoprotein IIb/IIIa inhibition, with reduced bleeding but increased early stent thrombosis.In the modified intent-to-treat population, 2,059 patients (18.8%) received bivalirudin, with 1,014 patients in the cangrelor treatment arm and 1,045 in the clopidogrel treatment arm.At 48 h, the primary endpoint of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis was lower with cangrelor versus clopidogrel (48 [4.7%] vs. 70 [6.7%]; odds ratio [OR]: 0.68, p = 0.047). Death was similar in both arms (2 [0.2%] vs. 2 [0.2%]). Myocardial infarction was reduced by cangrelor (37 [3.6%] vs. 59 [5.6%]; OR: 0.63, p = 0.03), as was death/myocardial infarction (39 [3.8%] vs. 61 [5.8%]; OR: 0.65, p = 0.04). Cangrelor was associated with a nonsignificant trend toward less stent thrombosis (7 [0.7%] vs. 15 [1.4%]; OR: 0.48, p = 0.10), which was evident within 2 h after percutaneous coronary intervention (p = 0.057). GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was similar in both arms (2 of 1,021 [0.2%] vs. 2 of 1,055 [0.2%]) as were other bleeding definitions and transfusions. Efficacy and safety results were consistent in patients with stable angina, non-ST-segment elevation acute coronary syndrome, and ST-segment elevation myocardial infarction (p for interaction: 0.62 and 0.29).Cangrelor may offer an attractive benefit risk profile when used in combination with bivalirudin.

    View details for DOI 10.1016/j.jcin.2014.09.025

    View details for Web of Science ID 000351221300014

    View details for PubMedID 25703887

  • Use and Outcomes Associated With Bridging During Anticoagulation Interruptions in Patients With Atrial Fibrillation: Findings From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Circulation Steinberg, B. A., Peterson, E. D., Kim, S., Thomas, L., Gersh, B. J., Fonarow, G. C., Kowey, P. R., Mahaffey, K. W., Sherwood, M. W., Chang, P., Piccini, J. P., Ansell, J. 2015; 131 (5): 488-494

    Abstract

    Temporary interruption of oral anticoagulation for procedures is often required, and some propose using bridging anticoagulation. However, the use and outcomes of bridging during oral anticoagulation interruptions in clinical practice are unknown.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry is a prospective, observational registry study of US outpatients with atrial fibrillation. We recorded incident temporary interruptions of oral anticoagulation for a procedure, including the use and type of bridging therapy. Outcomes included multivariable-adjusted rates of myocardial infarction, stroke or systemic embolism, major bleeding, cause-specific hospitalization, and death within 30 days. Of 7372 patients treated with oral anticoagulation, 2803 overall interruption events occurred in 2200 patients (30%) at a median follow-up of 2 years. Bridging anticoagulants were used in 24% (n=665), predominantly low-molecular-weight heparin (73%, n=487) and unfractionated heparin (15%, n=97). Bridged patients were more likely to have had prior cerebrovascular events (22% versus 15%; P=0.0003) and mechanical valve replacements (9.6% versus 2.4%; P<0.0001); however, there was no difference in CHA2DS2-VASc scores (scores ≥2 in 94% versus 95%; P=0.5). Bleeding events were more common in bridged than nonbridged patients (5.0% versus 1.3%; adjusted odds ratio, 3.84; P<0.0001). The incidence of myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days was also significantly higher in patients receiving bridging (13% versus 6.3%; adjusted odds ratio, 1.94; P=0.0001).Bridging anticoagulation is used in one quarter of anticoagulation interruptions and is associated with higher risk for bleeding and adverse events. These data do not support the use of routine bridging, and additional data are needed to identify best practices concerning anticoagulation interruptions.http://www.clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.114.011777

    View details for PubMedID 25499873

    View details for PubMedCentralID PMC4315748

  • Centralized adjudication of cardiovascular end points in cardiovascular and noncardiovascular pharmacologic trials: A report from the Cardiac Safety Research Consortium AMERICAN HEART JOURNAL Seltzer, J. H., Turner, J. R., Geiger, M. J., Rosano, G., Mahaffey, K. W., White, W. B., Sabol, M. B., Stockbridge, N., Sager, P. T. 2015; 169 (2): 197-204

    Abstract

    This white paper provides a summary of presentations and discussions at a cardiovascular (CV) end point adjudication think tank cosponsored by the Cardiac Safety Research Committee and the US Food and Drug Administration (FDA) that was convened at the FDA's White Oak headquarters on November 6, 2013. Attention was focused on the lack of clarity concerning the need for end point adjudication in both CV and non-CV trials: there is currently an absence of widely accepted academic or industry standards and a definitive regulatory policy on how best to structure and use clinical end point committees (CECs). This meeting therefore provided a forum for leaders in the fields of CV clinical trials and CV safety to develop a foundation of initial best practice recommendations for use in future CEC charters. Attendees included representatives from pharmaceutical companies, regulatory agencies, end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding when CV end point adjudication should be considered in trials conducted by cardiologists and by noncardiologists as well as detailing key issues in the composition of a CEC and its charter. In addition, it presents several recommended best practices for the establishment and operation of CECs. The science underlying CV event adjudication is evolving, and suggestions for additional areas of research will be needed to continue to advance this science. This manuscript does not constitute regulatory guidance.

    View details for DOI 10.1016/j.ahj.2014.11.003

    View details for Web of Science ID 000349212800003

  • Centralized adjudication of cardiovascular end points in cardiovascular and noncardiovascular pharmacologic trials: a report from the Cardiac Safety Research Consortium. American heart journal Seltzer, J. H., Turner, J. R., Geiger, M. J., Rosano, G., Mahaffey, K. W., White, W. B., Sabol, M. B., Stockbridge, N., Sager, P. T. 2015; 169 (2): 197-204

    Abstract

    This white paper provides a summary of presentations and discussions at a cardiovascular (CV) end point adjudication think tank cosponsored by the Cardiac Safety Research Committee and the US Food and Drug Administration (FDA) that was convened at the FDA's White Oak headquarters on November 6, 2013. Attention was focused on the lack of clarity concerning the need for end point adjudication in both CV and non-CV trials: there is currently an absence of widely accepted academic or industry standards and a definitive regulatory policy on how best to structure and use clinical end point committees (CECs). This meeting therefore provided a forum for leaders in the fields of CV clinical trials and CV safety to develop a foundation of initial best practice recommendations for use in future CEC charters. Attendees included representatives from pharmaceutical companies, regulatory agencies, end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding when CV end point adjudication should be considered in trials conducted by cardiologists and by noncardiologists as well as detailing key issues in the composition of a CEC and its charter. In addition, it presents several recommended best practices for the establishment and operation of CECs. The science underlying CV event adjudication is evolving, and suggestions for additional areas of research will be needed to continue to advance this science. This manuscript does not constitute regulatory guidance.

    View details for DOI 10.1016/j.ahj.2014.11.003

    View details for PubMedID 25641528

  • Higher risk of death and stroke in patients with persistent vs. paroxysmal atrial fibrillation: results from the ROCKET-AF Trial. European heart journal Steinberg, B. A., Hellkamp, A. S., Lokhnygina, Y., Patel, M. R., Breithardt, G., Hankey, G. J., Becker, R. C., Singer, D. E., Halperin, J. L., Hacke, W., Nessel, C. C., Berkowitz, S. D., Mahaffey, K. W., Fox, K. A., Califf, R. M., Piccini, J. P. 2015; 36 (5): 288-296

    Abstract

    Anticoagulation prophylaxis for stroke is recommended for at-risk patients with either persistent or paroxysmal atrial fibrillation (AF). We compared outcomes in patients with persistent vs. paroxysmal AF receiving oral anticoagulation.Patients randomized in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF) trial (n = 14 264) were grouped by baseline AF category: paroxysmal or persistent. Multivariable adjustment was performed to compare thrombo-embolic events, bleeding, and death between groups, in high-risk subgroups, and across treatment assignment (rivaroxaban or warfarin). Of 14 062 patients, 11 548 (82%) had persistent AF and 2514 (18%) had paroxysmal AF. Patients with persistent AF were marginally older (73 vs. 72, P = 0.03), less likely female (39 vs. 45%, P < 0.0001), and more likely to have previously used vitamin K antagonists (64 vs. 56%, P < 0.0001) compared with patients with paroxysmal AF. In patients randomized to warfarin, time in therapeutic range was similar (58 vs. 57%, P = 0.94). Patients with persistent AF had higher adjusted rates of stroke or systemic embolism (2.18 vs. 1.73 events per 100-patient-years, P = 0.048) and all-cause mortality (4.78 vs. 3.52, P = 0.006). Rates of major bleeding were similar (3.55 vs. 3.31, P = 0.77). Rates of stroke or systemic embolism in both types of AF did not differ by treatment assignment (rivaroxaban vs. warfarin, Pinteraction = 0.6).In patients with AF at moderate-to-high risk of stroke receiving anticoagulation, those with persistent AF have a higher risk of thrombo-embolic events and worse survival compared with paroxysmal AF.

    View details for DOI 10.1093/eurheartj/ehu359

    View details for PubMedID 25209598

    View details for PubMedCentralID PMC4313363

  • Effects of Cinacalcet on Atherosclerotic and Nonatherosclerotic Cardiovascular Events in Patients Receiving Hemodialysis: The EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Wheeler, D. C., London, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Dehmel, B., Drueeke, T. B., Floege, J., Kubo, Y., Mahaffey, K. W., Goodman, W. G., Moe, S. M., Trotman, M., Abdalla, S., Chertow, G. M., Herzog, C. A. 2015; 4 (1)
  • Efficacy and Safety of Vorapaxar in Non-ST-Segment Elevation Acute Coronary Syndrome Patients Undergoing Noncardiac Surgery. Journal of the American Heart Association van Diepen, S., Tricoci, P., Podder, M., Westerhout, C. M., Aylward, P. E., Held, C., Van de Werf, F., Strony, J., Wallentin, L., Moliterno, D. J., White, H. D., Mahaffey, K. W., Harrington, R. A., Armstrong, P. W. 2015; 4 (12)

    Abstract

    Perioperative antiplatelet agents potentially increase bleeding after non-ST-segment elevation (NSTE) acute coronary syndromes (ACS). The protease-activated receptor 1 antagonist vorapaxar reduced cardiovascular events and was associated with increased bleeding versus placebo in NSTE ACS, but its efficacy and safety in noncardiac surgery (NCS) remain unknown. We aimed to evaluate ischemic, bleeding, and long-term outcomes of vorapaxar in NCS after NSTE ACS.In the TRACER trial, 2202 (17.0%) patients underwent major or minor NCS after NSTE ACS over 1.5 years (median); continuing study treatment perioperatively was recommended. The primary ischemic end point for this analysis was cardiovascular death, myocardial infarction, stent thrombosis, or urgent revascularization within 30 days of NCS. Safety outcomes included 30-day NCS bleeding and GUSTO moderate/severe bleeding. Overall, 1171 vorapaxar and 1031 placebo patients underwent NCS. Preoperative aspirin and thienopyridine use was 96.8% versus 97.7% (P=0.235) and 89.1% versus 86.1% (P=0.036) for vorapaxar versus placebo, respectively. Within 30 days of NCS, no differences were observed in the primary ischemic end point between vorapaxar and placebo groups (3.4% versus 3.9%; adjusted odds ratio 0.81, 95% CI 0.50 to 1.33, P=0.41). Similarly, no differences in NCS bleeding (3.9% versus 3.4%; adjusted odds ratio 1.41, 95% CI 0.87 to 2.31, P=0.17) or GUSTO moderate/severe bleeding (4.2% versus 3.7%; adjusted odds ratio 1.15, 95% CI, 0.72 to 1.83, P=0.55) were observed. In a 30-day landmarked analysis, NCS patients had a higher long-term risk of the ischemic end point (adjusted hazard ratio 1.62, 95% CI 1.33 to 1.97, P<0.001) and GUSTO moderate/severe bleeding (adjusted hazard ratio 5.63, 95% CI 3.98 to 7.97, P<0.001) versus patients who did not undergo NCS, independent of study treatment.NCS after NSTE ACS is common and associated with more ischemic outcomes and bleeding. Vorapaxar after NSTE ACS was not associated with increased perioperative ischemic or bleeding events in patients undergoing NCS.

    View details for DOI 10.1161/JAHA.115.002546

    View details for PubMedID 26672080

    View details for PubMedCentralID PMC4845287

  • Alternative Calculations of Individual Patient Time in Therapeutic Range While Taking Warfarin: Results From the ROCKET AF Trial. Journal of the American Heart Association Singer, D. E., Hellkamp, A. S., Yuan, Z., Lokhnygina, Y., Patel, M. R., Piccini, J. P., Hankey, G. J., Breithardt, G., Halperin, J. L., Becker, R. C., Hacke, W., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2015; 4 (3)

    Abstract

    In the ROCKET AF (Rivaroxaban-Once-daily, oral, direct Factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) trial, marked regional differences in control of warfarin anticoagulation, measured as the average individual patient time in the therapeutic range (iTTR) of the international normalized ratio (INR), were associated with longer inter-INR test intervals. The standard Rosendaal approach can produce biased low estimates of TTR after an appropriate dose change if the follow-up INR test interval is prolonged. We explored the effect of alternative calculations of TTR that more immediately account for dose changes on regional differences in mean iTTR in the ROCKET AF trial.We used an INR imputation method that accounts for dose change. We compared group mean iTTR values between our dose change-based method with the standard Rosendaal method and determined that the differences between approaches depended on the balance of dose changes that produced in-range INRs ("corrections") versus INRs that were out of range in the opposite direction ("overshoots"). In ROCKET AF, the overall mean iTTR of 55.2% (Rosendaal) increased up to 3.1% by using the dose change-based approach, depending on assumptions. However, large inter-regional differences in anticoagulation control persisted.TTR, the standard measure of control of warfarin anticoagulation, depends on imputing daily INR values for the vast majority of follow-up days. Our TTR calculation method may better reflect the impact of warfarin dose changes than the Rosendaal approach. In the ROCKET AF trial, this dose change-based approach led to a modest increase in overall mean iTTR but did not materially affect the large inter-regional differences previously reported.ClinicalTrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/JAHA.114.001349

    View details for PubMedID 25736441

  • Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial EUROPEAN HEART JOURNAL Breithardt, G., Baumgartner, H., Berkowitz, S. D., Hellkamp, A. S., Piccini, J. P., Stevens, S. R., Lokhnygina, Y., Patel, M. R., Halperin, J. L., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2014; 35 (47): 3377-3385

    Abstract

    We investigated clinical characteristics and outcomes of patients with significant valvular disease (SVD) in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial.ROCKET AF excluded patients with mitral stenosis or artificial valve prostheses. We used Cox regression to adjust comparisons for potential confounders. Among 14 171 patients, 2003 (14.1%) had SVD; they were older and had more comorbidities than patients without SVD. The rate of stroke or systemic embolism with rivaroxaban vs. warfarin was consistent among patients with SVD [2.01 vs. 2.43%; hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.55-1.27] and without SVD (1.96 vs. 2.22%; HR 0.89, 95% CI 0.75-1.07; interaction P = 0.76). However, rates of major and non-major clinically relevant bleeding with rivaroxaban vs. warfarin were higher in patients with SVD (19.8% rivaroxaban vs. 16.8% warfarin; HR 1.25, 95% CI 1.05-1.49) vs. those without (14.2% rivaroxaban vs. 14.1% warfarin; HR 1.01, 95% CI 0.94-1.10; interaction P = 0.034), even when controlling for risk factors and potential confounders. In intracranial haemorrhage, there was no interaction between patients with and without SVD where the overall rate was lower among those randomized to rivaroxaban.Many patients with 'non-valvular atrial fibrillation' have significant valve lesions. Their risk of stroke is similar to that of patients without SVD after controlling for stroke risk factors. Efficacy of rivaroxaban vs. warfarin was similar in patients with and without SVD; however, the observed risk of bleeding was higher with rivaroxaban in patients with SVD but was the same among those without SVD. Atrial fibrillation patients with and without SVD experience the same stroke-preventive benefit of oral anticoagulants.

    View details for DOI 10.1093/eurheartj/ehu305

    View details for Web of Science ID 000346406800016

    View details for PubMedID 25148838

  • Effects of Cinacalcet on Atherosclerotic and Nonatherosclerotic Cardiovascular Events in Patients Receiving Hemodialysis: The EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Wheeler, D. C., London, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Dehmel, B., Drueeke, T. B., Floege, J., Kubo, Y., Mahaffey, K. W., Goodman, W. G., Moe, S. M., Trotman, M., Abdalla, S., Chertow, G. M., Herzog, C. A. 2014; 3 (6)

    Abstract

    Premature cardiovascular disease limits the duration and quality of life on long-term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial.EVOLVE was a randomized, double-blind, placebo-controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance.Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes.Unique identifier: NCT00345839. URL: ClinicalTrials.gov.

    View details for DOI 10.1161/JAHA.114.001363

    View details for Web of Science ID 000345067600025

  • Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: results from the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome trial. American heart journal Tricoci, P., Lokhnygina, Y., Huang, Z., Van de Werf, F., Cornel, J. H., Chen, E., Wallentin, L., Held, C., Aylward, P. E., Moliterno, D. J., Jennings, L. K., White, H. D., Armstrong, P. W., Harrington, R. A., Strony, J., Mahaffey, K. W. 2014; 168 (6): 869-77.e1

    Abstract

    Protease-activated receptor 1 antagonism with vorapaxar represents a novel strategy for platelet inhibition. In TRACER, vorapaxar was compared with placebo plus standard of care among 12,944 patients with non-ST-segment elevation acute coronary syndromes. We anticipated that most patients would have received clopidogrel as part of standard care. We investigated the modification of vorapaxar's effect associated with clopidogrel use over time.The marginal structural model method was used to estimate causal modification of vorapaxar effect by use of clopidogrel over time. The primary outcomes were the composite of cardiovascular death, myocardial infarction, or stroke and Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding. The event accrual period excluded the time during which clopidogrel was clinically warranted.Among 12,887 patients who received study medication, 11,117 (86.3%) received clopidogrel before randomization, of whom 38.5% stopped later in the trial (median time to stoppage 200 days with placebo; interquartile range [IQR] 14-367) (186 days with vorapaxar; IQR 17-366). In total, 1,770 (13.7%) patients were not on clopidogrel at randomization, of whom 47.8% started afterward (median time to start 2 days; IQR 2-4). During the period of event accrual, vorapaxar was associated with a 26% reduction in the composite of cardiovascular death, myocardial infarction, or stroke when used with clopidogrel (hazard ratio [HR] 0.74; 95% CI 0.60-0.91) and a 24% reduction when used without clopidogrel (HR 0.76; 95% CI 0.56-1.02) (interaction; P = .89). The hazard of Global Use of Strategies to Open Occluded Coronary Arteries bleeding with vorapaxar was not significantly different without clopidogrel (HR 1.33; 95% CI 0.81-2.20) or with clopidogrel (HR 1.09; 95% CI 0.76-1.56) (interaction; P = .53).We observed no interaction between vorapaxar and clopidogrel after non-ST-segment elevation acute coronary syndromes on efficacy or safety outcomes, supporting a complementary role of protease-activated receptor 1 and P2Y12 antagonism.

    View details for DOI 10.1016/j.ahj.2014.09.002

    View details for PubMedID 25458650

  • Effects of cinacalcet on atherosclerotic and nonatherosclerotic cardiovascular events in patients receiving hemodialysis: the EValuation Of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) trial. Journal of the American Heart Association Wheeler, D. C., London, G. M., Parfrey, P. S., Block, G. A., Correa-Rotter, R., Dehmel, B., Drüeke, T. B., Floege, J., Kubo, Y., Mahaffey, K. W., Goodman, W. G., Moe, S. M., Trotman, M., Abdalla, S., Chertow, G. M., Herzog, C. A. 2014; 3 (6)

    Abstract

    Premature cardiovascular disease limits the duration and quality of life on long-term hemodialysis. The objective of this study was to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms, risk factors for these events, and the effects of cinacalcet, using adjudicated data collected during the EValuation of Cinacalcet HCl Therapy to Lower CardioVascular Events (EVOLVE) Trial.EVOLVE was a randomized, double-blind, placebo-controlled clinical trial that randomized 3883 hemodialysis patients with moderate to severe secondary hyperparathyroidism to cinacalcet or matched placebo for up to 64 months. For this post hoc analysis, the outcome measure was fatal and nonfatal cardiovascular events reflecting atherosclerotic and nonatherosclerotic cardiovascular diseases. During the trial, 1518 patients experienced an adjudicated cardiovascular event, including 958 attributable to nonatherosclerotic disease. Of 1421 deaths during the trial, 768 (54%) were due to cardiovascular disease. Sudden death was the most frequent fatal cardiovascular event, accounting for 24.5% of overall mortality. Combining fatal and nonfatal cardiovascular events, randomization to cinacalcet reduced the rates of sudden death and heart failure. Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events (adjusted relative hazard 0.84, 95% CI 0.74 to 0.96), while the effect of cinacalcet on atherosclerotic events did not reach statistical significance.Accepting the limitations of post hoc analysis, any benefits of cinacalcet on cardiovascular disease in the context of hemodialysis may result from attenuation of nonatherosclerotic processes.Unique identifier: NCT00345839. URL: ClinicalTrials.gov.

    View details for DOI 10.1161/JAHA.114.001363

    View details for PubMedID 25404192

  • Vorapaxar with or without clopidogrel after non-ST-segment elevation acute coronary syndromes: Results from the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome trial AMERICAN HEART JOURNAL Tricoci, P., Lokhnygina, Y., Huang, Z., Van de Werf, F., Cornel, J. H., Chen, E., Wallentin, L., Held, C., Aylward, P. E., Moliterno, D. J., Jennings, L. K., White, H. D., Armstrong, P. W., Harrington, R. A., Strony, J., Mahaffey, K. W. 2014; 168 (6): 869-?

    Abstract

    Protease-activated receptor 1 antagonism with vorapaxar represents a novel strategy for platelet inhibition. In TRACER, vorapaxar was compared with placebo plus standard of care among 12,944 patients with non-ST-segment elevation acute coronary syndromes. We anticipated that most patients would have received clopidogrel as part of standard care. We investigated the modification of vorapaxar's effect associated with clopidogrel use over time.The marginal structural model method was used to estimate causal modification of vorapaxar effect by use of clopidogrel over time. The primary outcomes were the composite of cardiovascular death, myocardial infarction, or stroke and Global Use of Strategies to Open Occluded Coronary Arteries moderate or severe bleeding. The event accrual period excluded the time during which clopidogrel was clinically warranted.Among 12,887 patients who received study medication, 11,117 (86.3%) received clopidogrel before randomization, of whom 38.5% stopped later in the trial (median time to stoppage 200 days with placebo; interquartile range [IQR] 14-367) (186 days with vorapaxar; IQR 17-366). In total, 1,770 (13.7%) patients were not on clopidogrel at randomization, of whom 47.8% started afterward (median time to start 2 days; IQR 2-4). During the period of event accrual, vorapaxar was associated with a 26% reduction in the composite of cardiovascular death, myocardial infarction, or stroke when used with clopidogrel (hazard ratio [HR] 0.74; 95% CI 0.60-0.91) and a 24% reduction when used without clopidogrel (HR 0.76; 95% CI 0.56-1.02) (interaction; P = .89). The hazard of Global Use of Strategies to Open Occluded Coronary Arteries bleeding with vorapaxar was not significantly different without clopidogrel (HR 1.33; 95% CI 0.81-2.20) or with clopidogrel (HR 1.09; 95% CI 0.76-1.56) (interaction; P = .53).We observed no interaction between vorapaxar and clopidogrel after non-ST-segment elevation acute coronary syndromes on efficacy or safety outcomes, supporting a complementary role of protease-activated receptor 1 and P2Y12 antagonism.

    View details for DOI 10.1016/j.ahj.2014.09.002

    View details for Web of Science ID 000345506100009

  • Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes HEART Varenhorst, C., Alstrom, U., Braun, O. O., Storey, R. F., Mahaffey, K. W., Bertilsson, M., Cannon, C. P., Scirica, B. M., Himmelmann, A., James, S. K., Wallentin, L., Held, C. 2014; 100 (22): 1762-?

    Abstract

    To describe specific causes of death and evaluate whether bleeding events and infection contributed to mortality in all ticagrelor-treated and clopidogrel-treated patients with acute coronary syndromes.In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor significantly reduced rates of vascular and total death compared with clopidogrel. In the 905 patients who died postenrolment in the PLATO trial (n=18 624), reviewers, blinded to study treatment, subclassified direct causes of death and evaluated whether infection or bleeding events contributed to fatal events.Among vascular deaths, there were significantly fewer sudden deaths (63 (0.7%) vs 98 (1.1%), p<0.01) but no significant difference in deaths caused by acute myocardial infarction (179 (1.9%) vs 194 (2.1%), p=0.43) or heart failure (31 (0.3%) vs 42 (0.5%), p=0.20) with ticagrelor compared with clopidogrel. For non-vascular deaths, there was no difference between treatments in deaths directly caused by infection. Although, patients treated with ticagrelor were at lower risk for death where infection was either a direct cause or contributed to death (51 (0.5%) vs 76 (0.8%), HR 0.67 (0.47 to 0.95), p<0.05) but not for bleeding (42 (0.5%) vs 42 (0.5%), HR 0.99 (0.65 to 1.53), p=0.98).In this post hoc analysis, ticagrelor compared with clopidogrel reduced total and cardiovascular mortality, which appeared to be mainly mediated by a reduction in sudden death. Importantly, bleeding causing or contributing to death did not differ between treatments.NCT00391872 (http://www.clinicaltrial.gov).

    View details for DOI 10.1136/heartjnl-2014-305619

    View details for Web of Science ID 000345450400007

  • Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: Rationale and design of the ODYSSEY Outcomes trial AMERICAN HEART JOURNAL Schwartz, G. G., Bessac, L., Berdan, L. G., Bhatt, D. L., Bittner, V., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Rorick, T., Sasiela, W. J., Shirodaria, C., Szarek, M., Tamby, J., Tricoci, P., White, H., Zeiher, A., Steg, P. G. 2014; 168 (5): 682-689

    Abstract

    Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS.This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred.ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

    View details for DOI 10.1016/j.ahj.2014.07.028

    View details for Web of Science ID 000344434300010

  • Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. American heart journal Schwartz, G. G., Bessac, L., Berdan, L. G., Bhatt, D. L., Bittner, V., Diaz, R., Goodman, S. G., Hanotin, C., Harrington, R. A., Jukema, J. W., Mahaffey, K. W., Moryusef, A., Pordy, R., Roe, M. T., Rorick, T., Sasiela, W. J., Shirodaria, C., Szarek, M., Tamby, J. F., Tricoci, P., White, H., Zeiher, A., Steg, P. G. 2014; 168 (5): 682-9

    Abstract

    Following acute coronary syndrome (ACS), the risk for future cardiovascular events is high and is related to levels of low-density lipoprotein cholesterol (LDL-C) even within the setting of intensive statin treatment. Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates LDL receptor expression and circulating levels of LDL-C. Antibodies to PCSK9 can produce substantial and sustained reductions of LDL-C. The ODYSSEY Outcomes trial tests the hypothesis that treatment with alirocumab, a fully human monoclonal antibody to PCSK9, improves cardiovascular outcomes after ACS.This Phase 3 study will randomize approximately 18,000 patients to receive biweekly injections of alirocumab (75-150 mg) or matching placebo beginning 1 to 12 months after an index hospitalization for acute myocardial infarction or unstable angina. Qualifying patients are treated with atorvastatin 40 or 80 mg daily, rosuvastatin 20 or 40 mg daily, or the maximum tolerated and approved dose of one of these agents and fulfill one of the following criteria: LDL-C ≥ 70 mg/dL, non-high-density lipoprotein cholesterol ≥ 100 mg/dL, or apolipoprotein B ≥ 80 mg/dL. The primary efficacy measure is time to first occurrence of coronary heart disease death, acute myocardial infarction, hospitalization for unstable angina, or ischemic stroke. The trial is expected to continue until 1613 primary end point events have occurred with minimum follow-up of at least 2 years, providing 90% power to detect a 15% hazard reduction. Adverse events of special interest include allergic events and injection site reactions. Interim analyses are planned when approximately 50% and 75% of the targeted number of primary end points have occurred.ODYSSEY Outcomes will determine whether the addition of the PCSK9 antibody alirocumab to intensive statin therapy reduces cardiovascular morbidity and mortality after ACS.

    View details for DOI 10.1016/j.ahj.2014.07.028

    View details for PubMedID 25440796

  • Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes. Heart (British Cardiac Society) Varenhorst, C., Alström, U., Braun, O. Ö., Storey, R. F., Mahaffey, K. W., Bertilsson, M., Cannon, C. P., Scirica, B. M., Himmelmann, A., James, S. K., Wallentin, L., Held, C. 2014; 100 (22): 1762-9

    Abstract

    To describe specific causes of death and evaluate whether bleeding events and infection contributed to mortality in all ticagrelor-treated and clopidogrel-treated patients with acute coronary syndromes.In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor significantly reduced rates of vascular and total death compared with clopidogrel. In the 905 patients who died postenrolment in the PLATO trial (n=18 624), reviewers, blinded to study treatment, subclassified direct causes of death and evaluated whether infection or bleeding events contributed to fatal events.Among vascular deaths, there were significantly fewer sudden deaths (63 (0.7%) vs 98 (1.1%), p<0.01) but no significant difference in deaths caused by acute myocardial infarction (179 (1.9%) vs 194 (2.1%), p=0.43) or heart failure (31 (0.3%) vs 42 (0.5%), p=0.20) with ticagrelor compared with clopidogrel. For non-vascular deaths, there was no difference between treatments in deaths directly caused by infection. Although, patients treated with ticagrelor were at lower risk for death where infection was either a direct cause or contributed to death (51 (0.5%) vs 76 (0.8%), HR 0.67 (0.47 to 0.95), p<0.05) but not for bleeding (42 (0.5%) vs 42 (0.5%), HR 0.99 (0.65 to 1.53), p=0.98).In this post hoc analysis, ticagrelor compared with clopidogrel reduced total and cardiovascular mortality, which appeared to be mainly mediated by a reduction in sudden death. Importantly, bleeding causing or contributing to death did not differ between treatments.NCT00391872 (http://www.clinicaltrial.gov).

    View details for DOI 10.1136/heartjnl-2014-305619

    View details for PubMedID 24957530

  • Challenges and solutions to pre- and post-randomization subgroup analyses. Current cardiology reports Desai, M., Pieper, K. S., Mahaffey, K. 2014; 16 (10): 531-?

    Abstract

    Subgroup analyses are commonly performed in the clinical trial setting with the purpose of illustrating that the treatment effect was consistent across different patient characteristics or identifying characteristics that should be targeted for treatment. There are statistical issues involved in performing subgroup analyses, however. These have been given considerable attention in the literature for analyses where subgroups are defined by a pre-randomization feature. Although subgroup analyses are often performed with subgroups defined by a post-randomization feature--including analyses that estimate the treatment effect among compliers--discussion of these analyses has been neglected in the clinical literature. Such analyses pose a high risk of presenting biased descriptions of treatment effects. We summarize the challenges of doing all types of subgroup analyses described in the literature. In particular, we emphasize issues with post-randomization subgroup analyses. Finally, we provide guidelines on how to proceed across the spectrum of subgroup analyses.

    View details for DOI 10.1007/s11886-014-0531-2

    View details for PubMedID 25135344

  • Vorapaxar in patients with peripheral artery disease and acute coronary syndrome: insights from Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER). American heart journal Jones, W. S., Tricoci, P., Huang, Z., Moliterno, D. J., Harrington, R. A., Sinnaeve, P. R., Strony, J., Van de Werf, F., White, H. D., Held, C., Armstrong, P. W., Aylward, P. E., Chen, E., Patel, M. R., Mahaffey, K. W. 2014; 168 (4): 588-96

    Abstract

    In the TRACER trial, vorapaxar, a protease-activated receptor-1 antagonist, plus standard care in non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients did not significantly reduce the primary composite end point but reduced a key secondary end point and significantly increased bleeding. History of peripheral artery disease (PAD) was a risk-enrichment inclusion criterion. We investigated the efficacy and safety of vorapaxar in NSTE ACS patients with documented PAD.TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS.In total, 936 (7.2%) patients had a history of PAD. Ischemic events occurred more frequently among patients with PAD (25.3%) versus no PAD (12.2%, P < .001), and Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding was more common in PAD (9.1%) versus no PAD (5.0%, P = .004). Similar rates of the composite end point (cardiovascular death, myocardial infarction, or stroke) occurred in patients with PAD treated with vorapaxar and placebo (21.7% vs 24.8%, P interaction = .787). Patients with PAD treated with vorapaxar, when compared with placebo, also had a numerical reduction in peripheral revascularization procedures (8.1% vs 9.0%, P = .158) and a lower extremity amputation rate (0.9% vs 1.5%, P = .107). Vorapaxar increased Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding similarly in patients with PAD (hazard ratio 1.47, 95% CI 0.89-2.45) and without (hazard ratio 1.48, 95% CI 1.22-1.79; P interaction = .921).Patients with NSTE ACS and PAD were at increased risk for ischemic events. Lower rates of ischemic end points, peripheral revascularization, and amputation with vorapaxar did not reach statistical significance but warrant further investigation. Vorapaxar increased bleeding in both patients with and without PAD at a similar magnitude of risk.

    View details for DOI 10.1016/j.ahj.2014.06.017

    View details for PubMedID 25262270

  • Prognostic implications of creatine kinase-MB measurements in ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention AMERICAN HEART JOURNAL Bagai, A., Schulte, P. J., Granger, C. B., Mahaffey, K. W., Christenson, R. H., Bell, G., Lopes, R. D., Green, C. L., Lincoff, A. M., Armstrong, P. W., Roe, M. T. 2014; 168 (4): 503-?

    Abstract

    Peak creatine kinase (CK)-MB concentration is related to reperfusion success and clinical outcomes after fibrinolytic therapy for acute myocardial infarction. However, prognostic implications of CK-MB measurements after primary percutaneous coronary intervention (PCI), which provides more predictable and consistent reperfusion, are unknown.We pooled 2,042 primary PCI-treated ST-segment elevation myocardial infarction (STEMI) patients from 3 trials with serial core laboratory-determined CK-MB measurements; 1,799 patients (88.1%) who survived to 36 hours and had ≥4 CK-MB measurements were studied. Cox regression modeling was performed to quantify the association between peak CK-MB concentration (and area under the time-concentration curve [AUC]) and mortality at 6 months, and death or congestive heart failure at 90 days.The median (25th-75th percentiles) peak CK-MB concentration and AUC measurement through 36 hours were 239 (109-429) ng/mL and 4,263 (2,081-7,124) ng/(mL h), respectively. By multivariable analysis, peak CK-MB concentration and AUC measurement were independently associated with 6-month mortality (adjusted hazard ratio [HR] 1.15, 95% CI 1.05-1.25, per 100-ng/mL increase, P = .002; and adjusted HR 1.09, 95% CI 1.03-1.14, per 1,000-ng/[mL h] increase, P < .001, respectively) and 90-day death or congestive heart failure (adjusted HR 1.26, 95% CI 1.18-1.34, P < .001; and adjusted HR 1.15, 95% CI 1.11-1.19, P < .001, respectively).Peak CK-MB concentration and AUC measurement are independent predictors of 3- to 6-month cardiovascular outcomes in primary PCI-treated STEMI patients. Our findings guide application of these measurements as efficacy end points in early-phase studies evaluating new therapies for STEMI.

    View details for DOI 10.1016/j.ahj.2014.06.008

    View details for Web of Science ID 000343096900016

    View details for PubMedID 25262260

  • Reasons for warfarin discontinuation in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) AMERICAN HEART JOURNAL O'Brien, E. C., Simon, D. N., Allen, L. A., Singer, D. E., Fonarow, G. C., Kowey, P. R., Thomas, L. E., Ezekowitz, M. D., Mahaffey, K. W., Chang, P., Piccini, J. P., Peterson, E. D. 2014; 168 (4): 487-494

    Abstract

    Warfarin reduces thromboembolic risks in atrial fibrillation (AF), but therapeutic durability remains a concern.We used clinical data from ORBIT-AF, a nationwide outpatient AF registry conducted at 176 sites with follow-up data at 6 and 12 months, to examine longitudinal patterns of warfarin discontinuation. We estimated associations between patient and provider characteristics and report of any warfarin discontinuation using discrete time proportional odds models.Of 10,132 AF patients enrolled in ORBIT-AF from June 2010 to August 2011, 6,110 (60.3%) were prescribed warfarin, had follow-up data, and were not switched to an alternative oral anticoagulant enrolled from June 2010 to August 2011. Over 1 year, 617 patients (10.1% of baseline warfarin users) discontinued warfarin therapy. Among incident warfarin users (starting therapy within 1 year of baseline survey), warfarin discontinuation rates rose to 17.1%. The most commonly reported reasons for warfarin discontinuation were physician preference (47.7%), patient refusal/preference (21.1%), bleeding event (20.2%), frequent falls/frailty (10.8%), high bleeding risk (9.8%), and patient inability to adhere to/monitor therapy (4.7%). In multivariable analysis, the factors most strongly associated with warfarin discontinuation were bleeding hospitalization during follow-up (odds ratio 10.91, 95% CI 7.91-15.03), prior catheter ablation (1.83, 1.37-2.45), noncardiovascular/nonbleeding hospitalization (1.77, 1.40-2.24), cardiovascular hospitalization (1.64, 1.33-2.03), and permanent AF (0.25, 0.17-0.36).Discontinuation of warfarin is common among patients with AF, particularly among incident users. Warfarin is most commonly discontinued because of physician preference, patient refusal, and bleeding events.

    View details for DOI 10.1016/j.ahj.2014.07.002

    View details for Web of Science ID 000343096900014

  • Vorapaxar in patients with peripheral artery disease and acute coronary syndrome: Insights from Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) AMERICAN HEART JOURNAL Jones, W. S., Tricoci, P., Huang, Z., Moliterno, D. J., Harrington, R. A., Sinnaeve, P. R., Strony, J., Van de Werf, F., White, H. D., Held, C., Armstrong, P. W., Aylward, P. E., Chen, E., Patel, M. R., Mahaffey, K. W. 2014; 168 (4): 588-596

    Abstract

    In the TRACER trial, vorapaxar, a protease-activated receptor-1 antagonist, plus standard care in non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients did not significantly reduce the primary composite end point but reduced a key secondary end point and significantly increased bleeding. History of peripheral artery disease (PAD) was a risk-enrichment inclusion criterion. We investigated the efficacy and safety of vorapaxar in NSTE ACS patients with documented PAD.TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS.In total, 936 (7.2%) patients had a history of PAD. Ischemic events occurred more frequently among patients with PAD (25.3%) versus no PAD (12.2%, P < .001), and Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding was more common in PAD (9.1%) versus no PAD (5.0%, P = .004). Similar rates of the composite end point (cardiovascular death, myocardial infarction, or stroke) occurred in patients with PAD treated with vorapaxar and placebo (21.7% vs 24.8%, P interaction = .787). Patients with PAD treated with vorapaxar, when compared with placebo, also had a numerical reduction in peripheral revascularization procedures (8.1% vs 9.0%, P = .158) and a lower extremity amputation rate (0.9% vs 1.5%, P = .107). Vorapaxar increased Global Use of Strategies to Open Occluded Coronary Arteries moderate/severe bleeding similarly in patients with PAD (hazard ratio 1.47, 95% CI 0.89-2.45) and without (hazard ratio 1.48, 95% CI 1.22-1.79; P interaction = .921).Patients with NSTE ACS and PAD were at increased risk for ischemic events. Lower rates of ischemic end points, peripheral revascularization, and amputation with vorapaxar did not reach statistical significance but warrant further investigation. Vorapaxar increased bleeding in both patients with and without PAD at a similar magnitude of risk.

    View details for DOI 10.1016/j.ahj.2014.06.017

    View details for Web of Science ID 000343096900026

  • Challenges and Priorities for Research A Report From the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on Thrombosis in Pediatric Cardiology and Congenital Heart Disease CIRCULATION McCrindle, B. W., Li, J. S., Manlhiot, C., Tweddell, J. S., Giglia, T. M., Massicotte, M. P., Monagle, P., Krishnamurthy, R., Mahaffey, K. W., Michelson, A. D., Verdun, N., Almond, C. S., Newburger, J. W., Brandao, L. R., Esmon, C. T., Manco-Johnson, M. J., Ichord, R., Ortel, T. L., Chan, A. K., Portman, R., Rose, M., Strony, J., Kaltman, J. R. 2014; 130 (14): 1192-1203
  • Challenges and priorities for research: a report from the National Heart, Lung, and Blood Institute (NHLBI)/National Institutes of Health (NIH) Working Group on thrombosis in pediatric cardiology and congenital heart disease. Circulation McCrindle, B. W., Li, J. S., Manlhiot, C., Tweddell, J. S., Giglia, T. M., Massicotte, M. P., Monagle, P., Krishnamurthy, R., Mahaffey, K. W., Michelson, A. D., Verdun, N., Almond, C. S., Newburger, J. W., Brandão, L. R., Esmon, C. T., Manco-Johnson, M. J., Ichord, R., Ortel, T. L., Chan, A. K., Portman, R., Rose, M., Strony, J., Kaltman, J. R. 2014; 130 (14): 1192-203

    View details for DOI 10.1161/CIRCULATIONAHA.113.008428

    View details for PubMedID 25266860

  • Effect of Cangrelor on Ischemic Endpoints: Further Analyses from CHAMPION PHOENIX Bhatt, D. L., Stone, G. W., Mahaffey, K., Gibson, C., Steg, P. G., Hamm, C., Price, M. J., Liu, T., Deliargyris, E. N., Skerjanec, S., Prats, J., White, H. D., Harrington, R. ELSEVIER SCIENCE INC. 2014: B142
  • Vorapaxar, a platelet thrombin-receptor antagonist, in medically managed patients with non-ST-segment elevation acute coronary syndrome: results from the TRACER trial. European heart journal. Acute cardiovascular care Held, C., Tricoci, P., Huang, Z., Van de Werf, F., White, H. D., Armstrong, P. W., Ambrosio, G., Aylward, P. E., Moliterno, D. J., Wallentin, L., Chen, E., Erkan, A., Jiang, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 3 (3): 246-256

    Abstract

    This study characterized a medically managed population in a non-ST-segment elevation acute coronary syndrome (NSTEACS) cohort and evaluated prognosis and outcomes of vorapaxar vs. placebo.In the TRACER study, 12,944 NSTEACS patients were treated with standard care and vorapaxar (a novel platelet protease-activated receptor-1 antagonist) or placebo. Of those, 4194 patients (32.4%) did not undergo revascularization during index hospitalization, and 8750 (67.6%) underwent percutaneous coronary intervention or coronary artery bypass grafting. Patients managed medically were heterogeneous with different risk profiles, including 1137 (27.1%) who did not undergo coronary angiography. Patients who underwent angiography but were selected for medical management included those without evidence of significant coronary artery disease (CAD), with prior CAD but no new significant lesions, and with significant lesions who were not treated with revascularization.Cardiovascular event rates were highest among those without angiography and lowest in the group with angiography but without CAD. In the medically managed cohort, 2-year primary outcome (cardiovascular death, myocardial infarction, stroke, recurrent ischaemia with rehospitalization, urgent coronary revascularization) event rates were 16.3% with vorapaxar and 17.0% with placebo (HR 0.99, 95% CI 0.83-1.17), with no interaction between drug and management strategy (p=0.75). Key secondary endpoint (cardiovascular death, myocardial infarction, stroke) rates were 13.4% with vorapaxar and 14.9% with placebo (HR 0.89, 95% CI 0.74-1.07), with no interaction (p=0.58). Vorapaxar increased GUSTO moderate/severe bleeding numerically in medically managed patients (adjusted HR 1.46, 95% CI 0.99-2.15).NSTEACS patients who were initially medically managed had a higher risk-factor burden, and one-third had normal coronary arteries. Outcome in the medically managed cohort was significantly related to degree of CAD, highlighting the importance of coronary angiography. Efficacy and safety of vorapaxar appeared consistent with the overall trial results.

    View details for DOI 10.1177/2048872614527838

    View details for PubMedID 24627331

  • No misrepresentation of vital status follow-up in PLATO: Predefined analyses guarantee the integrity of the benefits of ticagrelor over clopidogrel in the PLATO trial Commentary on: DiNicolantonio JJ, Tomek A, Misrepresentation of vital status follow-up: Challenging the integrity of the PLATO trial and the claimed mortality benefit of ticagrelor versus clopidogrel, International Journal of Cardiology, 2013 Serebruany VL. Discrepancies in the primary PLATO trial publication and the FDA reviews, International Journal of Cardiology, 2014 INTERNATIONAL JOURNAL OF CARDIOLOGY Wallentin, L., Becker, R. C., Cannon, C. P., Held, C., Himmelmann, A., Husted, S., James, S. K., Katus, H. A., Mahaffey, K. M., Pieper, K. S., Storey, R. F., Steg, P., Harrington, R. A., PLATO Investigators 2014; 176 (1): 300–302

    View details for PubMedID 25005338

  • Usefulness and Safety of Vorapaxar in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention (from the TRACER Trial). American journal of cardiology Valgimigli, M., Tricoci, P., Huang, Z., Aylward, P. E., Armstrong, P. W., Van de Werf, F., Leonardi, S., White, H. D., Widimsky, P., Harrington, R. A., Cequier, A., Chen, E., Lokhnygina, Y., Wallentin, L., Strony, J., Mahaffey, K. W., Moliterno, D. J. 2014; 114 (5): 665-673

    Abstract

    The therapeutic potential of vorapaxar in patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention (PCI) is unknown. This prespecified analysis of a postrandomization subgroup evaluated the effects of vorapaxar compared with placebo among Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) participants undergoing PCI, focusing on the implanted stent type (drug-eluting stent [DES] vs bare-metal stent [BMS]). Among 12,944 recruited patients, 7,479 (57.8%) underwent PCI during index hospitalization, and 3,060 (40.9%) of those patients received exclusively BMS, whereas 4,015 (53.7%) received DES. The median (twenty-fifth, seventy-fifth percentiles) duration of thienopyridine therapy was 133 days (47, 246) with BMS and 221 days (88, 341) with DES. At 2 years among patients undergoing PCI, the primary (cardiovascular death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization) and secondary (cardiovascular death, myocardial infarction, or stroke) end points did not differ between vorapaxar and placebo groups, which was consistent with the treatment effect observed in the overall study population (p value for interaction = 0.540). However, the treatment effect trended greater (p value for interaction = 0.069) and the risk for bleeding in patients taking vorapaxar versus placebo appeared attenuated in BMS-only recipients. After adjustment for confounders, the interaction was no longer significant (p value = 0.301). The covariate that mostly explained the stent-type-by-treatment interaction was the duration of clopidogrel therapy. In conclusion, among patients with PCI, the effect of vorapaxar is consistent with the overall TRACER results. Patients who received a BMS underwent shorter courses of clopidogrel therapy and displayed trends toward greater ischemic benefit from vorapaxar and lesser bleeding risk, compared with patients who received a DES.

    View details for DOI 10.1016/j.amjcard.2014.05.054

    View details for PubMedID 25129064

  • Independent data monitoring committees: Preparing a path for the future. American heart journal Hess, C. N., Roe, M. T., Gibson, C. M., J Temple, R., Pencina, M. J., Zarin, D. A., Anstrom, K. J., Alexander, J. H., Sherman, R. E., Fiedorek, F. T., Mahaffey, K. W., Lee, K. L., Chow, S., Armstrong, P. W., Califf, R. M. 2014; 168 (2): 135-141 e1

    Abstract

    Independent data monitoring committees (IDMCs) were introduced to monitor patient safety and study conduct in randomized clinical trials (RCTs), but certain challenges regarding the utilization of IDMCs have developed. First, the roles and responsibilities of IDMCs are expanding, perhaps due to increasing trial complexity and heterogeneity regarding medical, ethical, legal, regulatory, and financial issues. Second, no standard for IDMC operating procedures exists, and there is uncertainty about who should determine standards and whether standards should vary with trial size and design. Third, considerable variability in communication pathways exist across IDMC interfaces with regulatory agencies, academic coordinating centers, and sponsors. Finally, there has been a substantial increase in the number of RCTs using IDMCs, yet there is no set of qualifications to help guide the training and development of the next generation of IDMC members. Recently, an expert panel of representatives from government, industry, and academia assembled at the Duke Clinical Research Institute to address these challenges and to develop recommendations for the future utilization of IDMCs in RCTs.

    View details for DOI 10.1016/j.ahj.2014.05.003

    View details for PubMedID 25066551

  • Long-term outcomes associated with hospital acquired thrombocytopenia among patients with non-ST-segment elevation acute coronary syndrome AMERICAN HEART JOURNAL Vora, A. N., Chenier, M., Schulte, P. J., Goodman, S., Peterson, E. D., Pieper, K., Jolicoeur, M. E., Mahaffey, K. W., White, H., Wang, T. Y. 2014; 168 (2): 189-?

    Abstract

    Acquired thrombocytopenia after a non-ST-segment-elevation-acute coronary syndrome (NSTE-ACS) has been associated with increased in-hospital mortality and hemorrhagic complications, but longer term outcomes are unclear. We examined the association between thrombocytopenia and long-term outcomes after accounting for thrombocytopenia severity and discharge medication use.Data from 7,435 NSTE-ACS patients enrolled in the SYNERGY trial were analyzed. Severe thrombocytopenia was defined as a nadir platelet count <100 × 10(9)/L or a ≥ 50% drop from baseline. Mild thrombocytopenia was defined as a nadir platelet count between 100 and 149 × 10(9)/L with a <50% drop from baseline. The primary outcomes of interest were in-hospital GUSTO moderate-severe bleeding and 1-year mortality.Overall, 675 patients (9.1%) developed mild thrombocytopenia and 139 patients (1.9%) developed severe thrombocytopenia. In-hospital bleeding risks were higher in patients with mild (7.7%, adjusted HR 1.63, 95% CI 1.16-2.29) or severe (28.2%, adjusted HR 6.93, 95% CI 4.55-10.56) thrombocytopenia than in patients without thrombocytopenia (5.2%). One-year mortality rates were 6.5%, 8.1%, and 28.1% among patients with no, mild, and severe thrombocytopenia, respectively (log rank P < 0.001) but only severe thrombocytopenia remained significantly associated with increased mortality after adjustment: HR 4.07, 95% CI 2.86-5.78. Patients who developed severe thrombocytopenia were less likely to be discharged on guideline-recommended antiplatelet therapy. The relationship between severe thrombocytopenia and mortality was attenuated by but persisted after adjusting for discharge medication use (HR 2.83, 95% CI 1.49-5.38).Thrombocytopenia occurs commonly during the course of NSTE-ACS care; even mild decreases are associated with clinically meaningful bleeding. Patients who developed severe thrombocytopenia were less likely to be discharged on guideline-recommended antiplatelet therapy; this may contribute to their higher associated long-term mortality.

    View details for DOI 10.1016/j.ahj.2014.04.010

    View details for Web of Science ID 000340207700013

    View details for PubMedID 25066558

  • Population Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Patients with Non-valvular Atrial Fibrillation: Results from ROCKET AF JOURNAL OF CLINICAL PHARMACOLOGY Girgis, I. G., Patel, M. R., Peters, G. R., Moore, K. T., Mahaffey, K. W., Nessel, C. C., Halperin, J. L., Califf, R. M., Fox, K. A., Becker, R. C. 2014; 54 (8): 917-927

    Abstract

    Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.

    View details for DOI 10.1002/jcph.288

    View details for Web of Science ID 000339163200013

    View details for PubMedID 24668660

  • Outcomes registry for better informed treatment of atrial fibrillation II: Rationale and design of the ORBIT-AF II registry. American heart journal Steinberg, B. A., Blanco, R. G., Ollis, D., Kim, S., Holmes, D. N., Kowey, P. R., Fonarow, G. C., Ansell, J., Gersh, B., Go, A. S., Hylek, E., Mahaffey, K. W., Thomas, L., Chang, P., Peterson, E. D., Piccini, J. P. 2014; 168 (2): 160-167

    Abstract

    Recent clinical trials have demonstrated the safety and efficacy of several non-vitamin K oral anticoagulants (NOACs) for the treatment of atrial fibrillation (AF). However, there are limited data on their use and outcomes in routine clinical practice, particularly among patients newly diagnosed as having AF and patients with AF recently transitioned to a NOAC.ORBIT-AF II is a multicenter, national registry of patients with AF that is enrolling up to 15,000 newly diagnosed patients with AF and/or those with AF recently transitioned to a NOAC from 300 US outpatient practices. These patients will be followed for up to 2 years, including clinical status, outcomes (major adverse cardiovascular events, bleeding), and management of anticoagulation surrounding bleeding events. In addition, detailed data regarding the use of these agents in and around cardiac procedures, their complications, and management of such complications will be collected.The ORBIT-AF II registry will provide valuable insights into the safety and effectiveness of NOACs used in AF in community practice settings.

    View details for DOI 10.1016/j.ahj.2014.04.005

    View details for PubMedID 25066554

  • Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. European heart journal Piccini, J. P., Garg, J., Patel, M. R., Lokhnygina, Y., Goodman, S. G., Becker, R. C., Berkowitz, S. D., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Nessel, C. C., Mahaffey, K. W., Singer, D. E., Califf, R. M., Fox, K. A. 2014; 35 (28): 1873-1880

    Abstract

    There are no data regarding management and outcomes of major bleeding events in patients treated with oral factor Xa inhibitors.Using data from ROCKET AF, we analysed the management and outcomes of major bleeding overall and according to the randomized treatment. During a median follow-up of 1.9 years, 779 (5.5%) patients experienced major bleeding at a rate of 3.52 events/100 patient-years with a similar event rate in each arm (n = 395 rivaroxaban vs. n = 384 warfarin). The median number of transfused packed red blood cells (PRBC) per episode was similar in both arms [2 (25th, 75th: 2, 4) units]. Overall, few transfusions of whole blood (n = 14), platelets (n = 10), or cryoprecipitate (n = 2) were used. Transfusion of fresh frozen plasma (FFP) was significantly less in the rivaroxaban arm (n = 45 vs. n = 81 units) after adjustment for covariates [odds ratio (OR) 0.43 (95% CI 0.29-0.66); P < 0.0001]. Prothrombin complex concentrates (PCC) were administered less in the rivaroxaban arm (n = 4 vs. n = 9). Outcomes after major bleeding, including stroke or non-central nervous system embolism (4.7% rivaroxaban vs. 5.4% warfarin; HR 0.89; 95% CI 0.42-1.88) and all-cause death (20.4% rivaroxaban vs. 26.1% warfarin; HR 0.69, 95% CI 0.46-1.04) were similar in patients treated with rivaroxaban and warfarin (interaction P = 0.51 and 0.11).Among high-risk patients with atrial fibrillation who experienced major bleeding in ROCKET AF, the use of FFP and PCC was less among those allocated rivaroxaban compared with warfarin. However, use of PRBCs and outcomes after bleeding were similar among patients randomized to rivaroxaban or to warfarin.

    View details for DOI 10.1093/eurheartj/ehu083

    View details for PubMedID 24658769

  • Efficacy and Safety of Rivaroxaban Compared With Warfarin Among Elderly Patients With Nonvalvular Atrial Fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) CIRCULATION Halperin, J. L., Hankey, G. J., Wojdyla, D. M., Piccini, J. P., Lokhnygina, Y., Patel, M. R., Breithardt, G., Singer, D. E., Becker, R. C., Hacke, W., Paolini, J. F., Nessel, C. C., Mahaffey, K. W., Califf, R. M., Fox, K. A. 2014; 130 (2): 138-U45

    Abstract

    Nonvalvular atrial fibrillation is common in elderly patients, who face an elevated risk of stroke but difficulty sustaining warfarin treatment. The oral factor Xa inhibitor rivaroxaban was noninferior to warfarin in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). This prespecified secondary analysis compares outcomes in older and younger patients.There were 6229 patients (44%) aged ≥75 years with atrial fibrillation and ≥2 stroke risk factors randomized to warfarin (target international normalized ratio=2.0-3.0) or rivaroxaban (20 mg daily; 15 mg if creatinine clearance <50 mL/min), double blind. The primary end point was stroke and systemic embolism by intention to treat. Over 10 866 patient-years, older participants had more primary events (2.57% versus 2.05%/100 patient-years; P=0.0068) and major bleeding (4.63% versus 2.74%/100 patient-years; P<0.0001). Stroke/systemic embolism rates were consistent among older (2.29% rivaroxaban versus 2.85% warfarin per 100 patient-years; hazard ratio=0.80; 95% confidence interval, 0.63-1.02) and younger patients (2.00% versus 2.10%/100 patient-years; hazard ratio=0.95; 95% confidence interval, 0.76-1.19; interaction P=0.313), as were major bleeding rates (≥75 years: 4.86% rivaroxaban versus 4.40% warfarin per 100 patient-years; hazard ratio=1.11; 95% confidence interval, 0.92-1.34; <75 years: 2.69% versus 2.79%/100 patient-years; hazard ratio=0.96; 95% confidence interval, 0.78-1.19; interaction P=0.336). Hemorrhagic stroke rates were similar in both age groups; there was no interaction between age and rivaroxaban response.Elderly patients had higher stroke and major bleeding rates than younger patients, but the efficacy and safety of rivaroxaban relative to warfarin did not differ with age, supporting rivaroxaban as an alternative for the elderly.

    View details for DOI 10.1161/CIRCULATIONAHA.113.005008

    View details for Web of Science ID 000338717500009

  • Efficacy and safety of rivaroxaban compared with warfarin among elderly patients with nonvalvular atrial fibrillation in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation Halperin, J. L., Hankey, G. J., Wojdyla, D. M., Piccini, J. P., Lokhnygina, Y., Patel, M. R., Breithardt, G., Singer, D. E., Becker, R. C., Hacke, W., Paolini, J. F., Nessel, C. C., Mahaffey, K. W., Califf, R. M., Fox, K. A. 2014; 130 (2): 138-146

    Abstract

    Nonvalvular atrial fibrillation is common in elderly patients, who face an elevated risk of stroke but difficulty sustaining warfarin treatment. The oral factor Xa inhibitor rivaroxaban was noninferior to warfarin in the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). This prespecified secondary analysis compares outcomes in older and younger patients.There were 6229 patients (44%) aged ≥75 years with atrial fibrillation and ≥2 stroke risk factors randomized to warfarin (target international normalized ratio=2.0-3.0) or rivaroxaban (20 mg daily; 15 mg if creatinine clearance <50 mL/min), double blind. The primary end point was stroke and systemic embolism by intention to treat. Over 10 866 patient-years, older participants had more primary events (2.57% versus 2.05%/100 patient-years; P=0.0068) and major bleeding (4.63% versus 2.74%/100 patient-years; P<0.0001). Stroke/systemic embolism rates were consistent among older (2.29% rivaroxaban versus 2.85% warfarin per 100 patient-years; hazard ratio=0.80; 95% confidence interval, 0.63-1.02) and younger patients (2.00% versus 2.10%/100 patient-years; hazard ratio=0.95; 95% confidence interval, 0.76-1.19; interaction P=0.313), as were major bleeding rates (≥75 years: 4.86% rivaroxaban versus 4.40% warfarin per 100 patient-years; hazard ratio=1.11; 95% confidence interval, 0.92-1.34; <75 years: 2.69% versus 2.79%/100 patient-years; hazard ratio=0.96; 95% confidence interval, 0.78-1.19; interaction P=0.336). Hemorrhagic stroke rates were similar in both age groups; there was no interaction between age and rivaroxaban response.Elderly patients had higher stroke and major bleeding rates than younger patients, but the efficacy and safety of rivaroxaban relative to warfarin did not differ with age, supporting rivaroxaban as an alternative for the elderly.

    View details for DOI 10.1161/CIRCULATIONAHA.113.005008

    View details for PubMedID 24895454

  • Use and outcomes of antiarrhythmic therapy in patients with atrial fibrillation receiving oral anticoagulation: Results from the ROCKET AF trial. Heart rhythm Steinberg, B. A., Hellkamp, A. S., Lokhnygina, Y., Halperin, J. L., Breithardt, G., Passman, R., Hankey, G. J., Patel, M. R., Becker, R. C., Singer, D. E., Hacke, W., Berkowitz, S. D., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Piccini, J. P. 2014; 11 (6): 925-932

    Abstract

    Antiarrhythmic drugs (AADs) and anticoagulation are mainstays of atrial fibrillation (AF) treatment.To study the use and outcomes of AAD therapy in anticoagulated patients with AF.Patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation trial (N = 14,264) were stratified by AAD use at baseline: amiodarone, other AAD, or no AAD. Multivariable adjustment was performed to compare stroke, bleeding, and death across AAD groups as well as across treatment assignment (rivaroxaban or warfarin).Of 14,264 patients randomized, 1681 (11.8%) were treated with an AAD (1144 [8%] with amiodarone and 537 [3.8%] with other AADs). Amiodarone-treated patients were less often female (38% vs 48%), had more persistent AF (64% vs 40%), and more concomitant heart failure (71% vs 41%) than were patients receiving other AADs. Patients receiving no AAD more closely resembled amiodarone-treated patients. Time in therapeutic range was significantly lower in warfarin-treated patients receiving amiodarone than in those receiving no AAD (50% vs 58%; P < .0001). Compared with no AAD, neither amiodarone (adjusted hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.74-1.31; P = .9) nor other AADs (adjusted HR 0.66; 95% CI 0.37-1.17; P = .15) were associated with increased mortality. Similar results were observed for embolic and bleeding outcomes. Treatment effects of rivaroxaban vs warfarin in patients receiving no AAD were consistent with results from the overall trial (primary end point: adjusted HR 0.82; 95% CI 0.68-0.98; Pinteraction = .06; safety end point: adjusted HR 1.12; 95% CI 0.90-1.24; Pinteraction = .33).Treatment with AADs was not associated with increased morbidity or mortality in anticoagulated patients with AF. The effect of amiodarone on outcomes in patients receiving rivaroxaban requires further investigation.

    View details for DOI 10.1016/j.hrthm.2014.03.006

    View details for PubMedID 24833235

    View details for PubMedCentralID PMC4035424

  • Comparison of clinical trial outcome patterns in patients following acute coronary syndromes and in patients with chronic stable atherosclerosis. Clinical cardiology Mahaffey, K. W., Wojdyla, D. M., Pieper, K. S., Tricoci, P., Alexander, J. H., Lincoff, A. M., Brennan, D. M., Bhatt, D. L., Wallentin, L., Harrington, R. A. 2014; 37 (6): 337-342

    Abstract

    The transition of patients with atherosclerotic vascular disease from the acute phase of the disease to the chronic stable atherosclerosis (CSA) phase has not been well characterized. We sought to compare ischemic and bleeding outcomes in hospitalized patients enrolled in clinical trials of non-ST-elevation acute coronary syndrome (ACS) with patients enrolled in outpatient trials of CSA.The risk for recurrent events will differ between the 2 populations.Patient-level outcome data were evaluated from 3 consecutive trials of patients with ACS with long-term follow-up and 2 trials of patients with CSA. Kaplan-Meier curves were generated for ischemic and bleeding outcomes.In total, 37 370 patients were included in these analyses. Of these, 28 489 (76.2%) were from ACS trials and 8881 (23.8%) from chronic trials. During the first year of follow-up, 1353 deaths, 1081 cardiovascular (CV) deaths, 2113 myocardial infarctions (MIs), and 397 strokes occurred across the trials. Six-month Kaplan-Meier event rates for CV death, MI, or stroke were higher in the ACS trials compared with the CSA trials (8.6% vs 2.7%), as were the 1-year CV death rate (3.6% vs 1.7%) and 1-year rates for GUSTO moderate or severe bleeding (6.0% vs 1.3%). Qualitatively, the Kaplan-Meier curves appear to show an early increased risk as well as a continued increased risk over time.Patients with ACS enrolled while in the hospital appear to have different risk profiles for ischemic and bleeding outcomes compared with outpatients enrolled with CSA, including those patients with ACS after the acute phase.

    View details for DOI 10.1002/clc.22255

    View details for PubMedID 24615711

  • Rivaroxaban for Stroke Prevention in East Asian Patients From the ROCKET AF Trial STROKE Wong, K. S., Hu, D. Y., Oomman, A., Tan, R., Patel, M. R., Singer, D. E., Breithardt, G., Mahaffey, K. W., Becker, R. C., Califf, R., Fox, K. A., Berkowitz, S. D., Hacke, W., Hankey, G. J. 2014; 45 (6): 1739-?

    Abstract

    In Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) trial, rivaroxaban was noninferior to dose-adjusted warfarin in preventing stroke or systemic embolism among patients with nonvalvular atrial fibrillation at moderate to high stroke risk. Because of differences in patient demographics, epidemiology, and stroke risk management in East Asia, outcomes and relative effects of rivaroxaban versus warfarin were assessed to determine consistency among East Asians versus other ROCKET AF participants.Baseline demographics and interaction of treatment effects of rivaroxaban and warfarin among patients within East Asia and outside were assessed.A total of 932 (6.5%) ROCKET AF participants resided in East Asia. At baseline, East Asians had lower weight, creatinine clearance, and prior vitamin K antagonist use; higher prevalence of prior stroke; and less congestive heart failure and prior myocardial infarction than other participants. Despite higher absolute event rates for efficacy and safety outcomes in East Asians, the relative efficacy of rivaroxaban (20 mg once daily; 15 mg once daily for creatinine clearance of 30-49 mL/min) versus warfarin with respect to the primary efficacy end point (stroke/systemic embolism) was consistent among East Asians and non-East Asians (interaction P=0.666). Relative event rates for the major or nonmajor clinically relevant bleeding in patients treated with rivaroxaban and warfarin were consistent among East Asians and non-East Asians (interaction P=0.867).Observed relative efficacy and safety of rivaroxaban versus warfarin were similar among patients within and outside East Asia. Rivaroxaban, 20 mg once daily, is an alternative to warfarin for stroke prevention in East Asians with nonvalvular atrial fibrillation.http://www.clinicaltrials.gov. Unique identifier: NCT00123456.

    View details for DOI 10.1161/STROKEAHA.113.002968

    View details for Web of Science ID 000337090700034

    View details for PubMedID 24763930

  • Comparison of Clinical Trial Outcome Patterns in Patients Following Acute Coronary Syndromes and in Patients With Chronic Stable Atherosclerosis CLINICAL CARDIOLOGY Mahaffey, K. W., Wojdyla, D. M., Pieper, K. S., Tricoci, P., Alexander, J. H., Lincoff, A. M., Brennan, D. M., Bhatt, D. L., Wallentin, L., Harrington, R. A. 2014; 37 (6): 337-342

    Abstract

    The transition of patients with atherosclerotic vascular disease from the acute phase of the disease to the chronic stable atherosclerosis (CSA) phase has not been well characterized. We sought to compare ischemic and bleeding outcomes in hospitalized patients enrolled in clinical trials of non-ST-elevation acute coronary syndrome (ACS) with patients enrolled in outpatient trials of CSA.The risk for recurrent events will differ between the 2 populations.Patient-level outcome data were evaluated from 3 consecutive trials of patients with ACS with long-term follow-up and 2 trials of patients with CSA. Kaplan-Meier curves were generated for ischemic and bleeding outcomes.In total, 37 370 patients were included in these analyses. Of these, 28 489 (76.2%) were from ACS trials and 8881 (23.8%) from chronic trials. During the first year of follow-up, 1353 deaths, 1081 cardiovascular (CV) deaths, 2113 myocardial infarctions (MIs), and 397 strokes occurred across the trials. Six-month Kaplan-Meier event rates for CV death, MI, or stroke were higher in the ACS trials compared with the CSA trials (8.6% vs 2.7%), as were the 1-year CV death rate (3.6% vs 1.7%) and 1-year rates for GUSTO moderate or severe bleeding (6.0% vs 1.3%). Qualitatively, the Kaplan-Meier curves appear to show an early increased risk as well as a continued increased risk over time.Patients with ACS enrolled while in the hospital appear to have different risk profiles for ischemic and bleeding outcomes compared with outpatients enrolled with CSA, including those patients with ACS after the acute phase.

    View details for DOI 10.1002/clc.22255

    View details for Web of Science ID 000337597900003

  • Lack of concordance between empirical scores and physician assessments of stroke and bleeding risk in atrial fibrillation: results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. Circulation Steinberg, B. A., Kim, S., Thomas, L., Fonarow, G. C., Hylek, E., Ansell, J., Go, A. S., Chang, P., Kowey, P., Gersh, B. J., Mahaffey, K. W., Singer, D. E., Piccini, J. P., Peterson, E. D. 2014; 129 (20): 2005-2012

    Abstract

    Physicians treating patients with atrial fibrillation (AF) must weigh the benefits of anticoagulation in preventing stroke versus the risk of bleeding. Although empirical models have been developed to predict such risks, the degree to which these coincide with clinicians' estimates is unclear.We examined 10 094 AF patients enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry between June 2010 and August 2011. Empirical stroke and bleeding risks were assessed by using the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and previous stroke or transient ischemic attack (CHADS2) and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) scores, respectively. Separately, physicians were asked to categorize their patients' stroke and bleeding risks: low risk (<3%); intermediate risk (3%-6%); and high risk (>6%). Overall, 72% (n=7251) in ORBIT-AF had high-risk CHADS2 scores (≥2). However, only 16% were assessed as high stroke risk by physicians. Although 17% (n=1749) had high ATRIA bleeding risk (score ≥5), only 7% (n=719) were considered so by physicians. The associations between empirical and physician-estimated stroke and bleeding risks were low (weighted Kappa 0.1 and 0.11, respectively). Physicians weighed hypertension, heart failure, and diabetes mellitus less significantly than empirical models in estimating stroke risk; physicians weighted anemia and dialysis less significantly than empirical models when estimating bleeding risks. Anticoagulation use was highest among patients with high stroke risk, assessed by either empirical model or physician estimates. In contrast, physician and empirical estimates of bleeding had limited impact on treatment choice.There is little agreement between provider-assessed risk and empirical scores in AF. These differences may explain, in part, the current divergence of anticoagulation treatment decisions from guideline recommendations.http://www.clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.114.008643

    View details for PubMedID 24682387

  • Lack of Concordance Between Empirical Scores and Physician Assessments of Stroke and Bleeding Risk in Atrial Fibrillation: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation Steinberg, B. A., Kim, S., Thomas, L., Fonarow, G. C., Hylek, E., Ansell, J., Go, A. S., Chang, P., Kowey, P., Gersh, B. J., Mahaffey, K. W., Singer, D. E., Piccini, J. P., Peterson, E. D. 2014; 129 (20): 2005-2012

    Abstract

    Physicians treating patients with atrial fibrillation (AF) must weigh the benefits of anticoagulation in preventing stroke versus the risk of bleeding. Although empirical models have been developed to predict such risks, the degree to which these coincide with clinicians' estimates is unclear.We examined 10 094 AF patients enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) registry between June 2010 and August 2011. Empirical stroke and bleeding risks were assessed by using the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and previous stroke or transient ischemic attack (CHADS2) and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) scores, respectively. Separately, physicians were asked to categorize their patients' stroke and bleeding risks: low risk (<3%); intermediate risk (3%-6%); and high risk (>6%). Overall, 72% (n=7251) in ORBIT-AF had high-risk CHADS2 scores (≥2). However, only 16% were assessed as high stroke risk by physicians. Although 17% (n=1749) had high ATRIA bleeding risk (score ≥5), only 7% (n=719) were considered so by physicians. The associations between empirical and physician-estimated stroke and bleeding risks were low (weighted Kappa 0.1 and 0.11, respectively). Physicians weighed hypertension, heart failure, and diabetes mellitus less significantly than empirical models in estimating stroke risk; physicians weighted anemia and dialysis less significantly than empirical models when estimating bleeding risks. Anticoagulation use was highest among patients with high stroke risk, assessed by either empirical model or physician estimates. In contrast, physician and empirical estimates of bleeding had limited impact on treatment choice.There is little agreement between provider-assessed risk and empirical scores in AF. These differences may explain, in part, the current divergence of anticoagulation treatment decisions from guideline recommendations.http://www.clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.114.008643

    View details for PubMedID 24682387

    View details for PubMedCentralID PMC4050636

  • Response to Letter Regarding Article, "Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO Trial" CIRCULATION Steg, P., Harrington, R. A., Emanuelsson, H., Katus, H. A., Mahaffey, K. W., Meier, B., Storey, R. F., Wojdyla, D. M., Lewis, B. S., Maurer, G., Wallentin, L., James, S. K. 2014; 129 (19): E494–E495
  • Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation: Results From the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Circulation Sherwood, M. W., Douketis, J. D., Patel, M. R., Piccini, J. P., Hellkamp, A. S., Lokhnygina, Y., Spyropoulos, A. C., Hankey, G. J., Singer, D. E., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Becker, R. C. 2014; 129 (18): 1850-1859

    Abstract

    During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI.In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non-central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3-30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36-1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80-2.00]; P=0.32).TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation.http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.113.005754

    View details for PubMedID 24552831

  • Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation CIRCULATION Sherwood, M. W., Douketis, J. D., Patel, M. R., Piccini, J. P., Hellkamp, A. S., Lokhnygina, Y., Spyropoulos, A. C., Hankey, G. J., Singer, D. E., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Becker, R. C. 2014; 129 (18): 1850-1859

    Abstract

    During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI.In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non-central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3-30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36-1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80-2.00]; P=0.32).TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation.http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.113.005754

    View details for Web of Science ID 000335367500012

  • Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes. The TRACER Pharmacodynamic Substudy. Thrombosis and haemostasis Storey, R. F., Kotha, J., Smyth, S. S., Moliterno, D. J., Rorick, T. L., Moccetti, T., Valgimigli, M., Dery, J. P., Cornel, J. H., Thomas, G. S., Huber, K., Harrington, R. A., Hord, E., Judge, H. M., Chen, E., Strony, J., Mahaffey, K. W., Tricoci, P., Becker, R. C., Jennings, L. K. 2014; 111 (5): 883-891

    Abstract

    Vorapaxar is an antagonist of the protease activated receptor-1 (PAR-1), the principal platelet thrombin receptor. The Thrombin Receptor Antagonist for Clinical Event Reduction (TRACER) trial evaluated vorapaxar compared to placebo in non-ST-elevation (NSTE)-acute coronary syndrome (ACS) patients. It was the study's objective to assess the pharmacodynamic effects of vorapaxar versus placebo that included aspirin or a thienopyridine or, frequently, a combination of both agents in NSTE-ACS patients. In a substudy involving 249 patients, platelet aggregation was assessed by light transmittance aggregometry (LTA) in 85 subjects (41 placebo, 44 vorapaxar) using the agonists thrombin receptor activating peptide (TRAP, 15 μM), adenosine diphosphate (ADP, 20 μM), and the combination of collagen-related peptide (2.5 μg/ml) + ADP (5 μM) + TRAP (15 μM) (CAT). VerifyNow® IIb/IIIa and vasodilator-stimulated phosphoprotein (VASP) phosphorylation assays were performed, and platelet PAR-1 expression, plasma platelet/endothelial and inflammatory biomarkers were determined before and during treatment. LTA responses to TRAP and CAT and VerifyNow results were markedly inhibited by vorapaxar. Maximal LTA response to TRAP (median, interquartile range) 2 hours post loading dose: placebo 68% (53-75%) and vorapaxar 3% (2-6%), p<0.0001. ADP inhibition was greater in the vorapaxar group at 4 hours and one month (p<0.01). In contrast to the placebo group, PAR-1 receptor number in the vorapaxar group at one month was significantly lower than the baseline (179 vs 225; p=0.004). There were significant changes in selected biomarker levels between the two treatment groups. In conclusion, vorapaxar caused a potent inhibition of PAR-1-mediated platelet aggregation. Further studies are needed to explore vorapaxar effect on P2Y12 inhibition, PAR-1 expression and biomarkers and its contribution to clinical outcomes.

    View details for DOI 10.1160/TH13-07-0624

    View details for PubMedID 24402559

  • Intracranial hemorrhage among patients with atrial fibrillation anticoagulated with warfarin or rivaroxaban: the rivaroxaban once daily, oral, direct factor xa inhibition compared with vitamin k antagonism for prevention of stroke and embolism trial in atrial fibrillation. Stroke; a journal of cerebral circulation Hankey, G. J., Stevens, S. R., Piccini, J. P., Lokhnygina, Y., Mahaffey, K. W., Halperin, J. L., Patel, M. R., Breithardt, G., Singer, D. E., Becker, R. C., Berkowitz, S. D., Paolini, J. F., Nessel, C. C., Hacke, W., Fox, K. A., Califf, R. M. 2014; 45 (5): 1304-1312

    Abstract

    Intracranial hemorrhage (ICH) is a life-threatening complication of anticoagulation.We investigated the rate, outcomes, and predictors of ICH in 14 264 patients with atrial fibrillation from Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Cox proportional hazards modeling was used.During 1.94 years (median) of follow-up, 172 patients (1.2%) experienced 175 ICH events at a rate of 0.67% per year. The significant, independent predictors of ICH were race (Asian: hazard ratio, 2.02; 95% CI, 1.39-2.94; black: hazard ratio, 3.25; 95% CI, 1.43-7.41), age (1.35; 1.13-1.63 per 10-year increase), reduced serum albumin (1.39; 1.12-1.73 per 0.5 g/dL decrease), reduced platelet count below 210×10(9)/L (1.08; 1.02-1.13 per 10×10(9)/L decrease), previous stroke or transient ischemic attack (1.42; 1.02-1.96), and increased diastolic blood pressure (1.17; 1.01-1.36 per 10 mm Hg increase). Predictors of a reduced risk of ICH were randomization to rivaroxaban (0.60; 0.44-0.82) and history of congestive heart failure (0.65; 0.47-0.89). The ability of the model to discriminate individuals with and without ICH was good (C-index, 0.69; 95% CI, 0.64-0.73).Among patients with atrial fibrillation treated with anticoagulation, the risk of ICH was higher among Asians, blacks, the elderly, and in those with previous stroke or transient ischemic attack, increased diastolic blood pressure, and reduced platelet count or serum albumin at baseline. The risk of ICH was significantly lower in patients with heart failure and in those who were randomized to rivaroxaban instead of warfarin. The external validity of these findings requires testing in other atrial fibrillation populations.

    View details for DOI 10.1161/STROKEAHA.113.004506

    View details for PubMedID 24743444

  • Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease NEW ENGLAND JOURNAL OF MEDICINE White, H. D., Held, C., Stewart, R., Tarka, E., Brown, R., Davies, R. Y., Budaj, A., Harrington, R. A., Steg, P. G., Ardis-Sino, D., Armstrong, P. W., Avezum, A., Aylward, P. E., Bryce, A., Chen, H., Chen, M., Corbalan, R., Dalby, A. J., Danchin, N., de Winter, R. J., Denchev, S., Diaz, R., Elisaf, M., Flather, M. D., Goudev, A. R., Granger, C. B., Grinfeld, L., Hochman, J. S., Husted, S., Kim, H., Koenig, W., Linhart, A., Lonn, E., Lopez-Sendon, J., Manolis, A. J., Mohler, E. R., Nicolau, J. C., Pais, P., Parkhomenko, A., Pedersen, T. R., Pella, D., Ramos-Corrales, M. A., Ruda, M., Sereg, M., Siddique, S., Sinnaeve, P., Smith, P., Sritara, P., Swart, H. P., Sy, R. G., Teramoto, T., Tse, H., Watson, D., Weaver, W. D., Weiss, R., Viigimaa, M., Vinereanu, D., Zhu, J., Cannon, C. P., Wallentin, L. 2014; 370 (18): 1702-1711

    Abstract

    Elevated lipoprotein-associated phospholipase A2 activity promotes the development of vulnerable atherosclerotic plaques, and elevated plasma levels of this enzyme are associated with an increased risk of coronary events. Darapladib is a selective oral inhibitor of lipoprotein-associated phospholipase A2.In a double-blind trial, we randomly assigned 15,828 patients with stable coronary heart disease to receive either once-daily darapladib (at a dose of 160 mg) or placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, or stroke. Secondary end points included the components of the primary end point as well as major coronary events (death from coronary heart disease, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) and total coronary events (death from coronary heart disease, myocardial infarction, hospitalization for unstable angina, or any coronary revascularization).During a median follow-up period of 3.7 years, the primary end point occurred in 769 of 7924 patients (9.7%) in the darapladib group and 819 of 7904 patients (10.4%) in the placebo group (hazard ratio in the darapladib group, 0.94; 95% confidence interval [CI], 0.85 to 1.03; P=0.20). There were also no significant between-group differences in the rates of the individual components of the primary end point or in all-cause mortality. Darapladib, as compared with placebo, reduced the rate of major coronary events (9.3% vs. 10.3%; hazard ratio, 0.90; 95% CI, 0.82 to 1.00; P=0.045) and total coronary events (14.6% vs. 16.1%; hazard ratio, 0.91; 95% CI, 0.84 to 0.98; P=0.02).In patients with stable coronary heart disease, darapladib did not significantly reduce the risk of the primary composite end point of cardiovascular death, myocardial infarction, or stroke. (Funded by GlaxoSmithKline; STABILITY ClinicalTrials.gov number, NCT00799903.).

    View details for DOI 10.1056/NEJMoa1315878

    View details for Web of Science ID 000335405200008

    View details for PubMedID 24678955

  • Effects of vorapaxar on platelet reactivity and biomarker expression in non-ST-elevation acute coronary syndromes THROMBOSIS AND HAEMOSTASIS Storey, R. F., Kotha, J., Smyth, S. S., Moliterno, D. J., Rorick, T. L., Moccetti, T., Valgimigli, M., Dery, J. P., Cornel, J. H., Thomas, G. S., Huber, K., Harrington, R. A., Hord, E., Judge, H. M., Chen, E., Strony, J., Mahaffey, K. W., Tricoci, P., Becker, R. C., Jennings, L. K. 2014; 111 (5): 883-891
  • Drivers of hospitalization for patients with atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) AMERICAN HEART JOURNAL Steinberg, B. A., Kim, S., Fonarow, G. C., Thomas, L., Ansell, J., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Hylek, E., Naccarelli, G., Go, A. S., Reiffel, J., Chang, P., Peterson, E. D., Piccini, J. P. 2014; 167 (5): 735-U131

    Abstract

    Atrial fibrillation (AF) is the most common cardiac dysrhythmia and contributes significantly to health care expenditures. We sought to assess the frequency and predictors of hospitalization in patients with AF.The ORBIT-AF registry is a prospective, observational study of outpatients with AF enrolled from June 29, 2010, to August 9, 2011. The current analysis included 9,484 participants with 1-year follow-up. Multivariable, logistic regression was used to identify baseline characteristics that were associated with first cause-specific hospitalization.Overall, 31% of patients with AF studied (n = 2,963) had 1 or more hospitalizations per year and 10% (n = 983) had 2 or more. The most common hospitalization cause was cardiovascular (20 per 100 patient-years vs 3.3 bleeding vs 17 noncardiovascular, nonbleeding). Compared with those not hospitalized, hospitalized patients were more likely to have concomitant heart failure (42% vs 28%, P < .0001), higher mean CHADS2 (1 point for congestive heart failure, hypertension, age ≥75, or diabetes; 2 points for prior stroke or transient ischemic attack) scores (2.5 vs 2.2, P < .0001), and more symptoms (baseline European Heart Rhythm Association class severe symptoms 18% vs 13%, P < .0001). In multivariable analysis, heart failure (adjusted hazard ratio [HR] 1.57 for New York Heart Association III/IV vs none, P < .0001), heart rate at baseline (adjusted HR 1.11 per 10-beats/min increase >66, P < .0001), and AF symptom class (adjusted HR 1.37 for European Heart Rhythm Association severe vs none, P < .0001) were the major predictors of incident hospitalization.Hospitalization is common in outpatients with AF and is independently predicted by heart failure and AF symptoms. Improved symptom control, rate control, and comorbid condition management should be evaluated as strategies to reduce health care use in these patients.

    View details for DOI 10.1016/j.ahj.2014.02.003

    View details for Web of Science ID 000335447800015

    View details for PubMedID 24766985

    View details for PubMedCentralID PMC4006943

  • Drivers of hospitalization for patients with atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). American heart journal Steinberg, B. A., Kim, S., Fonarow, G. C., Thomas, L., Ansell, J., Kowey, P. R., Mahaffey, K. W., Gersh, B. J., Hylek, E., Naccarelli, G., Go, A. S., Reiffel, J., Chang, P., Peterson, E. D., Piccini, J. P. 2014; 167 (5): 735-42 e2

    Abstract

    Atrial fibrillation (AF) is the most common cardiac dysrhythmia and contributes significantly to health care expenditures. We sought to assess the frequency and predictors of hospitalization in patients with AF.The ORBIT-AF registry is a prospective, observational study of outpatients with AF enrolled from June 29, 2010, to August 9, 2011. The current analysis included 9,484 participants with 1-year follow-up. Multivariable, logistic regression was used to identify baseline characteristics that were associated with first cause-specific hospitalization.Overall, 31% of patients with AF studied (n = 2,963) had 1 or more hospitalizations per year and 10% (n = 983) had 2 or more. The most common hospitalization cause was cardiovascular (20 per 100 patient-years vs 3.3 bleeding vs 17 noncardiovascular, nonbleeding). Compared with those not hospitalized, hospitalized patients were more likely to have concomitant heart failure (42% vs 28%, P < .0001), higher mean CHADS2 (1 point for congestive heart failure, hypertension, age ≥75, or diabetes; 2 points for prior stroke or transient ischemic attack) scores (2.5 vs 2.2, P < .0001), and more symptoms (baseline European Heart Rhythm Association class severe symptoms 18% vs 13%, P < .0001). In multivariable analysis, heart failure (adjusted hazard ratio [HR] 1.57 for New York Heart Association III/IV vs none, P < .0001), heart rate at baseline (adjusted HR 1.11 per 10-beats/min increase >66, P < .0001), and AF symptom class (adjusted HR 1.37 for European Heart Rhythm Association severe vs none, P < .0001) were the major predictors of incident hospitalization.Hospitalization is common in outpatients with AF and is independently predicted by heart failure and AF symptoms. Improved symptom control, rate control, and comorbid condition management should be evaluated as strategies to reduce health care use in these patients.

    View details for DOI 10.1016/j.ahj.2014.02.003

    View details for PubMedID 24766985

  • Ticagrelor Effects on Myocardial Infarction and the Impact of Event Adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) Trial. Journal of the American College of Cardiology Mahaffey, K. W., Held, C., Wojdyla, D. M., James, S. K., Katus, H. A., Husted, S., Steg, P. G., Cannon, C. P., Becker, R. C., Storey, R. F., Khurmi, N. S., Nicolau, J. C., Yu, C., Ardissino, D., Budaj, A., Morais, J., Montgomery, D., Himmelmann, A., Harrington, R. A., Wallentin, L. 2014; 63 (15): 1493-1499

    Abstract

    This study sought to report the treatment effect of ticagrelor on myocardial infarction (MI) and the strategy for and impact of event adjudication in the PLATO (Platelet Inhibition and Patient Outcomes) trial.In PLATO, ticagrelor reduced cardiovascular death, MI, or stroke in patients with acute coronary syndromes (ACS).A clinical events committee (CEC) prospectively defined and adjudicated all suspected MI events, on the basis of events reported by investigators and by triggers on biomarkers. Treatment comparisons used CEC-adjudicated data, and per protocol, excluded silent MI.Overall, 1,299 (610 ticagrelor, 689 clopidogrel) MIs reported by the CEC occurred during the trial. Of these, 1,097 (504 ticagrelor, 593 clopidogrel) contributed to the primary composite endpoint. Site investigators reported 1,198 (580 ticagrelor, 618 clopidogrel) MIs. Ticagrelor significantly reduced overall MI rates (12-month CEC-adjudicated Kaplan-Meier rates: 5.8% ticagrelor, 6.9% clopidogrel; hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.75 to 0.95). Nonprocedural MI (HR: 0.86; 95% CI: 0.74 to 1.01) and MI related to percutaneous coronary intervention or stent thrombosis tended to be lower with ticagrelor. MIs related to coronary artery bypass graft surgery were few, but numerical excess was observed in patients assigned ticagrelor. Analyses of overall MIs using investigator-reported data showed similar results but did not reach statistical significance (HR: 0.88; 95% CI: 0.78 to 1.00).In patients with ACS, ticagrelor significantly reduced the incidence of MI compared with clopidogrel, with consistent results across most MI subtypes. CEC procedures identified more MI endpoints compared with site investigators. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

    View details for DOI 10.1016/j.jacc.2014.01.038

    View details for PubMedID 24561148

  • Physician practices regarding contraindications to oral anticoagulation in atrial fibrillation: findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry. American heart journal O'Brien, E. C., Holmes, D. N., Ansell, J. E., Allen, L. A., Hylek, E., Kowey, P. R., Gersh, B. J., Fonarow, G. C., Koller, C. R., Ezekowitz, M. D., Mahaffey, K. W., Chang, P., Peterson, E. D., Piccini, J. P., Singer, D. E. 2014; 167 (4): 601-609 e1

    Abstract

    Oral anticoagulation (OAC) therapy reduces the risk of thromboembolic events associated with atrial fibrillation (AF), yet a substantial proportion of patients with AF are not prescribed OAC. The aim of this study is to describe the frequencies of and factors associated with OAC contraindications in contemporary clinical practice.We analyzed data from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent AF. Oral anticoagulation contraindications were uniformly collected at enrollment by site personnel using a predefined list. Baseline patient and provider characteristics were compared between participants with and without documented OAC contraindications.From June 2010 to August 2011, 10,130 patients 18 years or older with electrocardiographically documented AF were enrolled at 176 practices. Of these, 1,330 (13.1%) had contraindications documented at the baseline visit: prior bleed (27.7%), patient refusal/preference (27.5%), high bleeding risk (18.0%), frequent falls/frailty (17.6%), need for dual antiplatelet therapy (10.4%), unable to adhere/monitor warfarin (6.0%), comorbid illness (5.3%), prior intracranial hemorrhage (5.0%), allergy (2.4%), occupational risk (0.8%), pregnancy (0.2%), and other (12.6%). Among patients with reported contraindications, 30.3% were taking warfarin or dabigatran, as compared with 83.0% of those without reported contraindications. Besides "patient refusal/preference," being labeled as having frequent falls or being frail was associated with the lowest OAC use among patients with high stroke risk.Contraindications to OAC therapy among patients with AF are common but subjective. Many patients with reported contraindications were receiving OAC, suggesting that the perceived benefit outweighed the potential harm posed by the relative contraindication.

    View details for DOI 10.1016/j.ahj.2013.12.014

    View details for PubMedID 24655711

  • REDUCED DEATH, MYOCARDIAL INFARCTION, AND EARLY STENT THROMBOSIS WITH CANGRELOR VERSUS CLOPIDOGREL ON A BACKGROUND OF BIVALIRUDIN: INSIGHTS FROM CHAMPION PHOENIX White, H. D., Bhatt, D. L., Gibson, C., Hamm, C. W., Mahaffey, K. W., Price, M. J., Steg, P., Stone, G. W., Cortese, B., Wilensky, M., Deliargyris, E. N., Liu, T., Prats, J., Harrington, R. A. ELSEVIER SCIENCE INC. 2014: A36
  • Relationship Between Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results From the ROCKET AF Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Piccini, J. P., Hellkamp, A. S., Lokhnygina, Y., Patel, M. R., Harrell, F. E., Singer, D. E., Becker, R. C., Breithardt, G., Halperin, J. L., Hankey, G. J., Berkowitz, S. D., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2014; 3 (2)

    Abstract

    Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons.TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger-stick point-of-care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non-central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower-risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non-major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values.The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.

    View details for DOI 10.1161/JAHA.113.000521

    View details for Web of Science ID 000336798000039

    View details for PubMedID 24755148

  • Physician practices regarding contraindications to oral anticoagulation in atrial fibrillation: Findings from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry AMERICAN HEART JOURNAL O'Brien, E. C., Holmes, D. N., Ansell, J. E., Allen, L. A., Hylek, E., Kowey, P. R., Gersh, B. J., Fonarow, G. C., Koller, C. R., Ezekowitz, M. D., Mahaffey, K. W., Chang, P., Peterson, E. D., Piccini, J. P., Singer, D. E. 2014; 167 (4): 601-U229

    Abstract

    Oral anticoagulation (OAC) therapy reduces the risk of thromboembolic events associated with atrial fibrillation (AF), yet a substantial proportion of patients with AF are not prescribed OAC. The aim of this study is to describe the frequencies of and factors associated with OAC contraindications in contemporary clinical practice.We analyzed data from the ORBIT-AF study, a national, prospective, outpatient registry of incident and prevalent AF. Oral anticoagulation contraindications were uniformly collected at enrollment by site personnel using a predefined list. Baseline patient and provider characteristics were compared between participants with and without documented OAC contraindications.From June 2010 to August 2011, 10,130 patients 18 years or older with electrocardiographically documented AF were enrolled at 176 practices. Of these, 1,330 (13.1%) had contraindications documented at the baseline visit: prior bleed (27.7%), patient refusal/preference (27.5%), high bleeding risk (18.0%), frequent falls/frailty (17.6%), need for dual antiplatelet therapy (10.4%), unable to adhere/monitor warfarin (6.0%), comorbid illness (5.3%), prior intracranial hemorrhage (5.0%), allergy (2.4%), occupational risk (0.8%), pregnancy (0.2%), and other (12.6%). Among patients with reported contraindications, 30.3% were taking warfarin or dabigatran, as compared with 83.0% of those without reported contraindications. Besides "patient refusal/preference," being labeled as having frequent falls or being frail was associated with the lowest OAC use among patients with high stroke risk.Contraindications to OAC therapy among patients with AF are common but subjective. Many patients with reported contraindications were receiving OAC, suggesting that the perceived benefit outweighed the potential harm posed by the relative contraindication.

    View details for DOI 10.1016/j.ahj.2013.12.014

    View details for Web of Science ID 000333170900025

    View details for PubMedID 24655711

  • Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery: Subgroup Analysis From the TRACER Trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome). Journal of the American College of Cardiology Whellan, D. J., Tricoci, P., Chen, E., Huang, Z., Leibowitz, D., Vranckx, P., Marhefka, G. D., Held, C., Nicolau, J. C., Storey, R. F., Ruzyllo, W., Huber, K., Sinnaeve, P., Weiss, A. T., Dery, J., Moliterno, D. J., Van de Werf, F., Aylward, P. E., White, H. D., Armstrong, P. W., Wallentin, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 63 (11): 1048-1057

    Abstract

    This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG).Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients.Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method.Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%).In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).

    View details for DOI 10.1016/j.jacc.2013.10.048

    View details for PubMedID 24211500

  • Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Whellan, D. J., Tricoci, P., Chen, E., Huang, Z., Leibowitz, D., Vranckx, P., Marhefka, G. D., Held, C., Nicolau, J. C., Storey, R. F., Ruzyllo, W., Huber, K., Sinnaeve, P., Weiss, A. T., Dery, J., Moliterno, D. J., Van de Werf, F., Aylward, P. E., White, H. D., Armstrong, P. W., Wallentin, L., Strony, J., Harrington, R. A., Mahaffey, K. W. 2014; 63 (11): 1048-1057

    Abstract

    This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG).Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients.Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method.Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p = 0.005), with a significant interaction (p = 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p = 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%).In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).

    View details for DOI 10.1016/j.jacc.2013.10.048

    View details for Web of Science ID 000333090700004

  • Association of Aspirin Dose and Vorapaxar Safety and Efficacy in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (from the TRACER Trial). American journal of cardiology Mahaffey, K. W., Huang, Z., Wallentin, L., Storey, R. F., Jennings, L. K., Tricoci, P., White, H. D., Armstrong, P. W., Aylward, P. E., Moliterno, D. J., Van de Werf, F., Chen, E., Leonardi, S., Rorick, T., Held, C., Strony, J., Harrington, R. A. 2014; 113 (6): 936-944

    Abstract

    Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.

    View details for DOI 10.1016/j.amjcard.2013.11.052

    View details for PubMedID 24444781

  • Factors Associated With Major Bleeding Events JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Goodman, S. G., Wojdyla, D. M., Piccini, J. P., White, H. D., Paolini, J. F., Nessel, C. C., Berkowitz, S. D., Mahaffey, K. W., Patel, M. R., Sherwood, M. W., Becker, R. C., Halperin, J. L., Hacke, W., Singer, D. E., Hankey, G. J., Breithardt, G., Fox, K. A., Califf, R. M. 2014; 63 (9): 891-900
  • Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). Journal of the American College of Cardiology Goodman, S. G., Wojdyla, D. M., Piccini, J. P., White, H. D., Paolini, J. F., Nessel, C. C., Berkowitz, S. D., Mahaffey, K. W., Patel, M. R., Sherwood, M. W., Becker, R. C., Halperin, J. L., Hacke, W., Singer, D. E., Hankey, G. J., Breithardt, G., Fox, K. A., Califf, R. M. 2014; 63 (9): 891-900

    Abstract

    This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin.The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model.The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk.Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767).

    View details for DOI 10.1016/j.jacc.2013.11.013

    View details for PubMedID 24315894

  • Impact of Intraprocedural Stent Thrombosis During Percutaneous Coronary Intervention: Insights From the CHAMPION PHOENIX Trial (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention). Journal of the American College of Cardiology Généreux, P., Stone, G. W., Harrington, R. A., Gibson, C. M., Steg, P. G., Brener, S. J., Angiolillo, D. J., Price, M. J., Prats, J., Lasalle, L., Liu, T., Todd, M., Skerjanec, S., Hamm, C. W., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2014; 63 (7): 619-629

    Abstract

    This study sought to evaluate the clinical impact of intraprocedural stent thrombosis (IPST), a relatively new endpoint.In the prospective, double-blind, active-controlled CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST.An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment at any time during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee.IPST developed in 89 patients (0.8%), including 35 of 5,470 (0.6%) and 54 of 5,469 (1.0%) patients in the cangrelor and clopidogrel arms, respectively (odds ratio: 0.65; 95% confidence interval: 0.42 to 0.99; p = 0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction [MI], ischemia-driven revascularization, or new-onset out-of-laboratory stent thrombosis [Academic Research Consortium]) at 48 h and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, respectively; p < 0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points.In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous adenosine diphosphate antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 h and 30 days. (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX]; NCT01156571).

    View details for DOI 10.1016/j.jacc.2013.10.022

    View details for PubMedID 24184169

  • Impact of Intraprocedural Stent Thrombosis During Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Genereux, P., Stone, G. W., Harrington, R. A., Gibson, C. M., Steg, P. G., Brener, S. J., Angiolillo, D. J., Price, M. J., Prats, J., Lasalle, L., Liu, T., Todd, M., Skerjanec, S., Hamm, C. W., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2014; 63 (7): 619-629

    Abstract

    This study sought to evaluate the clinical impact of intraprocedural stent thrombosis (IPST), a relatively new endpoint.In the prospective, double-blind, active-controlled CHAMPION PHOENIX (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention) trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST.An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment at any time during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee.IPST developed in 89 patients (0.8%), including 35 of 5,470 (0.6%) and 54 of 5,469 (1.0%) patients in the cangrelor and clopidogrel arms, respectively (odds ratio: 0.65; 95% confidence interval: 0.42 to 0.99; p = 0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction [MI], ischemia-driven revascularization, or new-onset out-of-laboratory stent thrombosis [Academic Research Consortium]) at 48 h and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, respectively; p < 0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points.In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous adenosine diphosphate antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 h and 30 days. (Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention [PCI] [CHAMPION PHOENIX]; NCT01156571).

    View details for DOI 10.1016/j.jacc.2013.10.022

    View details for Web of Science ID 000331719800003

  • Release kinetics of circulating cardiac myosin binding protein-C following cardiac injury AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Kuster, D. W., Cardenas-Ospina, A., Miller, L., Liebetrau, C., Troidl, C., Nef, H. M., Moellmann, H., Hamm, C. W., Pieper, K. S., Mahaffey, K. W., Kleiman, N. S., Stuyvers, B. D., Marian, A. J., Sadayappan, S. 2014; 306 (4): H547-H556

    Abstract

    Diagnosis of myocardial infarction (MI) is based on ST-segment elevation on electrocardiographic evaluation and/or elevated plasma cardiac troponin (cTn) levels. However, troponins lack the sensitivity required to detect the onset of MI at its earliest stages. Therefore, to confirm its viability as an ultra-early biomarker of MI, this study investigates the release kinetics of cardiac myosin binding protein-C (cMyBP-C) in a porcine model of MI and in two human cohorts. Release kinetics of cMyBP-C were determined in a porcine model of MI (n = 6, pigs, either sex) by measuring plasma cMyBP-C level serially from 30 min to 14 days after coronary occlusion, with use of a custom-made immunoassay. cMyBP-C plasma levels were increased from baseline (76 ± 68 ng/l) at 3 h (767 ± 211 ng/l) and peaked at 6 h (2,418 ± 780 ng/l) after coronary ligation. Plasma cTnI, cTnT, and myosin light chain-3 levels were all increased 6 h after ligation. In a cohort of patients (n = 12) with hypertrophic obstructive cardiomyopathy undergoing transcoronary ablation of septal hypertrophy, cMyBP-C was significantly increased from baseline (49 ± 23 ng/l) in a time-dependent manner, peaking at 4 h (560 ± 273 ng/l). In a cohort of patients with non-ST segment elevation MI (n = 176) from the SYNERGY trial, cMyBP-C serum levels were significantly higher (7,615 ± 4,514 ng/l) than those in a control cohort (416 ± 104 ng/l; n = 153). cMyBP-C is released in the blood rapidly after cardiac damage and therefore has the potential to positively mark the onset of MI.

    View details for DOI 10.1152/ajpheart.00846.2013

    View details for Web of Science ID 000331895000009

    View details for PubMedID 24337456

  • Biomarkers in Relation to the Effects of Ticagrelor in Comparison With Clopidogrel in Non-ST-Elevation Acute Coronary Syndrome Patients Managed With or Without In-Hospital Revascularization A Substudy From the Prospective Randomized Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION Wallentin, L., Lindholm, D., Siegbahn, A., Wernroth, L., Becker, R. C., Cannon, C. P., Cornel, J. H., Himmelmann, A., Giannitsis, E., Harrington, R. A., Held, C., Husted, S., Katus, H. A., Mahaffey, K. W., Steg, P. G., Storey, R. F., James, S. K. 2014; 129 (3): 293-303

    Abstract

    Risk stratification and the use of specific biomarkers have been proposed for tailoring treatment in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). We investigated the prognostic importance of high-sensitivity troponin T (hs-TnT), N-terminal pro-brain natriuretic peptide (NT-proBNP), and growth differentiation factor-15 (GDF-15) in relation to randomized treatment (ticagrelor versus clopidogrel) and management strategy (with or without revascularization) in the NSTE-ACS subgroup of the Platelet Inhibition and Patient Outcomes (PLATO) trial.Of 18 624 patients in the PLATO trial, 9946 had an entry diagnosis of NSTE-ACS and baseline blood samples available. During index hospitalization, 5357 were revascularized, and 4589 were managed without revascularization. Hs-TnT, NT-proBNP, and GDF-15 were determined and assessed according to predefined cutoff levels. Median follow-up was 9.1 months. Increasing levels of hs-TnT were associated with increasing risk of cardiovascular death, myocardial infarction, and stroke in medically managed patients (P<0.001), but not in those managed invasively. NT-proBNP and GDF-15 levels were associated with the same events independent of management strategy. Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS and hs-TnT ≥14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT <14.0 ng/L, there was no difference between ticagrelor and clopidogrel in the noninvasive groupHs-TnT, NT-proBNP, and GDF-15 are predictors of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS managed noninvasively, and NT-proBNP and GDF-15 also in those managed invasively. Elevated hs-TnT predicts substantial benefit of ticagrelor over clopidogrel both in invasively and noninvasively managed patients, but no apparent benefit was seen at normal hs-TnT.URL:http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.113.004420

    View details for Web of Science ID 000329880700006

    View details for PubMedID 24170388

  • Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. European heart journal Mahaffey, K. W., Stevens, S. R., White, H. D., Nessel, C. C., Goodman, S. G., Piccini, J. P., Patel, M. R., Becker, R. C., Halperin, J. L., Hacke, W., Singer, D. E., Hankey, G. J., Califf, R. M., Fox, K. A., Breithardt, G. 2014; 35 (4): 233-241

    Abstract

    We investigated the prevalence of prior myocardial infarction (MI) and incidence of ischaemic cardiovascular (CV) events among atrial fibrillation (AF) patients.In ROCKET AF, 14 264 patients with nonvalvular AF were randomized to rivaroxaban or warfarin. The key efficacy outcome for these analyses was CV death, MI, and unstable angina (UA). This pre-specified analysis was performed on patients while on treatment. Rates are per 100 patient-years. Overall, 2468 (17%) patients had prior MI at enrollment. Compared with patients without prior MI, these patients were more likely to be male (75 vs. 57%), on aspirin at baseline (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischaemic attacks (46 vs. 54%). CV death, MI, or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [2.70 vs. 3.15; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73-1.00; P = 0.0509]. CV death, MI, or UA rates were higher in those with prior MI compared with no prior MI (6.68 vs. 2.19; HR 3.04, 95% CI 2.59-3.56) with consistent results for CV death, MI, or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI (P interaction = 0.10).Prior MI was common and associated with substantial risk for subsequent cardiac events. Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14% reduction of ischaemic cardiac events.

    View details for DOI 10.1093/eurheartj/eht428

    View details for PubMedID 24132190

  • Review of the accumulated PLATO documentation supports reliable and consistent superiority of ticagrelor over clopidogrel in patients with acute coronary syndrome: Commentary on: DiNicolantonio JJ, Tomek A, Inactivations, deletions, non-adjudications, and downgrades of clinical endpoints on ticagrelor: serious concerns over the reliability of the PLATO trial, International Journal of Cardiology, 2013. International journal of cardiology Wallentin, L., Becker, R. C., Cannon, C. P., Held, C., Himmelmann, A., Husted, S., James, S. K., Katus, H. S., Mahaffey, K. W., Pieper, K. S., Storey, R. F., Steg, P. G., Harrington, R. A. 2014; 170 (3): e59-62

    View details for DOI 10.1016/j.ijcard.2013.11.003

    View details for PubMedID 24299581

  • Efficacy and safety of rivaroxaban compared with warfarin in patients with peripheral artery disease and non-valvular atrial fibrillation: insights from ROCKET AF EUROPEAN HEART JOURNAL Jones, W. S., Hellkamp, A. S., Halperin, J., Piccini, J. P., Breithardt, G., Singer, D. E., Fox, K. A., Hankey, G. J., Mahaffey, K. W., Califf, R. M., Patel, M. R. 2014; 35 (4): 242-249

    Abstract

    Vascular disease is included in a risk scoring system to predict stroke in patients with non-valvular atrial fibrillation (AF). This post hoc analysis of ROCKET AF aimed to determine the absolute rates of stroke and bleeding, and the relative effectiveness and safety of rivaroxaban vs. warfarin in patients with and without peripheral artery disease (PAD). Peripheral artery disease was defined on the case-report form as the presences of intermittent claudication, amputation for arterial insufficiency, vascular reconstruction, bypass surgery, or percutaneous intervention to the extremities, or previously documented abdominal aortic aneurysm.ROCKET AF was a double-blind, double-dummy, randomized-controlled trial comparing rivaroxaban and warfarin for the prevention of stroke or systemic embolism. A total of 839 (5.9%) patients in ROCKET AF had PAD. Patients with and without PAD had similar rates of stroke or systemic embolism [HR: 1.04, 95% CI (0.72, 1.50), P = 0.84] and major or non-major clinically relevant (NMCR) bleeding [HR: 1.11, 95% CI (0.96, 1.28), P = 0.17], respectively. The efficacy of rivaroxaban when compared with warfarin for the prevention of stroke or systemic embolism was similar in patients with PAD (HR: 1.19, 95% CI: 0.63-2.22) and without PAD (HR: 0.86, 95% CI: 0.73-1.02; interaction P = 0.34). There was a significant interaction for major or NMCR bleeding in patients with PAD treated with rivaroxaban compared with warfarin (HR: 1.40, 95% CI: 1.06-1.86) compared with those without PAD (HR: 1.03, 95% CI: 0.95-1.11; interaction P = 0.037).Patients with PAD in ROCKET AF did not have a statistically significant higher risk of stroke or systemic embolism than patients without PAD, and there were similar efficacy outcomes in patients treated with rivaroxaban and warfarin. In PAD patients, there was a higher risk of major bleeding or NMCR bleeding with rivaroxaban when compared with warfarin (interaction P = 0.037). Further investigation is warranted to validate this subgroup analysis and determine the optimal treatment in this high-risk cohort of AF patients with PAD.

    View details for DOI 10.1093/eurheartj/eht492

    View details for Web of Science ID 000330837300010

    View details for PubMedID 24302273

  • Gastrointestinal ulcers, role of aspirin, and clinical outcomes: pathobiology, diagnosis, and treatment. Journal of multidisciplinary healthcare Cryer, B., Mahaffey, K. W. 2014; 7: 137-146

    Abstract

    Peptic ulcer disease is a major cause of morbidity and mortality in the US with more than six million diagnoses annually. Ulcers are reported as the most common cause of hospitalization for upper gastrointestinal (GI) bleeding and are often a clinical concern due to the widespread use of aspirin and nonsteroidal anti-inflammatory drugs, both of which have been shown to induce ulcer formation. The finding that Helicobacter pylori infection (independent of aspirin use) is associated with the development of ulcers led to a more thorough understanding of the causes and pathogenesis of ulcers and an improvement in therapeutic options. However, many patients infected with H. pylori are asymptomatic and remain undiagnosed. Complicating matters is a current lack of understanding of the association between aspirin use and asymptomatic ulcer formation. Low-dose aspirin prescriptions have increased, particularly for cardioprotection. Unfortunately, the GI side effects associated with aspirin therapy continue to be a major complication in both symptomatic and asymptomatic patients. These safety concerns should be important considerations in the decision to use aspirin and warrant further education. The medical community needs to continue to improve awareness of aspirin-induced GI bleeding to better equip physicians and improve care for patients requiring aspirin therapy.

    View details for DOI 10.2147/JMDH.S54324

    View details for PubMedID 24741318

    View details for PubMedCentralID PMC3970722

  • Reduction in Overall Occurrences of Ischemic Events With Vorapaxar: Results From TRACER. Journal of the American Heart Association White, H. D., Huang, Z., Tricoci, P., Van de Werf, F., Wallentin, L., Lokhnygina, Y., Moliterno, D. J., Aylward, P. E., Mahaffey, K. W., Armstrong, P. W. 2014; 3 (4)

    Abstract

    Clinical trials traditionally use time-to-first-event analysis embedded within the composite endpoint of cardiovascular death (CVD), myocardial infarction (MI), or stroke. However, many patients have >1 event, and this approach may not reflect overall experience. We addressed this by analyzing all cardiovascular events in TRACER.TRACER randomized 12 944 patients with non-ST-segment elevation acute coronary syndromes to placebo or to protease-activated receptor 1 antagonist vorapaxar with a median follow-up of 502 days (interquartile range, 349 to 667). Analysis of vorapaxar's effect on recurrent CVD, MI, or stroke was prespecified using the Wei, Lin, and Weissfeld approach. Vorapaxar did not reduce the first occurrence of the primary endpoint of CVD, MI, stroke, revascularization, or rehospitalization for recurrent ischemia, but reduced the secondary composite endpoint of CVD, MI, or stroke (14.7% vorapaxar vs. 16.4% placebo; hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.81 to 0.98; P=0.02; number needed to treat [NNT], 81). Recurrent secondary events occurred in 2.7% of patients. Vorapaxar reduced overall occurrences of ischemic events, first and subsequent (HR, 0.88; 95% CI, 0.80 to 0.98; P=0.02; NNT, 51). Also, there was a trend indicating that vorapaxar reduced the expanded endpoint, including revascularization and rehospitalization for recurrent ischemia (HR, 0.92; 95% CI, 0.84 to 1.01; P=0.09). Vorapaxar increased overall occurrences of moderate and severe Global Use of Strategies to Open Occluded Coronary Arteries bleeding (HR, 1.42; 95% CI, 1.21 to 1.66; P<0.001) and Thrombolysis in Myocardial Infarction clinically significant bleeding (HR, 1.550; 95% CI, 1.403 to 1.713; P<0.001).Vorapaxar reduced overall occurrences of ischemic events, but increased bleeding. These exploratory findings broaden our understanding of vorapaxar's potential and expand our understanding of the value of capturing recurrent events.ClinicalTrials.gov. Unique identifier: NCT00527943.

    View details for DOI 10.1161/JAHA.114.001032

    View details for PubMedID 25012288

  • Effect of cangrelor on periprocedural outcomes in percutaneous coronary interventions: a pooled analysis of patient-level data LANCET Steg, P. G., Bhatt, D. L., Hamm, C. W., Stone, G. W., Gibson, C. M., Mahaffey, K. W., Leonardi, S., Liu, T., Skerjanec, S., Day, J. R., Iwaoka, R. S., Stuckey, T. D., Gogia, H. S., Gruberg, L., French, W. J., White, H. D., Harrington, R. A. 2013; 382 (9909): 1981-1992

    Abstract

    Cangrelor is a potent, rapid-acting, reversible intravenous platelet inhibitor that was tested for percutaneous coronary intervention (PCI) in three large, double-blind, randomised trials. We did a pooled analysis of data from three trials that assessed the effectiveness of cangrelor against either clopidogrel or placebo in PCI.This prespecified, pooled analysis of patient-level data from three trials (CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX) compared cangrelor with control (clopidogrel or placebo) for prevention of thrombotic complications during and after PCI. Trial participants were patients undergoing PCI for ST-elevation myocardial infarction (11.6%), non-ST-elevation acute coronary syndromes (57.4%), and stable coronary artery disease (31.0%). Efficacy was assessed in the modified intention-to-treat population of 24,910 patients, with a prespecified primary efficacy composite of death, myocardial infarction, ischaemia-driven revascularisation, or stent thrombosis at 48 h. The primary safety outcome was non-coronary artery bypass graft-related GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) severe or life-threatening bleeding at 48 h.Cangrelor reduced the odds of the primary outcome by 19% (3.8% for cangrelor vs 4.7% for control; odds ratio [OR] 0.81, 95% CI 0.71-0.91, p=0.0007), and stent thrombosis by 41% (0.5% vs 0.8%, OR 0.59, 95% CI 0.43-0.80, p=0.0008). Cangrelor reduced the odds of the secondary triple composite (all-cause death, myocardial infarction, or ischaemia-driven revascularisation at 48 h) by 19% (3.6% vs 4.4%, OR 0.81, 95% CI 0.71-0.92, p=0.0014). Efficacy outcomes were consistent across the trials and main patient subsets. These benefits were maintained at 30 days. There was no difference in the primary safety outcome (0.2% in both groups), in GUSTO moderate bleeding (0.6% vs 0.4%), or in transfusion (0.7% vs 0.6%), but cangrelor increased GUSTO mild bleeding (16.8% vs 13.0%, p<0.0001).Compared with control (clopidogrel or placebo), cangrelor reduced PCI periprocedural thrombotic complications, at the expense of increased bleeding.The Medicines Company.

    View details for DOI 10.1016/S0140-6736(13)61615-3

    View details for Web of Science ID 000328223700025

    View details for PubMedID 24011551

  • Early Adoption of Dabigatran and Its Dosing in US Patients With Atrial Fibrillation: Results From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation JOURNAL OF THE AMERICAN HEART ASSOCIATION Steinberg, B. A., Holmes, D. N., Piccini, J. P., Ansell, J., Chang, P., Fonarow, G. C., Gersh, B., Mahaffey, K. W., Kowey, P. R., Ezekowitz, M. D., Singer, D. E., Thomas, L., Peterson, E. D., Hylek, E. M. 2013; 2 (6)

    Abstract

    Dabigatran is a novel oral anticoagulant approved for thromboprophylaxis in atrial fibrillation. Adoption patterns of this new agent in community practice are unknown.We studied patterns of dabigatran use among patients enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry between June 2010 and August 2011 and followed for 12 months. Among 9974 atrial fibrillation patients included, 1217 (12%) were treated with dabigatran during the study. Overall, patients receiving dabigatran were younger (median age 72 versus 75 years, P<0.0001), more likely to be white (92% versus 89%, P=0.005), more likely to have private insurance (33% versus 25%, P<0.0001), and less likely to have prior cardiovascular disease (4% versus 33%, P<0.0001). They had more new-onset atrial fibrillation (8.8% versus 4.1%, P<0.0001), lower CHADS2 scores (estimated risk based on the presence of congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack; mean 2.0 versus 2.3, P<0.0001), and lower Anticoagulation and Risk Factors in Atrial Fibrillation scores (mean 2.4 versus 2.8, P<0.0001). More than half (n=14/25, 56%) of patients with severe kidney disease were not prescribed reduced dosing, whereas 10% (n=91/920) with preserved renal function received lower dosing. Among patients not on dabigatran at baseline, 8% had dabigatran initiated during follow-up. Patient education was significantly associated with switching from warfarin to dabigatran (adjusted odds ratio for postgraduate 1.73, P=0.007), whereas antiarrhythmic drug use significantly correlated with de novo adoption of dabigatran (adjusted odds ratio 2.4, P<0.0001).Patients receiving dabigatran were younger and at a lower risk of stroke and bleeding. Patients appeared to drive switching from warfarin, whereas clinical characteristics influenced de novo start of dabigatran. These data suggest cautious early uptake of dabigatran, and more careful attention to dosing adjustments is warranted.Clinicaltrials.gov. Unique identifier: NCT01165710.

    View details for DOI 10.1161/JAHA.113.000535

    View details for Web of Science ID 000330177900042

    View details for PubMedID 24275632

    View details for PubMedCentralID PMC3886732

  • 5-Year Results of a Randomized Comparison of XIENCE V Everolimus-Eluting and TAXUS Paclitaxel-Eluting Stents Final Results From the SPIRIT III Trial (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) JACC-CARDIOVASCULAR INTERVENTIONS Gada, H., Kirtane, A. J., Newman, W., Sanz, M., Hermiller, J. B., Mahaffey, K. W., Cutlip, D. E., Sudhir, K., Hou, L., Koo, K., Stone, G. W. 2013; 6 (12): 1263-1266

    Abstract

    This study sought to evaluate the long-term safety and efficacy of everolimus-eluting stents (EES) and paclitaxel-eluting stents (PES) in patients with obstructive coronary artery disease.The use of EES compared to PES has been shown to result in improved clinical outcomes in patients undergoing PCI. However, there have been concerns regarding the durability of these benefits over longer-term follow-up.SPIRIT III was a prospective, multicenter trial in which 1,002 patients were randomized 2:1 to EES versus PES. Endpoints included ischemia-driven target vessel failure (TVF) (death, myocardial infarction (MI), or ischemia-driven target vessel revascularization [TVR]), the pre-specified primary endpoint), target lesion failure (TLF) (cardiac death, target-vessel MI, or ischemia-driven target lesion revascularization [TLR]), major adverse cardiac events (MACE) (cardiac death, MI, or ischemia-driven TLR), their individual components and stent thrombosis.Five-year follow-up was available in 91.9% of patients. Treatment with EES versus PES resulted in lower 5-year Kaplan-Meier rates of TVF (19.3% vs. 24.5%, p = 0.05), TLF (12.7% vs. 19.0%, p = 0.008), and MACE (13.2% vs. 20.7%, p = 0.007). EES also resulted in reduced rates of all-cause death (5.9% vs. 10.1%, p = 0.02), with nonsignificantly different rates of MI, stent thrombosis, and TLR, and no evidence of late catch-up of TLR over time.At 5 years after treatment, EES compared to PES resulted in durable benefits in composite safety and efficacy measures as well as all-cause mortality. Additionally, the absolute difference in TLR between devices remained stable over time without deterioration of effect during late follow-up.

    View details for DOI 10.1016/j.jcin.2013.07.009

    View details for Web of Science ID 000328458800007

    View details for PubMedID 24239202

  • The Clinical Course of Treated Hyperparathyroidism Among Patients Receiving Hemodialysis and the Effect of Cinacalcet: The EVOLVE Trial JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM Parfrey, P. S., Chertow, G. M., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Herzog, C. A., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Dehmel, B., Trotman, M., Modafferi, D. M., Goodman, W. G. 2013; 98 (12): 4834-4844

    Abstract

    The clinical course of secondary hyperparathyroidism (sHPT) in patients on hemodialysis is not well described, and the effect of the calcimimetic cinacalcet on disease progression is uncertain.Our objective was to describe 1) the clinical course of sHPT in patients treated with phosphate binders and/or vitamin D sterols and 2) the impact of cinacalcet on the occurrence of severe unremitting HPT, defined by the persistence of markedly elevated PTH concentrations together with hypercalcemia or parathyroidectomy (PTX).This was a randomized, double-blind, placebo-controlled, global, multicenter clinical trial.Of 5755 patients screened with moderate to severe sHPT, 3883 patients on hemodialysis were included in the trial.Outcomes included PTX; severe, unremitting HPT; and use of commercial cinacalcet (a protocol violation). Intervention: Intervention was cinacalcet (30-180 mg daily) or placebo for up to 64 months.In the 1935 patients randomized to placebo, 278 patients (14%) underwent PTX (median PTH 1872 pg/mL within the previous 12 weeks from surgery). Age, sex, geographic region, co-morbidity, calcium-containing phosphate binder use, and baseline serum calcium, phosphorus, and PTH concentrations were associated with PTX. Commercial cinacalcet was started in 443 (23%) patients (median PTH 1108 pg/mL before treatment began). Severe unremitting HPT developed in 470 patients (24%). In a multivariable Cox model, the relative hazard (comparing patients randomized to cinacalcet versus placebo) of severe unremitting HPT was 0.31 (95% confidence interval = 0.26-0.37). The relative hazard differed little when adjusted by baseline clinical characteristics.Severe unremitting HPT develops frequently in patients on hemodialysis despite conventional therapy, and cinacalcet substantially reduces its occurrence.

    View details for DOI 10.1210/jc.2013-2975

    View details for Web of Science ID 000328477200057

    View details for PubMedID 24108314

  • Vorapaxar in Non-ST-Segment Elevation Acute Coronary Syndrome Patients With Peripheral Artery Disease: Results From TRACER Jones, S., Tricoci, P., Huang, Z., Moliterno, D. J., Harrington, R. A., Sinnaeve, P., Strony, J., Van de Werf, F., White, H. D., Held, C., Armstrong, P. W., Aylward, P. E., Chen, E., Patel, M. R., Mahaffey, K. W. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Trends in Enrollment, Patient Characteristics, Treatments and Outcomes of Older Adults With Non-ST-segment Elevation Acute Coronary Syndromes (ACS) in Clinical Trials Bernacki, G. M., Alexander, K. P., Newby, L., Yang, Q., Schulte, P., White, H. D., Ohman, E., Mahaffey, K. W., Shah, B. R., Giugliano, R. P., Armstrong, P. W., Harrington, R. A., Tricoci, P., Van de Werf, F., Alexander, J., Califf, R. M., Lopes, R. D. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Arterial Access Site and Outcomes in Patients Undergoing Percutaneous Coronary Intervention With and Without Vorapaxar Dery, J. P., Mahaffey, K., Tricoci, P., White, H., Podder, M., Moliterno, D., Harrington, R., Chen, E., Strony, J., Van de Werf, F., Ziada, K. M., Held, C., Aylward, P., Armstrong, P. W., Rao, S. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Efficacy and Safety of Vorapaxar in Elderly Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: Insights From the TRACER Trial Armaganijan, L., Lopes, R., Huang, Z., Tricoci, P., Held, C., Van de Werf, F., Armstrong, P. W., Aylward, P. E., White, H. D., Moliterno, D. J., Wallentin, L., Chen, E., Harrington, R. A., Strony, J., Mahaffey, K. W. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Differential Prognostic Implications of Peak Troponin Level in Acute Coronary Syndrome Treated With and Without Revascularization Bagai, A., Huang, Z., Lokhnygina, Y., Harrington, R. A., Armstrong, P. W., Strony, J., Chen, E., White, H. D., Held, C., Van de Werf, F., Wallentin, L., Tricoci, P., Mahaffey, K. W. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Evolution of Differences in Women and Men With Non-ST-Segment Elevation Acute Coronary Syndromes: Insights From Clinical Trials Over 15 Years Halim, S., Yang, Q., Schulte, P., Hochman, J., Melloni, C., Mahaffey, K. W., Moliterno, D. J., Harrington, R. A., White, H. D., Armstrong, P. W., Ohman, E., Van de Werf, F., Giugliano, R. P., Newby, L. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • CYP2C19 Polymorphism and PON-1 Activity in NSTE ACS: Vorapaxar Effect in Relation to Clopidogrel Metabolism in the TRACER Trial Tricoci, P., Chen, E., Neely, M. L., Warner, A., Wong, P. H., Sinnaeve, P., Wallentin, L., Jennings, L. K., Storey, R. F., Aylward, P. E., White, H. D., Van de Werf, F., Armstrong, P. W., Held, C., Valgimigli, M., Harrington, R. A., Strony, J., Mahaffey, K. W., Moliterno, D. J. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Prognostic implications of left ventricular end-diastolic pressure during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: Findings from the Assessment of Pexelizumab in Acute Myocardial Infarction study AMERICAN HEART JOURNAL Bagai, A., Armstrong, P. W., Stebbins, A., Mahaffey, K. W., Hochman, J. S., Weaver, W. D., Patel, M. R., Granger, C. B., Lopes, R. D. 2013; 166 (5): 913-919

    Abstract

    Left ventricular end-diastolic pressure (LVEDP) is frequently measured during primary percutaneous coronary intervention (PCI). However, little is known of this measurement's utility in predicting outcomes or informing treatment decisions. We sought to determine the prognostic value of LVEDP measured during primary PCI for ST-segment elevation myocardial infarction (STEMI).We studied 1,909 (33.2%) of 5,745 STEMI patients in whom LVEDP was measured during primary PCI in the APEX-AMI trial. Cox regression analysis was used to evaluate whether LVEDP was an independent predictor of mortality and the composite of death, cardiogenic shock, or congestive heart failure (CHF) at 90 days.The median (25th, 75th percentiles) LVEDP level was 22 mm Hg (16, 29); compared with patients with LVEDP ≤ 22 mm Hg, those with LVEDP > 22 mm Hg had higher rates of CHF (7.3% vs 3.1%, P < .001), cardiogenic shock (4.6% vs 1.7%, P < .001), and death (4.1% vs 2.2%, P = .014) at 90 days. After multivariable adjustment, LVEDP was associated with increased risk of mortality through 90 days (adjusted hazard ratio 1.22, 95% CI 1.02-1.46, per 5-mmHg increase, P = .044) and the composite of death, cardiogenic shock, or CHF within the first 2 days (adjusted hazard ratio 1.40, 95% CI 1.23-1.59, per 5-mm Hg increase, P < .001), but not from day 3 to 90 (P = .25).Left ventricular end-diastolic pressure measured during primary PCI for STEMI is an independent predictor of inhospital and longer term cardiovascular outcomes. Measuring LVEDP may be useful to stratify patient risk and guide postinfarct treatment.

    View details for DOI 10.1016/j.ahj.2013.08.006

    View details for Web of Science ID 000326233500018

    View details for PubMedID 24176448

  • Prognostic relevance of baseline pro- and anti-inflammatory markers in STEMI: An APEX AMI substudy INTERNATIONAL JOURNAL OF CARDIOLOGY van Diepen, S., Newby, L. K., Lopes, R. D., Stebbins, A., Hasselblad, V., James, S., Roe, M. T., Ezekowitz, J. A., Moliterno, D. J., Neumann, F., Reist, C., Mahaffey, K. W., Hochman, J. S., Hamm, C. W., Armstrong, P. W., Granger, C. B., Theroux, P. 2013; 168 (3): 2127-2133

    Abstract

    Plaque rupture, acute ischemia, and necrosis in acute coronary syndromes are accompanied by concurrent pro- and anti-inflammatory cascades. Whether STEMI clinical prediction models can be improved with the addition of baseline inflammatory biomarkers remains unknown.In an APEX-AMI trial substudy, 772 patients had a panel of 9 inflammatory serum biomarkers, high sensitivity C reactive protein (hsCRP), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measured at baseline after randomization. Baseline biomarkers were incorporated into a clinical prediction model for a composite of 90-day death, shock, or heart failure. Incremental prognostic value was assessed using Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI).Individually, several biomarkers were independent predictors of clinical outcome: hsCRP (hazard ratio [HR] 1.12; 95% confidence interval [CI], 1.03-1.21; p=0.007, per doubling), NT-proBNP (HR 1.14; 95% CI, 1.06-1.23; p<0.001, per doubling), interleukin (IL)-6 (HR 1.26; 95% CI, 1.12-1.41;p<0.001, per doubling), and inducible protein-10 (IP-10) (HR 0.86; 95% CI, 0.76-0.98; p<0.025, per doubling). The addition of baseline NT-proBNP (NRI 8.6%, p=0.028; IDI 0.030, p<0.001) and IL-6 (NRI 8.8%, p=0.012; IDI 0.036, p<0.001) improved the clinical risk prediction model and the addition of hsCRP (NRI 6.5%, p=0.069; IDI 0.018, p=0.004) yielded minimal improvement. After incorporating NT-proBNP into the model, the remaining biomarkers added little additional predictive value.Multiple inflammatory biomarkers independently predicted 90-day death, shock or heart failure; however, they added little value to a clinical prediction model that included NT-proBNP. Future studies of inflammatory biomarkers in STEMI should report incremental value in a prediction model that includes NT-proBNP.

    View details for DOI 10.1016/j.ijcard.2013.01.004

    View details for Web of Science ID 000326184400068

    View details for PubMedID 23394896

  • Response to Letter Regarding Article, "Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation: Validation of the R(2)CHADS(2) Index in the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study Cohorts" CIRCULATION Piccini, J. P., Stevens, S. R., Chang, Y., Singer, D. E., Lokhnygina, Y., Go, A. S., Patel, M. R., Mahaffey, K. W., Halperin, J. L., Breithardt, G., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Fox, K. A., Califf, R. M. 2013; 128 (11): E172-E173
  • Stent Thrombosis With Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes: An Analysis From the Prospective, Randomized PLATO Trial CIRCULATION Steg, P. G., Harrington, R. A., Emanuelsson, H., Katus, H. A., Mahaffey, K. W., Meier, B., Storey, R. F., Wojdyla, D. M., Lewis, B. S., Maurer, G., Wallentin, L., James, S. K. 2013; 128 (10): 1055-1065

    Abstract

    We aimed to describe the effects of ticagrelor versus clopidogrel on stent thrombosis in the Platelet Inhibition and Patient Outcomes (PLATO) trial.Of 18 624 patients hospitalized for acute coronary syndromes, 11 289 (61%) had at least 1 intracoronary stent. Ticagrelor reduced stent thrombosis compared with clopidogrel across all definitions: definite, 1.37% (n=71) versus 1.93% (n=105; hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.50-0.90; P=0.0091); definite or probable, 2.21% (n=118) versus 2.87% (n=157; HR, 0.75; 95% CI, 0.59-0.95; P=0.017); and definite, probable, and possible, 2.94% (n=154) versus 3.77 (n=201; HR, 0.77; 95% CI, 0.62-0.95). The reduction in definite stent thrombosis was consistent regardless of acute coronary syndrome type, presence of diabetes mellitus, stent type (drug-eluting or bare metal stent), CYP2C19 genetic status, loading dose of aspirin, dose of clopidogrel before randomization, and use of glycoprotein IIb/IIIa inhibitors at randomization. The reduction in stent thrombosis with ticagrelor was numerically greater for late (>30 days; HR, 0.48; 95% CI, 0.24-0.96) and subacute (4 hours-30 days; HR, 0.60; 95% CI, 0.39-0.93) compared with acute (<24 hours; HR, 0.94; 95% CI, 0.43-2.05) stent thrombosis or for patients compliant to therapy (ie, taking blinded study treatment ≥80% of the time) compared with less compliant patients. Randomization to ticagrelor was a strong independent inverse predictor of definite stent thrombosis (HR, 0.65; 95% CI, 0.48-0.88).Ticagrelor compared with clopidogrel reduces the incidence of stent thrombosis in patients with acute coronary syndromes, with consistent benefit across a broad range of patient, stent, and treatment characteristics.

    View details for DOI 10.1161/CIRCULATIONAHA.113.002589

    View details for Web of Science ID 000323820200010

  • A novel approach to systematically implement the universal definition of myocardial infarction: insights from the CHAMPION PLATFORM trial HEART Leonardi, S., Truffa, A. A., Neely, M. L., Tricoci, P., White, H. D., Gibson, C. M., Wilson, M., Stone, G. W., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. 2013; 99 (17): 1282-1287

    Abstract

    OBJECTIVE: To reassess the efficacy of cangrelor efficacy using the universal definition of myocardial infarction (MI). DESIGN: We adopted a novel approach to systematically implement the universal definition of MI. Two physicians blinded to treatment allocation reviewed plots of CK-MB and troponin values in relation to time of randomisation and percutaneous coronary intervention (PCI) to identify patients with stable or falling biomarkers pre-PCI (ie, primary cohort), and those with post-PCI CK-MB elevations. SETTING: The CHAMPION PLATFORM trial. PATIENTS: Non-ST-elevation acute coronary syndromes (95%) and stable angina patients (5%). INTERVENTIONS: Cangrelor versus placebo. MAIN OUTCOME MEASURES: The efficacy of cangrelor compared with placebo using the reclassified events (type 4a MI) and the original clinical events committee-adjudicated (CEC PCI-MI) results was investigated. RESULTS: Of 5295 patients, 3406 (64.4%) were in the primary cohort. Type 4a MI occurred in 4.3% (226 events/5295 patients) while original CEC PCI-MI occurred in 6.5% (344 events/5295 patients), a significant difference (p<0.0001). Using the reclassified MI events, the primary composite endpoint of death, MI, or ischaemia-driven revascularisation through 48 h occurred in 5.4% of patients (4.9% cangrelor, 6.0% placebo; OR 0.80; 95% CI 0.63 to 1.02) as opposed to 7.5% of the primary analyses (7.0% cangrelor, 8.0% placebo; OR 0.87; 95% CI 0.71 to 1.07). CONCLUSIONS: Systematic, strict implementation of the universal MI definition with emphasis on baseline assessment may enhance discrimination in detecting PCI-MI and may allow for more rigorous assessment of interventions in patients undergoing early PCI.

    View details for DOI 10.1136/heartjnl-2012-303103

    View details for Web of Science ID 000323162800012

    View details for PubMedID 23434768

  • The Systemic Inflammatory Response Syndrome in Patients With ST-Segment Elevation Myocardial Infarction CRITICAL CARE MEDICINE van Diepen, S., Vavalle, J. P., Newby, L. K., Clare, R., Pieper, K. S., Ezekowitz, J. A., Hochman, J. S., Mahaffey, K. W., Armstrong, P. W., Granger, C. B. 2013; 41 (9): 2080-2087

    Abstract

    To assess whether systemic inflammatory response syndrome is associated with morbidity and mortality in ST-elevation myocardial infarction.Secondary analysis of multicenter randomized controlled trials.Complement and reduction of infarct size after angioplasty or lytics project patients (n=1,903) with ST-elevation myocardial infarction undergoing fibrinolysis or mechanical reperfusion.None.The prevalence of systemic inflammatory response syndrome was described in the 1,186 patients (64.4%) with data available for all systemic inflammatory response syndrome criteria. Using multiple imputations for the 1,843 patients (96.8%) with available endpoints, we compared the 90-day prevalence of death, shock, heart failure, or stroke between patients with and without systemic inflammatory response syndrome at presentation and at 24 hours post admission. Systemic inflammatory response syndrome was defined as ≥2 of 1) heart rate>90 beats/min, 2) respiratory rate>20 breaths/min, 3) body temperature>38 or <36°C, or 4) leukocyte count>12 or<4×10/L. At presentation, 25.0% of patients met systemic inflammatory response syndrome criteria; at 24 hours, 8.1% of patients met systemic inflammatory response syndrome criteria. The primary outcome was more frequent among patients with systemic inflammatory response syndrome at presentation (31.0% vs 16.7%; adjusted hazard ratio, 1.78 [95% CI, 1.35-2.34]; p<0.001) and at 24 hours (36.7% vs 11.1%; adjusted hazard ratio, 2.84 [95% CI, 2.03-3.97]; p<0.001). Mortality at 90 days was also higher among patients with systemic inflammatory response syndrome at either time point. Each additional systemic inflammatory response syndrome criterion was independently associated with 90-day outcomes at the time of presentation (adjusted hazard ratio, 1.41 per systemic inflammatory response syndrome criteria [95% CI, 1.24-1.61]; p<0.001) and at 24 hours (adjusted hazard ratio, 1.72 per systemic inflammatory response syndrome criteria [95% CI, 1.47-2.01]; p<0.001).The diagnosis of systemic inflammatory response syndrome and the cumulative number of systemic inflammatory response syndrome criteria were independently associated with 90-day clinical outcomes in a population of patients with ST-elevation myocardial infarction. The independent association of this simple composite measure of the inflammatory response with outcomes underscores the importance of the clinical inflammatory response in ST-elevation myocardial infarction.

    View details for DOI 10.1097/CCM.0b013e31828a67b2

    View details for Web of Science ID 000330537600003

    View details for PubMedID 23760155

  • Use and Associated Risks of Concomitant Aspirin Therapy With Oral Anticoagulation in Patients With Atrial Fibrillation Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry CIRCULATION Steinberg, B. A., Kim, S., Piccini, J. P., Fonarow, G. C., Lopes, R. D., Thomas, L., Ezekowitz, M. D., Ansell, J., Kowey, P., Singer, D. E., Gersh, B., Mahaffey, K. W., Hylek, E., Go, A. S., Chang, P., Peterson, E. D. 2013; 128 (7): 721-728

    Abstract

    The role of concomitant aspirin (ASA) therapy in patients with atrial fibrillation (AF) receiving oral anticoagulation (OAC) is unclear. We assessed concomitant ASA use and its association with clinical outcomes among AF patients treated with OAC.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry enrolled 10 126 AF patients from 176 US practices from June 2010 through August 2011. The study population was limited to those on OAC (n=7347). Hierarchical multivariable logistic regression models were used to assess factors associated with concomitant ASA therapy. Primary outcomes were 6-month bleeding, hospitalization, ischemic events, and mortality. Overall, 35% of AF patients (n=2543) on OAC also received ASA (OAC+ASA). Patients receiving OAC+ASA were more likely to be male (66% versus 53%; P<0.0001) and had more comorbid illness than those on OAC alone. More than one third of patients (39%) receiving OAC+ASA did not have a history of atherosclerotic disease, yet 17% had elevated Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding risk scores (≥5). Major bleeding (adjusted hazard ratio, 1.53; 95% confidence interval, 1.20-1.96) and bleeding hospitalizations (adjusted hazard ratio, 1.52; 95% confidence interval, 1.17-1.97) were significantly higher in those on OAC+ASA compared with those on OAC alone. Rates of ischemic events were low.Patients with AF receiving OAC are often treated with concomitant ASA, even when they do not have cardiovascular disease. Use of OAC+ASA was associated with significantly increased risk for bleeding, emphasizing the need to carefully determine if and when the benefits of concomitant ASA outweigh the risks in AF patients already on OAC.URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01165710.

    View details for DOI 10.1161/CIRCULATIONAHA.113.002927

    View details for Web of Science ID 000323102400016

    View details for PubMedID 23861512

  • Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)-A randomized placebo-controlled trial AMERICAN HEART JOURNAL Neal, B., Perkovic, V., de Zeeuw, D., Mahaffey, K. W., Fulcher, G., Stein, P., Desai, M., Shaw, W., Jiang, J., Vercruysse, F., Meininger, G., Matthews, D. 2013; 166 (2): 217-?

    Abstract

    Sodium glucose co-transporter 2 inhibition is a novel mode of treatment for type 2 diabetes mellitus (T2DM). The sodium glucose co-transporter 2 inhibitor canagliflozin lowered blood glucose, blood pressure, and body weight, with increased risk of urogenital infections in Phase 2 studies. Effects on macrovascular complications of diabetes remain to be determined. CANVAS is a double-blind, placebo-controlled trial designed to evaluate the effects of canagliflozin on the risk of cardiovascular disease and to assess safety and tolerability in patients with inadequately controlled T2DM and increased cardiovascular risk. The first of 2 planned phases randomized 4,330 individuals to placebo, canagliflozin 100 or 300 mg (1:1:1) with planned follow-up of about 2 years to substantiate potential cardiovascular protection by assessing key biomarkers and to achieve initial safety objectives. By the end of mid-September 2012, a total of 7174 patient-years of follow-up were accrued. Mean baseline age was 62 years, duration of diabetes 13 years; hemoglobin A1c 8.2%, fasting plasma glucose 9.3 mmol/L, and body mass index 32 kg/m(2). Of the participants, 34% are female and 57% had a history of atherosclerotic vascular disease. Participants will be followed up to achieve primary safety and tolerability objectives and to investigate secondary outcomes. The planned second phase will not be undertaken. CANVAS will define the effects of canagliflozin on biomarkers and provide data on cardiovascular safety against established regulatory parameters.

    View details for DOI 10.1016/j.ahj.2013.05.007

    View details for Web of Science ID 000322629000005

    View details for PubMedID 23895803

  • Methodology of a reevaluation of cardiovascular outcomes in the RECORD trial: Study design and conduct AMERICAN HEART JOURNAL Lopes, R. D., Dickerson, S., Hafley, G., Burns, S., Tourt-Uhlig, S., White, J., Newby, L. K., Komajda, M., McMurray, J., Bigelow, R., Home, P. D., Mahaffey, K. W. 2013; 166 (2): 208-?

    Abstract

    In 2010, after regulatory review of rosiglitazone licensing, the US Food and Drug Administration (FDA) requested a reevaluation of cardiovascular end points in the RECORD trial.Automated screening of the original clinical trial database and manual case report form review were performed to identify all potential cardiovascular and noncardiovascular deaths, and nonfatal myocardial infarction (MI) and stroke events. Search techniques were used to find participants lost to follow-up, and sites were queried for additional source documents. Suspected events underwent blinded adjudication using both original RECORD end point definitions and new FDA end point definitions, before analysis by the Duke Clinical Research Institute.The reevaluation effort included an additional 328 person-years of follow-up. Automated screening identified 396 suspected deaths, 2,052 suspected MIs, and 468 suspected strokes. Manual review of documents by Duke Clinical Research Institute clinical events classification (CEC) coordinators identified an additional 31 suspected deaths, 49 suspected MIs, and 28 suspected strokes. There were 127 CEC queries issued requesting additional information on suspected deaths; 43 were closed with no site response, 61 were closed with a response that no additional data were available, and additional data were received for 23. Seventy CEC queries were issued requesting additional information for suspected MI and stroke events; 31 were closed with no site response, 20 were closed with a response that no additional data were available, and 19 resulted in additional data.Comprehensive procedures were used for rigorous event reascertainment and readjudication in a previously completed open-label, global clinical trial. These procedures used in this unique situation were consistent with other common approaches in the field, were enhanced to address the FDA concerns about the original RECORD trial results, and could be considered by clinical trialists designing event readjudication protocols for drug development programs that have been completed.

    View details for DOI 10.1016/j.ahj.2013.05.005

    View details for Web of Science ID 000322629000004

    View details for PubMedID 23895802

  • Provider Specialty and Atrial Fibrillation Treatment Strategies in United States Community Practice: Findings From the ORBIT-AF Registry JOURNAL OF THE AMERICAN HEART ASSOCIATION Fosbol, E. L., Holmes, D. N., Piccini, J. P., Thomas, L., Reiffel, J. A., Mills, R. M., Kowey, P., Mahaffey, K., Gersh, B. J., Peterson, E. D. 2013; 2 (4)

    Abstract

    The prevalence of atrial fibrillation (AF) continues to increase; however, there are limited data describing the division of care among practitioners in the community and whether care differs depending on provider specialty.Using the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF) Registry, we described patient characteristics and AF management strategies in ambulatory clinic practice settings, including electrophysiology (EP), general cardiology, and primary care. A total of 10 097 patients were included; of these, 1544 (15.3%) were cared for by an EP provider, 6584 (65.2%) by a cardiology provider, and 1969 (19.5%) by an internal medicine/primary care provider. Compared with those patients who were cared for by cardiologists or internal medicine/primary care providers, patients cared for by EP providers were younger (median age, 73 years [interquartile range, IQR, 64, 80 years, Q1, Q3] versus 75 years [IQR, 67, 82 years] for cardiology and versus 76 years [IQR, 68, 82 years] for primary care). Compared with cardiology and internal medicine/primary care providers, EP providers used rhythm control (versus rate control) management more often (44.2% versus 29.7% and 28.8%, respectively, P<0.0001; adjusted odds ratio [OR] EP versus cardiology, 1.66 [95% confidence interval, CI, 1.05 to 2.61]; adjusted OR for internal medicine/primary care versus cardiology, 0.91 [95% CI, 0.65 to 1.26]). Use of oral anticoagulant therapy was high across all providers, although it was higher for cardiology and EP providers (overall, 76.1%; P=0.02 for difference between groups).Our data demonstrate important differences between provider specialties, the demographics of the AF patient population treated, and treatment strategies-particularly for rhythm control and anticoagulation therapy.

    View details for DOI 10.1161/JAHA.113.000110

    View details for Web of Science ID 000326340900011

    View details for PubMedID 23868192

  • Results of a reevaluation of cardiovascular outcomes in the RECORD trial AMERICAN HEART JOURNAL Mahaffey, K. W., Hafley, G., Dickerson, S., Burns, S., Tourt-Uhlig, S., White, J., Newby, L. K., Komajda, M., McMurray, J., Bigelow, R., Home, P. D., Lopes, R. D. 2013; 166 (2): 240-?

    Abstract

    The US Food and Drug Administration (FDA) required a reevaluation of cardiovascular (CV) outcomes in the RECORD trial. This provided an opportunity to assess the implications of event adjudication by 2 groups and quantify the differences as well as to use new FDA end point definitions in development.Original data were used to systematically identify all potential deaths, myocardial infarctions (MIs), and strokes. Site investigators were approached for additional source documents and information about participants lost to follow-up. Suspected events were adjudicated using standard procedures, and the results were compared with the original trial outcomes.Follow-up for mortality was 25,833 person-years, including an additional 328 person-years identified during the reevaluation effort. A total of 184 CV or unknown-cause deaths (88 rosiglitazone, 96 metformin/sulfonylurea), 128 participants with an MI (68 rosiglitazone, 60 metformin/sulfonylurea), and 113 participants with a stroke (50 rosiglitazone, 63 metformin/sulfonylurea) were included. The hazard ratio (HR) for rosiglitazone versus metformin/sulfonylurea for the end point of CV (or unknown cause) death, MI, or stroke was 0.95 (95% CI 0.78-1.17) compared with 0.93 (95% CI 0.74-1.15) for the original RECORD results. Treatment comparisons for MI (HR 1.13, 95% CI 0.80-1.59) and mortality (HR 0.86, 95% CI 0.68-1.08) were also the same compared with the original RECORD results. Sensitivity analyses were also consistent with the original RECORD results. Analyses using the FDA definitions showed similar results.Only a modest number of additional person-years of follow-up were ascertained from this reevaluation of CV end points in RECORD. Observed HRs and CIs from these analyses using the original RECORD or new FDA end point definitions showed similar treatment effects of rosiglitazone compared with the original RECORD results.

    View details for DOI 10.1016/j.ahj.2013.05.004

    View details for Web of Science ID 000322629000008

    View details for PubMedID 23895806

  • Trends in clinical trials of non-ST-segment elevation acute coronary syndromes over 15 years INTERNATIONAL JOURNAL OF CARDIOLOGY Chan, M. Y., Sun, J., Newby, L. K., Lokhnygina, Y., White, H. D., Moliterno, D. J., Theroux, P., Ohman, E. M., Simoons, M. L., Mahaffey, K. W., Pieper, K. S., Giugliano, R. P., Armstrong, P. W., Califf, R. M., Van de Werf, F., Harrington, R. A. 2013; 167 (2): 548-554

    Abstract

    BACKGROUND: Data are limited on whether clinical trials have randomized higher-risk patients over time and how trends in risk profiles and evidence-based pharmacotherapies have influenced trial outcomes. We quantified changes in baseline risk, treatment, and outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) randomized in 9 phase 3 clinical trials of antithrombotic therapy over 15years. METHODS: We studied 58,771 patients in GUSTO IIb, PURSUIT, PARAGON-A, PARAGON-B, PRISM, PRISM-PLUS, GUSTO IV-ACS, SYNERGY, and EARLY ACS. Patient-level data were mapped to 3 pre-specified 5-year randomization periods. Temporal trends in GRACE score-predicted mortality were compared with trends in observed mortality. RESULTS: Over time, in-hospital and discharge use of thienopyridines (p=0.001), statins (p<0.0001), and angiotensin-converting enzyme inhibitors (p<0.0001) increased, and hospital length-of-stay decreased (p=0.024). Blood transfusion use increased (8.3% [1994-98], 10.7% [1999-2003], 13% [2004-08], p=0.0002) despite stable rates of severe bleeding (0.9% [1994-98], 1.4% [1999-2003] and 1.1% [2004-08], p=0.127) and coronary artery bypass grafting (12.4% [1994-98], 13.7% [1999-2003] 13.1% [2004-08], p=0.880). Although predicted 6-month mortality increased (6.9% [1994-98], 9.0% [1999-2003], 7.9% [2004-08], p=0.017), observed 6-month mortality decreased (6.7% [1994-98], 5.8% [1999-2003], 5.1% [2004-08], p=0.025). Thirty-day myocardial infarction rates remained stable (9.2% [1994-98], 9.3% [1999-2003], 10% [2004-08], p=0.539). CONCLUSIONS: Despite enrolling higher-risk patients into these NSTE ACS trials, with better treatment, observed mortality declined over the past 15years. The appropriateness of increased blood transfusion despite unchanged bleeding rates deserves further study.

    View details for DOI 10.1016/j.ijcard.2012.01.065

    View details for Web of Science ID 000320768800050

    View details for PubMedID 22341697

  • Cardiac Troponin After Percutaneous Coronary Intervention and 1-Year Mortality in Non-ST-Segment Elevation Acute Coronary Syndrome Using Systematic Evaluation of Biomarker Trends JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tricoci, P., Leonardi, S., White, J., White, H. D., Armstrong, P. W., Montalescot, G., Giugliano, R. P., Gibson, C. M., Van de Werf, F., Califf, R. M., Harrington, R. A., Braunwald, E., Mahaffey, K. W., Newby, L. K. 2013; 62 (3): 242-251

    Abstract

    OBJECTIVES: We reviewed cardiac troponin (cTn) trends during non-ST-segment elevation acute coronary syndrome (NSTE ACS) in patients undergoing percutaneous coronary intervention (PCI) in EARLY ACS and SYNERGY and studied the relationship between post-PCI cTn and mortality. BACKGROUND: The prognostic value of cTn post-PCI is controversial. In patients with NSTE ACS, it is especially difficult to distinguish between cTn elevations due to PCI or index myocardial infarction (MI). METHODS: Time and cTn (indexed by upper limit of normal [ULN]) data pairs were plotted for 10,199 patients and independently reviewed by 2 physicians to identify patients in whom post-PCI cTn elevation could be distinguished from that of index MI. Post-PCI cTn peak was identified for each plot, and its relationship with 1-year mortality was evaluated using Cox modeling, correcting for 15 clinical variables from the EARLY ACS 1-year mortality model (including baseline cTn). We used an identical methodology to assess the association between creatine kinase-MB (CK-MB) and 1-year mortality. RESULTS: Patients with cTn (re)elevation post-PCI not evaluable were identified and excluded from further analysis (4198 [41%] with cTn rising prior to PCI; 229 [2%] with missing cTn). Among the remainder (N=5772 [57%]), in the multivariable model, peak cTn post-PCI was associated with a 7% increase in mortality (hazard ratio [HR] for 10x ULN increase, 1.07; 95% confidence interval [CI], 1.02-1.11; p=0.0038). Peak post-PCI CK-MB was significantly associated with 1-year mortality (HR for 1x ULN increase, 1.13; 95% CI, 1.05-1.21; p=0.0013). CONCLUSIONS: We used a methodology that differentiated post-PCI cTn (re)elevation from that of presenting MI in more than half of patients with NSTE ACS undergoing PCI. This identified a highly significant relationship between post-PCI cTn and 1-year mortality, with implication for both incorporating a cTn post-PCI MI definition and preventing PCI-related myonecrosis.

    View details for DOI 10.1016/j.jacc.2013.04.043

    View details for Web of Science ID 000321695500011

    View details for PubMedID 23684676

  • Use of Evidence-based Cardiac Prevention Therapy Among Outpatients with Atrial Fibrillation AMERICAN JOURNAL OF MEDICINE Hess, P. L., Kim, S., Piccini, J. P., Allen, L. A., Ansell, J. E., Chang, P., Freeman, J. V., Gersh, B. J., Kowey, P. R., Mahaffey, K. W., Thomas, L., Peterson, E. D., Fonarow, G. C. 2013; 126 (7): 625-?

    Abstract

    Patients with atrial fibrillation often have cardiovascular risk factors or known comorbid disease, yet the use of evidence-based primary and secondary prevention cardiac therapy among atrial fibrillation outpatients is unknown.Using baseline data collected between June 2010 and August 2011 from 174 sites participating in ORBIT-AF, a US national registry of patients with atrial fibrillation coordinated from Durham, NC, we examined professional guideline-recommended evidence-based therapy use for cardiovascular comorbid conditions and risk factors. Multivariable logistic regression was used to identify factors associated with receipt of all indicated evidence-based therapy.Among 10,096 enrolled patients, 93.5% were eligible for one or more evidence-based therapies. Among those eligible, 46.6% received all indicated therapies: 62.3% received an antiplatelet agent, 72.3% received a beta-blocker, 59.5% received an angiotensin-converting enzyme or angiotensin receptor blocker, 15.3% received an aldosterone antagonist, 65.7% received a statin, and 58.8% received an implantable cardioverter-defibrillator. A minority of patients with coronary artery disease, diabetes mellitus, heart failure, and peripheral vascular disease received all indicated therapies (25.1%, 43.2%, 42.5%, and 43.4%, respectively). A total of 52.4% of patients had controlled hypertension and 74.6% of patients with hyperlipidemia received a statin. Factors associated with nonreceipt of all indicated therapies included frailty, comorbid illness, geographic region, and antiarrhythmic drug therapy.The majority of eligible atrial fibrillation outpatients did not receive all guideline-recommended therapies for cardiovascular comorbid conditions and risk factors. This represents a potential opportunity to improve atrial fibrillation patients' quality of care and outcomes.

    View details for DOI 10.1016/j.amjmed.2013.01.037

    View details for Web of Science ID 000320649800028

    View details for PubMedID 23787195

  • Highlights from the fifth international symposium of thrombosis and anticoagulation (ISTA V), October 18-19, 2012, Belo Horizonte, Minas Gerais, Brazil. Journal of thrombosis and thrombolysis Lopes, R. D., Becker, R. C., Newby, L. K., Peterson, E. D., Hylek, E. M., Giugliano, R., Granger, C. B., Mahaffey, K. W., Carvalho, A. C., Berwanger, O., Giraldez, R. R., Feitosa-Filho, G. S., Barbosa, M. M., da Consolacao V Moreira, M., Kalil, R. A., Freitas, M., de Campos Guerra, J. C., Barros, M. V., da Rocha Rodrigues, T., Lopes, A. C., Garcia, D. A. 2013; 36 (1): 115-130

    Abstract

    To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fifth International Symposium of Thrombosis and Anticoagulation was held in Belo Horizonte, Minas Gerais, Brazil, on October 18-19, 2012. This scientific program was developed by clinicians for clinicians and was promoted by three major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, and Hospital do Coração Research Institute. Comprising 2 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

    View details for DOI 10.1007/s11239-013-0906-z

    View details for PubMedID 23494487

  • Efficacy and Safety of Rivaroxaban in Patients With Heart Failure and Nonvalvular Atrial Fibrillation Insights From ROCKET AF CIRCULATION-HEART FAILURE van Diepen, S., Hellkamp, A. S., Patel, M. R., Becker, R. C., Breithardt, G., Hacke, W., Halperin, J. L., Hankey, G. J., Nessel, C. C., Singer, D. E., Berkowitz, S. D., Califf, R. M., Fox, K. A., Mahaffey, K. W. 2013; 6 (4): 740-747

    Abstract

    In Rivaroxaban Once daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), rivaroxaban was noninferior to warfarin for the prevention of stroke and systemic embolic events and significantly reduced intracranial bleeding in patients with nonvalvular atrial fibrillation. We explore the safety and efficacy of rivaroxaban in patients with heart failure (HF).A total of 9033 (63.7%) patients had HF. The primary efficacy analysis was rates of stroke or systemic embolism (per 100 patient-years) by intention to treat. The safety outcomes were major or nonmajor clinically relevant bleeding and hemorrhagic stroke during treatment. Patients with HF were younger (72 versus 74 years), more likely to have persistent atrial fibrillation (83.0% versus 77.6%), and had higher mean CHADS2 scores (3.7 versus 3.1). The efficacy of rivaroxaban compared with warfarin was similar in patients with HF (1.90 versus 2.09) and without HF (2.10 versus 2.54; P-interaction=0.62). The risk of major or nonmajor clinically relevant bleeding with rivaroxaban was similar to warfarin in patients with HF (14.22 versus 14.02) and without HF (16.12 versus 15.35; P-interaction=0.99). A reduction in hemorrhagic stroke was observed with rivaroxaban in patients with HF as in the overall trial (adjusted hazard ratio, 0.38; 95% confidence interval, 0.19-0.76; P-interaction=0.067). Among patients with HF, the efficacy of rivaroxaban was similar, irrespective of ejection fraction <40 or ≥ 40% (P-interaction=0.38), New York Heart Association class I-II versus III-IV (P-interaction=0.68), HF preserved or reduced ejection fraction (P-interaction=0.35), or CHADS2 score 2 versus ≥ 3 (P-interaction=0.48).Treatment-related outcomes were similar in patients with and without HF and across HF subgroups. These findings support the use of rivaroxaban as an alternative to warfarin in patients with atrial fibrillation and HF. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCHEARTFAILURE.113.000212

    View details for Web of Science ID 000335157800023

    View details for PubMedID 23723250

  • End of Study Transition From Study Drug to Open-Label Vitamin K Antagonist Therapy: The ROCKET AF Experience CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Mahaffey, K. W., Hellkamp, A. S., Patel, M. R., Hannan, K. L., Schwabe, K., Nessel, C. C., Berkowitz, S. D., Halperin, J. L., Hankey, G. J., Becker, R. C., Piccini, J. P., Breithardt, G., Hacke, W., Singer, D. E., Califf, R. M., Fox, K. A. 2013; 6 (4): 470-478

    Abstract

    To evaluate the previously reported excess of thromboembolic events during the 30 days after the end of study (EOS) visit when participants transitioned from blinded therapy to open-label vitamin K antagonist.At the EOS visit, open-label vitamin K antagonist was recommended, and the international normalized ratio (INR) was not to be measured until 3 days later to preserve blinding. We analyzed transition strategies, clinical outcomes, and INR values. Event rates are per 100 patient-years. A total of 9248 (65%) participants were taking study drug at EOS, and, between days 3 and 30, an excess of stroke and systemic embolic events were observed in participants assigned to rivaroxaban (rivaroxaban 22 events, event rate 6.42; warfarin 6 events, event rate 1.73; hazard ratio, 3.72; 95% confidence interval, 1.51-9.16; P=0.0044). No INR values were reported for ≈5% of participants transitioned to warfarin. By 30 days after EOS, 83% of the warfarin group and 52% of the rivaroxaban group had ≥1 therapeutic INR value. Median time to first therapeutic INR was 3 days in the warfarin group and 13 days in the rivaroxaban group.The excess of events at EOS was likely because of a period of inadequate anticoagulation in rivaroxaban participants switched to vitamin K antagonist therapy. If transition from rivaroxaban to vitamin K antagonist is needed, timely monitoring and careful dosing should be used to ensure consistent and adequate anticoagulation.

    View details for DOI 10.1161/CIRCOUTCOMES.113.000132

    View details for Web of Science ID 000321898000015

    View details for PubMedID 23759472

  • Risks and Benefits of Anticoagulation in Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Cullen, M. W., Kim, S., Piccini, J. P., Ansell, J. E., Fonarow, G. C., Hylek, E. M., Singer, D. E., Mahaffey, K. W., Kowey, P. R., Thomas, L., Go, A. S., Lopes, R. D., Chang, P., Peterson, E. D., Gersh, B. J. 2013; 6 (4): 461-469

    Abstract

    Patients with atrial fibrillation (AF) at the highest stroke risk derive the largest benefit from oral anticoagulation (OAC). Those with the highest stroke risk have been paradoxically less likely to receive OAC. This study assessed the association between stroke and bleeding risk on rates of OAC.We analyzed OAC use among 10,098 patients with AF from 174 community-based outpatient practices enrolled in 2010-2011 in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). OAC was defined as warfarin or dabigatran use at study enrollment. Stroke and bleeding risk were calculated using congestive heart failure, hypertension, age, diabetes mellitus, prior stroke (CHADS₂), and anticoagulation and risk factors in AF (ATRIA) scores, respectively. The mean subject age was 73 years; 58% were men. Overall, 76% of patients received OAC (71% warfarin and 5% dabigatran). The use of OAC increased among those with higher CHADS₂ scores, from 53% for CHADS₂=0 to 80% for CHADS₂≥2 (P<0.001). OAC use fell slightly with increasing ATRIA bleeding risk score, from 81% for ATRIA=3 to 73% for ATRIA≥5 (P<0.001). A significant interaction existed between ATRIA and CHADS₂ scores (P=0.021). Among those with low bleeding risk, use of OAC increased significantly with increasing stroke risk. Among those with high bleeding risk, CHADS₂ stroke risk had a smaller impact on use of OAC.In community-based outpatients with AF, use of OAC was high and driven by not only predominantly stroke but also bleeding risk. Stroke risk significantly affects OAC use among those with low bleeding risk, whereas those with high bleeding risk demonstrate consistently lower use of OAC regardless of stroke risk.

    View details for DOI 10.1161/CIRCOUTCOMES.113.000127

    View details for Web of Science ID 000321898000014

    View details for PubMedID 23759473

  • Prognostic Significance of Bleeding Location and Severity Among Patients With Acute Coronary Syndromes JACC-CARDIOVASCULAR INTERVENTIONS Vavalle, J. P., Clare, R., Chiswell, K., Rao, S. V., Petersen, J. L., Kleiman, N. S., Mahaffey, K. W., Wang, T. Y. 2013; 6 (7): 709-717

    Abstract

    This study sought to determine if there is an association between bleed location and clinical outcomes in acute coronary syndromes (ACS) patients.The prognostic significance of bleeding location among ACS patients undergoing cardiac catheterization is not well known.We analyzed in-hospital bleeding events among 9,978 patients randomized in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) study. Bleeding events were categorized by location as access site, systemic, surgical, or superficial, and severity was graded using the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definition. We assessed the association of each bleeding location and severity with 6-month risk of death or myocardial infarction using a multicovariate-adjusted Cox proportional hazard model.A total of 4,900 bleeding events were identified among 3,694 ACS patients with in-hospital bleeding. Among 4,679 GUSTO mild/moderate bleeding events, only surgical and systemic bleeds were associated with an increased risk of 6-month death or myocardial infarction (adjusted hazard ratio [HR]: 2.52 [95% confidence interval (CI): 2.16 to 2.94, and 1.40 [95% CI: 1.16 to 1.69], respectively). Mild/moderate superficial and access-site bleeds were not associated with downstream risk (adjusted HR: 1.17 [95% CI: 0.97 to 1.40], and 0.96 [95% CI: 0.82 to 1.12], respectively). Among 221 GUSTO severe bleeds, surgical bleeds were associated with the highest risk (HR: 5.27 [95% CI: 3.80 to 7.29]), followed by systemic (HR: 4.48 [95% CI: 2.98 to 6.72]), and finally access-site bleeds (HR: 3.57 [95% CI: 2.35 to 5.40]).Among ACS patients who develop in-hospital bleeding, systemic and surgical bleeding are associated with the highest risks of adverse outcomes regardless of bleeding severity. Although the most frequent among bleeds, GUSTO mild/moderate access-site bleeding is not associated with increased risk. These data underscore the importance of strategies to minimize overall bleeding risk beyond vascular access site management.

    View details for DOI 10.1016/j.jcin.2013.03.010

    View details for Web of Science ID 000322129400013

    View details for PubMedID 23866183

  • Highlights from the fifth international symposium of thrombosis and anticoagulation (ISTA V), october 18-19, 2012, Belo Horizonte, Minas Gerais, Brazil JOURNAL OF THROMBOSIS AND THROMBOLYSIS Lopes, R. D., Becker, R. C., Newby, L. K., Peterson, E. D., Hylek, E. M., Giugliano, R., Granger, C. B., Mahaffey, K. W., Carvalho, A. C., Berwanger, O., Giraldez, R. R., Feitosa-Filho, G. S., Barbosa, M. M., Moreira, M. d., Kalil, R. A., Freitas, M., de Campos Guerra, J. C., Lins Barros, M. V., Rodrigues, T. d., Lopes, A. C., Garcia, D. A. 2013; 36 (1): 115-130
  • Clinical Outcomes With Rivaroxaban in Patients Transitioned From Vitamin K Antagonist Therapy A Subgroup Analysis of a Randomized Trial ANNALS OF INTERNAL MEDICINE Mahaffey, K. W., Wojdyla, D., Hankey, G. J., White, H. D., Nessel, C. C., Piccini, J. P., Patel, M. R., Berkowitz, S. D., Becker, R. C., Halperin, J. L., Singer, D. E., Califf, R. M., Fox, K. A., Breithardt, G., Hacke, W. 2013; 158 (12): 861-?

    Abstract

    In ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation), a large randomized, clinical trial, rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in patients with atrial fibrillation.To determine the efficacy and safety of rivaroxaban compared with warfarin among vitamin K antagonist (VKA)-naive and VKA-experienced patients.Prespecified subgroup analysis. (ClinicalTrials.gov: NCT00403767).Global.14,264 persons with atrial fibrillation.Interaction of the relative treatment effect of rivaroxaban and warfarin on stroke or systemic embolism among VKA-naive and VKA-experienced patients.Overall, 7897 (55.4%) patients were VKA-experienced and 6367 (44.6%) were VKA-naive. The effect of rivaroxaban versus warfarin on stroke or systemic embolism was consistent: Rates per 100 patient-years of follow-up were 2.32 versus 2.87 for VKA-naive patients (hazard ratio [HR], 0.81 [95% CI, 0.64 to 1.03]) and 1.98 versus 2.09 for VKA-experienced patients (HR, 0.94 [CI, 0.75 to 1.18]; interaction P = 0.36). During the first 7 days, rivaroxaban was associated with more bleeding than warfarin (HR in VKA-naive patients, 5.83 [CI, 3.25 to 10.44], and in VKA-experienced patients, 6.66 [CI, 3.83 to 11.58]; interaction P = 0.53). After 30 days, rivaroxaban was associated with less bleeding than warfarin in VKA-naive patients (HR, 0.84 [CI, 0.74 to 0.95]) and similar bleeding in VKA-experienced patients (HR, 1.06 [CI, 0.96 to 1.17]; interaction P = 0.003).The trial was not designed to detect differences in these subgroups.The efficacy of rivaroxaban in VKA-experienced and VKA-naive patients was similar to that of the overall trial. There were more bleeding events within 7 days of study drug initiation with rivaroxaban, but after 30 days, rivaroxaban was associated with less bleeding in VKA-naive patients and similar bleeding in VKA-experienced patients. This information may be useful to clinicians considering a transition to rivaroxaban for patients receiving VKA therapy.Johnson & Johnson and Bayer HealthCare.

    View details for Web of Science ID 000320645000014

    View details for PubMedID 23778903

  • Effect of vorapaxar on myocardial infarction in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome (TRA.CER) trial EUROPEAN HEART JOURNAL Leonardi, S., Tricoci, P., White, H. D., Armstrong, P. W., Huang, Z., Wallentin, L., Aylward, P. E., Moliterno, D. J., Van de Werf, F., Chen, E., Providencia, L., Nordrehaug, J. E., Held, C., Strony, J., Rorick, T. L., Harrington, R. A., Mahaffey, K. W. 2013; 34 (23): 1723-1731

    Abstract

    AimsThe TRA·CER trial compared vorapaxar, a novel platelet protease-activated receptor (PAR)-1 antagonist, with placebo in 12 944 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS). In this analysis, we explored the effect of vorapaxar on myocardial infarction (MI).Methods and resultsA blinded, independent central endpoint adjudication committee prospectively defined and classified MI according to the universal MI definition, including peak cardiac marker value (creatine kinase-MB [CK-MB] and/or troponin). Because the trial failed to meet its primary endpoint, these analyses are considered exploratory. During a median follow-up of 502 days, 1580 MIs occurred in 1319 patients. The majority (n = 1025, 64.9%) were type 1 (spontaneous) MI, followed by type 4a [percutaneous coronary intervention (PCI)-related] MI (n = 352; 22.3%). Compared with placebo, vorapaxar reduced the hazard of a first MI of any type by 12% [hazard ratio (HR), 0.88; 95% confidence interval (CI), 0.79-0.98; P = 0.021] and the hazard of total number of MIs (first and subsequent) by 14% (HR, 0.86; 95% CI, 0.77-0.97; P = 0.014), an effect that was sustained over time. Vorapaxar reduced type 1 MI by 17% (HR, 0.83; 95% CI, 0.73-0.95; P = 0.007). Type 4a MIs were not significantly reduced by vorapaxar (HR, 0.90; 95% CI, 0.73-1.12; P = 0.35). Vorapaxar effect was consistent across MI sizes defined by peak cardiac marker elevations and across key clinical subgroups; however, in patients not treated with thienopyridine at baseline (HR, 0.65; 95% CI, 0.46-0.92) compared with patients who received thienopyridine (HR, 0.91; 95% CI, 0.81-1.02), there was a trend towards a higher effect (Pint = 0.077).ConclusionThe PAR-1 antagonist vorapaxar was associated with a reduction of MI, including total number of infarctions. This reduction was sustained over time and was mostly evident in type 1 MI, the most common type of MI observed.

    View details for DOI 10.1093/eurheartj/eht104

    View details for Web of Science ID 000320408500009

    View details for PubMedID 23530022

  • Heart Failure Complicating Non-ST-Segment Elevation Acute Coronary Syndrome Timing, Predictors, and Clinical Outcomes JACC-HEART FAILURE Bahit, M. C., Lopes, R. D., Clare, R. M., Newby, L. K., Pieper, K. S., Van de Werf, F., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Diaz, R., Ohman, E. M., White, H. D., James, S., Granger, C. B. 2013; 1 (3): 223-229

    Abstract

    This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS).Little is known about HF-complicating NSTE-ACS.Using pooled patient-level data from 7 clinical trials from 1994 to 2008, we describe the occurrence and timing of HF, associated clinical factors, and 30-day outcomes in NSTE-ACS patients. HF at presentation was defined as Killip classes II to III; patients with Killip class IV or cardiogenic shock were excluded. New in-hospital cases of HF included new pulmonary edema. After adjusting for baseline variables, we created logistic regression models to identify clinical factors associated with HF at presentation and to determine the association between HF and 30-day mortality.Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization.In this large cohort of NSTE-ACS patients, presenting with or developing HF during hospitalization was associated with an increased risk of 30-day mortality. Research targeting new strategies to prevent and manage HF in this high-risk population is needed.

    View details for DOI 10.1016/j.jchf.2013.02.007

    View details for Web of Science ID 000209535500007

  • Quantification of the effect of clopidogrel on enzymatic infarct size related to a percutaneous coronary intervention in patients with acute coronary syndromes: insights from the CHAMPION percutaneous coronary intervention trial CORONARY ARTERY DISEASE Leonardi, S., Stebbins, A., Lopes, R. D., Lokhnygina, Y., Todd, M., Bhatt, D. L., Stone, G. W., Lincoff, A. M., Dauerman, H. L., Gibson, C. M., White, H. D., Parikh, K. H., Gruberg, L., Herrmann, H. C., McLaurin, B. T., Goodman, S. G., Mahaffey, K. W. 2013; 24 (4): 321-327

    Abstract

    Using data from the CHAMPION percutaneous coronary intervention (PCI), we determined the relationship between clopidogrel started at least 5 days before PCI (maintenance of clopidogrel) and PCI-related enzymatic infarct size.Clopidogrel is recommended in patients with acute coronary syndrome (ACS) managed with PCI, but its effect on PCI-related myonecrosis in contemporary patients has not been quantified.Patients with ACS (with or without ST-segment elevation) who underwent PCI and had at least three creatine kinase-MB (CK-MB) samples after PCI were included. Enzymatic infarct size was defined as the peak CK-MB concentration indexed by its upper limit of normal. Associations between maintenance clopidogrel and enzymatic infarct size were explored using multivariable linear regression (with and without missing data imputation) and propensity score analysis using inverse probability weighting.Of 8877 patients randomized, 6327 (71.3%) were included (median age 61 years, 73% male, 13% ACS with ST-segment elevation). Of these 6327 patients, 2015 (31.8%) were on maintenance clopidogrel. After multivariable adjustment, maintenance clopidogrel was associated with a reduction in enzymatic infarct size {β=-0.63; 47% decrease in peak CK-MB [95% confidence interval (CI) 35, 56%]}. Multivariable linear regression with multiple imputations and inverse probability weighting propensity score analysis yielded similar results, with maintenance clopidogrel associated with 44% (95% CI 33, 53%) and 29% (95% CI 24, 33%) infarct size reductions.In this subgroup analysis of modern ACS patients, clopidogrel maintenance was independently associated with smaller enzymatic infarct size after PCI. These results are consistent with previous observations suggesting a benefit of clopidogrel on the procedural outcome and quantify this benefit.

    View details for DOI 10.1097/MCA.0b013e32835f2fbd

    View details for Web of Science ID 000318154600010

    View details for PubMedID 23442944

  • Heart Failure Complicating Non-ST-Segment Elevation Acute Coronary Syndrome: Timing, Predictors, and Clinical Outcomes. JACC. Heart failure Bahit, M. C., Lopes, R. D., Clare, R. M., Newby, L. K., Pieper, K. S., Van de Werf, F., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Diaz, R., Ohman, E. M., White, H. D., James, S., Granger, C. B. 2013; 1 (3): 223-229

    Abstract

    This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS).Little is known about HF-complicating NSTE-ACS.Using pooled patient-level data from 7 clinical trials from 1994 to 2008, we describe the occurrence and timing of HF, associated clinical factors, and 30-day outcomes in NSTE-ACS patients. HF at presentation was defined as Killip classes II to III; patients with Killip class IV or cardiogenic shock were excluded. New in-hospital cases of HF included new pulmonary edema. After adjusting for baseline variables, we created logistic regression models to identify clinical factors associated with HF at presentation and to determine the association between HF and 30-day mortality.Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization.In this large cohort of NSTE-ACS patients, presenting with or developing HF during hospitalization was associated with an increased risk of 30-day mortality. Research targeting new strategies to prevent and manage HF in this high-risk population is needed.

    View details for DOI 10.1016/j.jchf.2013.02.007

    View details for PubMedID 24621874

  • Outcomes After Cardioversion and Atrial Fibrillation Ablation in Patients Treated With Rivaroxaban and Warfarin in the ROCKET AF Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Piccini, J. P., Stevens, S. R., Lokhnygina, Y., Patel, M. R., Halperin, J. L., Singer, D. E., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Mahaffey, K. W., Fox, K. A., Califf, R. M., Breithardt, G. 2013; 61 (19): 1998-2006

    Abstract

    This study sought to investigate the outcomes following cardioversion or catheter ablation in patients with atrial fibrillation (AF) treated with warfarin or rivaroxaban.There are limited data on outcomes following cardioversion or catheter ablation in AF patients treated with factor Xa inhibitors.We compared the incidence of electrical cardioversion (ECV), pharmacologic cardioversion (PCV), or AF ablation and subsequent outcomes in patients in a post hoc analysis of the ROCKET AF (Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation) trial.Over a median follow-up of 2.1 years, 143 patients underwent ECV, 142 underwent PCV, and 79 underwent catheter ablation. The overall incidence of ECV, PCV, or AF ablation was 1.45 per 100 patient-years (n = 321; 1.44 [n = 161] in the warfarin arm, 1.46 [n = 160] in the rivaroxaban arm). The crude rates of stroke and death increased in the first 30 days after cardioversion or ablation. After adjustment for baseline differences, the long-term incidence of stroke or systemic embolism (hazard ratio [HR]: 1.38; 95% confidence interval [CI]: 0.61 to 3.11), cardiovascular death (HR: 1.57; 95% CI: 0.69 to 3.55), and death from all causes (HR: 1.75; 95% CI: 0.90 to 3.42) were not different before and after cardioversion or AF ablation. Hospitalization increased after cardioversion or AF ablation (HR: 2.01; 95% CI: 1.51 to 2.68), but there was no evidence of a differential effect by randomized treatment (p value for interaction = 0.58). The incidence of stroke or systemic embolism (1.88% vs. 1.86%) and death (1.88% vs. 3.73%) were similar in the rivaroxaban-treated and warfarin-treated groups.Despite an increase in hospitalization, there were no differences in long-term stroke rates or survival following cardioversion or AF ablation. Outcomes were similar in patients treated with rivaroxaban or warfarin. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation [ROCKET AF]; NCT00403767).

    View details for DOI 10.1016/j.jacc.2013.02.025

    View details for Web of Science ID 000318910300011

    View details for PubMedID 23500298

  • Methods of creatine kinase-MB analysis to predict mortality in patients with myocardial infarction treated with reperfusion therapy TRIALS Lopes, R. D., Lokhnygina, Y., Hasselblad, V., Newby, K. L., Yow, E., Granger, C. B., Armstrong, P. W., Hochman, J. S., Mills, J. S., Ruzyllo, W., Mahaffey, K. W. 2013; 14

    Abstract

    Larger infarct size measured by creatine kinase (CK)-MB release is associated with higher mortality and has been used as an important surrogate endpoint in the evaluation of new treatments for ST-segment elevation myocardial infarction (STEMI). Traditional approaches to quantify infarct size include the observed CK-MB peak and calculated CK-MB area under the curve (AUC). We evaluated alternative approaches to quantifying infarct size using CK-MB values, and the relationship between infarct size and clinical outcomes.Of 1,850 STEMI patients treated with reperfusion therapy in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) (percutaneous coronary intervention (PCI)-treated) and the COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) (fibrinolytic-treated) trials, 1,718 (92.9%) (COMMA, n = 868; COMPLY, n = 850) had at least five of nine protocol-required CK-MB measures. In addition to traditional methods, curve-fitting techniques were used to determine CK-MB AUC and estimated peak CK-MB. Cox proportional hazards modeling assessed the univariable associations between infarct size and mortality, and the composite of death, heart failure, shock and stroke at 90 days.In COMPLY, CK-MB measures by all methods were significantly associated with higher mortality (hazard ratio range per 1,000 units increase: 1.09 to 1.13; hazard ratio range per 1 standard deviation increase: 1.41 to 1.62; P <0.01 for all analyses). In COMMA, the associations were similar but did not reach statistical significance. For the composite outcome of 90-day death, heart failure, shock and stroke, the associations with all CK-MB measures were statistically significant in both the COMMA and COMPLY trials.Sophisticated curve modeling is an alternative to infarct-size quantification in STEMI patients, but it provides information similar to that of more traditional methods. Future studies will determine whether the same conclusion applies in circumstances other than STEMI, or to studies with different frequencies and patterns of CK-MB data collection.

    View details for DOI 10.1186/1745-6215-14-123

    View details for Web of Science ID 000319397900001

    View details for PubMedID 23782531

  • Incorporation of bleeding as an element of the composite end point in clinical trials of antithrombotic therapies in patients with non-ST-segment elevation acute coronary syndrome: Validity, pitfalls, and future approaches AMERICAN HEART JOURNAL Subherwal, S., Ohman, E. M., Mahaffey, K. W., Rao, S. V., Alexander, J. H., Wang, T. Y., Alexander, K. P., Hasselblad, V., Roe, M. T. 2013; 165 (5): 644-?

    Abstract

    With the large number of antithrombotic therapies available and under investigation for the treatment of non-ST-segment elevation acute coronary syndromes (NSTE ACS), practice guidelines now stress the importance of selecting an antithrombotic strategy according to the efficacy and safety profiles of the chosen agent. Contemporary trials have incorporated bleeding along with ischemic end points into a composite end point commonly referred to as net clinical benefit, which allows for simultaneous evaluation of the differences between benefit and harm for an investigational antithrombotic therapy. However, incorporating major bleeding into a composite end point that includes ischemic events is not warranted and is associated with many pitfalls. In this article, we discuss the validity of combining efficacy and safety end points to form a net clinical benefit composite end point with the traditional time-to-event analysis for trials evaluating antithrombotic therapies for NSTE ACS. We describe alternative statistical approaches for concurrent assessment of the safety and efficacy of antithrombotic therapies used to treat patients with NSTE ACS.

    View details for DOI 10.1016/j.ahj.2012.11.012

    View details for Web of Science ID 000318724000005

    View details for PubMedID 23622901

  • Effect of Platelet Inhibition with Cangrelor during PCI on Ischemic Events NEW ENGLAND JOURNAL OF MEDICINE Bhatt, D. L., Stone, G. W., Mahaffey, K. W., Gibson, C. M., Steg, P. G., Hamm, C. W., Price, M. J., Leonardi, S., Gallup, D., Bramucci, E., Radke, P. W., Widimsky, P., Tousek, F., Tauth, J., Spriggs, D., McLaurin, B. T., Angiolillo, D. J., Genereux, P., Liu, T., Prats, J., Todd, M., Skerjanec, S., White, H. D., Harrington, R. A. 2013; 368 (14): 1303-1313

    Abstract

    The intensity of antiplatelet therapy during percutaneous coronary intervention (PCI) is an important determinant of PCI-related ischemic complications. Cangrelor is a potent intravenous adenosine diphosphate (ADP)-receptor antagonist that acts rapidly and has quickly reversible effects.In a double-blind, placebo-controlled trial, we randomly assigned 11,145 patients who were undergoing either urgent or elective PCI and were receiving guideline-recommended therapy to receive a bolus and infusion of cangrelor or to receive a loading dose of 600 mg or 300 mg of clopidogrel. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis at 48 hours after randomization; the key secondary end point was stent thrombosis at 48 hours. The primary safety end point was severe bleeding at 48 hours.The rate of the primary efficacy end point was 4.7% in the cangrelor group and 5.9% in the clopidogrel group (adjusted odds ratio with cangrelor, 0.78; 95% confidence interval [CI], 0.66 to 0.93; P=0.005). The rate of the primary safety end point was 0.16% in the cangrelor group and 0.11% in the clopidogrel group (odds ratio, 1.50; 95% CI, 0.53 to 4.22; P=0.44). Stent thrombosis developed in 0.8% of the patients in the cangrelor group and in 1.4% in the clopidogrel group (odds ratio, 0.62; 95% CI, 0.43 to 0.90; P=0.01). The rates of adverse events related to the study treatment were low in both groups, though transient dyspnea occurred significantly more frequently with cangrelor than with clopidogrel (1.2% vs. 0.3%). The benefit from cangrelor with respect to the primary end point was consistent across multiple prespecified subgroups.Cangrelor significantly reduced the rate of ischemic events, including stent thrombosis, during PCI, with no significant increase in severe bleeding. (Funded by the Medicines Company; CHAMPION PHOENIX ClinicalTrials.gov number, NCT01156571.).

    View details for DOI 10.1056/NEJMoa1300815

    View details for Web of Science ID 000316989900007

    View details for PubMedID 23473369

  • Left Bundle Branch Block in Non-ST-Segment Elevation Acute Coronary Syndromes Incidence, Angiographic Characteristics, and Clinical Outcomes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rose, J. J., Newby, L. K., Broderick, S., Chiswell, K., Van de Werf, F., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Ohman, E. M., Giugliano, R. P., Goodman, S. G., White, H. D., Califf, R. M., Granger, C. B., Lopes, R. D. 2013; 61 (13): 1461-1463

    View details for DOI 10.1016/j.jacc.2012.12.032

    View details for Web of Science ID 000317191200017

    View details for PubMedID 23500249

  • Rate versus rhythm control for management of atrial fibrillation in clinical practice: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry AMERICAN HEART JOURNAL Steinberg, B. A., Holmes, D. N., Ezekowitz, M. D., Fonarow, G. C., Kowey, P. R., Mahaffey, K. W., Naccarelli, G., Reiffel, J., Chang, P., Peterson, E. D., Piccini, J. P. 2013; 165 (4): 622-629

    Abstract

    All patients with atrial fibrillation (AF) require optimization of their ventricular rate. Factors leading to use of additional rhythm control in clinical practice have not been thoroughly defined.The ORBIT-AF registry enrolled patients with AF from a broad range of practice settings and collected data on rate versus rhythm control, as indicated by the treating physician. Multivariable logistic regression analysis was performed to identify factors associated with each strategy.Of 10,061 patients enrolled, 6,859 (68%) were managed with rate only control versus 3,202 (32%) with rhythm control. Patients managed with rate control were significantly older and more likely to have hypertension, heart failure, prior stroke, and gastrointestinal bleeds. They also had fewer AF-related symptoms (41% with no symptoms vs 31% for rhythm control). Systemic anticoagulation was prescribed for 5,448 (79%) rate-control patients versus 2,219 (69%) rhythm-control patients (P < .0001). After multivariable adjustment, patients with higher symptom scores (severe symptoms vs. none, OR 1.62, 95% CI 1.41-1.87) and those referred to electrophysiologists (OR 1.64, 95% CI 1.45-1.85) were more likely to be managed with a rhythm control strategy.In this outpatient registry of US clinical practice, the majority of patients with AF were managed with rate control alone. Patients with more symptoms and who were treated by an electrophysiologist were more likely to receive rhythm-control therapies. A significant proportion of AF patients, regardless of treatment strategy, were not treated with anticoagulation for thromboembolism prophylaxis.

    View details for DOI 10.1016/j.ahj.2012.12.019

    View details for Web of Science ID 000317184300026

    View details for PubMedID 23537981

  • Dynamic modeling of 90-day mortality in ST-elevation myocardial infarction patients undergoing primary percutaneous coronary intervention AMERICAN HEART JOURNAL Westerhout, C. M., Pieper, K. S., James, S. K., Mahaffey, K. W., Van de Werf, F., Califf, R. M., Granger, C. B., Armstrong, P. W. 2013; 165 (3): 354-?

    Abstract

    Dynamic risk models update the risk profile of ST-elevation myocardial infarction (STEMI) patients over the acute period following the event and have implications to clinical practice and research.Multivariable survival models were developed in 5,745 STEMI patients undergoing primary percutaneous coronary intervention (PCI) enrolled in the APEX-AMI trial to predict 90-day mortality from 4 clinically relevant times: baseline, 2 hours, 24 hours, and 96 hours. Culprit coronary thrombolysis in myocardial infarction flow grade, 30-minute post-PCI worst-lead ST-elevation residual, and in-hospital clinical events were considered in the models. The 90-day mortality was 4.7%; the cumulative proportion of mortality occurring within 2, 24, and 96 hours was 8%, 22%, and 40% respectively. Relative to the baseline risk factors, age and systolic blood pressure remained highly ranked in the post-baseline models. However, the relative importance of heart rate, Killip class, and creatinine declined, whereas markers of coronary reperfusion and in-hospital events (shock, congestive heart failure) became increasingly influential. The c-index increased from 0.819 at baseline to 0.847 at 96 hours. Over the forecasting periods, the proportion of "low-risk" (<1.1% 90-day mortality) patients increased from 20% to 49%. This approach derived from an unfolding series of models reveals the shifting levels of mortality risk from baseline to 96 hours.This novel approach in STEMI patients undergoing primary PCI demonstrates the dynamic nature of risk over time and may prove useful in understanding risk and in clinical decision making.

    View details for DOI 10.1016/j.ahj.2012.12.001

    View details for Web of Science ID 000315710500019

    View details for PubMedID 23453104

  • Outcomes of Discontinuing Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation Analysis From the ROCKET AF Trial (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Patel, M. R., Hellkamp, A. S., Lokhnygina, Y., Piccini, J. P., Zhang, Z., Mohanty, S., Singer, D. E., Hacke, W., Breithardt, G., Halperin, J. L., Hankey, G. J., Becker, R. C., Nessel, C. C., Berkowitz, S. D., Califf, R. M., Fox, K. A., Mahaffey, K. W. 2013; 61 (6): 651-658

    Abstract

    The purpose of this study was to understand the possible risk of discontinuation in the context of clinical care.Rivaroxaban is noninferior to warfarin for preventing stroke in atrial fibrillation patients. Concerns exist regarding possible increased risk of stroke and non-central nervous system (CNS) thromboembolic events early after discontinuation of rivaroxaban.We undertook a post-hoc analysis of data from the ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation, n = 14,624) for stroke or non-CNS embolism within 30 days after temporary interruptions of 3 days or more, early permanent study drug discontinuation, and end-of-study transition to open-label therapy.Stroke and non-CNS embolism occurred at similar rates after temporary interruptions (rivaroxaban: n = 9, warfarin: n = 8, 6.20 vs. 5.05/100 patient-years, hazard ratio [HR]: 1.28, 95% confidence interval [CI]: 0.49 to 3.31, p = 0.62) and after early permanent discontinuation (rivaroxaban: n = 42, warfarin: n = 36, 25.60 vs. 23.28/100 patient-years, HR: 1.10, 95% CI: 0.71 to 1.72, p = 0.66). Patients transitioning to open-label therapy at the end of the study had more strokes with rivaroxaban (n = 22) versus warfarin (n = 6, 6.42 vs. 1.73/100 patient-years, HR: 3.72, 95% CI: 1.51 to 9.16, p = 0.0044) and took longer to reach a therapeutic international normalized ratio with rivaroxaban versus warfarin. All thrombotic events within 30 days of any study drug cessation (including stroke, non-CNS embolism, myocardial infarction, and vascular death) were similar between groups (HR: 1.02, 95% CI: 0.83 to 1.26, p = 0.85).In atrial fibrillation patients who temporarily or permanently discontinued anticoagulation, the risk of stroke or non-CNS embolism was similar with rivaroxaban or warfarin. An increased risk of stroke and non-CNS embolism was observed in rivaroxaban-treated patients compared with warfarin-treated patients after the end of the study, underscoring the importance of therapeutic anticoagulation coverage during such a transition.

    View details for DOI 10.1016/j.jacc.2012.09.057

    View details for Web of Science ID 000314660700010

    View details for PubMedID 23391196

  • Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial JOURNAL OF THE AMERICAN HEART ASSOCIATION Singer, D. E., Hellkamp, A. S., Piccini, J. P., Mahaffey, K. W., Lokhnygina, Y., Pan, G., Halperin, J. L., Becker, R. C., Breithardt, G., Hankey, G. J., Hacke, W., Nessel, C. C., Patel, M. R., Califf, R. M., Fox, K. A. 2013; 2 (1)

    Abstract

    Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial.TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i-TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i-TTR was 55.2% (SD 21.3%) and the median i-TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i-TTR, dominant determinants were previous warfarin use (mean i-TTR of 61.1% for warfarin-experienced versus 47.4% in VKA-naïve patients) and geographic region where patients were managed (mean i-TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i-TTRs had INR distributions shifted toward lower INR values and had longer inter-INR test intervals.Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i-TTR in global studies of warfarin. Regional differences in mean i-TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing.URL: ClinicalTrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/JAHA.112.000067

    View details for Web of Science ID 000326336800033

    View details for PubMedID 23525418

  • Renal Dysfunction as a Predictor of Stroke and Systemic Embolism in Patients With Nonvalvular Atrial Fibrillation Validation of the R(2)CHADS(2) Index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) Study Cohorts CIRCULATION Piccini, J. P., Stevens, S. R., Chang, Y., Singer, D. E., Lokhnygina, Y., Go, A. S., Patel, M. R., Mahaffey, K. W., Halperin, J. L., Breithardt, G., Hankey, G. J., Hacke, W., Becker, R. C., Nessel, C. C., Fox, K. A., Califf, R. M. 2013; 127 (2): 224-?

    Abstract

    We sought to define the factors associated with the occurrence of stroke and systemic embolism in a large, international atrial fibrillation (AF) trial.In ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation), 14 264 patients with nonvalvular AF and creatinine clearance ≥30 mL/min were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards modeling was used to identify factors at randomization independently associated with the occurrence of stroke or non-central nervous system embolism based on intention-to-treat analysis. A risk score was developed in ROCKET AF and validated in ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation), an independent AF patient cohort. Over a median follow-up of 1.94 years, 575 patients (4.0%) experienced primary end-point events. Reduced creatinine clearance was a strong, independent predictor of stroke and systemic embolism, second only to prior stroke or transient ischemic attack. Additional factors associated with stroke and systemic embolism included elevated diastolic blood pressure and heart rate, as well as vascular disease of the heart and limbs (C-index 0.635). A model that included creatinine clearance (R(2)CHADS(2)) improved net reclassification index by 6.2% compared with CHA(2)DS(2)VASc (C statistic=0.578) and by 8.2% compared with CHADS(2) (C statistic=0.575). The inclusion of creatinine clearance <60 mL/min and prior stroke or transient ischemic attack in a model with no other covariates led to a C statistic of 0.590.Validation of R(2)CHADS(2) in an external, separate population improved net reclassification index by 17.4% (95% confidence interval, 12.1%-22.5%) relative to CHADS(2).In patients with nonvalvular AF at moderate to high risk of stroke, impaired renal function is a potent predictor of stroke and systemic embolism. Stroke risk stratification in patients with AF should include renal function.URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00403767.

    View details for DOI 10.1161/CIRCULATIONAHA.112.107128

    View details for Web of Science ID 000313637200019

    View details for PubMedID 23212720

  • Effect of Cinacalcet on Cardiovascular Disease in Patients Undergoing Dialysis NEW ENGLAND JOURNAL OF MEDICINE Chertow, G. M., Block, G. A., Correa-Rotter, R., Drueeke, T. B., Floege, J., Goodman, W. G., Herzog, C. A., Kubo, Y., London, G. M., Mahaffey, K. W., Mix, T. C., Moe, S. M., Trotman, M., Wheeler, D. C., Parfrey, P. S. 2012; 367 (26): 2482-2494

    Abstract

    Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients.In this clinical trial, we randomly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism (median level of intact parathyroid hormone, 693 pg per milliliter [10th to 90th percentile, 363 to 1694]) who were undergoing hemodialysis to receive either cinacalcet or placebo. All patients were eligible to receive conventional therapy, including phosphate binders, vitamin D sterols, or both. The patients were followed for up to 64 months. The primary composite end point was the time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. The primary analysis was performed on the basis of the intention-to-treat principle.The median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P=0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet.In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839.).

    View details for DOI 10.1056/NEJMoa1205624

    View details for Web of Science ID 000312714200006

  • Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. New England journal of medicine Chertow, G. M., Block, G. A., Correa-Rotter, R., Drüeke, T. B., Floege, J., Goodman, W. G., Herzog, C. A., Kubo, Y., London, G. M., Mahaffey, K. W., Mix, T. C., Moe, S. M., Trotman, M., Wheeler, D. C., Parfrey, P. S. 2012; 367 (26): 2482-2494

    Abstract

    Disorders of mineral metabolism, including secondary hyperparathyroidism, are thought to contribute to extraskeletal (including vascular) calcification among patients with chronic kidney disease. It has been hypothesized that treatment with the calcimimetic agent cinacalcet might reduce the risk of death or nonfatal cardiovascular events in such patients.In this clinical trial, we randomly assigned 3883 patients with moderate-to-severe secondary hyperparathyroidism (median level of intact parathyroid hormone, 693 pg per milliliter [10th to 90th percentile, 363 to 1694]) who were undergoing hemodialysis to receive either cinacalcet or placebo. All patients were eligible to receive conventional therapy, including phosphate binders, vitamin D sterols, or both. The patients were followed for up to 64 months. The primary composite end point was the time until death, myocardial infarction, hospitalization for unstable angina, heart failure, or a peripheral vascular event. The primary analysis was performed on the basis of the intention-to-treat principle.The median duration of study-drug exposure was 21.2 months in the cinacalcet group, versus 17.5 months in the placebo group. The primary composite end point was reached in 938 of 1948 patients (48.2%) in the cinacalcet group and 952 of 1935 patients (49.2%) in the placebo group (relative hazard in the cinacalcet group vs. the placebo group, 0.93; 95% confidence interval, 0.85 to 1.02; P=0.11). Hypocalcemia and gastrointestinal adverse events were significantly more frequent in patients receiving cinacalcet.In an unadjusted intention-to-treat analysis, cinacalcet did not significantly reduce the risk of death or major cardiovascular events in patients with moderate-to-severe secondary hyperparathyroidism who were undergoing dialysis. (Funded by Amgen; EVOLVE ClinicalTrials.gov number, NCT00345839.).

    View details for DOI 10.1056/NEJMoa1205624

    View details for PubMedID 23121374

  • Comparison of the Prognosis of Spontaneous and Percutaneous Coronary Intervention-Related Myocardial Infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Leonardi, S., Thomas, L., Neely, M. L., Tricoci, P., Lopes, R. D., White, H. D., Armstrong, P. W., Giugliano, R. P., Antman, E. M., Califf, R. M., Newby, L. K., Mahaffey, K. W. 2012; 60 (22): 2296-2304

    Abstract

    This study compared prognoses of myocardial infarction related to percutaneous coronary intervention (PCI, procedural MI) using increasing creatine kinase-myocardial band (CK-MB) thresholds with spontaneous MI.Procedural MI usually is defined by a CK-MB elevation of more than 3 times the upper limit of normal (ULN), but higher thresholds have been proposed.Patients from the EARLY-ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) study and the SYNERGY (Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors) study treated with PCI were included. The primary end point was 1-year all-cause mortality from 24 h after PCI. To determine an enzymatic threshold for procedural MI with a prognosis similar to that of spontaneous MI, we redefined procedural MI using increasing CK-MB thresholds and compared corresponding hazard ratios with those of spontaneous MI (CK-MB more than twice the ULN). Hazard ratios for mortality for procedural and spontaneous MI were calculated using Cox proportional hazards regression and Global Registry of Acute Cardiac Events covariates for risk adjustment.Nine thousand eighty-seven patients who underwent PCI (46.8%) were included; 773 procedural MI and 239 spontaneous MI occurred within 30 days. Adjusted hazard ratios for 1-year death were 1.39 (95% confidence interval [CI]: 1.01 to 1.89) for procedural MI and 5.37 (95% CI: 3.90 to 7.38) for spontaneous MI. The CK-MB threshold for procedural MI that achieved the same prognosis as spontaneous MI was 27.7 times the ULN (95% CI: 13.9 to 58.4), but this differed between the SYNERGY study (57.9 times the ULN, 95% CI: 17.9 to 63.6) and the EARLY-ACS study (20.4 times the ULN, 95% CI: 5.16 to 24.2). Of all procedural MI, 49 (6%) had CK-MB elevations of 27.7 or more times the ULN.The current enzymatic definition of procedural MI (CK-MB more than 3 times the ULN) used in clinical trials is less strongly associated with death than that of spontaneous MI. Procedural MI achieves similar prognosis for 1-year mortality when much higher CK-MB thresholds are applied.

    View details for DOI 10.1016/j.jacc.2012.09.005

    View details for Web of Science ID 000311680500007

    View details for PubMedID 23122801

  • ESC Guidelines on the management of acute myocardial infarction with persistent ST-segment elevation KARDIOLOGIA POLSKA Steg, G., James, S. K., Atar, D., Badano, L. P., Lundquist, C. B., Borger, M. A., Di Mario, C., Dickstein, K., Ducrocq, G., Fernandes-Aviles, F., Gershlick, A. H., Gianuzzi, P., Halvorsen, S., Huber, K., Juni, P., Kastrati, A., Knuuti, J., Lenzen, M. J., Mahaffey, K. W., Valgimigli, M., van't Hof, A., Widimsky, P., Zahger, D. 2012; 70: S255-S318
  • Factors Contributing to the Lower Mortality With Ticagrelor Compared With Clopidogrel in Patients Undergoing Coronary Artery Bypass Surgery JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Varenhorst, C., Alstrom, U., Scirica, B. M., Hogue, C. W., Asenblad, N., Storey, R. F., Steg, G., Horrow, J., Mahaffey, K. W., Becker, R. C., James, S., Cannon, C. P., Brandrup-Wognsen, G., Wallentin, L., Held, C. 2012; 60 (17): 1623-1630

    Abstract

    This study investigated the differences in specific causes of post-coronary artery bypass graft surgery (CABG) deaths in the PLATO (Platelet Inhibition and Patient Outcomes) trial.In the PLATO trial, patients assigned to ticagrelor compared with clopidogrel and who underwent CABG had significantly lower total and cardiovascular mortality.In the 1,261 patients with CABG performed within 7 days after stopping study drug, reviewers blinded to treatment assignment classified causes of death into subcategories of vascular and nonvascular, and specifically identified bleeding or infection events that either caused or subsequently contributed to death.Numerically more vascular deaths occurred in the clopidogrel versus the ticagrelor group related to myocardial infarction (14 vs. 10), heart failure (9 vs. 6), arrhythmia or sudden death (9 vs. 3), and bleeding, including hemorrhagic stroke (7 vs. 2). Clopidogrel was also associated with an excess of nonvascular deaths related to infection (8 vs. 2). Among factors directly causing or contributing to death, bleeding and infections were more common in the clopidogrel group compared with the ticagrelor group (infections: 16 vs. 6, p < 0.05, and bleeding: 27 vs. 9, p < 0.01, for clopidogrel and ticagrelor, respectively).The mortality reduction with ticagrelor versus clopidogrel following CABG in the PLATO trial was associated with fewer deaths from cardiovascular, bleeding, and infection complications. (Platelet Inhibition and Patient Outcomes [PLATO]; NCT00391872).

    View details for DOI 10.1016/j.jacc.2012.07.021

    View details for Web of Science ID 000310199700006

    View details for PubMedID 23021325

  • Venous Thromboembolism Yet Another Cardiovascular Complication of Chronic Kidney Disease? CIRCULATION Chertow, G. M., Mahaffey, K. W. 2012; 126 (16): 1937-1938
  • Antithrombotic therapy for atrial fibrillation and coronary artery disease in older patients AMERICAN HEART JOURNAL Hess, C. N., Broderick, S., Piccini, J. P., Alexander, K. P., Newby, L. K., Shaw, L. K., Mahaffey, K. W., Alexander, J. H., Peterson, E. D., Granger, C. B., Lopes, R. D. 2012; 164 (4): 607-615

    Abstract

    Older patients with atrial fibrillation (AF) and coronary artery disease (CAD) face high risk of stroke and bleeding with antithrombotic therapy. Balancing safe and effective use of aspirin, clopidogrel, and warfarin in this population is important.From the Duke Databank for Cardiovascular Disease, we identified patients with AF ≥65 years old with angiographically confirmed CAD from 2000 to 2010. Antithrombotic use was described across age and Congestive heart failure, Hypertension, Age >75 years, Diabetes, prior Stroke/transient ischemic attack (CHADS(2)) stroke risk and Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA) bleeding scores. Death and the composite of death, myocardial infarction, and stroke by antithrombotic strategy were reported.Of 2,122 patients ≥65 years old with AF and CAD, 477 (22.5%) were ≥80 years old; 1,133 (53.4%) had acute coronary syndromes. Overall rates of aspirin, clopidogrel, and warfarin use were 83.4%, 34.6%, and 38.9%, respectively. Compared with patients 65 to 79 years old, more patients ≥80 years old were at high stroke risk (CHADS(2) ≥2, 84.7% vs 57.8%) and high bleeding risk (ATRIA 5-10, 55.8% vs 23.3%). Warfarin use in both age groups increased with higher CHADS(2) scores and decreased with higher ATRIA scores. Of patients ≥80 years old with CHADS(2) ≥2, 150 (38.2%) received warfarin. Antithrombotic strategy was not associated with improved 1-year adjusted outcomes.Among older patients with AF and CAD, overall warfarin use was low. Patients ≥80 years old at highest stroke risk received warfarin in similar proportions to the overall cohort. Further investigation into optimizing antithrombotic strategies in this population is warranted.

    View details for DOI 10.1016/j.ahj.2012.07.004

    View details for Web of Science ID 000310506000026

    View details for PubMedID 23067921

  • ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation EUROPEAN HEART JOURNAL Steg, P. G., James, S. K., Atar, D., Badano, L. P., Blomstrom-Lundqvist, C., Borger, M. A., Di Mario, C., Dickstein, K., Ducrocq, G., Fernandez-Aviles, F., Gershlick, A. H., Giannuzzi, P., Halvorsen, S., Huber, K., Juni, P., Kastrati, A., Knuuti, J., Lenzen, M. J., Mahaffey, K. W., Valgimigli, M., van't Hof, A., Widimsky, P., Zahger, D. 2012; 33 (20): 2569-2619

    View details for DOI 10.1093/eurheartj/ehs215

    View details for Web of Science ID 000310167200015

    View details for PubMedID 22922416

  • Ticagrelor Versus Clopidogrel in Elderly Patients With Acute Coronary Syndromes A Substudy From the Prospective Randomized PLATelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Husted, S., James, S., Becker, R. C., Horrow, J., Katus, H., Storey, R. F., Cannon, C. P., Heras, M., Lopes, R. D., Morais, J., Mahaffey, K. W., Bach, R. G., Wojdyla, D., Wallentin, L. 2012; 5 (5): 680-688

    Abstract

    Elderly patients with acute coronary syndrome are at high risk of recurrent ischemic events and death, and for both antithrombotic therapy and catheter-based complications. This prespecified analysis investigates the effect and treatment-related complications of ticagrelor versus clopidogrel in elderly patients (≥75 years of age) with acute coronary syndrome compared with those <75 years of age.The association between age and the primary composite outcome, as well as major bleeding were evaluated in the PLATelet inhibition and patient Outcomes (PLATO) trial using Cox proportional hazards. Similar models were used to evaluate the interaction of age with treatment effects. Hazard ratios were adjusted for baseline characteristics. The clinical benefit of ticagrelor over clopidogrel was not significantly different between patients aged ≥75 years of age (n=2878) and those <75 years of age (n=15 744) with respect to the composite of cardiovascular death, myocardial infarction, or stroke (interaction P=0.56), myocardial infarction (P=0.33), cardiovascular death (P=0.47), definite stent thrombosis (P=0.81), or all-cause mortality (P=0.76). No increase in PLATO-defined overall major bleeding with ticagrelor versus clopidogrel was observed in patients aged ≥75 years (hazard ratio, 1.02; 95% confidence interval, 0.82-1.27) or patients aged <75 years (hazard ratio, 1.04; 95% confidence interval, 0.94-1.15). Dyspnea and ventricular pauses were more common during ticagrelor than clopidogrel treatment, with no evidence of an age-by-treatment interaction.The significant clinical benefit and overall safety of ticagrelor compared with clopidogrel in acute coronary syndrome patients in the PLATO cohort were not found to depend on age.

    View details for DOI 10.1161/CIRCOUTCOMES.111.964395

    View details for Web of Science ID 000309109000015

    View details for PubMedID 22991347

  • Search for a diagnostic/prognostic biomarker for the brain cancer glioblastoma multiforme by 2D-DIGE-MS technique MOLECULAR AND CELLULAR BIOCHEMISTRY Banerjee, H. n., Mahaffey, K., Riddick, E., Banerjee, A., Bhowmik, N., Patra, M. 2012; 367 (1-2): 59-63

    Abstract

    The prognosis of patients with glioblastoma multiforme, the most malignant adult glial brain tumor, remains poor in spite of advances in treatment procedures, including surgical resection, irradiation, and chemotherapy. Genetic heterogeneity of glioblastoma warrants extensive studies to gain a thorough understanding of the biology of this tumor. While there have been several studies of global transcript profiling of glioma with the identification of gene signatures for diagnosis and disease management, translation into clinics is yet to happen. In the present study, we report a novel proteomic approach by using two-dimensional difference gel electrophoresis followed by spot picking and analysis of proteins/peptides by Mass spectrometry. We report at least ten different novel proteins/peptides as identified by this technique which are differentially expressed in this cancer and could be of further importance for diagnostic, therapeutic, and prognostic approaches.

    View details for DOI 10.1007/s11010-012-1319-6

    View details for Web of Science ID 000305683100007

    View details for PubMedID 22547198

  • Baseline characteristics of subjects enrolled in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial NEPHROLOGY DIALYSIS TRANSPLANTATION Chertow, G. M., Correa-Rotter, R., Block, G. A., Drueke, T. B., Floege, J., Goodman, W. G., Herzog, C. A., Kubo, Y., London, G. M., Mahaffey, K. W., Mix, T., Moe, S. M., Wheeler, D. C., Parfrey, P. S. 2012; 27 (7): 2872-2879

    Abstract

    Secondary hyperparathyroidism (sHPT) and other abnormalities associated with chronic kidney disease-mineral bone disorder can contribute to dystrophic (including vascular) calcification. Dietary modification and variety of medications can be used to attenuate the severity of sHPT. However, it is unknown whether any of these approaches can reduce the high risks of death and cardiovascular disease in patients with end-stage renal disease.The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial was designed to test the hypothesis that treatment with the calcimimetic agent cinacalcet compared with placebo (on a background of conventional therapy including phosphate binders +/- vitamin D sterols) reduces time to death or non-fatal cardiovascular events (specifically myocardial infarction, unstable angina, heart failure and peripheral arterial disease events) among patients on hemodialysis with sHPT. This report describes baseline characteristics of enrolled subjects with a focus on regional variation.There were 3883 subjects randomized from 22 countries, including the USA, Canada, Australia, three Latin American nations, Russia and 15 European nations. The burden of overt cardiovascular disease at baseline was high (e.g. myocardial infarction 12.4%, heart failure 23.3%). The median plasma parathyroid hormone concentration at baseline was 692 pg/mL (10%, 90% range, 363-1694 pg/mL). At baseline, 87.2% of subjects were prescribed phosphate binders and 57.5% were prescribed activated vitamin D derivatives. Demographic data, comorbid conditions and baseline laboratory data varied significantly across regions.EVOLVE enrolled 3883 subjects on hemodialysis with moderate to severe sHPT. Inclusion of subjects from multiple global regions with varying degrees of disease severity will enhance the external validity of the trial results.

    View details for DOI 10.1093/ndt/gfr777

    View details for PubMedID 22529163

  • Baseline NT-proBNP and biomarkers of inflammation and necrosis in patients with ST-segment elevation myocardial infarction: insights from the APEX-AMI trial JOURNAL OF THROMBOSIS AND THROMBOLYSIS van Diepen, S., Roe, M. T., Lopes, R. D., Stebbins, A., James, S., Newby, L. K., Moliterno, D. J., Neumann, F., Ezekowitz, J. A., Mahaffey, K. W., Hochman, J. S., Hamm, C. W., Armstrong, P. W., Theroux, P., Granger, C. B. 2012; 34 (1): 106-113

    Abstract

    Coronary plaque rupture is associated with a systemic inflammatory response. The relationship between baseline N-terminal pro B-type natriuretic peptide (NT-proBNP), a prognostic marker in patients with acute coronary syndromes, and systemic inflammatory mediators in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) is not well described. Of 5,745 STEMI patients treated with primary PCI in the APEX-AMI trial, we evaluated the relationship between baseline NT-proBNP levels and baseline levels of inflammatory markers and markers of myonecrosis in a subset of 772 who were enrolled in a biomarker substudy. Spearman correlations (r (s)) were calculated between baseline NT-proBNP levels and a panel of ten systemic inflammatory biomarkers. Interleukin (IL)-6, a pro-inflammatory cytokine, was significantly positively correlated with NT-proBNP (r (s) = 0.317, P < 0.001). In a sensitivity analysis excluding all heart failure patients, the correlation between baseline IL-6 and NT-proBNP remained significant (n = 651, r (s) = 0.296, P < 0.001). A positive association was also observed with high sensitivity C-reactive protein (r (s) = 0.377, P < 0.001) and there was a weak negative correlation with the anti-inflammatory cytokine IL-10 (r (s) = -0.109, P = 0.003). No other significant correlations were observed among the other testes inflammatory cytokines and chemokines. In STEMI patients undergoing primary PCI, the pro-inflammatory cytokine IL-6 was modestly correlated with baseline NT-proBNP levels. This relationship remained significant in patients without heart failure. This finding is consistent with pre-clinical and clinical research suggesting that systemic inflammation may influence NT-proBNP expression independently of myocardial stretch.

    View details for DOI 10.1007/s11239-012-0691-0

    View details for Web of Science ID 000305523300015

    View details for PubMedID 22307842

  • Activated partial thromboplastin time measurement is not associated with clinical outcomes in patients with high-risk non-ST-segment elevation acute coronary syndromes treated with unfractionated heparin JOURNAL OF THROMBOSIS AND THROMBOLYSIS Thomas, M. P., Mahaffey, K. W., Chiswell, K., Cohen, M., Kontos, M. C., Antman, E. M., Ferguson, J. J., Califf, R. M., Goodman, S. G., Becker, R. C. 2012; 34 (1): 114-119

    Abstract

    Our objective was to determine the association of activated partial thromboplastin time (aPTT) with recurrent ischemic events and non-coronary artery bypass surgery-related thrombolysis in myocardial infarction major bleeding. We studied 4,985 patients with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS) participating in SYNERGY, a prospective, randomized, international trial designed to emulate contemporary practice wherein unfractionated heparin (UFH) is given intravenously and titrated according to a weight-adjusted dosing nomogram to a target aPTT of 1.5-2 times the upper limit of normal (approximately 50-70 s). Aspirin was administered to 95% of patients, clopidogrel to 63%, and glycoprotein IIb/IIIa receptor inhibitors to 58%. More than 90% of patients underwent early coronary angiography, and 69% were revascularized. Used as a time-dependent covariate, aPTT was evaluated as a predictor of time to ischemic or major hemorrhagic events in proportional hazards regression models. Using discrete variable analysis, aPTT was categorized as persistently below a lower threshold of anticoagulation (<50 vs. ≥50 s) for recurrent ischemic events and above an upper threshold (>70 vs. ≤70 s) for major hemorrhagic events. UFH treatment lasted a median of 42 (30, 78) h. At >6-12 (n = 3,021), >12-24 (n = 3,406), and >24-48 (n = 2,497) h, 34, 41, and 46% of patients achieved the target aPTT range, respectively. Both before and after adjusting for baseline predictors of anticoagulant response and risk score (age, hypertension, diabetes, smoking, ST depression, and renal function), no significant relationship between aPTT values and recurrent ischemic events or major bleeding was found. No relationship was observed between clinical outcomes and aPTT values persistently above or below the designated thresholds. Measurements of aPTT were not associated with clinical outcomes among patients with NSTE ACS treated with UFH. The required intensity of anticoagulation for benefit may be relatively modest when UFH is administered concomitantly with dual or triple platelet-directed therapy, particularly in patients undergoing early coronary revascularization.

    View details for DOI 10.1007/s11239-012-0693-y

    View details for Web of Science ID 000305523300016

    View details for PubMedID 22323092

  • Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes and a History of Stroke or Transient Ischemic Attack CIRCULATION James, S. K., Storey, R. F., Khurmi, N. S., Husted, S., Keltai, M., Mahaffey, K. W., Maya, J., Morais, J., Lopes, R. D., Nicolau, J. C., Pais, P., Raev, D., Lopez-Sendon, J. L., Stevens, S. R., Becker, R. C. 2012; 125 (23): 2914-?

    Abstract

    Patients with acute coronary syndromes and history of stroke or transient ischemic attack (TIA) have an increased rate of recurrent cardiac events and intracranial hemorrhages.We evaluated treatment effects of ticagrelor versus clopidogrel in patients with acute coronary syndrome with and without a history of prior stroke or TIA in the PLATelet inhibition and patient Outcomes (PLATO) trial. Of the 18 624 randomized patients, 1152 (6.2%) had a history of stroke or TIA. Such patients had higher rates of myocardial infarction (11.5% versus 6.0%), death (10.5% versus 4.9%), stroke (3.4% versus 1.2%), and intracranial bleeding (0.8% versus 0.2%) than patients without prior stroke or TIA. Among patients with a history of stroke or TIA, the reduction of the primary composite outcome and total mortality at 1 year with ticagrelor versus clopidogrel was consistent with the overall trial results: 19.0% versus 20.8% (hazard ratio, 0.87; 95% confidence interval, 0.66-1.13; interaction P=0.84) and 7.9% versus 13.0% (hazard ratio, 0.62; 95% confidence interval, 0.42-0.91). The overall PLATO-defined bleeding rates were similar: 14.6% versus 14.9% (hazard ratio, 0.99; 95% confidence interval, 0.71-1.37), and intracranial bleeding occurred infrequently (4 versus 4 cases, respectively).Patients with acute coronary syndrome with a prior history of ischemic stroke or TIA had higher rates of clinical outcomes than patients without prior stroke or TIA. However, the efficacy and bleeding results of ticagrelor in these high-risk patients were consistent with the overall trial population, with a favorable clinical net benefit and associated impact on mortality.URL: http://www.clinicatrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.082727

    View details for Web of Science ID 000306975100030

    View details for PubMedID 22572911

  • Rationale and design of the Cangrelor versus standard therapy to acHieve optimal Management of Platelet InhibitiON PHOENIX trial AMERICAN HEART JOURNAL Leonardi, S., Mahaffey, K. W., White, H. D., Gibson, C. M., Stone, G. W., Steg, P. G., Hamm, C. W., Price, M. J., Todd, M., Dietrich, M., Gallup, D., Liu, T., Skerjanec, S., Harrington, R. A., Bhatt, D. L. 2012; 163 (5): 768-?

    Abstract

    Despite robust efficacy in the reduction of ischemic events in patients who require percutaneous coronary intervention (PCI), current P2Y(12) inhibitors have limitations. In particular, they require hours to be effective, and they can only be administered orally. Cangrelor is an intravenous, potent, and reversible P2Y(12) inhibitor with fast onset and offset of action. We designed CHAMPION PHOENIX to evaluate the efficacy and safety of cangrelor in patients with atherosclerosis undergoing PCI.The CHAMPION PHOENIX is a randomized, double-blind, double-dummy, superiority trial comparing cangrelor with clopidogrel standard of care in approximately 10,900 patients who have not previously received a P2Y(12) inhibitor and who require PCI, including patients with stable angina and with acute coronary syndromes (with or without ST-segment elevation). The primary objective of the study is to demonstrate that cangrelor will reduce the incidence of the composite of death, myocardial infarction (MI), ischemia-driven revascularization, or stent thrombosis in the 48 hours after randomization compared with clopidogrel without excessive periprocedural bleeding. The key secondary objective is to demonstrate that cangrelor will reduce the incidence of stent thrombosis. Myocardial infarction will be defined according to the universal MI definition, adapting the definition of PCI-related (type 4a) MI. Bleeding will be assessed according to the thrombolysis in myocardial infarction, GUSTO, and Bleeding Academic Research Consortium (BARC) scales.The CHAMPION PHOENIX may establish the role of cangrelor in the care of patients who require PCI across the spectrum of stable and unstable coronary diseases in the setting of current treatment strategies.

    View details for DOI 10.1016/j.ahj.2012.02.018

    View details for Web of Science ID 000304261000011

    View details for PubMedID 22607853

  • Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF LANCET NEUROLOGY Hankey, G. J., Patel, M. R., Stevens, S. R., Becker, R. C., Breithardt, G., Carolei, A., Diener, H., Donnan, G. A., Halperin, J. L., Mahaffey, K. W., Mas, J., Massaro, A., Norrving, B., Nessel, C. C., Paolini, J. F., Roine, R. O., Singer, D. E., Wong, L., Califf, R. M., Fox, K. A., Hacke, W. 2012; 11 (4): 315-322

    Abstract

    In ROCKET AF, rivaroxaban was non-inferior to adjusted-dose warfarin in preventing stroke or systemic embolism among patients with atrial fibrillation (AF). We aimed to investigate whether the efficacy and safety of rivaroxaban compared with warfarin is consistent among the subgroups of patients with and without previous stroke or transient ischaemic attack (TIA).In ROCKET AF, patients with AF who were at increased risk of stroke were randomly assigned (1:1) in a double-blind manner to rivaroxaban 20 mg daily or adjusted dose warfarin (international normalised ratio 2·0-3·0). Patients and investigators were masked to treatment allocation. Between Dec 18, 2006, and June 17, 2009, 14 264 patients from 1178 centres in 45 countries were randomly assigned. The primary endpoint was the composite of stroke or non-CNS systemic embolism. In this substudy we assessed the interaction of the treatment effects of rivaroxaban and warfarin among patients with and without previous stroke or TIA. Efficacy analyses were by intention to treat and safety analyses were done in the on-treatment population. ROCKET AF is registered with ClinicalTrials.gov, number NCT00403767.7468 (52%) patients had a previous stroke (n=4907) or TIA (n=2561) and 6796 (48%) had no previous stroke or TIA. The number of events per 100 person-years for the primary endpoint in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (2·79% rivaroxaban vs 2·96% warfarin; hazard ratio [HR] 0·94, 95% CI 0·77-1·16) and those without (1·44%vs 1·88%; 0·77, 0·58-1·01; interaction p=0·23). The number of major and non-major clinically relevant bleeding events per 100 person-years in patients treated with rivaroxaban compared with warfarin was consistent among patients with previous stroke or TIA (13·31% rivaroxaban vs 13·87% warfarin; HR 0·96, 95% CI 0·87-1·07) and those without (16·69%vs 15·19%; 1·10, 0·99-1·21; interaction p=0·08).There was no evidence that the relative efficacy and safety of rivaroxaban compared with warfarin was different between patients who had a previous stroke or TIA and those who had no previous stroke or TIA. These results support the use of rivaroxaban as an alternative to warfarin for prevention of recurrent as well as initial stroke in patients with AF.Johnson and Johnson Pharmaceutical Research and Development and Bayer HealthCare.

    View details for DOI 10.1016/S1474-4422(12)70042-X

    View details for Web of Science ID 000301999600007

    View details for PubMedID 22402056

  • Prediction of enzymatic infarct size in ST-segment elevation myocardial infarction CORONARY ARTERY DISEASE Mills, J. S., Mahaffey, K. W., Lokhnygina, Y., Nicolau, J. C., Ruzyllo, W., Adams, P. X., Todaro, T. G., Armstrong, P. W., Granger, C. B. 2012; 23 (2): 118-125

    Abstract

    Predictors of adverse outcomes following myocardial infarction (MI) are well established; however, little is known about what predicts enzymatically estimated infarct size in patients with acute ST-elevation MI. The Complement And Reduction of INfarct size after Angioplasty or Lytics trials of pexelizumab used creatine kinase (CK)-MB area under the curve to determine infarct size in patients treated with primary percutaneous coronary intervention (PCI) or fibrinolysis.Prediction of infarct size was carried out by measuring CK-MB area under the curve in patients with ST-segment elevation MI treated with reperfusion therapy from January 2000 to April 2002. Infarct size was calculated in 1622 patients (PCI=817; fibrinolysis=805). Logistic regression was used to examine the relationship between baseline demographics, total ST-segment elevation, index angiographic findings (PCI group), and binary outcome of CK-MB area under the curve greater than 3000 ng/ml.Large infarcts occurred in 63% (515) of the PCI group and 69% (554) of the fibrinolysis group. Independent predictors of large infarcts differed depending on mode of reperfusion. In PCI, male sex, no prior coronary revascularization and diabetes, decreased systolic blood pressure, sum of ST-segment elevation, total (angiographic) occlusion, and nonright coronary artery culprit artery were independent predictors of larger infarcts (C index=0.73). In fibrinolysis, younger age, decreased heart rate, white race, no history of arrhythmia, increased time to fibrinolytic therapy in patients treated up to 2 h after symptom onset, and sum of ST-segment elevation were independently associated with a larger infarct size (C index=0.68).Clinical and patient data can be used to predict larger infarcts on the basis of CK-MB quantification. These models may be helpful in designing future trials and in guiding the use of novel pharmacotherapies aimed at limiting infarct size in clinical practice.

    View details for DOI 10.1097/MCA.0b013e32834e4f8f

    View details for Web of Science ID 000300406400007

    View details for PubMedID 22217457

  • Association of Proton Pump Inhibitor Use on Cardiovascular Outcomes With Clopidogrel and Ticagrelor Insights From the Platelet Inhibition and Patient Outcomes Trial CIRCULATION Goodman, S. G., Clare, R., Pieper, K. S., Nicolau, J. C., Storey, R. F., Cantor, W. J., Mahaffey, K. W., Angiolillo, D. J., Husted, S., Cannon, C. P., James, S. K., Kilhamn, J., Steg, P. G., Harrington, R. A., Wallentin, L. 2012; 125 (8): 978-986

    Abstract

    The clinical significance of the interaction between clopidogrel and proton pump inhibitors (PPIs) remains unclear.We examined the relationship between PPI use and 1-year cardiovascular events (cardiovascular death, myocardial infarction, or stroke) in patients with acute coronary syndrome randomized to clopidogrel or ticagrelor in a prespecified, nonrandomized subgroup analysis of the Platelet Inhibition and Patient Outcomes (PLATO) trial. The primary end point rates were higher for individuals on a PPI (n=6539) compared with those not on a PPI (n=12 060) at randomization in both the clopidogrel (13.0% versus 10.9%; adjusted hazard ratio [HR], 1.20; 95% confidence interval [CI], 1.04-1.38) and ticagrelor (11.0% versus 9.2%; HR, 1.24; 95% CI, 1.07-1.45) groups. Patients on non-PPI gastrointestinal drugs had similar primary end point rates compared with those on a PPI (PPI versus non-PPI gastrointestinal treatment: clopidogrel, HR, 0.98; 95% CI, 0.79-1.23; ticagrelor, HR, 0.89; 95% CI, 0.73-1.10). In contrast, patients on no gastric therapy had a significantly lower primary end point rate (PPI versus no gastrointestinal treatment: clopidogrel, HR, 1.29; 95% CI, 1.12-1.49; ticagrelor, HR, 1.30; 95% CI, 1.14-1.49).The use of a PPI was independently associated with a higher rate of cardiovascular events in patients with acute coronary syndrome receiving clopidogrel. However, a similar association was observed between cardiovascular events and PPI use during ticagrelor treatment and with other non-PPI gastrointestinal treatment. Therefore, in the PLATO trial, the association between PPI use and adverse events may be due to confounding, with PPI use more of a marker for, than a cause of, higher rates of cardiovascular events.http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.032912

    View details for Web of Science ID 000300951700013

    View details for PubMedID 22261200

  • Reduced immediate ischemic events with cangrelor in PCI: A pooled analysis of the CHAMPION trials using the universal definition of myocardial infarction AMERICAN HEART JOURNAL White, H. D., Chew, D. P., Dauerman, H. L., Mahaffey, K. W., Gibson, C. M., Stone, G. W., Gruberg, L., Harrington, R. A., Bhatt, D. L. 2012; 163 (2): 182-U275

    Abstract

    There is a clinical need for an intravenous P2Y(12) inhibitor in patients with acute coronary syndromes (ACS) for patients who are unable to take oral medications or might benefit from a rapidly reversible compound. As the time from admission to percutaneous coronary intervention (PCI) shortens, establishing the benefit of novel therapies impacting ischemic events is increasingly challenging. Cangrelor, an intravenous potent rapidly acting P2Y(12) inhibitor, bolus 30 μg/Kg plus infusion of 4 μg/Kg/min, was compared to a 600-mg loading dose of clopidogrel either before or early after PCI in patients with ACS undergoing PCI in The CHAMPION (Cangrelor versus standard tHerapy to Achieve optimal Management of Platelet InhibitiON) PLATFORM and PCI studies.As both CHAMPION studies used similar inclusion/exclusion criteria and death, myocardial infarction, or ischemia-driven revascularization (including stent thrombosis) at 48 hours as their primary end points, the studies were pooled. The clinical events committee adjudicated myocardial infarction. The universal definition was used to define myocardial infarction.A total of 13 049 patients were included. Cangrelor had no effect on the primary end point with the original MI definition (P = .646). With the use of the universal definition, the primary end point was decreased with cangrelor (odds ratio 0.82, 95% confidence interval 0.68-0.99, P = .037). Stent thrombosis was reduced from 0.4% to 0.2% (odds ratio 0.44, 95% confidence interval 0.22-0.87, P = .018). Thrombolysis in Myocardial Infarction major bleeding and transfusions were not increased with cangrelor.With the use of the universal definition of myocardial infarction, cangrelor was associated with a significant reduction in early ischemic events when compared with clopidogrel in patients with non-ST-elevation ACS undergoing PCI.

    View details for DOI 10.1016/j.ahj.2011.11.001

    View details for Web of Science ID 000300226600009

    View details for PubMedID 22305835

  • Promise of Factor Xa Inhibition in Atrial Fibrillation CURRENT CARDIOLOGY REPORTS Al-Khatib, S. M., Alexander, J. H., Lopes, R. D., Mahaffey, K. W., Patel, M. R., Granger, C. B. 2012; 14 (1)
  • Clopidogrel and PPI Interaction: Clinically Relevant or Not? CURRENT CARDIOLOGY REPORTS Harrison, R. W., Mahaffey, K. W. 2012; 14 (1)
  • Promises of PAR-1 inhibition in acute coronary syndrome. Current cardiology reports Leonardi, S., Tricoci, P., Mahaffey, K. W. 2012; 14 (1): 32-39

    Abstract

    Platelet activation is a key process in the pathogenesis of acute coronary syndromes (ACS). Of the many triggers involved in this process, three are presumed to be critical: thromboxane A(2) (TBXA(2)) via the TBXA(2) receptor, adenosine diphosphate via the P2Y(12) receptor, and thrombin via the protease-activated receptor (PAR)-1. Despite the effective inhibition of the first two pathways with aspirin and an expanding family of P2Y(12) inhibitors, the incidence of recurrent ischemic events remains high after ACS. PAR-1 inhibitors are a novel class of antiplatelet agents that inhibit thrombin-mediated platelet activation. Preclinical data and phase 2 clinical trials in patients with stable and unstable coronary disease support the potential of these compounds to improve clinical outcome. In this review we discuss the rationale for developing this novel class of agents with a focus on the two compounds in most advanced clinical development, vorapaxar (SCH 530348) and atopaxar (E5555).

    View details for DOI 10.1007/s11886-011-0232-z

    View details for PubMedID 22160877

  • Promise of factor Xa inhibition in atrial fibrillation. Current cardiology reports Al-Khatib, S. M., Alexander, J. H., Lopes, R. D., Mahaffey, K. W., Patel, M. R., Granger, C. B. 2012; 14 (1): 70-78

    Abstract

    Randomized clinical trials have conclusively demonstrated that warfarin prevents stroke in patients with atrial fibrillation. This evidence led the American College of Cardiology, the American Heart Association, and the European Society of Cardiology to designate warfarin as a Class I indication in patients at moderate to high risk for stroke. Despite the evidence from randomized clinical trials and clear practice guidelines, warfarin is underutilized in many eligible patients. This is, at least in part, due to the many challenges associated with warfarin use that have led to the development of many new anticoagulants including direct thrombin inhibitors and factor Xa inhibitors. In this article, we review the complexities of anticoagulation in patients with atrial fibrillation, underscoring the challenges related to warfarin use, and present an overview of new anticoagulants particularly, factor Xa inhibitors, with special emphasis on emerging data from randomized clinical trials on their efficacy and safety in the management of atrial fibrillation.

    View details for DOI 10.1007/s11886-011-0230-1

    View details for PubMedID 22109539

  • Promises of PAR-1 Inhibition in Acute Coronary Syndrome CURRENT CARDIOLOGY REPORTS Leonardi, S., Tricoci, P., Mahaffey, K. W. 2012; 14 (1)
  • Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes NEW ENGLAND JOURNAL OF MEDICINE Tricoci, P., Huang, Z., Held, C., Moliterno, D. J., Armstrong, P. W., Van de Werf, F., White, H. D., Aylward, P. E., Wallentin, L., Chen, E., Lokhnygina, Y., Pei, J., Leonardi, S., Rorick, T. L., Kilian, A. M., Jennings, L. H., Ambrosio, G., Bode, C., Cequier, A., Cornel, J. H., Diaz, R., Erkan, A., Huber, K., Hudson, M. P., Jiang, L., Jukema, J. W., Lewis, B. S., Lincoff, A. M., Montalescot, G., Nicolau, J. C., Ogawa, H., Pfisterer, M., Carlos Prieto, J., Ruzyllo, W., Sinnaeve, P. R., Storey, R. F., Valgimigli, M., Whellan, D. J., Widimsky, P., Strony, J., Harrington, R. A., Mahaffey, K. W. 2012; 366 (1): 20-33

    Abstract

    Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.In this multinational, double-blind, randomized trial, we compared vorapaxar with placebo in 12,944 patients who had acute coronary syndromes without ST-segment elevation. The primary end point was a composite of death from cardiovascular causes, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization.Follow-up in the trial was terminated early after a safety review. After a median follow-up of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031 of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo (Kaplan-Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval [CI], 0.85 to 1.01; P=0.07). A composite of death from cardiovascular causes, myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89; 95% CI, 0.81 to 0.98; P=0.02). Rates of moderate and severe bleeding were 7.2% in the vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58; P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events were similar in the two groups.In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

    View details for DOI 10.1056/NEJMoa1109719

    View details for Web of Science ID 000299968800004

    View details for PubMedID 22077816

  • Pattern of liver enzyme elevations in acute ST-elevation myocardial infarction CORONARY ARTERY DISEASE Lofthus, D. M., Stevens, S. R., Armstrong, P. W., Granger, C. B., Mahaffey, K. W. 2012; 23 (1): 22-30

    Abstract

    Liver enzyme elevations occur with ST-segment elevation myocardial infarction (STEMI); however, their significance in the modern era is not well-defined. The incidence of liver enzyme elevations in STEMI, temporal trends, correlations with creatine kinase-MB (CK-MB), and associations with clinical outcomes were evaluated.The Complement Inhibition in Myocardial Infarction Treated with Angioplasty and Complement Inhibition in Myocardial Infarction Treated with Thrombolytics trials evaluated 1903 patients with STEMI. A core lab analyzed liver enzymes at baseline, days 1, 6, and 14, and CK-MB measured sequentially over 72 h. The GUSTO model for 30-day mortality was used to predict clinical endpoints.A total of 1783 patients were included in the analysis. Aspartate transaminase (AST) was elevated above the upper limit of normal in 85.6% and alanine transaminase (ALT) was elevated in 48.2% of patients at baseline or day 1. CK-MB area under the curve correlated with maximum AST (r=0.727) and maximum ALT (r=0.456). Both AST and ALT elevations were independent predictors of worse outcomes in multivariable adjusted analysis, even after adjustment for CK-MB. Hazard ratios and 95% confidence intervals of AST elevation were 1.12 (1.05-1.19) for all-cause mortality, and 1.08 (1.02-1.13) for the composite endpoint of death, congestive heart failure, shock, or stroke. Hazard ratios and 95% confidence intervals of ALT elevation were 1.15 (1.04-1.27) for mortality and 1.47 (1.10-1.98) for the composite endpoint.AST and ALT elevations are common in STEMI. Both markers are correlated with CK-MB area under the curve, but independently associated with worse mortality and clinical outcomes.

    View details for DOI 10.1097/MCA.0b013e32834e4ef1

    View details for Web of Science ID 000298410100004

    View details for PubMedID 22113063

  • Bleeding complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet inhibition and patient Outcomes (PLATO) trial EUROPEAN HEART JOURNAL Becker, R. C., Bassand, J. P., Budaj, A., Wojdyla, D. M., James, S. K., Cornel, J. H., French, J., Held, C., Horrow, J., Husted, S., Lopez-Sendon, J., Lassila, R., Mahaffey, K. W., Storey, R. F., Harrington, R. A., Wallentin, L. 2011; 32 (23): 2933-2944

    Abstract

    AIMS More intense platelet-directed therapy for acute coronary syndrome (ACS) may increase bleeding risk. The aim of the current analysis was to determine the rate, clinical impact, and predictors of major and fatal bleeding complications in the PLATO study. METHODS AND RESULTS PLATO was a randomized, double-blind, active control international, phase 3 clinical trial in patients with acute ST elevation and non-ST-segment elevation ACS. A total of 18 624 patients were randomized to either ticagrelor, a non-thienopyridine, reversibly binding platelet P2Y(12) receptor antagonist, or clopidogrel in addition to aspirin. Patients randomized to ticagrelor and clopidogrel had similar rates of PLATO major bleeding (11.6 vs. 11.2%; P = 0.43), TIMI major bleeding (7.9 vs. 7.7%, P = 0.56) and GUSTO severe bleeding (2.9 vs. 3.1%, P = 0.22). Procedure-related bleeding rates were also similar. Non-CABG major bleeding (4.5 vs. 3.8%, P = 0.02) and non-procedure-related major bleeding (3.1 vs. 2.3%, P = 0.05) were more common in ticagrelor-treated patients, primarily after 30 days on treatment. Fatal bleeding and transfusion rates did not differ between groups. There were no significant interactions for major bleeding or combined minor plus major bleeding between treatment groups and age ≥75 years, weight <60 kg, region, chronic kidney disease, creatinine clearance <60 mL/min, aspirin dose >325 mg on the day of randomization, pre-randomization clopidogrel administration, or clopidogrel loading dose. CONCLUSION Ticagrelor compared with clopidogrel was associated with similar total major bleeding but increased non-CABG and non-procedure-related major bleeding, primarily after 30 days on study drug treatment. Fatal bleeding was low and did not differ between groups.

    View details for DOI 10.1093/eurheartj/ehr422

    View details for Web of Science ID 000297647400008

    View details for PubMedID 22090660

  • Determinants of plasma vitamin D levels in patients with acute coronary syndromes EUROPEAN JOURNAL OF CLINICAL INVESTIGATION Rodriguez, G., Starr, A. Z., Czernuszewicz, G. Z., Manhas, A., Alhariri, A., Willerson, J. T., Reist, C. J., Pieper, K., Mahaffey, K. W., Marian, A. J., Kleiman, N. S. 2011; 41 (12): 1299-1309

    Abstract

    Vitamin D is implicated in various biological functions ranging from cellular proliferation to immunity. Vitamin D deficiency is associated with an increased risk of several diseases including coronary atherosclerosis.We measured plasma 25(OH)D3 level in 224 patients with acute coronary syndromes (ACS) and 209 control individuals by ELISA. We genotyped the study populations for 11 single nucleotide polymorphisms (SNPs) in seven genes involved in vitamin D biosynthesis and metabolism by 5' nuclease assays.The mean and median plasma 25(OH)D3 levels were not significantly different between patients with ACS and controls (median: 22·06 vs. 22·24 ng mL(-1) , respectively, P = 0·618). Plasma 25(OH)D3 level was < 20 ng mL(-1) in 175/433 (40%) and < 30 ng mL(-1) in 333/433 (77%) participants. Only four individuals had plasma 25(OH)D3 levels of above 60 ng mL(-1) . African-American and Hispanic populations, women and those with diabetes mellitus had significantly lower plasma 25(OH)D3 levels. In multivariable regression analysis, age, sex, diabetes mellitus, body weight, rs2762933 (CYP24A1) and rs6055987 (PLCB1) SNPs were independent predictors of plasma 25(OH)D3 level in the Caucasian population.We found no difference in mean plasma vitamin D levels between patients with ACS and controls. Differences in population characteristics between the two study groups including medications use and the lack of data on vitamin D, calcium and multivitamin supplements intake as well as the relatively small sample size of the populations could confound the results. Ethnic background, sex, age, body weight and SNPs in CYP24A1 and PLCB1 were independent determinants of plasma vitamin D levels.

    View details for DOI 10.1111/j.1365-2362.2011.02540.x

    View details for Web of Science ID 000297146400006

    View details for PubMedID 21615392

  • Mode of Death and Hospitalization from the Second Follow-Up Serial Infusions of Nesiritide (FUSION II) Trial and Comparison of Clinical Events Committee Adjudicated Versus Investigator Reported Outcomes AMERICAN JOURNAL OF CARDIOLOGY O'Connor, C. M., Fiuzat, M., Lindenfeld, J., Miller, A., Lombardi, C., Carson, P., Shaw, L. K., Wang, L., Connolly, P., Mills, R., Yancy, C., Mahaffey, K. 2011; 108 (10): 1449-1457

    Abstract

    The aim of this study was to evaluate the mode of death and hospitalizations in advanced heart failure (HF) patients with renal dysfunction and to examine the rate of concordance between events reported by the clinical events committee and site investigators (using case report forms) in the Second Follow-Up Serial Infusions of Nesiritide (FUSION II) trial. Little is known about the cause of death and hospitalization in patients with advanced HF. FUSION II was a randomized, double-blind, placebo-controlled trial evaluating outpatient nesiritide infusions versus placebo, with 911 patients with advanced HF (New York Heart Association class III or IV) and renal dysfunction enrolled. There were 151 deaths and 1,041 hospitalizations at 24 weeks. The clinical events committee classified events as cardiac, renal, cardiorenal, other or noncardiovascular, or unknown. Kappa statistics and McNemar tests were used to assess agreement (overall and by individual modes of death and hospitalization indications). In conclusion, the most common cause of death or hospitalization was cardiac related, with 70% of deaths and 60% of hospitalizations due to cardiac causes. There was 74% agreement (26% disagreement) on cardiac cause of death (κ = 0.40, McNemar p = 0.001) and 75% agreement (25% disagreement) between the investigators and the clinical events committee on cardiac classification for hospitalization (κ = 0.49, McNemar p <0.0001).

    View details for DOI 10.1016/j.amjcard.2011.06.065

    View details for Web of Science ID 000297435100013

    View details for PubMedID 21890092

  • Outcomes registry for better informed treatment of atrial fibrillation: Rationale and design of ORBIT-AF AMERICAN HEART JOURNAL Piccini, J. P., Fraulo, E. S., Ansell, J. E., Fonarow, G. C., Gersh, B. J., Go, A. S., Hylek, E. M., Kowey, P. R., Mahaffey, K. W., Thomas, L. E., Kong, M. H., Lopes, R. D., Mills, R. M., Peterson, E. D. 2011; 162 (4): 606-U54

    Abstract

    Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with an increased risk of stroke, heart failure, and death. Data on contemporary treatment patterns and outcomes associated with AF in clinical practice are limited.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation is a multicenter, prospective, ambulatory-based registry of incident and prevalent AF. The registry will be a nationwide collaboration of health care providers, including internists, primary care physicians, cardiologists, and electrophysiologists. Initial target enrollment is approximately 10,000 patients to be recruited from approximately 200 US outpatient practices. Enrolled patients will be observed for ≥2 years. A patient-reported outcomes substudy in ≥1,500 patients will provide serial quality-of-life assessments. The goal is to characterize treatment and outcomes of patients with AF, thereby promoting better quality of AF care and improved patient outcomes.The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation will provide insights into "real-world" treatment including rate and rhythm control, stroke prevention, transitions to new therapies, and clinical and patient-centered outcomes among patients with AF in community practice settings (ClinicalTrials.gov NCT01165710).

    View details for DOI 10.1016/j.ahj.2011.07.001

    View details for Web of Science ID 000295925100007

    View details for PubMedID 21982650

  • Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment EUROPEAN HEART JOURNAL Fox, K. A., Piccini, J. P., Wojdyla, D., Becker, R. C., Halperin, J. L., Nessel, C. C., Paolini, J. F., Hankey, G. J., Mahaffey, K. W., Patel, M. R., Singer, D. E., Califf, R. M. 2011; 32 (19): 2387-2394

    Abstract

    Patients with non-valvular atrial fibrillation (AF) and renal insufficiency are at increased risk for ischaemic stroke and bleeding during anticoagulation. Rivaroxaban, an oral, direct factor Xa inhibitor metabolized predominantly by the liver, preserves the benefit of warfarin for stroke prevention while causing fewer intracranial and fatal haemorrhages.We randomized 14 264 patients with AF in a double-blind trial to rivaroxaban 20 mg/day [15 mg/day if creatinine clearance (CrCl) 30-49 mL/min] or dose-adjusted warfarin (target international normalized ratio 2.0-3.0). Compared with patients with CrCl >50 mL/min (mean age 73 years), the 2950 (20.7%) patients with CrCl 30-49 mL/min were older (79 years) and had higher event rates irrespective of study treatment. Among those with CrCl 30-49 mL/min, the primary endpoint of stroke or systemic embolism occurred in 2.32 per 100 patient-years with rivaroxaban 15 mg/day vs. 2.77 per 100 patient-years with warfarin [hazard ratio (HR) 0.84; 95% confidence interval (CI) 0.57-1.23] in the per-protocol population. Intention-to-treat analysis yielded similar results (HR 0.86; 95% CI 0.63-1.17) to the per-protocol results. Rates of the principal safety endpoint (major and clinically relevant non-major bleeding: 17.82 vs. 18.28 per 100 patient-years; P = 0.76) and intracranial bleeding (0.71 vs. 0.88 per 100 patient-years; P = 0.54) were similar with rivaroxaban or warfarin. Fatal bleeding (0.28 vs. 0.74% per 100 patient-years; P = 0.047) occurred less often with rivaroxaban.Patients with AF and moderate renal insufficiency have higher rates of stroke and bleeding than those with normal renal function. There was no evidence of heterogeneity in treatment effect across dosing groups. Dose adjustment in ROCKET-AF yielded results consistent with the overall trial in comparison with dose-adjusted warfarin.

    View details for DOI 10.1093/eurheartj/ehr342

    View details for Web of Science ID 000295684300017

    View details for PubMedID 21873708

  • Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation NEW ENGLAND JOURNAL OF MEDICINE Patel, M. R., Mahaffey, K. W., Garg, J., Pan, G., Singer, D. E., Hacke, W., Breithardt, G., Halperin, J. L., Hankey, G. J., Piccini, J. P., Becker, R. C., Nessel, C. C., Paolini, J. F., Berkowitz, S. D., Fox, K. A., Califf, R. M. 2011; 365 (10): 883-891

    Abstract

    The use of warfarin reduces the rate of ischemic stroke in patients with atrial fibrillation but requires frequent monitoring and dose adjustment. Rivaroxaban, an oral factor Xa inhibitor, may provide more consistent and predictable anticoagulation than warfarin.In a double-blind trial, we randomly assigned 14,264 patients with nonvalvular atrial fibrillation who were at increased risk for stroke to receive either rivaroxaban (at a daily dose of 20 mg) or dose-adjusted warfarin. The per-protocol, as-treated primary analysis was designed to determine whether rivaroxaban was noninferior to warfarin for the primary end point of stroke or systemic embolism.In the primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year) (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval [CI], 0.66 to 0.96; P<0.001 for noninferiority). In the intention-to-treat analysis, the primary end point occurred in 269 patients in the rivaroxaban group (2.1% per year) and in 306 patients in the warfarin group (2.4% per year) (hazard ratio, 0.88; 95% CI, 0.74 to 1.03; P<0.001 for noninferiority; P=0.12 for superiority). Major and nonmajor clinically relevant bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 in the warfarin group (14.5% per year) (hazard ratio, 1.03; 95% CI, 0.96 to 1.11; P=0.44), with significant reductions in intracranial hemorrhage (0.5% vs. 0.7%, P=0.02) and fatal bleeding (0.2% vs. 0.5%, P=0.003) in the rivaroxaban group.In patients with atrial fibrillation, rivaroxaban was noninferior to warfarin for the prevention of stroke or systemic embolism. There was no significant between-group difference in the risk of major bleeding, although intracranial and fatal bleeding occurred less frequently in the rivaroxaban group. (Funded by Johnson & Johnson and Bayer; ROCKET AF ClinicalTrials.gov number, NCT00403767.).

    View details for Web of Science ID 000294595600004

    View details for PubMedID 21830957

  • Ticagrelor Compared With Clopidogrel by Geographic Region in the Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION Mahaffey, K. W., Wojdyla, D. M., Carroll, K., Becker, R. C., Storey, R. F., Angiolillo, D. J., Held, C., Cannon, C. P., James, S., Pieper, K. S., Horrow, J., Harrington, R. A., Wallentin, L. 2011; 124 (5): 544-U78

    Abstract

    In the Platelet Inhibition and Patient Outcomes (PLATO) trial, a prespecified subgroup analysis showed a significant interaction between treatment and region (P=0.045), with less effect of ticagrelor in North America than in the rest of the world.Reasons for the interaction were explored independently by 2 statistical groups. Systematic errors in trial conduct were investigated. Statistical approaches evaluated the likelihood of play of chance. Cox regression analyses were performed to quantify how much of the regional interaction could be explained by patient characteristics and concomitant treatments, including aspirin maintenance therapy. Landmark Cox regressions at 8 time points evaluated the association of selected factors, including aspirin dose, with outcomes by treatment. Systematic errors in trial conduct were ruled out. Given the large number of subgroup analyses performed and that a result numerically favoring clopidogrel in at least 1 of the 4 prespecified regions could occur with 32% probability, chance alone cannot be ruled out. More patients in the United States (53.6%) than in the rest of the world (1.7%) took a median aspirin dose ≥300 mg/d. Of 37 baseline and postrandomization factors explored, only aspirin dose explained a substantial fraction of the regional interaction. In adjusted analyses, both Cox regression with median maintenance dose and landmark techniques showed that, in patients taking low-dose maintenance aspirin, ticagrelor was associated with better outcomes compared with clopidogrel, with statistical superiority in the rest of the world and similar outcomes in the US cohort.The regional interaction could arise from chance alone. Results of 2 independently performed analyses identified an underlying statistical interaction with aspirin maintenance dose as a possible explanation for the regional difference. The lowest risk of cardiovascular death, myocardial infarction, or stroke with ticagrelor compared with clopidogrel is associated with a low maintenance dose of concomitant aspirin.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

    View details for DOI 10.1161/CIRCULATIONAHA.111.047498

    View details for Web of Science ID 000293338400014

    View details for PubMedID 21709065

  • Highlights from the III International Symposium of Thrombosis and Anticoagulation (ISTA), October 14-16, 2010, Sao Paulo, Brazil JOURNAL OF THROMBOSIS AND THROMBOLYSIS Lopes, R. D., Becker, R. C., Alexander, J. H., Armstrong, P. W., Califf, R. M., Chan, M. Y., Crowther, M., Granger, C. B., Harrington, R. A., Hylek, E. M., James, S. K., Jolicoeur, E. M., Mahaffey, K. W., Newby, L. K., Peterson, E. D., Pieper, K. S., Van de Werf, F., Wallentin, L., White, H. D., Carvalho, A. C., Giraldez, R. R., Guimaraes, H. P., Nader, H. B., Kalil, R. A., Bizzachi, J. M., Lopes, A. C., Garcia, D. A. 2011; 32 (2): 242-266

    Abstract

    To discuss and share knowledge around advances in the care of patients with thrombotic disorders, the Third International Symposium of Thrombosis and Anticoagulation was held in São Paulo, Brazil, from October 14-16, 2010. This scientific program was developed by clinicians for clinicians, and was promoted by four major clinical research institutes: the Brazilian Clinical Research Institute, the Duke Clinical Research Institute of the Duke University School of Medicine, the Canadian VIGOUR Centre, and the Uppsala Clinical Research Center. Comprising 3 days of academic presentations and open discussion, the symposium had as its primary goal to educate, motivate, and inspire internists, cardiologists, hematologists, and other physicians by convening national and international visionaries, thought-leaders, and dedicated clinician-scientists. This paper summarizes the symposium proceedings.

    View details for DOI 10.1007/s11239-011-0592-7

    View details for Web of Science ID 000292833000017

    View details for PubMedID 21547405

  • Cardiogenic shock and heart failure post-percutaneous coronary intervention in ST-elevation myocardial infarction: Observations from "Assessment of Pexelizumab in Acute Myocardial Infarction" AMERICAN HEART JOURNAL French, J. K., Armstrong, P. W., Cohen, E., Kleiman, N. S., O'Connor, C. M., Hellkamp, A. S., Stebbins, A., Holmes, D. R., Hochman, J. S., Granger, C. B., Mahaffey, K. W. 2011; 162 (1): 89-97

    Abstract

    Mortality after ST-elevation myocardial infarction (STEMI) has reduced with reperfusion by primary percutaneous coronary intervention (PCI), which may have impacted on the adverse outcomes of cardiogenic shock (CS) and congestive heart failure (CHF).In the APEX-AMI trial, 5,745 patients with STEMI and planned primary PCI were randomly assigned pexelizumab or matching placebo. Post-randomization CS or CHF was adjudicated by a clinical endpoints committee. Treatment assignment to pexelizumab did not influence either endpoint or mortality rates. Cardiogenic shock developed in 196 patients (3.4%) at a median of 6.0 hours (interquartile range 3.9-28.3) post-randomization, and mortality at 90 days was 54.6%. Congestive heart failure occurred in 254 of patients (4.4%) at a median of 2.6 days (IQR 1.0-16.6), and mortality through 90 days was 10.2%; mortality among those with neither endpoint was 2.1%. Patients with CS or CHF were older, were more often female, and had more hypertension and diabetes, but smoked less compared with non-CS/CHF patients (all P < .05). Independent mortality predictors among those with CS or CHF were hyperlipidemia and a history of angina (interaction P = .011 and .008, respectively); procedural predictors among survivors to PCI were pre-PCI Thrombolysis In Myocardial Infarction (TIMI) flow 0-1 and post-PCI TIMI flow <3 (P = .013 and <.0001, respectively).Survival after CS remains poor despite aggressive reperfusion. Both CS and CHF remain the major causes of death among STEMI patients undergoing primary PCI. Future studies should examine treatments that aim to reduce mortality in these highest risk patients.

    View details for DOI 10.1016/j.ahj.2011.04.009

    View details for Web of Science ID 000292542400022

    View details for PubMedID 21742094

  • Inference on treatment effects from a randomized clinical trial in the presence of premature treatment discontinuation: the SYNERGY trial BIOSTATISTICS Zhang, M., Tsiatis, A. A., Davidian, M., Pieper, K. S., Mahaffey, K. W. 2011; 12 (2): 258-269

    Abstract

    The Superior Yield of the New Strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) was a randomized, open-label, multicenter clinical trial comparing 2 anticoagulant drugs on the basis of time-to-event endpoints. In contrast to other studies of these agents, the primary, intent-to-treat analysis did not find evidence of a difference, leading to speculation that premature discontinuation of the study agents by some subjects may have attenuated the apparent treatment effect and thus to interest in inference on the difference in survival distributions were all subjects in the population to follow the assigned regimens, with no discontinuation. Such inference is often attempted via ad hoc analyses that are not based on a formal definition of this treatment effect. We use SYNERGY as a context in which to describe how this effect may be conceptualized and to present a statistical framework in which it may be precisely identified, which leads naturally to inferential methods based on inverse probability weighting.

    View details for DOI 10.1093/biostatistics/kxq054

    View details for Web of Science ID 000288800600006

    View details for PubMedID 20797983

  • The Impact of Postrandomization Crossover of Therapy in Acute Coronary Syndromes Care CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Mahaffey, K. W., Pieper, K. S., Lokhnygina, Y., Califf, R. M., Antman, E. M., Kleiman, N. S., Goodman, S. G., White, H. D., Rao, S. V., Hochman, J. S., Cohen, M., Col, J. J., Roe, M. T., Ferguson, J. J. 2011; 4 (2): 211-U119

    Abstract

    In the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) study, patients assigned enoxaparin or unfractionated heparin (UFH) were treated with alternative anticoagulant therapy after randomization at physician discretion, a practice made possible because the trial was open label. Using SYNERGY as an example, we demonstrate the difficulty of evaluating the effect of postrandomization events in clinical trials and discuss possible methodology.Patients with and without postrandomization crossovers were characterized and event rates analyzed. Statistical modeling was performed using inverse probability weighting and landmark analyses to evaluate the potential impact of postrandomization crossovers on event rates and treatment effect. Of 9978 SYNERGY patients, 9613 (96.3%) received at least 1 dose of randomized therapy and are included in these analyses. Of these, 740 (7.7%; 554 enoxaparin; 186 UFH) had postrandomization crossover. Crossover patients had higher unadjusted rates of 30-day death/myocardial infarction (MI) (18.9% versus 14.0%), thrombolysis in MI (TIMI) bleeding (16.9% versus 7.6%), Global Use of Strategies to Open Occluded Coronary Arteries bleeding (4.5% versus 2.3%), and transfusions (32.3% versus 15.2%). Adjustment for timing of crossover relative to the events attenuated the difference noted in death/MI but accentuated the association with TIMI bleeding. After adjustment using the inverse probability weighting technique, only a modest difference in the absolute treatment effect was observed between enoxaparin and UFH on death/MI (0.6% [unadjusted] versus 0.8% [adjusted]) and TIMI major bleeding (1.5% [unadjusted] versus 1.0% [adjusted]). The landmark analysis indicated a significant association between crossover from enoxaparin to UFH and TIMI bleeding but not in the other direction, and no crossover association was found in death/MI.Postrandomization events in clinical trials are accompanied by substantial confounders that require careful consideration. In SYNERGY, postrandomization crossovers occurred in nearly 10% of patients, abetted by the open-label trial design. These patients had increased incidence of bleeding and death/MI, but after adjustment using several modeling techniques, only a modest impact of postrandomization crossovers on treatment effect was observed. The usual methods of analyzing end points cannot adequately address biases in changing treatment in these patients. The potential biases of membership in a postrandomization subgroup, as well as the methods used to account for the biases, should be considered when weighing the strength of results. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00043784.

    View details for DOI 10.1161/CIRCOUTCOMES.109.853598

    View details for Web of Science ID 000288372200013

    View details for PubMedID 21304094

  • Mortality Implications of Primary Percutaneous Coronary Intervention Treatment Delays: Insights From the Assessment of Pexelizumab in Acute Myocardial Infarction Trial CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Hudson, M. P., Armstrong, P. W., O'Neil, W. W., Stebbins, A. L., Weaver, W. D., Widimsky, P., Aylward, P. E., Ruzyllo, W., Holmes, D., Mahaffey, K. W., Granger, C. B. 2011; 4 (2): 183-192

    Abstract

    Prior studies demonstrate a direct relationship between treatment delays to primary percutaneous intervention and mortality in patients with ST-segment elevation myocardial infarction (STEMI). This analysis compared the relationship of symptom onset-to-balloon time and door-to-balloon time on mortality in patients with STEMI.We analyzed different treatment delays (symptom onset-to-balloon time, door-to-balloon time) and mortality in 5745 STEMI patients. Baseline characteristics, flow grade, 90-day mortality, and clinical outcomes were compared in patients stratified by treatment delay. Multivariable logistic regression modeling was performed to assess the independent and relative effect of each treatment delay on 90-day mortality. Female sex, increased age, and worse thrombolysis in myocardial infarction flow grade were significantly associated with longer symptom onset-to-balloon times and door-to-balloon times. Longer symptom onset-to-balloon time was significantly associated with worse 90-day mortality (3.7%, 4.2%, and 6.5% for time delays <3 hours, 3 to 5 hours, and >5 hours, respectively, P<0.0001). Similarly, longer door-to-balloon times were significantly associated with worse 90-day mortality (3.2%, 4.0%, 4.6%, and 5.3% for delays <60 minutes, 60 to 90 minutes, 90 to 120 minutes, and ≥120 minutes respectively, P<0.0001). In a multivariate model of 90-day mortality, door-to-balloon time (χ(2) 6.0, P<0.014), and symptom onset-to-hospital arrival (χ(2) 9.8, P<0.007) remained independent determinants.Both symptom onset-to-balloon time and hospital door-to-balloon time are strongly associated with 90-day mortality following STEMI. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00091637.

    View details for DOI 10.1161/CIRCOUTCOMES.110.945311

    View details for Web of Science ID 000288372200009

    View details for PubMedID 21304097

  • Strategic lessons from the clinical event classification process for the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial CONTEMPORARY CLINICAL TRIALS Mahaffey, K. W., Wampole, J. L., Stebbins, A., Berdan, L. G., Mcafee, D., Rorick, T. L., French, J. K., Kleiman, N. S., O'Connor, C. M., Cohen, E. A., Granger, C. B., Armstrong, P. W. 2011; 32 (2): 178-187

    Abstract

    Independent adjudication of clinical trial events is traditionally performed by physicians on a clinical event classification (CEC) committee.The experience of the centralized CEC group of the APEX-AMI trial is described. This group adjudicated key secondary pre-specified outcome measures of congestive heart failure (CHF) and cardiogenic shock through 90 days using an algorithmic approach for some events.Data were collected via an electronic data capture (EDC) tool on all subjects, and additional information was provided via EDC for patients identified by site investigators with CHF or shock. Two strategies were used to adjudicate potential events: 1) a computer algorithm (followed by physician confirmation) analyzed data to determine whether events met trial end point definitions; or 2) physician review was used if EDC data were inadequate to allow classification by algorithm.Of 5745 patients, 282 suspected cardiogenic shock and 465 suspected CHF events were identified. The computer algorithm or physicians confirmed 196/282 cardiogenic shock and 277/465 CHF end points. Overall, 242/742 (32.6%) of suspected events were classified by algorithm. Of the 500 events not resolved by computer algorithm, the CEC physicians agreed with site investigator assessments in 126/277 (45%) of CHF and 151/196 (77%) of cardiogenic shock events. The CEC committee completed adjudication of all suspected 30- and 90-day CHF and cardiogenic shock events within 7 days of the last patient 30-day follow-up visit and within 1 day of the last patient 90-day follow-up visit. Only 27% of patients required source document collection in addition to EDC-collected information.A complementary approach of a computerized assessment and physician review was used in the CEC effort of the APEX-AMI trial. The algorithm categorized approximately one third of suspected CHF/cardiogenic shock events. The APEX-AMI CEC experience shows that an algorithmic approach may be a useful strategy for end point evaluation but requires validation.

    View details for DOI 10.1016/j.cct.2010.12.013

    View details for Web of Science ID 000288056700006

    View details for PubMedID 21220052

  • Association of Myocardial Enzyme Elevation and Survival Following Coronary Artery Bypass Graft Surgery JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Domanski, M. J., Mahaffey, K., Hasselblad, V., Brener, S. J., Smith, P. K., Hillis, G., Engoren, M., Alexander, J. H., Levy, J. H., Chaitman, B. R., Broderick, S., Mack, M. J., Pieper, K. S., Farkouh, M. E. 2011; 305 (6): 585-591

    Abstract

    Several small studies have suggested that cardiac enzyme elevation in the 24 hours following coronary artery bypass graft (CABG) surgery is associated with worse prognosis, but a definitive study is not available. Also, the long-term prognostic impact of small increases of perioperative enzyme has not been reported.To quantify the relationship between peak post-CABG elevation of biomarkers of myocardial damage and early, intermediate-, and long-term mortality, including determining whether there is a threshold below which elevations lack prognostic significance.Studies (randomized clinical trials or registries) of patients undergoing CABG surgery in which postprocedural biomarker and mortality data were collected and included. A search of the PubMed database was performed in July 2008 using the search terms coronary artery bypass, troponin, CK-MB, and mortality.Studies evaluating mortality and creatine kinase (CK-MB), troponin, or both were included. One study investigator declined to participate and 3 had insufficient data.Two independent reviewers determined study eligibility. The principal investigator from each eligible study was contacted to request his/her participation. Once institutional review board approval for the use of these data for this purpose was obtained, we requested patient-level data from each source. Data were examined to ensure that cardiac markers had been measured within 24 hours after CABG surgery, key baseline covariates, and mortality were available.A total of 18,908 patients from 7 studies were included. Follow-up varied from 3 months to 5 years. Mortality was found to be a monotonically increasing function of the CK-MB ratio. The 30-day mortality rates by categories of CK-MB ratio were 0.63% (95% confidence interval [CI], 0.36%-1.02%) for 0 to <1, 0.86% (95% CI, 0.49%-1.40%) for 1 to <2, 0.95% (95% CI, 0.72%-1.22%) for 2 to <5, 2.09% (95% CI, 1.69%-2.57%) for 5 to <10, 2.78% (95% CI, 2.12%-3.58%) for 10 to <20, and 7.06% (95% CI, 5.46%-8.96%) for 20 to ≥40. Of the variables considered, the CK-MB ratio was the strongest independent predictor of death to 30 days and remained significant even after adjusting for a wide range of baseline risk factors (χ(2) = 143, P < .001; hazard ratio [HR] for each 5 point-increment above the upper limits of normal [ULN] = 1.12; 95% CI, 1.10-1.14). This result was strongest at 30 days, but the adjusted association persisted from 30 days to 1 year (χ(2) = 24; P < .001; HR for each 5-point increment above ULN = 1.17; 95% CI, 1.10-1.24) and a trend was present from 1 year to 5 years (χ(2) = 2.8; P = .10; HR for each 5-point increment above ULN = 1.05; 95% CI, 0.99-1.11). Similar analyses using troponin as the marker of necrosis led to the same conclusions (χ(2) = 142 for 0-30 days and χ(2) = 40 for 30 days to 6 months, both P < .001; HR for each 50 points above the ULN = 1.28; 95% CI, 1.23-1.33 and 1.15; 95% CI, 1.10-1.21, respectively).Among patients who had undergone CABG surgery, elevation of CK-MB or troponin levels within the first 24 hours was independently associated with increased intermediate- and long-term risk of mortality.

    View details for Web of Science ID 000287080500023

    View details for PubMedID 21304084

  • Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery Results From the PLATO (Platelet Inhibition and Patient Outcomes) Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Held, C., Asenblad, N., Bassand, J. P., Becker, R. C., Cannon, C. P., Claeys, M. J., Harrington, R. A., Horrow, J., Husted, S., James, S. K., Mahaffey, K. W., Nicolau, J. C., Scirica, B. M., Storey, R. F., Vintila, M., Ycas, J., Wallentin, L. 2011; 57 (6): 672-684

    Abstract

    The purpose of this study is to evaluate the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome undergoing coronary artery bypass graft surgery (CABG), as a post-randomization strategy.Ticagrelor is a novel, reversibly binding, oral, direct-acting P2Y(12)-receptor antagonist. In the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized 18,624 patients with acute coronary syndromes, ticagrelor compared with clopidogrel significantly reduced the risk of the primary composite end point of cardiovascular (CV) death, myocardial infarction, or stroke (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.77 to 0.92; p < 0.001). This report investigated the outcomes of patients treated with CABG during the trial.In total, 1,899 patients underwent CABG post-randomization. The protocol recommended ticagrelor/placebo to be withheld for 24 to 72 h and clopidogrel/placebo for 5 days preoperatively. In all, 1,261 patients underwent CABG and were receiving study drug treatment <7 days before surgery. The statistical analysis was based on events occurring from the CABG procedure until the end of the study, excluding 3 patients with CABG after study end.In the 1,261 patient cohort, the relative reduction of primary composite end point at 12 months (10.6% [66 of 629] with ticagrelor versus 13.1% [79 of 629] with clopidogrel; HR: 0.84; 95% CI: 0.60 to 1.16; p = 0.29) was consistent with the results of the whole trial. Total mortality was reduced from 9.7% (58 of 629) to 4.7% (29 of 629; HR: 0.49; 95% CI: 0.32 to 0.77; p < 0.01), CV death from 7.9% (47 of 629) to 4.1% (25 of 629; HR: 0.52; 95% CI: 0.32 to 0.85; p < 0.01), and non-CV death numerically from 2.0% to 0.7% (p = 0.07). There was no significant difference in CABG-related major bleeding between the randomized treatments.In the subgroup of patients undergoing CABG within 7 days after the last study drug intake, ticagrelor compared with clopidogrel was associated with a substantial reduction in total and CV mortality without excess risk of CABG-related bleeding.

    View details for DOI 10.1016/j.jacc.2010.10.029

    View details for Web of Science ID 000286880100006

    View details for PubMedID 21194870

  • Heparin-associated anti-Xa activity and platelet-derived prothrombotic and proinflammatory biomarkers in moderate to high-risk patients with acute coronary syndrome JOURNAL OF THROMBOSIS AND THROMBOLYSIS Becker, R. C., Mahaffey, K. W., Yang, H., Marian, A. J., Furman, M. I., Lincoff, A. M., Hazen, S. L., Petersen, J. L., Reist, C. J., Kleiman, N. S. 2011; 31 (2): 146-153

    Abstract

    Heparin compounds, to include fractionated and unfractionated preparations, exert both antithrombotic and antiinflammatory effects through combined inhibition of factor Xa and thrombin. The contribution of modulated platelet activity in vivo is less clearly defined. The SYNERGY library was a prospectively designed repository for candidate clinical, hemostatic, platelet, and molecular biomarkers from patients participating in SYNERGY--a large-scale, randomized clinical trial evaluating the comparative benefits of unfractionated heparin (UFH) and enoxaparin in high-risk patients with acute coronary syndrome (ACS). Samples were collected from 201 patients enrolled at 26 experienced, participating sites and shipped to established core laboratories for analysis of platelet, endothelium-derived, inflammatory and coagulation activity biomarkers. Tissue factor pathway inhibitor (TFPI)--a vascular endothelial cell-derived factor Xa regulatory protein-correlated directly with plasma anti-Xa activity (unadjusted: r = 0.23, P < 0.0001; adjusted: β = 0.10; P = 0.001), as did TFPI-fXa complexes (unadjusted: r = 0.34, P < 0.0001; adjusted: β = 0.38; P = < 0.0001). In contrast, there was a direct and inverse relationship between anti-Xa activity and two platelet-derived biomarkers-plasminogen activator inhibitor-1 (unadjusted: r = -0.18, P = 0.0012; adjusted: β = -0.10; P = 0.021) and soluble CD40 ligand (unadjusted: r = -0.11, P = 0.05; adjusted: β = -0.13; P = 0.049). All measured analyte relationships persisted after adjustment for age, creatinine clearance, weight, sex, and duration of treatment. Differences in biomarkers between patients receiving UFH and those randomized to enoxaparin were not observed. The ability of heparin compounds to affect the prothrombotic and proinflammatory states which characterize ACS may involve factor Xa-related modulation of platelet activation and expression. Whether this potentially beneficial effect is direct or indirect and achieved, at least in part, through the release of endothelial cell-derived coagulation regulatory proteins will require further investigation.

    View details for DOI 10.1007/s11239-010-0532-y

    View details for Web of Science ID 000286467400003

    View details for PubMedID 21086021

  • ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. Circulation Abraham, N. S., Hlatky, M. A., Antman, E. M., Bhatt, D. L., Bjorkman, D. J., Clark, C. B., Furberg, C. D., Johnson, D. A., Kahi, C. J., Laine, L., Mahaffey, K. W., Quigley, E. M., Scheiman, J., Sperling, L. S., Tomaselli, G. F. 2010; 122 (24): 2619-2633

    View details for DOI 10.1161/CIR.0b013e318202f701

    View details for PubMedID 21060077

  • ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents CIRCULATION Abraham, N. S., Hlatky, M. A., Antman, E. M., Bhatt, D. L., Bjorkman, D. J., Clark, C. B., Furberg, C. D., Johnson, D. A., Kahi, C. J., Laine, L., Mahaffey, K. W., Quigley, E. M., Scheiman, J., Sperling, L. S., Tomaselli, G. F., Harrington, R. A., Bates, E. R., Bhatt, D. L., Ferrari, V. A., Fisher, J. D., Gardner, T. J., Gentile, F., Hlatky, M. A., Jacobs, A. K., Kaul, S., Moliterno, D. J., Weitz, H. H., Wesley, D. J. 2010; 122 (24): 2619-2633
  • ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Abraham, N. S., Hlatky, M. A., Antman, E. M., Bhatt, D. L., Bjorkman, D. J., Clark, C. B., Furberg, C. D., Johnson, D. A., Kahi, C. J., Laine, L., Mahaffey, K. W., Quigley, E. M., Scheiman, J., Sperling, L. S., Tomaselli, G. F. 2010; 56 (24): 2051-2066

    View details for DOI 10.1016/j.jacc.2010.09.010

    View details for Web of Science ID 000284822500014

    View details for PubMedID 21126648

  • ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use AMERICAN JOURNAL OF GASTROENTEROLOGY Abraham, N. S., Hlatky, M. A., Antman, E. M., Bhatt, D. L., Bjorkman, D. J., Clark, C. B., Furberg, C. D., Johnson, D. A., Kahi, C. J., Laine, L., Mahaffey, K. W., Quigley, E. M., Scheiman, J., Sperling, L. S., Tomaselli, G. F. 2010; 105 (12): 2533-2549

    View details for DOI 10.1038/ajg.2010.445

    View details for Web of Science ID 000284940900004

    View details for PubMedID 21131924

  • Patterns of discharge antiplatelet therapy and late outcomes among 8,582 patients with bleeding during acute coronary syndrome: A pooled analysis from PURSUIT, PARAGON-A, PARAGON-B, and SYNERGY AMERICAN HEART JOURNAL Chan, M. Y., Sun, J. L., Wang, T. Y., Lopes, R. D., Jolicoeur, M. E., Pieper, K. S., Rao, S. V., Newby, L. K., Mahaffey, K. W., Harrington, R. A., Peterson, E. D. 2010; 160 (6): 1056-U95

    Abstract

    Major bleeding during an acute coronary syndrome (ACS) is associated with increased late ischemic events. Patients with bleeding are often discharged without antiplatelet therapy (AT). The association between discharge AT use and late ischemic outcomes among ACS patients with bleeding is uncertain.We examined discharge AT use among 8,582 ACS patients with in-hospital bleeding from a total of 26,451 patients enrolled in 4 randomized trials. After adjusting for the propensity to receive AT, we compared 6-month postdischarge outcomes between patients discharged with and those discharged without AT.Almost 1 in 10 patients with bleeding was discharged without AT (n=826). Compared with those receiving discharge AT, those not receiving discharge AT had a higher risk of 6-month death, myocardial infarction, and stroke (14.3% vs 7.8%, propensity-adjusted hazard ratio [HR]=1.36, 95% confidence interval=1.01-1.85). Nonuse of AT at discharge was associated with worse outcomes among patients treated with percutaneous coronary intervention compared with those treated without it (adjusted HR=4.22 vs 1.13, interaction P=.0003). Discharge monotherapy was associated with worse outcomes than dual AT among patients receiving stents (adjusted HR=1.78, 95% CI=1.04-3.03).Bleeding occurred commonly among patients with ACS. AT was often not used in these patients at discharge, and lack of discharge AT was associated with an increased risk of 6-month ischemic events. These data raise the possibility that lack of AT use among patients with in-hospital bleeding may contribute to their excess risk of long-term ischemic outcomes.

    View details for DOI 10.1016/j.ahj.2010.09.001

    View details for Web of Science ID 000285187600015

    View details for PubMedID 21146658

  • Effect of Home Testing of International Normalized Ratio on Clinical Events. NEW ENGLAND JOURNAL OF MEDICINE Matchar, D. B., Jacobson, A., Dolor, R., Edson, R., Uyeda, L., Phibbs, C. S., Vertrees, J. E., Shih, M., Holodniy, M., Lavori, P. 2010; 363 (17): 1608-1620

    Abstract

    Warfarin anticoagulation reduces thromboembolic complications in patients with atrial fibrillation or mechanical heart valves, but effective management is complex, and the international normalized ratio (INR) is often outside the target range. As compared with venous plasma testing, point-of-care INR measuring devices allow greater testing frequency and patient involvement and may improve clinical outcomes.We randomly assigned 2922 patients who were taking warfarin because of mechanical heart valves or atrial fibrillation and who were competent in the use of point-of-care INR devices to either weekly self-testing at home or monthly high-quality testing in a clinic. The primary end point was the time to a first major event (stroke, major bleeding episode, or death).The patients were followed for 2.0 to 4.75 years, for a total of 8730 patient-years of follow-up. The time to the first primary event was not significantly longer in the self-testing group than in the clinic-testing group (hazard ratio, 0.88; 95% confidence interval, 0.75 to 1.04; P=0.14). The two groups had similar rates of clinical outcomes except that the self-testing group reported more minor bleeding episodes. Over the entire follow-up period, the self-testing group had a small but significant improvement in the percentage of time during which the INR was within the target range (absolute difference between groups, 3.8 percentage points; P<0.001). At 2 years of follow-up, the self-testing group also had a small but significant improvement in patient satisfaction with anticoagulation therapy (P=0.002) and quality of life (P<0.001).As compared with monthly high-quality clinic testing, weekly self-testing did not delay the time to a first stroke, major bleeding episode, or death to the extent suggested by prior studies. These results do not support the superiority of self-testing over clinic testing in reducing the risk of stroke, major bleeding episode, and death among patients taking warfarin therapy. (Funded by the Department of Veterans Affairs Cooperative Studies Program; ClinicalTrials.gov number, NCT00032591.).

    View details for Web of Science ID 000283242700005

    View details for PubMedID 20961244

  • An evaluation of patient self-testing competency of prothrombin time for managing anticoagulation: pre-randomization results of VA Cooperative Study #481-The Home INR Study (THINRS) JOURNAL OF THROMBOSIS AND THROMBOLYSIS Dolor, R. J., Ruybalid, R. L., Uyeda, L., Edson, R. G., Phibbs, C., Vertrees, J. E., Shih, M., Jacobson, A. K., Matchar, D. B. 2010; 30 (3): 263-275

    Abstract

    Prior studies suggest patient self-testing (PST) of prothrombin time (PT) can improve the quality of anticoagulation (AC) and reduce complications (e.g., bleeding and thromboembolic events). "The Home INR Study" (THINRS) compared AC management with frequent PST using a home monitoring device to high-quality AC management (HQACM) with clinic-based monitoring on major health outcomes. A key clinical and policy question is whether and which patients can successfully use such devices. We report the results of Part 1 of THINRS in which patients and caregivers were evaluated for their ability to perform PST. Study-eligible patients (n = 3643) were trained to use the home monitoring device and evaluated after 2-4 weeks for PST competency. Information about demographics, medical history, warfarin use, medications, plus measures of numeracy, literacy, cognition, dexterity, and satisfaction with AC were collected. Approximately 80% (2931 of 3643) of patients trained on PST demonstrated competency; of these, 8% (238) required caregiver assistance. Testers who were not competent to perform PST had higher numbers of practice attempts, higher cuvette wastage, and were less able to perform a fingerstick or obtain blood for the cuvette in a timely fashion. Factors associated with failure to pass PST training included increased age, previous stroke history, poor cognition, and poor manual dexterity. A majority of patients were able to perform PST. Successful home monitoring of PT with a PST device required adequate levels of cognition and manual dexterity. Training a caregiver modestly increased the proportion of patients who can perform PST.

    View details for DOI 10.1007/s11239-010-0499-8

    View details for Web of Science ID 000282215300002

    View details for PubMedID 20628787

  • Relationship between renal function and outcomes in high-risk patients with non-ST-segment elevation acute coronary syndromes: Results from SYNERGY INTERNATIONAL JOURNAL OF CARDIOLOGY Spinler, S. A., Mahaffey, K. W., Gallup, D., Levine, G. N., Ferguson, J. J., Rao, S. V., Gallo, R., Ducas, J., Goodman, S. G., Antman, E., White, H. D., Biasucci, L., Becker, R. C., Col, J. J., Cohen, M., Harrington, R. A., Califf, R. M. 2010; 144 (1): 36-41

    Abstract

    Chronic kidney disease (CKD) is a risk factor for coronary heart disease and bleeding with antithrombotic therapy in patients with acute coronary syndromes (ACS). We evaluated the effect of renal function on efficacy and outcomes in high-risk patients with NSTE ACS in the SYNERGY trial.Creatinine clearance (CrCl) at the time of randomization was analyzed as a continuous variable added to multivariable logistic regression models for 30-day death or MI, non-CABG-associated TIMI major bleeding, GUSTO severe bleeding, and transfusion in the overall study population, patients undergoing coronary angiography, and patients undergoing PCI.Of 9838 patients with a CrCl value, 70.6% (N=6950) had CrCl≥60 mL/min, 27.8% (N=2732) had CrCl 30-59 mL/min, and 1.6% (N=156) had CrCl<30 mL/min. No randomized treatment by CrCl interaction test was found to be statistically significant, suggesting renal insufficiency affected enoxaparin and unfractionated heparin outcomes similarly. After adjustment, CrCl was an independent predictor of 30-day death or MI (OR 1.06, 95% CI 1.03-1.09), TIMI major bleeding (OR 1.06, 95% CI 1.02-1.10), GUSTO severe bleeding (OR 1.10, 95% CI 1.03-1.17), and transfusion (OR 1.07, 95% CI 1.04-1.11).Patients with CKD had higher rates of 30-day death or MI and bleeding than those without CKD, regardless of randomized antithrombin therapy. While this analysis suggests that there is a rise in bleeding events as CrCl falls for patients in either treatment group, it is unknown whether a reduction in dose would decrease bleeding risk.

    View details for DOI 10.1016/j.ijcard.2009.03.119

    View details for Web of Science ID 000282679000013

    View details for PubMedID 19406493

  • Independent Adjudication of Symptomatic Heart Failure With the Use of Doxorubicin and Cyclophosphamide Followed by Trastuzumab Adjuvant Therapy: A Combined Review of Cardiac Data From the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 Clinical Trials JOURNAL OF CLINICAL ONCOLOGY Russell, S. D., Blackwell, K. L., Lawrence, J., Pippen, J. E., Roe, M. T., Wood, F., Paton, V., Holmgren, E., Mahaffey, K. W. 2010; 28 (21): 3416-3421

    Abstract

    An independent Adjuvant Cardiac Review and Evaluation Committee (ACREC) systematically reviewed cases of symptomatic heart failure events to uniformly define the cardiac event rate across two large trials (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-31 and North Central Cancer Treatment Group [NCCTG] N9831) that assessed the addition of trastuzumab to standard adjuvant chemotherapy.The committee was composed of six independent oncologists and cardiologists. A retrospective review of patients with a cardiac event was performed by the primary investigators of the trials. The ACREC prospectively established criteria for determining a symptomatic heart failure event. Recovery status was determined from documented resolution of signs and symptoms. Potential risk factors were also assessed.Medical records for a total of 173 patients were reviewed: 40 in the chemotherapy-alone arm and 133 in the trastuzumab arm. Trastuzumab-treated patients had a 2.0% incidence of symptomatic heart failure events compared with 0.45% in the chemotherapy-alone arm. Complete or partial recovery was observed in 86.1% of trastuzumab-treated patients with symptomatic heart failure events. Of five patients who died, only one patient had received trastuzumab. Independent predictors for cardiac events were age older than 50 years, a low ejection fraction at the start of paclitaxel treatment, and trastuzumab treatment.The incidence of symptomatic heart failure events is 2.0% in patients treated with adjuvant trastuzumab, and the majority of these patients recover with appropriate treatment.

    View details for DOI 10.1200/JCO.2009.23.6950

    View details for Web of Science ID 000280003700004

    View details for PubMedID 20530275

  • Oral factor Xa inhibitors for the prevention of stroke in atrial fibrillation CURRENT OPINION IN CARDIOLOGY Piccini, J. P., Lopes, R. D., Mahaffey, K. W. 2010; 25 (4): 312-320

    Abstract

    Prevention of stroke and systemic emboli is paramount in the management of atrial fibrillation. Although warfarin is the predominant anticoagulant used in patients with atrial fibrillation, it has significant limitations that have impeded appropriate use of stroke prophylaxis in eligible patients with atrial fibrillation. Consequently, much research has been focused on finding an alternative to warfarin. We review the potential alternatives in development and evaluate the current evidence concerning their safety and efficacy.Oral direct factor Xa inhibitors are potentially well tolerated and effective replacements for warfarin. These agents do not require cofactors and offer selective inhibition at a critical step of amplification in the coagulation cascade. Multiple direct anti-factor Xa agents are currently undergoing evaluation in phase I, II, and III trials. Early results suggest that these novel anticoagulants have favorable pharmacokinetic and pharmacodynamic profiles with minimal-to-no requirements for therapeutic monitoring. Two direct factor Xa inhibitors are emerging from phase II trials (betrixaban and YM150) and three are being evaluated in phase III trials (apixaban, edoxaban, and rivaroxaban) for the prevention of stroke and systemic emboli in patients with atrial fibrillation. The phase III trials of apixaban and rivaroxaban have completed enrollment and are in the follow-up phase.Given the growing population of patients with atrial fibrillation, there is a great interest in finding new therapies for oral anticoagulation. The direct factor Xa inhibitors may offer several promising alternatives to warfarin therapy.

    View details for DOI 10.1097/HCO.0b013e32833a524f

    View details for Web of Science ID 000278569800004

    View details for PubMedID 20520539

  • Enoxaparin 0.3 mg/kg IV Supplement for Patients Transitioning to PCI after Subcutaneous Enoxaparin Therapy for NSTE ACS: A Subgroup Analysis from the SYNERGY Trial CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Cohen, M., Levine, G. N., Pieper, K. S., Lan, L., Antman, E. M., Aylward, P. E., White, H. D., Kleiman, N. S., Califf, R. M., Mahaffey, K. W. 2010; 75 (6): 928-935

    Abstract

    To explore clinical and bleeding outcomes in patients enrolled in the SYNERGY trial who had percutaneous coronary intervention (PCI) based on adherence to the dosing regimens of enoxaparin mandated by the protocol.In SYNERGY, 4,687 patients underwent PCI during index hospitalization. Patients in the subcutaneous (sc) enoxaparin group were to be given an 0.3 mg/kg IV bolus immediately before PCI if balloon inflation occurred > or = 8 hr after their last sc dose of enoxaparin.The incidence of the 1 degrees efficacy end point (death/myocardial infarction [MI] post PCI and through 30 days), and the rates of post-PCI in-hospital TIMI major and GUSTO severe bleeding were compared between patients randomized to unfractionated heparin (UFH) and those randomized to sc enoxaparin who did or did not receive a supplemental IV bolus of enoxaparin in accord with protocol-mandates.A total of 4,687 patients had PCI; 2,323 were assigned sc enoxaparin and 1,332 received protocol-mandated IV enoxaparin bolus, while 215 enoxaparin patients received inappropriate IV therapy (either receiving IV enoxaparin before the 8-hr protocol time or not receiving the IV enoxaparin as directed after 8 hr). Death or MI occurring post PCI through 30-day follow-up tended to be lower in the enoxaparin patients who were treated according to protocol than in those who were not (12.3% vs. 14.4%; adjusted P = 0.25), as was TIMI major bleeding (3.0% vs. 4.7%, adjusted P = 0.08).These exploratory analyses show that patients in SYNERGY who received the protocol-mandated supplemental IV bolus of 0.3 mg/kg enoxaparin before PCI performed 8-12 hr after their last sc enoxaparin dose tended to have improved outcomes compared with those who did not. Strategies to ensure adherence to dosing guidelines of enoxaparin during PCI should be considered.

    View details for DOI 10.1002/ccd.22340

    View details for Web of Science ID 000277396200026

    View details for PubMedID 20432399

  • A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development Program for Type 2 Diabetes POSTGRADUATE MEDICINE Frederich, R., Alexander, J. H., Fiedorek, F. T., Donovan, M., Berglind, N., Harris, S., Chen, R., Wolf, R., Mahaffey, K. W. 2010; 122 (3): 16-27

    Abstract

    The objective was to assess the relative risk (RR) for cardiovascular (CV) events across all 8 randomized phase 2/3 trials evaluating saxagliptin in patients with type 2 diabetes mellitus.Cardiovascular events (death, myocardial infarction [MI], stroke, revascularization procedures, and cardiac ischemia) were reported by investigators through standard adverse event reporting procedures and were systematically identified. Post hoc blinded adjudication of all deaths, MIs, and strokes was performed using prespecified endpoint definitions by an independent clinical events committee (CEC).A total of 4607 randomized and treated patients (n = 3356 treated with saxagliptin [2.5-100 mg/d]; n = 1251, comparator [n = 656, placebo; n = 328, metformin; n = 267, uptitrated glyburide]) were included. The median ages were 54 years (saxagliptin) and 55 years (comparator) (interquartile range, 47-61 each); 51% were female, 73% were white, 52% were hypertensive, 44% had hypercholesterolemia, 39% had a smoking history, 20% had a first-degree family member with premature coronary heart disease, and 12% had prior CV disease. Cardiovascular events were experienced by 61 patients (38 [1.1%], saxagliptin; 23 [1.8%], comparator), and CV death/MI/stroke events were reported by investigators in 41 patients: 23 (0.7%), saxagliptin; 18 (1.4%), comparator (relative risk, 95% confidence interval [CI], 0.44 [0.24-0.82]). The CEC reviewed 147 patients with potential CV events and identified a total of 40 patients with CV death/MI/stroke: 22 (0.7%), saxagliptin; 18 (1.4%), comparator (RR, 0.43 [0.23-0.80]). Component proportions for CV death, MI, and stroke were (saxagliptin vs comparator): 7 (0.2%) vs 10 (0.8%), 8 (0.2%) vs 8 (0.6%), and 11 (0.3%) vs 5 (0.4%), respectively.No increased risk of CV death/MI/stroke was observed in patients randomly assigned saxagliptin across a broad drug development program. Although this systematic overview has inherent and important limitations, the data support a potential reduction in CV events with saxagliptin. The hypothesis of CV protection with saxagliptin will be tested prospectively in a large randomized clinical outcome trial evaluating saxagliptin compared with standard of care in patients with type 2 diabetes at increased risk for CV events.

    View details for Web of Science ID 000281249000002

    View details for PubMedID 20463410

  • Prognostic utility of quantifying evolutionary ST-segment depression on early follow-up electrocardiogram in patients with non-ST-segment elevation acute coronary syndromes EUROPEAN HEART JOURNAL Yan, R. T., Yan, A. T., Mahaffey, K. W., White, H. D., Pieper, K., Sun, J., Pepine, C. J., Biasucci, L. M., Gulba, D. C., Lopez-Sendon, J., Goodman, S. G. 2010; 31 (8): 958-966

    Abstract

    Although ST-segment depression (STD) on the admission electrocardiogram (ECG) confers adverse prognosis in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), the implications of STD on follow-up ECG remain uncertain. We determined the prognostic significance of STD on follow-up ECG performed within 12-24 h of admission and whether its quantitative evaluation can further refine risk stratification.The admission and follow-up ECGs of 3877 patients in the SYNERGY trial were analysed for the presence (>or=1 mm) and extent (maximum magnitude on any single lead) of STD. Of the 1110 patients presenting with STD on admission, 534 (48.1%) with persistent STD at follow-up had higher mortality at 30 days (7.1 vs. 3.6%, P = 0.01) and 6 months (10.7 vs. 5.2%, P = 0.001) than those with normalized STD. Among 2767 patients without STD on admission, 174 (6.3%) developed new STD on follow-up ECG and experienced increased mortality compared with those without such interval change (30 days: 4.0 vs. 1.7%, P = 0.035; 6 months: 8.0 vs. 3.3%, P = 0.001). After adjustment for established clinical prognosticators and the extent of STD on admission, every 1 mm increment of STD on the follow-up ECG independently predicted a graded increase in 30-day mortality [hazards ratio (HR) = 1.60, 95% confidence interval (CI) = 1.29-1.98, P < 0.0001], and death/myocardial infarction at 30 days (HR = 1.19, 95% CI = 1.03-1.36, P = 0.017) and 6 months (HR = 1.17, 95% CI = 1.03-1.32, P = 0.016).The magnitude of STD on a routine 12-24 h follow-up ECG provides incremental prognostic information beyond established clinical prognosticators and the extent of STD on admission. Incorporating a follow-up ECG and its quantitative evaluation for STD may further refine risk stratification of patients with NSTE-ACS.

    View details for DOI 10.1093/eurheartj/ehp548

    View details for Web of Science ID 000277278900018

    View details for PubMedID 20034973

  • Obesity in patients with non-ST-segment elevation acute coronary syndromes: Results from the SYNERGY trial INTERNATIONAL JOURNAL OF CARDIOLOGY Mahaffey, K. W., Tonev, S. T., Spinler, S. A., Levine, G. N., Gallo, R., Ducas, J., Goodman, S. G., Antman, E. M., Becker, R. C., Langer, A., White, H. D., Aylward, P. E., Col, J. J., Ferguson, J. J., Califf, R. M. 2010; 139 (2): 123-133

    Abstract

    Obese patients are at increased risk of acute coronary syndromes (ACS). We evaluated the prevalence of obesity in a large ACS population, as well as the relationship between body mass index (BMI) and the use of cardiac medications and procedures, clinical outcomes, and treatment effects between enoxaparin and unfractionated heparin (UFH).Using the database of the SYNERGY trial, we identified 9978 patients in 12 countries who were randomly assigned to receive enoxaparin or UFH. Patient weight at baseline and 30-day follow-up was recorded. BMI information was available on 9837 patients. BMI was analyzed in clinically meaningful categories (<20, 20-25, 30-35, > or =35 kg/m(2)) and as a continuous variable.Thirty-two percent of patients were obese (BMI> or =30), with a greater proportion of patients with obesity from North America (36%) compared with other regions. Enoxaparin was dosed as 1 mg/kg regardless of body weight without maximum. The first dose of enoxaparin was underdosed in 15% of patients assigned enoxaparin, and obese patients were more likely to be underdosed than non-obese patients. Obese patients were younger, less often white, had more diabetes, hypertension, hyperlipidemia, family history of coronary artery disease, and congestive heart failure but fewer strokes, less peripheral vascular disease, and less often smoked. After adjustment, increased BMI was not an independent predictor of bleeding outcomes or 30-day death/myocardial infarction (MI), but increased BMI was predictive of lower 1-year mortality in the subgroup of patients with BMI at baseline below approximately 30 kg/m(2). No statistical interaction term was observed between obesity and randomized therapy for the outcomes of death/MI at 30 days and 6 months; death at 30 days, 6 months, and 1 year; and GUSTO or TIMI bleeding.Nearly one third of patients in SYNERGY were obese. Despite multiple comorbidities, obese patients had better unadjusted short- and long-term outcomes. After adjustment, higher BMI was not an independent predictor of in-hospital bleeding events or 30-day death/MI, but increased BMI was an independent predictor of 1-year mortality in patients with lower BMI but not in heavier patients. No interaction between the randomized treatment and obesity for efficacy and safety outcomes was observed across the range of BMI in this dataset. Standard dosing of enoxaparin should be used in patients without extreme obesity due to limited outcome data in these patients.

    View details for DOI 10.1016/j.ijcard.2008.10.008

    View details for Web of Science ID 000274955700004

    View details for PubMedID 19012977

  • Resolution of ST-segment depression: a new prognostic marker in ST-segment elevation myocardial infarction EUROPEAN HEART JOURNAL Tjandrawidjaja, M. C., Fu, Y., Westerhout, C. M., White, H. D., Todaro, T. G., Van de Werf, F., Mahaffey, K. W., Wagner, G. S., Granger, C. B., Armstrong, P. W. 2010; 31 (5): 573-581

    Abstract

    To evaluate the prognostic impact of ST depression resolution among patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI in the Assessment of Pexelizumab in Acute Myocardial Infarction (APEX-AMI) trial.In this study, 4729 of 5745 patients had analysable ECGs demonstrating concomitant ST-segment depression. Resolution of summation operatorST elevation (STE-R) and summation operatorST depression (STD-R) on 30 min post-PCI ECGs was dichotomized into those with > or =50 vs. <50% ST-segment resolution. Overall, 1143 patients (24%) had STD-R<50%. These patients had higher risk characteristics including older age, female sex, diabetes, hypertension, prior CHF/MI, Killip class >I, triple vessel disease, and less frequent TIMI 3 flow in the culprit coronary vessel post-PCI. After multivariable adjustment and accounting for STE-R, STD-R<50% remained an independent predictor for 90 day death and the composite of death, cardiogenic shock, or CHF. When compared with patients with both STE-R and STD-R> or =50%, patients with both STE-R and STD-R<50% had the worst outcomes [hazard ratios (HR) 90 day death: 2.54; 95% confidence intervals (CI): 1.71-3.77; HR 90 day composite: 2.18; 95% CI: 1.63-2.91].When ST depression is present in STEMI patients undergoing primary PCI, STD-R<50% provides independent prognostic value that is incremental to STE-R.

    View details for DOI 10.1093/eurheartj/ehp494

    View details for Web of Science ID 000275241900015

    View details for PubMedID 19952006

  • Influence of Clinical Trial Participation on Subsequent Antithrombin Use CLINICAL CARDIOLOGY Shah, B. R., Peterson, E. D., Chen, A. Y., Mahaffey, K. W., DeLong, E. R., Ohman, E. M., Pollack, C. V., Gibler, W. B., Roe, M. T. 2010; 33 (3): E49-E55

    View details for DOI 10.1002/clc.20581

    View details for Web of Science ID 000208373800011

  • Influence of clinical trial participation on subsequent antithrombin use. Clinical cardiology Shah, B. R., Peterson, E. D., Chen, A. Y., Mahaffey, K. W., DeLong, E. R., Ohman, E. M., Pollack, C. V., Gibler, W. B., Roe, M. T. 2010; 33 (3): E49-55

    Abstract

    Results from the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial showed that the low-molecular-weight heparin (LMWH) enoxaparin was non-inferior compared with unfractionated heparin (UFH) in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) managed invasively.We explored the influence of SYNERGY trial site participation on subsequent patterns of heparin use for NSTE-ACS patients treated in routine practice.We examined temporal patterns of LMWH use compared with UFH use among 122 764 patients with NSTE-ACS enrolled in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative between January 1, 2002 and June 30, 2006, to determine whether site participation in SYNERGY influenced the type of heparin used before and after publication of the SYNERGY results in July 2004.A total of 118 out of 388 (30%) U.S. hospitals participating in CRUSADE simultaneously participated in SYNERGY. SYNERGY sites in the CRUSADE registry were more likely to have a teaching affiliation and have more hospital beds than non-SYNERGY centers in the registry. There was no difference in the proportion of patients treated with LMWH at SYNERGY and non-SYNERGY sites prior to July 2004 compared with after July 2004. However, at SYNERGY sites, there was a slight decrease in the proportion of patients treated with both UFH and LMWH within 24 hours of presentation.The results of the SYNERGY trial did not appear to influence temporal patterns of LMWH use at sites in the CRUSADE registry. Furthermore, site participation in the SYNERGY trial did not alter patterns of LMWH use for NSTE-ACS after publication of the trial results in July 2004.

    View details for DOI 10.1002/clc.20581

    View details for PubMedID 20127904

  • Warfarin Use and Outcomes in Patients with Atrial Fibrillation Complicating Acute Coronary Syndromes AMERICAN JOURNAL OF MEDICINE Lopes, R. D., Starr, A., Pieper, C. F., Al-Khatib, S. M., Newby, L. K., Mehta, R. H., Van de Werf, F., Mahaffey, K. W., Armstrong, P. W., Harrington, R. A., White, H. D., Wallentin, L., Granger, C. B. 2010; 123 (2): 134-140

    Abstract

    We examined warfarin use at discharge (according to Congestive heart failure, Hypertension, Age>75 years, Diabetes, Prior Stroke/transient ischemic attack score and bleeding risk) and its association with 6-month death or myocardial infarction in patients with post-acute coronary syndrome atrial fibrillation.Of the 23,208 patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network A, and Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors trials, 4.0% (917 patients) had atrial fibrillation as an in-hospital complication and were discharged alive. Cox proportional hazards models were performed to assess 6-month outcomes after discharge.Overall, 13.5% of patients with an acute coronary syndrome complicated by atrial fibrillation received warfarin at discharge. Warfarin use among patients with atrial fibrillation had no relation with estimated stroke risk; similar rates were observed across Congestive heart failure, Hypertension, Age>75 years, Diabetes, Prior Stroke/transient ischemic attack (CHADS(2)) scores (0, 13%; 1, 14%; > or = 2, 13%) and across different bleeding risk categories (low risk, 11.9%; intermediate risk, 13.3%; high risk, 11.1%). Among patients with in-hospital atrial fibrillation, warfarin use at discharge was independently associated with a lower risk of death or myocardial infarction within 6 months of discharge (hazard ratio 0.39; 95% confidence interval, 0.15-0.98).Warfarin is associated with better 6-month outcomes among patients with atrial fibrillation complicating an acute coronary syndrome, but its use is not related to CHADS(2) score or bleeding risk.

    View details for DOI 10.1016/j.amjmed.2009.09.015

    View details for Web of Science ID 000274346200011

    View details for PubMedID 20103022

  • Mechanical Complications After Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction (from APEX-AMI) AMERICAN JOURNAL OF CARDIOLOGY French, J. K., Hellkamp, A. S., Armstrong, P. W., Cohen, E., Kleiman, N. S., O'Connor, C. M., Holmes, D. R., Hochman, J. S., Granger, C. B., Mahaffey, K. W. 2010; 105 (1): 59-63

    Abstract

    A decrease in mechanical complications after ST-elevation myocardial infarction may have contributed to improved survival rates associated with reperfusion by primary percutaneous coronary intervention (PCI). Mechanical complications occurred in 52 of 5,745 patients (0.91%) in the largest reported randomized trial in which primary PCI was the reperfusion strategy. The frequencies were 0.52% (30) for cardiac free-wall rupture (tamponade), 0.17% (10) for ventricular septal rupture, and 0.26% (15) for papillary muscle rupture (3 patients had 2 complications). Ninety-day survival rates were 37% (11) for cardiac free-wall rupture, 20% (2) for ventricular septal rupture, and 73.3% (11) for papillary muscle rupture. These mechanical complications occurred at a median of 23.5 hours (interquartile range 5.0 to 76.8) after symptom onset and were associated with 44% (23 of 52) survival through 90 days, which accounted for 11% of the 90-day mortality. Factors associated with mechanical complications were older age, female gender, Q waves, presence of radiologic pulmonary edema, and increased prerandomization troponin levels. In conclusion, rates of mechanical complications are lower with primary PCI than those previously reported after fibrinolytic therapy.

    View details for DOI 10.1016/j.amjcard.2009.08.653

    View details for Web of Science ID 000278136200010

    View details for PubMedID 20102891

  • Intravenous Platelet Blockade with Cangrelor during PCI. NEW ENGLAND JOURNAL OF MEDICINE Bhatt, D. L., Lincoff, A. M., Gibson, C. M., Stone, G. W., McNulty, S., Montalescot, G., Kleiman, N. S., Goodman, S. G., White, H. D., Mahaffey, K. W., Pollack, C. V., Manoukian, S. V., Widimsky, P., Chew, D. P., Cura, F., Manukov, I., Tousek, F., Jafar, M. Z., Arneja, J., Skerjanec, S., Harrington, R. A. 2009; 361 (24): 2330-2341

    Abstract

    Intravenous cangrelor, a rapid-acting, reversible adenosine diphosphate (ADP) receptor antagonist, might reduce ischemic events during percutaneous coronary intervention (PCI).In this double-blind, placebo-controlled study, we randomly assigned 5362 patients who had not been treated with clopidogrel to receive either cangrelor or placebo at the time of PCI, followed by 600 mg of clopidogrel. The primary end point was a composite of death, myocardial infarction, or ischemia-driven revascularization at 48 hours. Enrollment was stopped when an interim analysis concluded that the trial would be unlikely to show superiority for the primary end point.The primary end point occurred in 185 of 2654 patients receiving cangrelor (7.0%) and in 210 of 2641 patients receiving placebo (8.0%) (odds ratio in the cangrelor group, 0.87; 95% confidence interval [CI], 0.71 to 1.07; P=0.17) (modified intention-to-treat population adjusted for missing data). In the cangrelor group, as compared with the placebo group, two prespecified secondary end points were significantly reduced at 48 hours: the rate of stent thrombosis, from 0.6% to 0.2% (odds ratio, 0.31; 95% CI, 0.11 to 0.85; P=0.02), and the rate of death from any cause, from 0.7% to 0.2% (odds ratio, 0.33; 95% CI, 0.13 to 0.83; P=0.02). There was no significant difference in the rate of blood transfusion (1.0% in the cangrelor group and 0.6% in the placebo group, P=0.13), though major bleeding on one scale was increased in the cangrelor group, from 3.5% to 5.5% (P<0.001), because of more groin hematomas.The use of periprocedural cangrelor during PCI was not superior to placebo in reducing the primary end point. The prespecified secondary end points of stent thrombosis and death were lower in the cangrelor group, with no significant increase in the rate of transfusion. Further study of intravenous ADP blockade with cangrelor may be warranted. (ClinicalTrials.gov number, NCT00385138.)

    View details for DOI 10.1056/NEJMoa0908629

    View details for Web of Science ID 000272547600007

    View details for PubMedID 19915222

  • Platelet Inhibition with Cangrelor in Patients Undergoing PCI. NEW ENGLAND JOURNAL OF MEDICINE Harrington, R. A., Stone, G. W., McNulty, S., White, H. D., Lincoff, A. M., Gibson, C. M., Pollack, C. V., Montalescot, G., Mahaffey, K. W., Kleiman, N. S., Goodman, S. G., Amine, M., Angiolillo, D. J., Becker, R. C., Chew, D. P., French, W. J., Leisch, F., Parikh, K. H., Skerjanec, S., Bhatt, D. L. 2009; 361 (24): 2318-2329

    Abstract

    Cangrelor, a nonthienopyridine adenosine triphosphate analogue, is an intravenous blocker of the adenosine diphosphate receptor P2Y(12). This agent might have a role in the treatment of patients who require rapid, predictable, and profound but reversible platelet inhibition.We performed a large-scale international trial comparing cangrelor with 600 mg of oral clopidogrel administered before percutaneous coronary intervention (PCI) in patients with acute coronary syndromes. The primary efficacy end point was a composite of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours.We enrolled 8877 patients, and 8716 underwent PCI. At 48 hours, cangrelor was not superior to clopidogrel with respect to the primary composite end point, which occurred in 7.5% of patients in the cangrelor group and 7.1% of patients in the clopidogrel group (odds ratio, 1.05; 95% confidence interval [CI], 0.88 to 1.24; P=0.59). Likewise, cangrelor was not superior at 30 days. The rate of major bleeding (according to Acute Catheterization and Urgent Intervention Triage Strategy criteria) was higher with cangrelor, a difference that approached statistical significance (3.6% vs. 2.9%; odds ratio, 1.26; 95% CI, 0.99 to 1.60; P=0.06), but this was not the case with major bleeding (according to the Thrombolysis in Myocardial Infarction criteria) or severe or life-threatening bleeding (according to Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria). A secondary exploratory end point of death from any cause, Q-wave myocardial infarction, or ischemia-driven revascularization showed a trend toward a reduction with cangrelor, but it was not significant (0.6% vs. 0.9%; odds ratio, 0.67; 95% CI, 0.39 to 1.14; P=0.14).Cangrelor, when administered intravenously 30 minutes before PCI and continued for 2 hours after PCI, was not superior to an oral loading dose of 600 mg of clopidogrel, administered 30 minutes before PCI, in reducing the composite end point of death from any cause, myocardial infarction, or ischemia-driven revascularization at 48 hours. (ClinicalTrials.gov number, NCT00305162.)

    View details for DOI 10.1056/NEJMoa0908628

    View details for Web of Science ID 000272547600006

    View details for PubMedID 19915221

  • Comparison of Site-Reported and Core Laboratory-Reported Creatine Kinase-MB Values in Non-ST-Segment Elevation Acute Coronary Syndrome (from the International Trial SYNERGY) AMERICAN JOURNAL OF CARDIOLOGY Linefsky, J. P., Lin, M., Pieper, K. S., Reist, C. J., Berdan, L. G., Antman, E. M., Goodman, S. G., French, J. K., Guneri, S., Roe, M. T., Newby, L. K., Harrington, R. A., Ferguson, J. J., Califf, R. M., Mahaffey, K. W. 2009; 104 (10): 1330-1335

    Abstract

    The effect of nonstandardized creatine kinase (CK)-MB assays on the assessment of myocardial infarction (MI) end points in multicenter international trials has not been evaluated. We compared the site-reported and corresponding core laboratory CK-MB measures from 5 countries participating in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Samples for CK-MB were collected locally, with corresponding samples sent to a core laboratory at enrollment and after recurrent ischemic events, percutaneous coronary intervention, or coronary artery bypass grafting. The measured values were compared to the reported assay upper limits of normal (ULN) used at the site (or core laboratory for the core laboratory samples). The CK-MB results were available locally and from the core laboratory for 913 patients, constituting 4,693 time-matched laboratory values. The agreement between the core and site laboratory CK-MB/ULN ratio was moderate (concordance correlation coefficient 0.45) and varied considerably by geographic location and site. The CK-MB values were elevated (>or=2 times the ULN) by the core laboratory but normal (<2 times the ULN) by local standards in 708 instances (15%). There were 162 MI end points according to the core laboratory values versus 91 MI end points using the site-reported CK-MB data (kappa statistic 0.48). Compared with patients with no MI by the core or site laboratory values, patients with MI, as determined by both the core and the site laboratories, had significantly lower unadjusted 1-year survival rates (80.6% vs 93.5%, p <0.0001). Patients with MI, as determined by the core laboratory but not by the site laboratory, showed a trend toward a lower 1-year survival rate (89.8% vs 93.5%, p = 0.20). In conclusion, a substantial variation in CK-MB ratios and MI outcomes between the site and core laboratory data was observed in the SYNERGY trial. More MI outcomes were identified by the core laboratory, and patients with MI as defined by core laboratory data had lower 1-year survival, making these events potentially clinically important.

    View details for DOI 10.1016/j.amjcard.2009.06.056

    View details for Web of Science ID 000271998500003

    View details for PubMedID 19892046

  • Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes NEW ENGLAND JOURNAL OF MEDICINE Wallentin, L., Becker, R. C., Budaj, A., Cannon, C. P., Emanuelsson, H., Held, C., Horrow, J., Husted, S., James, S., Katus, H., Mahaffey, K. W., Scirica, B. M., Skene, A., Steg, P. G., Storey, R. F., Harrington, R. A. 2009; 361 (11): 1045-1057

    Abstract

    Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)

    View details for DOI 10.1056/NEJMoa0904327

    View details for Web of Science ID 000269659400007

    View details for PubMedID 19717846

  • The Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRA.CER) trial: study design and rationale AMERICAN HEART JOURNAL Harrington, R. A., Van de Werf, F., Armstrong, P. W., Aylward, P., Veltri, E., Mahaffey, K. W., Moliterno, D. J., Strony, J., Wallentin, L., White, H. D., Diaz, R., Huber, K., Nicolau, J. C., Carlos Prieto, J., Isaza, D., Widimsky, P., Grande, P., Nieminen, M., Montalescot, G., Bode, C., Wong, L., Ofner, P., Lewis, B. S., Ambrosio, G., Valgimigli, M., Ogawa, H., Yamaguchi, J., Jukema, J. W., Cornel, J. H., Nordrehaug, J. E., Ruzyllo, W., Providencia, L., Tan, H., Dalby, A., Seung-Jung, P., Betriu, A., Cequier, A., Held, C., Pfisterer, M., Ming-Fong, C., Timurkaynak, T., Storey, R. F., Chen, E., Hudson, M. P., Lincoff, A. M., Morrow, D. A., Tricoci, P., Whellan, D. 2009; 158 (3): 327-U5

    Abstract

    The protease-activated receptor 1 (PAR-1), the main platelet receptor for thrombin, represents a novel target for treatment of arterial thrombosis, and SCH 530348 is an orally active, selective, competitive PAR-1 antagonist. We designed TRA*CER to evaluate the efficacy and safety of SCH 530348 compared with placebo in addition to standard of care in patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) and high-risk features.TRA*CER is a prospective, randomized, double-blind, multicenter, phase III trial with an original estimated sample size of 10,000 subjects. Our primary objective is to demonstrate that SCH 530348 in addition to standard of care will reduce the incidence of the composite of cardiovascular death, myocardial infarction (MI), stroke, recurrent ischemia with rehospitalization, and urgent coronary revascularization compared with standard of care alone. Our key secondary objective is to determine whether SCH 530348 will reduce the composite of cardiovascular death, MI, or stroke compared with standard of care alone. Secondary objectives related to safety are the composite of moderate and severe GUSTO bleeding and clinically significant TIMI bleeding. The trial will continue until a predetermined minimum number of centrally adjudicated primary and key secondary end point events have occurred and all subjects have participated in the study for at least 1 year. The TRA*CER trial is part of the large phase III SCH 530348 development program that includes a concomitant evaluation in secondary prevention.TRA*CER will define efficacy and safety of the novel platelet PAR-1 inhibitor SCH 530348 in the treatment of high-risk patients with NSTE ACS in the setting of current treatment strategies.

    View details for DOI 10.1016/j.ahj.2009.07.001

    View details for Web of Science ID 000269641200002

    View details for PubMedID 19699853

  • Influence of body mass index on the efficacy of revascularization in patients with coronary artery disease JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Turer, A. T., Mahaffey, K. W., Honeycutt, E., Tuttle, R. H., Shaw, L. K., Sketch, M. H., Smith, P. K., Califf, R. M., Alexander, J. H. 2009; 137 (6): 1468-1474

    Abstract

    We examined the effect of body mass index on the association between revascularization strategy and survival in patients with coronary artery disease.Using the Duke Database for Cardiovascular Disease, we selected 22,877 patients who underwent cardiac catheterization from January 1986 to August 2004 and were found to have significant coronary artery disease. Patients were categorized into three coronary disease management groups: no revascularization, percutaneous coronary intervention, and coronary artery bypass surgery. Propensity scoring was used to control for coronary artery revascularization strategy. The relationship between body mass index, coronary disease treatment, and survival was assessed via Cox multivariable models adjusting for baseline demographic, clinical, and angiographic characteristics.The median body mass index was 27.2 kg/m(2) (24.4-30.4) in the overall cohort, 27.1 kg/m(2) (24.1-30.3) in the no revacularization group, 27.4 kg/m(2) (24.8-30.9) in the percutaneous intervention group, and 26.9 kg/m(2) (24.4-30.1) in the coronary bypass group. Body mass index was a significant, but weak, predictor of revascularization, with higher indexes predicting lower rates of coronary bypass. Thirty-day survival did not differ across body mass indexes among treatment groups, but survival curves appeared to separate over longer-term follow-up. An inverted U-shaped survival function was noted across all time points after 30 days, with the lowest risk of death at a body mass index of approximately 26 kg/m(2) (independent of revascularization strategy). Coronary bypass was associated with the highest survival at all later time points, whereas no revascularization was associated with the lowest.Extremes of body mass index are associated with lower long-term survival in patients with significant coronary disease. Revascularization, particularly with coronary bypass, is consistently associated with the best survival across the spectrum of body mass indexes.

    View details for DOI 10.1016/j.jtcvs.2008.11.047

    View details for Web of Science ID 000266275200026

    View details for PubMedID 19464466

  • Baseline Q-Wave Surpasses Time From Symptom Onset as a Prognostic Marker in ST-Segment Elevation Myocardial Infarction Patients Treated With Primary Percutaneous Coronary Intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Armstrong, P. W., Fu, Y., Westerhout, C. M., Hudson, M. P., Mahaffey, K. W., White, H. D., Todaro, T. G., Adams, P. X., Aylward, P. E., Granger, C. B. 2009; 53 (17): 1503-1509

    Abstract

    We assessed the incremental value of baseline Q waves over time from symptom onset as a marker of clinical outcome in ST-segment elevation myocardial infarction (STEMI).Time from symptom onset is a central focus in STEMI patients. The presence of Q waves on the baseline electrocardiogram (ECG) has been suggested to be of incremental value to time from symptom onset in evaluating clinical outcomes.We evaluated baseline Q waves and ST-segment resolution 30 min after primary percutaneous intervention (PCI) ECGs in 4,530 STEMI patients without prior infarction. Additionally, peak biomarkers; 90-day mortality; and the composite of death, congestive heart failure (CHF), or cardiogenic shock were assessed.Fifty-six percent of patients had baseline Q waves: they were older, more frequently male and diabetic, and had a more advanced Killip class. Patients with baseline Q waves had greater mortality and a higher composite rate of death, CHF, and shock versus patients without baseline Q waves at 90 days (5.3% vs. 2.1% and 12.1% vs. 4.8%, respectively, both p < 0.001). Complete ST-segment resolution was highest, whereas 90-day mortality and the composite outcome were lowest among those randomized < or =3 h without baseline Q waves. After multivariable adjustment, baseline Q-wave but not time from symptom onset was significantly associated with a 78% relative increase in the hazard of 90-day mortality and a 90% relative increase in the hazard of death, shock, and CHF.Baseline Q waves in STEMI patients treated with primary PCI provide an independent prognostic marker of clinical outcome. These data might be useful in designing future clinical trials as well as in evaluating patients for triage and potential transfer for planned primary PCI. (Pexelizumab in Conjunction With Angioplasty in Acute Myocardial Infarction [APEX-AMI]; NCT00091637).

    View details for DOI 10.1016/j.jacc.2009.01.046

    View details for Web of Science ID 000265515100004

    View details for PubMedID 19389560

  • Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study LANCET Becker, R. C., Moliterno, D. J., Jennings, L. K., Pieper, K. S., Pei, J., Niederman, A., Ziada, K. M., Berman, G., Strony, J., Joseph, D., Mahaffey, K. W., Van de Werf, F., Veltri, E., Harrington, R. A. 2009; 373 (9667): 919-928

    Abstract

    An antithrombotic drug is needed that safely reduces cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We therefore assessed the tolerability and safety of SCH 530348-an oral platelet protease-activated receptor-1 antagonist.We randomly assigned patients aged 45 years or older and undergoing non-urgent PCI or coronary angiography with planned PCI to an oral loading dose of SCH 530348 (10 mg, 20 mg, or 40 mg) or matching placebo in a 3:1 ratio in a multicentre international study. Those in the SCH 530348 group who subsequently underwent PCI (primary PCI cohort) continued taking an oral maintenance dose (0.5 mg, 1.0 mg, or 2.5 mg per day), and patients in the placebo group continued placebo for 60 days. The primary endpoint was the incidence of clinically significant major or minor bleeding according to the thrombolysis in myocardial infarction (TIMI) scale. Both investigators and patients were unaware of treatment allocation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00132912.257 patients were assigned to placebo and 773 to SCH 530348. The primary endpoint occurred in 2 (2%) of 129, 3 (3%) of 120, and 7 (4%) of 173 patients, respectively, in the SCH 530348 10 mg, 20 mg, and 40 mg groups compared with 5 (3%) of 151 patients in the placebo group (p=0.5786). TIMI major plus minor bleeding occurred in 3 (2%) of 136, 5 (4%) of 139, and 4 (3%) of 138 patients given SCH 530348 0.5 mg, 1.0 mg, and 2.5 mg once per day, respectively (p=0.7561).Oral SCH 530348 was generally well tolerated and did not cause increased TIMI bleeding, even when administered concomitantly with aspirin and clopidogrel. Further testing in phase III trials to accurately define the safety and efficacy of SCH 530348 is warranted.

    View details for Web of Science ID 000264158700033

    View details for PubMedID 19286091

  • Integrating ancillary studies in a large clinical trial: The design and rationale of the APEX library CONTEMPORARY CLINICAL TRIALS Mahaffey, K. W., Reist, C. J., Fu, Y., Brener, S. J., Theroux, P., Patel, M. R., Stebbins, A., Westerhout, C. M., Todaro, T. G., Adams, P. X., Granger, C. B., Armstrong, P. W. 2008; 29 (6): 887-895

    Abstract

    The APEX library was a coordinated and integrated set of ancillary analyses and substudies that were a part of the large APEX-AMI trial. The library included electrocardiogram, angiographic, blood biomarker, genetics, and MRI components. Operationally, the goals and administration of the APEX library were developed concurrently with the design of the parent trial. The goal recruitment in the library was met due to this approach. These data will provide important insights into the pathobiology of acute myocardial infarction and the relationships between inflammation, thrombosis, genetics, and classic clinical markers from angiograms, electrocardiograms, and patient demographics. In conclusion, the APEX library is an example of successful collaboration among academic trial leaders, site investigators, and pharmaceutical sponsors. The operational paradigm of this effort should be considered in future investigations so that important advances in clinical care of disease can be realized efficiently.

    View details for DOI 10.1016/j.cct.2008.06.003

    View details for Web of Science ID 000260990300010

    View details for PubMedID 18644468

  • ST-segment recovery and outcome after primary percutaneous coronary intervention for ST-elevation myocardial infarction - Insights from the Assessment of PEXelizumab in Acute Myocardial Infarction (APEX-AMI) trial 56th Annual Scientific Session of the American-College-of-Cardiology Buller, C. E., Fu, Y., Mahaffey, K. W., Todaro, T. G., Adams, P., Westerhout, C. M., White, H. D., 't Hof, A. W., de Werf, F. J., Wagner, G. S., Granger, C. B., Armstrong, P. W. LIPPINCOTT WILLIAMS & WILKINS. 2008: 1335–46

    Abstract

    Primary percutaneous coronary angioplasty is an effective and widely adopted treatment for acute myocardial infarction. A simple method of determining prognosis after primary percutaneous coronary intervention (PCI) would facilitate appropriate care and expedite hospital discharge. Thus, we determined the prognostic importance of various measures of ST-segment-elevation recovery after primary PCI in a large, contemporary cohort of patients with ST-elevation myocardial infarction.We analyzed ECG data describing the magnitude and extent of ST-segment elevation and deviation before and early after (ie, 30 minutes) primary PCI in the study cohort of 4866 subjects with electrocardiographically high-risk ST-elevation myocardial infarction enrolled in the Assessment of PEXelizumab in Acute Myocardial Infarction (APEX-AMI) trial. Associations among 6 methods for calculating ST-segment recovery, biomarker estimates of infarct size (ie, peak creatine kinase, creatine kinase-MB, and troponin I and T), and prespecified clinical outcomes (ie, rates of 90-day death and 90-day death, heart failure, or shock) were examined. All ST-segment-recovery methods provided strong prognostic information regarding clinical outcomes. A simple ST-segment-recovery method of residual ST-segment elevation measurement in the most affected lead on the post-PCI ECG performed as well as complex methods that required comparison of pre- and post-PCI ECGs or calculation of summed ST-segment deviation in multiple leads (ie, worst-lead residual ST elevation: adjusted hazard ratio for 90-day death rate [reference <1 mm]: 1 to <2 mm, 1.23 [95% CI 0.74 to 2.03]; > or =2 mm, 2.22 [95% CI 1.35 to 3.65], corrected c-index=0.832; 90-day death/congestive heart failure/shock [reference <1 mm]: 1 to <2 mm, 1.55 [95% CI 1.06 to 2.26]; > or =2 mm, 2.33 [95% CI 1.59 to 3.41], corrected c-index=0.802). Biomarker estimates of infarct size declined in association with enhanced ST-segment recovery.An ECG performed early after primary PCI is a simple, widely available, inexpensive, and powerful prognostic tool applicable to patients with ST-elevation myocardial infarction.

    View details for DOI 10.1161/CIRCULATIONAHA.108.767772

    View details for Web of Science ID 000259402300006

    View details for PubMedID 18779444

  • Impact of perioperative myocardial infarction on angiographic and clinical outcomes following coronary artery bypass grafting (from PRoject of Ex-vivo Vein Graft ENgineering via Transfection [PREVENT] IV) AMERICAN JOURNAL OF CARDIOLOGY Yau, J. M., Alexander, J. H., Hafley, G., Mahaffey, K. W., Mack, M. J., Kouchoukos, N., Goyal, A., Peterson, E. D., Gibson, C. M., Califf, R. M., Harrington, R. A., Ferguson, T. B. 2008; 102 (5): 546-551

    Abstract

    Myocardial infarction (MI) after coronary artery bypass grafting (CABG) is associated with significant morbidity and mortality. Frequency, management, mechanisms, and angiographic and clinical outcomes associated with perioperative MI remain poorly understood. PREVENT IV was a multicenter, randomized, placebo-controlled trial of edifoligide in 3,014 patients undergoing CABG. Angiographic and 2-year clinical follow-up were complete for 1,920 and 2,956 patients, respectively. Perioperative MI was defined as creatinine kinase-MB increase >or=10 times the upper limit of normal or >or=5 times the upper limit of normal with new 30-ms Q waves within 24 hours of surgery. Baseline characteristics, in-hospital management, and angiographic and clinical outcomes of patients with and without perioperative MI were compared. Perioperative MI occurred in 294 patients (9.8%). Patients with perioperative MI had longer surgery (250 vs 230 minutes; p <0.001), more on-pump surgery (83% vs 78%; p = 0.048), and worse target-artery quality (p <0.001). Patients with perioperative MI more frequently underwent angiography within 30 days of enrollment (1.7% vs 0.6%; p = 0.021). One-year angiographic vein graft failure occurred in 62.4% of patients with and 43.8% of patients without perioperative MI (p <0.001). Two-year composite clinical outcome (death, MI, or revascularization) was worse in patients with perioperative MI before (19.4% vs 15.2%; p = 0.039) and after (hazard ratio 1.33, 95% confidence interval 1.00 to 1.76, p = 0.046) adjusting for differences in significant predictors. In conclusion, perioperative MI was relatively common, was associated with worse outcomes, and mechanisms other than vein graft failure accounted for a substantial proportion of these MIs. Further research is needed into the prevention and treatment of perioperative MI in patients undergoing CABG.

    View details for DOI 10.1016/j.amjcard.2008.04.069

    View details for Web of Science ID 000258784500008

    View details for PubMedID 18721510

  • Prevalence, Predictors, and Impact of Conservative Medical Management for Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Who Have Angiographically Documented Significant Coronary Disease JACC-CARDIOVASCULAR INTERVENTIONS Chan, M. Y., Mahaffey, K. W., Sun, L. J., Pieper, K. S., White, H. D., Aylward, P. E., Ferguson, J. J., Califf, R. M., Roe, M. T. 2008; 1 (4): 369-378

    Abstract

    We sought to characterize the utilization and impact of a conservative medical management strategy for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and significant coronary artery disease on early angiography.Practice guidelines recommend an early invasive management strategy for NSTE ACS, but revascularization procedures may not always be performed after early angiography, even when significant coronary artery disease is present.We evaluated 8,225 intermediate- to high-risk NSTE ACS patients with at least 1 coronary lesion >50% stenosis on early angiography from the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial (2001 to 2003), comparing patients treated with conservative medical management with those who underwent in-hospital percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) within 7 days of randomization.A total of 2,633 patients (32%) were medically managed, 4,294 (52%) underwent PCI, and 1,298 (16%) underwent CABG. The strongest independent predictors of conservative medical management versus any intervention were prior CABG, lower body weight, lack of a reinfarction between randomization and catheterization, and 3-vessel disease. With conservative medical management, the cumulative risk of 1-year mortality after discharge increased rapidly during the first 90 days and thereafter remained higher at 7.7% compared with that seen in patients treated with PCI (3.6%) or CABG (6.2%).One-third of patients with NSTE ACS and significant coronary disease on early angiography were managed without in-hospital revascularization in the SYNERGY trial, and these patients had an increased risk of late mortality. These findings highlight the need for novel treatment approaches for NSTE ACS patients who are not candidates for revascularization. (SYNERGY trial; NCT00043784).

    View details for Web of Science ID 000207586200005

    View details for PubMedID 19463332

  • Initial risk stratification and presenting characteristics of patients with evolving myocardial infarctions EMERGENCY MEDICINE JOURNAL Miller, C. D., Fermann, G. J., Lindsell, C. J., Mahaffey, K. W., Peacock, W. F., Pollack, C. V., Hollander, J. E., Diercks, D. B., Gibler, W. B., Hoekstra, J. W. 2008; 25 (8): 492-497

    Abstract

    To describe the presenting characteristics and risk stratification of patients presenting to the emergency department with chest pain who have a normal initial troponin level followed by a raised troponin level within 12 h (evolving myocardial infarction (EMI)).Data from the Internet Tracking Registry for Acute Coronary Syndromes (i*trACS), a registry of patients presenting with undifferentiated chest pain, were used. This analysis included patients without ST segment elevation with at least two troponin assay results < or = 12 h apart. Patients were stratified into three groups: EMI (initial troponin assay negative, second troponin assay positive), non-ST elevation myocardial infarction (NSTEMI) (initial troponin assay positive) and no MI (all troponin assays negative).Of 4136 eligible patients, 5% had EMI, 8% had NSTEMI and 87% had no MI. Patients with EMI were more similar to those with NSTEMI than those with no MI with respect to demographic characteristics, presentation, admission patterns and revascularisation. The initial ECG in patients with EMI was most commonly non-diagnostic (51%), but physicians' initial impressions commonly reflected MI, unstable angina or high-risk chest pain (76%). This risk assessment was followed by a high rate of critical care admissions (32%) and revascularisation (percutaneous coronary intervention 17%) among patients with EMI.Patients with EMI appear similar at presentation to those with NSTEMI. Patients with EMI are perceived as being at high risk, evidenced by similar diagnostic impressions, admission practices and revascularisation rates to patients with NSTEMI.

    View details for DOI 10.1136/emj.2007.052183

    View details for Web of Science ID 000257922500009

    View details for PubMedID 18660397

  • Outcomes in elderly patients with acute coronary syndromes randomized to enoxaparin vs. unfractionated heparin: results from the SYNERGY trial EUROPEAN HEART JOURNAL Lopes, R. D., Alexander, K. P., Marcucci, G., White, H. D., Spinler, S., Col, J., Aylward, P. E., Califf, R. M., Mahaffey, K. W. 2008; 29 (15): 1827-1833

    Abstract

    Elderly patients are at high risk from non-ST-segment elevation acute coronary syndromes (NSTE ACS) as well as from treatment-related complications. Age-associated changes in physiology may alter the risk and benefit expected from therapy. The SYNERGY database was used to study the influence of age on treatment outcomes with enoxaparin vs. unfractionated heparin (UFH) in patients with high-risk NSTE ACS.Age was analysed as a continuous and categorical variable (<65, 65-74, and >or=75 years, and <75 and >or=75 years) for descriptive purposes. Logistic regression was used to adjust the outcomes of 30-day death, death or myocardial infarction (MI), and major bleeding for baseline characteristics. Odds ratios compared outcomes by age and by treatment within age groups. Model interaction terms were used to test for statistically different outcomes by treatment and age. Overall, 9977 randomized patients had age information, of whom 25.5% (2540) were >or=75 years of age. Elderly patients (>or=75 years) had more cardiovascular risk factors, prior cardiac disease, and higher acuity at presentation. After adjustment, advanced age (per 10 years) was associated with 30-day death or MI [risk odds ratios (ROR): 1.14, P = 0.002], 30-day death (ROR: 1.54, P < 0.0001), and 1-year death (ROR: 1.47, P < 0.0001), as well with TIMI major bleeding (ROR: 1.21, P = 0.001), GUSTO severe bleeding (ROR: 1.20, P = 0.047), and transfusion (ROR: 1.04, P = 0.324). Although there was a higher rate of GUSTO severe bleeding noted with enoxaparin in elderly patients, the overall relationships between treatment (UFH or enoxaparin) and outcomes did not vary significantly as a function of the patient's age.Although higher rates of adverse events are seen in the oldest subgroup (age >or=75 years) treated with enoxaparin, statistical comparisons confirm similar efficacy and safety of enoxaparin and UFH across age subgroups as was demonstrated overall in SYNERGY.

    View details for DOI 10.1093/eurheartj/ehn236

    View details for Web of Science ID 000258137200010

    View details for PubMedID 18519426

  • Smoking status and antithrombin therapy in patients with non-ST-segment elevation acute coronary syndrome AMERICAN HEART JOURNAL Leung, S., Gallup, D., Mahaffey, K. W., Cohen, M., Antman, E. M., Goodman, S. G., Harrington, R. A., Langer, A., Aylward, P., Ferguson, J. J., Califf, R. M. 2008; 156 (1): 177-184

    Abstract

    Smoking remains a major public health issue. We investigated the incidence of smoking and outcomes in high-risk patients with acute coronary syndromes. Differences in treatment effect of antithrombin therapies were also investigated.Using data from SYNERGY, patients were categorized by their self-reported smoking status. They were followed at 30 days and 6 months for death, nonfatal myocardial infarction (MI), revascularization procedures, stroke, and need for rehospitalization, and at 1 year for occurrences of death.Overall, 9,971 patients were evaluated, of whom 2,404 (24%) were current smokers, 3,491 (35%) were former smokers, and 4076 (41%) had never smoked. Current smokers were younger (median age 61 years, interquartile range [IQR] 52-67) than former smokers (median age 69 years, IQR 63-75) and never smokers (median age 70 years, IQR 64-77) and had fewer additional coronary artery disease risk factors (hypertension, diabetes, hypercholesterolemia). The 30-day death/MI rate was similar for former versus never smokers (15% vs 13.6%, P = .079) and for current versus never smokers (14% vs 13.6%, P = .585). Adjusted odds ratios for 30-day death/MI in patients receiving enoxaparin compared with those receiving unfractionated heparin were 1.065 (95% CI 0.883-1.283, P = .51) in never smokers, 1.034 (95% CI 0.853-1.254, P = .733) in former smokers, and 0.742 (95% CI 0.582-0.948, P = .017) in current smokers. A significant interaction for treatment and smoking status was found at 30 days (P = .0215), but not at 6 months (P = .1381) or 1 year (P = .1054). One-year unadjusted mortality rates were higher for former versus never smokers (9.1% vs 6.7%, P = .0002) but were similar for current versus never smokers (6.5% vs 6.7%, P = .7226). On follow-up at 30 days, 62.3% (n =1397) of current smokers reported not smoking.Smokers with non-ST-segment elevation acute coronary syndrome are generally younger and have fewer cardiac risk factors. A significant interaction of smoking and enoxaparin was seen at 30 days, but not sustained at 6 months and 1 year. More than 60% of smokers quit within 30 days of their cardiac event. There was little difference in outcomes from 30 days to 1 year for these smokers who quit versus those who did not.

    View details for DOI 10.1016/j.ahj.2008.02.002

    View details for Web of Science ID 000257329900025

    View details for PubMedID 18585514

  • Short- and long-term outcomes following atrial fibrillation in patients with acute coronary syndromes with or without ST-segment elevation HEART Lopes, R. D., Pieper, K. S., Horton, J. R., Al-Khatib, S. M., Newby, L. K., Mehta, R. H., De Werf, F. V., Armstrong, P. W., Mahaffey, K. W., Harrington, R. A., Ohman, E. M., White, H. D., Wallentin, L., Granger, C. B. 2008; 94 (7): 867-873

    Abstract

    To assess variables associated with the occurrence of atrial fibrillation (AF) and the relation of AF with short- and long-term outcomes and with other in-hospital complications in patients with acute coronary syndromes (ACS) with and without ST-segment elevation.Pooled database of 120 566 patients with ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation (NSTE) ACS enrolled in 10 clinical trials. Multivariable logistic regression and Cox proportional hazards modelling were used to identify factors associated with AF and its relation with clinical outcomes.ACS complicated by AF.120,566 patients with STEMI and NSTE-ACS in 10 clinical trials.None evaluated.Short- and long-term mortality.Occurrence of AF was 7.5% in the overall population (STEMI 8.0% (n = 84 161); NSTE-ACS = 6.4% (n = 36,405)). Seven-day mortality was higher for patients with AF (5.1%) than for those without (1.6%). After adjusting for confounders, association of AF with 7-day mortality was present in STEMI (hazards ratio (HR) = 1.65; 95% CI 1.44 to 1.90) and NSTE-ACS (HR = 2.30; 95% CI 1.83 to 2.90; p interaction = 0.015). Risk of long-term mortality (day 8 to 1 year) was also higher in STEMI (HR = 2.37; 95% CI 1.79 to 3.15) and NSTE-ACS (HR = 1.67; 95% CI 1.41 to 1.99). AF had a larger impact in NSTE-ACS on risk of short-term mortality (p<0.001), stroke (p<0.001), ischaemic stroke (p<0.001) and moderate or severe bleeding (p<0.001).AF is more common in patients with STEMI. An association of AF with short- and long-term mortality among patients with STEMI and NSTE-ACS was found. Understanding these findings may lead to better care of patients with this common arrhythmia.

    View details for DOI 10.1136/hrt.2007.134486

    View details for Web of Science ID 000256721000013

    View details for PubMedID 18332062

  • Management of acute coronary syndromes in patients with renal dysfunction CURRENT OPINION IN CARDIOLOGY Melloni, C., Mahaffey, K. W. 2008; 23 (4): 320-326

    Abstract

    Chronic kidney disease is becoming common among patients with acute coronary syndromes and is associated with substantial cardiovascular morbidity and mortality. Often, patients with chronic kidney disease are excluded from clinical trials, so in clinical practice physicians may not have definitive evidence to support treatment decisions.Recent studies have shown that chronic kidney disease is an independent risk factor for outcomes in patients with acute coronary syndromes and that there is a stepwise increase in mortality with progressive decline of glomerular filtration rate. It has been demonstrated that the use of aggressive treatment strategies in these patients may be associated with improved outcome that is similar to, if not higher than, in those patients without renal disease. Yet, although critical for the correct dose adjustment of many antithrombotic and antiplatelet therapies, accurate renal function estimation often is not done.Chronic kidney disease is common, and the stages of chronic kidney disease are strongly related to the risk of adverse in-hospital outcomes and to the use of evidence-based therapies. Many antithrombotic drugs are eliminated mainly by the kidneys, so an accurate assessment of renal function is required in all patients with acute coronary syndromes for a proper dose adjustment. There is a clear need for clinical trials in patients with moderate-to-severe kidney dysfunction to further refine their optimal management in the setting of acute coronary syndromes.

    View details for Web of Science ID 000256868200006

    View details for PubMedID 18520715

  • Rivaroxaban, an oral direct factor Xa inhibitor EXPERT OPINION ON INVESTIGATIONAL DRUGS Piccini, J. P., Patel, M. R., Mahaffey, K. W., Fox, K. A., Califf, R. M. 2008; 17 (6): 925-937

    Abstract

    Rivaroxaban is a small molecule, direct Factor Xa inhibitor and may be a potentially attractive alternative to vitamin K antagonists. Rivaroxaban is being investigated for the prevention and treatment of venous and arterial thrombosis. A broad search of Medline, clinicaltrials.gov and the annual proceedings of the American Society of Hematology and the International Society on Thrombosis and Hemostasis was conducted. This review addresses the findings of this systematic search, including the need for new oral anticoagulants, the development and pharmacology of rivaroxaban, and the results of completed as well as ongoing trials with rivaroxaban. At present, the safety and efficacy of rivaroxaban for the prophylaxis and treatment of venous thromboembolism has been evaluated in Phase II and Phase III trials involving over 24,000 patients. Additionally, rivaroxaban is being evaluated for the treatment of pulmonary embolism, secondary prevention after acute coronary syndromes and the prevention of stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation. The drug may have its greatest impact in providing a much-needed and attractive alternative to warfarin. Further data (especially large Phase III trials) are required.

    View details for DOI 10.1517/13543784.17.6.925

    View details for Web of Science ID 000256576800009

    View details for PubMedID 18491993

  • Coronary artery bypass surgery in patients with acute coronary syndromes is difficult to predict AMERICAN HEART JOURNAL Chew, D. P., Mahaffey, K. W., White, H. D., Huang, Z., Hockstra, J. W., Ferguson, J. J., Califf, R. M., Aylward, P. E. 2008; 155 (5): 841-847

    Abstract

    Although the use of clopidogrel in patients "unlikely" to require coronary artery bypass grafting (CABG) is recommended in current guidelines of acute coronary syndrome (ACS) management, an important minority of patients require CABG. We assessed the ability to predict need for CABG from demographics known at the time of ACS presentation, using data from SYNERGY.Patients undergoing CABG at any time after the index angiogram were included. Early CABG was defined as surgery <72 hours after angiography. The relationship between cessation of enoxaparin and glycoprotein IIb/IIIa inhibition, CABG timing, and 30-day death or MI and bleeding events was assessed. Demographic and clinical factors and geographic location were assessed as predictors of early CABG or CABG at any time. The discriminatory utility is reported with the c-index.Of the 9053 patients undergoing angiography, 1793 (18.1%) received CABG. Early CABG (n = 972) was associated with more bleeding events (39.2% vs 29.4%, P < .001) but not death or MI. The risk of bleeding events diminished when surgery was delayed >18 hours after cessation of enoxaparin and glycoprotein IIb/IIIa inhibition. Clinical factors associated with early CABG included diabetes and lack of prior CABG or clopidogrel. However, overall the logistic regression model had poor discriminatory ability to predict patients likely to require CABG in the setting of an ACS presentation (c-index 0.671).It is difficult to predict those high-risk patients with ACS who will undergo surgical revascularization based on baseline clinical characteristics.

    View details for DOI 10.1016/j.ahj.2007.12.002

    View details for Web of Science ID 000256001500007

    View details for PubMedID 18440330

  • Comparison of an everolimus-eluting stent and a paclitaxel-eluting stent in patients with coronary artery disease - A randomized trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Stone, G. W., Midei, M., Newman, W., Sanz, M., Hermiller, J. B., Williams, J., Farhat, N., Mahaffey, K. W., Cutlip, D. E., Fitzgerald, P. J., Sood, P., Su, X., Lansky, A. J. 2008; 299 (16): 1903-1913

    Abstract

    A thin, cobalt-chromium stent eluting the antiproliferative agent everolimus from a nonadhesive, durable fluoropolymer has shown promise in preliminary studies in improving clinical and angiographic outcomes in patients with coronary artery disease.To evaluate the safety and efficacy of an everolimus-eluting stent compared with a widely used paclitaxel-eluting stent. Design, Setting, andThe SPIRIT III trial, a prospective, randomized, single-blind, controlled trial enrolling patients at 65 academic and community-based US institutions between June 22, 2005, and March 15, 2006. Patients were 1002 men and women undergoing percutaneous coronary intervention in lesions 28 mm or less in length and with reference vessel diameter between 2.5 and 3.75 mm. Angiographic follow-up was prespecified at 8 months in 564 patients and completed in 436 patients. Clinical follow-up was performed at 1, 6, 9, and 12 months.Patients were randomized 2:1 to receive the everolimus-eluting stent (n = 669) or the paclitaxel-eluting stent (n = 333).The primary end point was noninferiority or superiority of angiographic in-segment late loss. The major secondary end point was noninferiority assessment of target vessel failure events (cardiac death, myocardial infarction, or target vessel revascularization) at 9 months. An additional secondary end point was evaluation of major adverse cardiac events (cardiac death, myocardial infarction, or target lesion revascularization) at 9 and 12 months.Angiographic in-segment late loss was significantly less in the everolimus-eluting stent group compared with the paclitaxel group (mean, 0.14 [SD, 0.41] mm vs 0.28 [SD, 0.48] mm; difference, -0.14 [95% CI, -0.23 to -0.05]; P < or = .004). The everolimus stent was noninferior to the paclitaxel stent for target vessel failure at 9 months (7.2% vs 9.0%, respectively; difference, -1.9% [95% CI, -5.6% to 1.8%]; relative risk, 0.79 [95% CI, 0.51 to 1.23]; P < .001). The everolimus stent compared with the paclitaxel stent resulted in significant reductions in composite major adverse cardiac events both at 9 months (4.6% vs 8.1%; relative risk, 0.56 [95% CI, 0.34 to 0.94]; P = .03) and at 1 year (6.0% vs 10.3%; relative risk, 0.58 [95% CI, 0.37 to 0.90]; P = .02), due to fewer myocardial infarctions and target lesion revascularization procedures.In this large-scale, prospective randomized trial, an everolimus-eluting stent compared with a paclitaxel-eluting stent resulted in reduced angiographic late loss, noninferior rates of target vessel failure, and fewer major adverse cardiac events during 1 year of follow-up.clinicaltrials.gov Identifier: NCT00180479.

    View details for Web of Science ID 000255163800024

    View details for PubMedID 18430909

  • Prediction of one-year survival in high-risk patients with acute coronary syndromes: Results from the SYNERGY trial JOURNAL OF GENERAL INTERNAL MEDICINE Mahaffey, K. W., Yang, Q., Pieper, K. S., Antman, E. M., White, H. D., Goodman, S. G., Cohen, M., Kleiman, N. S., Langer, A., Aylward, P. E., Col, J. J., Reist, C., Ferguson, J. J., Califf, R. M. 2008; 23 (3): 310-316

    Abstract

    Despite advances in pharmacologic therapy and invasive management strategies for patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS), these patients still suffer substantial morbidity and mortality.The objective of this study was to analyze independent predictors of 1-year mortality in patients with high-risk NSTE ACS.A total of 9,978 patients were assigned to receive enoxaparin or unfractionated heparin (UFH) in this prospective, randomized, open-label, international trial.Vital status at 1 year was collected. Univariable and multivariable predictors of 1-year mortality were identified. Three different multivariable regression models were constructed to identify: (1) predictors of 30-day mortality; (2) predictors of 1-year mortality; (3) predictors of 1-year mortality in 30-day survivors. The last model is the focus of this paper.Overall, 9,922 (99.4%) of patients had 1-year follow-up. Of the 56 patients (37 UFH-assigned and 19 enoxaparin-assigned) without 1-year data, 11 patients were excluded because of withdrawal of consent, and 45 could not be located. One-year mortality was 7.5% (7.7% enoxaparin-assigned patients; 7.3% UFH-assigned patients; P = 0.4). In patients surviving 30 days after enrollment, independent predictors of 1-year mortality included factors known at baseline such as increased age, male sex, decreased weight, having ever smoked, decreased creatinine clearance, ST-segment depression, history of diabetes, history of angina, congestive heart failure, coronary artery bypass grafting, increased heart rate, rales, increased hematocrit, lowered hemoglobin, and higher platelet count. Factors predictive of mortality during the hospitalization and 30-day follow-up period were decreased weight at 30 days from baseline, atrial fibrillation, decreased nadir platelet, no use of beta-blockers and statins up to 30 days, and not receiving an intervention (c-index = 0.82).Easily determined baseline clinical characteristics can be used to predict 1-year mortality with reasonable discriminative power. These models corroborate prior work in a contemporary aggressively managed population. A model to predict 1-year mortality in patients surviving at least 30 days may be quite helpful to healthcare providers in setting expectations and goals with patients after ACS.

    View details for DOI 10.1007/s11606-007-0498-4

    View details for Web of Science ID 000253214000015

    View details for PubMedID 18196350

  • Patients with non-ST-elevation acute coronary syndromes undergoing coronary artery bypass grafting in the modern era of antithrombotic therapy AMERICAN HEART JOURNAL Chew, D. P., Huang, Z., Pieper, K. S., White, H., Mahaffey, K. W., Ferguson, J. J., Califf, R. M., Aylward, P. G. 2008; 155 (2): 239-244

    Abstract

    Many high-risk patients with non-ST-elevation acute coronary syndromes within the SYNERGY trial required coronary artery bypass grafting (CABG) for optimal revascularization. We explored the clinical outcomes among high-risk patients undergoing CABG and the impact of modern pharmacology.We evaluated 180-day rates of death and myocardial infarction (MI) and 30-day GUSTO severe bleeding among patients undergoing CABG, contrasting them with patients undergoing percutaneous coronary intervention (PCI) or medical management. The relationships between perioperative MI, bleeding events, and 6-month mortality were explored. The effect of random assignment to unfractionated heparin or enoxaparin and the relationships between use of clopidogrel and glycoprotein IIb/IIIa inhibitors and clinical outcomes were assessed.Death or MI at 6 months was more common among patients requiring CABG (CABG 31.2%, PCI 15.9%, medical 9.9%). Thirty-day GUSTO severe bleeding was also higher (CABG 6.4%, PCI 1.1%, medical 0.9%). Perioperative MI and GUSTO severe bleeding were associated with excess 6-month mortality (hazard ratio 2.1, 95% CI 1.27-3.53 and hazard ratio 7.6, CI 4.78-12.09, respectively). Randomization to enoxaparin was not associated with an increase in bleeding or a reduction in death or MI. No differences in ischemic outcomes were observed among patients given glycoprotein IIb/IIIa inhibition or clopidogrel.High-risk patients still commonly require CABG with greater bleeding and ischemic event rates observed. Current definitions of perioperative MI and GUSTO severe bleeding portend an increased in 6-month mortality among CABG patients. Modern pharmacotherapies do not appear to impact these higher event rates.

    View details for DOI 10.1016/j.ahj.2007.10.002

    View details for Web of Science ID 000252812800008

    View details for PubMedID 18215592

  • Time to coronary angiography and outcomes among patients with high-risk non-ST-segment-elevation acute coronary syndromes: Results from the SYNERGY trial CIRCULATION Tricoci, P., Lokhnygina, Y., Berdan, L. G., Steinhubl, S. R., Gulba, D. C., White, H. D., Kleiman, N. S., Aylward, P. E., Langer, A., Califf, R. M., Ferguson, J. J., Antman, E. M., Newby, L. K., Harrington, R. A., Goodman, S. G., Mahaffey, K. W. 2007; 116 (23): 2669-2677

    Abstract

    Optimal timing for an early invasive strategy in patients with non-ST-segment-elevation acute coronary syndrome remains unclear. We evaluated the relationship between time from hospital admission to coronary angiography and outcomes in high-risk patients with non-ST-segment-elevation acute coronary syndrome who underwent angiography within 48 hours of admission.Data from 10 027 patients enrolled in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial were analyzed. Patients were grouped by 6-hour intervals of time from hospital admission to coronary angiography. Primary outcomes were 30-day death or myocardial infarction, in-hospital Thrombolysis In Myocardial Infarction (TIMI) and Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) major bleeding, and blood transfusion. Adjusted estimates of event rates were obtained by use of a multivariable methodology that included possible confounders through baseline and accounted for propensity of time to angiography. The landmark method was used to calculate odds ratios and 95% confidence intervals of outcomes for each time period adjusted for baseline and postbaseline clinical events. Overall, 9216 patients (92%) underwent angiography, 6352 (63%) within 48 hours. Unadjusted and adjusted rates of death/myocardial infarction increased with increasing time to angiography. The adjusted odds ratio for death/myocardial infarction in patients receiving angiography in <6 hours was 0.56 (95% confidence interval 0.41 to 0.74), whereas after 30 hours, there was no significant benefit compared with further delayed angiography. Major bleeding and transfusion did not vary significantly across time-to-angiography intervals.A decrease in the time to coronary angiography was associated with fewer ischemic outcomes and no increase in bleeding. Randomized clinical trials are needed to provide definitive evidence on optimal timing of coronary angiography but are difficult to design and conduct. Ongoing trials should instead clarify whether delaying angiography to administer aggressive upstream antithrombotic therapies is effective in the current setting of non-ST-segment-elevation acute coronary syndrome management.

    View details for DOI 10.1161/CIRCULATIONAHA.107.690081

    View details for Web of Science ID 000251361400005

    View details for PubMedID 18025532

  • Evaluation of cinacalcet therapy to lower cardiovascular events (EVOLVE): Rationale and design overview CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chertow, G. M., Pupim, L. B., Block, G. A., Correa-Rotter, R., Drueke, T. B., Floege, J., Goodman, W. G., London, G. M., Mahaffey, K. W., Moe, S. M., Wheeler, D. C., Albizem, M., Olson, K., Klassen, P., Parfrey, P. 2007; 2 (5): 898-905

    Abstract

    The dramatically high rates of mortality and cardiovascular morbidity observed among dialysis patients highlights the importance of identifying and implementing strategies to lower cardiovascular risk in this population. Results from clinical trials undertaken thus far, including trials on lipid reduction, normalization of hematocrit, and increased dialysis dosage, have been unsuccessful. Available data indicate that abnormalities in calcium and phosphorus metabolism, as a result of either secondary hyperparathyroidism alone or the therapeutic measures used to manage secondary hyperparathyroidism, are associated with an increased risk for death and cardiovascular events. However, no prospective trials have evaluated whether interventions that modify these laboratory parameters result in a reduction in adverse cardiovascular outcomes.Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events is a global, phase 3, double-blind, randomized, placebo-controlled trial evaluating the effects of cinacalcet on mortality and cardiovascular events in hemodialysis patients with secondary hyperparathyroidism. Approximately 3800 patients from 22 countries will be randomly assigned to cinacalcet or placebo. Flexible use of traditional therapies will be permitted. The primary end point is the composite of time to all-cause mortality or first nonfatal cardiovascular event (myocardial infarction, hospitalization for unstable angina, heart failure, or peripheral vascular disease, including lower extremity revascularization and nontraumatic amputation).The study will be event driven (terminated at 1882 events) with an anticipated duration of approximately 4 yr.Evaluation of Cinacalcet Therapy to Lower Cardiovascular Events will determine whether management of secondary hyperparathyroidism with cinacalcet reduces the risk for mortality and cardiovascular events in hemodialysis patients.

    View details for DOI 10.2215/CJN.04381206

    View details for Web of Science ID 000249039500007

    View details for PubMedID 17702710

  • Baseline glucose and left ventricular remodeling after acute myocardial infarction JOURNAL OF DIABETES AND ITS COMPLICATIONS Nicolau, J. C., Maia, L. N., Vitola, J. V., Mahaffey, K. W., Machado, M. N., Ramires, J. A. 2007; 21 (5): 294-299

    Abstract

    In patients with acute myocardial infarction (AMI), the mechanisms behind the increased mortality related to glucose levels (GL) are poorly understood. The main purpose of this study is to analyze the relationship between baseline glucose and left ventricular enlargement (LVE). We analyzed 52 patients with a first ST-elevation AMI <24 h of evolution. Glucose levels were obtained upon admission (median time, 3 h after the beginning of chest pain). The median GL was 123.5 mg/dl, and patients above this limit were considered hyperglycemic (n=26). Left ventricular enlargement was analyzed comparing two radionuclide ventriculographies, the first obtained within 4 days post-AMI (median, 55 h) and the second 6 months later (median, 188.5 days), taking into account the difference in the obtained end-systolic volumes. Myocardial reperfusion was evaluated comparing ST resolution between a first ECG done immediately upon hospital arrival with a second ECG performed 2 h after treatment. By univariate analysis, LVE correlated significantly with baseline hyperglycemia (P<.001), failed reperfusion by ECG criteria (P<.001), and no use of ACE inhibitors or AT1 blockers (P=.046) and aspirin (P=.046). A history of previous diabetes did not correlate significantly with LVE at 6 months. In the adjusted model, basal hyperglycemia (P<.001) and failed reperfusion (P=.001) were the only variables independently correlated with LVE. In conclusion, baseline glucose is a powerful and independent predictor of LVE after AMI, which reinforces the importance of a tight glucose control during the initial phase of the disease.

    View details for DOI 10.1016/j.jdiacomp.2006.01.003

    View details for Web of Science ID 000249622500004

    View details for PubMedID 17825753

  • Efficacy and safety of the low-molecular weight heparin enoxaparin compared with unfractionated heparin across the acute coronary syndrome spectrum: a meta-analysis EUROPEAN HEART JOURNAL Murphy, S. A., Gibson, C. M., Morrow, D. A., de Werf, F. V., Menown, I. B., Goodman, S. G., Mahaffey, K. W., Cohen, M., McCabe, C. H., Antman, E. M., Braunwald, E. 2007; 28 (17): 2077-2086

    Abstract

    To determine whether the low-molecular weight heparin enoxaparin remains favourable when compared with unfractionated heparin (UFH) among patients with acute coronary syndromes (ACS) when incorporating efficacy and safety of these adjunctive therapies using a net clinical endpoint.We performed a meta-analysis of randomized trials of enoxaparin vs. UFH in ST-elevation-MI (STEMI) or non-ST-elevation-ACS (NSTEACS) (n = 49,088 patients in 12 trials). The net clinical endpoint was defined as death, MI, or major bleeding by 30 days. Death or myocardial infarction (MI) was significantly reduced with enoxaparin when compared with UFH (9.8 vs. 11.4%, OR 0.84, P < 0.001). The net clinical endpoint occurred less frequently with enoxaparin than UFH (12.5 vs. 13.5%, OR 0.90, P = 0.051). Major bleeding was higher with enoxaparin (4.3 vs. 3.4%, OR 1.25, P = 0.019). Among STEMI trials, the net clinical endpoint was significantly lower with enoxaparin (OR 0.84, P = 0.015), but there was no difference in NSTEACS trials (OR 0.97).When compared with UFH, enoxaparin was associated with superior efficacy as adjunctive antithrombin therapy among >49 000 patients across the ACS spectrum. Although bleeding was increased with enoxaparin, this increase was offset by a reduction in death or MI. The net clinical benefit in favour of enoxaparin was evident among the STEMI population and was neutral among the NSTEACS population.

    View details for DOI 10.1093/eurheartj/ehm224

    View details for Web of Science ID 000249763800009

    View details for PubMedID 17600038

  • Treatment and outcomes of patients with evolving myocardial infarction: experiences from the SYNERGY trial EUROPEAN HEART JOURNAL Miller, C. D., Banerjee, A., Mahaffey, K. W., Kontos, M. C., Fermann, G., Pollack, C. V., Antman, E., Aylward, P., Goodman, S. G., Santos, R., Ferguson, J. J., Califf, R. M., Hoekstra, J. W. 2007; 28 (9): 1079-1084

    Abstract

    Patients with myocardial infarction (MI) presenting immediately after symptom onset may be treated less aggressively due to their non-elevated troponin status. We compared the initial treatment and clinical outcomes of patients presenting with evolving MI (EMI) with those presenting with MI.This study analysed data from the Superior Yield of the New strategy of Enoxaparin, Revascularisation, and Glycoprotein IIb/IIIa inhibitors (SYNERGY) trial, which enrolled patients meeting at least two of the following: age >or= 60 years, elevated cardiac biomarkers, or ST-segment changes. Patients were stratified by troponin results obtained within 12 h of presentation: EMI [initial troponin (-), second troponin (+)], MI [initial troponin (+)], and no MI at enrolment [first and second troponin (-)]. Comparisons were made using Wilcoxon rank-sum and chi(2) tests. Of the 8,309 patients with complete data, 5,503 (66%) had MI, 1,686 (20%) had EMI, and 1,120 (13%) had no MI. Treatment patterns prior to enrolment were similar among EMI and MI patients [aspirin (88 vs. 86%), beta-blockers (62 vs. 61%), heparin (83 vs. 81%), and glycoprotein IIb/IIIa inhibitors (23 vs. 24%)]. Similar rates of percutaneous coronary intervention (48 vs. 50%) and coronary artery bypass grafting (21 vs. 22%) were seen after enrolment. Patients presenting with MI had a higher rate of death or recurrent MI compared with patients with EMI [16 vs. 13%, adjusted OR 1.22 (95% CI 1.04, 1.44)].Initial treatment patterns were similar among patients with EMI and MI in the SYNERGY trial. Patients with EMI had lower rates of death or re-infarction at 30 days compared with patients presenting with positive troponin results.

    View details for DOI 10.1093/eurheartj/ehm016

    View details for Web of Science ID 000247071200013

    View details for PubMedID 17405770

  • Publication or presentation of results from multicenter clinical trials: Evidence from an academic medical center AMERICAN HEART JOURNAL Turer, A. T., Mahaffey, K. W., Compton, K. L., Califf, R. M., Schulman, K. A. 2007; 153 (4): 674-680

    Abstract

    Nonpublication of research results threatens the integrity of clinical research, but the extent of nonpublication and factors associated with publication remain poorly documented. We sought to examine rates of publication or presentation of research findings from multicenter clinical trials and determine what factors are associated with dissemination of results.We conducted a follow-up study of 217 prospective, multicenter clinical trials of treatment approved in 1998 by the institutional review board of a large academic medical center, of which 197 had enrolled participants and were not known to be ongoing. Follow-up included searches of the literature and the Internet and telephone and e-mail inquiries to investigators and research sponsors. The main outcome measures were manuscript publication or other presentation of research results.Results of 110 (56%) out of 197 multicenter clinical trials have been published in the peer-reviewed literature. Results of 87 (44%) studies have not been published, and results of 52 (26%) studies have not been disseminated in any form. The rate of dissemination of trial results was highest for studies that were phase 3 (81%), lowest risk (86%), and investigational (76%). The dissemination rate was lowest for studies that were supported by internal funds (50%). However, none of these associations were statistically significant.Results of almost half of the multicenter clinical trials conducted in part at a large academic medical center have never been published. Mechanisms to ensure public dissemination of clinical trial results are needed.

    View details for DOI 10.1016/j.ahj.2007.01.005

    View details for Web of Science ID 000245784200035

    View details for PubMedID 17383311

  • Creatine kinase-MB elevation after coronary artery bypass grafting surgery in patients with non-ST-segment elevation acute coronary syndromes predict worse outcomes: results from four large clinical trials EUROPEAN HEART JOURNAL Mahaffey, K. W., Roe, M. T., Kilaru, R., Alexander, J. H., Van de Werf, F., Califf, R. M., Simoons, M. L., Topol, E. J., Harrington, R. A. 2007; 28 (4): 425-432

    Abstract

    To assess the significance of creatine kinase (CK)-MB elevations in outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who have undergone coronary artery bypass grafting (CABG) surgery.This analysis includes data from 26 465 patients with NSTE ACS enrolled in four major trials. In total, 4626 (17.5%) of patients had CABG within 30 days. Patients were excluded if CK-MB was elevated within 24 h before surgery and there was no CK-MB measured after surgery. Overall, 4401 patients were included in these analyses. The incidence of mortality increased with peak CK-MB ratios of 0-1, >1-3, >3-5, >5-10, and>10x the upper limit of normal measured at the local lab (P<0.001 across categories): 1.1, 2.8, 2.4, 3.1, and 10.8% in hospital; 1.1, 3.0, 2.9, 3.5, and 10.2% at 30 days; and 1.6, 4.4, 4.7, 6.0, and 10.9% at 180 days. Multivariable predictors of 6-month mortality included age, heart rate and randomization, peak CK-MB ratio, time to CABG, prior angina, signs of congestive heart failure and randomization, three- and two-vessel coronary disease, enrolment infarction, ST-segment depression at enrolment, female sex, experimental treatment, and systolic blood pressure.CK-MB elevations after CABG are independently associated with increased risk of mortality in patients with NSTE ACS.

    View details for DOI 10.1093/eurheartj/ehl483

    View details for Web of Science ID 000245177000010

    View details for PubMedID 17267458

  • Methylmercury exposure and health effects in humans: A worldwide concern AMBIO Mergler, D., Anderson, H. A., Chan, L. H., Mahaffey, K. R., Murray, M., Sakamoto, M., Stern, A. H. 2007; 36 (1): 3-11

    Abstract

    The paper builds on existing literature, highlighting current understanding and identifying unresolved issues about MeHg exposure, health effects, and risk assessment, and concludes with a consensus statement. Methylmercury is a potent toxin, bioaccumulated and concentrated through the aquatic food chain, placing at risk people, throughout the globe and across the socioeconomic spectrum, who consume predatory fish or for whom fish is a dietary mainstay. Methylmercury developmental neurotoxicity has constituted the basis for risk assessments and public health policies. Despite gaps in our knowledge on new bioindicators of exposure, factors that influence MeHg uptake and toxicity, toxicokinetics, neurologic and cardiovascular effects in adult populations, and the nutritional benefits and risks from the large number of marine and freshwater fish and fish-eating species, the panel concluded that to preserve human health, all efforts need to be made to reduce and eliminate sources of exposure.

    View details for Web of Science ID 000244817800003

    View details for PubMedID 17408186

  • Racial differences among high-risk patients presenting with non-ST-segment elevation acute coronary syndromes (results from the SYNERGY trial) AMERICAN JOURNAL OF CARDIOLOGY Echols, M. R., Mahaffey, K. W., Banerjee, A., Pieper, K. S., Stebbins, A., Lansky, A., Cohen, M. G., Velazquez, E., Santos, R., Newby, L. K., Gurfinkel, E. P., Biasucci, L., Ferguson, J. J., Califf, R. M. 2007; 99 (3): 315-321

    Abstract

    Management and outcomes of patients with acute coronary syndromes (ACSs) may vary according to patient race and ethnicity. To assess racial differences in presentation and outcome in high-risk North American patients with non-ST-segment elevation (NSTE) ACS, we analyzed baseline racial/ethnic differences and all-cause death or nonfatal myocardial infarction (MI) in 6,077 white, 586 African-American, and 344 Hispanic patients through 30-day, 6-month, and 1-year follow-up. Frequencies of hypertension were 66% for whites, 83% for African-Americans, and 78% for Hispanics (overall p <0.001). Use of angiography was similar across groups. Use of percutaneous coronary intervention (46% for whites, 41% for African-Americans, and 45% for Hispanics, overall p = 0.046) and coronary artery bypass grafting (20% for whites, 16% for African-Americans, and 22% for Hispanics, overall p = 0.044) differed. African-American patients had significantly fewer diseased vessels compared with white patients (p = 0.0001). Thirty-day death or MI was 14% for whites, 10% for African-Americans, and 14% for Hispanics (overall p = 0.034). After adjustment for baseline variables, African-American patients had lower 30-day death or MI compared with white patients (odds ratio 0.73, 95% confidence interval 0.55 to 0.98). There were no differences in 6-month death or MI across racial/ethnic groups. In conclusion, baseline clinical characteristics differed across North American racial/ethnic groups in the SYNERGY trial. African-American patients had significantly better adjusted 30-day outcomes but similar 6-month outcomes compared with white patients.

    View details for DOI 10.1016/j.amjcard.2006.08.031

    View details for Web of Science ID 000243947900005

    View details for PubMedID 17261389

  • Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Cantor, W. J., Mahaffey, K. W., Huang, Z., Das, P., Gulba, D. C., Glezer, S., Gallo, R., Ducas, J., Cohen, M., Antman, E. M., Langer, A., Kleiman, N. S., White, H. D., Chisholm, R. J., Harrington, R. A., Ferguson, J. J., Califf, R. M., Goodman, S. G. 2007; 69 (1): 73-83

    Abstract

    Our objective was to analyze the impact of arterial access site, sheath size, timing of sheath removal, and use of access site closure devices on high-risk patients with acute coronary syndromes (ACS).In the SYNERGY trial, 9,978 patients with ACS were randomly assigned to receive enoxaparin or unfractionated heparin.This analysis includes 9,404 patients for whom sheath access information was obtained for the first PCI procedure or diagnostic catheterization. Comparisons of baseline, angiographic, and procedural characteristics were carried out according to access site and sheath size.Overall, 9,404 (94%) patients underwent angiography at a median of 21 hr (25th and 75th percentiles: 5, 42) and 4,687 (50%) underwent PCI at a median of 23 hr (6,49) of enrollment. The access site was femoral for 94.9% of cases, radial for 4.4%, and brachial for 0.7%. Radial access was associated with fewer transfusions than femoral access (0.9% vs. 4.8%, P=0.007). For femoral access, the rates of noncoronary artery bypass grafting (CABG)-related TIMI major bleeding by sheath size was 1.5% for 4 or 5 French (Fr), 1.6% for 6 Fr, 3.3% for 7 Fr, and 3.8% for >or=8 Fr (P<0.0001). After adjustment for baseline characteristics, femoral access site, larger sheath size, and delayed sheath removal were independent predictors of need for transfusion.Smaller sheaths, radial access, and timely sheath removal may mitigate the bleeding risk associated with potent antithrombotic/platelet therapy and early catheterization.

    View details for DOI 10.1002/ccd.20897

    View details for Web of Science ID 000243330300015

    View details for PubMedID 17139670

  • Efficacy and safety of enoxaparin compared with unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial AMERICAN HEART JOURNAL White, H. D., Kleiman, N. S., Mahaffey, K. W., Lokhnygina, Y., Pieper, K. S., Chiswell, K., Cohen, M., Harrington, R. A., Chew, D. P., Petersen, J. L., Berdan, L. G., Aylward, P. E., Nessel, C. C., Ferguson, J. J., Califf, R. M. 2006; 152 (6): 1042-1050

    Abstract

    Enoxaparin reduces ischemic events more effectively than unfractionated heparin (UFH) in patients treated conservatively for non-ST-segment elevation acute coronary syndrome. The SYNERGY trial compared these agents in high-risk patients undergoing early invasive treatment. Enoxaparin was noninferior to UFH for the 30-day primary end point of death/myocardial infarction (MI), but modestly increased bleeding.This article compares the outcomes of the 4687 SYNERGY patients (47%) undergoing percutaneous coronary intervention, who were randomized to receive enoxaparin or UFH. Antithrombotic therapy was administered prerandomization in 78%. Crossover (usually in the catheterization laboratory) to the alternative antithrombotic occurred in 14.6% of enoxaparin patients and 2.9% of UFH-treated patients (P < .0001). Stenting was performed in 86.3%. Abrupt vessel closure occurred in 1.3% of enoxaparin patients and 1.7% of UFH-treated patients (P = .318). The rates of death/MI were similar at 30 days (13.1% with enoxaparin vs 14.2% with UFH, P = .289). GUSTO severe bleeding occurred with similar frequency in both groups (1.5% vs 1.6%, P = .688). TIMI major bleeding was more common with enoxaparin (3.7% vs 2.5% with UFH, P = .028). Transfusions were more frequent with enoxaparin than with UFH (6.8% vs 5.4%, P = .047). TIMI major bleeding increased with crossover from enoxaparin to UFH (from 3.7% to 7.8%) and from UFH to enoxaparin (from 2.5% to 8.6%). Statistical adjustment to model reasons for crossover did not affect the overall safety and efficacy outcomes.In high-risk patients undergoing early percutaneous coronary intervention for acute coronary syndrome, enoxaparin avoids the need for monitoring and achieves similar effectiveness to UFH but is associated with more bleeding.

    View details for DOI 10.1016/j.ahj.2006.08.002

    View details for Web of Science ID 000243110400008

    View details for PubMedID 17161049

  • A subgroup analysis of the impact of prerandomization antithrombin therapy on outcomes in the SYNERGY trial: Enoxaparin versus unfractionated heparin in non-ST-segment elevation acute coronary syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Cohen, M., Mahaffey, K. W., Pieper, K., Pollack, C. V., Antman, E. M., Hoekstra, J., Goodman, S. G., Langer, A., Col, J. J., White, H. D., Califf, R. M., Ferguson, J. J. 2006; 48 (7): 1346-1354

    Abstract

    The purpose of this study was to compare the effect of receiving pretreatment with antithrombin before randomization as well as overall efficacy and safety of enoxaparin versus unfractionated heparin (UFH) in the SYNERGY (Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors) trial.The SYNERGY trial results demonstrated noninferiority in outcomes with enoxaparin compared with UFH. Randomized treatment was independent of prerandomization treatment.Analyses were first performed on the 4 prerandomization subgroups: patients who received no antithrombin therapy and those who were treated with enoxaparin or UFH or both. Then, we focused on the subgroup of patients who received no pretreatment or were pretreated with and randomized to the same drug. Of the 9,978 patients, 2,440 did not receive prerandomization therapy and 6,138 received consistent therapy through randomization. The primary end point was the composite of death and nonfatal myocardial infarction (MI) at 30 days.After adjustment for differences among the subgroups, no significant difference in the association between the 4 pretreatment groups and death or MI remained (p = 0.171). The randomized treatment effect on 30-day death or MI tended to vary with pretreatment (p = 0.055 for interaction test after adjustment). Patients who received consistent therapy with enoxaparin had significantly less death or MI than patients randomized to UFH (adjusted p = 0.041) with a trend toward increased bleeding.Treatment with antithrombin therapy before randomization had potential impact on comparison of study drug effects. After adjustment for differences in baseline characteristics between subgroups, consistent therapy with enoxaparin might be superior to UFH in reducing death or nonfatal MI, with a modest excess in bleeding.

    View details for DOI 10.1016/j.jacc.2006.05.058

    View details for Web of Science ID 000240924400010

    View details for PubMedID 17010793

  • Effect of pexelizumab on mortality in patients with acute myocardial infarction or undergoing coronary artery bypass surgery: A systematic overview AMERICAN HEART JOURNAL Mahaffey, K. W., Van de Werf, F., Shernan, S. K., Granger, C. B., Verrier, E. D., Filloon, T. G., Todaro, T. G., Adams, P. X., Levy, J. H., Hasselblad, V., Armstrong, P. W. 2006; 152 (2): 291-296

    Abstract

    Recent trials evaluating the C5 complement inhibitor, pexelizumab, have shown that modulation of inflammation during ischemia/reperfusion in patients with acute myocardial infarction (MI) or undergoing coronary artery bypass graft (CABG) surgery may improve clinical outcomes.We performed a systematic overview of individual patient data from all completed randomized controlled trials of pexelizumab to evaluate the effect on all-cause mortality at 30 and 180 days after treatment. We used a random effects model and included all 5916 patients randomized in 4 clinical trials. Patients received placebo, pexelizumab bolus only or pexelizumab bolus followed by a 24-hour infusion.A significant reduction in mortality at 30 days was observed in patients treated with bolus plus infusion (n = 2476) compared with placebo (n = 2492) (2.9% vs 4.2%; relative risk [RR], 0.70; 95% confidence interval [CI], 0.52-0.95; P = .02), with no interaction according to disease state of CABG or acute MI (P for interaction .33). A trend toward a reduction in mortality was observed in patients who received bolus plus infusion or bolus only (n = 3429) compared with placebo (n = 2476) (3.5% vs 4.2%; RR, 0.85; 95% CI, 0.66-1.0975; P = .215), but not in patients who received bolus only (n = 937) compared with placebo (n = 937) (5.2% vs 5.4%; RR, 0.96; 95% CI, 0.66-1.41; P = .918). The mortality benefit with bolus plus infusion compared with placebo persisted through 180 days (P = .05).Pexelizumab reduced 30-day mortality in this systematic evaluation. Bolus plus infusion dose is being studied in ongoing trials in acute MI and CABG populations.

    View details for DOI 10.1016/j.ahj.2006.03.027

    View details for Web of Science ID 000239573000017

    View details for PubMedID 16875911

  • Prognosis of patients taking selective serotonin reuptake inhihitors before coronary artery bypass grafting AMERICAN JOURNAL OF CARDIOLOGY Xiong, G. L., Jiang, W., Clare, R., Shaw, L. K., Smith, P. K., Mahaffey, K. W., O'Connor, C. M., Krishnan, K. R., Newby, L. K. 2006; 98 (1): 42-47

    Abstract

    Depression is increasingly recognized as an independent prognostic risk factor in patients with coronary artery disease and coronary artery bypass grafting (CABG). The use of selective serotonin reuptake inhibitors (SSRIs) for depression in patients with cardiac disease is becoming more prevalent. We examined the long-term outcomes of patients on SSRIs before CABG. We prospectively examined collected data in the Duke Databank for Cardiovascular Disease from January 1, 1999 to December 31, 2003. The median and maximum follow-up periods were 3 and 6 years, respectively. We screened patients who underwent CABG (n = 5,364) and excluded those who underwent simultaneous CABG and valvular surgery (n = 570). SSRI antidepressants included fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, escitalopram, venlafaxine, and clomipramine, and their use was determined from the inpatient pharmacy records during the index hospitalization. Outcomes included event-free survival from all-cause mortality, rehospitalization, and a composite end point of all-cause mortality or rehospitalization. Of 4,794 CABG-only patients, 246 (5.1%) took SSRIs before CABG. The SSRI group had a higher prevalence of diabetes, hypercholesterolemia, hypertension, cerebrovascular disease, peripheral vascular disease, and previous cardiovascular intervention. After adjustment for baseline differences, patients on SSRIs before CABG had increased risks of mortality, rehospitalization, and the composite end point (hazard ratio 1.61, 95% confidence interval 1.17 to 2.21, p = 0.003; hazard ratio 1.52, 95% confidence interval 1.30 to 1.77, p <0.0001; and hazard ratio 1.46, 95% confidence interval 1.26 to 1.70, p <0.0001, respectively). In conclusion, SSRI use before CABG was associated with a higher risk of long-term post-CABG mortality and rehospitalization. The explanation behind these findings requires further research.

    View details for DOI 10.1016/j.amjcard.2006.01.051

    View details for Web of Science ID 000238896900010

    View details for PubMedID 16784918

  • Prognostic significance of the change in glucose level in the first 24 h after acute myocardial infarction: results from the CARDINAL study EUROPEAN HEART JOURNAL Goyal, A., Mahaffey, K. W., Garg, J., Nicolau, J. C., Hochman, J. S., Weaver, W. D., Theroux, P., Oliveira, G. B., Todaro, T. G., Mojcik, C. F., Armstrong, P. W., Granger, C. B. 2006; 27 (11): 1289-1297

    Abstract

    In acute myocardial infarction (AMI), baseline hyperglycaemia predicts adverse outcomes, but the relation between subsequent change in glucose levels and outcomes is unclear. We evaluated the prognostic significance of baseline glucose and the change in glucose in the first 24 h following AMI.We analysed 1469 AMI patients with baseline and 24 h glucose data from the CARDINAL trial database. Baseline glucose and the 24 h change in glucose (24 h glucose level subtracted from baseline glucose) were included in multivariable models for 30- and 180-day mortality. By 30 and 180 days, respectively, 45 and 74 patients had died. In the multivariable 30-day mortality model, neither baseline glucose nor the 24 h change in glucose predicted mortality in diabetic patients (n=250). However, in nondiabetic patients (n=1219), higher baseline glucose predicted higher mortality [hazard ratio (HR) 1.12, 95% confidence interval (CI) 1.04-1.20, per 0.6 mmol/L increase], and a greater 24 h change in glucose predicted lower mortality (HR 0.91, 95% CI 0.86-0.96, for every 0.6 mmol/L drop in glucose in the first 24 h) at 30 days. Baseline glucose and the 24 h change in glucose remained significant multivariable mortality predictors at 180 days in nondiabetic patients.Both higher baseline glucose and the failure of glucose levels to decrease in the first 24 h after AMI predict higher mortality in nondiabetic patients.

    View details for DOI 10.1093/eurheartj/ehi884

    View details for Web of Science ID 000238679300009

    View details for PubMedID 16611669

  • Low-molecular-weight heparin compared with unfractionated heparin for patients with non-ST-segment elevation acute coronary syndromes treated with glycoprotein IIb/IIIa inhibitors: Results from the CRUSADE initiative JOURNAL OF THROMBOSIS AND THROMBOLYSIS Singh, K. P., Roe, M. T., Peterson, E. D., Chen, A. Y., Mahaffey, K. W., Goodman, S. G., Harrington, R. A., Smith, S. C., Gibler, W. B., Ohman, E. M., Pollack, C. V. 2006; 21 (3): 211-220

    Abstract

    Both heparin and glycoprotein (GP) IIb/IIIa inhibitor therapy and early invasive management strategies are recommended by the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for the treatment of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). However, controversy exists about which form of heparin-unfractionated (UF) or low-molecular-weight (LMW)-is preferable. We sought to compare the efficacy and safety of these treatment strategies in a large contemporary population of patients with NSTE ACS.Using data from the CRUSADE Initiative, we evaluated LMWH and UFH in high-risk NSTE ACS patients (positive cardiac markers and/or ischemic ST-segment changes) who had received early (< 24 hours) GP IIb/IIIa inhibitor therapy and underwent early invasive management. In-hospital outcomes were compared among treatment groups.From a total of 11,358 patients treated at 407 hospitals in the US from January 2002-June 2003, 6881 (60.6%) received UFH and 4477 (39.4%) received LMWH. Patients treated with UFH were more often admitted to a cardiology inpatient service (73.6% vs. 65.5%, P < 0.0001) and more frequently underwent diagnostic catheterization (91.8% vs. 85.9%, P < 0.0001) and percutaneous coronary intervention (PCI) (69.7% vs. 56.9%, P < 0.0001) than patients treated with LMWH. The point estimate of the adjusted risk of in-hospital death or reinfarction was slightly lower among patients treated with LMWH (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.67-0.99) and the risk of red blood cell transfusion was similar (OR 1.01, 95% CI 0.89-1.15). Among patients who underwent PCI within 48 hours, adjusted rates of death (OR 1.14, 95% CI 0.71-1.85), death or reinfarction (OR 0.93, 0.67-1.31), and transfusion (OR 1.16, 0.89-1.50) were similar. Patients who underwent PCI more than 48 hours into hospitalization had reduced rates of death (OR 0.64, 0.46-0.88), death or reinfarction (OR 0.57, 0.44-0.73), and transfusion (OR 0.66, 0.52-0.84).In routine clinical practice, patients treated with GP IIb/IIIa inhibitors have slightly improved outcomes and similar bleeding risks with LMWH than with UFH. These findings are consistent with current ACC/AHA guidelines but raise important questions about the safety and effectiveness of antithrombotic therapy in real-world clinical practice. Using data from the CRUSADE Initiative, we evaluated low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) in high-risk patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) who received early (<24 hours) glycoprotein (GP) IIb/IIIa inhibitors and early invasive management. In-hospital outcomes were compared among treatment groups. LMWH was associated with slightly improved clinical outcomes and similar rates of transfusion compared with UFH. Our results support the current ACC/AHA guidelines recommendations but raise concerns about the safety and efficacy of UFH in the setting of background use of upstream GP IIb/IIIa inhibitors for patients with NSTE ACS in routine clinical practice.

    View details for DOI 10.1007/s11239-006-5708-0

    View details for Web of Science ID 000237437200001

    View details for PubMedID 16683212

  • Statin use and sex-specific stroke outcomes in patients with vascular disease STROKE Bushnell, C. D., Griffin, J., Newby, L. K., Goldstein, L. B., Mahaffey, K. W., Graffagnino, C. A., Harrington, R. A., White, H. D., Simes, R. J., Califf, R. M., Topol, E. J., Easton, J. D. 2006; 37 (6): 1427-1431

    Abstract

    Although statins reduce the risk of stroke in patients with coronary heart disease, possible differing effects of statins on stroke outcomes based on sex remain uncertain. We investigated the relationships between statin use and sex-specific stroke incidence, severity, and mortality.Data from 3 trials of oral glycoprotein IIb/IIIa inhibitors (first and second Sibrafiban versus aspirin to Yield Maximum Protection from ischemic Heart events postacute cOroNary sYndromes [SYMPHONY] and Blockade of the glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion [BRAVO]) were pooled and stroke outcomes compared among 8191 baseline statin users versus 14,752 nonusers. Time-to-event data were modeled with proportional hazards regression. Stroke severity was assessed retrospectively with the Canadian Neurological Scale (CNS) based on records with scoreable neurological examinations.A total of 217 subjects had strokes (0.95%). Statin users had a lower risk of stroke in unadjusted (hazard ratio [HR], 0.69; 95% CI, 0.51 to 0.92) and risk-adjusted models (HR, 0.72; 95% CI, 0.53 to 0.97). There was no difference in stroke mortality with statin use (P=0.8). CNS scores could be assigned to 106 of the subjects, with no difference in severity among statin users and nonusers (median CNS=10.5 in users versus CNS=9.75 in nonusers; P=0.14). Women had more severe strokes than men (median CNS=10.5 in men versus 9.5 in women; Poisson regression P=0.035). Women had more severe strokes after adjustment for statin use (P=0.03) and the combination of statin use, atrial fibrillation, and age (P=0.03).In patients included in these clinical trials of oral glycoprotein IIb/IIIa inhibitors, statin use is associated with a reduced risk of stroke but not severity or mortality. Women had more severe strokes than men, a difference that was not explained by baseline characteristics or statin use.

    View details for DOI 10.1161/01.STR.0000221315.60282.ca

    View details for Web of Science ID 000237925000027

    View details for PubMedID 16645137

  • Comparing classifications of death in the Mode Selection Trial: Agreement and disagreement among site investigators and a clinical events committee CONTEMPORARY CLINICAL TRIALS Petersen, J. L., Haque, G., Hellkarnp, A. S., Flaker, G. C., Estes, N. A., Marchlinski, F. E., McAnulty, J. H., Greenspon, A. J., Marinchak, R. A., Lee, K. L., Lamas, G. A., Mahaffey, K. W. 2006; 27 (3): 260-268

    Abstract

    Clinical events committees (CECs) are the current standard for endpoint adjudication in clinical trials. However, little data exist with which to compare CEC and site investigator determinations or to evaluate internal agreement among CEC members. Using data from the Mode Selection Trial in Sinus Node Dysfunction (MOST), we analyzed classifications of death in order to compare internal agreement among CEC physician reviewers and agreement between the CEC and site investigators. Death was classified at 2 levels: by major cause (cardiac, noncardiac, or unknown) and by minor subclassification of the major classifications. Reviewer agreement was tabulated at the major and minor levels, and standard and weighted kappa statistics were calculated. Disagreement at both levels was also determined. Individual decision-making was tabulated in terms of frequency in classifying death as unknown. All 404 deaths were classified by the CEC. Site investigators determined major classifications in 382 cases and minor classification in 379 cases. The CEC and the site investigators disagreed in classifying 41 cases (10.7%) at the major level and 117 (30.9%) at the minor level. CEC reviewers disagreed internally at the major level in 64 cases (15.8%), at the minor level in 63 cases (15.6%), and at any level in 127 cases (31.4%) (kappa = 0.60, 95% confidence interval (CI) [0.55, 0.66]; weighted kappa = 0.66, 95% CI [0.62, 0.75]). In resolving internal disagreements, the full CEC agreed with 1 of 2 CEC reviewers in 85.9% of cases. Disagreements occurred between site investigators and CEC reviewers in classifying deaths. Endpoint determination and decision-making varied among individual CEC reviewers, but second-tier reviews by the full CEC resolved all disagreements. These findings support continued use of CECs for endpoint adjudication in clinical trials.

    View details for DOI 10.1016/j.cct.2006.02.002

    View details for Web of Science ID 000237791900006

    View details for PubMedID 16574497

  • N-terminal pro-brain natriuretic peptide and the timing, extent and mortality in ST elevation myocardial infarction CANADIAN JOURNAL OF CARDIOLOGY Ezekowitz, J. A., Theroux, P., Chang, W. C., Mahaffey, K. W., Granger, C. B., Weaver, W. D., Hochman, J. S., Armstrong, P. W. 2006; 22 (5): 393-397

    Abstract

    While natriuretic peptides have demonstrated diagnostic and prognostic potential in cardiac disorders, little is known about their relationship with the onset and quantification of myocardial infarction. The relationship of serial N-terminal pro-brain natriuretic peptide (NT-proBNP) with duration from symptom onset, infarct size and prognosis in ST elevation myocardial infarction (STEMI) patients treated with primary percutaneous intervention was examined.Three hundred thirty-one STEMI patients in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial, which evaluated pexelizumab versus placebo, were studied. NT-proBNP (pg/mL) was measured at randomization, 24 h and 72 h; creatine kinase-MB area under the curve was measured at 72 h; and QRS score was assessed at discharge. Prognosis was ascertained from the 90-day composite clinical outcome of death, shock, stroke and congestive heart failure. Multivariate logistical regression was used to adjust for baseline characteristics for models at randomization, 24 h and 72 h. NT-proBNP was higher in patients with longer time from symptom onset (P<0.001) and correlated with measures of infarct size, including the area under the curve (P<0.001) and QRS score (P<0.001). Patients reaching the primary end point had markedly higher NT-proBNP at each sampling period (P<0.001). NT-proBNP at all time points was the strongest independent predictor of the primary end point in the multivariate model: in the 24 h model, only age and 24 h NT-proBNP (C-index 0.83); and only age, Killip class and NT-proBNP was in the 72 h model (C-index 0.85).Higher NT-proBNP at 24 h correlated with larger infarct size and worse clinical outcomes. NT-proBNP at baseline, 24 h and 72 h after presentation with acute STEMI, is an independent predictor of a poor outcome and adds clinically useful prognostic information.

    View details for Web of Science ID 000236992200004

    View details for PubMedID 16639474

  • Concerning the mechanism of pexelizumab's benefit in acute myocardial infarction AMERICAN HEART JOURNAL Armstrong, P. W., Mahaffey, K. W., Chang, W. C., Weaver, W. D., Hochman, J. S., Theroux, P., Rollins, S., Todaro, T. G., Granger, C. B. 2006; 151 (4): 787-790

    Abstract

    The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial previously demonstrated an unexpected dose-dependent reduction in 90-day mortality after bolus/infusion of pexelizumab despite no reduction in the primary end point of myocardial infarction (MI) size. We examined whether the mortality benefit was related to established modulators of clinical benefit such as baseline demographics, time to treatment from symptom onset, myocardial perfusion post-percutaneous coronary intervention (PCI), and extent of ST resolution.Eight hundred fourteen patients were randomized into 3 groups; (1) placebo, (2) pexelizumab bolus 2.0 mg/kg and placebo infusion for 20 hours, and (3) pexelizumab bolus 2.0 and 0.05 mg/kg per hour infusion for 20 hours commencing 4 hours after the bolus. Subjects presented with ST elevation MI within 6 hours of symptom onset and underwent PCI, creatine kinase (CK), and CK-MB measurements taken sequentially to define CK-MB area under the curve (AUC) and sequential ECG's defined ST resolution and QRS infarct size. Whereas mortality for both placebo and bolus pexelizumab groups rose during later time after presentation, it remained low and did not change appreciably during the 6-hour randomization window when patients received pexelizumab bolus infusion. Amplification of the mortality benefit was evident in patients with the highest quartile of hemodynamic compromise, that is, heart rate > or = 90 beat/min and systolic blood pressure < or = 118 mm Hg (3.2% vs 11.3% P = .004). A significant interaction between treatment assignment and hemodynamic status (P = .013) existed after adjusting for age, race, and MI location. Clinical benefit was not related to infarct size, extent of ST elevation, or evidence of angiographic or electrocardiographic reperfusion.These data raise the possibility that the clinical benefit of pexelizumab is mediated through novel pathways such as reduction in apoptosis or other mechanisms.

    View details for DOI 10.1016/j.ahj.2005.06.008

    View details for Web of Science ID 000236721000008

    View details for PubMedID 16569534

  • A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Rao, S. V., O'Grady, K., Pieper, K. S., Granger, C. B., Newby, L. K., Mahaffey, K. W., Moliterno, D. J., Lincof, A. M., Armstrong, P. W., Van de Werf, F., Califf, R. M., Harrington, R. A. 2006; 47 (4): 809-816

    Abstract

    The goal of this study was to determine the association between Thrombolysis In Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) bleeding and clinical outcomes.There are limited data on the relative utility of either scale at predicting clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes (ACS).Pooled data from two randomized trials of patients with ACS (n = 15,454) were analyzed to determine the association between TIMI and GUSTO bleeding and 30-day and 6-month death/myocardial infarction (MI) using Cox proportional hazards modeling that included bleeding as a time-dependent covariate.There was a stepwise increase in the adjusted hazard of 30-day death/MI with worsening GUSTO bleeding (hazard ratio [95% confidence interval], GUSTO mild 1.20 [1.05 to 1.37]; moderate 3.28 [2.88 to 3.73]; severe 5.57 [4.33 to 7.17]), and an increased risk with all three levels of TIMI bleeding (TIMI minimal 1.84 [1.63 to 2.08]; TIMI minor 1.64 [1.31 to 2.04]; major 1.45 [1.23 to 1.70]). When both bleeding scales were included in the same model, the risk with GUSTO bleeding persisted; however, the association between TIMI bleeding and outcome was no longer significant.Both scales identify ACS patients with bleeding complications at risk for adverse outcomes. In a model that included both definitions, the risk with GUSTO bleeding persisted while the risk with TIMI bleeding did not. This suggests that bleeding assessed with clinical criteria is more important than that assessed by laboratory criteria in terms of outcomes. Future clinical trials should consider using a combination of the GUSTO bleeding scale and the need for transfusion to assess bleeding complications.

    View details for DOI 10.1016/j.jacc.2005.09.060

    View details for Web of Science ID 000235422900021

    View details for PubMedID 16487850

  • Forecasting mortality: dynamic assessment of risk in ST-segment elevation acute myocardial infarction EUROPEAN HEART JOURNAL Chang, W. C., Kaul, P., Fu, Y. L., Westerhout, C. M., Granger, C. B., Mahaffey, K. W., Wallentin, L., Van de Werf, F., Armstrong, P. W. 2006; 27 (4): 419-426

    Abstract

    To demonstrate the feasibility and clinical utility of developing dynamic risk assessment models for ST-segment elevation myocardial infarction (STEMI) patients.In 6066 STEMI patients enrolled in the Assessment of the Safety and Efficacy of a New Thrombolytic-3 (ASSENT-3) trial with complete electrocardiographic data, we assessed the probability of 30-day mortality over the following forecasting periods beginning at day 0 (baseline), 3 h, day 2, and day 5 using multiple-logistic regression. These models were validated and simplified in independent samples of 1622 similar fibrinolytic-treated patients from the ASSENT-3 PLUS trial and in 814 STEMI patients undergoing primary percutaneous coronary intervention in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial. The discriminatory power of these predictive models, from baseline to day 5, was excellent (c-statistics 0.80 to 0.87); and their predictive ability was supported by strong gradients in mortality outcomes as the risk score increased. Dynamic modelling also provided information on the change in prognosis over time which may be used to advise more appropriate therapeutic decisions, e.g. the identification of high-risk patients for possible co-interventions.Dynamic modelling for STEMI patients enhances the risk assessment and stratification and should provide valuable ongoing guidance for their management.

    View details for DOI 10.1093/eurheartj/ehi700

    View details for Web of Science ID 000235278100010

    View details for PubMedID 16407373

  • Elevated creatine kinase-MB with normal creatine kinase predicts worse outcomes in patients with acute coronary syndromes: Results from 4 large clinical trials AMERICAN HEART JOURNAL Galla, J. M., Mahaffey, K. W., Sapp, S. K., Alexander, J. H., Roe, M. T., Ohman, E. M., Granger, C. B., Armstrong, P. W., Harrington, R. A., White, H. D., Simoons, M. L., Newby, L. K., Califf, R. M., Topol, E. J. 2006; 151 (1): 16-24

    Abstract

    The degree to which elevated creatine kinase (CK)-MB in the presence of normal CK is predictive of outcome is not well understood despite having been studied for decades. This analysis examined whether normal CK with elevated CK-MB in patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) is an independent predictor of worse outcomes. A concomitant goal was to contribute insight to the debate over how patients with NSTE ACS should be managed.Data for 25,960 patients from the GUSTO IIb, PARAGON A and B, and PURSUIT trials were analyzed. Of these patients, 6402 were excluded from primary analysis because of missing (unmeasured) biomarkers. Patients with complete laboratory data (n = 19,558) were grouped by CK and CK-MB results. To confirm the primary analysis results, data from patients with missing biomarkers were used in an imputation model.Patients were categorized in 1 of 4 groups: normal CK + normal CK-MB; normal CK + elevated CK-MB; elevated CK + normal CK-MB; or elevated CK + elevated CK-MB. For the primary outcome, 180-day death, or myocardial infarction, Kaplan-Meier estimates were 14.9%, 20.8%, 14.5%, and 18.2%, respectively. Regardless of total CK, elevated CK-MB was associated with a 25% to 49% increased relative risk of worse outcomes. Findings from the analyses were verified by the multivariable model.CK-MB remains a reliable marker for myocardial necrosis and a strong predictor of worse prognosis. All patients with ACS should have CK-MB measurement to search for cardiac ischemia. Patients with elevated CK-MB should receive aggressive management commensurate with their increased risks.

    View details for DOI 10.1016/j.ahj.2005.01.045

    View details for Web of Science ID 000234485100003

    View details for PubMedID 16368286

  • High-risk patients with acute coronary syndromes treated with low-molecular-weight or unfractionated heparin - Outcomes at 6 months and 1 year in the SYNERGY trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Mahaffey, K. W., Cohen, M., Garg, J., Antman, E., Kleiman, N. S., Goodman, S. G., Berdan, L. G., Reist, C. J., Langer, A., White, H. D., Aylward, P. E., Col, J. J., Ferguson, J. J., Califf, R. M. 2005; 294 (20): 2594-2600

    Abstract

    The SYNERGY trial comparing enoxaparin and unfractionated heparin in high-risk patients with acute coronary syndromes (ACS) showed that enoxaparin was not inferior to unfractionated heparin in reducing death or nonfatal myocardial infarction (MI) at 30 days.To evaluate continued risk in this patient cohort through 6-month and 1-year follow-up.Overall, 9978 patients were randomized from August 2001 through December 2003 in 487 hospitals in 12 countries. Patients were followed up for 6 months and for 1 year.Six-month outcomes were death, nonfatal MI, revascularization procedures, stroke, and site-investigator-reported need for rehospitalization; 1-year outcome was all-cause death.Six-month and 1-year follow-up data were available for 9957 (99.8%) and 9608 (96.3%) of 9978 patients, respectively; 541 patients (5.4%) had died at 6 months and 739 (7.4%) at 1 year. Death or nonfatal MI at 6 months occurred in 872 patients receiving enoxaparin (17.6%) vs 884 receiving unfractionated heparin (17.8%) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.89-1.07; P = .65). In the subgroup of patients receiving consistent therapy, ie, only enoxaparin or unfractionated heparin during the index hospitalization (n = 6138), a reduction in death or nonfatal MI with enoxaparin was maintained at 180 days (HR, 0.85; 95% CI, 0.75-0.95; P = .006). Rehospitalization within 180 days occurred in 858 patients receiving enoxaparin (17.9%) and 911 receiving unfractionated heparin (19.0%) (HR, 0.94; 95% CI, 0.85-1.03; P = .17). One-year all-cause death rates were similar in the 2 treatment groups (380/4974 [7.6%] for enoxaparin vs 359/4948 [7.3%] for unfractionated heparin; HR, 1.06; 95% CI, 0.92-1.22; P = .44). One-year death rates in patients receiving consistent therapy were also similar (251/3386 [7.4%] for enoxaparin vs 213/2720 [7.8%] for unfractionated heparin; HR, 0.95; 95% CI, 0.79-1.14; P = .55).In the SYNERGY trial, patients continued to experience adverse cardiac events through long-term follow-up. The effect of enoxaparin on death or MI compared with that of unfractionated heparin at 6 months was similar to that observed at 30 days in the overall trial and in the consistent-therapy group. One-year death rates were also similar in both groups. High-risk patients with ACS remain susceptible to continued cardiac events despite aggressive therapies.ClinicalTrials.gov Identifier: NCT00043784.

    View details for Web of Science ID 000233436200024

    View details for PubMedID 16304073

  • Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Rao, S. V., O'Grady, K., Pieper, K. S., Granger, C. B., Newby, L. K., Van de Werf, F., Mahaffey, K. W., Califf, R. M., Harrington, R. A. 2005; 96 (9): 1200-1206

    Abstract

    Bleeding is a complication of current therapies for acute coronary syndrome (ACS). No studies have examined the effect of bleeding events on clinical outcomes. We analyzed pooled data from 4 multicenter, randomized clinical trials of patients who had ACS (n = 26,452) to determine an association between bleeding severity as measured by the GUSTO scale and 30-day and 6-month mortality rates using Cox proportional hazards modeling that incorporated bleeding as a time-dependent covariate. The analysis was repeated to examine procedure- and non-procedure-related bleeding and after censoring at the time of coronary artery bypass grafting. Of all the patients included, 27.6% had > or =1 bleeding episode. Patients who bled were older and sicker at presentation than were those who did not bleed. Unadjusted rates of 30-day and 6-month mortality increased as bleeding severity increased. There were stepwise increases in the adjusted hazards of 30-day mortality (mild bleeding, hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.3 to 1.9; moderate bleeding, HR 2.7, 95% CI l 2.3 to 3.4; severe bleeding, HR 10.6, 95% CI 8.3 to 13.6) and 6-month mortality (mild bleeding, HR 1.4, 95% CI 1.2 to 1.6; moderate bleeding, HR 2.1, 95% CI 1.8 to 2.4; severe bleeding, HR 7.5, 95% CI 6.1 to 9.3) as bleeding severity increased. Results were consistent after censoring for coronary artery bypass grafting and for procedure- and non-procedure-related bleeds. In conclusion, the GUSTO bleeding classification identifies patients who are at risk for short- and long-term adverse events. Therapies that minimize bleeding risk and maintain an anticoagulant effect may improve outcomes among patients who have ACS.

    View details for DOI 10.1016/j.amjcard.2005.06.056

    View details for Web of Science ID 000233343500005

    View details for PubMedID 16253582

  • Utilization of catheterization and revascularization procedures in patients with non-ST segment elevation acute coronary syndrome over the last decade CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Levine, G. N., Lincoff, A. M., Ferguson, J. J., Mahaffey, K. W., Goodman, S. G., Cannon, C. P., Theroux, P., Fox, K. A. 2005; 66 (2): 149-157

    Abstract

    The degree to which catheterization and revascularization procedures are utilized in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) during hospitalization has broad implications with respect to initial pharmacotherapeutic decisions (upfront therapies), treatment and hospital transfer protocols, guideline recommendations, and allocation of training, material, and financial resources. Analysis of data from multiple trials and registries of patients with NSTE-ACS has the potential to assess more broadly utilization of invasive and revascularization procedures and provide a wide angle or bird's-eye view of the management of such patients, complementing the data obtained from any one trial or registry. We therefore undertook a systematic overview of all large trials and registries of patients with NSTE-ACS conducted over the last decade that were deemed appropriate to provide information on catheterization and revascularization procedures. Although not unexpectedly the percentage of patients with NSTE-ACS managed with cardiac catheterization, percutaneous coronary intervention (PCI), and coronary artery bypass grafting varies in different clinical trials and registries, general findings and trends were still discernable from these studies. During the initial treatment period, the majority of patients were ultimately treated with medical therapy alone (e.g., without revascularization). The percentage of those NSTE-ACS patients undergoing diagnostic cardiac catheterization who were then managed with PCI increased over the last decade and now stands at approximately 50%. Of NSTE-ACS patients who undergo revascularization, the percentage of those patients who are revascularized via PCI similarly increased, and PCI is currently the revascularization procedure utilized in approximately three-fourths of patients undergoing revascularization. The percentages of patients undergoing invasive and revascularization procedures were consistently higher in the U.S. cohorts of study subjects when compared to non-U.S. cohorts of study subjects.

    View details for DOI 10.1002/ccd.20469

    View details for Web of Science ID 000232387600001

    View details for PubMedID 16152646

  • Heart failure on admission and the risk of stroke following acute myocardial infarction: the VALIANT registry EUROPEAN HEART JOURNAL Szummer, K. E., Solomon, S. D., Velazquez, E. J., Kilaru, R., McMurray, J., Rouleau, J. L., Mahaffey, K. W., Maggioni, A. P., Califf, R. M., Pfeffer, M. A., White, H. D. 2005; 26 (20): 2114-2119

    Abstract

    We sought to assess the relative contribution of heart failure (HF) on admission for an acute myocardial infarction (MI) to the subsequent in-hospital stroke risk.The VALsartan In Acute myocardial iNfarcTion (VALIANT) registry enrolled 5573 consecutive MI patients at 84 international sites from 1999 to 2001. We calculated odds ratios (ORs) for stroke and adjusted for baseline characteristics, Killip Class, and risk factors for stroke, such as diabetes and prior HF. In-hospital stroke occurred in 81 (1.5%) patients. HF was present on admission in 38% of patients who developed a stroke and in 24% who did not (P=0.001). Older age (OR 1.03 increase/year, 95% confidence interval (CI) 1.01-1.04), Killip Class III (OR 1.66, CI 0.86-3.19) or IV (OR 4.85, CI 1.69-13.93), history of hypertension (OR 1.73, CI 1.06-2.82), and history of stroke (OR 1.89, CI 1.06-3.37) were more common in patients who had in-hospital stroke. In-hospital mortality in patients with and without stroke was 27.2 and 6.5%, respectively (P<0.001).Patients with stroke after MI have a dismal prognosis. The presence of HF on admission for an acute MI increases in-hospital stroke risk. HF treatments may modify the risk of stroke.

    View details for DOI 10.1093/eurheartj/ehi352

    View details for Web of Science ID 000232278500010

    View details for PubMedID 15972293

  • Electrocardiographic infarct size assessment after thrombolysis: Insights from the Acute Myocardial Infarction STudy ADenosine (AMISTAD) trial AMERICAN HEART JOURNAL Barbagelata, A., Di Carli, M. F., Califf, R. M., Garg, J., Birnbaum, Y., Grinfeld, L., Gibbons, R. J., Granger, C. B., Goodman, S. G., Wagner, G. S., Mahaffey, K. W. 2005; 150 (4): 659-665

    Abstract

    Noninvasive methods are needed to evaluate reperfusion success in patients with acute myocardial infarction (MI). The AMISTAD trial was analyzed to compare MI size and myocardial salvage determined by electrocardiogram (ECG) with technetium Tc 99m sestamibi single-photon emission computerized tomography (SPECT) imaging.Of 236 patients enrolled in AMISTAD, 166 (70 %) with no ECG confounding factors and no prior MI were included in this analysis. Of these, group 1 (126 patients, 53%) had final infarct size (FIS) available by both ECG and SPECT. Group 2 (56 patients, 24%) had myocardium at risk, FIS, and salvage index (SI) assessed by both SPECT and ECG techniques. Aldrich/Clemmensen scores for myocardium at risk and the Selvester QRS score for final MI size were used. Salvage index was calculated as follows: SI = (myocardium at risk-FIS)/(myocardium at risk).In group 1, FIS was 15% (6, 24) as measured by ECG and 11% (2, 27) as measured by SPECT. In the adenosine group, FIS was 12% (6, 21) and 11% (2, 22). In the placebo group, FIS was 16.5% (7.5, 24) and 11.5% (3.0, 38.5) by ECG and SPECT, respectively. The overall correlation between SPECT and ECG for FIS was 0.58 (P = .0001): 0.60 in the placebo group (P = .0001) and 0.54 (P = .0001) in the adenosine group. In group 2, myocardium at risk was 23% (17, 30) and 26% (10, 50) with ECG and SPECT, respectively (P = .0066). Final infarct size was 17% (6, 21) and 12% (1, 24) (P < .0001). The SI was 29% (-7, 57) and 46% (15, 79) with ECG and SPECT, respectively (P = .0510).The ECG measurement of infarct size has a moderate relationship with SPECT infarct size measurements in the population with available assessments. This ECG algorithm must further be validated on clinical outcomes.

    View details for DOI 10.1016/j.ahj.2004.10.014

    View details for Web of Science ID 000232953300007

    View details for PubMedID 16209961

  • Prognostic significance of blood markers of inflammation in patients with ST-segment elevation myocardial infarction undergoing primary angioplasty and effects of pexelizumab, a C5 inhibitor: a substudy of the COMMA trial EUROPEAN HEART JOURNAL Theroux, P., Armstrong, P. W., Mahaffey, K. W., Hochman, J. S., Malloy, K. J., Rollins, S., Nicolau, J. C., Lavoie, J., Luong, T. M., Burchenal, J., Granger, C. B. 2005; 26 (19): 1964-1970

    Abstract

    Pexelizumab, a monoclonal antibody inhibiting C5, reduced 90 day mortality and shock in the COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial without apparent reductions in infarct size. Inflammation is a critical component of ST-elevation myocardial infarction (STEMI); this substudy examines prognostic values of selected markers and treatment effects.C-reactive protein, interleukin-6 (IL-6), and tumour necrosis factor-alpha (TNF-alpha) serum levels were assessed in 337 patients enrolled in either the placebo or the pexelizumab 24 h infusion group. Higher C-reactive protein and IL-6 levels at baseline, 24 h, and 72 h were strongly associated with increased subsequent death (P<0.002 at baseline and 24 h, P<0.02 at 72 h); and all baseline marker levels with death or cardiogenic shock (P<0.03) within 90 days. C-reactive protein and IL-6 levels were similar at baseline, but significantly lower 24 h later with pexelizumab, when compared with placebo (17.1 vs. 25.5 mg/L, P=0.03 and 51.0 vs. 63.8 pg/mL, P=0.04, respectively). At 72 h, corresponding levels were similar, whereas TNF-alpha was slightly higher (P=0.04) in the treated group.Inflammation markers and their serial changes predict death and shock in patients with STEMI undergoing primary angioplasty. Pexelizumab reduced C-reactive protein and IL-6, suggesting treatment benefits mediated through anti-inflammatory effects.

    View details for DOI 10.1093/eurheartj/ehi292

    View details for Web of Science ID 000232103200008

    View details for PubMedID 15872036

  • Enzyme estimates of infarct size correlate with functional and clinical outcomes in the setting of ST-segment elevation myocardial infarction CURRENT CONTROLLED TRIALS IN CARDIOVASCULAR MEDICINE Turer, A. T., Mahaffey, K. W., Gallup, D., Weaver, W. D., Christenson, R. H., Every, N. R., Ohman, E. M. 2005; 6

    Abstract

    Cardiac biomarkers are routinely obtained in the setting of suspected myocardial ischemia and infarction. Evidence suggests these markers may correlate with functional and clinical outcomes, but the strength of this correlation is unclear. The relationship between enzyme measures of myocardial necrosis and left ventricular performance and adverse clinical outcomes were explored.Creatine kinase (CK) and CK-MB data were analyzed, as were left ventricular ejection fraction (LVEF) by angiogram, and infarct size by single-photon emission computed tomography (SPECT) imaging in patients in 2 trials: Prompt Reperfusion In Myocardial-infarction Evolution (PRIME), and Efegatran and Streptokinase to Canalize Arteries Like Accelerated Tissue plasminogen activator (ESCALAT). Both trials evaluated efegatran combined with thrombolysis for treating acute ST-segment elevation myocardial infarction (STEMI).Peak CK and CK area-under-the-curve (AUC) correlated significantly with SPECT-determined infarct size 5 to 10 days after enrollment. Peak CK had a statistically significant correlation with LVEF, but CK-AUC and LVEF correlation were less robust. Statistically significant correlations exist between SPECT-determined infarct size and peak CK-MB and CK-MB AUC. However, there was no correlation with LVEF for peak CK-MB and CK-MB AUC. The combined outcome of congestive heart failure and death were significantly associated with CK AUC, CK-MB AUC, peak CK, and peak CK-MB measurements.Peak CK and CK-MB values and AUC calculations have significant correlation with functional outcomes (LVEF- and SPECT-determined infarct size) and death or CHF outcomes in the setting of STEMI. Cardiac biomarkers provide prognostic information and may serve as valid endpoint measurements for phase II clinical trials.

    View details for DOI 10.1186/1468-6708-6-12

    View details for Web of Science ID 000232280400001

    View details for PubMedID 16115321

  • Characterization of myocardial infarction as an end point in two large trials of acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Mahaffey, K. W., Roe, M. T., Kilaru, R., French, J. K., Alexander, J. H., Berdan, L. G., Van de Werf, F., Simoons, M. L., Weaver, W. D., White, H. D., Lincoff, A. M., Kleiman, N. S., Topol, E. J., Harrington, R. A. 2005; 95 (12): 1404-1408

    Abstract

    Myocardial infarction (MI) is a key component of composite end points in trials that evaluate new therapies in non-ST-segment elevation acute coronary syndromes. Types of MI events in these trials have not been well characterized. A similar clinical-events classification process adjudicated all suspected MI end points in the PURSUIT and PARAGON B trials. All MI end points were classified as nonprocedural, related to percutaneous coronary intervention, or related to coronary artery bypass grafting. A total of 16,173 patients was enrolled in the 2 trials, and 1,802 MI end points occurred during a 30-day follow-up. Nearly 66% of MI end points were not related to percutaneous coronary intervention or coronary artery bypass grafting. Patients who had MI compared with those who did not had higher 30-day mortality rates (13.6% vs 2.3%, p <0.001) and 6-month mortality rates (18.4% vs 4.4%, p <0.001). Patients who had been randomized to glycoprotein IIb/IIIa inhibition showed trends toward fewer MI events regardless of type. Two-thirds of MI end points in 2 large trials of acute coronary syndrome were not related to procedure. All MI types were associated with worse short- and long-term outcomes. Characterization of the type of MI provides an opportunity for more informed interpretation of clinical trial results and improved planning for future trials.

    View details for DOI 10.1016/j.amjcard.2005.02.005

    View details for Web of Science ID 000229952900002

    View details for PubMedID 15950560

  • Clinical use of enoxaparin in the management of non-ST segment elevation acute coronary syndromes EXPERT OPINION ON PHARMACOTHERAPY Galla, J. M., Mahaffey, K. W. 2005; 6 (7): 1241-1251

    Abstract

    Enoxaparin (Lovenox; Roule-Poulenc Rorer, Inc.), a low molecular weight heparin (LMWH), is commonly used in the management of non-ST-segment elevation acute coronary syndromes (NSTE ACS) based on clinical trial outcomes. It is one of a group of glycosaminoglycan compounds that accelerate the inactivation of factor Xa by inducing a conformational change in antithrombin. In contrast to unfractionated heparin (UFH), LMWH have greater bioavailability, a more predictable anticoagulant response, longer half-life and a higher proportion of anti-factor Xa to anti-factor IIa activity. As a consequence, laboratory monitoring of the anticoagulant effect is typically unnecessary. Antithrombin therapy with LMWH or UFH has the highest-level recommendation (IA) in the 2002 professional guidelines for the management of unstable angina and non-ST-elevation myocardial infarction, where enoxaparin has a IIA recommendation over UFH unless early coronary artery bypass surgery is planned. In a recent systematic overview of > 20,000 patients with NSTE ACS from six clinical trials, including conservative and invasively managed patients, enoxaparin provided a statistically significant reduction in 30-day death or nonfatal myocardial infarction (MI) compared with UFH with no significant excess in transfusions, or major bleeding. These data support the role of enoxaparin as an anti-coagulant in patients with NSTE ACS.

    View details for DOI 10.1517/146566566.6.7.1241

    View details for Web of Science ID 000230945100017

    View details for PubMedID 15957976

  • A perspective on trials comparing enoxaparin and unfractionated heparin in the treatment of non-ST-elevation acute coronary syndromes Symposium on Staying the Course - Evidence-based Management of ACS Califf, R. M., Petersen, J. L., Hasselblad, V., Mahaffey, K. W., Ferguson, J. J. MOSBY-ELSEVIER. 2005: S91–S99

    Abstract

    Non-ST-elevation (NSTE) acute coronary syndrome (ACS) is a serious, acute illness characterized by a high rate of death and morbid events, and antithrombin therapy is integral to its management. Contemporary guidelines from the American College of Cardiology/American Heart Association call for use of low-molecular-weight heparin or unfractionated heparin (UFH).A systematic overview of six randomized, controlled trials comparing enoxaparin to UFH in the treatment of NSTE ACS was performed using a random-effects empirical Bayes model. Efficacy end points included the incidence of death or the composite of death and myocardial infarction (MI) at 30 days. Safety end points included major bleeding and transfusion at 7 days.For the aggregate of 21,946 patients, the incidence of the composite of death and MI at 30 days was lower in enoxaparin-treated patients (10.1% vs 11.0% for UFH, OR 0.91, 95% CI 0.83-0.99, number need to treat 107). For the 9,835 patients in these trials who received no prerandomization antithrombin therapy, the composite of death and MI at 30 days occurred in 8.0% and 9.4% of enoxaparin- and UFH-treated patients, respectively (OR 0.81, 95% CI 0.70-0.94, number need to treat 94). There was no significant difference in the incidence of death at 30 days in either population. A nonsignificant trend toward higher rates of major bleeding was seen at 7 days for enoxaparin-treated patients, in both the overall safety population and the population of patients who did not receive antithrombin treatment before randomization, but there was no difference in blood transfusions.In a systematic overview of six randomized, controlled trials comparing enoxaparin to UFH in the treatment of NSTE ACS in approximately 22,000 patients, the use of enoxaparin rather than UFH was associated with a modest reduction in the incidence of the composite of death and MI at 30 days without a significant increase in the rate of major bleeding or transfusion at 7 days.

    View details for DOI 10.1016/j.ahj.2005.02.021

    View details for Web of Science ID 000228754500003

    View details for PubMedID 16124953

  • Exploring the role of enoxaparin in the management of high-risk patients with non-ST-elevation acute coronary syndromes: The SYNERGY trial AMERICAN HEART JOURNAL Mahaffey, K. W., Ferguson, J. J. 2005; 149 (4): S81-S90

    Abstract

    In patients with non-ST-elevation acute coronary syndromes (NSTE ACS), enoxaparin has been shown to be superior to unfractionated heparin (UFH) and is associated with a reduction in ischemic end points with nonsignificant increases in bleeding. However, the critical trials comparing enoxaparin with UFH were conducted before the widespread use of early invasive management and the availability of clopidogrel and glycoprotein IIb/IIIa receptor antagonists.SYNERGY was an international, multicenter, randomized, open-label trial that compared enoxaparin with UFH in high-risk NSTE ACS patients managed with an early invasive strategy. For enrollment, 2 out of 3 high-risk features were required: age > or =60 years, elevated cardiac biomarkers, or ST-segment changes. The primary efficacy end point was death/myocardial infarction (MI) at 30 days. The primary safety end point was inhospital major bleeding or stroke through 30 days.The incidence of death/MI at 30 days was 14.0% in the enoxaparin group and 14.5% in the UFH group (hazard ratio 0.96, 95% CI 0.86-1.06), demonstrating noninferiority of enoxaparin relative to UFH. Enoxaparin was associated with a small but significant excess of Thrombolysis In Myocardial Infarction (TIMI) major bleeding, but there was no statistically significant increase in Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) severe bleeding or the rate of transfusion. There was no difference in complications of percutaneous coronary intervention. Interpretation of trial results was complicated by widespread use of enoxaparin or UFH before randomization, and by postrandomization crossover to the nonrandomized agent.In patients with NSTE ACS, including high-risk patients proceeding rapidly to catheterization, enoxaparin is an effective and safe alternative to UFH.

    View details for DOI 10.1016/j.ahj.2005.02.023

    View details for Web of Science ID 000228754500002

    View details for PubMedID 16124952

  • Prognostic usefulness of White Blood Cell count and temperature in acute myocardial infarction (from the CARDINAL Trial) AMERICAN JOURNAL OF CARDIOLOGY Patel, M. R., Mahaffey, K. W., Armstrong, P. W., Weaver, W. D., Tasissa, G., Hochman, J. S., Todaro, T. G., Malloy, K. J., Rollins, S., Theroux, P., Ruzyllo, W., Nicolau, J. C., Granger, C. B. 2005; 95 (5): 614-618

    Abstract

    White blood cell (WBC) count and temperature are 2 global measures of inflammation that are systematically gathered and easily identifiable in a clinical setting, unlike many other markers of inflammation being investigated in patients with coronary artery disease. The prognostic usefulness of the WBC count and temperature were evaluated in a large acute myocardial infarction trial, the Complement And ReDuction of INfarct size after Angioplasty or Lytics program. Baseline and serial measurements of WBC counts and temperature were correlated with infarct size and clinical outcome.

    View details for Web of Science ID 000227156400013

    View details for PubMedID 15721102

  • Platelet glycoprotein IIb/IIIa receptor antagonists in non-ST segment elevation acute coronary syndromes - A review and guide to patient selection DRUGS Atwater, B. D., Roe, M. T., Mahaffey, K. W. 2005; 65 (3): 313-324

    Abstract

    Platelet glycoprotein (Gp) IIb/IIIa receptor antagonists improve outcomes in patients with acute coronary syndromes without persistent ST-segment elevation, but relative effects depend on appropriate patient selection. Recent data from the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines) quality improvement initiative suggests that GpIIb/IIIa antagonists are underused in clinical practice. The relationship between GpIIb/IIIa inhibition and the magnitude of clinical benefit in the setting of acute coronary syndromes is complex. Several key factors should be considered for proper patient selection, including accurate patient risk stratification, incorporation of these agents with an early invasive management strategy and the concomitant use of other anti-thrombotic therapies. Current practice guidelines for the treatment of patients with non-ST-segment elevation acute coronary syndromes support the integration of an early invasive management with optimal pharmacological therapy, including GpIIb/IIIa antagonists.

    View details for Web of Science ID 000227006600002

    View details for PubMedID 15669877

  • Incidence and characteristics of stroke during 90-day follow-up in patients stabilized after an acute coronary syndrome AMERICAN HEART JOURNAL Kassem-Moussa, H., Mahaffey, K. W., Graffagnino, C., Tasissa, G., Sila, C. A., Simes, R. J., White, H. D., Califf, R. M., Bhapkar, M. V., Newby, L. K. 2004; 148 (3): 439-446

    Abstract

    Stroke is a rare but serious event that complicates the course of patients with acute coronary syndromes (ACS). The type, outcome, and risk factors of stroke occurring in stabilized patients with ACS have not been previously reported.We evaluated stroke incidence, subtypes, and outcomes, in addition to demographics and clinical risk characteristics associated with stroke among patients enrolled in the Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes (SYMPHONY) and 2nd SYMPHONY trials.Of 15,904 stabilized patients with ACS, 113 (0.71%) had a stroke over a median follow-up of 90 days. The majority of strokes occurred within 30 days of presentation, and the time course for stroke occurrence paralleled that of myocardial (re)infarction. Most strokes were ischemic (78%), and 52% resulted in moderate or severe disability or death. Patients with stroke were older and more often had hypertension, diabetes, peripheral vascular disease, and atrial fibrillation. Among patients with stroke who had cardiac catheterization, percutaneous coronary intervention, or coronary artery bypass grafting, stroke occurred predominantly after the procedure. No difference in occurrence or type of stroke was observed in the assigned treatment groups. In multivariable modeling age, heart failure, prior stroke, left bundle branch block, and systolic blood pressure predicted the occurrence of stroke.In patients stabilized after presenting with a spectrum of ACS and treated with sibrafiban and/or aspirin, stroke occurred in fewer than 1% within 90 days but carried a significant mortality and morbidity risk.

    View details for DOI 10.1016/j.ahj.2004.01.028

    View details for Web of Science ID 000224339600010

    View details for PubMedID 15389230

  • Coordinated series of studies to evaluate characteristics and mechanisms of acute coronary syndromes in high-risk patients randomly assigned to enoxaparin or unfractionated heparin: Design and rationale of the SYNERGY Library AMERICAN HEART JOURNAL Petersen, J. L., Mahaffey, K. W., Becker, R. C., Goodman, S. G., Kleiman, N. S., Marian, A. J., Stone, G. W., Lansky, A. J., Lincoff, A. M., Hazen, S. L., Nessel, C. C., Toro-Figueroa, L., Tate, L., Reist, C. J., Cohen, M., Califf, R. M., Ferguson, J. J. 2004; 148 (2): 269-276

    Abstract

    Clinical trials and accompanying substudies in patients with acute coronary syndromes (ACS) have over the last several years yielded a wealth of knowledge about the pathophysiology and management of this high-risk condition. The Superior Yield of the New strategy of Enoxaparin, Revascularization, and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is a large-scale, randomized, controlled trial evaluating the effect of enoxaparin and unfractionated heparin on death and myocardial infarction in high-risk patients presenting with non-ST-segment elevation ACS. The SYNERGY Library has been designed as a coordinated series of investigations with simultaneous data acquisition on the same cohort of approximately 500 SYNERGY patients at 60 centers in North America. Specifically, electrocardiograms, coronary arteriograms, inflammatory markers, coagulation studies, and genetic samples will be collected and processed at core laboratory facilities, and the results will be stored in a central repository. This novel strategy for substudy investigation is unprecedented in cardiovascular clinical trials. The goal is to gain significant understanding about this patient population, discover new principles of pathophysiology, identify novel pharmacologic targets, and streamline further drug development. It is hoped that the SYNERGY Library will serve as a model for future substudy design to maximize academic insight within the framework of a large-scale, multicenter trial.

    View details for DOI 10.1016/j.ahj.2004.03.022

    View details for Web of Science ID 000223494000013

    View details for PubMedID 15308996

  • Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes - A systematic overview JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Petersen, J. L., Mahaffey, K. W., Hasselblad, V., Antman, E. M., Cohen, M., Goodman, S. G., Langer, A., Blazing, M. A., Le-Moigne-Amrani, A., de Lemos, J. A., Nessel, C. C., Harrington, R. A., Ferguson, J. J., Braunwald, E., Califf, R. M. 2004; 292 (1): 89-96

    Abstract

    Antithrombin therapy has become a guidelines-recommended standard of care in the treatment of acute coronary syndromes (ACS), but recent trials comparing use of enoxaparin and unfractionated heparin in ACS have yielded less robust efficacy and safety results than have earlier trials of these antithrombin therapies.To systematically evaluate the end points of all-cause death and nonfatal myocardial infarction (MI), transfusion, and major bleeding observed in the 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in treatment of ACS.The primary data sets for ESSENCE, A to Z, and SYNERGY were available at the Duke Clinical Research Institute. Baseline characteristics and event frequencies for TIMI 11B, ACUTE II, and INTERACT were provided by the principal investigator of each study.All 6 randomized controlled trials comparing enoxaparin and unfractionated heparin in non-ST-segment elevation ACS were selected for analysis.Efficacy and safety end points were extracted from the overall trial populations and the subpopulation receiving no antithrombin therapy prior to randomization.Systematic evaluation of the outcomes for 21 946 patients was performed using a random-effects empirical Bayes model. No significant difference was found in death at 30 days for enoxaparin vs unfractionated heparin (3.0% vs 3.0%; odds ratio [OR], 1.00; 95% confidence interval [CI], 0.85-1.17). A statistically significant reduction in the combined end point of death or nonfatal MI at 30 days was observed for enoxaparin vs unfractionated heparin in the overall trial populations (10.1% vs 11.0%; OR, 0.91; 95% CI, 0.83-0.99; number needed to treat, 107). A statistically significant reduction in the combined end point of death or MI at 30 days was also observed for enoxaparin in the populations receiving no prerandomization antithrombin therapy (8.0% vs 9.4%; OR, 0.81; 95% CI, 0.70-0.94; number needed to treat, 72). No significant difference was found in blood transfusion (OR, 1.01; 95% CI, 0.89-1.14) or major bleeding (OR, 1.04; 95% CI, 0.83-1.30) at 7 days after randomization in the overall safety population or in the population of patients receiving no prerandomization antithrombin therapy.In a systematic overview of approximately 22 000 patients across the spectrum of ACS, enoxaparin is more effective than unfractionated heparin in preventing the combined end point of death or MI.

    View details for Web of Science ID 000222448100032

    View details for PubMedID 15238596

  • Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy - Primary results of the SYNERGY randomized trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Ferguson, J. J., Califf, R. M., Antman, E. M., Cohen, M., Grines, C. L., Goodman, S., Kereiakes, D. J., Langer, A., Mahaffey, K. W., Langer, A., Mahaffey, K. W., Nessel, C. C., Armstrong, P. W., Avezum, A., Aylward, P., Becker, R. C., Biasucci, L., Borzak, S., Col, J., Frey, M. J., Fry, E., Gulba, D. C., Guneri, S., Gurfinkel, E., Harrington, R., Hochman, J. S., Kleiman, N. S., Leon, M. B., Lopez-Sendon, J. L., Pepine, C. J., Ruzyllo, W., Steinhubl, S. R., Teirstein, P. S., Toro-Figueroa, L., White, H. 2004; 292 (1): 45-54

    Abstract

    Enoxaparin has demonstrated advantages over unfractionated heparin in low- to moderate-risk patients with non-ST-segment elevation acute coronary syndromes (ACS) treated with a conservative strategy.To compare the outcomes of patients treated with enoxaparin vs unfractionated heparin and to define the role of enoxaparin in patients with non-ST-segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach.The Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial was a prospective, randomized, open-label, multicenter, international trial conducted between August 2001 and December 2003. A total of 10 027 high-risk patients with non-ST-segment elevation ACS to be treated with an intended early invasive strategy were recruited.Subcutaneous enoxaparin (n = 4993) or intravenous unfractionated heparin (n = 4985) was to be administered immediately after enrollment and continued until the patient required no further anticoagulation, as judged by the treating physician.The primary efficacy outcome was the composite clinical end point of all-cause death or nonfatal myocardial infarction during the first 30 days after randomization. The primary safety outcome was major bleeding or stroke.The primary end point occurred in 14.0% (696/4993) of patients assigned to enoxaparin and 14.5% (722/4985) of patients assigned to unfractionated heparin (odds ratio [OR], 0.96; 95% confidence interval [CI], 0.86-1.06). No differences in ischemic events during percutaneous coronary intervention (PCI) were observed between enoxaparin and unfractionated heparin groups, respectively, including similar rates of abrupt closure (31/2321 [1.3%] vs 40/2364 [1.7%]), threatened abrupt closure (25/2321 [1.1%] vs 24/2363 [1.0%]), unsuccessful PCI (81/2281 [3.6%] vs 79/2328 [3.4%]), or emergency coronary artery bypass graft surgery (6/2323 [0.3%] vs 8/2363 [0.3%]). More bleeding was observed with enoxaparin, with a statistically significant increase in TIMI (Thrombolysis in Myocardial Infarction) major bleeding (9.1% vs 7.6%, P =.008) but nonsignificant excess in GUSTO (Global Utilization of Streptokinase and t-PA for Occluded Arteries) severe bleeding (2.7% vs 2.2%, P =.08) and transfusions (17.0% vs 16.0%, P =.16).Enoxaparin was not superior to unfractionated heparin but was noninferior for the treatment of high-risk patients with non-ST-segment elevation ACS. Enoxaparin is a safe and effective alternative to unfractionated heparin and the advantages of convenience should be balanced with the modest excess of major bleeding.

    View details for Web of Science ID 000222448100026

    View details for PubMedID 15238590

  • The evaluation and management of dyslipidemia and impaired glucose metabolism during acute coronary syndromes. Current cardiology reports Goyal, A., Petersen, J. L., Mahaffey, K. W. 2004; 6 (4): 300-307

    Abstract

    Dyslipidemia and hyperglycemia are common among patients presenting with acute coronary syndromes (ACS), and patients with ACS and metabolic disorders are at increased risk for worse outcomes. Although guidelines for the diagnosis and management of dyslipidemia, diabetes, and the metabolic syndrome have been published, these guidelines have not specifically focused on the ACS patient population. Recent observational registries and clinical trials have advanced the appreciation of these disorders in ACS populations and data from these studies support aggressive efforts to diagnose and treat dyslipidemia and hyperglycemia in patients admitted for ACS.

    View details for PubMedID 15182608

  • Risk factors for intracranial hemorrhage and nonhemorrhagic stroke after fibrinolytic therapy (from the GUSTO-I trial) AMERICAN JOURNAL OF CARDIOLOGY Kandzari, D. E., Granger, C. B., Simoons, M. L., White, H. D., Simes, J., Mahaffey, K. W., Gore, J., Weaver, W. D., Longstreth, W. T., Stebbins, A., Lee, K. L., Califf, R. M., Topol, E. J. 2004; 93 (4): 458-461

    Abstract

    Of 592 patients in the Global Utilization of Streptokinase and tPA for Occluded Arteries-I trial who had a stroke during initial hospitalization, the risk for intracranial hemorrhage was significantly greater in those with recent facial or head trauma (odds ratio 13.0, 95% confidence interval 3.4 to 85.5); dementia was additionally associated with an increased risk for intracranial hemorrhage (odds ratio 3.4, 95% confidence interval 1.2 to 10.2). Because facial or head trauma may greatly influence treatment decisions, this risk factor should be incorporated into models designed to estimate the risks and benefits of fibrinolytic therapy.

    View details for DOI 10.1016/j.amjcard.2003.10.043

    View details for Web of Science ID 000188968800016

    View details for PubMedID 14969623

  • Creatine kinase-MB elevation after percutaneous coronary intervention predicts adverse outcomes in patients with acute coronary syndromes EUROPEAN HEART JOURNAL Roe, M. T., Mahaffey, K. W., Kilaru, R., Alexander, J. H., Akkerhuis, K. M., Simoons, M. L., Harrington, R. A., Tardiff, B. E., Granger, C. B., Ohman, E. M., Moliterno, D. J., Lincoff, A. M., Armstrong, P. W., Van de Werf, F., Califf, R. M., Topol, E. J. 2004; 25 (4): 313-321

    Abstract

    To study the relationship between outcomes and peak creatine kinase (CK)-MB levels after percutaneous coronary intervention (PCI) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS).Peak CK-MB ratios (peak CK-MB level/upper limit of normal [ULN]) after PCI were analysed in 6164 patients with NSTE ACS from four randomized trials who underwent in-hospital PCI. We excluded 696 patients with elevated CK or CK-MB levels <24h before PCI; the primary analysis included 2384 of the remaining 5468 patients (43.6%) with CK-MB levels measured <==24h after PCI. The incidence of in-hospital heart failure (0.1%, 0.8%, 3.4%, 4.1%, and 6.1%; P<0.001), arrhythmias (0.8%, 1.9%, 6.9%, 4.1%, and 7.9%; P<0.001), cardiogenic shock (0.1%, 1.3%, 2.0%, 2.3%, and 2.6%; P=0.004), and mortality through 6 months (2.1%, 2.4%, 4.9%, 4.1%, and 5.7%, P=0.005) was increased with peak CK-MB ratios of 0-1, 1-3, 3-5, 5-10, and >10xULN, respectively. The continuous peak CK-MB ratio after PCI significantly predicted adjusted 6-month mortality (risk ratio, 1.06 per unit increase above ULN; 95% confidence interval, 1.01-1.11; P=0.017).Greater CK-MB elevation after PCI is independently associated with adverse outcomes in NSTE ACS. These results underscore the adverse implications of elevated CK-MB levels after PCI in this high-risk population.

    View details for DOI 10.1016/j.ehj.2003.12.009

    View details for Web of Science ID 000220194100007

    View details for PubMedID 14984920

  • Integrating antithrombin and antiplatelet therapies with early invasive management for non-ST-segment elevation acute coronary syndromes AMERICAN JOURNAL OF MEDICINE Rebeiz, A. G., Roe, M. T., Alexander, J. H., Mahaffey, K. W., Granger, C. B., Peterson, E. D., Califf, R. M., Harrington, R. A. 2004; 116 (2): 119-129

    Abstract

    Non-ST-segment elevation acute coronary syndromes are a dramatic manifestation of coronary artery disease. Multiple clinical trials have shown that early cardiac catheterization improves clinical outcomes in patients with non-ST-segment elevation acute coronary syndromes. Many antithrombotic agents effectively manage unstable coronary syndromes and serve as adjuncts to percutaneous coronary intervention. Yet, the growing number of pharmacologic agents makes early management of non-ST-segment elevation acute coronary syndromes increasingly complex. We review the current evidence regarding the optimal integration of early antithrombotic and antiplatelet therapies with early coronary angiography and subsequent revascularization.

    View details for DOI 10.1016/j.amjmed.2003.09.028

    View details for Web of Science ID 000188246900008

    View details for PubMedID 14715326

  • Prognostic importance of new small Q waves following non-ST-elevation acute coronary syndromes AMERICAN JOURNAL OF MEDICINE Alexander, J. H., Harrington, R. A., Bhapkar, M., Mahaffey, K. W., Lincoff, A. M., Ohman, E. M., Klootwijk, P., Pahlm, O., Henden, B., Deckers, J. W., Simoons, M. L., Califf, R. M., Wagner, G. S. 2003; 115 (8): 613-619

    Abstract

    To investigate the prognostic importance of new small Q waves following an acute coronary syndrome.We assessed 6-month mortality in 10501 patients with non-ST-elevation acute coronary syndromes who had survived 30 days and had both admission and 30-day electrocardiograms. Patients were stratified by whether they had no new Q waves (n = 9447), new 30- to 40-ms Q waves (n = 733), or new > or =40-ms Q waves (n = 321).Mortality was higher in patients with 30- to 40-ms Q waves than in those with no new Q waves (3.4% [25/733] vs. 2.4% [227/9447], P = 0.005), and even higher in those with > or =40-ms Q waves (5.3% [17/321], P = 0.002). After adjustment for baseline risk predictors, mortality remained higher in patients with new 30- to 40-ms Q waves (odds ratio [OR] = 1.30; 95% confidence interval [CI]: 0.85 to 1.98; P = 0.23) and those with new > or =40-ms Q waves (OR = 1.87; 95% CI: 1.13 to 3.09; P = 0.01).Patients with new small Q waves following a non-ST-elevation acute coronary syndrome are at increased risk of adverse outcomes. These small Q waves should be considered diagnostic of myocardial infarction. Further research should investigate whether even smaller QRS changes are prognostically important.

    View details for DOI 10.1016/j.amjmed.2003.08.007

    View details for Web of Science ID 000186883800003

    View details for PubMedID 14656613

  • Current perspectives on reperfusion therapy for acute ST-segment elevation myocardial infarction: integrating pharmacologic and mechanical reperfusion strategies AMERICAN HEART JOURNAL Waters, R. E., Mahaffey, K. W., Granger, C. B., Roe, M. T. 2003; 146 (6): 958-968

    Abstract

    The therapeutic approach to patients with acute ST-segment elevation myocardial infarction (STEMI) has advanced rapidly over the past decade. Intravenous fibrinolytic therapy remains the most common form of reperfusion therapy worldwide, since fibrinolytics are associated with a dramatic reduction in mortality rates. However, primary percutaneous coronary intervention (PCI) is associated with improved outcomes and less bleeding complications compared with fibrinolytic therapy, but it is not widely available. Adjunctive therapies with intracoronary stents, glycoprotein (GP) IIb/IIIa inhibitors, and more potent antithrombin agents have shown great promise for the initial treatment of STEMI and have stimulated further investigation of combined pharmacological/mechanical reperfusion strategies that may be synergistic. Although the optimal combination of fibrinolytics, antiplatelet agents, antithrombins, and mechanical reperfusion at hospitals with and without primary PCI facilities remains elusive, results from recent studies suggest that such a combined approach may facilitate transfer of patients with STEMI from a referral hospital to an invasive hospital for definitive primary PCI after administration of a potent pharmacologic regimen designed to enhance early infarct-related artery reperfusion. Thus, as the reperfusion era continues to evolve, the ideal treatment strategy for patients with STEMI is being redefined to integrate pharmacologic and mechanical approaches to reperfusion.

    View details for DOI 10.1016/S0002-8703(03)00439-3

    View details for Web of Science ID 000187080200009

    View details for PubMedID 14660986

  • Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both NEW ENGLAND JOURNAL OF MEDICINE Pfeffer, M. A., McMurray, J. J., Velazquez, E. J., Rouleau, J. L., Kober, L., Maggioni, A. P., Solomon, S. D., Swedberg, K., Van de Werf, F., White, H., Leimberger, J. D., Henis, M., Edwards, S., Zelenkofske, S., Sellers, M. A., Califf, R. M., Aylward, P., ARMSTRONG, P., Barvik, S., Belenkov, Y., Dalby, A., Diaz, R., Drexler, H., Ertl, G., Francis, G., Hampton, J., Harsanyi, A., Kvasnicka, J., Mareev, V., Marin-Neto, J., Murin, J., Myers, M., Nordlander, R., Opolski, G., Soler-Soler, J., Spac, J., Stefenelli, T., Sugrue, D., van Gilst, W., Varshavsky, S., Weaver, D., Zannad, F., Aguilar, D., Alvarez, A., Al-Taweel, M., Anavekar, N., Finn, P., Lopez-Jimenez, F., Mercier, R., Lewis, E., Massoom, S., Manes, C., Mirza, A., Sampson, U., Skali, H., Skali, N., Szummer, K., Tokmakova, M., Zornoff, L., Mahaffey, K., BOZEMAN, T., Doletski, R., Lail, R., Smith, M., Taylor, L., Thomas, B., Schulman, K., Radeva, J., Reed, S., Weinfurt, W., Leizorovicz, A., Boutitie, F., Cody, R., Dargie, H., HENNEKENS, C., Pocock, S., Guerrero, R. A., Albisu, J. P., Amuchastegui, M., Avila, E. M., Arrieta, C. A., BASTIANELLI, R., Becker, C., Bono, J., Bortman, G., Labarta, G. B., Caccavo, A., Caime, G. D., Castellanos, C. R., Castro, H., Covelli, G., CUNEO, C. A., Del Rio, A., Fernandez, A., Cid, G. F., Queirel, E. F., Fuselli, J. J., Garcia, M. A., Duran, R. G., Garrido, M., Gentile, A., Gorini, N. U., Grancelli, H., Hasbani, E., Hominal, M. A., Hrabar, A. D., Leiva, J. E., Lopez, R., Luciardi, H. L., Macin, S. M., Mariano, L., Marinesco, A., Martingano, R., Martino, G. D., Marzetti, E. M., Mezzina, V., Moreno, H. L., Muntaner, J., Nordaby, R., Nul, D., Orlandini, A. D., Pavich, M. A., POMPOSIELLO, J. C., Quijano, R. A., Rusculleda, M., RYBA, D., Sampo, E., Sanchez, J. A., SERRA, C. M., Sokn, F., Sosa, C. H., Liprandi, A. S., Trivi, M., Vallejos, F., Vico, M., Vita, N. A., Vogel, D., Volmaro, J. A., Arnolda, L., Aroney, G., Aylward, P., Bett, N., Carroll, P., Carroll, P., Cross, D., Fitzpatrick, D., Garrahy, P., Hill, A., Horowitz, J., HUNT, D., Ireland, M., Lane, G., Lefkovits, J., Leitch, J. W., Nelson, G., Rajappa, K., Rankin, J., Rees, D., Russell, A., Singh, B., Taylor, R., Thomson, A., Waites, J., Walsh, W., Eber, B., Krempler, F. W., Kuhn, P., Pichler, M., Roggla, G., Siostrzonek, P., Stefenelli, T., Tragl, K. H., BERGEZ, B., El Allaf, D., Smolders, W., Van Dorpe, A., VANDENBOSSCHE, J. P., Vanneste, L., Albuquerque, D., Ayoub, J., Bassan, R., Carvalho, A. C., Castro, L. R., Coelho, O., Costa, F. A., Esteves, J., Feitosa, G., Filho, J., Gun, C., Saraiva, J. K., Leaes, P., Maia, L., Marin-Neto, J. A., Marino, R., Mesquita, E., PIEGAS, L. S., Rabelo, A., Rassi, S., Rassi, A., Scherr, C., Spadaro, J., Vaz, R., Arnold, M., Bedard, J., Bernstein, V., BHESANIA, T., Bonafede, N., Brossoit, R., Burke, B., CASTAN, R., Charles, J., Cheung, M. T., Chua, G., Costi, P., Davies, R., Descoings, B., Desrochers, D., Dhingra, S., Dion, D., Duchesne, L., Dupuis, J., Dupuis, R., Ervin, F., Fowlis, R., Gendreau, R., Germain, C., Giannoccaro, P., Goode, E., Gossard, D., Gosselin, G., Goulet, G., Heath, J., Heath, V. A., Hess, A., Honos, G., Howlett, J., Huynh, T., Javier, J., Kincade, D., Klinke, W. P., Kouz, S., Kwok, K., LEE, R., Lenis, J., Lepage, S., Lubelsky, B., McKelvie, R., Minkovitz, J., Moe, G., Montigny, M., Nadeau, R., Nitkin, C., O'Kelly, B., PALAIC, M., Parker, J., Parker, T., Pesant, Y., Phaneuf, D., Pistawaka, K., Proulx, G., Roux, R., Rupka, D., Saulnier, D., Senaratne, M., Sestier, F., Sharma, N., St Hilaire, R., Stone, J., Strauss, H., Sussex, B., Talbot, P., Tremblay, B., Vizel, S., Warnica, J. W., Weigel, M., Wisenberg, G., Drazka, J., Filipovsky, J., Horky, K., Jansky, P., Kral, R., Kvasnicka, J., Martinek, A., Spinar, J., Svitil, P., Agner, E., ANDERSEN, H. K., Angelo-Nielsen, K., Asklund, M., Berning, J., BRONS, M., Buhl, J., Eliasen, P., Flogstad, T., Jensen, T., KLARLUND, K., Kober, L., Kristensen, K. S., Kroell, L., Larsen, J., Rasmussen, S. L., Madsen, H., Markenvard, J., Mortensen, B., Nielsen, H., Nielsen, I., Nielsen, T., Davidson, A. N., Nyvad, O., Ottesen, M., Pedersen, O. L., Rickers, H., Rokkedal, J., Scheibel, M., SEJERSEN, H., SORENSEN, E. V., SORENSEN, P. J., Stenteberg, S. E., Bareiss, P., Barraine, R., Battistella, P. D., Beaufils, P., Bonneau, A., Boulenc, J. M., Bouvier, J. M., Cheggour, S., Citron, B., Coisne, D., Delahaye, F., Ferriere, M., Fournier, C., Kahn, J. C., Koenig, A., Laperche, T., Loiselet, P., Luccioni, R., Martelet, M., MATINA, D., Ouakli, A., Parisot, M., Pavin, D., Quiret, J. C., Rifai, A., Tran-Thanh, X., Angermann, C. E., Bauriedel, G., Bethge, H., Borst, M., Braun, M., Drexler, H., Echternach, C., Engberding, R., Epping, J., Ertl, G., Figulla, H. R., Gaudron, P., Hambrecht, R., Hanrath, P., Hey, D., Jany, B., Karmann, W., Keller, H. J., Kohler, B., Kreider-Stempfle, H. U., Maisch, B., Matthes, T., Munzel, T., Nast, H. P., Nienaber, C., Nitsch, J., Pfeiffer, D., Pieske, B., Rommele, U., Rupp, W., Schatz, R., Schultheiss, H. P., Senges, J., Simon, R., Solzbach, U., Strasser, R. H., Tebbe, U., Topp, H., Unger, T., Urbaszek, W., von Knorre, G. H., von Olshausen, K., Wagner, J., Wirth, M., Wolf, M. W., Csanady, M., Edes, I., Erdei, A., Hanis, B., Harsanyi, A., Janosi, A., Kalo, E., Karpati, P., KOMIVES, S., KUTOR, G., Moser, G., Rumi, G., Simon, G., Szaboki, F., Tarjan, J., Timar, S., Toth, K., Barton, J. J., Crean, P., Daly, K., Fitzgerald, D., Kearney, P., Sugrue, D., Alboni, P., ALOISI, B., Antenucci, C., Bellet, C., Bernardi, D., Bini, A., Bortolini, F., Branzi, A., BUGATTI, U., Bugiardini, R., Capuano, V., Carrone, M., Celli, P., Chiesa, F., Ciconte, V., Corsini, G., De Angelis, G., Di Pasquale, G., Fanelli, R., Filorizzo, G., Fioretti, P., Grieco, A., Ignone, G., Mafrici, A., Maglia, G., Mangia, R., Maras, P., Masini, F., Mauric, A., Paci, A., Pettinati, G., Pirani, R., Rauhe, W., Sala, L., Sibilio, G., Slavich, G., Soravia, G., Tartarini, G., Tavazzi, L., Terrosu, P., Trevi, G., Trimarco, B., Turri, M., Turrini, P., Valagussa, F., Vassanelli, C., Volpe, M., Arnold, A. E., Bijl, M., De Milliano, P. A., Dunselman, P. H., Fels, P. W., Kupper, A. F., Herweijer, A. H., Jaarsma, W., Kamp, O., Koornstra, H. J., Kragten, J. A., Kuijer, P. J., Leenders, C. M., Liem, A. H., Linssen, G. C., LIONARONS, R. J., Lok, D. J., Louridtz, W. J., Michels, H. R., van de Moer, W. M., Nierop, P. R., Posma, J. L., van der Burgh, P. H., van Kalmthout, P. M., Van Kempen, L. H., van Veldhuisen, D. J., Wesdorp, J. C., Withagen, A. J., Abdul-Ghaffar, N., French, J., Friedlander, D., Gerber, I., Hamer, A., Hammet, C., Hedley, J., Ikram, H., Mann, S., Matsis, P., Rankin, R., Scott, D., White, H., Wilkins, G., Williams, M., Wong, C. K., Barvik, S., Dickstein, K., Hoeg, V., Banasiak, W., Demczuk, M., Dyduszynski, A., Goch, J. H., Gorny, J., Janion, M., Kawecka-Jaszcz, K., Kopaczewski, J., Loboz-Grudzien, K., Ogorek, M., Opolski, G., Piotrowski, W., Ruszkowski, P., Rynkiewicz, A., SCIBORSKI, R., Stopinski, M., Trusz-Gluza, M., Waszyrowski, T., Wojciechowski, D., Wrabec, K., Zambrzycki, J., ANANCHENKO, V., Arutyunov, G., Baluda, M., Barbarash, O., Belenkiy, D., Belousov, S., Belousov, Y. B., BOIARKIN, M., Bokarev, I., CHARCHOGLIAN, R. A., Chepky, D. A., Chumakova, G., Doschicyn, V., Dovgalevsky, P., Ermoshkina, L., FILONENKO, G. S., Fomin, I., Fomina, I., Foytanov, S., Freydlina, M., Glezer, M., Golikov, A., Goloshchekin, B., Gospodarenko, A., Gratsiansky, N., Ivanov, G., Katelnitskaya, L., Khrakovskaya, M., Khrustalev, O., Klenina, I., Kostenko, V., Kozlova, M., Lapin, O., Leontieva, N., Lopatin, Y. M., Lusov, V., Markov, V., Martioushov, S., Martynov, A., Mezentseva, N., Michailov, A., MKRTCHYAN, V. R., Moiseev, V., Nedogoda, S., Nefedov, A. V., Nefedov, M., Nikitin, Y., Olbinskaya, L., Perepech, N., Rebrov, A., Rogalev, K., Ruda, M., Shlyahto, E., Shmyrova, V., Shpector, A., Shustov, S., Shwartz, Y., Sidorenko, B., Simonenko, V., Sobolev, K., Sorokin, L., Stefanenko, M., Stepura, O., Striouk, R., Sulimov, V., Sumin, A., Syrkin, A., Tankhilevitch, B., Tarasov, N., Tchutchalin, A., Troshina, E., Tuev, A. V., Vaniev, S., Vertkin, A., Vishnevsky, A., Yacushin, S., Yarokhno, N., Zadiontchenko, V., ZBOROVSKY, A., Zemtsovsky, E., Zverev, D., Brunclik, P., Duris, T., Hasilla, J., Kohn, R., Kovar, F., Murin, J., Renker, B., Rybar, R., Slanina, M., Uhliar, R., BENNET, J. M., Dalby, A. J., Duncan, D. I., Essop, M. R., Kok, A., Manga, P., Posen, B. M., ROOS, J. S., SNYDERS, F. A., Steingo, L., Ruiz, A. B., Fernandez, J. B., Fernandez, J. M., Basilio, E. G., Diaz, M. D., Minguell, E. R., CUSI, L. S., Tudela, V. V., Rami, J. A., Ahremark, U., Astrom, L., Boman, K., Brunmark, P., Dahlstrom, U., Fredholm, O., FRISELL, J. E., HARDHAMMAR, P., Hartford, M., HURTIG, U., Jonasson, L., Klintberg, L., Larsson, L. E., Nicol, P., Nilsson, O., NILSSON, S. B., Ohlin, H., Ohlsson, A., Perk, J., Perrson, H., Peterson, M., Rasmanis, G., Ringquist, C., Stenberg, A., Swedberg, K., Ticic, D., Timberg, I., Bugge, K. W., Wodlin, P., Adgey, J., Al-Khoffash, M., Andrews, R., Avery, P., Ball, S., Baxter, R., Been, M., Birkhead, J., Bridges, A., Broadhurst, P., ANSON, R. C., Cleland, J., Clifford, P., CONNELLY, D., Crake, T., DAVIES, J., Davies, M., Dhawan, J., Dunn, F., Findlay, I., Hampton, J., Hanley, S., Higham, P., Jacob, A., Jones, C., Kaski, J., Lip, G., MacFadyen, R., Mattu, R., McAlpine, H., McMurray, J., Metcalfe, M., Moriarty, A., Morley, C., Murdoch, D., MUSHAHWAR, S., Penny, W., Pitcher, D., Puri, S., Purvis, J., Ramsey, M., Reid, C., Richardson, G., Rowlands, D., Saltissi, S., Senior, R., Shahi, J., Smith, L., Spyrou, N., Squire, I., Stephens, J., Swan, J., Travill, C., Uren, N., Vincent, R., Wheeldon, N., ACHEATEL, R., Ackell, P., ADLER, D., Akosah, K., Amidi, M., AMSTERDAM, P., Anand, I., Anderson, J., Aranda, J., Ashar, R., Ayala, K., Badger, R., Balk, M., Bannon, P., BASNIGHT, M., Battles, V., Bayron, C., Becker, J., Belkin, R., Bellamy, B., Bellinger, R., Bengtson, J., Bennett, S., Bhalodkar, N., Bhat, G., BIRKHEAD, R., Bittl, J., Boland, M., Book, W., Brachfeld, C., Broderick, G., Brodsky, M., Brown, C., Bruns, D., Butler, J., Calnon, D., Calvin, J., Camacho, A., Cambier, P., Camp, A., Campbell, P., Cannon, J. D., Cansino, S., Carlson, R., Carr, K., Casale, P., Chadow, H., Chalasani, P., Chandna, H., Chapman, D., Charlton, G., Cheirif, J., Childs, D., Chin, J., Chu, A., Churchill, D., Clark, L., Cobb, F., Colfer, H., Corder, C., Croitoru, M., Cullinane, D., Cunningham, M., Dauber, I., Davis, T., Dawley, D., Deedwania, P., Delemos, J., DeLeon, A., Dennish, G., Denny, D. M., Desai, S., D'Haem, C., Dhruva, N., Dionisopoulos, P., Dixon, E., Dodin, E., Dohad, S., Dowdy, D., Drury, J., Duvernoy, C., Edin, A., Edwards, T., Eelani, F., El Shahawy, M., Ellestad, M., ENSLEY, R. D., Fahey, F., Farahi, J., Farnham, J., Fattal, P., Fernandez, J., Fialkow, J., Figueredo, V., Fintel, D., Fishbein, G., Fishberg, R., Fisher, B., Fitzpatrick, P., Flaker, G., Foster, M., French, W., Frey, M., Friedman, B., Furiasse, J., George, J., Ghali, J., Gilbert, J., Giles, P., Glassman, J., Gleva, M., Glynn, R., Goldman, S., Goldner, D., Goodfield, P., GORDON, D., Gottdeiner, J., GOULAH, R., Grady, T., Graf, R., Graham, B., Graziano, J., Gredler, F., Greenberg, D., Greenspan, M., Gros, B., Hall, J., HANLEY, H., Harris, B., Harris, K., Hartman, C., Hashimi, M. W., Hassett, A., Haught, W. H., Hill, D., HILLERT, M., Hochman, J., HODSDEN, J., Hoffmann, R., HONAN, M., Hsi, D., Hudson, M., INGERSOLL, H., Israel, N., Jackman, D., Jackson, B., Jafri, S., Jain, A., Jamal, N., Jenkins, L., Jennison, S., Jones, M., Joseph, J., Josephson, R., KANNAM, J., Karamali, A., Karns, R., Katz, W., Kereiakes, D., Kerut, E. K., Kesselbrenner, M., Kieval, J., KING, J., Kipperman, R., Kizilbash, A., Klancke, K., Klein, M., Kmonicek, J., Kosolcharoen, P., Kowalski, B., Kraemer, M., KREISMAN, K., Kwan, M., Lafoe, W., Lai, P., LAKOW, M., Lamas, G., Lancaster, L., Langager, J., Larsen, G., Lash, J., Lauer, M., Laufer, N., Laughrun, D., Lee, C. 2003; 349 (20): 1893-1906

    Abstract

    Angiotensin-converting-enzyme (ACE) inhibitors such as captopril reduce mortality and cardiovascular morbidity among patients with myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both. In a double-blind trial, we compared the effect of the angiotensin-receptor blocker valsartan, the ACE inhibitor captopril, and the combination of the two on mortality in this population of patients.Patients receiving conventional therapy were randomly assigned, 0.5 to 10 days after acute myocardial infarction, to additional therapy with valsartan (4909 patients), valsartan plus captopril (4885 patients), or captopril (4909 patients). The primary end point was death from any cause.During a median follow-up of 24.7 months, 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group (hazard ratio in the valsartan group as compared with the captopril group, 1.00; 97.5 percent confidence interval, 0.90 to 1.11; P=0.98; hazard ratio in the valsartan-and-captopril group as compared with the captopril group, 0.98; 97.5 percent confidence interval, 0.89 to 1.09; P=0.73). The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P<0.001). The valsartan-and-captopril group had the most drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group.Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival.

    View details for Web of Science ID 000186502400004

    View details for PubMedID 14610160

  • The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results. journal of invasive cardiology Mahaffey, K. W., Lewis, B. E., Wildermann, N. M., Berkowitz, S. D., Oliverio, R. M., Turco, M. A., Shalev, Y., Ver Lee, P., Traverse, J. H., Rodriguez, A. R., Ohman, E. M., Harrington, R. A., Califf, R. M. 2003; 15 (11): 611-616

    Abstract

    Up to 5% of patients given heparin develop heparin-induced thrombocytopenia (HIT). These patients may need anticoagulation for acute coronary syndromes (ACS) or percutaneous coronary intervention (PCI), a clinical challenge given the limited alternatives. In a prospective, open-label study, we evaluated the safety and efficacy of bivalirudin in patients with HIT or HIT with thrombotic syndrome (HITTS) undergoing PCI. Patients aged 18 years were enrolled in 24 centers in 2 countries. Bivalirudin was given 5 minutes before PCI (1 mg/kg bolus; 2.5 mg/kg/hour infusion for 4 hours [high-dose group] or 0.75 mg/kg bolus; 1.75 mg/kg/hour infusion [low-dose group]). Clinical and hematological measures were assessed within 24 hours after starting bivalirudin, just before PCI, just before sheath removal, and 48 hours after treatment or at discharge, whichever occurred first. The primary endpoint was major bleeding 48 hours after discontinuation or until discharge, whichever occurred first. From July 1999 to February 2003, 52 patients were recruited. Procedural success (TIMI grade 3 flow and < 50% stenosis) was achieved in 98% of patients, and clinical success (absence of death, emergency bypass surgery, or Q-wave infarction) was achieved in 96%. One high-dose patient who underwent elective bypass surgery had major bleeding (1.9%; 95% CI: 0.05 10.65%), and 7 patients had minor bleeding. No patient had significant thrombocytopenia (platelet count < 50 109/L) after treatment. One patient in the low-dose group died from cardiac arrest ~46 hours after uncomplicated PCI. Bivalirudin appeared safe and provided effective anticoagulation during PCI. These data, and extensive experience with bivalirudin in PCI, support its use in high-risk patients with HIT requiring PCI.

    View details for PubMedID 14608128

  • Effect of pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to fibrinolysis in acute myocardial infarction - The COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) trial CIRCULATION Mahaffey, K. W., Granger, C. B., Nicolau, J. C., Ruzyllo, W., Weaver, W. D., Theroux, P., Hochman, J. S., Filloon, T. G., Mojcik, C. F., Todaro, T. G., Armstrong, P. W. 2003; 108 (10): 1176-1183

    Abstract

    Complement activation mediates myocardial damage that occurs during ischemia and reperfusion through multiple pathways. We performed 2 separate, parallel, double-blind, placebo-controlled trials to determine the effects of pexelizumab (a novel C5 complement monoclonal antibody fragment) on infarct size in patients receiving reperfusion therapy: COMPlement inhibition in myocardial infarction treated with thromboLYtics (COMPLY) and COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA). The COMPLY trial is reported here.Overall, 943 patients with acute ST-segment elevation myocardial infarction (MI) (20% with isolated inferior MI) receiving fibrinolysis were randomly assigned <6 hours after symptom onset to placebo, pexelizumab 2.0-mg/kg bolus, or pexelizumab 2.0-mg/kg bolus plus 0.05 mg/kg per h for 20 hours. Infarct size determined by creatine kinase-MB area under the curve was the primary analysis, which included patients who received at least some study drug and fibrinolysis (n=920). The median infarct size did not differ by treatment (placebo, 5230; bolus, 4952; bolus plus infusion, 5557 [ng/mL] x h; bolus versus placebo, P=0.85; bolus plus infusion versus placebo, P=0.81), nor did the 90-day composite incidence of death, new or worsening congestive heart failure, shock, or stroke (placebo, 18.6%; bolus, 18.4%; bolus plus infusion, 19.7%). Pexelizumab inhibited complement for 4 hours with bolus-only dosing and for 20 to 24 hours with bolus-plus-infusion dosing, with no increase in infections.When used adjunctively with fibrinolysis, pexelizumab blocked complement activity but reduced neither infarct size by creatine kinase-MB assessment nor adverse clinical outcomes.

    View details for DOI 10.1161/01.CIR.0000087404.53661.F8

    View details for Web of Science ID 000185187800004

    View details for PubMedID 12925455

  • Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction - The COMplement inhibition in myocardial infarction treated with angioplasty (COMMA) trial CIRCULATION Granger, C. B., Mahaffey, K. W., Weaver, W. D., Theroux, P., Hochman, J. S., Filloon, T. G., Rollins, S., Todaro, T. G., Nicolau, J. C., Ruzyllo, W., Armstrong, P. W. 2003; 108 (10): 1184-1190

    Abstract

    Complement, activated during myocardial ischemia and reperfusion, causes myocardial damage through multiple processes. The COMplement inhibition in Myocardial infarction treated with Angioplasty (COMMA) trial was performed to determine the effect of pexelizumab, a C5 complement inhibitor, on infarct size in patients with ST-segment-elevation myocardial infarction (MI) undergoing primary percutaneous coronary intervention.In COMMA, 960 patients with MI (20% isolated inferior MI) were randomized to placebo, pexelizumab 2.0-mg/kg bolus, or pexelizumab 2.0-mg/kg bolus and 0.05-mg/kg per h infusion for 20 hours. Infarct size by creatine kinase-MB area under the curve, the primary outcome, did not differ significantly between groups (placebo median, 4393; bolus pexelizumab, 4526; bolus plus infusion pexelizumab, 4713 [ng/mL] x h; P=0.89 for bolus versus placebo; P=0.76 for bolus plus infusion versus placebo), nor did the composite of 90-day death, new or worsening heart failure, shock, or stroke (placebo, 11.1%; bolus, 10.7%; bolus plus infusion, 8.5%). The ninety-day mortality rate was significantly lower with pexelizumab bolus plus infusion (1.8% versus 5.9% with placebo; nominal P=0.014); the bolus-only group had an intermediate mortality rate (4.2%).In patients with ST-elevation MI undergoing percutaneous coronary intervention, pexelizumab had no measurable effect on infarct size. However, the significant reduction in mortality suggests that pexelizumab may benefit patients through alternative novel mechanisms and provides impetus for additional investigation.

    View details for DOI 10.1161/01.CIR.0000087447.12918.85

    View details for Web of Science ID 000185187800005

    View details for PubMedID 12925454

  • Does the discharge ECG provide additional prognostic insight(s) in non-ST elevation ACS patients from that acquired on admission? European heart journal HERSI, A., Fu, Y., Wong, B., Mahaffey, K. W., Harrington, R. A., Califf, R. M., Van de Werf, F., Armstrong, P. W. 2003; 24 (6): 522-531

    Abstract

    Although the prognostic value of admission ST changes in patients with non-ST elevation acute coronary syndrome (ACS) is established, the utility of the discharge ECG is unknown. Accordingly, using the PARAGON-B Troponin substudy, we assessed the prevalence of ST depression on both admission and discharge ECG, the likelihood of developing new Q-waves at discharge and the additional prognostic value of these changes.Nine hundred and eighteen patients were studied; 542 patients (59%) had admission ST downward arrow > or =1mm and 376 patients (41%) did not and their 6-month mortality was 4.4 vs 0.8%, P=0.002, respectively. Of patients with ST downward arrow on admission, 320 (59%) normalized their ST segment at discharge. Of patients without ST downward arrow on admission, 35 (9.3%) developed new ST downward arrow at discharge. Patients with persistent ST downward arrow on discharge had a higher 6-month mortality (6.0 vs 0.9%), (re)MI (16.3 vs 7.4%), and death/(re)MI (20.0 vs 8.3%) than those who never had ST downward arrow (all P< or =0.002). Two hundred and fifty-six patients had Q-waves on admission whereas by discharge 320 had Q-waves. Patients with Q-waves on discharge vs those without had a higher mortality (4.8 vs 1.9%), (re)MI (13.8 vs 8.3%), and death/(re)MI (16.4 vs 9.6%) at 6 months (all P< or =0.021).This study highlights that the dynamic ECG changes which occur between admission and discharge in non-ST elevation ACS patients allows further risk stratification in determining the likelihood of 6-month death and/or re(MI).

    View details for PubMedID 12643885

  • Does the discharge ECG provide additional prognostic insight(s) in non-ST elevation ACS patients from that acquired on admission? EUROPEAN HEART JOURNAL HERSI, A., Fu, Y., Wong, B., Mahaffey, K. W., Harrington, R. A., Califf, R. M., Van de Werf, F., Armstrong, P. W. 2003; 24 (6): 524-533
  • Troponin T and quantitative ST-segment depression offer complementary prognostic information in the risk stratification of acute coronary syndrome patients JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kaul, P., Newby, L. K., Fu, Y. L., Hasselblad, V., Mahaffey, K. W., Christenson, R. H., Harrington, R. A., Ohman, E. M., Topol, E. J., Califf, R. M., Van de Werf, F., Armstrong, P. W. 2003; 41 (3): 371-380

    Abstract

    Our primary objective was to examine the prognostic relationship between baseline quantitative ST-segment depression (ST) and cardiac troponin T (cTnT) elevation. The secondary objectives were to: 1) examine whether ST provided additional insight into therapeutic efficacy of glycoprotein IIb/IIIa therapy similar to that demonstrated by cTnT; and 2) explore whether the time to evaluation impacted on each marker's relative prognostic utility.The relationship between the baseline electrocardiogram (ECG) and cTnT measurements in risk-stratifying patients presenting with acute coronary syndromes (ACS) has not been evaluated comprehensively.The study population consisted of 959 patients enrolled in the cTnT substudy of the Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON)-B trial. Patients were classified as having no ST (n = 387), 1 mm ST (n = 433), and ST > or =2 mm (n = 139). Forty-percent (n = 381) were classified as cTnT-positive based on a definition of > or =0.1 ng/ml.Six-month death/(re)myocardial infarction rates were 8.4% among cTnT-negative patients with no ST and 26.8% among cTnT-positive patients with ST > or =2 mm. On ECGs done after 6 h of symptom onset, ST > or =2 mm was associated with higher risk compared to its presence on ECGs done earlier (odds ratio [OR] 7.3 vs. 2.1). In contrast, the presence of elevated cTnT within 6 h of symptom was associated with a higher risk of adverse events compared with elevations after 6 h (OR 2.4 vs. 1.5).Quantitative ST and cTnT status are complementary in assessing risk among ACS patients and both should be employed to determine prognosis and assist in medical decision making.

    View details for DOI 10.1016/S0735-1097(02)02824-3

    View details for Web of Science ID 000180759800003

    View details for PubMedID 12575962

  • Evaluation of a novel point-of-care enoxaparin monitor with central laboratory anti-Xa levels THROMBOSIS RESEARCH Saw, J., Kereiakes, D. J., Mahaffey, K. W., Applegate, R. J., Braden, G. A., Brent, B. N., Brodie, B. R., Groce, J. B., Levine, G. N., Leya, F., Moliterno, D. J. 2003; 112 (5-6): 301-306

    Abstract

    Measurement of enoxaparin's anticoagulant activity has been limited to specialized coagulation laboratories and has been impractical for areas needing rapid results, such as during coronary angioplasty. A new point-of-care device, Rapidpoint ENOX, was recently developed to measure clotting times with enoxaparin use.To correlate ENOX times with anti-Xa levels among patients receiving enoxaparin.A total of 166 patients receiving enoxaparin for the prevention of deep venous thrombosis or as treatment during acute coronary syndromes or angioplasty were prospectively studied. Citrated and non-citrated whole-blood (CWB and NCWB) samples were obtained at baseline and peak enoxaparin activity. ENOX times were measured with whole-blood, and the Stachrom anti-Xa assay was performed on the plasma from the remainder of the samples. The Pearson correlation coefficient was used to assess the relationship between these two assays.There was a strong linear correlation between the ENOX times and the anti-Xa activities for both CWB (r=0.89, p<0.001) and NCWB (r=0.82, p<0.001) when considering all 332 samples (baseline and peak). When baseline samples were excluded, the correlation remained strong for CWB ENOX times and anti-Xa levels (r=0.84, p<0.001), but was only moderate for NCWB (r=0.73, p<0.001). A CWB ENOX time of /=200 s corresponded to anti-Xa levels >/=0.8 IU/ml in 96% (93/96) of patients.Rapidpoint ENOX times correlate strongly to anti-Xa activities measured by the Stachrom Heparin Assays for citrated whole-blood samples. This novel test can be used for rapid bedside measurements of enoxaparin anticoagulant activity.

    View details for DOI 10.1016/j.thromres.2004.01.006

    View details for Web of Science ID 000220595700008

    View details for PubMedID 15041274

  • Promise of combined low-molecular-weight heparin and platelet glycoprotein IIb/IIIa inhibition: Results from platelet IIb/IIIa antagonist for the reduction of Acute Coronary Syndrome Events in a Global Organization Network B (PARAGON b) AMERICAN HEART JOURNAL Mukherjee, D., Mahaffey, K. W., Moliterno, D. J., Harrington, R. A., Yadav, J. S., Pieper, K. S., Gallup, D., Dyke, C., Roe, M. T., Berdan, L., Lauer, M. S., MANTTARI, M., White, H. D., Califf, R. M., Topol, E. J. 2002; 144 (6): 995-1002

    Abstract

    Low-molecular-weight heparin (LMWH) has a more predictable anticoagulant effect than unfractionated heparin (UFH), is easier to administer, and does not require monitoring. Minimal data are available on LMWH combined with platelet glycoprotein (GP) IIb/IIIa inhibitors.In the Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network B (PARAGON B) trial, patients with an acute coronary syndrome were randomized to receive the IIb/IIIa inhibitor lamifiban or a placebo. To rigorously explore the potential benefits of LWMH and GP IIb/IIIa inhibition, we analyzed the rates of ischemic complications and safety outcomes in PARAGON B.Approximately one fifth of the patients received LMWH (805 vs 4395 UFH). For the overall cohort, the incidence of death/myocardial infarction (MI)/severe recurrent ischemia (SRI) was 12.2%, and this composite end point was numerically lowest in the lamifiban with LMWH group (10.2%). Similarly, the incidence of death/MI was 11.0% for the entire cohort and lowest in the lamifiban and LMWH group (9.0%). The lower event rate for patients taking LMWH in the lamifiban group was sustained at 6 months, with a lower revascularization rate (51.5% vs 42.8%) and a lower composite of death/MI (13.8% vs 11.9%). Bleeding was comparable in the 2 heparin groups (1.4% with UFH vs 0.9% with LMWH). The propensity adjusted odds ratio for 30-day revascularization was significantly lower with LMWH (odds ratio 0.67, 95% CI 0.57-0.79, P <.001). There were no significant differences in death/MI/SRI at 30 days (P =.465), death/MI at 30 days (P =.264), and stroke at 30 days with the type of heparin use (P =.201) after propensity risk adjustment.In the PARAGON B trial, use of LMWH in conjunction with a GP IIb/IIIa inhibitor was safe and associated with a lower revascularization rate. These findings support the rationale and promise for combining GP IIb/IIIa blockers and LMWH for future management of acute coronary syndrome.

    View details for DOI 10.1067/mhj.2002.126118

    View details for Web of Science ID 000180186200008

    View details for PubMedID 12486423

  • Troponin T levels in patients with acute coronary syndromes, with or without renal dysfunction NEW ENGLAND JOURNAL OF MEDICINE Aviles, R. J., Askari, A. T., Lindahl, B., Wallentin, L., Jia, G., Ohman, E. M., Mahaffey, K. W., Newby, L. K., Califf, R. M., Simoons, M. L., Topol, E. J., Lauer, M. S., Berger, P. 2002; 346 (26): 2047-2052

    Abstract

    Among patients with suspected acute coronary syndromes, cardiac troponin T levels have prognostic value. However, there is concern that renal dysfunction may impair the prognostic value, because cardiac troponin T may be cleared by the kidney.We analyzed the outcomes in 7033 patients enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries IV trial who had complete base-line data on troponin T levels and creatinine clearance rates. The troponin T level was considered abnormal if it was 0.1 ng per milliliter or higher, and creatinine clearance was assessed in quartiles. The primary end point was a composite of death or myocardial infarction within 30 days.Death or myocardial infarction occurred in 581 patients. Among patients with a creatinine clearance above the 25th percentile value of 58.4 ml per minute, an abnormally elevated troponin T level was predictive of an increased risk of myocardial infarction or death (7 percent vs. 5 percent; adjusted odds ratio, 1.7; 95 percent confidence interval, 1.3 to 2.2; P<0.001). Among patients with a creatinine clearance in the lowest quartile, an elevated troponin T level was similarly predictive of increased risk (20 percent vs. 9 percent; adjusted odds ratio, 2.5; 95 percent confidence interval, 1.8 to 3.3; P<0.001). When the creatinine clearance rate was considered as a continuous variable and age, sex, ST-segment depression, heart failure, previous revascularization, diabetes mellitus, and other confounders had been accounted for, elevation of the troponin T level was independently predictive of risk across the entire spectrum of renal function.Cardiac troponin T levels predict short-term prognosis in patients with acute coronary syndromes regardless of their level of creatinine clearance.

    View details for Web of Science ID 000176411900005

    View details for PubMedID 12087140

  • The SYNERGY trial: Study design and rationale AMERICAN HEART JOURNAL Ferguson, J. J., Califf, R. M., Antman, E. M., Cohen, M., Grines, C. L., Kereiakes, D. J., Langer, A., Mahaffey, K. W., Nessel, C. C., Rios-Nogales, L. 2002; 143 (6): 952-960

    Abstract

    Enoxaparin was shown to be superior to unfractionated heparin in the patients with non-ST-segment elevation acute coronary syndromes (ACS) in the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events study and the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. However, enoxaparin has had limited acceptance in clinical practice, in part because of the contemporary management of these patients, which includes glycoprotein IIb/IIIa inhibition and the use of early invasive management strategies.The Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial is an 8000-patient, prospective, randomized, open-label, multicenter investigation of enoxaparin compared with unfractionated heparin in patients at high risk with non-ST-segment elevation ACS treated with an early invasive strategy. The primary efficacy end point is death or nonfatal myocardial infarction 30 days after enrollment.The SYNERGY trial is the largest study currently planned for the acute therapy of patients with non-ST-segment elevation ACS and the first large trial since the publication of the revised American College of Cardiology/American Heart Association guidelines for the management of these patients. In addition to evaluating the potential superiority of enoxaparin over unfractionated heparin, this investigation will provide important observations of current treatment strategies in patients with ACS.

    View details for DOI 10.1067/mhj.2002.122120

    View details for Web of Science ID 000176525400008

    View details for PubMedID 12075248

  • Safety and efficacy of only 2 weeks of ticlopidine therapy in patients at increased risk of coronary stent thrombosis: Results from the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial AMERICAN HEART JOURNAL Berger, P. B., Mahaffey, K. W., Meier, S. J., Buller, C. E., Batchelor, W., Fry, E. T., Zidar, J. P. 2002; 143 (5): 841-846

    Abstract

    Controversy exists regarding the frequency of late stent thrombosis among patients treated with intracoronary stents and the most appropriate duration of treatment with a thienopyridine that is required to prevent this complication.We analyzed the frequency of stent thrombosis and other ischemic events in the Antiplatelet Therapy alone versus Lovenox plus Antiplatelet therapy in patients at increased risk of Stent Thrombosis (ATLAST) trial. In the ATLAST trial, 1102 patients at increased risk of stent thrombosis (ST-elevation myocardial infarction within 48 hours, diffuse distal disease, a large amount of thrombus, acute closure, residual dissection, etc) were randomly assigned to receive either enoxaparin (40 or 60 mg given every 12 hours for 14 days) or placebo; all patients received aspirin (325 mg daily) and ticlopidine (250 mg twice daily) for only 14 days.The primary end point, the 30-day combined incidence of death, nonfatal myocardial infarction, and urgent revascularization, was reached in 2.3% of patients (1.8% of patients taking enoxaparin vs 2.7% of patients taking placebo; P =.295). However, during the 15th through 30th days, the frequency of ischemic events was only 0.73%, and only 0.27% (3/1102) of patients had possible stent thrombosis (95% CI 0.06, 0.77).The frequency of stent thrombosis and other adverse ischemic events in the 15th through 30th days after stent placement in even high-risk stent patients treated with ticlopidine for only 2 weeks is low whether or not enoxaparin is administered.

    View details for DOI 10.1067/mhj.2002.121929

    View details for Web of Science ID 000176063800015

    View details for PubMedID 12040346

  • Experience with glycoprotein IIb/IIIa antagonists in patients with acute coronary syndromes. Journal of interventional cardiology Kandzari, D. E., Mahaffey, K. W. 2002; 15 (2): 121-129

    View details for PubMedID 12063807

  • Misreporting of myocardial infarction end points: Results of adjudication by a central clinical events committee in the PARAGON-B trial AMERICAN HEART JOURNAL Mahaffey, K. W., Roe, M. T., Dyke, C. K., Newby, L. K., Kleiman, N. S., Connolly, P., Berdan, L. G., Sparapani, R., Lee, K. L., Armstrong, P. W., Topol, E. J., Califf, R. M., Harrington, R. A. 2002; 143 (2): 242-248
  • Misreporting of myocardial infarction end points: results of adjudication by a central clinical events committee in the PARAGON-B trial. Second Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network Trial. American heart journal Mahaffey, K. W., Roe, M. T., Dyke, C. K., Newby, L. K., Kleiman, N. S., Connolly, P., Berdan, L. G., Sparapani, R., Lee, K. L., Armstrong, P. W., Topol, E. J., Califf, R. M., Harrington, R. A. 2002; 143 (2): 242-248

    Abstract

    Myocardial (re)infarction (MI), a common trial end point, can be difficult to identify because of inconclusive signs and symptoms. We examined disagreement between investigator and clinical events committee (CEC) reporting of MIs in an international, randomized trial.The primary end point of the PARAGON-B trial was a 30-day composite of death, MI (CEC adjudicated), or ischemia-driven intervention. If CEC and investigator determinations of MI differed, we sent investigators event summaries and rationales for CEC decisions and asked whether they now agreed with the CEC assessment. If they still disagreed, they were to provide a rationale and supporting data. Such cases were reviewed, and a final decision was made.Overall, 1736 of 5225 (33%) patients had suspected MIs; the CEC adjudicated 483 of 1736 (28%) as MIs. In 404 patients (23%), investigator and CEC assessments of MI differed; 270 MIs were identified by the CEC but not investigators, and 134 were identified by investigators but not the CEC. Most disagreements concerned periprocedural MIs, but some reflected clinical ischemia and enzyme elevations. Letters for 382 disagreements were sent and returned by investigators, and investigators came to agree with CEC assessments in 307 cases (80%). For the other 75 cases (20%), after review the investigators' assessments were confirmed in 10 cases, and the original CEC decisions were supported in the other 65 cases.Investigators misreport MI end points, but most later agree with CEC assessments. These data support standard, independent adjudication of suspected MIs for accurate reporting, which may affect evaluations of therapies, sample-size calculations, and event-rate comparisons across trials.

    View details for PubMedID 11835026

  • Grade III ischemia on presentation with acute myocardial infarction predicts rapid progression of necrosis and less myocardial salvage with thrombolysis CARDIOLOGY Birnbaum, Y., Mahaffey, K. W., Criger, D. A., Gates, K. B., Barbash, G. I., Barbagelata, A., Clemmensen, P., Sgarbossa, E. B., Gibbons, R. J., Rahman, M. A., Califf, R. M., Granger, C. B., Wagner, G. S. 2002; 97 (3): 166-174

    Abstract

    We assessed the relation between baseline electrocardiographic ischemia grades and initial myocardial area at risk (AR) and final infarct size (IS) in 49 patients who had undergone (99m)Tc sestamibi single-photon emission computed tomography before and 6 +/- 1 days after thrombolysis. Patients were classed as having grade III ischemia (ST segment elevation with terminal QRS distortion, n = 19) or grade II ischemia (ST elevation but no terminal QRS distortion, n = 30). We compared AR and IS by baseline ischemia grade and treatment (adenosine vs. placebo) and assessed relations of infarction index (IS/AR ratio x100) to time to thrombolysis, baseline ischemia grade, and adenosine therapy. Time to thrombolysis was similar for grade II and grade III. For placebo- treated patients, the median AR did not differ significantly between grade II (38%) and grade III patients (46%, p = 0.47), nor did median IS (16 vs. 40%, p = 0.096), but the median infarction index was 66 vs. 90% (p = 0.006). For adenosine-treated patients, median AR (21 vs. 26%, p = 0.44), median IS (5 vs. 17%, p = 0.15), and their ratio (31 vs. 67%, p = 0.23) did not differ significantly between grade II and grade III patients. The infarction index independently related to grade III ischemia (p = 0.0121) and adenosine therapy (p = 0.045). Infarct size related to baseline ischemia grade and was reduced by adenosine treatment. Necrosis progressed slowlier with baseline grade II versus III ischemia, which could offer more time for myocardial salvage with reperfusion.

    View details for Web of Science ID 000176567200009

    View details for PubMedID 12077570

  • A randomized, placebo-controlled trial of enoxaparin after high-risk coronary stenting: The ATLAST trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Batchelor, W. B., Mahaffey, K. W., Berger, P. B., DEUTSCH, E., Meier, S., Hasselblad, V., Fry, E. T., Teirstein, P. S., Ross, A. M., Binanay, C. A., Zidar, J. P. 2001; 38 (6): 1608-1613

    Abstract

    We performed a multicenter, double-blind placebo-controlled trial to examine the efficacy and safety of enoxaparin in patients at high risk for stent thrombosis (ST).The optimal antithrombotic regimen for such patients is unknown.We randomized 1,102 patients with clinical, angiographic or ultrasonographic features associated with an increased risk of ST to receive either twice-daily injections of weight-adjusted enoxaparin or placebo for 14 days after stenting. All patients received aspirin and ticlopidine. The primary end point was a 30-day composite end point of death, myocardial infarction (MI) or urgent revascularization.The target enrollment for the study was 2,000 patients. However, the trial was terminated prematurely at 1,102 patients after interim analysis revealed an unexpectedly low event rate. The primary outcome occurred in 1.8% enoxaparin-treated patients versus 2.7% treated with placebo (odds ratio [OR] 0.66; 95% confidence interval [CI] 0.29 to 1.5, p = 0.30); for death or MI the rates were 0.9% vs. 2.2%, respectively (OR 0.41, 95% CI 0.14 to 1.2, p =0.13); and for MI, 0.4% vs. 1.6%, respectively (OR 0.22, 95% CI 0.05 to 0.99, p = 0.04). The groups had comparable rates of major bleeding (3.3% for enoxaparin, 1.6% for placebo, p =0.08), but minor nuisance bleeding was increased with enoxaparin (25% vs. 5.1%, p < 0.001).The clinical outcomes of patients at increased risk of ST are more favorable than previously reported, rendering routine oral antiplatelet therapy adequate for most. However, given its relative safety and potential to reduce the risk of subsequent infarction, a 14-day course of enoxaparin may be considered for carefully selected patients.

    View details for Web of Science ID 000172254600005

    View details for PubMedID 11704394

  • Atrial fibrillation and mortality among patients with acute coronary syndromes without ST-segment elevation: results from the PURSUIT trial. American journal of cardiology Al-Khatib, S. M., Pieper, K. S., Lee, K. L., Mahaffey, K. W., Hochman, J. S., Pepine, C. J., Kopecky, S. L., Akkerhuis, M., Stepinska, J., Simoons, M. L., Topol, E. J., Califf, R. M., Harrington, R. A. 2001; 88 (1): A7-?

    View details for PubMedID 11423065

  • Atrial fibrillation and mortality among patients with acute coronary syndromes without ST-segment elevation: Results from the PURSUIT trial AMERICAN JOURNAL OF CARDIOLOGY Al-Khatib, S. M., Pieper, K. S., Lee, K. L., Mahaffey, K. W., Hochman, J. S., Pepine, C. J., Kopecky, S. L., Akkerhuis, M., Stepinska, J., Simoons, M. L., Topol, E. J., Califf, R. M., Harrington, R. A. 2001; 88 (1): 76-79
  • Disagreements between central clinical events committee and site investigator assessments of myocardial infarction endpoints in an international clinical trial: review of the PURSUIT study CURRENT CONTROLLED TRIALS IN CARDIOVASCULAR MEDICINE Mahaffey, K. W., Harrington, R. A., Akkerhuis, M., Kleiman, N. S., Berdan, L. G., Crenshaw, B. S., Tardiff, B. E., Granger, C. B., DeJong, I., Bhapkar, M., Widimsky, P., Corbalon, R., Lee, K. L., Deckers, J. W., Simoons, M. L., Topol, E. J., Califf, R. M. 2001; 2 (4): 187-194
  • Shifting the open-artery hypothesis downstream: The quest for optimal reperfusion JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Roe, M. T., Ohman, E. M., Maas, A. C., Christenson, R. H., Mahaffey, K. W., Granger, C. B., Harrington, R. A., Califf, R. M., Krucoff, M. W. 2001; 37 (1): 9-18

    Abstract

    Successful reperfusion after acute myocardial infarction (MI) has traditionally been considered to be restoration of epicardial patency, but increasing evidence suggests that disordered microvascular function and inadequate myocardial tissue perfusion are often present despite infarct vessel patency. Thus, optimal reperfusion is being redefined to include intact microvascular flow and restored myocardial perfusion, as well as sustained epicardial patency. Coronary angiography has been used as the gold standard to define failed reperfusion, according to the Thrombolysis In Myocardial Infarction (TIMI) flow grades. However, new angiographic techniques, including the corrected TIMI frame count and myocardial blush grade, have been used to show that epicardial TIMI flow grade 3 may be an incomplete measure of reperfusion success. Furthermore, evolving noninvasive diagnostic techniques, including measurement of infarct size with cardiac marker release patterns or technetium-99m-sestamibi single-photon emission computed tomographic imaging and analysis of ST segment resolution appear to be useful complements to angiography for the assessment of myocardial tissue reperfusion. Promising adjunctive therapies that target microvascular dysfunction, including platelet glycoprotein IIb/IIIa inhibitors, and agents designed to improve tissue perfusion and attenuate reperfusion injury are being evaluated to further improve clinical outcomes after acute MI. To accelerate development of these new reperfusion regimens, an integrated approach to phase II clinical trials that incorporates multiple efficacy variables, including angiography and noninvasive biomarkers of microvascular dysfunction, should be considered. Thus, as the reperfusion era moves into the next millennium, the open-artery hypothesis is expected to shift downstream and guide efforts to further improve myocardial salvage and clinical outcomes after acute MI.

    View details for Web of Science ID 000166238100002

    View details for PubMedID 11153779

  • Systematic adjudication of myocardial infarction end-points in an international clinical trial CURRENT CONTROLLED TRIALS IN CARDIOVASCULAR MEDICINE Mahaffey, K. W., Harrington, R. A., Akkerhuis, M., Kleiman, N. S., Berdan, L. G., Crenshaw, B. S., Tardiff, B. E., Granger, C. B., DeJong, I., Bhapkar, M., Widimsky, P., Corbalon, R., Lee, K. L., Deckers, J. W., Simoons, M. L., Topol, E. J., Califf, R. M. 2001; 2 (4): 180-186
  • Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial LANCET Tcheng, J. E., O'Shea, J. C., Cohen, E. A., Pacchiana, C. M., Kitt, M. M., Lorenz, T. J., Greenberg, S., Strony, J., Califf, R. M., Buller, C., Cantor, W. J., Joseph, D. M., Kitt, M. M., Lincoff, A. M., Madan, M., Popma, J., Teirstein, P., Cohen, E., Balleza, L., Parsons, P., Lui, H., Young, J., Fox, R., Labinaz, M., Jelley, J., Williams, J., Cohen, D., Trovato, M., Smith, J., Henry, P., Chisholm, R., O'Donnell, D., Talley, J. D., Pacheco, R., Timmis, S., Muraka, A., Mann, T., Cubeddu, G., Tannenbaum, M., Greene, J., Santoian, E., Wash, M., Sheldon, S., Pronesti, L., Jain, A., Alonzo, M., Seidelin, P., Richards, J., Lopez, M., Dittenber, R., Johnson, K., Levine, G., Maresh, K., Ferrando, T., Sarembock, I., Snyder, L., Kieval, J., Herlan, L., Miller, M., Bembridge, D., Nair, R., Hickel, L., Kiernan, F., Murphy, D., Cloutier, J., Conn, E., Beardsley, J., Ritchie, M., Cragen, D., Jafar, M. Z., Counihan, P., Rosenfelder, D., Ducas, J., Montebruno, L., Carere, R., Radons, B., Williams, L., Owens, W., Dougal, R., Feldman, R., Audrain, D., Karamali, A., Smith, M., Blankenship, J., Demko, S. L., Thompson, M., Gacoich, G., Chiodo, V., Noll, P., Ledley, G., Miller, C., Felten, W., Garner, B., Chandler, A. B., Easler, P., Albin, G., Page, A., Maddox, W., Allen, S., Gilchrist, I., Moore, R., Zimmerman, H., Curtis, M., Hildebrand, K., Greene, R., Healy, E., Meengs, W., Carson, D., George, J., Roncevich, T., Aharonian, V., Browning, R., Kostuk, W., Carr, S., Feit, F., Gostomsky, B., BUTMAN, S., Hannah, E., Hassel, C. D., Hartley, D., Shook, T., Hiller-Mullin, S., Brill, D., Dillion, M., Armstrong, B., Kerns, D., Pichard, A., Okubagzi, P., Nasser, T., Driver, L., GARRETT, J., Boltey, L., Stouffer, G., Potter, M., Amidon, T., Eggert, S., Taussig, A., Potter, K., Natarajan, M., Tartaglia, C., WERNER, J., Dunlap, T., Harrold-Runge, P., Davidson, C., Goodreau, L., Herzog, W., Calamunci, N., Slater, A., Tormey, D., Phillips, W., White, D., Sridhar, K., WHITE, J., Goodman, D., Buchbinder, M., Nasser, V., Rapeport, K., Vorman, P., Weiner, B., Borbone, M., Shadoff, N., Paap, C., Rehman, A., Haag, E., Burchenal, J., Kioussopoulos, K., Senior, D., Senior, J., Piana, R., Kirshenbaum, J., Chan, S., Chowdry, A., Kraft, P., Clark, V., Fox, M., DEUTSCH, E., Shannon, T., Quesada, R., Brotherton, J., Murrin, C., Cinderella, J., Hearne, S., Seefried, V., Farah, T., Pakstis, D., Bartolet, B., Bond, C., Debarardinis, C., Montory, D., Smith, G., Gray, D., Phillips, P., Hathaway, S., Manoukian, S., Patrick, C., Yakubov, S., Brooks, J., Block, P., Block, B., Muhlestein, J. B., Kim, S., Shalev, Y., Schmidt, W., Resar, J., Citro, K., Stine, R., Zumbuhl, J., Moreyra, A., Kreiger, S., Berger, P., Cannon, C. P., Fisher, L., Hasselblad, V., Foster, A., Joseph, D., Madan, M., McLendon, C., Rund, M., Tillery, N., Wood, F., Mahaffey, K. W., Irwin, C., Kulick, D., Johnson, N., Chen, J., Greenberg, S., Hogeboom, C., Lorenz, T. J., Terifay, R., Strony, J., Veltri, E. 2000; 356 (9247): 2037-2044

    Abstract

    The platelet glycoprotein IIb/IIIa inhibitors, although effective in reducing ischaemic complications of percutaneous coronary intervention, are used in few coronary stent implantation procedures. ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy) is a randomised, placebo-controlled trial to assess whether a novel, double-bolus dose of eptifibatide could improve outcomes of patients undergoing coronary stenting.We recruited 2064 patients undergoing stent implantation in a native coronary artery. Immediately before percutaneous coronary intervention, patients were randomly allocated to receive eptifibatide, given as two 180 microg/kg boluses 10 min apart and a continuous infusion of 2.0 microg/kg/min for 18-24 h, or placebo, in addition to aspirin, heparin, and a thienopyridine. The primary endpoint was the composite of death, myocardial infarction, urgent target vessel revascularisation, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy within 48 h after randomisation. The key secondary endpoint was the composite of death, myocardial infarction, or urgent target vessel revascularisation at 30 days.The trial was terminated early for efficacy. The primary endpoint was reduced from 10.5% (108 of 1024 patients on placebo [95% CI 8.7-12.4%]) to 6.6% (69 of 1040 [5.1-8.1%]) with treatment (p=0.0015). The key 30 day secondary endpoint was also reduced, from 10.5% (107 of 1024 patients on placebo [8.6-12.3%]) to 6.8% (71 of 1040 [5.3-8.4%]; p=0.0034). There was consistency in reduction of events across all components of the composite endpoint and among the major subgroups. Major bleeding was infrequent but arose more often with eptifibatide than placebo (1.3%, 13 of 1040 [0.7-2.1%]) vs 0.4%, 4 of 1024 [0.1-1.0%]; p=0.027).Routine glycoprotein IIb/IIIa inhibitor pretreatment with eptifibatide substantially reduces ischaemic complications in coronary stent intervention and is better than a strategy of reserving treatment to the bailout situation.

    View details for Web of Science ID 000165994300009

    View details for PubMedID 11145489

  • Bivalirudin in patients with heparin-induced thrombocytopenia undergoing percutaneous coronary intervention. journal of invasive cardiology Campbell, K. R., Mahaffey, K. W., Lewis, B. E., Weitz, J. I., Berkowitz, S. D., Ohman, E. M., Califf, R. M. 2000; 12: 14F-9

    View details for PubMedID 11156729

  • Geographic variability in outcomes within an international trial of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes - Results from PURSUIT EUROPEAN HEART JOURNAL Akkerhuis, K. M., Deckers, J. W., Boersma, E., Harrington, R. A., Stepinska, J., Mahaffey, K. W., Wilcox, R. G., Lincoff, A. M., Keltai, M., Topol, E. J., Califf, R. M., Simoons, M. L. 2000; 21 (5): 371-381

    Abstract

    Variations in outcome of patients from different geographic regions have been observed in many large international trials. We analysed the factors that might contribute to the geographic variations in patient outcome and treatment effect as observed in the PURSUIT trial.In PURSUIT, 9461 patients with acute coronary syndromes without persistent ST-elevation were randomized to the platelet inhibitor eptifibatide or placebo for 72 h in 27 countries in four geographic regions: Western (n=3697) and Eastern Europe (n=1541) as well as North (n=3827) and Latin America (n=396). The primary end-point was the 30-day composite of death or myocardial infarction. In the initial univariate analysis, the treatment effect appeared greater in N. America than in W. Europe, while no benefit was apparent in L. America and E. Europe. However, the confidence intervals were wide and overlapping. To study these differences, a subdivision in an early and late patient outcome and treatment effect was made. Accordingly, we analysed the rate of death or infarction at 72 h censored for percutaneous coronary intervention and the rate between 3 and 30 days, respectively. Additional analyses were performed with different definitions of myocardial infarction using progressively higher thresholds of CK(-MB) elevation. Multivariable analysis was used to evaluate the relation between region and outcome and to determine the adjusted odds ratios for the eptifibatide treatment effect.Major differences in baseline demographics were apparent among the four regions; in particular, more patients from E. Europe had characteristics associated with impaired outcome. Interventional treatment also varied considerably, with more patients from N. America undergoing revascularization. Despite differences in the 72 h event rate, eptifibatide showed a consistent trend towards a reduction in the composite end-point among all four regions and for all definitions of infarction. Relative reductions ranged from 17-42% in W. Europe, 23-35% in N. America, 0-33% in E. Europe, and 55-82% in L. America. After multivariable adjustment, the pattern of benefit with eptifibatide was consistent among the regions. In patients undergoing percutaneous coronary intervention during study drug infusion in W. Europe (n=266) and N. America (n=931), the relative reduction in myocardial infarction during medical therapy ranged from 56-75% in W. Europe and 14-67% in N. America, while the reduction in procedure-related events ranged from 12-44% and 25-61% for different definitions of infarction. After multivariable adjustment neither benefit nor rebound were apparent after study drug discontinuation, or after 3 days in all regions, except in L. America. In general, the differences in outcome and treatment effect were greatest when the protocol definition of myocardial infarction (CK(-MB) >1 upper normal limit) was applied. Under stricter definitions, these differences became smaller and disappeared with the investigator's assessment.The analysis suggests that the apparent differences in patient outcome and eptifibatide treatment effect can be explained largely by differences in baseline demographics and adjunctive treatment strategies as well as by the methodology of myocardial infarction definition and the adjudication process.

    View details for Web of Science ID 000085515100010

    View details for PubMedID 10666351

  • Cost-effectiveness of platelet glycoprotein IIb/IIIa inhibition with eptifibatide in patients with non-ST-elevation acute coronary syndromes CIRCULATION Mark, D. B., Harrington, R. A., Lincoff, A. M., Califf, R. M., Nelson, C. L., Tsiatis, A. A., Buell, H., Mahaffey, K. W., Davidson-Ray, L., Topol, E. J. 2000; 101 (4): 366-371

    Abstract

    In the PURSUIT trial, eptifibatide significantly reduced the 30-day incidence of death and myocardial infarction relative to placebo in 9461 patients with an acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction).We conducted a 2-part prospective economic substudy of the 3522 US patients enrolled in PURSUIT: (1) an empirical intention-to-treat comparison of medical costs (hospital plus physician) up to 6 months after hospitalization and (2) a lifetime cost-effectiveness analysis. The base-case cost-effectiveness ratio was expressed as the 1996 US dollars required to add 1 life-year with eptifibatide therapy. The 2 treatment arms had equivalent resource consumption and medical costs (exclusive of the cost of the eptifibatide regimen) during the index (enrollment) hospitalization (P=0.78) and up to 6 months afterward (P=0.60). The average wholesale price of the eptifibatide regimen was $1217, but a typical hospital discounted price was $1014. The estimated life expectancy from randomization in the US patients was 15.96 years for eptifibatide and 15.85 years for placebo, an incremental difference of 0.111. The incremental cost-effectiveness ratio for eptifibatide therapy in US PURSUIT patients was $16 491 per year of life saved. This result was robust through a wide range of sensitivity analyses. The cost-utility ratio for eptifibatide (using time trade-off defined utilities) was $19 693 per added quality-adjusted life-year.Based on the results observed in the US PURSUIT patients, the routine addition of eptifibatide to standard care for non-ST-elevation acute coronary syndrome patients is economically attractive by conventional standards.

    View details for Web of Science ID 000085064400011

    View details for PubMedID 10653826

  • Association between minor elevations of creatine kinase-MB level and mortality in patients with acute coronary syndromes without ST-segment elevation JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Alexander, J. H., Sparapani, R. A., Mahaffey, K. W., Deckers, J. W., Newby, L. K., Ohman, E. M., Corbalan, R., Chierchia, S. L., Boland, J. B., Simoons, M. L., Califf, R. M., Topol, E. J., Harrington, R. A. 2000; 283 (3): 347-353

    Abstract

    Controversy surrounds the diagnostic and prognostic importance of slightly elevated cardiac markers in patients with acute coronary syndromes without ST-segment elevation.To investigate the relationship between peak creatine kinase (CK)-MB level and outcome and to determine whether a threshold CK-MB level exists below which risk is not increased.Retrospective observational analysis of data from the international Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, conducted from November 1995 to January 1997.A total of 8250 patients with acute coronary syndromes without ST-segment elevation who had at least 1 CK-MB sample collected during their index hospitalization.Mortality at 30 days and 6 months, was assessed by category of index-hospitalization peak CK-MB level (0-1, >1-2, >2-3, >3-5, >5-10, or >10 times the upper limit of normal). Multivariable logistic regression was used to determine the independent prognostic significance of peak CK-MB level after adjustment for baseline predictors of 30-day and 6-month mortality.Mortality at 30 days and 6 months increased from 1.8% and 4.0%, respectively, in patients with normal peak CK-MB levels, to 3.3% and 6.2 % at peak CK-MB levels 1 to 2 times normal, to 5.1% and 7.5% at peak CK-MB levels 3 to 5 times normal, and to 8.3% and 11.0% at peak CK-MB levels greater than 10 times normal. Log-transformed peak CK-MB levels were predictive of adjusted 30-day and 6-month mortality (P<.001 for both).Our data show that elevation of CK-MB level is strongly related to mortality in patients with acute coronary syndromes without ST-segment elevation, and that the increased risk begins with CK-MB levels just above normal. In the appropriate clinical context, even minor CK-MB elevations should be considered indicative of myocardial infarction.

    View details for Web of Science ID 000084732400026

    View details for PubMedID 10647797

  • Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction - Results of a multicenter, randomized, placebo-controlled trial: The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) Trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Mahaffey, K. W., Puma, J. A., Barbagelata, N. A., DiCarli, M. F., Leesar, M. A., Browne, K. F., Eisenberg, P. R., Bolli, R., Casas, A. C., Molina-Viamonte, V., Orlandi, C., Blevins, R., Gibbons, R. J., Califf, R. M., Granger, C. B. 1999; 34 (6): 1711-1720

    Abstract

    The Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial was designed to test the hypothesis that adenosine as an adjunct to thrombolysis would reduce myocardial infarct size.Reperfusion therapy for acute myocardial infarction (MI) has been shown to reduce mortality, but reperfusion itself also may have deleterious effects.The AMISTAD trial was a prospective, open-label trial of thrombolysis with randomization to adenosine or placebo in 236 patients within 6 h of infarction onset. The primary end point was infarct size as determined by Tc-99 m sestamibi single-photon emission computed tomography (SPECT) imaging 6+/-1 days after enrollment based on multivariable regression modeling to adjust for covariates. Secondary end points were myocardial salvage index and a composite of in-hospital clinical outcomes (death, reinfarction, shock, congestive heart failure or stroke).In all, 236 patients were enrolled. Final infarct size was assessed in 197 (83%) patients. There was a 33% relative reduction in infarct size (p = 0.03) with adenosine. There was a 67% relative reduction in infarct size in patients with anterior infarction (15% in the adenosine group vs. 45.5% in the placebo group) but no reduction in patients with infarcts located elsewhere (11.5% for both groups). Patients randomized to adenosine tended to reach the composite clinical end point more often than those assigned to placebo (22% vs. 16%; odds ratio, 1.43; 95% confidence interval, 0.71 to 2.89).Many agents thought to attenuate reperfusion injury have been unsuccessful in clinical investigation. In this study, adenosine resulted in a significant reduction in infarct size. These data support the need for a large clinical outcome trial.

    View details for Web of Science ID 000083778300011

    View details for PubMedID 10577561

  • Neurosurgical evacuation of intracranial hemorrhage after thrombolytic therapy for acute myocardial infarction: Experience from the GUSTO-I Trial AMERICAN HEART JOURNAL Mahaffey, K. W., Granger, C. B., Sloan, M. A., Green, C. L., Gore, J. M., Weaver, W. D., White, H. D., Simoons, M. L., Barbash, G. I., Topol, E. J., Califf, R. M. 1999; 138 (3): 493-499

    Abstract

    Intracranial hemorrhage is an uncommon but very dangerous complication in patients receiving thrombolytic therapy for acute myocardial infarction. Neurosurgical evacuation is often an available treatment option. However, the association between neurosurgical evacuation and clinical outcomes in these patients has yet to be determined.The GUSTO-I trial randomly assigned 41,021 patients with acute myocardial infarction to 1 of 4 thrombolytic strategies in 1081 hospitals in 15 countries. A total of 268 patients (0.65%) had an intracranial hemorrhage. We assessed differences in clinical characteristics, neuroimaging features, Glasgow coma scale scores, functional status (disabled: moderate or severe deficit; not disabled: no or minor deficit) and 30-day mortality rate between the 46 patients who underwent neurosurgical evacuation and the 222 patients who did not.Mortality rate at 30 days for all patients with intracranial hemorrhage was 60%; an additional 27% were disabled. Evacuation was associated with significantly higher 30-day survival (65% versus 35%, P <.001) and a trend toward improved functional status (nondisabling stroke: 20% versus 12%, P =.15).Although intracranial hemorrhage is uncommon after thrombolysis for acute myocardial infarction, 87% of patients die or have disabling stroke. Although not definitive, these data indicate that neurosurgical evacuation may be associated with improved clinical outcomes. Physicians treating such patients should consider early neurosurgical consultation and intervention in these patients.

    View details for Web of Science ID 000082401900019

    View details for PubMedID 10467200

  • Stroke in patients with acute coronary syndromes - Incidence and outcomes in the platelet glycoprotein IIb/IIIa in unstable angina: Receptor suppression using integrilin therapy (PURSUIT) trial CIRCULATION Mahaffey, K. W., Harrington, R. A., Simoons, M. L., Granger, C. B., Graffagnino, C., Alberts, M. J., Laskowitz, D. T., MILLER, J. M., Sloan, M. A., Berdan, L. G., MacAulay, C. M., Lincoff, A. M., Deckers, J., Topol, E. J., Califf, R. M. 1999; 99 (18): 2371-2377

    Abstract

    The incidence of stroke in patients with acute coronary syndromes has not been clearly defined because few trials in this patient population have been large enough to provide stable estimates of stroke rates.We studied the 10 948 patients with acute coronary syndromes without persistent ST-segment elevation who were randomly assigned to placebo or the platelet glycoprotein IIb/IIIa receptor inhibitor eptifibatide in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial to determine stroke rates, stroke types, clinical outcomes in patients with stroke, and independent baseline clinical predictors for nonhemorrhagic stroke. Stroke occurred in 79 (0.7%) patients, with 66 (0.6%) nonhemorrhagic, 6 intracranial hemorrhages, 3 cerebral infarctions with hemorrhagic conversion, and 4 of uncertain cause. There were no differences in stroke rates between patients who received placebo and those assigned high-dose eptifibatide (odds ratios and 95% confidence intervals 0.82 [0.59, 1.14] and 0.70 [0.49, 0.99], respectively). Of the 79 patients with stroke, 17 (22%) died within 30 days, and another 26 (32%) were disabled by hospital discharge or 30 days, whichever came first. Higher heart rate was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by older age, prior anterior myocardial infarction, prior stroke or transient ischemic attack, and diabetes mellitus. These factors were used to develop a simple scoring nomogram that can predict the risk of nonhemorrhagic stroke.Stroke was an uncommon event in patients with acute coronary syndromes in the PURSUIT trial. These strokes are, however, associated with substantial morbidity and mortality rates. The majority of strokes were of nonhemorrhagic causes. Eptifibatide was not associated with an increase in intracranial hemorrhage, and no significant effect on nonhemorrhagic stroke was observed. We developed a useful nomogram for assigning baseline nonhemorrhagic stroke risk in this patient population.

    View details for Web of Science ID 000080143300005

    View details for PubMedID 10318656

  • Effects of stroke on medical resource use and costs in acute myocardial infarction CIRCULATION Tung, C. Y., Granger, C. B., Sloan, M. A., Topol, E. J., KNIGHT, J. D., Weaver, W. D., Mahaffey, K. W., White, H., Clapp-Channing, N., Simoons, M. L., Gore, J. M., Califf, R. M., Mark, D. B. 1999; 99 (3): 370-376

    Abstract

    Stroke occurs concurrently with myocardial infarction (MI) in approximately 30 000 US patients each year. This number is expected to rise with the increasing use of thrombolytic therapy for MI. However, no data exist for the economic effect of stroke in the setting of acute MI (AMI). The purpose of this prospective study was to assess the effect of stroke on medical resource use and costs in AMI patients in the United States.Medical resource use and cost data were prospectively collected for 2566 randomly selected US GUSTO I patients (from 23 105 patients) and for the 321 US GUSTO I patients who developed non-bypass surgery-related stroke during the baseline hospitalization. Follow-up was for 1 year. All costs are expressed in 1993 US dollars. During the baseline hospitalization, stroke was associated with a reduction in cardiac procedure rates and an increase in length of stay, despite a hospital mortality rate of 37%. Together with stroke-related procedural costs of $2220 per patient, the baseline medical costs increased by 44% ($29 242 versus $20 301, P<0.0001). Follow-up medical costs were substantially higher for stroke survivors ($22 400 versus $5282, P<0.0001), dominated by the cost of institutional care. The main determinant for institutional care was discharge disability status. The cumulative 1-year medical costs for stroke patients were $15 092 higher than for no-stroke patients. Hemorrhagic stroke patients had a much higher hospital mortality rate than non-hemorrhagic stroke patients (53% versus 15%, P<0.001), which was associated with approximately $7200 lower mean baseline hospitalization cost. At discharge, hemorrhagic stroke patients were more likely to be disabled (68% versus 46%, P=0.002).In this first large prospective economic study of stroke in AMI patients, we found that strokes were associated with a 60% ($15 092) increase in cumulative 1-year medical costs. Baseline hospitalization costs were 44% higher because of longer mean lengths of stay. Stroke type was a key determinant of baseline cost. Follow-up costs were more than quadrupled for stroke survivors because of the need for institutional care. Disability level was the main determinant of institutional care and thus of follow-up costs.

    View details for Web of Science ID 000078211300009

    View details for PubMedID 9918523

  • The use of tomographic myocardial perfusion scanning to evaluate an electrocardiographic salvage estimation method in patients with acute myocardial infarction: An AMISTAD substudy 24th Annual ISCE Conference on Research and Technology Transfer in Computerized Electrocardiology Barbagelata, A., Di Carli, M. F., Sgarbossa, E. B., Califf, R. M., Clemmensen, P., Criger, D. A., Gates, K. B., Gibbons, R. J., Casabe, H., Granger, C. B., Wagner, G. S., Mahaffey, K. W. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 1999: 111–113

    View details for Web of Science ID 000085220300023

    View details for PubMedID 10688313

  • Clinical outcomes after detection of elevated cardiac enzymes in patients undergoing percutaneous intervention JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tardiff, B. E., Califf, R. M., Tcheng, J. E., Lincoff, A. M., Sigmon, K. N., Harrington, R. A., Mahaffey, K. W., Ohman, E. M., Teirstein, P. S., Blankenship, J. C., Kitt, M. M., Topol, E. J. 1999; 33 (1): 88-96

    Abstract

    We examined the relations of elevated creatine kinase (CK) and its myocardial band isoenzyme (CK-MB) to clinical outcomes after percutaneous coronary intervention (PCI) in patients enrolled in Integrilin (eptifibatide) to Minimize Platelet Aggregation and Coronary Thrombosis-II (trial) (IMPACT-II), a trial of the platelet glycoprotein IIb/IIIa inhibitor eptifibatide.Elevation of cardiac enzymes often occurs after PCI, but its clinical implications are uncertain.Patients undergoing elective, scheduled PCI for any indication were analyzed. Parallel analyses investigated CK (n=3,535) and CK-MB (n=2,341) levels after PCI (within 4 to 20 h). Clinical outcomes at 30 days and 6 months were stratified by postprocedure CK and CK-MB (multiple of the site's upper normal limit).Overall, 1,779 patients (76%) had no CK-MB elevation; CK-MB levels were elevated to 1 to 3 times the upper normal limit in 323 patients (13.8%), to 3 to 5 times normal in 84 (3.6%), to 5 to 10 times normal in 86 (3.7%), and to >10 times normal in 69 patients (2.9%). Elevated CK-MB was associated with an increased risk of death, reinfarction, or emergency revascularization at 30 days, and of death, reinfarction, or surgical revascularization at 6 months. Elevated total CK to above three times normal was less frequent, but its prognostic significance paralleled that seen for CK-MB. The degree of risk correlated with the rise in CK or CK-MB, even for patients with successful procedures not complicated by abrupt closure.Elevations in cardiac enzymes, including small increases (between one and three times normal) often not considered an infarction, are associated with an increased risk for short-term adverse clinical outcomes after successful or unsuccessful PCI.

    View details for Web of Science ID 000078088300015

    View details for PubMedID 9935014

  • Prediction of 30-day mortality among patients with thrombolysis-related intracranial hemorrhage CIRCULATION Sloan, M. A., Sila, C. A., Mahaffey, K. W., Granger, C. B., Longstreth, W. T., Koudstaal, P., White, H. D., Gore, J. M., Simoons, M. L., Weaver, W. D., Green, C. L., Topol, E. J., Califf, R. M. 1998; 98 (14): 1376-1382

    Abstract

    Limited information exists on risk factors for mortality after thrombolysis-related intracranial hemorrhage. We wished to determine the characteristics associated with 30-day mortality after thrombolysis-related intracranial hemorrhage.We performed an observational analysis within a randomized trial of 4 thrombolytic therapies, conducted in 1081 hospitals in 15 countries. Patients presented with ST-segment elevation within 6 hours of symptom onset. Our population was composed of the 268 patients who had primary intracranial hemorrhage after thrombolysis. With univariable and multivariable analyses, we identified clinical and brain imaging characteristics that would predict 30-day mortality among these patients. CT or MRI were available for 240 patients (90%). The 30-day mortality rate was 59.7%. Glasgow Coma Scale score, age, time from thrombolysis to symptoms of intracranial hemorrhage, hydrocephalus, herniation, mass effect, intraventricular extension, and volume and location of intracranial hemorrhage were significant univariable predictors. Multivariable analysis of 170 patients with complete data, 98 of whom died, identified the following independent, significant predictors: Glasgow Coma Scale score (chi2, 19.3; P<0. 001), time from thrombolysis to intracranial hemorrhage (chi2, 15.8; P<0.001), volume of intracranial hemorrhage (chi2, 11.6; P<0.001), and baseline clinical predictors of mortality in the overall GUSTO-I trial (chi2, 10.3; P=0.001). The final model had a C-index of 0.931.This model provides excellent discrimination between patients who are likely to live and those who are likely to die after thrombolytic-related intracranial hemorrhage; this may aid in making decisions about the appropriate level of care for such patients.

    View details for Web of Science ID 000076219500005

    View details for PubMedID 9760291

  • Comparison of the ABC/2 estimation technique to computer-assisted volumetric analysis of intraparenchymal and subdural hematomas complicating the GUSTO-1 trial STROKE Gebel, J. M., Sila, C. A., Sloan, M. A., Granger, C. B., Weisenberger, J. P., Green, C. L., Topol, E. J., Mahaffey, K. W. 1998; 29 (9): 1799-1801

    Abstract

    The volume of an intracerebral hemorrhage has been shown to be an important independent predictor of mortality in several reports. A technique for estimating hematoma volume, known as the ABC/2 method, has been proven a reliable, simple bedside technique for the volume measurement of intraparenchymal intracerebral hemorrhage. Subdural hematomas also carry a significant mortality risk but are more amenable to surgical evacuation. A reliable, simple bedside measurement of subdural hematoma volume may prove a valuable tool in prognostication and management of patients with this entity.Computed tomographic (CT) brain scans of 244 patients suffering from intracranial hemorrhage in the GUSTO-1 trial were systematically reviewed. The volumes of 298 intraparenchymal hematomas were measured by the ABC/2 technique, and the volumes of 44 subdural hematomas were measured by an adaptation of this technique and compared to computer-assisted volumetric analysis.Excellent correlation between the techniques were achieved for both subdural (r=0.842; slope, 0.982) and intraparenchymal hematoma volume measurements (r=0.929; slope, 1.11).The ABC/2 method is a simple and accurate technique for the measurement of intraparenchymal hematoma volume, and a simple adaptation allows for a similarly accurate measurement of subdural hematoma volume as well.

    View details for Web of Science ID 000075651800008

    View details for PubMedID 9731597

  • Risk factors for in-hospital nonhemorrhagic stroke in patients with acute myocardial infarction treated with thrombolysis CIRCULATION Mahaffey, K. W., Granger, C. B., Sloan, M. A., Thompson, T. D., Gore, J. M., Weaver, W. D., White, H. D., Simoons, M. L., Barbash, G. I., Topol, E. J., Califf, R. M. 1998; 97 (8): 757-764

    Abstract

    Nonhemorrhagic stroke occurs in 0.1% to 1.3% of patients with acute myocardial infarction who are treated with thrombolysis, with substantial associated mortality and morbidity. Little is known about the risk factors for its occurrence.We studied the 247 patients with nonhemorrhagic stroke who were randomly assigned to one of four thrombolytic regimens within 6 hours of symptom onset in the GUSTO-I trial. We assessed the univariable and multivariable baseline risk factors for nonhemorrhagic stroke and created a scoring nomogram from the baseline multivariable modeling. We used time-dependent Cox modeling to determine multivariable in-hospital predictors of nonhemorrhagic stroke. Baseline and in-hospital predictors were then combined to determine the overall predictors of nonhemorrhagic stroke. Of the 247 patients, 42 (17%) died and another 98 (40%) were disabled by 30-day follow-up. Older age was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by higher heart rate, history of stroke or transient ischemic attack, diabetes, previous angina, and history of hypertension. These factors remained statistically significant predictors in the combined model, along with worse Killip class, coronary angiography, bypass surgery, and atrial fibrillation/flutter.Nonhemorrhagic stroke is a serious event in patients with acute myocardial infarction who are treated with thrombolytic, antithrombin, and antiplatelet therapy. We developed a simple nomogram that can predict the risk of nonhemorrhagic stroke on the basis of baseline clinical characteristics. Prophylactic anticoagulation may be an important treatment strategy for patients with high probability for nonhemorrhagic stroke, but further study is needed.

    View details for Web of Science ID 000072200800009

    View details for PubMedID 9498539

  • Thrombolysis-related intracranial hemorrhage - A radiographic analysis of 244 cases from the GUSTO-1 trial with clinical correlation STROKE Gebel, J. M., Sila, C. A., Sloan, M. A., Granger, C. B., Mahaffey, K. W., Weisenberger, J., Green, C. L., White, H. D., Gore, J. M., Weaver, W. D., Califf, R. M., Topol, E. J. 1998; 29 (3): 563-569

    Abstract

    Intracranial hemorrhage (ICH) is a serious complication of thrombolytic therapy. We systematically reviewed the radiographic features of 244 cases of symptomatic ICH complicating thrombolysis for acute myocardial infarction in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial, correlated these observations with clinical data, and speculated on hemorrhage pathogenesis.CT scans from 244 patients suffering symptomatic ICH were systematically reviewed for selected radiographic features, including ICH type, location, hematoma characteristics, mass effect features, hydrocephalus, and preexisting lesions. Hematoma volume was estimated by computer-assisted volumetric analysis. Data from this analysis were correlated with clinical data including hypertension, anticoagulation, age, thrombolytic regimen, and ICH timing.Most hemorrhages were large (median [25th, 75th percentile] volume, 72 mL [39, 118]), solitary (66%), lobar (77%), confluent (80%), and intraparenchymal (82%) with a blood/fluid level (82%) and little edema (median [25th, 75th percentile] volume, 9 mL [5, 16]). Hydrocephalus (P<.001), any one mass effect feature (P<.001), intraventricular hemorrhage (P=.022), mottled hematoma appearance (P=.050), and hematoma blood/fluid level (P<.001) were associated with higher hemorrhage volume in the radiographic analysis, as were older age (P=.005), treatment with combined streptokinase and tissue plasminogen activator (P=.034), and hemorrhage onset 8 to 13 hours after treatment (P=.008) in the clinical analysis. Subdural hemorrhage was a high-volume subgroup whose risk increased with antecedent trauma (P=.026) or syncope (P=.006). Deep intraparenchymal hemorrhage was associated with hypertension (P=.016), and multifocal ICH occurred significantly earlier after treatment (P=.002).Although the majority of postthrombolytic ICH are large, solitary, and supratentorial, the spectrum is diverse. Features of mass effect reflected the large volumes, and hematoma characteristics of mottling and blood/fluid levels were frequent. Thrombolysis-related coagulopathy and age appear to be the most important identifiable factors in the genesis of postthrombolytic ICH, but the hemorrhage subtype seen may reflect an interaction with other factors such as hypertension, ICH timing, antecedent head trauma, and syncope.

    View details for Web of Science ID 000072348900001

    View details for PubMedID 9506593

  • Myonecrosis after revascularization procedures JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Califf, R. M., Abdelmeguid, A. E., Kuntz, R. E., Popma, J. J., Davidson, C. J., Cohen, E. A., Kleiman, N. S., Mahaffey, K. W., Topol, E. J., Pepine, C. J., Lipicky, R. J., Granger, C. B., Harrington, R. A., Tardiff, B. E., Crenshaw, B. S., Bauman, R. P., Zuckerman, B. D., Chaitman, B. R., Bittl, J. A., Ohman, E. M. 1998; 31 (2): 241-251

    Abstract

    The detection of elevated cardiac enzyme levels and the occurrence of electrocardiographic (ECG) abnormalities after revascularization procedures have been the subject of recent controversy. This report represents an effort to achieve a consensus among a group of researchers with data on this subject. Creatine kinase (CK) or CK-MB isoenzyme (CK-MB) elevations occur in 5% to 30% of patients after a percutaneous intervention and commonly during coronary artery bypass graft surgery (CABG). Although Q wave formation is rare, other ECG changes are common. The rate of detection is highly dependent on the intensity of enzyme and ECG measurement. Because most events occur without the development of a Q wave, the ECG will not definitively diagnose them; even the ECG criteria for Q wave formation signifying an important clinical event have been variable. At least 10 studies evaluating > 10,000 patients undergoing percutaneous intervention have demonstrated that elevation of CK or CK-MB is associated not only with a higher mortality, but also with a higher risk of subsequent cardiac events and higher cost. Efforts to identify a specific cutoff value below which the prognosis is not impaired have not been successful. Rather, the risk of adverse outcomes increases with any elevation of CK or CK-MB and increases further in proportion to the level of intervention. This information complements similar previous data on CABG. Obtaining preprocedural and postprocedural ECGs and measurement of serial cardiac enzymes after revascularization are recommended. Patients with enzyme levels elevated more than threefold above the upper limit of normal or with ECG changes diagnostic for Q wave myocardial infarction (MI) should be treated as patients with an MI. Patients with more modest elevations should be observed carefully. Clinical trials should ensure systematic evaluation for myocardial necrosis, with attention paid to multivariable analysis of risk factors for poor long-term outcome, to determine the extent to which enzyme elevation is an independent risk factor after considering clinical history, coronary anatomy, left ventricular function and clinical evidence of ischemia. In addition, tracking of enzyme levels in clinical trials is needed to determine whether interventions that reduce periprocedural enzyme elevation also improve mortality.

    View details for Web of Science ID 000071796900001

    View details for PubMedID 9462562

  • Diabetic retinopathy should not be a contraindication to thrombolytic therapy for acute myocardial infarction: Review of ocular hemorrhage incidence and location in the GUSTO-I trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Mahaffey, K. W., Granger, C. B., Toth, C. A., White, H. D., Stebbins, A. L., Barbash, G. I., Vahanian, A., Topol, E. J., Califf, R. M. 1997; 30 (7): 1606-1610

    Abstract

    This study sought to evaluate the incidence of ocular hemorrhage in patients with and without diabetes after thrombolytic therapy for acute myocardial infarction.Ocular hemorrhage after thrombolysis has been reported rarely. However, there is concern that the risk is increased in patients with diabetes. In fact, diabetic hemorrhagic retinopathy has been identified as a contraindication to thrombolytic therapy without clear evidence that these patients have an increased risk for ocular hemorrhage.We identified all suspected ocular hemorrhages from bleeding complications reported in patients enrolled in the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO)-I trial. Additional information was collected on a one-page data form. We compared the incidence and location of ocular hemorrhages in patients with and without diabetes.There were 40,899 patients (99.7%) with information about diabetic history and ocular bleeding. Twelve patients (0.03%) had an ocular hemorrhage. Intraocular hemorrhage was confirmed in only one patient. There were 6,011 patients (15%) with diabetes, of whom only 1 had an ocular hemorrhage (eyelid hematoma after a documented fall). The upper 95% confidence intervals for the incidence of intraocular hemorrhage in patients with and without diabetes were 0.05% and 0.006%, respectively.Ocular hemorrhage and, more important, intraocular hemorrhage after thrombolytic therapy for acute myocardial infarction is extremely uncommon. The calculated upper 95% confidence interval for the incidence of intraocular hemorrhage in patients with diabetes was only 0.05%. We conclude that diabetic retinopathy should not be considered a contraindication to thrombolysis in patients with an acute myocardial infarction.

    View details for Web of Science ID A1997YH37900003

    View details for PubMedID 9385883

  • A comparison of reteplase with alteplase for acute myocardial infarction NEW ENGLAND JOURNAL OF MEDICINE Topol, E., Califf, R., Ohman, E., Wilcox, R., Grinfeld, L., Aylward, P., Simes, R., Probst, P., VandeWerf, F., ARMSTRONG, P., HEIKKILA, J., Vahanian, A., Bode, C., Ostor, E., Ardissino, D., Deckers, J., White, H., Sadowski, Z., SEABRAGOMES, R., Dalby, A., Betriu, A., Emanuelsson, H., Hartford, M., Follath, D., Hampton, J., Bates, E., Gibler, W., Gore, J., Granger, C., Guerci, A., Hochman, J., Holmes, D., Kleiman, N., Moliterno, D., Morris, D., Smalling, R., Weaver, W., Neuhaus, K., Cheitlin, M., Debono, D., Fisher, L., Frye, R., Jensen, G., Alberts, M., Mahaffey, K., Miller, J., Sloan, M. 1997; 337 (16): 1118-1123
  • Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization NEW ENGLAND JOURNAL OF MEDICINE Topol, E. J., Califf, R. M., Lincoff, A. M., Tcheng, J. E., Cabot, C. F., Weisman, H. F., Kereiakes, D., Lausten, D., Runyon, J. P., Howard, W., Kelly, T., Muncy, D., Timmis, G., SAFIAN, M., Davey, D., Kleiman, N. S., Rose, D., Basinger, L., Rouse, C., Kramer, J., Wilson, R., Talley, J. D., Boyles, M., Navetta, F. I., LeBueuf, R., Kraft, P., Dvorak, L., Smigla, R. M., Ferguson, J., Harlan, M., Browne, K., Telatnik, M., Blankenship, J., Demko, L., Ivanhoe, R. J., Jackson, C., Shadoff, N., Goebel, S., Taylor, M., Cleary, E., GACIOCH, G., Chiodo, V., Bates, E., QUAIN, L., Snyder, H., Bass, T. A., Rohman, C., Gradman, A., Boltey, L., Tannenbaum, M., Stengl, D., Gordon, P., Wright, N., Cummins, F., Nonnweiler, J., Aversano, T., PELTZER, L., Bear, P., Craig, M. B., HATTEL, L., Tooke, G., Anderson, H. V., Weigelt, L., Hettleman, B., Kennedy, S., Teirstein, P. S., Claire, D., Sarembock, I., Sayre, S., Davidson, C. J., Schaechter, A., Aguirre, F., Stonner, T., Azrin, M., BODETT, J., Barry, M. B., Worley, S., Frey, L. A., SPRIGGS, D. J., Wahl, S. A., Weston, M. W., Yedinak, K., George, B., Smith, D., Gilliland, C., Smith, D., Ricci, D. R., Fox, R., Hartman, C., Lunow, S., Farah, T., Petruolo, S., Sander, G., Stevens, A., Delise, K., Reen, B., Whisnant, D., Henderson, L., Heuser, R., Swiderski, K., Kaluzniak, M., Larkin, T., JACKSON, B. J., Popma, J., Prunka, N., Sanz, M., Mayer, D., Mackey, K., Burton, J., Hogg, N., Brown, R., Stevens, K., French, W., Wang, S., Adelman, A. G., Foulger, V., Weber, S., Gottlieb, R., Lavoie, J., King, S., Frerichs, F., Hollywood, L., Ducas, J., Schick, U., Hochman, J. S., Slater, J., Tormey, D., ONEILL, B. J., Foshay, K., Fitzgerald, N., Cheung, P. K., Bedard, D., Knudtson, M. L., Galbraith, D., Watt, H., Samaha, J., Hamilton, B., Klein, L. W., Hebson, L., Almond, D., WHITE, J., Rosenberg, M. J., Teully, S., UNKS, M., Rodgers, K., Faxon, D., Gore, J., Kelsey, S., Lee, K., Sane, D., Walters, L., Booth, J., Cannata, R., Castle, V., Cohen, H., DeLuca, S., Kutner, M., Knuth, T., McCollough, T., McPherson, J., Melton, J., Miller, D., Pulliam, M., Sapp, S., Sigmon, K. N., Montague, E., Alexander, K., Augostini, R., Bajzer, C., Bart, B., Belli, G., Carlson, J., Challapalli, R., Crenshaw, B., Dawson, I., Dickey, A., Echols, A., Erickson, B., FONTANA, M. B., Ghaffari, S., Gordon, C., Granger, C., Grano, G., Grimm, R., Johnson, T., Juran, N., Kingsley, A., Kruse, K., Lauer, M., Mahaffey, K., Malone, K., Mark, D., Marwick, T., Migrino, R., Miller, J., Newby, K., Pace, C., Peterson, E., Rabbani, R., Ragan, J., Rimmerman, C., Rodkey, S., Savor, V., Shaw, W. F., Sila, C., Silver, M., Tan, W., Tobiasz, D., Vandervoort, P., Wang, C. W., Ward, C., Waters, J., Wiehle, D., Winchell, M., Underwood, D., Clemons, P., Heupler, S., Powers, J., Rubin, D., Sgarbossa, E., Steinhubl, S., Moliterno, D., Debowey, D., Balazs, E., Crowe, T., Ivanc, T., Ols, L., POLISZCZUK, R., VILSACK, H., Witherspoon, B., DAVIDSONRAY, L., Anderson, K. M., Giel, K. M., Musco, M. H., Stoner, G. L. 1997; 336 (24): 1689-1696
  • Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II LANCET Tcheng, J. E., Lincoff, A. M., Sigmon, K. N., Lee, K. L., Kitt, M. M., Califf, R. M., Topol, E. J., Juran, N., Worley, S., Tuzi, J., Hollywood, L., Kleiman, N. S., Ali, M. N., Rose, D., Kereiakes, D. J., Higby, N., George, J., HEILBRUNN, S., Roncevich, T., Burnheimer, B., IVANHOE, R., Meade, L., Rund, M., Tannenaum, M., Stangle, D., Yakubov, S., Rusk, K., Ferguson, J. J., Willerson, J. T., Thomas, C., Harlan, M., Browne, K., Telatnik, M., Blankenship, J., Demko, L., Timmis, G., SAFIAN, M., Resar, J., Dudek, A., Spriggs, D., Wahl, S., Gilchrist, I. C., Dabbs, A., Shadoff, N., Goebel, S., Miller, M., Burdick, M., Owens, B., McIvor, M., Reddinger, J., Hartman, C., Lunow, S., Conn, E., McWilliams, C., Aycock, R., Wilcox, T., Corbelli, J., Cooke, B., Teirstein, P., Haas, G., Talley, J. D., Rawert, M., GHALILI, K., MAHAFFEY, T., Toggart, E., Fowler, P., Davidson, C., BERGELSON, B., Schaechter, A., Navetta, F., BYARS, S., Durbin, B., Muhlestein, J. B., Jerman, J., Nygaard, T., WHITE, J., Sanz, M., Mayer, D., White, R., Reatta, K., Aguirre, F. V., Stonner, T., Gottlieb, R., Lavoie, J., McDonough, T., WESZT, S., MICALE, P., Berry, S., Taylor, M., Clark, D., Brewer, D., Black, S., Roubin, G., SUTOR, C., Heinsimer, J., Allar, N., Crawford, R., PIERSON, M., Siegel, R., Vermillion, J., Bengtson, J., Prochnow, L., Griffin, J., Theodosiou, J., Parr, K., Thomas, L., Toole, J., Wise, C., Lerrick, K., Spinagotti, B., French, W., Nagelhout, D., Miller, K., Seaworth, J., Jenson, J., Collins, G., MARK, R., Sheikh, K., Rosner, E., Tenaglia, A., Friedman, I., Weiner, B., Borbone, M., Kuehl, W., Allen, S., KRAUTHAMER, D., Chait, V., Belkin, R., Steinberg, R., Carey, D., Rogers, K., Cates, C., Davis, D., Arnold, A., Sommers, T., Herzog, W., Calamunci, N., COWFER, J., Cohen, M., Lee, D., SLOSKY, D., Kaczinski, J., Simonton, C., Porter, B., Hinohara, T., Johnson, M., DELCORE, M., Stangal, L., GACIOCH, G., Chiodo, V., Sullebarger, J. T., Ford, L., Kleavel, P., Fedak, C., Popma, J., Prunka, N., Davis, C., Faxon, D., Guerci, A., Loscalzo, J., Weaver, W. D., Batts, K., Hughes, D., Joseph, D., Karnash, S., Lilley, P., Liu, M., Melton, J., Messick, M., Owens, E., Passmore, D., Pullium, M., Shavender, J., Smith, D., Smith, M., Snapp, J., Stosik, V., Sumner, D., Thel, M. C., Thompson, G., Workman, J., By, S., Carter, J., Gordon, C., Gothard, P., Granger, C. B., Harrington, R. A., Kruse, K. R., Mahaffey, K. W., McClanahan, M., Miller, M., Ohman, E. M., Pitzer, L., Tardiff, B., Winchell, M., Crowe, T., Debowey, D., Gates, K., Starr, S., Wagner, G. S., DAVIDSONRAY, L., Mark, D. B., DUMEE, C., Kitt, M., Lorenz, T., Obrien, M., Scarborough, R., Swift, R. 1997; 349 (9063): 1422-1428
  • Overview of randomized trials of intravenous heparin in patients with acute acute myocardial infarction treated with thrombolytic therapy AMERICAN JOURNAL OF CARDIOLOGY Mahaffey, K. W., Granger, C. B., Collins, R., OCONNOR, C. M., Ohman, E. M., Bleich, S. D., Col, J. J., Califf, R. M. 1996; 77 (8): 551-556

    Abstract

    Intravenous heparin is routinely given after thrombolytic therapy for patients with acute myocardial infarction in the United States and in some, but by no means all, other countries. Several trials have documented improved infarct-artery patency in patients treated with heparin; however, none was large enough individually to assess the effect of heparin on clinical outcomes. We performed a systematic overview of the 6 randomized controlled trials (1,735 patients) to summarize the available data concerning the risks and benefits of intravenous heparin versus no heparin after thrombolytic therapy. Mortality before hospital discharge was 5.1% for patients allocated to intravenous heparin compared with 5.6% for controls (relative risk reduction of 9%, odds ratio 0.91, 95% confidence interval 0.59 to 1.39). Similar rates of recurrent ischemia and reinfarction were observed among those allocated to heparin therapy or control. The rates of total stroke, intracranial hemorrhage, and severe bleeding were similar in patients allocated to heparin; however, the risk of any severity of bleeding was significantly higher (22.7% vs 16.2%; odds ratio 1.55, 95% confidence interval 1.21 to 1.98). There was no significant difference in the observed effects of heparin between patients receiving tissue-type plasminogen activator and those receiving streptokinase or anisoylated plasminogen streptokinase activator complex, or between patients who did and did not receive aspirin. The findings of this overview demonstrate that insufficient clinical outcome data are available to support or to refute the routine use of intravenous heparin therapy after thrombolysis. It is not known if these findings are due to lack of statistical power, inappropriate levels of anticoagulation, or lack of benefit of intravenous heparin. Large randomized studies of heparin (and of new antithrombotic regimens) are needed to establish the role of such therapy.

    View details for Web of Science ID A1996UD08300001

    View details for PubMedID 8610601

  • LEFT-VENTRICULAR PERFORMANCE AND REMODELING IN RABBITS AFTER MYOCARDIAL-INFARCTION - EFFECTS OF A THYROID-HORMONE ANALOG CIRCULATION Mahaffey, K. W., Raya, T. E., Pennock, G. D., Morkin, E., Goldman, S. 1995; 91 (3): 794-801

    Abstract

    Because the rat postinfarction model differs from human heart failure with respect to the composition of myosin heavy chain (MHC) isoforms and other contractile proteins, alternative animal models are needed for the development of new treatments for human heart failure. The purpose of this study was threefold: (1) to test the feasibility of using the V3(beta,beta) rabbit postinfarction model for the study of heart failure by characterizing the effects of chronic coronary artery occlusion on the left ventricle; (2) to determine whether the thyroid hormone analogue 3,5-diiodothyropropionic acid (DITPA) produces improvements in left ventricular function; and (3) to determine the effects of myocardial infarction and treatment with DITPA on MHC protein isoforms.Male New Zealand White rabbits underwent proximal circumflex coronary artery ligation. After infarction, rabbits were treated with DITPA (3.75 mg/kg body wt) or placebo for 21 days and then underwent conscious and open-chest hemodynamic studies. In separate groups of rabbits, beta- and alpha-MHC isoforms were separated, and relative proportions were measured using gradient sodium dodecyl sulfate-polyacrylamide gel electrophoresis and laser densitometry. Infarction resulted in increased left ventricular end-diastolic pressure and prolonged left ventricular relaxation (tau) (P = .001 for both variables). Postinfarction treatment with DITPA decreased left ventricular end-diastolic pressure and tau (P = .002 and P = .001, respectively) and increased maximum positive and negative dP/dt (P = .002 and P = .016, respectively). Infarcted rabbits treated with DITPA had no significant changes in heart rate or left ventricular systolic pressure compared with untreated rabbits with infarction. There were no significant differences in heart rate, positive dP/dt, peak systolic pressure, or tau between sham-operated rabbits and sham-operated rabbits treated with DITPA. Although infarction resulted in increased left ventricular diameter, there were no effects of DITPA on left ventricular remodeling. Neither myocardial infarction nor treatment with DITPA altered the ratio of MHC isoforms.Rabbits that survive occlusion of the circumflex artery will develop myocardial dysfunction and left ventricular remodeling. Therapy with DITPA, a thyroid hormone analogue, produces improvement in ventricular performance and reduces end-diastolic pressure. The hemodynamic effects of DITPA were not associated with alterations of MHC isoforms. Whether DITPA represents the prototype of a previously undescribed class of agents for the treatment of heart failure will need to be determined by clinical trials.

    View details for Web of Science ID A1995QD43400027

    View details for PubMedID 7828308

  • RAPID BIOASSAY SYSTEM FOR LEAD USING YOUNG JAPANESE QUAIL JOURNAL OF ENVIRONMENTAL PATHOLOGY AND TOXICOLOGY Stone, C. L., Mahaffey, K. R., FOX, M. R. 1979; 2 (3): 767-779

    Abstract

    A rapid bioassay of lead was established in young japanese quail. Each group of 10 day-old birds received deionized water and a purified diet ad libitum for 2 wk. The diet contained 0.2 microgram lead/g. Lead acetate was added to give 14.8, 34.4, 51.2, 74.4, 234, 563, or 1223 microgram total lead/g by analysis. The duodenum, kidneys, liver and tibias were assayed for lead. Consumption of a diet containing either 563 or 1223 ppm lead caused a decrease (P less than or equal to 0.05) in body weight after 1 wk and an increase in free erythrocyte protoporphyrin after 2wk. Inhibition of red blood cell delta-aminolevulinic acid dehydratase (RBC-ALAD) activity occurred in birds consuming as little as 14.8 ppm lead. Packed cell volumes and hemoglobin concentrations were not affected by the dietary treatments. Lead concentrations in tissues from birds fed the lowest level of added lead were greater than those found in the corresponding tissues of control birds. The concentration of lead in the tibia showed the most distinguishable group means and the most nearly linear response; the highest slope was between 14.8 and 110 ppm dietary lead, using log-log transformations. The rapid bioassay is suitable for investigating high lead foods.

    View details for Web of Science ID A1979GM37600014

    View details for PubMedID 422934

  • DELTA-AMINOLEVULINIC-ACID DEHYDRATASE - SENSITIVE INDICATOR OF LEAD-EXPOSURE IN JAPANESE QUAIL POULTRY SCIENCE Stone, C. L., FOX, M. R., Jones, A. L., Mahaffey, K. R. 1977; 56 (1): 174-181
  • INFLUENCE OF ETHANOL INGESTION ON LEAD TOXICITY IN RATS FED ISOCALORIC DIETS ARCHIVES OF ENVIRONMENTAL HEALTH Mahaffey, K. R., Goyer, R. A., Wilson, M. H. 1974; 28 (4): 217-222

    View details for Web of Science ID A1974S835100007

    View details for PubMedID 4814957