Robert Harrington

All Publications

• Triglyceride Levels, Alirocumab Treatment, and Cardiovascular Outcomes After an Acute Coronary Syndrome. Journal of the American College of Cardiology Zahger, D., Schwartz, G. G., Du, W., Szarek, M., Bhatt, D. L., Bittner, V. A., Budaj, A. J., Diaz, R., Goodman, S. G., Jukema, J. W., Kiss, R. G., Harrington, R. A., Moriarty, P. M., Scemama, M., Manvelian, G., Pordy, R., White, H. D., Zeiher, A. M., Fazio, S., Geba, G. P., Steg, P. G. 2024; 84 (11): 994-1006

  Abstract

  It is unknown whether clinical benefit of proprotein convertase subtilisin/kexin type 9 inhibitors is associated with baseline or on-treatment triglyceride concentrations.This study sought to examine relations between triglyceride levels and the effect of alirocumab vs placebo on cardiovascular outcomes using prespecified and post hoc analyses of the ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial.Patients with recent acute coronary syndrome (ACS) (n = 18,924) and elevated atherogenic lipoproteins despite optimized statin therapy were randomized to alirocumab 75 to 150 mg or matching placebo every 2 weeks subcutaneously. Major adverse cardiovascular events (MACE) were examined in relation to continuous or dichotomous triglyceride concentrations.Median baseline triglyceride concentration was 129 mg/dL. In both treatment groups, a 10-mg/dL higher baseline concentration was associated with an adjusted MACE HR of 1.008 (95% CI: 1.003-1.013; P < 0.005). Baseline triglycerides ≥150 vs <150 mg/dL were associated with a HR of 1.184 (95% CI: 1.080-1.297; P < 0.005). Versus placebo, alirocumab reduced low-density lipoprotein cholesterol from baseline (average, 54.7%) and reduced MACE (HR: 0.85; 95% CI: 0.78-0.93). At month 4, triglyceride levels were reduced from baseline by median 17.7 mg/dL (P < 0.001) and 0.9 mg/dL (P = NS) with alirocumab and placebo, respectively. A 10-mg/dL decline from baseline in triglycerides was associated with lower subsequent risk of MACE with placebo (HR: 0.988; 95% CI: 0.982-0.995; P < 0.005) but not with alirocumab (HR: 0.999; 95% CI: 0.987-1.010; P = 0.82).Among patients with recent ACS on optimized statin therapy, baseline triglycerides was associated with cardiovascular risk. However, the reduction in triglycerides with alirocumab did not contribute to its clinical benefit. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

  View details for DOI 10.1016/j.jacc.2024.06.035

  View details for PubMedID 39232634

• Apolipoprotein A-I Infusions and Cardiovascular Outcomes in Acute Myocardial Infarction According to Baseline LDL-Cholesterol Levels: The AEGIS-II Trial. European heart journal Gibson, C. M., Duffy, D., Bahit, M. C., Chi, G., White, H., Korjian, S., Alexander, J. H., Lincoff, A. M., Heise, M., Kingwell, B. A., Nicolau, J. C., Lopes, R. D., Cornel, J. H., Lewis, B. S., Vinereanu, D., Goodman, S. G., Bode, C., Steg, P. G., Libby, P., Sacks, F. M., Bainey, K. R., Ridker, P. M., Mahaffey, K. W., Aylward, P., Nicholls, S. J., Pocock, S. J., Mehran, R., Harrington, R. A. 2024

  Abstract

  In the AEGIS-II trial (NCT03473223), CSL112, a human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity, did not significantly reduce the risk of the primary endpoint through 90 days versus placebo after acute myocardial infarction (MI). Nevertheless, given the well-established relationship between higher low-density lipoprotein cholesterol (LDL-C) and plaque burden, as well as greater risk reductions seen with PCSK9 inhibitors in patients with baseline LDL-C ≥100 mg/dL on statin therapy, the efficacy of CSL112 may be influenced by baseline LDL-C.Overall, 18,219 patients with acute MI, multivessel coronary artery disease, and additional risk factors were randomized to either four weekly infusions of 6 g CSL112 or placebo. This exploratory post-hoc analysis evaluated cardiovascular outcomes by baseline LDL-C in patients prescribed guideline-directed statin therapy at the time of randomization (n=15,731).As baseline LDL-C increased, risk of the primary endpoint at 90 days lowered in those treated with CSL112 compared with placebo. In patients with LDL-C ≥100 mg/dL at randomization, there was a significant risk reduction of cardiovascular death, MI, or stroke in the CSL112 vs. placebo group at 90, 180, and 365 days (hazard ratio 0.69 [0.53-0.90], 0.71 [0.57-0.88], and 0.78 [0.65-0.93]). In contrast, there was no difference between treatment groups among those with LDL-C <100 mg/dL at baseline.In this population, treatment with CSL112 compared to placebo was associated with a significantly lower risk of recurrent cardiovascular events among patients with a baseline LDL-C ≥100 mg/dL. Further studies need to confirm that CSL112 efficacy is influenced by baseline LDL-C.

  View details for DOI 10.1093/eurheartj/ehae614

  View details for PubMedID 39221651

• Milvexian vs apixaban for stroke prevention in atrial fibrillation: The LIBREXIA atrial fibrillation trial rationale and design. American heart journal Jain, S. S., Mahaffey, K. W., Pieper, K. S., Shimizu, W., Potpara, T., Ruff, C. T., Kamel, H., Lewis, B. S., Cornel, J. H., Kowey, P. R., Horrow, J., Strony, J., Plotnikov, A. N., Li, D., Weng, S., Donahue, J., Gibson, C. M., Steg, P. G., Mehran, R., Weitz, J. I., Johnston, S. C., Hankey, G. J., Harrington, R. A., Lam, C. S. 2024

  Abstract

  Direct oral anticoagulants are the standard of care for stroke prevention in eligible patients with atrial fibrillation and atrial flutter; however, bleeding remains a significant concern, limiting their use. Milvexian is an oral Factor XIa inhibitor that may offer similar anticoagulant efficacy with less bleeding risk.LIBREXIA AF (NCT05757869) is a global phase III, randomized, double-blind, parallel-group, event-driven trial to compare milvexian with apixaban in participants with atrial fibrillation or atrial flutter. Participants are randomly assigned to milvexian 100 mg or apixaban (5 mg or 2.5 mg per label indication) twice daily. The primary efficacy objective is to evaluate if milvexian is noninferior to apixaban for the prevention of stroke and systemic embolism. The principal safety objective is to evaluate if milvexian is superior to apixaban in reducing the endpoint of International Society of Thrombosis and Hemostasis (ISTH) major bleeding events and the composite endpoint of ISTH major and clinically relevant nonmajor (CRNM) bleeding events. In total, 15,500 participants from approximately 1,000 sites in over 30 countries are planned to be enrolled. They will be followed until both 430 primary efficacy outcome events and 530 principal safety events are observed, which is estimated to take approximately 4 years.The LIBREXIA AF study will determine the efficacy and safety of the oral Factor XIa inhibitor milvexian compared with apixaban in participants with either atrial fibrillation or atrial flutter.ClinicalTrials.gov NCT05757869.

  View details for DOI 10.1016/j.ahj.2024.08.011

  View details for PubMedID 39214801

• ApoA-I Infusions and Burden of Ischemic Events After Acute Myocardial Infarction: Insights From the AEGIS-II Trial. Journal of the American College of Cardiology Gibson, C. M., Chi, G., Duffy, D., Bahit, M. C., White, H., Korjian, S., Alexander, J. H., Lincoff, A. M., Anschuetz, G., Girgis, I. G., Nicolau, J. C., Lopes, R. D., Cornel, J. H., Bainey, K. R., Libby, P., Sacks, F. M., Ridker, P. M., Goodman, S. G., Mahaffey, K. W., Nicholls, S. J., Pocock, S. J., Mehran, R., Harrington, R. A. 2024

  Abstract

  Following an acute myocardial infarction (AMI), patients remain at risk for subsequent cardiovascular (CV) events. In the AEGIS-II trial, CSL112, a human apolipoprotein A-I derived from plasma that enhances cholesterol efflux, did not significantly reduce the first occurrence of CV death, myocardial infarction (MI), or stroke through 90 days compared with placebo. However, an analysis involving only the first event may not capture the totality of the clinical impact of an intervention because patients may experience multiple events.This prespecified exploratory analysis examines the effect of CSL112 on total burden of nonfatal ischemic events (ie, recurrent MI and stroke) and CV death.A total of 18,219 patients with AMI, multivessel coronary artery disease, and additional CV risk factors were randomized to either 4 weekly infusions of 6 g CSL112 (n = 9,112) or matching placebo (n = 9,107). A negative binomial regression model was applied to estimate the effect of CSL112 compared with placebo on the rate ratio (RR) of ischemic events.For CV death, MI, and stroke, there were numerically fewer total events at 90 days (503 vs 545 events; rate ratio [RR]: 0.88; 95% CI: 0.76-1.03, P = 0.11), and nominally significantly fewer total events at 180 days (745 vs 821 events, RR: 0.87; 95% CI: 0.77-0.99; P = 0.04) and 365 days (1,120 vs 1,211 events; RR 0.89; 95% CI: 0.80-0.99; P = 0.04). Subsequent events constituted 13% of events at 90 days, 17% at 180 days, and 22% at 1 year. Similar findings were seen with the total occurrence of nonfatal MI and CV death. When type II MIs, unlikely to be modified by enhancing cholesterol efflux, were excluded, there were nominally significant reductions in the total occurrence of nonfatal MI (excluding type 2) and CV death at all timepoints (90 days: RR: 0.81; 95% CI: 0.68-0.97; P = 0.02; 180 days: RR: 0.82; 95% CI: 0.71-0.95; P < 0.01; 365 days: RR: 0.86; 95% CI: 0.76-0.98; P = 0.02).In this prespecified exploratory analysis of the AEGIS-II trial, 4 weekly infusions of CSL112 among high-risk patients after AMI significantly reduced the total burden of nonfatal ischemic events and CV death at 180 and 365 days compared with placebo. (AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome]; NCT03473223).

  View details for DOI 10.1016/j.jacc.2024.08.001

  View details for PubMedID 39230545

• Impact of aspirin dose according to race in secondary prevention of atherosclerotic cardiovascular disease: a secondary analysis of the ADAPTABLE randomised controlled trial. BMJ open Marquis-Gravel, G., Mulder, H., Wruck, L. M., Benziger, C. P., Effron, M. B., Farrehi, P. M., Girotra, S., Gupta, K., Kripalani, S., Muñoz, D., Polonsky, T. S., Whittle, J., Harrington, R., Rothman, R., Hernandez, A. F., Jones, W. S. 2024; 14 (8): e078197

  Abstract

  To evaluate whether the effectiveness and safety of low (81 mg daily) versus high-dose (325 mg daily) aspirin is consistent across races among patients with established atherosclerotic cardiovascular disease (ASCVD).A secondary analysis of the randomised controlled trial ADAPTABLE was performed.The study was conducted in 40 centres and one health plan participating in the National Patient-Centred Clinical Research Network (PCORnet) in the USA.Among 15 076 participants with established ASCVD, 14 096 had self-reported race available and were included in the analysis. Participants were divided according to self-reported race as Black (n=1311, 9.3%), White (n=11 990, 85.1%) or other race (n=795, 5.6%).Participants were randomised to open-label daily aspirin doses of 81 mg versus 325 mg in a 1:1 ratio for a median of 26.2 months.The primary effectiveness endpoint was a composite of death from any cause, hospitalisation for myocardial infarction or hospitalisation for stroke. The primary safety endpoint was hospitalisation for bleeding requiring blood product transfusion.Estimated cumulative incidence of the primary effectiveness endpoint at median follow-up with the 81 mg and the 325 mg daily doses were 6.70% and 7.12% in White participants (adjusted HR: 1.00 [95% CI: 0.88 to 1.15]); 12.27% and 10.69% in Black participants (adjusted HR: 1.40 [95% CI: 1.02 to 1.93]); and 6.88% and 7.69% in other participants (adjusted HR: 0.86 [95% CI: 0.54 to 1.39]) (p-interaction=0.12), respectively. There was no significant interaction between self-reported race and assigned aspirin dose regarding the secondary effectiveness and the primary safety endpoints.Race is not an effect modifier on the impact of aspirin dosing on effectiveness and safety in patients with established ASCVD. In clinical practice, treatment decisions regarding aspirin dose in secondary prevention of ASCVD should not be influenced by race.NCT02697916.

  View details for DOI 10.1136/bmjopen-2023-078197

  View details for PubMedID 39117415

• Contribution of Clinical Trial Event Data by Data Source: A Prespecified Analysis of the ADAPTABLE Randomized Clinical Trial. JAMA cardiology Rymer, J. A., Mulder, H., Wruck, L. M., Muñoz, D., Kripalani, S., Effron, M. B., Gupta, K., Handberg, E., Jain, S., Girotra, S., Whittle, J., Hess, R., Benziger, C. P., Knowlton, K. U., Curtis, L. H., Roe, M. T., Hammill, B. G., Rothman, R. L., Harrington, R., Hernandez, A., Jones, W. S. 2024

  Abstract

  Pragmatic randomized clinical trials (RCTs) often use multiple data sources to examine clinical events, but the relative contribution of data sources to clinical end-point rates is understudied.To assess the contribution of data sources (electronic health records [EHRs], public/private insurance claims, and/or participant-reported data) to clinical end points among ADAPTABLE participants who had available data.The ADAPTABLE study was an open-label, pragmatic RCT from April 2016 through June 2019 conducted in research networks within clinical practice. Participants had existing atherosclerotic cardiovascular disease and available data to analyze. The characteristics of patients by combinations of data source availability were compared to examine the contribution of each of the data sources to end-point ascertainment. Data for this prespecified analysis were examined from January 2022 to June 2023.Randomized exposure to 81 mg or 325 mg of aspirin daily.Number of events for the primary end point (composite of death, hospitalization for myocardial infarction, and hospitalization for stroke) that were contributed by EHR or claims data and then number of events contributed by each additional data source.Of 15 006 participants randomized with at least 1 other source of data available beyond participant-reported data, there were 8756 (58.3%) with participant-reported and EHR data; 4291 (28.6%) with participant-reported, EHR, and claims data; 1412 (9.4%) with EHR-only data; 262 (1.7%) with participant-reported and claims data; 202 (1.3%) with EHR and claims data; and 83 (0.6%) with claims-only data. Participants with EHR-only data were younger (median age, 63.7 years; IQR, 55.8-71.4) compared with the other groups (range, 65.6-71.9 years). Among participants with both EHR and claims data, with or without participant-reported data (n = 4493), for each outcome, most events (92%-100%) were identified in the EHR or in claims data. For all clinical end points, participant-reported data contributed less than 10% of events not otherwise available from claims or EHR data.In this analysis of a pragmatic RCT, claims and EHR data provided the most clinical end-point data when compared with participant-reported events. These findings provide a framework for collecting end points in pragmatic clinical trials. Further work is needed to understand the data source combinations that most effectively provide clinical end-point data in RCTs.

  View details for DOI 10.1001/jamacardio.2024.2019

  View details for PubMedID 39046724

• Aspirin Dosing for Secondary Prevention of Atherosclerotic Cardiovascular Disease in Male and Female Patients: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial. JAMA cardiology Benziger, C. P., Stebbins, A., Wruck, L. M., Effron, M. B., Marquis-Gravel, G., Farrehi, P. M., Girotra, S., Gupta, K., Kripalani, S., Munoz, D., Polonsky, T. S., Sharlow, A., Whittle, J., Harrington, R. A., Rothman, R. L., Hernandez, A. F., Jones, W. S. 2024

  Abstract

  Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in the US. Although aspirin is recommended for secondary prevention of ASCVD, there was no difference in safety and effectiveness of aspirin dosed daily at 81 mg or 325 mg in the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) randomized clinical trial. However, it is unknown whether differences by sex exist in the safety and effectiveness of the different aspirin doses.To evaluate sex-specific differences in the safety and effectiveness of 2 aspirin doses in the ADAPTAPLE trial.The ADAPTABLE study was an open-label, pragmatic, randomized clinical trial that randomly assigned participants with chronic, stable ASCVD to 81 mg vs 325 mg of aspirin daily. Using Cox proportional-hazard models, male and female participants were compared for outcomes. In addition, it was assessed whether sex was an effect modifier in the association between aspirin dose and outcomes. The ADAPTABLE trial was conducted at 40 medical centers and 1 health plan. Eligible patients were 18 years and older and had established ASCVD. Study data were analyzed from December 2021 to March 2024.Patients received 81 mg or 325 mg of aspirin daily for the secondary prevention of ASCVD.The primary effectiveness outcomes included all-cause death and hospitalization for myocardial infarction (MI) or stroke. The primary safety outcome was hospitalization for major bleeding requiring transfusion.A total of 15 076 patients (median [IQR] age, 67.6 [60.7-73.6] years; 10 352 male [68.7%]) were followed up for a median (IQR) of 26.2 (19.0-34.9) months. Overall, 4724 (31.3%) were female, and 2307 of the female participants (48.8%) received aspirin 81 mg. Compared with males, female participants were younger (median [IQR] age, 66.3 [59.4-72.6] years vs 68.2 (61.4-73.9) years, less likely to self-report White race (3426 [72.5%] vs 8564 [82.7%]), more likely to smoke (564 [12.9%] vs 818 [8.4%]), and more likely to have a history of peripheral arterial disease (1179 [25.7%] vs 2314 [23.0%]). The primary effectiveness outcome of all-cause death and hospitalization for MI or stroke occurred in 379 female participants (8.1%) and 780 male participants (7.1%). There was no significant interaction by sex for the primary effectiveness end point between the 2 aspirin doses (female adjusted hazard ratio [aHR], 1.01; 95% CI, 0.82-1.26 and male aHR, 1.06; 95% CI, 0.91-1.23; P interaction term for sex = .74). During the trial, female participants had fewer revascularization procedures (237 [5.0%] vs 680 [6.6%]; aHR, 0.79; 95% CI, 0.68-0.92; P = .002) but had a higher risk of hospitalization for stroke (aHR, 1.72; 95% CI, 1.27-2.33; P < .001). Among female participants, there was a slightly higher rate of bleeding in the 81-mg aspirin cohort compared with the 325-mg cohort (20 [0.83%] vs 13 [0.52%]; aHR, 2.21; 95% CI, 1.04-4.70; P interaction term for sex = .07). There were no significant differences between female and male participants regarding aspirin dose adherence.In this secondary analysis of the ADAPTABLE trial, there were no significant sex-specific differences in the effectiveness and safety of 2 aspirin doses for secondary prevention of ASCVD events.ClinicalTrials.gov Identifier: NCT02697916.

  View details for DOI 10.1001/jamacardio.2024.1712

  View details for PubMedID 38985488

  View details for PubMedCentralID PMC11238071

• Factors Associated With Coronary Angiography Performed Within 6 Months of Randomization to the Conservative Strategy in the ISCHEMIA Trial. Circulation. Cardiovascular interventions Pracoń, R., Spertus, J. A., Broderick, S., Bangalore, S., Rockhold, F. W., Ruzyllo, W., Demchenko, E., Nageh, T., Grossman, G. B., Mavromatis, K., Manjunath, C. N., Smanio, P. E., Stone, G. W., Mancini, G. B., Boden, W. E., Newman, J. D., Reynolds, H. R., Hochman, J. S., Maron, D. J. 2024: e013435

  Abstract

  ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) did not find an overall reduction in cardiovascular events with an initial invasive versus conservative management strategy in chronic coronary disease; however, there were conservative strategy participants who underwent invasive coronary angiography early postrandomization (within 6 months). Identifying factors associated with angiography in conservative strategy participants will inform clinical decision-making in patients with chronic coronary disease.Factors independently associated with angiography performed within 6 months of randomization were identified using Fine and Gray proportional subdistribution hazard models, including demographics, region of randomization, medical history, risk factor control, symptoms, ischemia severity, coronary anatomy based on protocol-mandated coronary computed tomography angiography, and medication use.Among 2591 conservative strategy participants, angiography within 6 months of randomization occurred in 8.7% (4.7% for a suspected primary end point event, 1.6% for persistent symptoms, and 2.6% due to protocol nonadherence) and was associated with the following baseline characteristics: enrollment in Europe versus Asia (hazard ratio [HR], 1.81 [95% CI, 1.14-2.86]), daily and weekly versus no angina (HR, 5.97 [95% CI, 2.78-12.86] and 2.63 [95% CI, 1.51-4.58], respectively), poor to fair versus good to excellent health status (HR, 2.02 [95% CI, 1.23-3.32]) assessed with Seattle Angina Questionnaire, and new/more frequent angina prerandomization (HR, 1.80 [95% CI, 1.34-2.40]). Baseline low-density lipoprotein cholesterol <70 mg/dL was associated with a lower risk of angiography (HR, 0.65 [95% CI, 0.46-0.91) but not baseline ischemia severity nor the presence of multivessel or proximal left anterior descending artery stenosis >70% on coronary computed tomography angiography.Among ISCHEMIA participants randomized to the conservative strategy, angiography within 6 months of randomization was performed in <10% of patients. It was associated with frequent or increasing baseline angina and poor quality of life but not with objective markers of disease severity. Well-controlled baseline low-density lipoprotein cholesterol was associated with a reduced likelihood of angiography. These findings point to the importance of a comprehensive assessment of symptoms and a review of guideline-directed medical therapy goals when deciding the initial treatment strategy for chronic coronary disease.URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

  View details for DOI 10.1161/CIRCINTERVENTIONS.123.013435

  View details for PubMedID 38629312

• Variation in Health Status With Invasivevs Conservative Management ofChronic Coronary Disease. Journal of the American College of Cardiology Arnold, S. V., Jones, P. G., Maron, D. J., Cohen, D. J., Mark, D. B., Reynolds, H. R., Bangalore, S., Chen, J., Newman, J. D., Harrington, R. A., Stone, G. W., Hochman, J. S., Spertus, J. A., ISCHEMIA Research Group 2024; 83 (15): 1353-1366

  Abstract

  BACKGROUND: The ISCHEMIA trial found that patients with chronic coronary disease randomized to invasive strategy had better health status than those randomized to conservative strategy. It is unclear how best to translate these population-level results to individual patients.OBJECTIVES: The authors sought to identify patient characteristics associated with health status from invasive and conservative strategies, and develop a prediction algorithm for shared decision-making.METHODS: One-year disease-specific health status was assessed in ISCHEMIA with the Seattle Angina Questionnaire (SAQ) Summary Score (SAQ SS) and Angina Frequency, Physical Limitations (PL), and Quality of Life (QL) domains (range 0-100, higher=less angina/better health status).RESULTS: Among 4,617 patients from 320 sites in 37 countries, mean SAQ SS was 74.1 ± 18.9 at baseline and 85.7±15.6 at 1 year. Lower baseline SAQ SS and younger age were associated with better 1-year health status with invasive strategy (P interaction=0.009 and P interaction=0.004, respectively). For the individual domains, there were significant treatment interactions for baseline SAQ score (Angina Frequency, PL), age (PL, QL), anterior ischemia (PL), and number of baseline antianginal medications (QL), with more benefit of invasive in patients with worse baseline health status, younger age, anterior ischemia, and on more antianginal medications. Parsimonious prediction models were developed for 1-year SAQ domains with invasive or conservative strategies to support shared decision-making.CONCLUSIONS: In the management of chronic coronary disease, individual patient characteristics are associated with 1-year health status, with younger age and poorer angina-related health status showing greater benefit from invasive management. This prediction algorithm can support the translation of the ISCHEMIA trial results to individual patients. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

  View details for DOI 10.1016/j.jacc.2024.02.019

  View details for PubMedID 38599711

• Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study. Journal of clinical lipidology Bittner, V. A., Schwartz, G. G., Bhatt, D. L., Chua, T., De Silva, H. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., McGinniss, J., Pordy, R., Garon, G., Scemama, M., White, H. D., Steg, P. G., Szarek, M. 2024

  Abstract

  The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS).We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level.This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment.Women were older, had higher baseline LDL-C levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes.Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).

  View details for DOI 10.1016/j.jacl.2024.04.122

  View details for PubMedID 38960812

• Apolipoprotein A1 Infusions and Cardiovascular Outcomes after Acute Myocardial Infarction. The New England journal of medicine Gibson, C. M., Duffy, D., Korjian, S., Bahit, M. C., Chi, G., Alexander, J. H., Lincoff, A. M., Heise, M., Tricoci, P., Deckelbaum, L. I., Mears, S. J., Nicolau, J. C., Lopes, R. D., Merkely, B., Lewis, B. S., Cornel, J. H., Trebacz, J., Parkhomenko, A., Libby, P., Sacks, F. M., Povsic, T. J., Bonaca, M., Goodman, S. G., Bhatt, D. L., Tendera, M., Steg, P. G., Ridker, P. M., Aylward, P., Kastelein, J. J., Bode, C., Mahaffey, K. W., Nicholls, S. J., Pocock, S. J., Mehran, R., Harrington, R. A. 2024

  Abstract

  Cardiovascular events frequently recur after acute myocardial infarction, and low cholesterol efflux - a process mediated by apolipoprotein A1, which is the main protein in high-density lipoprotein - has been associated with an increased risk of cardiovascular events. CSL112 is human apolipoprotein A1 derived from plasma that increases cholesterol efflux capacity. Whether infusions of CSL112 can reduce the risk of recurrent cardiovascular events after acute myocardial infarction is unclear.We conducted an international, double-blind, placebo-controlled trial involving patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors. Patients were randomly assigned to receive either four weekly infusions of 6 g of CSL112 or matching placebo, with the first infusion administered within 5 days after the first medical contact for the acute myocardial infarction. The primary end point was a composite of myocardial infarction, stroke, or death from cardiovascular causes from randomization through 90 days of follow-up.A total of 18,219 patients were included in the trial (9112 in the CSL112 group and 9107 in the placebo group). There was no significant difference between the groups in the risk of a primary end-point event at 90 days of follow-up (439 patients [4.8%] in the CSL112 group vs. 472 patients [5.2%] in the placebo group; hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.05; P = 0.24), at 180 days of follow-up (622 patients [6.9%] vs. 683 patients [7.6%]; hazard ratio, 0.91; 95% CI, 0.81 to 1.01), or at 365 days of follow-up (885 patients [9.8%] vs. 944 patients [10.5%]; hazard ratio, 0.93; 95% CI, 0.85 to 1.02). The percentage of patients with adverse events was similar in the two groups; a higher number of hypersensitivity events was reported in the CSL112 group.Among patients with acute myocardial infarction, multivessel coronary artery disease, and additional cardiovascular risk factors, four weekly infusions of CSL112 did not result in a lower risk of myocardial infarction, stroke, or death from cardiovascular causes than placebo through 90 days. (Funded by CSL Behring; AEGIS-II ClinicalTrials.gov number, NCT03473223.).

  View details for DOI 10.1056/NEJMoa2400969

  View details for PubMedID 38587254

• Effect of CSL112 on Recurrent Myocardial Infarction and Cardiovascular Death: Insights from the AEGIS-II Trial. Journal of the American College of Cardiology Povsic, T. J., Korjian, S., Bahit, M. C., Chi, G., Duffy, D., Alexander, J. H., Vinereanu, D., Tricoci, P., Mears, S. J., Deckelbaum, L. I., Bonaca, M., Ridker, P. M., Goodman, S. G., Cornel, J. H., Lewis, B. S., Parkhomenko, A., Lopes, R. D., Aylward, P., Lincoff, A. M., Heise, M., Sacks, F., Nicolau, J. C., Merkely, B., Trebacz, J., Libby, P., Nicholls, S. J., Pocock, S., Bhatt, D. L., Kastelein, J., Bode, C., Mahaffey, K. W., Steg, P. G., Tendera, M., Bainey, K. R., Harrington, R. A., Mehran, R., Duerschmied, D., Kingwell, B. A., Gibson, C. M. 2024

  Abstract

  The AEGIS-II trial hypothesized that CSL112, an intravenous formulation of human apoA-I, would lower the risk of plaque disruption, decreasing the risk of recurrent events such as myocardial infarction (MI) among high-risk patients with MI.This exploratory analysis evaluates the effect of CSL112 therapy on the incidence of CV death and recurrent MI.The AEGIS-II trial was an international, multicenter, randomized, double-blind, placebo-controlled trial that randomized 18,219 high-risk acute MI patients to 4 weekly infusions of apoA-I (6g CSL112) or placebo.The incidence of the composite of cardiovascular death and type 1 MI was 11-16% lower in the CSL112 group over the study period (HR of 0.84 [95% CI 0.7-1.0; p=0.056] day 90, HR 0.86, [95% CI 0.74-0.99; p=0.048] day 180, and HR 0.89, [95% CI 0.79-1.01 p=0.07; p=0.07] day 365). Similarly, the incidence of CV death or any MI was numerically lower in CSL112 treated patients throughout the follow-up period (HR 0.92 [95% CI 0.8-1.05], 0.89 [95% CI 0.79-0.996], 0.91 [0.82-1.01]. The effect of CSL112 treatment on MI was predominantly observed for type 1 MI and type 4b (MI due to stent thrombosis).While CSL112 did not significantly reduce the occurrence of the primary study endpoints, patients treated with CSL112 infusions had numerically lower rates of CV death and MI, type-1 MI, and stent thrombosis-related MI compared to placebo. These findings could suggest a role of apoA-I in reducing subsequent plaque disruption events via enhanced cholesterol efflux. Further prospective data would be needed to confirm these observations.

  View details for DOI 10.1016/j.jacc.2024.03.396

  View details for PubMedID 38588930

• Sex Differences in Revascularization, Treatment Goals, and Outcomes of Patients With Chronic Coronary Disease: Insights From the ISCHEMIA Trial. Journal of the American Heart Association Reynolds, H. R., Cyr, D. D., Merz, C. N., Shaw, L. J., Chaitman, B. R., Boden, W. E., Alexander, K. P., Rosenberg, Y. D., Bangalore, S., Stone, G. W., Held, C., Spertus, J., Goetschalckx, K., Bockeria, O., Newman, J. D., Berger, J. S., Elghamaz, A., Lopes, R. D., Min, J. K., Berman, D. S., Picard, M. H., Kwong, R. Y., Harrington, R. A., Thomas, B., O'Brien, S. M., Maron, D. J., Hochman, J. S., ISCHEMIA Research Group *, Mavromatis, K., Linefsky, J., Miller, T., Banerjee, S., Reynolds, H. R., Newman, J. D., Bangalore, S., Donnino, R. M., Phillips, L. M., Saric, M., Abdul-Nour, K., Stone, P. H., Jang, J. J., Yee, G., Weitz, S., Arnold, S., O'Keefe, J. H., Shapiro, M. D., El-Hajjar, M., Sidhu, M. S., Fein, S. A., Torosoff, M. T., Lyubarova, R., Mookherjee, S., Drzymalski, K., McFalls, E. O., Garcia, S. A., Bertog, S. C., Siddiqui, R. A., Ishani, A., Hansen, R. A., Khouri, M. G., Goldberg, J. L., Goldweit, R., Cohen, R. A., Mirrer, B., Navarro, V., Winchester, D. E., Kronenberg, M., Rogal, P., McFarren, C., Heitner, J. F., Dauber, I. M., Cannan, C., Sudarshan, S., Mehta, P. K., McDaniel, M., Lerakis, S., Quyyumi, A., Wenger, N. K., Hedgepeth, C. M., Hurlburt, H., Rosen, A., Sahul, Z., Booth, D., Leung, S., Abdel-Latif, A., Reda, H., Ziada, K., Setty, S., Barua, R. S., Hage, F., Caldeira, C., Davies, J. E., Leesar, M., Heo, J., Iskandrian, A., Al Solaiman, F., Singh, S., Dajani, K., El-Hajjar, M., Der Mesropian, P., Sacco, J., McCandless, B., Orgera, M., Sidhu, M. S., Arif, I., Kerr, H., Trejo Gutierrez, J. F., Fletcher, G., Lane, G. E., Neeson, L. M., Parikh, P. P., Pollak, P. M., Shapiro, B. P., Landolfo, K., Gemignani, A., O'Rourke, D., Meadows, J. L., Call, J. T., Hannan, J., Bojar, R., Kumar, D., Mukai, J., Martin, E. T., Vorobiof, G., Moorman, A., Kinlay, S., Hamburger, R. J., Rocco, T. P., Bhatt, D. L., Croce, K., Quin, J. A., Anumpa, J., Zenati, M., Faxon, D. P., Rayos, G., Seedhom, A., Sullenberger, L., Kumkumian, G., Sedlis, S. P., Donnino, R. M., Lorin, J., Tamis-Holland, J. E., Kornberg, R., Leber, R., Saba, S., Lee, M. W., Small, D. R., Nona, W., Alexander, P. B., Rehman, I., Badami, U., Marzo, K., Robbins, I. H., Levite, H. A., Shetty, S., Patel, M., Hamroff, G. S., Little, R. W., Zimbelman, B. D., Lui, C. Y., Smith, B. R., Vezina, D. P., Khor, L. L., Abraham, J. D., Bull, D. A., McKellar, S. H., Booth, D., Kotter, J., Abdel-Latif, A., Hu, B., Labovitz, A. J., Berlowitz, M., Rogal, P., McFarren, C., Matar, F., Caldeira, C., Maron, D. J., Rodriguez, F., Schnittger, I., Fearon, W. F., Deedwania, P., Reddy, K., Sweeny, J., Spizzieri, C., Hochberg, C. P., Salerno, W. D., Wyman, R., Zarka, A., Shah, A. V., Haldis, T., Kohn, J. A., Girotra, S., Almousalli, O., Krishnam, M. S., Milliken, J. C., Patel, P. M., Seto, A. H., Harley, K. T., Gibson, M. A., Allen, B. J., Coram, R., Thomas, S., Schwartz, R. G., Chen, W., El Shahawy, M., Stafford, J., Abernethy, W. B., Zurick, A., Meyer, T. M., Morford, R. G., Rutkin, B., Bokhari, S., Sokol, S. I., Meisner, J., Hamzeh, I., Misra, A., Wall, M., De Rosen, V. L., Alam, M., Turner, M. C., Mulhearn, T. J., Good, A. P., Shammas, N. W., Chilton, R., Nguyen, P. K., Jezior, M., Gordon, P. C., Crain, T., Stenberg, R., Pedalino, R. P., Wiesel, J., Juang, G. J., Al-Amoodi, M., Wohns, D., Lader, E. W., Mumma, M., Dharmarajan, L., McGarvey, J. F., Downes, T. R., Luckasen, G. J., Cheong, B., Potluri, S., Mastouri, R. A., Breall, J. A., Revtyak, G. E., Bazeley, J. W., Li, D., Giedd, K., Old, W., Burt, F., Sokhon, K., Gopal, D., Valeti, U. S., Kobashigawa, J., Govindan, S. C., Nair, R. G., Manjunath, C. N., Moorthy, N., Manjunath, S. C., Narayanappa, S., Pandit, N., Nath, R. K., Dwivedi, S. K., Narain, V. S., Chandra, S., Wander, G. S., Tandon, R., Ralhan, S., Aslam, N., Goyal, A., Bhargava, B., Karthikeyan, G., Ramakrishnan, S., Seth, S., Yadav, R., Singh, S., Roy, A., Parakh, N., Verma, S. K., Narang, R., Mishra, S., Naik, N., Sharma, G., Choudhary, S. K., Patel, C., Gulati, G., Sharma, S., Bahl, V. K., Mathew, A., Punnoose, E., Gadkari, M. A., Gadage, S., Pillay, T. U., Satheesh, S., Mathur, A., Kaul, U., Christopher, J., Menon, R., Kumar, N., Oomman, A., Mao, R., Solomon, H., Naik, S., Khan, S. P., Christopher, J., Kumar, N., Grant, P., Kachru, R., Ajit Kumar, V. K., Ganapathi, S., Jayakumar, K., Sivadasanpillai, H., Sasidharan, B., Kapilamoorthy, T. R., Christopher, J., Polamuri, P., Kaul, U., Senior, R., Elghamaz, A., Gurunathan, S., Karogiannis, N., Shah, B. N., Trimlett, R. H., Rubens, M. B., Nicol, E. D., Mittal, T. K., Hampson, R., Gamma, R. A., de Belder, M. A., Thambyrajah, J., Nageh, T., Davies, J. R., Lindsay, S. J., Kurian, J., Jamil, H., Raheem, O., Hoye, A., Donnelly, P., Valecka, B., Chauhan, A., Barr, C., Alfakih, K., Byrne, J., Webb, I., Henriksen, P., OKane, P., de Silva, R., Conway, D. S., Sirker, A. A., Hoole, S. P., Witherow, F. N., Johnston, N., Harbinson, M., Walsh, S., Douglas, H., Luckie, M., Sobolewska, J., Jeetley, P., Patel, N., Kotecha, T., Travill, C., Karimullah, I., Al-Bustami, M., Braganza, D., Henderson, R., Pointon, K., Naik, S., Mathew, T., Berry, C., Collison, D., Roditi, G., Moriarty, A. J., Glover, J. D., Pradhan, J., Mikhail, G., Francis, D. P., Gosselin, G., Diaz, A., Rheault, P., Barrero, M., Gagne, C., Pepin-Dubois, Y., Costa, R., Sia, Y. T., Lemay, C., Gisbert, A., Gervais, P., Rheault, A., Phaneuf, D. C., Gosselin, G., Garg, P., Chow, B. J., Hessian, R. C., Beanlands, R. S., Davies, R. F., Bainey, K. R., Cheema, A. N., Bagai, A., Wald, R., Goodman, S., Graham, J. J., Peterson, M., Chow, C., Abramson, B., Cheema, A. N., Vakani, M. T., Cha, J., Howarth, A. G., Wong, G., Uxa, A., Galiwango, P., Kassam, S., Mukherjee, A., Ricci, A. J., Lam, A., Mehta, S., Udell, J., Genereux, P., Hameed, A., Daba, L., Hueb, W., Rezende, P. C., Silva, E. E., Hueb, A. C., Smanio, P. E., de Quadros, A. S., Kalil, R. A., da Costa Vieira, J. L., Grossmann, G., de Oliveira, P. P., Bridi, L., Savaris, S., Vitola, J. V., Cerci, R. J., Farias, F. R., Fernandes, M. M., Marin-Neto, J. A., Schmidt, A., de Oliveira Lima Filho, M., Oliveira, R. M., Chierice, J. R., Polanczyk, C. A., Furtado, M. V., Smidt, L. F., Carvalho, A. C., Pucci, G., Lyra, F., Junior, A. R., Dracoulakis, M. D., Lima, R. G., Figueiredo, E., Caramori, P. R., Tumelero, R., Dall'Orto, F., Mesquita, C. T., Colafranseschi, A. S., Oliveira, A. C., Carvalho, L. A., Palazzo, I. C., Sousa, A. S., da Silva, E. E., de Barros, P. G., de Padua Silva Baptista, L., Rodrigues, M. J., de Resende, M. V., Saraiva, J. F., Costantini, C., Demkow, M., Pracon, R., Kepka, C., Teresinska, A., Kryczka, K., Henzel, J., Solecki, M., Kaczmarska, E., Mazurek, T., Drozdz, J., Czarniak, B., Frach, M., Szymczyk, K., Niedzwiecka, I., Sobczak, S., Ciurus, T., Jakubowski, P., Misztal-Teodorczyk, M., Teodorczyk, D., Fratczak, A., Szkopiak, M., Lebioda, P., Wlodarczyk, M., Plachcinska, A., Kusmierek, J., Miller, M., Marciniak, H., Wojtczak-Soska, K., Luczak, K., Tarchalski, T., Cichocka-Radwan, A., Szwed, H., Szulczyk, G. A., Witkowski, A., Kukula, K., Celinska-Spodar, M., Zalewska, J., Gajos, G., Bury, K., Pruszczyk, P., Roik, M., Loboz-Grudzien, K., Sokalski, L., Brzezinska, B., Lesiak, M., Lanocha, M., Reczuch, K. W., Kalarus, Z., Swiatkowski, A., Szulik, M., Musial, W. J., Bockeria, L., Petrosyan, K., Trifonova, T., Chernyavskiy, A. M., Kretov, E. I., Grazhdankin, I. O., Bershtein, L. L., Sayganov, S. A., Kuzmina-Krutetskaya, A. M., Zbyshevskaya, E. V., Katamadze, N. O., Demchenko, E. A., Kozlov, P. S., Kozulin, V. Y., Lubinskaya, E. I., Lopez-Sendon, J., Castro, A., Salicio, E. R., Guzman, G., Galeote, G., Valbuena, S., Peteiro, J., Martinez-Ruiz, M. D., Perez-Fernandez, R., Cuenca-Castillo, J. J., Flores-Rios, X., Prada-Delgado, O., Barge-Caballero, G., Juanatey, J. R., Bayarri, M. S., Nunez, V. P., Sanchez, R. O., Alvarez, B. C., Gil, C. P., Monzonis, A. M., Sionis, A., Perales, M. V., Padro, J. M., Penaranda, A. S., Picart, J. G., Iglesias, A. G., Marimon, X. G., Llado, G. P., Costa, F. C., Miro, V., Diez, J. L., Calvillo, P., Ortuno, F. M., Chavarri, M. V., Montolliu, A. T., Bermudez, E. P., De La Morena, G., Blancas, M. G., Luena, J. E., Fernandez-Aviles, F., Chen, J., Wu, Y., Ma, Y., Yang, Y., Ji, Z., Yang, X., Lin, W., Zeng, H., Fu, X., Yang, B., Wang, S., Cheng, G., Zhao, Y., Fang, X., Zeng, Q., Su, X., Li, Q., Nie, S., Yu, Q., Wang, J., Zhang, S., Liu, Z., Perna, G. P., Marini, M., Gabrielli, G., Provasoli, S., Verna, E., Monti, L., Nardi, B., Di Chiara, A., Mortara, A., Galvani, M., Ottani, F., Sicuro, M., Calabro, P., Formisano, T., Tarantini, G., Cucchini, U., Andres, A. L., Racca, E., Briguori, C., Amati, R., Vergoni, W., Russo, A., Fanelli, R., Poh, K., Chai, P., Lau, T., Loh, J. P., Tay, E. L., Teoh, K., Teo, L. L., Ong, C., Wong, R. C., Loh, P., Kofidis, T., Chan, W. X., Chan, K. H., Foo, D., Kong, J. L., Er, C. M., Jafary, F. H., Chua, T., Doerr, R., Stumpf, J., Matschke, K., Simonis, G., Kadalie, C. T., Sechtem, U., Ong, P., Schulze, P. C., Goebel, B., Lenk, K., Nickenig, G., Schuchlenz, H., Weikl, S., Lang, I. M., Huber, K., Jakl-Kotauschek, G., Vertes, A., Varga, A., Fontos, G., Merkely, B., Kerecsen, G., Hinic, S., Zdravkovic, M., Mudrenovic, V., Crnokrak, B., Beleslin, B. D., Boskovic, N. N., Petrovic, M. T., Dobric, M. R., Markovic, Z. Z., Mladenovic, A. S., Cemerlic-Adjic, N., Davidovic, G., Vucic, R., Dekleva, M. N., Stankovic, G., Apostolovic, S., Escobedo, J., Baleon-Espinosa, R., Campos-Santaolalla, A. S., Duran-Cortes, E., Flores-Palacios, J. M., Garcia-Rincon, A., Jimenez-Santos, M., Penafiel, J. V., Ortega-Ramirez, J. A., Valdespino-Estrada, A., Rosas, E. A., Selvanayagam, J. B., Joseph, M. X., Thambar, S. T., Beltrame, J. F., Hillis, G. S., Thuaire, C., Dutoiu, T., Steg, P. G., Juliard, J., Slama, M. S., El Mahmoud, R., Nicollet, E., Goube, P., Barone-Rochette, G., Furber, A., Biere, L., Laucevicius, A., Celutkiene, J., Kedhi, E., Timmer, J., Hermanides, R., Kaplan, E., Riezebos, R. K., Samadi, P., van Dongen, E., Niehe, S. R., Suryapranata, H., van Vugt, S., Ramos, R., Cacela, D., Santana, A., Fiarresga, A., Sousa, L., Marques, H., Patricio, L., Bernanrdes, L., Rio, P., Carvalho, R., Ferreira, R., Silva, T., Rodrigues, I., Modas, P., Portugal, G., Fragata, J., Pinto, F. J., Menezes, M. N., Lopes, G. C., Almeida, A. G., Silva, P. C., Nobre, A., Francisco, A. R., Ferreira, N., Lopes, R. L., Guzman, L., Figal, J. C., Mendiz, O., Cortes, C., Favaloro, R. R., Alvarez, C., Courtis, J., Zeballos, G., Schiavi, L., Rubio, M., Devlin, G. P., Fisher, R., Stewart, R. A., White, H. D., Benatar, J., Kedev, S., Mitevska, I. P., Kostovska, E. S., Pejkov, H., Held, C., Eggers, K., Frostfelt, G., Johnston, N., Olsowka, M., Akerblom, A., Soveri, I., Aspberg, J., Sharir, T., Elian, D., Kerner, A., Massalha, S., Fukuda, K., Kohsaka, S., Yasuda, S., Nishimura, S., Goetschalckx, K., Van de Werf, F., Claes, K., Hung, C., Yun, C., Hou, C. J., Kuo, J., Yeh, H., Hung, T., Li, J., Chien, C., Tsai, C., Liu, C., Yu, F., Lin, Y., Lan, W., Yen, C., Tsai, J., Sung, K., Ntsekhe, M., Pandie, S., Viljoen, C. A., De Andrade, M., Moccetti, T., Rossi, M. G., Abdelhamid, M., Adel, A., Kamal, A., Mahrous, H., El Kaffas, S., El Fishawy, H., Pop, C., Claudia, M., Popescu, B. A., Ginghina, C., Deleanu, D., Iliescu, V. A., Al-Mallah, M. H., Aljzeeri, A., Najm, H., Alghamdi, A., Ramos, W. E., Kuanprasert, S., Prommintikul, A., Nawarawong, W., Woragidpoonpol, S., Tepsuwan, T., Taksaudom, N., Rimsukcharoenchai, C., Euathrongchit, J., Wannasopha, Y., Yamwong, S., Sritara, P., Aramcharoen, S., Meemuk, K., Khairuddin, A., Hadi, H. A., Yahaya, S. A. 2024: e029850

  Abstract

  BACKGROUND: Women with chronic coronary disease are generally older than men and have more comorbidities but less atherosclerosis. We explored sex differences in revascularization, guideline-directed medical therapy, and outcomes among patients with chronic coronary disease with ischemia on stress testing, with and without invasive management.METHODS AND RESULTS: The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial randomized patients with moderate or severe ischemia to invasive management with angiography, revascularization, and guideline-directed medical therapy, or initial conservative management with guideline-directed medical therapy alone. We evaluated the primary outcome (cardiovascular death, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest) and other end points, by sex, in 1168 (22.6%) women and 4011 (77.4%) men. Invasive group catheterization rates were similar, with less revascularization among women (73.4% of invasive-assigned women revascularized versus 81.2% of invasive-assigned men; P<0.001). Women had less coronary artery disease: multivessel in 60.0% of invasive-assigned women and 74.8% of invasive-assigned men, and no ≥50% stenosis in 12.3% versus 4.5% (P<0.001). In the conservative group, 4-year catheterization rates were 26.3% of women versus 25.6% of men (P=0.72). Guideline-directed medical therapy use was lower among women with fewer risk factor goals attained. There were no sex differences in the primary outcome (adjusted hazard ratio [HR] for women versus men, 0.93 [95% CI, 0.77-1.13]; P=0.47) or the major secondary outcome of cardiovascular death/myocardial infarction (adjusted HR, 0.93 [95% CI, 0.76-1.14]; P=0.49), with no significant sex-by-treatment-group interactions.CONCLUSIONS: Women had less extensive coronary artery disease and, therefore, lower revascularization rates in the invasive group. Despite lower risk factor goal attainment, women with chronic coronary disease experienced similar risk-adjusted outcomes to men in the ISCHEMIA trial.REGISTRATION: URL: http://wwwclinicaltrials.gov. Unique identifier: NCT01471522.

  View details for DOI 10.1161/JAHA.122.029850

  View details for PubMedID 38410945

• Age and Aspirin Dosing in Secondary Prevention of Atherosclerotic Cardiovascular Disease. Journal of the American Heart Association Marquis-Gravel, G., Stebbins, A., Wruck, L. M., Roe, M. T., Effron, M. B., Hammill, B. G., Whittle, J., VanWormer, J. J., Robertson, H. R., Alikhaani, J. D., Kripalani, S., Farrehi, P. M., Girotra, S., Benziger, C. P., Polonsky, T. S., Merritt, J. G., Gupta, K., McCormick, T. E., Knowlton, K. U., Jain, S. K., Kochar, A., Rothman, R. L., Harrington, R. A., Hernandez, A. F., Jones, W. S. 2024: e026921

  Abstract

  In patients with atherosclerotic cardiovascular disease, increasing age is concurrently associated with higher risks of ischemic and bleeding events. The objectives are to determine the impact of aspirin dose on clinical outcomes according to age in atherosclerotic cardiovascular disease.In the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) trial, patients with atherosclerotic cardiovascular disease were randomized to daily aspirin doses of 81 mg or 325 mg. The primary effectiveness end point was death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke. The primary safety end point was hospitalization for bleeding requiring transfusion. A total of 15 076 participants were randomized to aspirin 81 mg (n=7540) or 325 mg (n=7536) daily (median follow-up: 26.2 months; interquartile range: 19.0-34.9 months). Median age was 67.6 years (interquartile range: 60.7-73.6 years). Among participants aged <65 years (n=5841 [38.7%]), a primary end point occurred in 226 (7.54%) in the 81 mg group, and in 191 (6.80%) in the 325 mg group (adjusted hazard ratio [HR], 1.23 [95% CI, 1.01-1.49]). Among participants aged ≥65 years (n=9235 [61.3%]), a primary end point occurred in 364 (7.12%) in the 81 mg group, and in 378 (7.96%) in the 325 mg group (adjusted HR, 0.95 [95% CI, 0.82-1.10]). The age-dose interaction was not significant (P=0.559). There was no significant interaction between age and the randomized aspirin dose for the secondary effectiveness and the primary safety bleeding end points (P>0.05 for all).Age does not modify the impact of aspirin dosing (81 mg or 325 mg daily) on clinical end points in secondary prevention of atherosclerotic cardiovascular disease.

  View details for DOI 10.1161/JAHA.122.026921

  View details for PubMedID 38348779

• Two of a kind: mass and molar immunoassay-based lipoprotein (a) concentrations are similarly prognostic for MACE risk and predictive of alirocumab benefit in ODYSSEY OUTCOMES Szarek, M., Steg, P. G., Jukema, J. W., Reijders, E., Schwertfeger, M., Bhatt, D., Bittner, V., Diaz, R., Fazio, S., Garon, G., Goodman, S. G., Harrington, R. A., White, H., Cobbaert, C., Schwartz, G. G. OXFORD UNIV PRESS. 2023

  View details for Web of Science ID 001115619402268

• GDF-15 is associated with worse ischemic and bleeding outcomes in the acute phase and during follow-up in patients with acute coronary syndrome: insights from the TRACER trial Wassberg, C., Batra, G., Westerbergh, J., Lindback, J., Lopes, R. D., Mahaffey, K. W., Harrington, R. A., Held, C., Wallentin, L. OXFORD UNIV PRESS. 2023

  View details for Web of Science ID 001115619402244

• Aspirin Dosing for Secondary Prevention of Atherosclerotic Cardiovascular Disease in Patients Treated With P2Y12 Inhibitors. Journal of the American Heart Association Girotra, S., Stebbins, A., Wruck, L., Marquis-Gravel, G., Gupta, K., Farrehi, P., Benziger, C. P., Effron, M. B., Whittle, J., Muñoz, D., Kripalani, S., Anderson, R. D., Jain, S. K., Polonsky, T. S., Ahmad, F. S., Roe, M. T., Rothman, R. L., Harrington, R. A., Hernandez, A. F., Jones, W. S. 2023: e030385

  Abstract

  Background The ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) was a large, pragmatic, randomized controlled trial that found no difference between high- versus low-dose aspirin for secondary prevention of atherosclerotic cardiovascular disease. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear. Methods and Results Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). The primary effectiveness end point was a composite of death, myocardial infarction, or stroke; and the primary safety end point was major bleeding requiring blood transfusions. We used multivariable Cox regression to compare the relative effectiveness and safety of aspirin dose within P2Y12 and non-P2Y12 groups. Of 13 815 (91.6%) participants with available data, 3051 (22.1%) were receiving clopidogrel (2849 [93.4%]) or prasugrel (203 [6.7%]) at baseline. P2Y12 inhibitor use was associated with higher risk of the primary effectiveness end point (10.86% versus 6.31%; adjusted hazard ratio [HR], 1.40 [95% CI, 1.22-1.62]) but was not associated with bleeding (0.95% versus 0.53%; adjusted HR, 1.42 [95% CI, 0.91-2.22]). We found no interaction in the relative effectiveness and safety of high- versus low-dose aspirin by P2Y12 inhibitor use. Overall, dose switching or discontinuation was more common in the high-dose compared with low-dose aspirin group, but the pattern was not modified by P2Y12 inhibitor use. Conclusions In this prespecified analysis of ADAPTABLE, we found that the relative effectiveness and safety of high- versus low-dose aspirin was not modified by baseline P2Y12 inhibitor use. Registration https://www.clinical.trials.gov. Unique identifier: NCT02697916.

  View details for DOI 10.1161/JAHA.123.030385

  View details for PubMedID 37830344

• Effectiveness and Safety of Enteric-Coated vs Uncoated Aspirin in Patients With Cardiovascular Disease: A Secondary Analysis of the ADAPTABLE Randomized Clinical Trial. JAMA cardiology Sleem, A., Effron, M. B., Stebbins, A., Wruck, L. M., Marquis-Gravel, G., Muñoz, D., Re, R. N., Gupta, K., Pepine, C. J., Jain, S. K., Girotra, S., Whittle, J., Benziger, C. P., Farrehi, P. M., Knowlton, K. U., Polonsky, T. S., Roe, M. T., Rothman, R. L., Harrington, R. A., Jones, W. S., Hernandez, A. F. 2023

  Abstract

  Clinicians recommend enteric-coated aspirin to decrease gastrointestinal bleeding in secondary prevention of coronary artery disease even though studies suggest platelet inhibition is decreased with enteric-coated vs uncoated aspirin formulations.To assess whether receipt of enteric-coated vs uncoated aspirin is associated with effectiveness or safety outcomes.This is a post hoc secondary analysis of ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic study of 15 076 patients with atherosclerotic cardiovascular disease having data in the National Patient-Centered Clinical Research Network. Patients were enrolled from April 19, 2016, through June 30, 2020, and randomly assigned to receive high (325 mg) vs low (81 mg) doses of daily aspirin. The present analysis assessed the effectiveness and safety of enteric-coated vs uncoated aspirin among those participants who reported aspirin formulation at baseline. Data were analyzed from November 11, 2019, to July 3, 2023.ADAPTABLE participants were regrouped according to aspirin formulation self-reported at baseline, with a median (IQR) follow-up of 26.2 (19.8-35.4) months.The primary effectiveness end point was the cumulative incidence of the composite of myocardial infarction, stroke, or death from any cause, and the primary safety end point was major bleeding events (hospitalization for a bleeding event with use of a blood product or intracranial hemorrhage). Cumulative incidence at median follow-up for primary effectiveness and primary safety end points was compared between participants taking enteric-coated or uncoated aspirin using unadjusted and multivariable Cox proportional hazards models. All analyses were conducted for the intention-to-treat population.Baseline aspirin formulation used in ADAPTABLE was self-reported for 10 678 participants (median [IQR] age, 68.0 [61.3-73.7] years; 7285 men [68.2%]), of whom 7366 (69.0%) took enteric-coated aspirin and 3312 (31.0%) took uncoated aspirin. No significant difference in effectiveness (adjusted hazard ratio [AHR], 0.94; 95% CI, 0.80-1.09; P = .40) or safety (AHR, 0.82; 95% CI, 0.49-1.37; P = .46) outcomes between the enteric-coated aspirin and uncoated aspirin cohorts was found. Within enteric-coated aspirin and uncoated aspirin, aspirin dose had no association with effectiveness (enteric-coated aspirin AHR, 1.13; 95% CI, 0.88-1.45 and uncoated aspirin AHR, 0.99; 95% CI, 0.83-1.18; interaction P = .41) or safety (enteric-coated aspirin AHR, 2.37; 95% CI, 1.02-5.50 and uncoated aspirin AHR, 0.89; 95% CI, 0.49-1.64; interaction P = .07).In this post hoc secondary analysis of the ADAPTABLE randomized clinical trial, enteric-coated aspirin was not associated with significantly higher risk of myocardial infarction, stroke, or death or with lower bleeding risk compared with uncoated aspirin, regardless of dose, although a reduction in bleeding with enteric-coated aspirin cannot be excluded. More research is needed to confirm whether enteric-coated aspirin formulations or newer formulations will improve outcomes in this population.ClinicalTrials.gov Identifier: NCT02697916.

  View details for DOI 10.1001/jamacardio.2023.3364

  View details for PubMedID 37792369

• Personalized digital behaviour interventions increase short-term physical activity: a randomized control crossover trial substudy of the MyHeart Counts Cardiovascular Health Study. European heart journal. Digital health Javed, A., Kim, D. S., Hershman, S. G., Shcherbina, A., Johnson, A., Tolas, A., O'Sullivan, J. W., McConnell, M. V., Lazzeroni, L., King, A. C., Christle, J. W., Oppezzo, M., Mattsson, C. M., Harrington, R. A., Wheeler, M. T., Ashley, E. A. 2023; 4 (5): 411-419

  Abstract

  Physical activity is associated with decreased incidence of the chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity.We offered enrolment to community-living iPhone-using adults aged ≥18 years in the USA, UK, and Hong Kong who downloaded the MyHeart Counts app. After completion of a 1-week baseline period, e-consented participants were randomized to four 7-day interventions. Interventions consisted of: (i) daily personalized e-coaching based on the individual's baseline activity patterns, (ii) daily prompts to complete 10 000 steps, (iii) hourly prompts to stand following inactivity, and (iv) daily instructions to read guidelines from the American Heart Association (AHA) website. After completion of one 7-day intervention, participants subsequently randomized to the next intervention of the crossover trial. The trial was completed in a free-living setting, where neither the participants nor investigators were blinded to the intervention. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in a modified intention-to-treat analysis (modified in that participants had to complete 7 days of baseline monitoring and at least 1 day of an intervention to be included in analyses). This trial is registered with ClinicalTrials.gov, NCT03090321.Between 1 January 2017 and 1 April 2022, 4500 participants consented to enrol in the trial (a subset of the approximately 50 000 participants in the larger MyHeart Counts study), of whom 2458 completed 7 days of baseline monitoring (mean daily steps 4232 ± 73) and at least 1 day of one of the four interventions. Personalized e-coaching prompts, tailored to an individual based on their baseline activity, increased step count significantly (+402 ± 71 steps from baseline, P = 7.1⨯10-8). Hourly stand prompts (+292 steps from baseline, P = 0.00029) and a daily prompt to read AHA guidelines (+215 steps from baseline, P = 0.021) were significantly associated with increased mean daily step count, while a daily reminder to complete 10 000 steps was not (+170 steps from baseline, P = 0.11). Digital studies have a significant advantage over traditional clinical trials in that they can continuously recruit participants in a cost-effective manner, allowing for new insights provided by increased statistical power and refinement of prior signals. Here, we present a novel finding that digital interventions tailored to an individual are effective in increasing short-term physical activity in a free-living cohort. These data suggest that participants are more likely to react positively and increase their physical activity when prompts are personalized. Further studies are needed to determine the effects of digital interventions on long-term outcomes.

  View details for DOI 10.1093/ehjdh/ztad047

  View details for PubMedID 37794870

  View details for PubMedCentralID PMC10545510

• Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease and Diabetes Mellitus: A Subgroup Analysis of the ADAPTABLE Trial. Diabetes care Narcisse, D. I., Kim, H., Wruck, L. M., Stebbins, A. L., Muñoz, D., Kripalani, S., Effron, M. B., Gupta, K., Anderson, R. D., Jain, S. K., Girotra, S., Whittle, J., Benziger, C. P., Farrehi, P., Zhou, L., Polonsky, T. S., Ahmad, F. S., Roe, M. T., Rothman, R. L., Harrington, R. A., Hernandez, A. F., Jones, W. S. 2023

  Abstract

  Patients with diabetes mellitus (DM) and concomitant atherosclerotic cardiovascular disease (ASCVD) must be on the most effective dose of aspirin to mitigate risk of future adverse cardiovascular events.ADAPTABLE, an open-label, pragmatic study, randomized patients with stable, chronic ASCVD to 81 mg or 325 mg of daily aspirin. The effects of aspirin dosing was assessed on the primary effectiveness outcome, a composite of all-cause death, hospitalization for myocardial infarction, or hospitalization for stroke, and the primary safety outcome of hospitalization for major bleeding. In this prespecified analysis, we used Cox proportional hazards models to compare aspirin dosing in patients with and without DM for the primary effectiveness and safety outcome.Of 15,076 patients, 5,676 (39%) had DM of whom 2,820 (49.7%) were assigned to 81 mg and 2,856 (50.3%) to 325 mg of aspirin. Patients with versus without DM had higher rates of the composite cardiovascular outcome (9.6% vs. 5.9%; P < 0.001) and bleeding events (0.78% vs. 0.50%; P < 0.001). When comparing 81 mg vs. 325 mg of aspirin, patients with DM had no difference in the primary effectiveness outcome (9.3% vs. 10.0%; hazard ratio [HR] 0.98 [95% CI 0.83-1.16]; P = 0.265) or safety outcome (0.87% vs. 0.69%; subdistribution HR 1.25 [95% CI 0.72-2.16]; P = 0.772).This study confirms the inherently higher risk of patients with DM irrespective of aspirin dosing. Our findings suggest that a higher dose of aspirin yields no added clinical benefit, even in a more vulnerable population.

  View details for DOI 10.2337/dc23-0749

  View details for PubMedID 37713477

• Long-Term Efficacy, Safety, and Tolerability of Alirocumab in 8242 Patients Eligible for 3 to 5 Years of Placebo-Controlled Observation in the ODYSSEY OUTCOMES Trial. Journal of the American Heart Association Goodman, S. G., Steg, P. G., Poulouin, Y., Bhatt, D. L., Bittner, V. A., Diaz, R., Garon, G., Harrington, R. A., Jukema, J. W., Manvelian, G., Stipek, W., Szarek, M., White, H. D., Schwartz, G. G. 2023: e029216

  View details for DOI 10.1161/JAHA.122.029216

  View details for PubMedID 37702079

• Relating Lipoprotein(a) Concentrations to Cardiovascular Event Risk After Acute Coronary Syndrome: A Comparison of Three Tests. Circulation Szarek, M., Reijnders, E., Jukema, J. W., Bhatt, D. L., Bittner, V. A., Diaz, R., Fazio, S., Garon, G., Goodman, S. G., Harrington, R. A., Ruhaak, L. R., Schwertfeger, M., Tsimikas, S., White, H. D., Steg, P. G., Cobbaert, C., Schwartz, G. G. 2023

  Abstract

  Background: Lipoprotein(a) is a risk factor for cardiovascular events and modifies the benefit of pcsk9 inhibitors (pcsk9i). Lipoprotein(a) concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system employing mass spectrometry. Whether the relationships between lipoprotein(a) concentrations and cardiovascular events in a high-risk cohort differ across lipoprotein(a) methods is unknown. We compared the prognostic and predictive value of these types of lipoprotein(a) tests for major adverse cardiovascular events (mace). Methods: The odyssey outcomes trial compared the pcsk9i alirocumab with placebo in patients with recent acute coronary syndrome (acs). We compared risk of mace in the placebo group and mace risk reduction with alirocumab according to baseline lipoprotein(a) concentration measured by siemens n-latex nephelometric immunoassay (ia-mass, mg/dl), roche tina-quant® turbidimetric immunoassay (ia-molar, nmol/l), and a non-commercial mass spectrometry-based test (ms, nmol/l). Lipoprotein(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline lipoprotein(a) and outcomes in each treatment group. Event rates were also determined across baseline lipoprotein(a) quartiles defined by each assay. Results: Among 11,970 trial participants with results from all 3 tests, baseline median (q1, q3) lipoprotein(a) concentrations were 21.8 (6.9, 60.0) mg/dl, 45.0 (13.2, 153.8) nmol/l, and 42.2 (14.3, 143.1) nmol/l for ia-mass, ia-molar, and ms, respectively. The strongest correlation was between ia-molar and ms (r=0.990), with nominally weaker correlations between ia-mass and ms (r=0.967) and ia-mass and ia-molar (r=0.972). Relationships of lipoprotein(a) with mace risk in the placebo group were nearly identical with each test with estimated cumulative incidences differing by ≤0.4% across lipoprotein(a) percentiles, and all were incrementally prognostic after accounting for ldl-c (all spline p≤0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the three tests, with estimated treatment hazard ratios (hrs) differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all three tests. Absolute risk reduction with alirocumab increased with increasing lipoprotein(a) measured by each test, with significant linear trends across quartiles. Conclusions: In patients with recent acs, three lipoprotein(a) tests were similarly prognostic for mace in the placebo group and predictive of mace reductions with alirocumab at the cohort level.

  View details for DOI 10.1161/CIRCULATIONAHA.123.066398

  View details for PubMedID 37632469

• Impact of Complete Revascularization inthe ISCHEMIA Trial. Journal of the American College of Cardiology Stone, G. W., Ali, Z. A., O'Brien, S. M., Rhodes, G., Genereux, P., Bangalore, S., Mavromatis, K., Horst, J., Dressler, O., Poh, K. K., Nath, R. K., Moorthy, N., Witkowski, A., Dwivedi, S. K., Bockeria, O., Chen, J., Smanio, P. E., Picard, M. H., Chaitman, B. R., Berman, D. S., Shaw, L. J., Boden, W. E., White, H. D., Fremes, S. E., Rosenberg, Y., Reynolds, H. R., Spertus, J. A., Hochman, J. S., Maron, D. J., ISCHEMIA Research Group, Boden, W., Harrington, R., Williams, D., Alexander, K. P., Berger, J., Mark, D., Ballantyne, C., Beyar, R., Bhargava, B., Buller, C., Carvalho, A. T., Diaz, R., Doerr, R., Dzavik, V., Goodman, S., Gosselin, G., Hachamovitch, R., Hamm, C., Held, C., Helm, M., Huber, K., Jiang, L., Keltai, M., Kohsaka, S., Lang, I., Lopes, R., Lopez-Sendon, J., Maggioni, A., Mancini, J., Bairey Merz, C. N., Min, J., Peterson, E., Ruzyllo, W., Selvanayagam, J., Senior, R., Sharir, T., Steg, G., Szwed, H., Van de Werf, F., Weintraub, W., White, H., Calfas, K., Champagne, M. A., Davidson, M., Fleg, J., McCullough, P. A., Newman, J., Stone, P., Menasche, P., Davidson, M., Fremes, S., Guyton, R., Mack, M., Mohr, F., Rao, A., Sabik, J., Shapira, O., Taggart, D., Tatoulis, J., Blankenship, J., Brener, S., Buller, C., Colombo, A., de Bruyne, B., Kereiakes, D., Lefevre, T., Moses, J., Alexander, K. P., Mahaffey, K., White, H., Cruz-Flores, S., Danchin, N., Feen, E., Garcia, M. J., Hauptman, P., Laddu, A. A., Passamani, E., Pina, I. L., Simoons, M., Skali, H., Thygesen, K., Waters, D., Alexander, K. P., Endsley, P., Esposito, G., Kanters, J., Pownall, J., Stournaras, D., Friedrich, M., Hachamovitch, R., Kwong, R., Mancini, J., Min, J., Oliver, D., Harrell, F., Blume, J., Lee, K., Held, C., Kullo, I., McManus, B., Newby, K., Cohen, D., Weintraub, W., Bairey Merz, C. N., Bugiardini, R., Celutkiene, J., Escobedo, J., Hoye, A., Lyubarova, R., Mattina, D., Peteiro, J., Smanio, P., Alexander, K. P., Berman, D., Fleg, J., Kwong, R., Senior, R., Min, J., Leipsic, J., Mancini, J., Newman, J., Alexander, K. P., Mathew, R., Sidhu, M., Friedman, L., Anderson, J., Berg, J., DeMets, D., Gibson, C. M., Lamas, G., Deming, N., Himmelfarb, J., Ouyang, P., Woodard, P., Harrell, F., Nwosu, S., Kirby, R., Jeffries, N., Newman, J., Sidhu, M., Denaro, J. E., Mavromichalis, S., Chan, K., Cobb, G., Contreras, A., Cukali, D., Ferket, S., Gabriel, A., Hansen, A., Roberts, A., Naumova, A., Chang, M., Islam, S., Wayser, G., Yakubov, S., Yee, M., Callison, C., Hogan, I., Qelaj, A., Pirro, C., Van Loo, K., Wisniewski, B., Gilsenan, M., Lang, B., Mohamed, S., Esquenazi-Karonika, S., Mathews, P., Setang, V., Xavier, M., Alexander, K. P., Bagai, A., Broderick, S., Crowder, M., Cyr, D., Endsley, P., Garg, J., Gu, X., Hatch, L., Heath, A., Huang, Z., Kanters, J., Lee, K., Leimberger, J., Marcus, J., Page, C., Parker, W., Pennachi, W., Pownall, J., Rockhold, F., Stevens, S., Stone, A., Stournaras, D., Thompson, O., Ussery, S., White, J., Williams, M. K., Xing, W., Zhu, S., Anstrom, K., Baloch, K., Blount, J., Cowper, P., Davidson-Ray, L., Drew, L., Harding, T., Knight, J. D., Minshall Liu, D., O'Neal, B., Redick, T., Jones, P., Nugent, K., Jingyan Wang, G., Phillips, L., Goyal, A., Hetrick, H., Oliver, D., Hayes, S. W., Friedman, J. D., Gerlach, R. J., Hyun, M., Miranda-Peats, R., Slomka, P., Thomson, L., Kwong, R. Y., Friedrich, M., Mongeon, F. P., Michael, S., Hung, J., Scherrer-Crosbie, M., Zeng, X., Eckstein, J., Guruge, B., Streif, M., Alfonso, M. A., Corral, M. P., Garcia, J. J., Jankovic, I., Konigstein, M., Lustre, M. B., Peralta, Y., Sanchez, R., Min, J., Arsanjani, R., Budoff, M., Elmore, K., Gomez, M., Hague, C., Hindoyan, N., Leipsic, J., Mancini, G. J., Nakanishi, R., Srichai-Parsia, M. B., Yeoh, E., Youn, T., Maggioni, A. P., Bianchini, F., Ceseri, M., Lorimer, A., Magnoni, M., Orso, F., Sarti, L., Tricoli, M., Carvalho, A., Lopes, R., Barbosa, L. M., Bello Duarte, T., Colaiacovo Soares, T., de Aveiro Morata, J., Carvalho, P., de Carvalho Maffei, N., Egydio, F., Kawakami, A., Oliveira, J., Restelli Piloto, E., Pozzibon, J., Goodman, S., Camara, D., Mowafy, N., Spindler, C., Jiang, L., Dai, H., Feng, F., Li, J., Li, L., Liu, J., Xie, Q., Zhang, H., Zhang, J., Zhang, L., Zhang, L., Zhang, N., Zhong, H., Diaz, R., Escobar, C., Martin, M. E., Pascual, A., Lopez-Sendon, J., Moraga, P., Hernandez, V., Castro, A., Posada, M., Fernandez, S., Narro Villanueva, J. L., Selgas, R., Steg, G., Abergel, H., Juliard, J. M., White, H., Alsweiler, C., Van de Werf, F., Claes, K., Goetschalckx, K., Luyten, A., Robesyn, V., Selvanayagam, J. B., Murphy, D., Garcevic, N., Stojkovic, J., Ahmed, A., Bhatt, R., Chadha, N., Kumar, V., Lubna, S., Naik, P., Pandey, S., Ramasamy, K., Saleem, M., Sharma, P., Siddaram, H. 2023

  Abstract

  BACKGROUND: Anatomic complete revascularization (ACR) and functional complete revascularization (FCR) have been associated with reduced death and myocardial infarction (MI) in some prior studies. The impact of complete revascularization (CR) in patients undergoing an invasive (INV) compared with a conservative (CON) management strategy has not been reported.OBJECTIVES: Among patients with chronic coronary disease without prior coronary artery bypass grafting randomized to INV vs CON management in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial, we examined the following: 1) the outcomes of ACR and FCR compared with incomplete revascularization; and 2) the potential impact of achieving CR in all INV patients compared with CON management.METHODS: ACR and FCR in the INV group were assessed at an independent core laboratory. Multivariable-adjusted outcomes of CR were examined in INV patients. Inverse probability weighted modeling was then performed to estimate the treatment effect had CR been achieved in all INV patients compared with CON management.RESULTS: ACR and FCR were achieved in 43.4% and 58.4% of 1,824 INV patients. ACR was associated with reduced 4-year rates of cardiovascular death or MI compared with incomplete revascularization. By inverse probability weighted modeling, ACR in all 2,296 INV patients compared with 2,498 CON patients was associated with a lower 4-year rate of cardiovascular death or MI (difference-3.5; 95%CI:-7.2% to 0.0%). In comparison, the event rate difference of cardiovascular death or MI for INV minus CON in the overall ISCHEMIA trial was-2.4%. Results were similar but less pronounced with FCR.CONCLUSIONS: The outcomes of an INV strategy may be improved if CR (especially ACR) is achieved. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

  View details for DOI 10.1016/j.jacc.2023.06.015

  View details for PubMedID 37462593

• Internet Versus Noninternet Participation in a Decentralized Clinical Trial: Lessons From the ADAPTABLE Study. Journal of the American Heart Association Shen, R., Mulder, H., Wruck, L., Weissler, E. H., Robertson, H. R., Sharlow, A. G., Kripalani, S., Munoz, D., Effron, M. B., Gupta, K., Girotra, S., Whittle, J., Benziger, C. P., VanWormer, J. J., Polonsky, T. S., Rothman, R. L., Harrington, R. A., Hernandez, A. F., Jones, W. S. 2023: e027899

  Abstract

  Background Internet-based participation has the potential to enhance pragmatic and decentralized trials, where representative study populations and generalizability to clinical practice are key. We aimed to study the differences between internet and noninternet/telephone participants in a large remote, pragmatic trial. Methods and Results In a subanalysis of the ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness) study, we compared internet participants with those who opted for noninternet participation. Study process measures examined included participant characteristics at consent, study medication adherence, and study retention. The clinical outcome examined was a composite of all-cause mortality, hospitalization for myocardial infarction, or hospitalization for stroke. Noninternet participants were older (mean 69.4 versus 67.4years), more likely to be female (38.9% versus 30.2%), more likely to be Black (27.3% versus 6.0%) or Hispanic (11.1% versus 2.0%), and had a higher number of comorbid conditions. The composite clinical outcome was more than twice as high in noninternet participants. The hazard of nonadherence to the assigned aspirin dosage was 46% higher in noninternet participants than internet participants. Conclusions Noninternet participants differed from internet participants in notable demographic characteristics while having poorer baseline health. Over the course of ADAPTABLE, they also had worse clinical outcomes and greater likelihood of study drug nonadherence. These results suggest that trials focused on internet participation select for younger, healthier participants with a higher proportion of traditionally overrepresented patients. Allowing noninternet participation enhances diversity; however, additional steps may be needed to promote study retention and study medication adherence. Registration Information clinicaltrials.gov. Identifier: NCT02697916.

  View details for DOI 10.1161/JAHA.122.027899

  View details for PubMedID 37345815

• Comparison of the effectiveness and safety of two aspirin doses in secondary prevention of cardiovascular outcomes in patients with chronic kidney disease: a subgroup analysis of ADAPTABLE. American heart journal Gupta, K., Mehta, H., Kim, H., Stebbins, A., Wruck, L. M., Muñoz, D., Effron, M. B., Anderson, R. D., Pepine, C. J., Jain, S. K., Girotra, S., DeWalt, D. A., Whittle, J., Benziger, C. P., Farrehi, P., Zhou, L., Knowlton, K. U., Polonsky, T. S., Bradley, S. M., Harrington, R. A., Rothman, R. L., Jones, W. S., Hernandez, A. F. 2023

  Abstract

  Among patients with established cardiovascular disease, the ADAPTABLE trial found no significant differences in cardiovascular events and bleeding rates between 81 mg and 325 mg of aspirin (ASA) daily. In this secondary analysis from the ADAPTABLE trial, we studied the effectiveness and safety of ASA dosing in patients with a history of chronic kidney disease (CKD).ADAPTABLE participants were stratified based on the presence or absence of CKD, defined using ICD-9/10-CM codes. Within the CKD group, we compared outcomes between patients taking ASA 81 mg and 325 mg. The primary effectiveness outcome was defined as a composite of all cause death, myocardial infarction, or stroke and the primary safety outcome was hospitalization for major bleeding. Adjusted Cox proportional hazard models were utilized to report differences between the groups.After excluding 414 (2.7%) patients due to missing medical history, a total of 14,662 patients were included from the ADAPTABLE cohort, of whom 2648 (18%) patients had CKD. Patients with CKD were older (median age 69.4 vs. 67.1 years; p<0.0001) and less likely to be white (71.5% vs. 81.7%; p<0.0001) when compared to those without CKD. At a median follow-up of 26.2 months, CKD was associated with an increased risk of both the primary effectiveness outcome (adjusted HR 1.79 (1.57, 2.05) P<0.001 and the primary safety outcome (adjusted HR 4.64 (2.98, 7.21), p<0.001 and p<0.05, respectively) regardless of ASA dose. There was no significant difference in effectiveness (adjusted HR 1.01 95% CI 0.82, 1.23; p=0.95) or safety (adjusted HR 0.93; 95% CI 0.52, 1.64; P=0.79) between ASA groups.Patients with CKD were more likely than those without CKD to have adverse cardiovascular events or death and were also more likely to have major bleeding requiring hospitalization. However, there was no association between ASA dose and study outcomes among these patients with CKD.

  View details for DOI 10.1016/j.ahj.2023.06.001

  View details for PubMedID 37290700

• Lipoprotein(a) and the Effect of Alirocumab on Revascularization Following Acute Coronary Syndrome. The Canadian journal of cardiology Steg, P. G., Szarek, M., Valgimigli, M., Islam, S., Zeiher, A. M., Bhatt, D. L., Bittner, V. A., Chiang, C. E., Diaz, R., Goodman, S. G., Gotcheva, N., Harrington, R. A., Jukema, J. W., Kim, H. S., Kim, S. H., Morais, J., Pordy, R., Scemama, M., White, H. D., Schwartz, G. G. 2023

  Abstract

  Many patients require revascularization after an index acute coronary syndrome (ACS). Lipoprotein(a) is thought to play a pathogenic role in atherothrombosis. In ODYSSEY OUTCOMES, alirocumab reduced major adverse cardiovascular events after ACS, with greater reduction among those with higher lipoprotein(a) levels. We explored whether risk of revascularization after ACS was modified by the level of lipoprotein(a) and treatment with alirocumab or placebo.ODYSSEY OUTCOMES compared alirocumab with placebo in 18 924 patients with ACS and elevated atherogenic lipoproteins despite optimized statin treatment. In this post hoc analysis, treatment effects are summarized by competing-risks proportional hazard models.A total of 1559 (8.2%) patients had coronary, 204 (1.1%) had limb, and 40 (0.2%) had carotid revascularization. Alirocumab reduced coronary revascularization (2.8 versus 3.2 events per 100 patient-years; HR, 0.88 [95% CI, 0.80-0.97]; P=0.01) and any revascularization (3.2 versus 3.7 events per 100 patient-years; HR, 0.85 [95% CI, 0.78-0.94]; P=0.001). Baseline lipoprotein(a) quartile was directly associated with risk of coronary or any revascularization in the placebo arm and inversely related to treatment HRs (all Ptrend <0.001). Alirocumab produced the greatest reduction of coronary revascularization in patients with baseline lipoprotein(a) in the top quartile (≥59.6 mg/dL) (HR, 0.69 [95% CI, 0.57-0.84]), but no apparent reduction in the bottom quartile (HR, 1.00 [95% CI, 0.82-1.22]). Findings were similar for the effect of alirocumab on any revascularization.Alirocumab reduced revascularization after ACS. The risk of revascularization and reduction in that risk with alirocumab were greatest in patients with elevated lipoprotein(a) at baseline. (ODYSSEY OUTCOMES NCT01663402).

  View details for DOI 10.1016/j.cjca.2023.04.018

  View details for PubMedID 37116789

• Transiently achieved very low LDL-cholesterol levels by statin and alirocumab after acute coronary syndrome are associated with cardiovascular risk reduction: the ODYSSEY OUTCOMES trial. European heart journal Schwartz, G. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Bujas-Bobanovic, M., Diaz, R., Fazio, S., Fras, Z., Goodman, S. G., Harrington, R. A., Jukema, J. W., Manvelian, G., Pordy, R., Ray, K. K., Scemama, M., White, H. D., Steg, P. G. 2023

  Abstract

  Long-term, placebo-controlled cholesterol-lowering trials have demonstrated legacy effects (clinical benefits that persist or emerge after trial end). It is unknown whether legacy effects follow a short period of very low low-density lipoprotein cholesterol (LDL-C) levels achieved with statin plus PCSK9 inhibitor.In 18,924 patients post-acute coronary syndrome, the ODYSSEY OUTCOMES trial compared the PCSK9 inhibitor alirocumab with placebo, each added to high-intensity or maximum-tolerated statin therapy. Patients with two consecutive LDL-C levels <0.39 mmol/L (15 mg/dL) on alirocumab had blinded placebo substitution for the remainder of the trial with continued statin treatment. In post hoc analyses, major adverse cardiovascular events (MACE) in these patients were compared to MACE in propensity score-matched patients from the placebo group with similar baseline characteristics and study medication adherence. In the alirocumab group, 730 patients had blinded placebo substitution at a median 8.3 months from randomization, after a median 6.0 months with LDL-C < 0.39 mmol/L. They were matched to 1460 placebo patients. Both groups had lower baseline LDL-C and lipoprotein(a) and better study medication adherence than the overall cohort. Over a median follow-up of 2.8 years, MACE occurred in 47 (6.4%) alirocumab patients with limited-duration, very low achieved LDL-C versus 122 (8.4%) matched placebo patients (treatment hazard ratio 0.72; 95% confidence interval 0.51, 0.997; P = 0.047).A short period of LDL-C levels <0.39 mmol/L achieved with statin and alirocumab, followed by statin monotherapy, was associated with lower risk of MACE than statin monotherapy throughout the observation period. Clinical benefit persisted for several years.ClinicalTrials.gov NCT01663402.

  View details for DOI 10.1093/eurheartj/ehad144

  View details for PubMedID 36879424

• Sociodemographic determinants of oral anticoagulant prescription in patients with atrial fibrillations: findings from the PINNACLE registry using machine learning. Heart rhythm O2 Azizi, Z., Ward, A. T., Lee, D. J., Gad, S. S., Bhasin, K., Beetel, R. J., Ferreira, T., Shankar, S., Rumsfeld, J. S., Harrington, R. A., Virani, S. S., Gluckman, T. J., Dash, R., Rodriguez, F. 2023; 4 (3): 158-168

  Abstract

  Current risk scores that are solely based on clinical factors have shown modest predictive ability for understanding of factors associated with gaps in real-world prescription of oral anticoagulation (OAC) in patients with atrial fibrillation (AF).In this study, we sought to identify the role of social and geographic determinants, beyond clinical factors associated with variation in OAC prescriptions using a large national registry of ambulatory patients with AF.Between January 2017 and June 2018, we identified patients with AF from the American College of Cardiology PINNACLE (Practice Innovation and Clinical Excellence) Registry. We examined associations between patient and site-of-care factors and prescription of OAC across U.S. counties. Several machine learning (ML) methods were used to identify factors associated with OAC prescription.Among 864,339 patients with AF, 586,560 (68%) were prescribed OAC. County OAC prescription rates ranged from 26.8% to 93%, with higher OAC use in the Western United States. Supervised ML analysis in predicting likelihood of OAC prescriptions and identified a rank order of patient features associated with OAC prescription. In the ML models, in addition to clinical factors, medication use (aspirin, antihypertensives, antiarrhythmic agents, lipid modifying agents), and age, household income, clinic size, and U.S. region were among the most important predictors of an OAC prescription.In a contemporary, national cohort of patients with AF underuse of OAC remains high, with notable geographic variation. Our results demonstrated the role of several important demographic and socioeconomic factors in underutilization of OAC in patients with AF.

  View details for DOI 10.1016/j.hroo.2022.11.004

  View details for PubMedID 36993910

  View details for PubMedCentralID PMC10041076

• Temporal Trends in Gender of Principal Investigators and Patients in Cardiovascular Clinical Trials. Journal of the American College of Cardiology Yong, C., Suvarna, A., Harrington, R., Gummidipundi, S., Krumholz, H. M., Mehran, R., Heidenreich, P. 2023; 81 (4): 428-430

  View details for DOI 10.1016/j.jacc.2022.10.038

  View details for PubMedID 36697143

• External validation of the ADA score for predicting thrombosis among acutely ill hospitalized medical patients from the APEX Trial. Journal of thrombosis and thrombolysis Chi, G., Violi, F., Pignatelli, P., Vestri, A., Spagnoli, A., Loffredo, L., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z., Gibson, C. M. 2022

  Abstract

  The ADA (Age-D-dimer-Albumin) score was developed to identify hospitalized patients at an increased risk for thrombosis in the coronavirus infectious disease-19 (COVID-19) setting. The study aimed to validate the ADA score for predicting thrombosis in a non-COVID-19 medically ill population from the APEX trial. The APEX trial was a multinational, randomized trial that evaluated the efficacy and safety of betrixaban vs. enoxaparin among acutely ill hospitalized patients at risk for venous thromboembolism. The study endpoints included the composite of arterial or venous thrombosis and its components. Metrics of model calibration and discrimination were computed for assessing the performance of the ADA score as compared to the IMPROVE score, a well-validated VTE risk assessment model. Among 7,119 medical inpatients, 209 (2.9%) had a thrombosis event up to 77 days of follow-up. The ADA score demonstrated good calibration for both arterial and venous thrombosis, whereas the IMPROVE score had adequate calibration for venous thrombosis (p > 0.05 from the Hosmer-Lemeshow test). For discriminating arterial and venous thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.620 [95% CI: 0.582 to 0.657] vs. 0.590 [95% CI: 0.556 to 0.624]; ∆ c statistic = 0.030 [95% CI: -0.022 to 0.081]; p = 0.255). Similarly, for discriminating arterial thrombosis, there was no significant difference between the ADA vs. IMPROVE score (c statistic = 0.582 [95% CI: 0.534 to 0.629] vs. 0.609 [95% CI: 0.564 to 0.653]; ∆ c statistic = -0.027 [95% CI: -0.091 to 0.036]; p = 0.397). For discriminating venous thrombosis, the ADA score was modestly superior to the IMPROVE score (c statistic = 0.664 [95% CI: 0.607 to 0.722] vs. 0.573 [95% CI: 0.521 to 0.624]; ∆ c statistic = 0.091 [95% CI: 0.011 to 0.172]; p = 0.026). The ADA score had a higher sensitivity (0.579 [95% CI: 0.512 to 0.646]; vs. 0.440 [95% CI: 0.373 to 0.507]) but lower specificity (0.625 [95% CI: 0.614 to 0.637] vs. 0.747 [95% CI: 0.737 to 0.758]) than the IMPROVE score for predicting thrombosis. Among acutely ill hospitalized medical patients enrolled in the APEX trial, the ADA score demonstrated good calibration but suboptimal discrimination for predicting thrombosis. The findings support the use of either the ADA or IMPROVE score for thrombosis risk assessment. The applicability of the ADA score to non-COVID-19 populations warrants further research.Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

  View details for DOI 10.1007/s11239-022-02757-8

  View details for PubMedID 36566304

• Survival After Invasive or Conservative Management of Stable Coronary Disease. Circulation Hochman, J. S., Anthopolos, R., Reynolds, H. R., Bangalore, S., Xu, Y., O'Brien, S. M., Mavromichalis, S., Chang, M., Contreras, A., Rosenberg, Y., Kirby, R., Bhargava, B., Senior, R., Banfield, A., Goodman, S. G., Lopes, R. D., Pracon, R., Lopez-Sendon, J., Maggioni, A. P., Newman, J. D., Berger, J. S., Sidhu, M. S., White, H. D., Troxel, A. B., Harrington, R. A., Boden, W. E., Stone, G. W., Mark, D. B., Spertus, J. A., Maron, D. J., ISCHEMIA-EXTEND Research Group 2022

  Abstract

  Background: The ISCHEMIA trial compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes over a median of 3.2 years. Extended follow-up for mortality is ongoing. Methods: ISCHEMIA participants were randomized to an initial invasive strategy (INV) added to guideline-directed medical therapy or a conservative strategy (CON). Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and non-cardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models and Bayesian methods. Undetermined deaths were classified as cardiovascular as pre-specified in the trial protocol. Results: Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23 % women, 16% Hispanic, 4% Black, 42% diabetes, and median EF 0.60. A total of 557 deaths accrued over a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 non-cardiovascular deaths and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate 12.7% in INV, 13.4% in CON; adjusted hazard ratio (HR)=1.00, 95% CI: 0.85-1.18). There was a lower 7-year rate cardiovascular mortality (6.4% vs. 8.6%, adjusted HR=0.78, 95% CI: 0.63-0.96) with an initial invasive strategy but a higher 7-year rate of non-cardiovascular mortality (5.6% vs. 4.4%, adjusted HR=1.44, 95% CI: 1.08-1.91) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. Conclusions: There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of non-cardiovascular mortality with an initial invasive strategy over a median follow-up of 5.7 years. Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT04894877; https://clinicaltrials.gov/ct2/show/NCT04894877.

  View details for DOI 10.1161/CIRCULATIONAHA.122.062714

  View details for PubMedID 36335918

• Biomarker-Based Prediction of RecurrentIschemic Events in Patients With Acute Coronary Syndromes. Journal of the American College of Cardiology Batra, G., Lindback, J., Becker, R. C., Harrington, R. A., Held, C., James, S. K., Kempf, T., Lopes, R. D., Mahaffey, K. W., Steg, P. G., Storey, R. F., Swahn, E., Wollert, K. C., Siegbahn, A., Wallentin, L. 2022; 80 (18): 1735-1747

  Abstract

  BACKGROUND: In patients with acute coronary syndrome (ACS), there is residual and variable risk of recurrent ischemic events.OBJECTIVES: This study aimed to develop biomarker-based prediction models for 1-year risk of cardiovascular (CV) death and myocardial infarction (MI) in patients with ACS undergoing percutaneous coronary intervention.METHODS: We included 10,713 patients from the PLATO (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome) trial in the development cohort and externally validated in 3,508 patients from the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial. Variables contributing to risk of CV death/MI were assessed using Cox regression models, and a score was derived using subsets of variables approximating the full model.RESULTS: There were 632 and 190 episodes of CV death/MI in the development and validation cohorts. The most important predictors of CV death/MI were the biomarkers, growth differentiation factor 15, and N-terminal pro-B-type natriuretic peptide, which had greater prognostic value than all candidate variables. The final model included 8 items: age (A), biomarkers (B) (growth differentiation factor 15 and N-terminal pro-B-type natriuretic peptide), and clinical variables (C) (extent of coronary artery disease, previous vascular disease, Killip class, ACS type, P2Y12 inhibitor). The model, named ABC-ACS ischemia, was well calibrated and showed good discriminatory ability for 1-year risk of CV death/MI with C-indices of 0.71 and 0.72 in the development and validation cohorts, respectively. For CV death, the score performed better, with C-indices of 0.80 and 0.84 in the development and validation cohorts, respectively.CONCLUSIONS: An 8-item score for the prediction of CV death/MI was developed and validated for patients with ACS undergoing percutaneous coronary intervention. The ABC-ACS ischemia score showed good calibration and discrimination and might be useful for risk prediction and decision support in patients with ACS. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872; Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER]; NCT00527943).

  View details for DOI 10.1016/j.jacc.2022.08.767

  View details for PubMedID 36302586

• External applicability of the Effect of ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) trial: An analysis of patients with diabetes and coronary artery disease in the REduction of Atherothrombosis for Continued Health (REACH) registry. International journal of cardiology Abtan, J., Bhatt, D. L., Elbez, Y., Ducrocq, G., Goto, S., Smith, S. C., Ohman, E. M., Eagle, K. A., Fox, K., Harrington, R. A., Leiter, L. A., Mehta, S. R., Simon, T., Petrov, I., Sinnaeve, P. R., Pais, P., Lev, E., Bueno, H., Wilson, P., Steg, P. G., REACH Registry Investigators 2022

  Abstract

  AIMS: THEMIS is a double-blind, randomized trial of 19,220 patients with diabetes mellitus and stable coronary artery disease (CAD) comparing ticagrelor to placebo, in addition to aspirin. The present study aimed to describe the proportion of patients eligible and reasons for ineligibility for THEMIS within a population of patients with diabetes and CAD included in the Reduction of Atherothrombosis for Continued Health (REACH) registry.METHODS AND RESULTS: The THEMIS eligibility criteria were applied to REACH patients. THEMIS included patients ≥50 years with type 2 diabetes and stable CAD as determined by either a history of previous percutaneous coronary intervention, coronary artery bypass grafting, or documentation of angiographic stenosis of ≥50% of at least one coronary artery. Patients with prior myocardial infarction or stroke were excluded. In REACH, 10,156 patients had stable CAD and diabetes. Of these, 6515 (64.1%) patients had at least one exclusion criteria. From the remaining population, 784 patients did not meet inclusion criteria (7.7%) mainly due to absence of aspirin treatment (7.2%), yielding a 'THEMIS-eligible population' of 2857 patients (28.1% of patients with diabetes and stable CAD). The main reasons for exclusion were a history of myocardial infarction (53.1%), use of oral anticoagulation (14.5%), or history of stroke (12.9%). Among the 4208 patients with diabetes and a previous PCI, 1196 patients (28.4%) were eligible for inclusion in the THEMIS-PCI substudy.CONCLUSIONS: In a population of patients with diabetes and stable coronary artery disease, a sizeable proportion appear to be 'THEMIS eligible.'CLINICAL TRIAL REGISTRATION: http://www.CLINICALTRIALS: gov identifier: NCT01991795.

  View details for DOI 10.1016/j.ijcard.2022.10.132

  View details for PubMedID 36270493

• Lipoprotein(a) and the effect of alirocumab on coronary and non -coronary revascularization following acute coronary syndrome Steg, P., Szarek, M., Valgimigli, M., Islam, S., Zeiher, A. M., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Pordy, R., Scemama, M., White, H. D., Schwartz, G. G., ODYSSEY OUTCOMES Investigators OXFORD UNIV PRESS. 2022: 1386

  View details for Web of Science ID 000894947900525

• Blood pressure and clinical outcomes in patients with diabetes and stable coronary artery disease in THEMIS Pareek, M., Bhatti, D. L., Zheng, L., Lee, J. J., Leiter, L. A., Simon, T., Mehta, S. R., Harrington, R. A., Fox, K., Himmelmann, A., Vidal-Petiot, E., Steg, P. G., Themis Investigators OXFORD UNIV PRESS. 2022: 1226

  View details for Web of Science ID 000894947900349

• Longer-term safety of alirocumab with 24,610 patient-years of placebo-controlled observation: further insights from the ODYSSEY OUTCOMES trial Goodman, S., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Harrington, R. A., Jukema, J. W., White, H. D., Zeiher, A. M., Manvelian, G., Poulouin, Y., Scemama, M., Stipek, W., Schwartz, G. G. OXFORD UNIV PRESS. 2022: 1233

  View details for Web of Science ID 000894947900357

• Relation of red blood cell distribution width to risk of major adverse cardiovascular events, death, and effect of alirocumab after acute coronary syndromes. Journal of clinical lipidology Moriarty, P. M., Steg, P. G., McGinniss, J., Zeiher, A. M., White, H. D., Manvelian, G., Pordy, R., Loy, M., Jukema, J. W., Harrington, R. A., Gray, J. V., Gorby, L. K., Goodman, S. G., Diaz, R., Bittner, V. A., Bhatt, D. L., Szarek, M., Schwartz, G. G., ODYSSEY OUTCOMES Investigators 2022

  Abstract

  Elevated red blood cell distribution width (RDW) is associated with increased risk for major adverse cardiovascular events (MACE) and death in patients with cardiovascular disease. The ODYSSEY OUTCOMES trial compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome (ACS) and elevated atherogenic lipoproteins despite optimized statin treatment. This post hoc analysis determined whether RDW independently predicts risk of MACE and death in patients after recent ACS, whether RDW influences MACE reduction with alirocumab, and whether alirocumab treatment affects RDW. Associations of baseline RDW with risk of MACE and death were analyzed in the placebo group in adjusted proportional hazards models. Interactions of RDW and treatment on the risk of MACE and death were evaluated. An increasing quartile of RDW was associated with characteristics that predicted risk of MACE and death including age, hypertension, diabetes, atherosclerotic conditions and events, revascularizations, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. After adjusting for baseline characteristics associated with the risk of MACE or death, baseline RDW remained independently associated with the risk of MACE and death in the placebo group (hazard ratios [95% confidence intervals] 1.08 [1.02-1.15] and 1.13 [1.03-1.24] per 1% increase of RDW, respectively, both p <0.001). There was no interaction of RDW and treatment on MACE or death, nor did alirocumab affect RDW. RDW was associated with an increased risk of MACE and death, independent of established risk factors.

  View details for DOI 10.1016/j.jacl.2022.08.004

  View details for PubMedID 36153281

• Trials and Tribulations of Randomized Clinical Trials. Circulation Harrington, R. A. 2022

  View details for DOI 10.1161/CIRCULATIONAHA.122.060649

  View details for PubMedID 35775415

• Response by Cavender et al to Letter Regarding Article, "Ischemic Events Occur Early in Patients Undergoing Percutaneous Coronary Intervention and Are Reduced With Cangrelor: Findings From CHAMPION PHOENIX" CIRCULATION-CARDIOVASCULAR INTERVENTIONS Cavender, M. A., Harrington, R. A., Bhatt, D. L. 2022; 15 (7): 636-637

  View details for DOI 10.1161/CIRCINTERVENTIONS.122.012222

  View details for Web of Science ID 000823963500008

  View details for PubMedID 35861800

• Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab. Circulation Hagström, E., Steg, P. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Danchin, N., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Liberopoulos, E., Marx, N., McGinniss, J., Manvelian, G., Pordy, R., Scemama, M., White, H. D., Zeiher, A. M., Schwartz, G. G. 2022: 101161CIRCULATIONAHA121057807

  Abstract

  Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain.The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACEs; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACEs were assessed in adjusted Cox proportional hazards and propensity score-matched models.Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9-3.6], 4.0 [95% CI, 3.6-4.5], and 5.5 [95% CI, 5.0-6.1] events per 100 patient-years in strata <75, 75-<90, ≥90 mg/dL, respectively; Ptrend<0.0001) and after adjustment for low-density lipoprotein cholesterol (Ptrend=0.035). Higher baseline apoB stratum was associated with greater relative (Ptrend<0.0001) and absolute reduction in MACEs with alirocumab versus placebo. In the alirocumab group, the incidence of MACEs after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78-4.79], 3.09 [95% CI, 2.69-3.54], and 2.41 [95% CI, 2.11-2.76] events per 100 patient-years in strata ≥50, >35-<50, and ≤35 mg/dL, respectively). Compared with propensity score-matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACEs after adjustment for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol but not vice versa.In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACEs increased across baseline apoB strata. Alirocumab reduced MACEs across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACEs, even after accounting for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of an apoB level ≤35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome.URL: https://www.gov. Unique identifier: NCT01663402.

  View details for DOI 10.1161/CIRCULATIONAHA.121.057807

  View details for PubMedID 35770629

• A Retrospective Analysis of Medical Student Performance Evaluations, 2014-2020: Recommend with Reservations. Journal of general internal medicine Tisdale, R. L., Filsoof, A. R., Singhal, S., Caceres, W., Nallamshetty, S., Rogers, A. J., Verghese, A. C., Harrington, R. A., Witteles, R. M. 2022

  Abstract

  BACKGROUND: The Medical Student Performance Evaluations (MSPE) is a cornerstone of residency applications. Little is known regarding adherence to Association of American Medical Colleges (AAMC) MSPE recommendations and longitudinal changes in MSPE content.OBJECTIVES: Evaluate current MSPE quality and longitudinal changes in MSPE and grading practices.DESIGN: Retrospective analysis.PARTICIPANTS: Students from all Liaison Committee on Medical Education (LCME)-accredited medical schools from which the Stanford University Internal Medicine residency program received applications between 2014-2015 and 2019-2020.MAIN MEASURES: Inclusion of key words to describe applicant performance and metrics thereof, including distribution among students and key word assignment explanation; inclusion of clerkship grades, grade distributions, and grade composition; and evidence of grade inflation over time.KEY RESULTS: MSPE comprehensiveness varied substantially among the 149 schools analyzed. In total, 25% of schools provided complete information consistent with AAMC recommendations regarding key word/categorization of medical students and clerkship grades in 2019-2020. Seventy-seven distinct key word terms appeared across the 139 schools examined in 2019-2020. Grading practices markedly varied, with 2-83% of students receiving the top internal medicine clerkship grade depending on the year and school. Individual schools frequently changed key word and grading practices, with 33% and 18% of schools starting and/or stopping use of key words and grades, respectively. Significant grade inflation occurred over the 6-year study period, with an average 14% relative increase in the proportion of students receiving top clerkship grades.CONCLUSIONS: A minority of schools complies with AAMC MSPE guidelines, and MSPEs are inconsistent across time and schools. These practices may impair evaluation of students within and between schools.

  View details for DOI 10.1007/s11606-022-07502-8

  View details for PubMedID 35710660

• Iterative approaches to the use of electronic health records data for large pragmatic studies. Contemporary clinical trials Jones, W. S., Wruck, L. M., Harrington, R. A., Hernandez, A. F. 2022: 106789

  Abstract

  Randomized controlled trials (RCT) are the gold standard for evaluating the effectiveness and safety of interventions and treatments, yet traditional clinical trials have relied on cumbersome and redundant processes such as electronic data entry which involves manual abstraction of already available electronic health record (EHR) data. This review focuses on the opportunities to expand the use of EHR data for pragmatic clinical trials using methods and lessons learned from the Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) study, the demonstration project from PCORnet® (the National Patient-Centered Clinical Research Network).

  View details for DOI 10.1016/j.cct.2022.106789

  View details for PubMedID 35545204

• Cost-effectiveness of ticagrelor in patients with type 2 diabetes and coronary artery disease: a European economic evaluation of the THEMIS trial. European heart journal. Cardiovascular pharmacotherapy Steg, P. G., Bhatt, D. L., James, S. K., Darlington, O., Hoskin, L., Simon, T., Fox, K. M., Leiter, L. A., Mehta, S. R., Harrington, R. A., Himmelmann, A., Ridderstrale, W., Andersson, M., Bueno, H., De Luca, L., Tank, A., Mellstrom, C., McEwan, P. 2022

  Abstract

  AIMS: To conduct a health economic evaluation of ticagrelor in patients with type 2 diabetes and coronary artery disease, from a multinational payer perspective. Cost-effectiveness and cost-utility of ticagrelor was evaluated in the overall THEMIS (effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study) trial population and in the predefined patient group with prior percutaneous coronary intervention.METHODS AND RESULTS: A Markov model was developed to extrapolate patient outcomes over a lifetime horizon. The primary outcome was incremental cost-effectiveness ratios (ICERs), which was compared with conventional willing to pay (WTP) thresholds (47,000 /quality-adjusted life year [QALY] in Sweden, 30,000 /QALY in other countries).Treatment with ticagrelor resulted in QALY gains of up to 0.045 in the overall population and 0.099 in patients with PCI. Increased costs and benefits translated to ICERs ranged between 27,894 and 42,252/QALY across Sweden, Germany, Italy, and Spain in the overall population. In patients with prior PCI, estimated ICERs improved to 18,449, 20,632, 20,233, and 13,228/QALY in Sweden, Germany, Italy, and Spain, respectively, driven by higher event rates and treatment benefit.CONCLUSION: Based on THEMIS results, ticagrelor plus aspirin compared with aspirin alone may be cost-effective in some European countries in patients with T2DM and CAD and no prior MI or stroke. Additionally, ticagrelor is likely to be cost-effective across European countries in patients with a history of PCI.

  View details for DOI 10.1093/ehjcvp/pvac032

  View details for PubMedID 35488865

• Outcomes With Intermediate Left Main Disease: Analysis From the ISCHEMIA Trial. Circulation. Cardiovascular interventions Bangalore, S., Spertus, J. A., Stevens, S. R., Jones, P. G., Mancini, G. B., Leipsic, J., Reynolds, H. R., Budoff, M. J., Hague, C. J., Min, J. K., Boden, W. E., O'Brien, S. M., Harrington, R. A., Berger, J. S., Senior, R., Peteiro, J., Pandit, N., Bershtein, L., de Belder, M. A., Szwed, H., Doerr, R., Monti, L., Alfakih, K., Hochman, J. S., Maron, D. J., ISCHEMIA Research Group 2022: CIRCINTERVENTIONS121010925

  Abstract

  BACKGROUND: Patients with significant (≥50%) left main disease (LMD) have a high risk of cardiovascular events, and guidelines recommend revascularization to improve survival. However, the impact of intermediate LMD (stenosis, 25%-49%) on outcomes is unclear.METHODS: Randomized ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) participants who underwent coronary computed tomography angiography at baseline were categorized into those with (25%-49%) and without (<25%) intermediate LMD. The primary outcome was a composite of cardiovascular mortality, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. The primary quality of life outcome was the Seattle Angina Questionnaire summary score.RESULTS: Among the 3699 participants who satisfied the inclusion criteria, 962 (26%) had intermediate LMD. Among invasive strategy participants with intermediate LMD on coronary computed tomography angiography, 49 (7.0%) had significant (≥50% stenosis) left main stenosis on invasive angiography. Patients with intermediate LMD had a higher risk of cardiovascular events in the unadjusted but not in the fully adjusted model compared with those without intermediate LMD. An invasive strategy increased procedural MI and decreased nonprocedural MI with no significant difference for other outcomes including the primary end point. There was no meaningful heterogeneity of treatment effect based on intermediate LMD status except for nonprocedural MI for which there was a greater absolute reduction with invasive management in the intermediate LMD group (-6.4% versus -2.0%; Pinteraction=0.049). The invasive strategy improved angina-related quality of life and the benefit was durable throughout follow-up without significant heterogeneity based on intermediate LMD status.CONCLUSIONS: In the ISCHEMIA trial, there was no meaningful heterogeneity of treatment benefit from an invasive strategy regardless of intermediate LMD status except for a greater absolute risk reduction in nonprocedural MI with invasive management in those with intermediate LMD. An invasive strategy increased procedural MI, reduced nonprocedural MI, and improved angina-related quality of life.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT01471522.

  View details for DOI 10.1161/CIRCINTERVENTIONS.121.010925

  View details for PubMedID 35411785

• Balance of Benefit and Risk of Ticagrelor in Patients With Diabetes and Stable Coronary Artery Disease According to Bleeding Risk Assessment With the CRUSADE Score: Data From THEMIS and THEMIS PCI: Abbreviated title: Bleeding risk stratification of ticagrelor. American heart journal Ducrocq, G., Bhatt, D. L., Lee, J. J., Kui, N., Fox, K. M., Harrington, R. A., Leiter, L. A., Mehta, S. R., Kiss, R. G., James, S., Vinereanu, D., Huber, K., Andersson, M., Himmelmann, A., Simon, T., Gabriel Steg, P. 2022

  Abstract

  BACKGROUND: The THEMIS trial demonstrated that in high-risk patients with stable coronary artery disease and diabetes without previous myocardial infarction or stroke, ticagrelor, in addition to aspirin, reduced the incidence of ischemic events but increased major bleeding. Identification of patients who could derive the greatest net benefit from the addition of ticagrelor appears important. We used the CRUSADE bleeding risk score to risk stratify the THEMIS population.METHODS: The population was divided into tertiles: score ≤22, 23-33, and ≥34. In each tertile, primary efficacy (composite of cardiovascular death, myocardial infarction, or stroke) and safety (TIMI major bleeding) outcomes were analyzed. NACE (Net Adverse Clinical Events) was defined as the irreversible harm composite, in which all-cause death, myocardial infarction, stroke, amputations, fatal bleeds, and intracranial hemorrhage were counted.RESULTS: Patients in the lower risk tertile experienced fewer ischemic events with ticagrelor than placebo, whereas there was no significant benefit from ticagrelor in the other tertiles (Pinteraction = .008). Bleeding rates were consistently increased with ticagrelor across all tertiles (Pinteraction = .79). Ticagrelor reduced NACE in the first tertile (HR = 0.74, 95% CI = 0.61-0.90) but not in the others (HR = 1.03, 95% CI = 0.86-1.23 and HR = 1.05, 95% CI = 0.91-1.22, respectively; Pinteraction = .012).CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, only those at the lower end of the bleeding risk spectrum according to the CRUSADE score derived net benefit from ticagrelor.

  View details for DOI 10.1016/j.ahj.2022.03.008

  View details for PubMedID 35321823

• Effect of Alirocumab on Incidence of Atrial Fibrillation After Acute Coronary Syndromes: Insights from the ODYSSEY OUTCOMES Randomized Trial. The American journal of medicine Lopes, R. D., Guimaraes, P. O., Schwartz, G. G., Bhatt, D. L., Bittner, V. A., Budaj, A., Dalby, A. J., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Kiss, R. G., Loy, M., Pordy, R., Poulouin, Y., Szarek, M., White, H. D., Steg, P. G., ODYSSEY OUTCOMES Investigators 2022

  Abstract

  BACKGROUND: Using data from the ODYSSEY OUTCOMES trial (NCT01663402), we sought to identify factors associated with the development of incident atrial fibrillation in patients with recent acute coronary syndrome without prior atrial fibrillation and to determine whether alirocumab treatment influenced risk of incident atrial fibrillation.METHODS: ODYSSEY OUTCOMES compared alirocumab treatment with placebo in 18,924 patients with recent acute coronary syndrome and dyslipidemia despite high-intensity or maximum-tolerated statin therapy. The primary outcome of major adverse cardiovascular events (MACE) comprised death from coronary heart disease, non-fatal myocardial infarction, fatal or non-fatal ischemic stroke, or unstable angina requiring hospitalization. Patients were classified as having previous atrial fibrillation (present before or at randomization) or no previous atrial fibrillation. A multivariable model was used to determine factors associated with incident atrial fibrillation.RESULTS: Among 18,262 participants without prior atrial fibrillation at baseline, 499 (2.7%) had incident atrial fibrillation during follow-up. Older age, history of heart failure or myocardial infarction, and higher body mass index were significantly associated with incident atrial fibrillation. Treatment with alirocumab or placebo did not influence the cumulative incidence of atrial fibrillation (hazard ratio, 0.91; 95% confidence interval, 0.77-1.09). Patients with versus without a history of atrial fibrillation had a higher incidence of MACE (8.8 vs. 3.7 events per 100 patient-years), without significant interaction between atrial fibrillation and randomized treatment on risk of MACE (Pinteraction=0.78).CONCLUSIONS: While alirocumab did not modify risk of incident atrial fibrillation after acute coronary syndrome, it did reduce the risk of MACE, regardless of prior atrial fibrillation history. History of atrial fibrillation is an independent predictor of recurrent cardiovascular events after acute coronary syndrome.

  View details for DOI 10.1016/j.amjmed.2022.02.016

  View details for PubMedID 35296402

• Changing the Trajectory of Heart Failure and Kidney Disease. Clinical journal of the American Society of Nephrology : CJASN Rangaswami, J., Bhalla, V., Chertow, G., Harrington, R., Staruschenko, A., Tuttle, K., Braunwald, E. 2022

  View details for DOI 10.2215/CJN.00470122

  View details for PubMedID 35232819

• Effects of early myocardial reperfusion and perfusion on myocardial necrosis/dysfunction and inflammation in patients with ST-segment and non-ST-segment elevation acute coronary syndrome: results from the PLATelet inhibition and patients Outcomes (PLATO) trial. European heart journal. Acute cardiovascular care Batra, G., Renlund, H., Kunadian, V., James, S. K., Storey, R. F., Steg, P. G., Katus, H. A., Harrington, R. A., Gibson, C. M., Budaj, A., Siegbahn, A., Wallentin, L. 2022

  Abstract

  AIMS: Restoration of myocardial blood flow and perfusion during percutaneous coronary intervention (PCI) measured using Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG) and perfusion grade (TMPG) is associated with improved outcomes in acute coronary syndrome (ACS). Associations between TFG/TMPG and changes in biomarkers reflecting myocardial damage/dysfunction and inflammation is unknown.METHODS AND RESULTS: Among 2606 patients included, TFG was evaluated in 2198 and TMPG in 1874 with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment ACS (NSTE-ACS). Biomarkers reflecting myocardial necrosis [troponin T (TnT)], myocardial dysfunction [N-terminal prohormone brain natriuretic peptide (NT-proBNP)], inflammation [interleukin-6 (IL-6) and C-reactive protein (CRP)], and oxidative stress/ageing/inflammation [growth differentiation factor-15 (GDF-15)] were measured at baseline, discharge, and 1- and 6-month post-randomization. Associations between TFG/TMPG and changes in biomarker levels were evaluated using the Mann-Whitney-Wilcoxon signed test. In total, 1423 (54.6%) patients had STEMI and 1183 (45.4%) NSTE-ACS. Complete reperfusion after PCI with TFG = 3 was achieved in 1110 (85.3%) with STEMI and in 793 (88.5%) with NSTE-ACS. Normal myocardial perfusion with TMPG = 3 was achieved in 475 (41.6%) with STEMI and in 396 (54.0%) with NSTE-ACS. Levels of TnT, NT-proBNP, IL-6, CRP, and GDF-15 were substantially lower at discharge in patients with complete vs. incomplete TFG and STEMI (P < 0.01). This pattern was not observed for patients with NSTE-ACS. Patients with normal vs. abnormal TMPG and NSTE-ACS had lower levels of NT-proBNP at discharge (P = 0.01).CONCLUSIONS: Successful restoration of epicardial blood flow in STEMI was associated with less myocardial necrosis/dysfunction and inflammation. Attainment of normal myocardial perfusion was associated with less myocardial dysfunction in NSTE-ACS.

  View details for DOI 10.1093/ehjacc/zuac020

  View details for PubMedID 35213721

• Effect of Platelet Inhibition by Cangrelor Among Obese Patients Undergoing Coronary Stenting: Insights From CHAMPION. Circulation. Cardiovascular interventions Peterson, B. E., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Lopes, R. D., Leonardi, S., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2022: CIRCINTERVENTIONS121011069

  Abstract

  BACKGROUND: In randomized trials, cangrelor reduced periprocedural ischemic events related to percutaneous coronary intervention without increasing GUSTO severe bleeding. However, some antiplatelet agents have shown a differential treatment effect by body mass index (BMI).METHODS: Patients from the 3 CHAMPION trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition) who were randomized to cangrelor versus clopidogrel during percutaneous coronary intervention were stratified by BMI. The primary efficacy end point was a composite of death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis within 48 hours. The principal safety outcome was GUSTO moderate or severe bleeding at 48 hours, although more sensitive bleeding measures such as Thrombolysis in Myocardial Infarction major bleeding were also assessed. We examined obese patients (defined as BMI≥30) versus nonobese patients.RESULTS: There were 24 893 patients, with 8979 (36.1%) having BMI of ≥30. There was no significant difference in the primary efficacy end point among obese versus nonobese patients (4.3% versus 4.2%; rate ratio, 1.01 [95% CI, 0.89-1.15]; P=0.82). There was a consistent benefit in the primary efficacy end point in patients who received cangrelor versus placebo who were obese (3.9% versus 4.7%, rate ratio, 0.83 [95% CI, 0.68-1.02]; P=0.07) and not obese (3.8% versus 4.7%; rate ratio, 0.81 [95% CI, 0.69-0.94]; P=0.0053); interaction P=0.77. There was no difference in GUSTO moderate or severe bleeding among patients who received cangrelor versus placebo who were obese (0.6% versus 0.6%; rate ratio, 0.99 [95% CI, 0.58-1.67]; P=0.96).CONCLUSIONS: Cangrelor at the time of percutaneous coronary intervention is effective and safe in obese and nonobese patients. There was no difference in short-term efficacy between obese and nonobese patients. Periprocedural cangrelor is an effective and safe antiplatelet agent, irrespective of BMI.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01156571, NCT00385138, NCT00305162.

  View details for DOI 10.1161/CIRCINTERVENTIONS.121.011069

  View details for PubMedID 35196863

• Diagnosis and Treatment of Acute Coronary Syndromes: A Review. JAMA Bhatt, D. L., Lopes, R. D., Harrington, R. A. 2022; 327 (7): 662-675

  Abstract

  Importance: Acute coronary syndromes (ACS) are characterized by a sudden reduction in blood supply to the heart and include ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), and unstable angina. Each year, an estimated more than 7 million people in the world are diagnosed with ACS, including more than 1 million patients hospitalized in the US.Observations: Chest discomfort at rest is the most common presenting symptom of ACS and affects approximately 79% of men and 74% of women presenting with ACS, although approximately 40% of men and 48% of women present with nonspecific symptoms, such as dyspnea, either in isolation or, more commonly, in combination with chest pain. For patients presenting with possible ACS, electrocardiography should be performed immediately (within 10 minutes of presentation) and can distinguish between STEMI and non-ST-segment elevation ACS (NSTE-ACS). STEMI is caused by complete coronary artery occlusion and accounts for approximately 30% of ACS. ACS without significant ST-segment elevation on electrocardiography, termed NSTE-ACS, account for approximately 70% of ACS, are caused by partial or intermittent occlusion of the artery and are associated with ST-segment depressions (approximately 31%), T-wave inversions (approximately 12%), ST-segment depressions combined with T-wave inversions (16%), or neither (approximately 41%). When electrocardiography suggests STEMI, rapid reperfusion with primary percutaneous coronary intervention (PCI) within 120 minutes reduces mortality from 9% to 7%. If PCI within 120 minutes is not possible, fibrinolytic therapy with alteplase, reteplase, or tenecteplase at full dose should be administered for patients younger than 75 years without contraindications and at half dose for patients 75 years or older (or streptokinase at full dose if cost is a consideration), followed by transfer to a facility with the goal of PCI within the next 24 hours. High-sensitivity troponin measurements are the preferred test to evaluate for NSTEMI. In high-risk patients with NSTE-ACS and no contraindications, prompt invasive coronary angiography and percutaneous or surgical revascularization within 24 to 48 hours are associated with a reduction in death from 6.5% to 4.9%.Conclusions and Relevance: Each year, an estimated more than 7 million people are diagnosed with ACS worldwide. For patients with STEMI, coronary catheterization and PCI within 2 hours of presentation reduces mortality, with fibrinolytic therapy reserved for patients without access to immediate PCI. For high-risk patients with NSTE-ACS without contraindications, prompt invasive coronary angiography followed by percutaneous or surgical revascularization is associated with lower rates of death.

  View details for DOI 10.1001/jama.2022.0358

  View details for PubMedID 35166796

• Inverse relationship between body mass index and risk of venous thromboembolism among medically ill hospitalized patients: Observations from the APEX trial. Thrombosis research Kalayci, A., Gibson, C. M., Hernandez, A. F., Hull, R. D., Cohen, A. T., Fitzgerald, C., Hussain, S. D., Chi, G., Alkhalfan, F., Harrington, R. A., Goldhaber, S. Z. 1800; 211: 63-69

  Abstract

  Obesity is associated with cardiovascular complications such as diabetes and hypertension. However, obesity and high body mass index (BMI) can also be linked to improved clinical outcomes in certain patient populations. This counterintuitive observation is called the "obesity paradox." The effect of BMI on the risk of developing venous thromboembolism (VTE) in acutely ill medical patients remains unclear. In the Acute Medically Ill VTE Prevention with Extended Duration Betrixaban (APEX) trial, acutely ill hospitalized medical patients were randomized to receive either extended-duration betrixaban or shorter-duration enoxaparin and followed for 77days. A total of 7372 patients with evaluable VTE endpoints had BMI measured at baseline. The association between BMI and VTE risk was assessed after adjusting for potential confounders. The multivariable adjusted ORs of VTE risk associated with BMI levels referencing the median BMI value (15, 18.5, 28.3 [reference], 35, 40, 45) were: 2.82 (95% CI, 1.32-6.04, [change from 28.3 to 15]), 1.85 (95% CI, 1.14-2.99, [change from 28.3 to 18.5]), 1.30 (95% CI, 1.04-1.63, [change from 28.3 to 35]), 1.13 (95% CI, 0.84-1.52, [change from 28.3 to 40]), and 0.91 (95% CI, 0.57-1.47, [change from 28.3 to 45]), respectively (p=0.022). In conclusion, acutely ill hospitalized patients with lower BMI had a higher VTE risk through 77days, which appears to be a manifestation of the BMI paradox.

  View details for DOI 10.1016/j.thromres.2022.01.016

  View details for PubMedID 35091313

• Ischemic Events Occur Early in Patients Undergoing Percutaneous Coronary Intervention and Are Reduced With Cangrelor: Findings From CHAMPION PHOENIX. Circulation. Cardiovascular interventions Cavender, M. A., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., 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 PHOENIX Investigators, Harrington, R. A., Huber, K., Lima, V. C., Jorgova-Makedonska, J. B., Widimsky, P., Kobulia, B., Radke, P. W., Bramucci, E., Witkowski, A., Shlyakhto, E., Van de Werf, F., Faxon, D. P., Ohman, E. M., Verheugt, F. W., Weaver, W. D., Tijssen, J. G., Wilson, M., Mangum, S., Melloni, C., Brennan, M. J., Tricoci, P., Harrison, R., Barros, P., Armaganijan, L., Anderson, M., Bagai, A., Genereux, P., Brener, S. J., LaSalle, L., Benzer, W., Delle-Karth, G., Huber, K., Leisch, F., Abdalla Saad, J., Abizaid, A., Augusto Formiga Areas, C., Ribeiro, E. E., Rossi Dos Santos, F., Tadeu Tumelero, R., Vieira Botelho, R., Atzev, B., Boichev, B., Grigorov, G., Penkov, N., Petrov, I., Zehirov, B., Cervinka, P., Coufal, Z., Hajek, P., Horak, D., Kala, P., Kmonicek, P., Kocka, V., Mrozek, J., Simek, S., Sitar, J., Stasek, J., Tousek, F., Chapidze, G., Emukhvari, N., Khabeishvili, G., Mamatsashvili, M., Shaburishvili, T., Behrens, S., Darius, H., Dissmann, M., Fichtlscherer, S., Franz, W., Geisler, T., Genth-Zotz, S., Goldmann, B., Heuer, H., Hoffmann, S., Mugge, A., Poerner, T., Radke, P., Richardt, G., Stellbrink, C., Werner, N., Bramucci, E., De Servi, S., Galasso, G., Menozzi, A., Musumeci, G., Picchi, A., Presbitero, P., Devlin, G., Sasse, A., Scott, D., Stewart, R., Andrzej, S., Dubaniewicz, W., Gasior, Z., Kasprzak, J., Kleinrok, A., Kornacewicz-Jach, Z., Rynkiewicz, A., Sosnowski, C., Targonski, R., Trebacz, J., Witkowski, A., Zinka, E., Barbarash, O., Dovgalevsky, Y., Gordeev, I., Kalinina, S., Kosmachova, E., Markov, V., Pavlov, P., Shalaev, S., Shogenov, Z., Sukmanova, I., Vasilieva, E., Yakovlev, A., Boonbaichaiyapruck, S., Chamnarnphol, N., Kaewsuwanna, P., Kuanprasert, S., Piyayotai, D., Amine, M., Angiolillo, D., Arif, I., Blankenship, J., Brilakis, E., Chan, M., Cinderella, J., Davis, B., Devireddy, C., Dorogy, M., Douglas, J., Ferrier, N., Fisher, D., Foster, R., French, W., Galla, J., Gimple, L., Gogia, H., Gogo, P., Gollapudi, R., Gruberg, L., Hermiller, J., Heuser, R., Iwaoka, R., Jafar, Z., Kimmelstiel, C., Kinlay, S., Leggett, J., Leimgruber, P., Letts, D., Lipsitt, M., Low, R., Martinez-Arraras, J., Mayhew, M., McLaurin, B., McWhirter, P., Mirza, A., Negus, B., Nygaard, T., O'Riordan, W., Paulus, R., Petersen, J., Picon, H., Picone, M., Rivera, E., Rizik, D., Rizik, D., Rodriguez, A., Saucedo, J., Scott, J. C., Sethi, V., Shroff, A., Siegel, C., Spriggs, D., Steinberg, D., Stillabower, M., Stuckey, T., Suarez, J., Tauth, J., Temizer, D., Vidovich, M., Voeltz, M., Waltman, J., Wilensky, M. 1800: CIRCINTERVENTIONS120010390

  Abstract

  BACKGROUND: Thrombotic events are reduced with cangrelor, an intravenous P2Y12 inhibitor. We sought to characterize the timing, number, and type of early events (within 2 hours of randomization) in CHAMPION PHOENIX (A Clinical Trial Comparing Cangrelor to Clopidogrel Standard of Care Therapy in Subjects Who Require Percutaneous Coronary Intervention).METHODS: CHAMPION PHOENIX was a double-blind, placebo-controlled trial that randomized patients undergoing percutaneous coronary intervention to cangrelor or clopidogrel. For this analysis, we evaluated the efficacy of cangrelor in the first 2 hours postrandomization with regards to the primary end point (death, myocardial infarction, ischemia-driven revascularization, or stent thrombosis). Sensitivity analyses were performed evaluating a secondary, post hoc end point (death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium definite stent thrombosis).RESULTS: The majority of events (63%) that occurred in the trial occurred within 2 hours of randomization. The most common early event was myocardial infarction; next were stent thrombosis, ischemia driven revascularization, and death. In the first 2 hours after randomization, cangrelor significantly decreased the primary composite end point compared with clopidogrel (4.1% versus 5.4%; hazard ratio, 0.76 [95% CI, 0.64-0.90], P=0.002). Similar findings were seen for the composite end point of death, Society of Coronary Angiography and Intervention myocardial infarction, ischemia-driven revascularization, or Academic Research Consortium stent thrombosis at 2 hours (0.9% versus 1.6%; hazard ratio, 0.57 [95% CI, 0.40-0.80], P=0.001). Between 2 and 48 hours, there was no difference in the primary composite end point (0.6% versus 0.5%; odds ratio, 1.17 [95% CI, 0.71-1.93]; P=0.53). Early (≤2 hours of randomization) GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) moderate or severe bleeding events were infrequent, and there was no significant difference with cangrelor compared with clopidogrel (0.2% [n=10] versus 0.1% [n=4]; adjusted odds ratio, 1.41 [95% CI, 0.37-5.40]; P=0.62).CONCLUSIONS: The reductions in ischemic events and overall efficacy seen with cangrelor in CHAMPION PHOENIX occurred early and during the period of time in which patients were being actively treated with cangrelor. These findings provide evidence that supports the importance of potent platelet inhibition during percutaneous coronary intervention.REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01156571.

  View details for DOI 10.1161/CIRCINTERVENTIONS.120.010390

  View details for PubMedID 34915723

• The Pivotal Role of Women in Cardiology Sections in Medical Organizations: From Leadership Training to Personal Enrichment. CJC open Sharma, G., Lewis, S., Singh, T., Mehta, L. S., Mieres, J., Poppas, A., Harrington, R., Pina, I. L., Volgman, A. S., Aggarwal, N. R. 1800; 3 (12 Suppl): S95-S101

  Abstract

  Women in cardiology (WIC) sections have emerged as important leadership, career development, and advocacy forums for female cardiologists. Over the past 3 decades, they have grown from small groups to large sections within volunteer science organizations. In addition to providing a sense of community and promulgating the principles of diversity, equity, inclusion, and belonging, the WIC sections have contributed to improving workplace culture and dynamics by generating evidence-based and actionable data, fostering leadership by and scientific enrichment of women, developing task forces and health policy documents targeted toward reduction of burnout and bias in medicine, and providing a platform to voice the unique challenges and opportunities of female cardiologists. The future holds great promise, as the WIC sections continue to play a pivotal role by being intentional, transparent, iterative, and sustainable, and working with important stakeholders, including men, to share data, best practices, and strategies to create and maintain a culture of equity and achieve its core principles.

  View details for DOI 10.1016/j.cjco.2021.07.015

  View details for PubMedID 34993439

• p Women's health in Serbia - past, present, and future SRPSKI ARHIV ZA CELOKUPNO LEKARSTVO Parapid, B., Kanjuh, V., Kostic, V., Polovina, S., Dinic, M., Loncar, Z., Lalic, K., Gojnic-Dugalic, M., Nedeljkovic, M., Lazic, B., Milosevic, M., Simic, D., Neskovic, A., Harrington, R. A., Valentine, C., Volgman, A., Lewis, S. J., Dukic-Dejanovic, S., Mitchell, S., Bond, R. M., Waksman, R., Alasnag, M., Bairey-Merz, C., Gaita, D., Mischie, A., Karamarkovic, N., Rakic, S., Mrkic, M., Tasovac, M., Devrnja, V., Bubanja, D., Wenger, N. 2021; 149 (11-12): 745-754

  View details for DOI 10.2298/SARH211208105P

  View details for Web of Science ID 000744642700018

• Efficacy and safety of cangrelor in patients with peripheral artery disease undergoing percutaneous coronary intervention - Insights from the CHAMPION program. American heart journal plus : cardiology research and practice Gutierrez, J. A., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Lopes, R. D., Leonardi, S., Prats, J., Deliargyris, E. N., Mahaffey, K. W., White, H. D., Bhatt, D. L. 2021; 9: 100043

  Abstract

  Peripheral artery disease (PAD) is associated with an increased risk of ischemic events following percutaneous coronary intervention (PCI). More aggressive antiplatelet therapy may mitigate this risk. The present study evaluates the efficacy of cangrelor in patients with PAD undergoing PCI.This is a pooled analysis from the CHAMPION PCI, CHAMPION PLATFORM, AND CHAMPION PHOENIX trials, evaluating cangrelor versus either clopidogrel or placebo in PCI patients. The occurrence of the primary endpoint of death, myocardial infarction, or ischemia-driven revascularization (IDR) was assessed in patients with and without PAD. GUSTO severe bleeding at 48 h was also evaluated. There were 1720 (7%) patients with PAD and 22,802 (93%) without PAD. After adjustment for differences in baseline variables, PAD patients, compared with those without PAD, experienced increased odds of the primary endpoint (OR [95% CI] = 1.27 [0.91, 1.77], P = 0.16) and GUSTO severe bleeding (OR [95% CI] = 3.24 [1.28, 8.21], P = 0.01). In PAD patients, the primary endpoint was 4.7% with cangrelor vs. 7.2% with clopidogrel (OR [95% CI] = 0.64 [0.42,0.96]); in patients without PAD the primary endpoint was 3.5% with cangrelor vs. 4.2% with clopidogrel (OR [95% CI] = 0.83 [0.72,0.95]), P-interaction 0.23. Among patients with or without PAD, there was no significant difference in the rate of GUSTO severe bleeding with cangrelor compared with control, P-interaction 0.86.In a pooled analysis of the CHAMPION studies, PAD was associated with increased rates of ischemic and bleeding complications. Cangrelor reduced the odds of ischemic events, without increasing GUSTO severe bleeding.clinicaltrials.gov identifiers: CHAMPION PCI (NCT00305162), CHAMPION PLATFORM(NCT00385138), CHAMPION PHOENIX (NCT01156571).

  View details for DOI 10.1016/j.ahjo.2021.100043

  View details for PubMedID 38551015

  View details for PubMedCentralID PMC10978113

• 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

• Increases in SARS-CoV-2 Test Positivity Rates Among Hispanic People in a Northern California Health System. Public health reports (Washington, D.C. : 1974) Rodriguez, F., Coquet, J., Harrington, R., Hernandez-Boussard, T. 2021: 333549211026778

  Abstract

  Racial/ethnic minority groups are disproportionately affected by the COVID-19 pandemic. We examined ethnic differences in SARS-CoV-2 testing patterns and positivity rates in a large health care system in Northern California. The study population included patients tested for SARS-CoV-2 from March 4, 2020, through January 12, 2021, at Stanford Health Care. We used adjusted hierarchical logistic regression models to identify factors associated with receiving a positive test result. During the study period, 282 916 SARS-CoV-2 tests were administered to 179 032 unique patients, 32 766 (18.3%) of whom were Hispanic. Hispanic patients were 3 times more likely to receive a positive test result than patients in other racial/ethnic groups (odds ratio = 3.16; 95% CI, 3.00-3.32). The rate of receiving a positive test result for SARS-CoV-2 among Hispanic patients increased from 5.4% in mid-March to 15.7% in mid-July, decreased to 3.9% in mid-October, and increased to 21.2% toward the end of December. Hispanic patients were more likely than non-Hispanic patients to receive a positive test result for SARS-CoV-2, with increasing trends during regional surges. The disproportionate and growing overrepresentation of Hispanic people receiving a positive test result for SARS-CoV-2 demonstrates the need to focus public health prevention efforts on these communities.

  View details for DOI 10.1177/00333549211026778

  View details for PubMedID 34161176

• Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease NEW ENGLAND JOURNAL OF MEDICINE Jones, W., Mulder, H., Wruck, L. M., Pencina, M. J., Kripalani, S., Munoz, D., Crenshaw, D. L., Effron, M. B., Re, R. N., Gupta, K., Anderson, R., Pepine, C. J., Handberg, E. M., Manning, B. R., Jain, S. K., Girotra, S., Riley, D., DeWalt, D. A., Whittle, J., Goldberg, Y. H., Roger, V. L., Hess, R., Benziger, C. P., Farrehi, P., Zhou, L., Ford, D. E., Haynes, K., VanWormer, J. J., Knowlton, K. U., Kraschnewski, J. L., Polonsky, T. S., Fintel, D. J., Ahmad, F. S., McClay, J. C., Campbell, J. R., Bell, D. S., Fonarow, G. C., Bradley, S. M., Paranjape, A., Roe, M. T., Robertson, H. R., Curtis, L. H., Sharlow, A. G., Berdan, L. G., Hammill, B. G., Harris, D. F., Qualls, L. G., Marquis-Gravel, G., Modrow, M. F., Marcus, G. M., Carton, T. W., Nauman, E., Waitman, L. R., Kho, A. N., Shenkman, E. A., McTigue, K. M., Kaushal, R., Masoudi, F. A., Antman, E. M., Davidson, D. R., Edgley, K., Merritt, J. G., Brown, L. S., Zemon, D. N., McCormick, T. E., Alikhaani, J. D., Gregoire, K. C., Rothman, R. L., Harrington, R. A., Hernandez, A. F., ADAPTABLE Team 2021; 384 (21): 1981-1990

  View details for DOI 10.1056/NEJMoa2102137Copyright<(c)>2021Massachusetts

  View details for Web of Science ID 000665641200015

• Global Prevalence and Impact of Hostility, Discrimination, and Harassment in the Cardiology Workplace. Journal of the American College of Cardiology Sharma, G., Douglas, P. S., Hayes, S. N., Mehran, R., Rzeszut, A., Harrington, R. A., Poppas, A., Walsh, M. N., Singh, T., Parekh, R., Blumenthal, R. S., Mehta, L. S. 2021; 77 (19): 2398-2409

  Abstract

  BACKGROUND: Discrimination and emotional and sexual harassment create a hostile work environment (HWE). The global prevalence of HWE in cardiology is unknown, as is its impact.OBJECTIVES: This study sought to evaluate emotional harassment, discrimination, and sexual harassment experienced by cardiologists and its impact on professional satisfaction and patient interactions worldwide.METHODS: The American College of Cardiology surveyed cardiologists from Africa, Asia, the Caribbean, Eastern Europe, the European Union, the Middle East, Oceana, and North, Central, and South America. Demographics, practice information, and HWE were tabulated and compared, and their impact was assessed. The p values were calculated using the chi-square, Fisher exact, and Mann-Whitney U tests. Univariate and multivariate logistic regression analysis determined the association of characteristics with HWE and its subtypes.RESULTS: Of 5,931 cardiologists (77% men; 23% women), 44% reported HWE. Higher rates were found among women (68% vs. 37%; odds ratio [OR]: 3.58 vs. men), Blacks (53% vs. 43%; OR: 1.46 vs. Whites), and North Americans (54% vs. 38%; OR: 1.90 vs. South Americans). Components of HWE included emotional harassment (29%; n=1,743), discrimination (30%; n=1,750), and sexual harassment (4%; n=221), and they were more prevalent among women: emotional harassment (43% vs. 26%), discrimination (56% vs. 22%), and sexual harassment (12% vs. 1%). Gender was the most frequent cause of discrimination (44%), followed by age (37%), race (24%), religion (15%), and sexual orientation (5%). HWE adversely affected professional activities with colleagues (75%) and patients (53%). Multivariate analysis showed that women (OR: 3.39; 95% confidence interval: 2.97 to 3.86; p<0.001) and cardiologists early in their career (OR: 1.27; 95% confidence interval: 1.14 to 1.43; p<0.001) had the highest odds of experiencing HWE.CONCLUSIONS: There is a high global prevalence of HWE in cardiology, including discrimination, emotional harassment, and sexual harassment. HWE has an adverse effect on professional and patient interactions, thus confirming concerns about well-being and optimizing patient care. Institutions and practices should prioritize combating HWE.

  View details for DOI 10.1016/j.jacc.2021.03.301

  View details for PubMedID 33985685

• Comparative Effectiveness of Aspirin Dosing in Cardiovascular Disease. The New England journal of medicine Jones, W. S., Mulder, H., Wruck, L. M., Pencina, M. J., Kripalani, S., Munoz, D., Crenshaw, D. L., Effron, M. B., Re, R. N., Gupta, K., Anderson, R. D., Pepine, C. J., Handberg, E. M., Manning, B. R., Jain, S. K., Girotra, S., Riley, D., DeWalt, D. A., Whittle, J., Goldberg, Y. H., Roger, V. L., Hess, R., Benziger, C. P., Farrehi, P., Zhou, L., Ford, D. E., Haynes, K., VanWormer, J. J., Knowlton, K. U., Kraschnewski, J. L., Polonsky, T. S., Fintel, D. J., Ahmad, F. S., McClay, J. C., Campbell, J. R., Bell, D. S., Fonarow, G. C., Bradley, S. M., Paranjape, A., Roe, M. T., Robertson, H. R., Curtis, L. H., Sharlow, A. G., Berdan, L. G., Hammill, B. G., Harris, D. F., Qualls, L. G., Marquis-Gravel, G., Modrow, M. F., Marcus, G. M., Carton, T. W., Nauman, E., Waitman, L. R., Kho, A. M., Shenkman, E. A., McTigue, K. M., Kaushal, R., Masoudi, F. A., Antman, E. M., Davidson, D. R., Edgley, K., Merritt, J. G., Brown, L. S., Zemon, D. N., McCormick, T. E., Alikhaani, J. D., Gregoire, K. C., Rothman, R. L., Harrington, R. A., Hernandez, A. F., ADAPTABLE Team 2021

  Abstract

  BACKGROUND: The appropriate dose of aspirin to lower the risk of death, myocardial infarction, and stroke and to minimize major bleeding in patients with established atherosclerotic cardiovascular disease is a subject of controversy.METHODS: Using an open-label, pragmatic design, we randomly assigned patients with established atherosclerotic cardiovascular disease to a strategy of 81 mg or 325 mg of aspirin per day. The primary effectiveness outcome was a composite of death from any cause, hospitalization for myocardial infarction, or hospitalization for stroke, assessed in a time-to-event analysis. The primary safety outcome was hospitalization for major bleeding, also assessed in a time-to-event analysis.RESULTS: A total of 15,076 patients were followed for a median of 26.2 months (interquartile range [IQR], 19.0 to 34.9). Before randomization, 13,537 (96.0% of those with available information on previous aspirin use) were already taking aspirin, and 85.3% of these patients were previously taking 81 mg of daily aspirin. Death, hospitalization for myocardial infarction, or hospitalization for stroke occurred in 590 patients (estimated percentage, 7.28%) in the 81-mg group and 569 patients (estimated percentage, 7.51%) in the 325-mg group (hazard ratio, 1.02; 95% confidence interval [CI], 0.91 to 1.14). Hospitalization for major bleeding occurred in 53 patients (estimated percentage, 0.63%) in the 81-mg group and 44 patients (estimated percentage, 0.60%) in the 325-mg group (hazard ratio, 1.18; 95% CI, 0.79 to 1.77). Patients assigned to 325 mg had a higher incidence of dose switching than those assigned to 81 mg (41.6% vs. 7.1%) and fewer median days of exposure to the assigned dose (434 days [IQR, 139 to 737] vs. 650 days [IQR, 415 to 922]).CONCLUSIONS: In this pragmatic trial involving patients with established cardiovascular disease, there was substantial dose switching to 81 mg of daily aspirin and no significant differences in cardiovascular events or major bleeding between patients assigned to 81 mg and those assigned to 325 mg of aspirin daily. (Funded by the Patient-Centered Outcomes Research Institute; ADAPTABLE ClinicalTrials.gov number, NCT02697916.).

  View details for DOI 10.1056/NEJMoa2102137

  View details for PubMedID 33999548

• Antithrombotic Therapy after Acute Coronary Syndromes REPLY NEW ENGLAND JOURNAL OF MEDICINE Rodriguez, F., Harrington, R. A. 2021; 384 (19): 1873-1874

  View details for Web of Science ID 000651509400029

• Nonprofit Advocacy at the American Heart Association: Creating a Visionary Way Forward at Our 40th Anniversary: An American Heart Association Policy Statement CIRCULATION Churchwell, K., Antman, E., Birnbaum, J., Desai, N. R., Harrington, R. A., Holubowich, E. J., Ivy, K. N., Schoeberl, M., Warner, J. J., White, C. J., Whitsel, L. P., Yancy, C., Amer Heart Assoc Advocacy Coordina 2021; 143 (19): E947-E958

  Abstract

  In 2021, the American Heart Association celebrates its 40th anniversary in advocacy. This policy statement details the arc of the organization's nonpartisan, evidence-based, equity-focused approach to advocating for public policy change, highlighting key milestones and describing the core components of the association's capacity and activity at all levels of government. This policy statement presents a vision and strategic imperative for future American Heart Association advocacy efforts to inform and influence policy changes that advance equitable, impactful societal solutions that transform and improve cardiovascular health for everyone. The American Heart Association maintains accountability by measuring and evaluating the totality of this work and its impact on equitable health outcomes. The American Heart Association will apply these lessons to constantly refine its own strategic policy focus and advocacy efforts. The association will also serve as a resource and catalyst to other organizations working to engage and educate policy makers, partners, the media, and funders about the important role and contribution of public policy change to achieve shared goals.

  View details for DOI 10.1161/CIR.0000000000000972

  View details for Web of Science ID 000649074100005

  View details for PubMedID 33840208

• GENDER DISPARITIES IN CARDIOLOGY-RELATED COVID-19 PUBLICATIONS Vasti, E., Ouyang, D., Ngo, S., Harrington, R., Rodriguez, F. ELSEVIER SCIENCE INC. 2021: 3105

  View details for Web of Science ID 000647487503129

• A Return to Normal Is Not Good Enough. Circulation Elkind, M. S., Harrington, R. A., Lloyd-Jones, D. M. 2021; 143 (18): e893–e897

  View details for DOI 10.1161/CIRCULATIONAHA.121.054920

  View details for PubMedID 33939527

• Establishing a Data Science Unit in an Academic Medical Center: An Illustrative Model. Academic medicine : journal of the Association of American Medical Colleges Desai, M., Boulos, M., Pomann, G. M., Steinberg, G. K., Longo, F. M., Leonard, M., Montine, T., Blomkalns, A. L., Harrington, R. A. 2021

  Abstract

  The field of data science has great potential to address critical questions relevant for academic medical centers. Data science initiatives are consequently being established within academic medicine. At the cornerstone of such initiatives are scientists who practice data science. These scientists include biostatisticians, clinical informaticians, database and software developers, computational scientists, and computational biologists. Too often, however, those involved in the practice of data science are viewed by academic leadership as providing a noncomplex service to facilitate research and further the careers of other academic faculty. The authors contend that the success of data science initiatives relies heavily on the understanding that the practice of data science is a critical intellectual contribution to the overall science conducted at an academic medical center. Further, careful thought by academic leadership is needed for allocation of resources devoted to the practice of data science. At the Stanford University School of Medicine, the authors have developed an innovative model for a data science collaboratory based on 4 fundamental elements: an emphasis on collaboration over consultation; a subscription-based funding mechanism that reflects commitment by key partners; an investment in the career development of faculty who practice data science; and a strong educational component for data science members in team science and for clinical and translational investigators in data science. As data science becomes increasingly essential to learning health systems, centers that specialize in the practice of data science are a critical component of the research infrastructure and intellectual environment of academic medical centers.

  View details for DOI 10.1097/ACM.0000000000004079

  View details for PubMedID 33769342

• Temporal Trends in the Proportion of Women Physician Speakers at Major Cardiovascular Conferences. Circulation Yong, C. M., Balasubramanian, S., Douglas, P. S., Agarwal, P., Birgersdotter-Green, U., Gummidipundi, S., Batchelor, W., Duvernoy, C. S., Harrington, R. A., Mehran, R. 2021; 143 (7): 755–57

  View details for DOI 10.1161/CIRCULATIONAHA.120.052663

  View details for PubMedID 33587663

• Taking a Stand Against Air Pollution - The Impact on Cardiovascular Disease: A Joint Opinion from the World Heart Federation, American College of Cardiology, American Heart Association, and the European Society of Cardiology. Global heart Brauer, M., Casadei, B., Harrington, R. A., Kovacs, R., Sliwa, K., WHF Air Pollution Expert Group 2021; 16 (1): 8

  Abstract

  Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts and may also interact with COVID-19. Air pollution is one crucial example. Established evidence from other respiratory viruses and emerging evidence for COVID-19 specifically indicates that air pollution alters respiratory defense mechanisms leading to worsened infection severity. Air pollution also contributes to co-morbidities that are known to worsen outcomes amongst those infected with COVID-19, and air pollution may also enhance infection transmission due to its impact on more frequent coughing. Yet despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield. Thus, the urgency to combat air pollution is not diminished, but instead heightened in the context of the pandemic.

  View details for DOI 10.5334/gh.948

  View details for PubMedID 33598388

• Taking a Stand Against Air Pollution-The Impact on Cardiovascular Disease: A Joint Opinion from the World Heart Federation, American College of Cardiology, American Heart Association, and the European Society of Cardiology. Journal of the American College of Cardiology Brauer, M., Casadei, B., Harrington, R. A., Kovacs, R., Sliwa, K., WHF Air Pollution Expert Group 2021

  Abstract

  Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts and may also interact with COVID-19. Air pollution is one crucial example. Established evidence from other respiratory viruses and emerging evidence for COVID-19 specifically indicates that air pollution alters respiratory defense mechanisms leading to worsened infection severity. Air pollution also contributes to co-morbidities that are known to worsen outcomes amongst those infected with COVID-19, and air pollution may also enhance infection transmission due to its impact on more frequent coughing. Yet despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield. Thus, the urgency to combat air pollution is not diminished, but instead heightened in the context of the pandemic.

  View details for DOI 10.1016/j.jacc.2020.12.003

  View details for PubMedID 33518378

• COVID-19 at 1 Year: American Heart Association Presidents Reflect on the Pandemic. Circulation Elkind, M. S., Harrington, R. A., Lloyd-Jones, D. M. 2021; 143 (9): e746–e748

  View details for DOI 10.1161/CIRCULATIONAHA.120.053439

  View details for PubMedID 33646828

• Incidence of Myocardial Infarction Types in Patients Treated With Ticagrelor in the THEMIS Trial. Circulation. Cardiovascular interventions Abtan, J., Bhatt, D. L., Held, C., Simon, T., Fox, K., Mehta, S. R., Harrington, R. A., Gao, Q., Leiter, L. A., Steg, P. G. 2021: CIRCINTERVENTIONS120011035

  View details for DOI 10.1161/CIRCINTERVENTIONS.120.011035

  View details for PubMedID 34814698

• The Need to Expand the Framework of Environmental Determinants of Cardiovascular Health From Climate Change to Planetary Health: Trial by Wildfire. Circulation Chang, A. Y., Barry, M., Harrington, R. A. 2021; 143 (21): 2029-2031

  View details for DOI 10.1161/CIRCULATIONAHA.120.051892

  View details for PubMedID 34029138

• Gender Disparities in Cardiology-Related COVID-19 Publications. Cardiology and therapy Vasti, E. C., Ouyang, D., Ngo, S., Sarraju, A., Harrington, R. A., Rodriguez, F. 2021

  Abstract

  Female authors are underrepresented in cardiology journals, although prior work suggested improvement in reducing disparities over time. Early in the recent COVID-19 pandemic, female authorship continued to lag that of their male counterparts despite a surge in publications. The cumulative impact of the COVID-19 pandemic on authorship gender disparities remains unclear. We aimed to characterize gender disparities in COVID-19-related cardiology publications across the duration of the ongoing pandemic.We retrospectively analyzed COVID-19-related research articles published in the top 20 impact factor cardiology journals between March and June 2021. Gender representation data were extracted for any author, first authors, and senior authors.We found that 841 articles were related to COVID-19, with a total of 5586 authors and an average of 42 articles per journal. Less than a third (29.9%) of the total authors from publications were women. Women represented a smaller proportion of first authors (21.3%) and senior authors (16.4%).Female authorship has continued to lag male authorship for the duration of the ongoing COVID-19 pandemic. The pandemic may have impeded progress in reducing gender disparities in academic cardiology publications. The low proportions of first and senior female authors may reflect the impact of the pandemic on women in cardiology in leadership domains.

  View details for DOI 10.1007/s40119-021-00234-6

  View details for PubMedID 34268712

• Antithrombotic Therapy after Acute Coronary Syndromes. Reply. The New England journal of medicine Rodriguez, F. n., Harrington, R. A. 2021; 384 (19): 1873–74

  View details for DOI 10.1056/NEJMc2103789

  View details for PubMedID 33979504

• Management of Antithrombotic Therapy after Acute Coronary Syndromes. The New England journal of medicine Rodriguez, F. n., Harrington, R. A. 2021; 384 (5): 452–60

  View details for DOI 10.1056/NEJMra1607714

  View details for PubMedID 33534976

• Taking a Stand Against Air Pollution-The Impact on Cardiovascular Disease: A Joint Opinion From the World Heart Federation, American College of Cardiology, American Heart Association, and the European Society of Cardiology. Circulation Brauer, M. n., Casadei, B. n., Harrington, R. A., Kovacs, R. n., Sliwa, K. n. 2021: CIRCULATIONAHA120052666

  Abstract

  Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts and may also interact with COVID-19. Air pollution is one crucial example. Established evidence from other respiratory viruses and emerging evidence for COVID-19 specifically indicates that air pollution alters respiratory defense mechanisms leading to worsened infection severity. Air pollution also contributes to comorbidities that are known to worsen outcomes among those infected with COVID-19, and air pollution may also enhance infection transmission due to its impact on more frequent coughing. Yet despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield. Thus, the urgency to combat air pollution is not diminished, but instead heightened in the context of the pandemic.

  View details for DOI 10.1161/CIRCULATIONAHA.120.052666

  View details for PubMedID 33506685

• Taking a stand against air pollution - the impact on cardiovascular disease. European heart journal Brauer, M. n., Casadei, B. n., Harrington, R. A., Kovacs, R. n., Sliwa, K. n. 2021

  Abstract

  Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts and may also interact with COVID-19. Air pollution is one crucial example. Established evidence from other respiratory viruses and emerging evidence for COVID-19 specifically indicates that air pollution alters respiratory defense mechanisms leading to worsened infection severity. Air pollution also contributes to co-morbidities that are known to worsen outcomes amongst those infected with COVID-19, and air pollution may also enhance infection transmission due to its impact on more frequent coughing. Yet despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield. Thus, the urgency to combat air pollution is not diminished, but instead heightened in the context of the pandemic.

  View details for DOI 10.1093/eurheartj/ehaa1025

  View details for PubMedID 33507239

• Risk Stratification Science Goes to a New Level. JAMA cardiology Harrington, R. A., Ohman, E. M. 2020

  View details for DOI 10.1001/jamacardio.2020.6325

  View details for PubMedID 33295937

• Low-density lipoprotein cholesterol < 50 mg/dL is an appropriate target after acute coronary syndrome: propensity score-matched analysis of the ODYSSEY OUTCOMES trial Schwartz, G. G., Szarek, M., Bhatt, D. L., Bittner, V. A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Kim, Y. U., Li, Q. H., Manvelian, G., White, H. D., Zeiher, A. M., Steg, P. G., ODYSSEY OUTCOMES Investigators OXFORD UNIV PRESS. 2020: 1736

  View details for Web of Science ID 000606106301739

• Cost-effectiveness of ticagrelor in patients with type 2 diabetes and coronary artery disease with a history of PCI: an economic evaluation of THEMIS-PCI using a Swedish healthcare perpective Steg, P., Bhatt, D. L., James, S. K., Darlington, O., Hoskin, L., Simons, T., Fox, K., Leiter, L. A., Mehta, S., Harrington, R. A., Himmelmann, A., Ridderstrale, W., Andersson, M., Mellstrom, C., Mcewan, P. OXFORD UNIV PRESS. 2020: 3538

  View details for Web of Science ID 000606106303545

• Effect of alirocumab on incidence of atrial fibrillation after acute coronary syndromes: insights from ODYSSEY OUTCOMES Lopes, R., Steg, P. G., Bhatt, D. L., Bittner, V. A., Dauchy, A., Diaz, R., Goodman, S. G., Harrington, R. A., Jukema, J. W., Pordy, R., Sourdille, T., Szarek, M., White, H. D., Zeiher, A. M., Schwartz, G. G., ODYSSEY OUTCOMES Investigators OXFORD UNIV PRESS. 2020: 500

  View details for Web of Science ID 000606106300501

• Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial. European heart journal Szarek, M., Bittner, V. A., Aylward, P., Baccara-Dinet, M., Bhatt, D. L., Diaz, R., Fras, Z., Goodman, S. G., Halvorsen, S., Harrington, R. A., Jukema, J. W., Moriarty, P. M., Pordy, R., Ray, K. K., Sinnaeve, P., Tsimikas, S., Vogel, R., White, H. D., Zahger, D., Zeiher, A. M., Steg, P. G., Schwartz, G. G., ODYSSEY OUTCOMES Investigators 2020

  Abstract

  AIMS: Lipoprotein(a) concentration is associated with first cardiovascular events in clinical trials. It is unknown if this relationship holds for total (first and subsequent) events. In the ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome (ACS), the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab reduced lipoprotein(a), low-density lipoprotein cholesterol (LDL-C), and cardiovascular events compared with placebo. This post hoc analysis determined whether baseline levels and alirocumab-induced changes in lipoprotein(a) and LDL-C [corrected for lipoprotein(a) cholesterol] independently predicted total cardiovascular events.METHODS AND RESULTS: Cardiovascular events included cardiovascular death, non-fatal myocardial infarction, stroke, hospitalization for unstable angina or heart failure, ischaemia-driven coronary revascularization, peripheral artery disease events, and venous thromboembolism. Proportional hazards models estimated relationships between baseline lipoprotein(a) and total cardiovascular events in the placebo group, effects of alirocumab treatment on total cardiovascular events by baseline lipoprotein(a), and relationships between lipoprotein(a) reduction with alirocumab and subsequent risk of total cardiovascular events. Baseline lipoprotein(a) predicted total cardiovascular events with placebo, while higher baseline lipoprotein(a) levels were associated with greater reduction in total cardiovascular events with alirocumab (hazard ratio Ptrend = 0.045). Alirocumab-induced reductions in lipoprotein(a) (median -5.0 [-13.6, 0] mg/dL) and corrected LDL-C (median -51.3 [-67.1, -34.0] mg/dL) independently predicted lower risk of total cardiovascular events. Each 5-mg/dL reduction in lipoprotein(a) predicted a 2.5% relative reduction in cardiovascular events.CONCLUSION: Baseline lipoprotein(a) predicted the risk of total cardiovascular events and risk reduction by alirocumab. Lipoprotein(a) lowering contributed independently to cardiovascular event reduction, supporting the concept of lipoprotein(a) as a treatment target after ACS.

  View details for DOI 10.1093/eurheartj/ehaa649

  View details for PubMedID 33051646

• The Impact of Novel Coronavirus COVID-19 on Non-Communicable Disease Patients and Health Systems: A Review. Journal of internal medicine Chang, A. Y., Cullen, M. R., Harrington, R. A., Barry, M. 2020

  Abstract

  Coronavirus Disease 2019 (COVID-19) is an ongoing global pandemic affecting all levels of health systems. This includes the care of patients with noncommunicable diseases (NCDs) who bear a disproportionate burden of both COVID-19 itself and the public health measures enacted to combat it. In this review, we summarize major COVID-19 related considerations for NCD patients and their care providers, focusing on cardiovascular, pulmonary, renal, hematologic, oncologic, traumatic, obstetric/gynecologic, operative, psychiatric, rheumatologic/immunologic, neurologic, gastrointestinal, ophthalmologic, and endocrine disorders. Additionally, we offer a general framework for categorizing the pandemic's disruptions by disease-specific factors, direct health system factors, and indirect health system factors. We also provide references to major NCD medical specialty professional society statements and guidelines on COVID-19. COVID-19 and its control policies have already resulted in major disruptions to the screening, treatment, and surveillance of NCD patients. In addition, it differentially impacts those with pre-existing NCDs and may lead to de novo NCD sequelae. Likely, there will be long-term effects from this pandemic that will continue to affect practitioners and patients in this field for years to come.

  View details for DOI 10.1111/joim.13184

  View details for PubMedID 33020988

• In patients with stable coronary heart disease, low-density lipoprotein-cholesterol levels < 70 mg/dL and glycosylated hemoglobin A1c < 7% are associated with lower major cardiovascular events. American heart journal White, H. D., Stewart, R. A., Dalby, A. J., Stebbins, A., Cannon, C. P., Budaj, A., Linhart, A., Pais, P., Diaz, R., Steg, P. G., Krug-Gourley, S., Granger, C. B., Hochman, J. S., Koenig, W., Harrington, R. A., Held, C., Wallentin, L., STABILITY Investigators 2020; 225: 97–107

  Abstract

  BACKGROUND: In patients with stable coronary heart disease, it is not known whether achievement of standard of care (SOC) targets in addition to evidence-based medicine (EBM) is associated with lower major adverse cardiovascular events (MACE): cardiovascular death, myocardial infarction, and stroke.METHODS: EBM use was recommended in the STabilisation of Atherosclerotic plaque By Initiation of darapLadIb TherapY trial. SOC targets were blood pressure (BP) <140/90 mm Hg and low-density lipoprotein-cholesterol (LDL-C) <100 mg/dL and <70 mg/dL. In patients with diabetes, glycosylated hemoglobin A1c (HbA1c) < 7% and BP of <130/80 mm Hg were recommended. Feedback to investigators about rates of EBM and SOC was provided regularly.RESULTS: In 13,623 patients, 1-year landmark analysis assessed the association between EBM, SOC targets, and MACE during follow-up of 2.7 years (median) after adjustment in a Cox proportional hazards model. At 1 year, aspirin was prescribed in 92.5% of patients, statins in 97.2%, beta-blockers in 79.0%, and angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers in 76.9%. MACE was lower with LDL-C < 100 mg/dL (70-99 mg/dL) compared with LDL-C ≥ 100 mg/dL (hazard ratio [HR] 0.694, 95% CI 0.594-0.811) and lower with LDL-C < 70 mg/dL compared with LDL-C < 100 mg/dL (70-99 mg/dL) (HR 0.834, 95% CI 0.708-0.983). MACE was lower with HbA1c < 7% compared with HbA1c ≥ 7% (HR 0.705, 95% CI 0.573-0.866). There was no effect of BP targets on MACE.CONCLUSIONS: MACE was lower with LDL-C < 100 mg/dL (70-99 mg/dL) and even lower with LDL-C < 70 mg/dL. MACE in patients with diabetes was lower with HbA1c < 7%. Achievement of targets is associated with improved patient outcomes.

  View details for DOI 10.1016/j.ahj.2020.04.004

  View details for PubMedID 32480059

• Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 2019) Treatment. Heart rhythm Roden, D. M., Harrington, R. A., Poppas, A., Russo, A. M. 2020

  View details for DOI 10.1016/j.hrthm.2020.04.016

  View details for PubMedID 32302703

• Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 2019) Treatment. Journal of the American College of Cardiology Roden, D. M., Harrington, R. A., Poppas, A., Russo, A. M. 2020

  View details for DOI 10.1016/j.jacc.2020.04.016

  View details for PubMedID 32283123

• Protecting Medical Trainees on the COVID-19 Frontlines Saves Us All. Circulation Harrington, R. A., Elkind, M. S., Benjamin, I. J. 2020

  View details for DOI 10.1161/CIRCULATIONAHA.120.047454

  View details for PubMedID 32250654

• Video-based AI for beat-to-beat assessment of cardiac function. Nature Ouyang, D., He, B., Ghorbani, A., Yuan, N., Ebinger, J., Langlotz, C. P., Heidenreich, P. A., Harrington, R. A., Liang, D. H., Ashley, E. A., Zou, J. Y. 2020; 580 (7802): 252-256

  Abstract

  Accurate assessment of cardiac function is crucial for the diagnosis of cardiovascular disease1, screening for cardiotoxicity2 and decisions regarding the clinical management of patients with a critical illness3. However, human assessment of cardiac function focuses on a limited sampling of cardiac cycles and has considerable inter-observer variability despite years of training4,5. Here, to overcome this challenge, we present a video-based deep learning algorithm-EchoNet-Dynamic-that surpasses the performance of human experts in the critical tasks of segmenting the left ventricle, estimating ejection fraction and assessing cardiomyopathy. Trained on echocardiogram videos, our model accurately segments the left ventricle with a Dice similarity coefficient of 0.92, predicts ejection fraction with a mean absolute error of 4.1% and reliably classifies heart failure with reduced ejection fraction (area under the curve of 0.97). In an external dataset from another healthcare system, EchoNet-Dynamic predicts the ejection fraction with a mean absolute error of 6.0% and classifies heart failure with reduced ejection fraction with an area under the curve of 0.96. Prospective evaluation with repeated human measurements confirms that the model has variance that is comparable to or less than that of human experts. By leveraging information across multiple cardiac cycles, our model can rapidly identify subtle changes in ejection fraction, is more reproducible than human evaluation and lays the foundation for precise diagnosis of cardiovascular disease in real time. As a resource to promote further innovation, we also make publicly available a large dataset of 10,030 annotated echocardiogram videos.

  View details for DOI 10.1038/s41586-020-2145-8

  View details for PubMedID 32269341

• Video-based AI for beat-to-beat assessment of cardiac function NATURE Ouyang, D., He, B., Ghorbani, A., Yuan, N., Ebinger, J., Langlotz, C. P., Heidenreich, P. A., Harrington, R. A., Liang, D. H., Ashley, E. A., Zou, J. Y. 2020

  View details for DOI 10.1038/s41586-020-2145-8

  View details for Web of Science ID 000521531000001

• Rationale and Design of the Aspirin Dosing-A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE) Trial. JAMA cardiology Marquis-Gravel, G., Roe, M. T., Robertson, H. R., Harrington, R. A., Pencina, M. J., Berdan, L. G., Hammill, B. G., Faulkner, M., Munoz, D., Fonarow, G. C., Nallamothu, B. K., Fintel, D. J., Ford, D. E., Zhou, L., Daugherty, S. E., Nauman, E., Kraschnewski, J., Ahmad, F. S., Benziger, C. P., Haynes, K., Merritt, J. G., Metkus, T., Kripalani, S., Gupta, K., Shah, R. C., McClay, J. C., Re, R. N., Geary, C., Lampert, B. C., Bradley, S. M., Jain, S. K., Seifein, H., Whittle, J., Roger, V. L., Effron, M. B., Alvarado, G., Goldberg, Y. H., VanWormer, J. L., Girotra, S., Farrehi, P., McTigue, K. M., Rothman, R., Hernandez, A. F., Jones, W. S. 2020

  Abstract

  Importance: Determining the right dosage of aspirin for the secondary prevention treatment of atherosclerotic cardiovascular disease (ASCVD) remains an unanswered and critical question.Objective: To report the rationale and design for a randomized clinical trial to determine the optimal dosage of aspirin to be used for secondary prevention of ASCVD, using an innovative research method.Design, Setting, and Participants: This pragmatic, open-label, patient-centered, randomized clinical trial is being conducted in 15 000 patients within the National Patient-Centered Clinical Research Network (PCORnet), a distributed research network of partners including clinical research networks, health plan research networks, and patient-powered research networks across the United States. Patients with established ASCVD treated in routine clinical practice within the network are eligible. Patient recruitment began in April 2016. Enrollment was completed in June 2019. Final follow-up is expected to be completed by June 2020.Interventions: Participants are randomized on a web platform in a 1:1 fashion to either 81 mg or 325 mg of aspirin daily.Main Outcomes and Measures: The primary efficacy end point is the composite of all-cause mortality, hospitalization for nonfatal myocardial infarction, or hospitalization for a nonfatal stroke. The primary safety end point is hospitalization for major bleeding associated with a blood-product transfusion. End points are captured through regular queries of the health systems' common data model within the structure of PCORnet's distributed data environment.Conclusions and Relevance: As a pragmatic study and the first interventional trial conducted within the PCORnet electronic data infrastructure, this trial is testing several unique and innovative operational approaches that have the potential to disrupt and transform the conduct of future patient-centered randomized clinical trials by evaluating treatments integrated in clinical practice while at the same time determining the optimal dosage of aspirin for secondary prevention of ASCVD.Trial Registration: ClinicalTrials.gov Identifier: NCT02697916.

  View details for DOI 10.1001/jamacardio.2020.0116

  View details for PubMedID 32186653

• Role of the American Heart Association in the Global COVID-19 Pandemic. Circulation Elkind, M. S., Harrington, R. A., Benjamin, I. J. 2020

  View details for DOI 10.1161/CIRCULATIONAHA.120.046749

  View details for PubMedID 32181680

• Advancing Healthcare Reform: The American Heart Association's 2020 Statement of Principles for Adequate, Accessible, and Affordable Health Care: A Presidential Advisory From the American Heart Association CIRCULATION Warner, J. J., Benjamin, I. J., Churchwell, K., Firestone, G., Gardner, T. J., Johnson, J. C., Ng-Osorio, J., Rodriguez, C. J., Todman, L., Yaffe, K., Yancy, C. W., Harrington, R. A., Amer Heart Assoc Advocacy Coordina 2020; 141 (10): E601–E614

  Abstract

  The mission of the American Heart Association is to be a relentless force for a world of longer, healthier lives. The American Heart Association has consistently prioritized the needs and perspective of the patient in taking positions on healthcare reform while recognizing the importance of biomedical research, providers, and healthcare delivery systems in advancing the care of patients and the prevention of disease. The American Heart Association's vision for healthcare reform describes the foundational changes needed for the health system to serve the best interests of patients and to achieve health care and coverage that are adequate, accessible, and affordable for everyone living in the United States. The American Heart Association is committed to advancing the dialogue around healthcare reform and has prepared this updated statement of our principles, placed in the context of the advances in coverage and care that have occurred after the passage of the Affordable Care Act, the rapidly changing landscape of healthcare delivery systems, and our evolving recognition that efforts to prevent cardiovascular disease can have synergistic benefit in preventing other diseases and improving overall well-being. These updated principles focus on expanding access to affordable health care and coverage; enhancing the availability of evidence-based preventive services; eliminating disparities that limit the availability and equitable delivery of health care; strengthening the public health infrastructure to respond to social determinants of health; prioritizing and accelerating investments in biomedical research; and growing a diverse, culturally competent health and healthcare workforce prepared to meet the challenges of delivering high-value health care.

  View details for DOI 10.1161/CIR.0000000000000759

  View details for Web of Science ID 000528596700003

  View details for PubMedID 32008369

• Call to Action: Rural Health: A Presidential Advisory From the American Heart Association and American Stroke Association CIRCULATION Harrington, R. A., Califf, R. M., Balamurugan, A., Brown, N., Benjamin, R. M., Braund, W. E., Hipp, J., Konig, M., Sanchez, E., Maddox, K. 2020; 141 (10): E615–E644

  Abstract

  Understanding and addressing the unique health needs of people residing in rural America is critical to the American Heart Association's pursuit of a world with longer, healthier lives. Improving the health of rural populations is consistent with the American Heart Association's commitment to health equity and its focus on social determinants of health to reduce and ideally to eliminate health disparities. This presidential advisory serves as a call to action for the American Heart Association and other stakeholders to make rural populations a priority in programming, research, and policy. This advisory first summarizes existing data on rural populations, communities, and health outcomes; explores 3 major groups of factors underlying urban-rural disparities in health outcomes, including individual factors, social determinants of health, and health delivery system factors; and then proposes a set of solutions spanning health system innovation, policy, and research aimed at improving rural health.

  View details for DOI 10.1161/CIR.0000000000000753

  View details for Web of Science ID 000528596700004

  View details for PubMedID 32078375

• Machine learning to predict venous thrombosis in acutely ill medical patients. Research and practice in thrombosis and haemostasis Nafee, T., Gibson, C. M., Travis, R., Yee, M. K., Kerneis, M., Chi, G., AlKhalfan, F., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. 2020; 4 (2): 230-237

  Abstract

  The identification of acutely ill patients at high risk for venous thromboembolism (VTE) may be determined clinically or by use of integer-based scoring systems. These scores demonstrated modest performance in external data sets.To evaluate the performance of machine learning models compared to the IMPROVE score.The APEX trial randomized 7513 acutely medically ill patients to extended duration betrixaban vs. enoxaparin. Including 68 variables, a super learner model (ML) was built to predict VTE by combining estimates from 5 families of candidate models. A "reduced" model (rML) was also developed using 16 variables that were thought, a priori, to be associated with VTE. The IMPROVE score was calculated for each patient. Model performance was assessed by discrimination and calibration to predict a composite VTE end point. The frequency of predicted risks of VTE were plotted and divided into tertiles. VTE risks were compared across tertiles.The ML and rML algorithms outperformed the IMPROVE score in predicting VTE (c-statistic: 0.69, 0.68 and 0.59, respectively). The Hosmer-Lemeshow goodness-of-fit P-value was 0.06 for ML, 0.44 for rML, and <0.001 for the IMPROVE score. The observed event rate in the lowest tertile was 2.5%, 4.8% in tertile 2, and 11.4% in the highest tertile. Patients in the highest tertile of VTE risk had a 5-fold increase in odds of VTE compared to the lowest tertile.The super learner algorithms improved discrimination and calibration compared to the IMPROVE score for predicting VTE in acute medically ill patients.

  View details for DOI 10.1002/rth2.12292

  View details for PubMedID 32110753

  View details for PubMedCentralID PMC7040551

• Deep learning interpretation of echocardiograms. NPJ digital medicine Ghorbani, A., Ouyang, D., Abid, A., He, B., Chen, J. H., Harrington, R. A., Liang, D. H., Ashley, E. A., Zou, J. Y. 2020; 3 (1): 10

  Abstract

  Echocardiography uses ultrasound technology to capture high temporal and spatial resolution images of the heart and surrounding structures, and is the most common imaging modality in cardiovascular medicine. Using convolutional neural networks on a large new dataset, we show that deep learning applied to echocardiography can identify local cardiac structures, estimate cardiac function, and predict systemic phenotypes that modify cardiovascular risk but not readily identifiable to human interpretation. Our deep learning model, EchoNet, accurately identified the presence of pacemaker leads (AUC = 0.89), enlarged left atrium (AUC = 0.86), left ventricular hypertrophy (AUC = 0.75), left ventricular end systolic and diastolic volumes ([Formula: see text] = 0.74 and [Formula: see text] = 0.70), and ejection fraction ([Formula: see text] = 0.50), as well as predicted systemic phenotypes of age ([Formula: see text] = 0.46), sex (AUC = 0.88), weight ([Formula: see text] = 0.56), and height ([Formula: see text] = 0.33). Interpretation analysis validates that EchoNet shows appropriate attention to key cardiac structures when performing human-explainable tasks and highlights hypothesis-generating regions of interest when predicting systemic phenotypes difficult for human interpretation. Machine learning on echocardiography images can streamline repetitive tasks in the clinical workflow, provide preliminary interpretation in areas with insufficient qualified cardiologists, and predict phenotypes challenging for human evaluation.

  View details for DOI 10.1038/s41746-019-0216-8

  View details for PubMedID 33483633

• Machine learning to predict venous thrombosis in acutely ill medical patients RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS Nafee, T., Gibson, C., Travis, R., Yee, M. K., Kerneis, M., Chi, G., AlKhalfan, F., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. 2020

  View details for DOI 10.1002/rth2.12292

  View details for Web of Science ID 000508877500001

• Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After AcuteCoronary Syndrome. Journal of the American College of Cardiology Bittner, V. A., Szarek, M., Aylward, P. E., Bhatt, D. L., Diaz, R., Edelberg, J. M., Fras, Z., Goodman, S. G., Halvorsen, S., Hanotin, C., Harrington, R. A., Jukema, J. W., Loizeau, V., Moriarty, P. M., Moryusef, A., Pordy, R., Roe, M. T., Sinnaeve, P., Tsimikas, S., Vogel, R., White, H. D., Zahger, D., Zeiher, A. M., Steg, P. G., Schwartz, G. G., ODYSSEY OUTCOMES Committees and Investigators 2020; 75 (2): 133–44

  Abstract

  BACKGROUND: Lipoprotein(a) concentration is associated with cardiovascular events. Alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, lowers lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C).OBJECTIVES: A pre-specified analysis of the placebo-controlled ODYSSEY Outcomes trial in patients with recent acute coronary syndrome (ACS) determined whether alirocumab-induced changes in lipoprotein(a) and LDL-C independently predicted major adverse cardiovascular events (MACE).METHODS: One to 12months after ACS, 18,924 patients on high-intensity statin therapy were randomized to alirocumab or placebo and followed for 2.8 years (median). Lipoprotein(a) was measured at randomization and 4 and 12months thereafter. The primary MACE outcome was coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina.RESULTS: Baseline lipoprotein(a) levels (median: 21.2mg/dl; interquartile range [IQR]: 6.7 to 59.6mg/dl) and LDL-C [corrected for cholesterol content in lipoprotein(a)] predicted MACE. Alirocumab reduced lipoprotein(a) by 5.0mg/dl (IQR: 0 to 13.5mg/dl), corrected LDL-C by 51.1mg/dl (IQR: 33.7 to 67.2mg/dl), and reduced the risk of MACE (hazardratio [HR]: 0.85; 95% confidence interval [CI]: 0.78 to 0.93). Alirocumab-induced reductions of lipoprotein(a) and corrected LDL-C independently predicted lower risk of MACE, after adjustment for baseline concentrations of both lipoproteins and demographic and clinical characteristics. A 1-mg/dl reduction in lipoprotein(a) with alirocumab was associated with a HR of 0.994 (95%CI: 0.990 to 0.999; p=0.0081).CONCLUSIONS: Baseline lipoprotein(a) and corrected LDL-C levels and their reductions by alirocumab predicted the risk of MACE after recent ACS. Lipoprotein(a) lowering by alirocumab is an independent contributor to MACE reduction, which suggests that lipoprotein(a) should be an independent treatment target after ACS. (ODYSSEY Outcomes: Evaluationof Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

  View details for DOI 10.1016/j.jacc.2019.10.057

  View details for PubMedID 31948641

• Deep learning interpretation of echocardiograms. NPJ digital medicine Ghorbani, A., Ouyang, D., Abid, A., He, B., Chen, J. H., Harrington, R. A., Liang, D. H., Ashley, E. A., Zou, J. Y. 2020; 3: 10

  Abstract

  Echocardiography uses ultrasound technology to capture high temporal and spatial resolution images of the heart and surrounding structures, and is the most common imaging modality in cardiovascular medicine. Using convolutional neural networks on a large new dataset, we show that deep learning applied to echocardiography can identify local cardiac structures, estimate cardiac function, and predict systemic phenotypes that modify cardiovascular risk but not readily identifiable to human interpretation. Our deep learning model, EchoNet, accurately identified the presence of pacemaker leads (AUC=0.89), enlarged left atrium (AUC=0.86), left ventricular hypertrophy (AUC=0.75), left ventricular end systolic and diastolic volumes ( R 2 =0.74 and R 2 =0.70), and ejection fraction ( R 2 =0.50), as well as predicted systemic phenotypes of age ( R 2 =0.46), sex (AUC=0.88), weight ( R 2 =0.56), and height ( R 2 =0.33). Interpretation analysis validates that EchoNet shows appropriate attention to key cardiac structures when performing human-explainable tasks and highlights hypothesis-generating regions of interest when predicting systemic phenotypes difficult for human interpretation. Machine learning on echocardiography images can streamline repetitive tasks in the clinical workflow, provide preliminary interpretation in areas with insufficient qualified cardiologists, and predict phenotypes challenging for human evaluation.

  View details for DOI 10.1038/s41746-019-0216-8

  View details for PubMedID 31993508

• Considerations for Drug Interactions on QTc in Exploratory COVID-19 (Coronavirus Disease 2019) Treatment. Circulation Roden, D. M., Harrington, R. A., Poppas, A. n., Russo, A. M. 2020

  View details for DOI 10.1161/CIRCULATIONAHA.120.047521

  View details for PubMedID 32267732

• Protecting Our Front Line. Circulation. Cardiovascular interventions Harrington, R. A., Warner, J. J. 2020; 13 (5): e009406

  View details for DOI 10.1161/CIRCINTERVENTIONS.120.009406

  View details for PubMedID 32408818

• A Path Forward. Journal of the American Heart Association Elkind, M. S., Harrington, R. A., Lloyd-Jones, D. M. 2020: e018288

  Abstract

  In March, the Journal of the American Heart Association (JAHA) published a manuscript entitled Diversity, Inclusion, and Equity: Evolution of Race and Ethnicity Considerations for the Cardiology Workforce in the United States of America From 1969 to 2019 (J Am Heart Assoc. 2020;9:e015959. https://doi.org/10.1161/JAHA.120.015959) authored by Norman C. Wang, MD, MS, from the University of Pittsburgh Medical Center (UPMC).

  View details for DOI 10.1161/JAHA.120.019210

  View details for PubMedID 32941093

• Safe Reintroduction of Cardiovascular Services during the COVID-19 Pandemic: Guidance from North American Society Leadership. Journal of the American College of Cardiology Wood, D. A., Mahmud, E. n., Thourani, V. H., Sathananthan, J. n., Virani, A. n., Poppas, A. n., Harrington, R. A., Dearani, J. A., Swaminathan, M. n., Russo, A. M., Blankstein, R. n., Dorbala, S. n., Carr, J. n., Virani, S. n., Gin, K. n., Packard, A. n., Dilsizian, V. n., Légaré, J. F., Leipsic, J. n., Webb, J. G., Krahn, A. D. 2020

  View details for DOI 10.1016/j.jacc.2020.04.063

  View details for PubMedID 32380033

• Safe Reintroduction of Cardiovascular Services during the COVID-19 Pandemic: Guidance from North American Society Leadership. The Annals of thoracic surgery Wood, D. A., Mahmud, E. n., Thourani, V. H., Sathananthan, J. n., Virani, A. n., Poppas, A. n., Harrington, R. n., Dearani, J. A., Swaminathan, M. n., Russo, A. M., Blankstein, R. n., Dorbala, S. n., Carr, J. n., Virani, S. n., Gin, K. n., Packard, A. n., Dilsizian, V. n., Légaré, J. F., Leipsic, J. n., Webb, J. G., Krahn, A. D. 2020

  View details for DOI 10.1016/j.athoracsur.2020.04.017

  View details for PubMedID 32380058

• Safe Reintroduction of Cardiovascular Services during the COVID-19 Pandemic: Guidance from North American Societies. The Canadian journal of cardiology Wood, D. A., Mahmud, E. n., Thourani, V. H., Sathananthan, J. n., Virani, A. n., Poppas, A. n., Harrington, R. n., Dearani, J. A., Swaminathan, M. n., Russo, A. M., Blankstein, R. n., Dorbala, S. n., Carr, J. n., Virani, S. n., Gin, K. n., Packard, A. n., Dilsizian, V. n., Légaré, J. F., Leipsic, J. n., Webb, J. G., Krahn, A. D. 2020

  View details for DOI 10.1016/j.cjca.2020.04.031

  View details for PubMedID 32380228

• Generating evidence for therapeutic effects: the need for well-conducted randomized trials. The Journal of clinical investigation Califf, R. M., Curtis, L. H., Harrington, R. A., Hernandez, A. F., Peterson, E. D. 2020

  Abstract

  In this viewpoint, Robert Califf, former commissioner of the U.S. Food and Drug Administration, and colleagues reflect on how to approach questions about which patient treatments and strategies work, particularly in light of the tremendous pressure on the government and biomedical research enterprise to quickly develop safe, effective therapies during the SARS-CoV-2 pandemic.

  View details for DOI 10.1172/JCI146391

  View details for PubMedID 33270604

• Randomized Trials Versus Common Sense and Clinical Observation: JACC Review Topic of the Week. Journal of the American College of Cardiology Fanaroff, A. C., Califf, R. M., Harrington, R. A., Granger, C. B., McMurray, J. J., Patel, M. R., Bhatt, D. L., Windecker, S. n., Hernandez, A. F., Gibson, C. M., Alexander, J. H., Lopes, R. D. 2020; 76 (5): 580–89

  Abstract

  Concerns about the external validity of traditional randomized clinical trials (RCTs), together with the widespread availability of real-world data and advanced data analytic tools, have led to claims that common sense and clinical observation, rather than RCTs, should be the preferred method to generate evidence to support clinical decision-making. However, over the past 4 decades, results from well-done RCTs have repeatedly contradicted practices supported by common sense and clinical observation. Common sense and clinical observation fail for several reasons: incomplete understanding of pathophysiology, biases and unmeasured confounding in observational research, and failure to understand risks and benefits of treatments within complex systems. Concerns about traditional RCT models are legitimate, but randomization remains a critical tool to understand the causal relationship between treatments and outcomes. Instead, development and promulgation of tools to apply randomization to real-world data are needed to build the best evidence base in cardiovascular medicine.

  View details for DOI 10.1016/j.jacc.2020.05.069

  View details for PubMedID 32731936

• Machine learning and atherosclerotic cardiovascular disease risk prediction in a multi-ethnic population. NPJ digital medicine Ward, A., Sarraju, A., Chung, S., Li, J., Harrington, R., Heidenreich, P., Palaniappan, L., Scheinker, D., Rodriguez, F. 2020; 3 (1): 125

  Abstract

  The pooled cohort equations (PCE) predict atherosclerotic cardiovascular disease (ASCVD) risk in patients with characteristics within prespecified ranges and has uncertain performance among Asians or Hispanics. It is unknown if machine learning (ML) models can improve ASCVD risk prediction across broader diverse, real-world populations. We developed ML models for ASCVD risk prediction for multi-ethnic patients using an electronic health record (EHR) database from Northern California. Our cohort included patients aged 18 years or older with no prior CVD and not on statins at baseline (n = 262,923), stratified by PCE-eligible (n = 131,721) or PCE-ineligible patients based on missing or out-of-range variables. We trained ML models [logistic regression with L2 penalty and L1 lasso penalty, random forest, gradient boosting machine (GBM), extreme gradient boosting] and determined 5-year ASCVD risk prediction, including with and without incorporation of additional EHR variables, and in Asian and Hispanic subgroups. A total of 4309 patients had ASCVD events, with 2077 in PCE-ineligible patients. GBM performance in the full cohort, including PCE-ineligible patients (area under receiver-operating characteristic curve (AUC) 0.835, 95% confidence interval (CI): 0.825-0.846), was significantly better than that of the PCE in the PCE-eligible cohort (AUC 0.775, 95% CI: 0.755-0.794). Among patients aged 40-79, GBM performed similarly before (AUC 0.784, 95% CI: 0.759-0.808) and after (AUC 0.790, 95% CI: 0.765-0.814) incorporating additional EHR data. Overall, ML models achieved comparable or improved performance compared to the PCE while allowing risk discrimination in a larger group of patients including PCE-ineligible patients. EHR-trained ML models may help bridge important gaps in ASCVD risk prediction.

  View details for DOI 10.1038/s41746-020-00331-1

  View details for PubMedID 34552202

• Association of Burnout, Professional Fulfillment, and Self-care Practices of Physician Leaders With Their Independently Rated Leadership Effectiveness. JAMA network open Shanafelt, T. D., Makowski, M. S., Wang, H. n., Bohman, B. n., Leonard, M. n., Harrington, R. A., Minor, L. n., Trockel, M. n. 2020; 3 (6): e207961

  Abstract

  Although leadership behavior of physician supervisors is associated with the occupational well-being of the physicians they supervise, the factors associated with leadership behaviors are poorly understood.To evaluate the associations between burnout, professional fulfillment, and self-care practices of physician leaders and their independently assessed leadership behavior scores.This survey study of physicians and physician leaders at Stanford University School of Medicine (n = 1924) was conducted from April 1 to May 13, 2019. The survey included assessments of professional fulfillment, self-valuation, sleep-related impairment, and burnout. Physicians also rated the leadership behaviors of their immediate physician supervisors using a standardized assessment. Leaders' personal well-being metrics were paired with their leadership behavior scores as rated by the physicians they supervised. All assessment scores were converted to a standardized scale (range, 0-10). Data were analyzed from October 20, 2019, to March 10, 2020.Association between leaders' own well-being scores and their independently assessed leadership behavior.Of 1924 physicians invited to participate, 1285 (66.8%) returned surveys, including 67 of 117 physician leaders (57.3%). Among these respondents, 651 (50.7%) were women and 729 (56.7%) were 40 years or older. Among the 67 leaders, 57 (85.1%) had their leadership behaviors evaluated by at least 5 physicians (median, 11 [interquartile range, 9-15]) they supervised. Overall, 9.8% of the variation in leaders' aggregate leadership behavior scores was associated with their own degree of burnout. In models adjusted for age and sex, each 1-point increase in burnout score of the leaders was associated with a 0.19-point decrement in leadership behavior score (β = -0.19; 95% CI, -0.35 to -0.03; P = .02), whereas each 1-point increase in their professional fulfillment and self-valuation scores was associated with a 0.13-point (β = 0.13; 95% CI, 0.01-0.26; P = .03) and 0.15-point (β = 0.15; 95% CI, 0.02-0.29; P = .03) increase in leadership behavior score, respectively. Each 1-point increase in leaders' sleep-related impairment was associated with a 0.15-point increment in sleep-related impairment among those they supervised (β = 0.15; 95% CI, 0.02-0.29; P = .03). The associations between leaders' well-being scores in other dimensions and the corresponding well-being measures of those they supervised were not significant.In this survey study, burnout, professional fulfillment, and self-care practices of physician leaders were associated with their independently assessed leadership effectiveness. Training, skill building, and support to improve leader well-being should be considered a dimension of leadership development rather than simply a dimension of self-care.

  View details for DOI 10.1001/jamanetworkopen.2020.7961

  View details for PubMedID 32543700

• Health Status after Invasive or Conservative Care in Coronary and Advanced Kidney Disease. The New England journal of medicine Spertus, J. A., Jones, P. G., Maron, D. J., Mark, D. B., O'Brien, S. M., Fleg, J. L., Reynolds, H. R., Stone, G. W., Sidhu, M. S., Chaitman, B. R., Chertow, G. M., Hochman, J. S., Bangalore, S. n. 2020

  Abstract

  In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of <30 ml per minute per 1.73 m2 or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status.We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy.Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, -0.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, -2.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, -1.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, -2.2 to 3.4).Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy. (Funded by the National Heart, Lung, and Blood Institute; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

  View details for DOI 10.1056/NEJMoa1916374

  View details for PubMedID 32227754

• Management of Coronary Disease in Patients with Advanced Kidney Disease. The New England journal of medicine Bangalore, S. n., Maron, D. J., O'Brien, S. M., Fleg, J. L., Kretov, E. I., Briguori, C. n., Kaul, U. n., Reynolds, H. R., Mazurek, T. n., Sidhu, M. S., Berger, J. S., Mathew, R. O., Bockeria, O. n., Broderick, S. n., Pracon, R. n., Herzog, C. A., Huang, Z. n., Stone, G. W., Boden, W. E., Newman, J. D., Ali, Z. A., Mark, D. B., Spertus, J. A., Alexander, K. P., Chaitman, B. R., Chertow, G. M., Hochman, J. S. 2020

  Abstract

  Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease.We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest.At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03).Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

  View details for DOI 10.1056/NEJMoa1915925

  View details for PubMedID 32227756

• Initial Invasive or Conservative Strategy for Stable Coronary Disease. The New England journal of medicine Maron, D. J., Hochman, J. S., Reynolds, H. R., Bangalore, S. n., O'Brien, S. M., Boden, W. E., Chaitman, B. R., Senior, R. n., López-Sendón, J. n., Alexander, K. P., Lopes, R. D., Shaw, L. J., Berger, J. S., Newman, J. D., Sidhu, M. S., Goodman, S. G., Ruzyllo, W. n., Gosselin, G. n., Maggioni, A. P., White, H. D., Bhargava, B. n., Min, J. K., Mancini, G. B., Berman, D. S., Picard, M. H., Kwong, R. Y., Ali, Z. A., Mark, D. B., Spertus, J. A., Krishnan, M. N., Elghamaz, A. n., Moorthy, N. n., Hueb, W. A., Demkow, M. n., Mavromatis, K. n., Bockeria, O. n., Peteiro, J. n., Miller, T. D., Szwed, H. n., Doerr, R. n., Keltai, M. n., Selvanayagam, J. B., Steg, P. G., Held, C. n., Kohsaka, S. n., Mavromichalis, S. n., Kirby, R. n., Jeffries, N. O., Harrell, F. E., Rockhold, F. W., Broderick, S. n., Ferguson, T. B., Williams, D. O., Harrington, R. A., Stone, G. W., Rosenberg, Y. n. 2020

  Abstract

  Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain.We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction.Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32).Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

  View details for DOI 10.1056/NEJMoa1915922

  View details for PubMedID 32227755

• Machine learning and atherosclerotic cardiovascular disease risk prediction in a multi-ethnic population. NPJ digital medicine Ward, A. n., Sarraju, A. n., Chung, S. n., Li, J. n., Harrington, R. n., Heidenreich, P. n., Palaniappan, L. n., Scheinker, D. n., Rodriguez, F. n. 2020; 3: 125

  Abstract

  The pooled cohort equations (PCE) predict atherosclerotic cardiovascular disease (ASCVD) risk in patients with characteristics within prespecified ranges and has uncertain performance among Asians or Hispanics. It is unknown if machine learning (ML) models can improve ASCVD risk prediction across broader diverse, real-world populations. We developed ML models for ASCVD risk prediction for multi-ethnic patients using an electronic health record (EHR) database from Northern California. Our cohort included patients aged 18 years or older with no prior CVD and not on statins at baseline (n = 262,923), stratified by PCE-eligible (n = 131,721) or PCE-ineligible patients based on missing or out-of-range variables. We trained ML models [logistic regression with L2 penalty and L1 lasso penalty, random forest, gradient boosting machine (GBM), extreme gradient boosting] and determined 5-year ASCVD risk prediction, including with and without incorporation of additional EHR variables, and in Asian and Hispanic subgroups. A total of 4309 patients had ASCVD events, with 2077 in PCE-ineligible patients. GBM performance in the full cohort, including PCE-ineligible patients (area under receiver-operating characteristic curve (AUC) 0.835, 95% confidence interval (CI): 0.825-0.846), was significantly better than that of the PCE in the PCE-eligible cohort (AUC 0.775, 95% CI: 0.755-0.794). Among patients aged 40-79, GBM performed similarly before (AUC 0.784, 95% CI: 0.759-0.808) and after (AUC 0.790, 95% CI: 0.765-0.814) incorporating additional EHR data. Overall, ML models achieved comparable or improved performance compared to the PCE while allowing risk discrimination in a larger group of patients including PCE-ineligible patients. EHR-trained ML models may help bridge important gaps in ASCVD risk prediction.

  View details for DOI 10.1038/s41746-020-00331-1

  View details for PubMedID 33043149

  View details for PubMedCentralID PMC7511400

• 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

• Characteristics and Strength of Evidence of COVID-19 Studies Registered on ClinicalTrials.gov. JAMA internal medicine Pundi, K. n., Perino, A. C., Harrington, R. A., Krumholz, H. M., Turakhia, M. P. 2020

  View details for DOI 10.1001/jamainternmed.2020.2904

  View details for PubMedID 32730617

• 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

• Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke. Stroke Warner, J. J., Harrington, R. A., Sacco, R. L., Elkind, M. S. 2019; 50 (12): 3331–32

  View details for DOI 10.1161/STROKEAHA.119.027708

  View details for PubMedID 31662117

• Association Between Current and Future Annual Hospital Percutaneous Coronary Intervention Mortality Rates JAMA CARDIOLOGY Sandhu, A. T., Kohsaka, S., Bhattacharya, J., Fearon, W. F., Harrington, R. A., Heidenreich, P. A. 2019; 4 (11): 1077–83

  View details for DOI 10.1001/jamacardio.2019.3221

  View details for Web of Science ID 000501300400005

• The effect of digital physical activity interventions on daily step count: a randomised controlled crossover substudy of the MyHeart Counts Cardiovascular Health Study LANCET DIGITAL HEALTH Shcherbina, A., Hershman, S. G., Lazzeroni, L., King, A. C., O'Sullivan, J. W., Hekler, E., Moayedi, Y., Pavlovic, A., Waggott, D., Sharma, A., Yeung, A., Christle, J. W., Wheeler, M. T., McConnell, M. V., Harrington, R. A., Ashley, E. A. 2019; 1 (7): E344–E352

  View details for DOI 10.1016/S2589-7500(19)30129-3

  View details for Web of Science ID 000525872200012

• The effect of digital physical activity interventions on daily step count: a randomised controlled crossover substudy of the MyHeart Counts Cardiovascular Health Study. The Lancet. Digital health Shcherbina, A., Hershman, S. G., Lazzeroni, L., King, A. C., O'Sullivan, J. W., Hekler, E., Moayedi, Y., Pavlovic, A., Waggott, D., Sharma, A., Yeung, A., Christle, J. W., Wheeler, M. T., McConnell, M. V., Harrington, R. A., Ashley, E. A. 2019; 1 (7): e344-e352

  Abstract

  Smartphone apps might enable interventions to increase physical activity, but few randomised trials testing this hypothesis have been done. The MyHeart Counts Cardiovascular Health Study is a longitudinal smartphone-based study with the aim of elucidating the determinants of cardiovascular health. We aimed to investigate the effect of four different physical activity coaching interventions on daily step count in a substudy of the MyHeart Counts Study.In this randomised, controlled crossover trial, we recruited adults (aged ≥18 years) in the USA with access to an iPhone smartphone (Apple, Cupertino, CA, USA; version 5S or newer) who had downloaded the MyHeart Counts app (version 2.0). After completion of a 1 week baseline period of interaction with the MyHeart Counts app, participants were randomly assigned to receive one of 24 permutations (four combinations of four 7 day interventions) in a crossover design using a random number generator built into the app. Interventions consisted of either daily prompts to complete 10 000 steps, hourly prompts to stand following 1 h of sitting, instructions to read the guidelines from the American Heart Association website, or e-coaching based upon the individual's personal activity patterns from the baseline week of data collection. Participants completed the trial in a free-living setting. Due to the nature of the interventions, participants could not be masked from the intervention. Investigators were not masked to intervention allocation. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in the modified intention-to-treat analysis set, which included all participants who had completed 7 days of baseline monitoring and at least 1 day of one of the four interventions. This trial is registered with ClinicalTrials.gov, NCT03090321.Between Dec 12, 2016, and June 6, 2018, 2783 participants consented to enrol in the coaching study, of whom 1075 completed 7 days of baseline monitoring and at least 1 day of one of the four interventions and thus were included in the modified intention-to-treat analysis set. 493 individuals completed the full set of assigned interventions. All four interventions significantly increased mean daily step count from baseline (mean daily step count 2914 [SE 74]): mean step count increased by 319 steps (75) for participants in the American Heart Association website prompt group (p<0·0001), 267 steps (74) for participants in the hourly stand prompt group (p=0·0003), 254 steps (74) for participants in the cluster-specific prompts group (p=0·0006), and by 226 steps (75) for participants in the 10 000 daily step prompt group (p=0·0026 vs baseline).Four smartphone-based physical activity coaching interventions significantly increased daily physical activity. These findings suggests that digital interventions delivered via a mobile app have the ability to increase short-term physical activity levels in a free-living cohort.Stanford Data Science Initiative.

  View details for DOI 10.1016/S2589-7500(19)30129-3

  View details for PubMedID 33323209

• 2019 ACC Health Policy Statement on Cardiologist Compensation and Opportunity Equity JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Douglas, P. S., Biga, C., Burns, K. M., Chazal, R. A., Cuffe, M. S., Daniel, J. M., Garzio, C., Harrington, R. A., Patel, H. N., Walsh, M., Wolk, M. J. 2019; 74 (15): 1947–65

  View details for DOI 10.1016/j.jacc.2019.07.040

  View details for Web of Science ID 000489157600014

  View details for PubMedID 31537317

• Efficacy of alirocumab treatment after acute coronary syndrome according to new ACC/AHA guidelines for lipid-lowering therapy Roe, M. T., Szarek, M., Li, Q. H., Bhatt, D. L., Bittner, V., Goodman, S. G., Harrington, R. A., Lopez-Jaramillo, P., Lopes, R. D., Louie, M. J., Moriarty, P. M., Vogel, R. A., Baccara-Dinet, M. T., Steg, P. G., Schwartz, G. G. OXFORD UNIV PRESS. 2019: 2474

  View details for Web of Science ID 000507313000430

• Beyond duty hours: leveraging large-scale paging data to monitor resident workload NPJ DIGITAL MEDICINE Kaushal, A., Katznelson, L., Harrington, R. A. 2019; 2: 87

  Abstract

  Monitoring and managing resident workload is a cornerstone of policy in graduate medical education, and the duty hours metric is the backbone of current regulations. While the duty hours metric measures hours worked, it does not capture differences in intensity of work completed during those hours, which may independently contribute to fatigue and burnout. Few such metrics exist. Digital data streams generated during the usual course of hospital operations can serve as a novel source of insight into workload intensity by providing high-resolution, minute-by-minute data at the individual level; however, study and use of these data streams for workload monitoring has been limited to date. Paging data is one such data stream. In this work, we analyze over 500,000 pages-two full years of pages in an academic internal medicine residency program-to characterize paging patterns among housestaff. We demonstrate technical feasibility, validity, and utility of paging burden as a metric to provide insight into resident workload beyond duty hours alone, and illustrate a general framework for evaluation and incorporation of novel digital data streams into resident workload monitoring.

  View details for DOI 10.1038/s41746-019-0165-2

  View details for Web of Science ID 000484610000001

  View details for PubMedID 31531394

  View details for PubMedCentralID PMC6733865

• 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

  View details for DOI 10.1016/j.jacc.2019.03.013

  View details for Web of Science ID 000483334800001

• 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

• Consequences of Slow Progress Toward Pragmatism in Randomized Clinical Trials: It Is Time to Get Practical. JAMA cardiology Rodriguez, F., Califf, R. M., Harrington, R. A. 2019

  View details for DOI 10.1001/jamacardio.2019.3922

  View details for PubMedID 31473764

• Ticagrelor in Patients with Stable Coronary Disease and Diabetes. The New England journal of medicine Steg, P. G., Bhatt, D. L., Simon, T., Fox, K., Mehta, S. R., Harrington, R. A., Held, C., Andersson, M., Himmelmann, A., Ridderstrale, W., Leonsson-Zachrisson, M., Liu, Y., Opolski, G., Zateyshchikov, D., Ge, J., Nicolau, J. C., Corbalan, R., Cornel, J. H., Widimsky, P., Leiter, L. A., THEMIS Steering Committee and Investigators 2019

  Abstract

  BACKGROUND: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear.METHODS: In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria.RESULTS: A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P=0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P<0.001), as was the incidence of intracranial hemorrhage (0.7% vs. 0.5%; hazard ratio, 1.71; 95% CI, 1.18 to 2.48; P=0.005). There was no significant difference in the incidence of fatal bleeding (0.2% vs. 0.1%; hazard ratio, 1.90; 95% CI, 0.87 to 4.15; P=0.11). The incidence of an exploratory composite outcome of irreversible harm (death from any cause, myocardial infarction, stroke, fatal bleeding, or intracranial hemorrhage) was similar in the ticagrelor group and the placebo group (10.1% vs. 10.8%; hazard ratio, 0.93; 95% CI, 0.86 to 1.02).CONCLUSIONS: In patients with stable coronary artery disease and diabetes without a history of myocardial infarction or stroke, those who received ticagrelor plus aspirin had a lower incidence of ischemic cardiovascular events but a higher incidence of major bleeding than those who received placebo plus aspirin. (Funded by AstraZeneca; THEMIS ClinicalTrials.gov number, NCT01991795.).

  View details for DOI 10.1056/NEJMoa1908077

  View details for PubMedID 31475798

• Ticagrelor in patients with diabetes and stable coronary artery disease with a history of previous percutaneous coronary intervention (THEMIS-PCI): a phase 3, placebo-controlled, randomised trial. Lancet (London, England) Bhatt, D. L., Steg, P. G., Mehta, S. R., Leiter, L. A., Simon, T., Fox, K., Held, C., Andersson, M., Himmelmann, A., Ridderstrale, W., Chen, J., Song, Y., Diaz, R., Goto, S., James, S. K., Ray, K. K., Parkhomenko, A. N., Kosiborod, M. N., McGuire, D. K., Harrington, R. A., THEMIS Steering Committee and Investigators, Santos, V., Jain, A., Lendel, I., Russo, M., Haught, W. H., Bouza, M., Gogia, H., Banerjee, S., Kichura, G., Kantaros, L., Padron, F., Passi, R., Stone, J., Pursley, M., D'Urso, M., Gardner, T., Bennett, J., Nour, K., Saini, S., Zhang, W., Kumbhani, D., Thomas, D., Angiolillo, D., Bertolet, B., Roman-Miranda, A., Black, R., Manshadi, R., Vaca, C., Blanco, A., Napoli, M., Brabham, D., Akyea-Djamson, A., Desai, P., Prasada, S., Khaira, A., Forgosh, L., Lieber, I., Umpierrez, G., Singal, D., Londono, J., Fraser, N., Ruiz, J., Vega, D., Rodriguez, L., Brown, C., Syed, F., Aggarwala, G., Eaves, W., Foster, M., Gupta, D., Avino, D., Asfour, W., Tonnessen, G., Zhao, X., Singh, N., Brockmyre, A., Lepor, N., Shammas, N., Blick, D., Hearne, S., Prodafikas, J., Carell, E., Izzo, M., Karim, A., Zakhary, B., Atieh, M., Leichter, S., Meadows, C., Hotchkiss, D., Abu-Fadel, M., Wiseman, A., Bander, J., Shah, M., Banerjee, S., Ganim, R., Sopko, K., Khan, M., Lloret, R., Weirick, T., Mehta, R., Thadani, U., Bhargava, A., Kosiborod, M., Moya, J., Staniloae, C., Guerra, Y. D., Chhabra, A., Kosmicki, D., Shaheen, W., Mohammed, A., Bitters, J., Pattanayak, J., Javier, J., Srivastava, S., Phillips, R., Al-Amin, J., Lillestol, M., Simpson, P., Hazan, L., Amin, A., Shah, G., Korpas, D., Platt, B., Dickert, J., Puente, O., Hiotis, L., Doyle, T., Rajan, R., Meholick, A., Gring, C., Hage-Korban, E., Feldman, R., Colfer, H., Butman, S., Foster, M., Hart, T., Huling, R., Eshaghian, S., Quintana, O., Cheung, D., Handel, F., Rodriguez, M., Suh, D., Gordon, P., Pressman, G., Bauer, M., French, W., Barettella, M., Chatrathi, S., Suresh, D., Goldberg, R., Huth, M., Younis, L., Rahman, A., Mascolo, R., Welch, M., Suneja, R., Smith, S., Shurmur, S., Agaiby, J., Jingo, A., Johnston, J., Beth, M., Vlastaris, A., Kemp, S., Taheri, H., Pereira, E., Deyoung, M., Hawa, Z., Smith, R., Galski, T., Garas, S., Reddy, M., Sharma, S., Hargrove, J., Treasure, C., Emerson, R., Haddad, T., Rohr, K., Levinson, L., Gaona, R., Uretsky, B., Maheshwari, H., Lee, D., Kinnaman, S., Singal, R., Geohas, J., Gigliotti, O., Raisinghani, A., Khurana, C., Hella, B., Kelberman, M., Voyce, S., Singh, S., Lo, E., Singh, P., Goodfellow, R., Fischer, S., Lorraine, R., Turner, T., Shanes, J., Busch, R., Broker, R., Zaniewski, M., Pounds, K., Debs-Perez, G., Ong, S., Frandsen, B., Fullington, D., Jaffrani, N., Khan, A., Lee, M., Pouzar, J., Revtyak, G., Gonzalez, J., Nakhle, S., Murillo, A., Young, D., Makam, S., Syed, M., Woolf, K., Grena, P., Alfata, S., Mahal, S., Hoffman, D., Kizhakekuttu, T., Deering, J., Bhavsar, J., Mikesell, S., Wilson, W., Wilson, V., El, S., Spinale, F., Kannarkat, V., Rao, S., Hanson, L., Bertsch, J., Gonzalez-Ortiz, E., Severino, N., Willis, J., Schock, J., Bakhtari, L., Gazmuri, R., Ansari, S., Hall, J., Mehta, A., Shealy, N., Zarich, S., Singh, D., Vora, K., Andrawis, N., Molter, D., Maron, D., Cardona, J., D'Agostino, R., Arshad, T., Samaan, R., Jones, D., Presser, D., Heath, J., Green, S., Bittar, G., Henry, S., Korn, D., Schmedtje, J., Nadar, V., Graham, B., Labroo, A., Clavijo, L., Roseman, H., Ledesma, G., Rosen, R., Dor, I., Kirby, W., Sutton, J., Eder, F., Iteld, B., Gomez-Cortes, J., Buchbinder, M., Kasper, J., Terrelonge, A., Torres, G., Jagielo, T., Alvarez, J., Handelsman, Y., Guillen, M., Richwine, R., Lewy-Alterbaum, L., Corder, C., Arvind, M., Bolshoun, D., Mikhail, M., Minton, S., Alvarado, O., Abbott, J., Cauthen, B., Welter, R., Mintz, R., Cox, J., Quick, A., Weiss, M., Dy, J., Zebrack, J., Gandelman, G., Hegde, V., Silver, M., DeGregorio, M., Lawson, W., Paa, C., Bortnick, A., Krolick, M., Sotolongo, R., Cheirif, J., Kumar, P., Nadar, V., Jetty, P., Patel, A., Kruk, M., Kobielusz-Gembala, I., Rewerska, B., Madrzejewski, A., Milewski, K., Cygler, J., Petryka-Mazurkiewicz, J., Jastrzebski, W., Korecki, J., Fil, W., Prokopczuk, J., Bochenek, A., Wujkowski, M., Witek, R., Konczakowski, P., Miekus, P., Szczasny, M., Musial, W., Cymerman, K., Lampart, J., Mikosinski, J., Szynal, S., Fares, I., Opolski, G., Mazur, S., Wozakowska-Kaplon, B., Bijata-Bronisz, R., Wierucki, L., Losa, B., Drelich, G., Konieczny, M., Starczewski, P., Pawlowicz, L., Jesionowski, P., Jurowiecki, J., Gniot, J., Czyzycki, M., Stania, K., Kucharczyk-Bauman, I., Busz-Papiez, B., Karczmarczyk, A., Sudnik, W., Koszek, A., Kolodziej, P., Skwarna, B., Jaramillo, N., Jankowski, M., Czochra, W., Kinasz, L., Miklaszewicz, B., Stasinska, T., Pluta, W., Basiak, M., Rusicka, T., Niedbal-Yahfouf, I., Popenda, G., Korzeniak, R., Mirek, A., Mariankowski, R., Wojnowski, L., Korol, M., Baszak, J., Podolec, P., Piesiewicz, W., Zurakowski, A., Luengas, C., Skura, M., Pilecki, P., Majchrzak, P., Krzyzagorska, E., Drozd, M., Kaczmarek, B., Sliwinska, T., Zelazowska, K., Sztembis, R., Landa, K., Matyszczak-Toniak, L., Strojek, K., Piepiorka, M., Malinowski, R., Gorska, M., Stolarczyk-Sowa, E., Romanowski, L., Zinka, E., Reszka, Z., Skierkowska, J., Uzunow, A., Laskowska-Derlaga, E., Puntus, E., Kosmacheva, E. D., Koziolova, N., Pavlov, P., Supryadkina, T., Didenko, Y., Kopylov, P., Kazakov, A., Aksentiev, S., Vishneva, E., Repin, A., Smolenskaya, O., Mantserova, O., Khrustalev, O., Privalova, E., Konstantinov, V., Boldueva, S., Ezhov, A., Chernyavsky, A., Kamalov, G., Galyavich, A., Zubeeva, G., Nechaeva, G., Shustov, S., Dzhaiani, N., Treshkur, T., Osokina, N., Panov, A., Shutemova, E., Makukhin, V., Kropotina, T., Tsyba, L., Karpov, Y., Sizova, J. M., Ballyuzek, M., Tarasov, N., Demchenko, E., Barbarash, O., Moiseev, V., Markov, V., Kuznetsov, V., Viktorova, I., Sergienko, I., Ermoshkina, L., Khasanov, N., Khlevchuk, T., Baglikov, A., Shalaev, S., Zonova, E., Reznik, E., Haisheva, L., Morugova, T., Lomakin, N., Vishnevsky, A., Shvarts, Y., Magnitskaya, O., Mikhailusova, M., Pavlysh, E., Libov, I., Zateyschikova, A., Kostenko, V., Edin, A., Khovaeva, Y., Zakharov, K., Stryuk, R., Khirmanov, V., Kanorskiy, S., Yakushin, S., Barabashkina, A., Li, H., Zhao, Q., Zhang, J., Ma, J., He, Y., Luo, M., Zhang, A., Zhang, N., Chai, Y., Ma, G., Wang, H., Liu, Z., He, L., Song, Z., Dong, X., Tao, L., Li, Z., Su, X., Kong, X., Niu, H., Ge, J., Luo, Z., Huang, W., Peng, D., Yuan, Z., Milanova, M., Tenev, D., Gogov, A., Karageorgiev, D., Kolchev, T., Rusev, N., Georgieva, N., Kondov, R., Rusinov, V., Petrov, I., Stanchev, G., Konteva, M., Dincheva, A., Yaneva, Z., Vatova, R., Ilieva, K., Runev, N., Kolomanov, B., Petrov, I., Iliev, N., Tisheva, S., Chompalova, B., Tokmakova, M., Raev, D., Byanov, K., Markov, D., Mihov, L., Mihov, A., Milcheva, N., Minchev, M., Mollov, M., Borisov, B., Tihchev, T., Karakolev, V., Dimov, B., Georgiev, S., Smilov, L., Koo, B. K., Ahn, T., Hong, S. J., Yoon, J., Oh, S. K., Jeong, M. H., Kim, D., Chang, K., Kim, W., Hahn, J., Cha, K. S., Lee, J., Choi, S., Nam, C., Chae, I., Park, Y. H., Tahk, S., Shin, W., Chae, J., Kim, B. J., Bae, J., Park, W. J., Rha, S. W., Choi, Y. J., Hwang, J., Park, H. S., Baracioli, L., Guimaraes, F., Vasconcellos, E., Saraiva, J., Pereira, A., Santos, Q., Rossi, P., Maia, L., Madeira, M., Pereira, M., Botelho, R., Reis, G., Eliaschewitz, F., Borges, J., Nascimento, C., Fortes, J. A., de Souza, W., Pimentel, P., Hissa, M., Franchetti, M., Precoma, D., Ortiz, C., Hernandes, M., Saporito, W., Dos Santos, F. R., Kormann, A., Neuenschwander, F., Dutra, O., Rassi, N., Tanajura, L., Souza, J., Junior, D. S., Leaes, P., Forte, A., Bonansea, T. C., Marin, J., Machado, B., Cerqueira, M. J., Silva, F., Michalaros, Y., Manenti, E., Cercato, C., Figueiredo, E., Liu, M., Wang, Y., Lee, T., Fang, C., Wu, Y., Ueng, K., Sheu, H., Lai, W. T., Hsieh, I., Chen, Z., Lee, M., Chiang, C., Shyu, K., Hsia, C., Mar, G., Chan, S., Wu, C., Tseng, W., Chang, K., Yeh, H., Wang, J., Hou, C., Sorokina, I., Dolzhenko, M., Horoshko, O., Karpenko, O., Rudenko, L., Vakaliuk, I., Kulyk, A., Levchenko, O., Prokhorov, O., Reshotko, D., Sorokivskyy, M., Velichko, N., Maslovskyi, V., Teliatnikova, Z., Dotsenko, S., Krakhmalova, O., Kraiz, I., Zharinova, V., Bula, L., Kaydashev, I., Molodtsov, V., Rasputina, L., Pidlisna, V., Lysunets, O., Kravchenko, A., Glushko, L., Khomazyuk, T., Svyshchenko, Y., Parkhomenko, O., Mankovsky, B., Abrahamovych, O., Yagensky, A., Stanislavchuk, M., Vasilyeva, L., Sokolova, L., Sychov, O., Tseluyko, V., Kyrychenko, I., Rishko, M., Furkalo, S., Gallo, R., Bertrand, O., Mehta, S., Constance, C., Sussex, B., Zadra, R., Kouz, S., Chehayeb, R., Pandey, A., Dion, D., Bailey, G., Hill, L., Ramanathan, K., Dorsch, M., Nanji, A., Babapulle, M., Montigny, M., Gosselin, G., Dehghani, P., Rupka, D., Le May, M., Pichette, F., St-Maurice, F., Teefy, P., Mansour, S., Kassam, S., Cheung, S., Siega, A. D., O'Keefe, D., Sabbah, E., Bell, A., Chouinard, G., Wong, B., Miller, M., Gaudet, D., Lachance, P., Bata, I., Petrella, R., Gossard, D., Dumas, R., Ing, D., Boyrazian, H., Bessoudo, R., Huynh, T. T., Hart, R., Belle-Isle, J., Shukla, D., Kelly, A., Mazza, G., Cha, J., Henein, S., Frechette, A., Vizel, S., Liutkus, J. F., O'Mahony, M., Halperin, F., Kooy, J., Graham, J., Bailey, A., Wojcik, R., Wilderman, I., Turi, T., Motyovszki, A., Merkely, B., Kiss, R. G., Kiraly, C., Andrassy, P., Sarszegi, Z., Fulop, T., Zilahi, Z., Edes, I., Papp, A., Muller, G., Czigany, A., Zolyomi, S., Koranyi, L., Takacs, J., Juhasz, F., Benczur, B., Kancz, S., Foldi, A., Nagy, A. C., Bakai, J., Greschik, I., Puski, L., Nagy, L., Kirschner, R., Kuchar, R., Hajek, P., Busak, L., Michalik, D., Matyasek, I., Marusincova, I., Kucera, D., Jerabek, O., Honkova, M., Dedek, V., Rihacek, I., Kos, P., Slaby, J., Machkova, M., Zidkova, E., Elbl, L., Grunfeldova, H., Carda, J., Mrozek, V., Maly, J., Milkovic, R., Malecha, J., Skalicka, H., Oral, I., Krcova, E., Lisa, L., Belohlavek, J., Miklik, R., Cermak, O., Bednarova, J., Peroutka, Z., Spinar, J., Wilke, A., Appel, K., Taggeselle, J., Forster, A., Toursarkissian, N., Schmidt, E., Bott, J., Al-Zoebi, A., Hennig, D., Fischer, S., Schon, N., Sauter, J., Simonis, G., Nischik, R., Rieker, W., Schenkenberger, I., Behnke, T., Klausmann, G., Jeserich, M., Trenk, D., Weigmann, I., Reuter, H., Rummel, R., von Munchhausen, C., von Engelhardt, C., Horibe, E., Shibasaki, T., Sato, T., Kakuta, T., Michishita, I., Tan, M., Ishiki, R., Aoyama, T., Higashiue, S., Niijima, Y., Idogaki, A., Hasegawa, T., Kiyosue, A., Tomobuchi, Y., Kawamitsu, K., Kawasaki, S., Hata, Y., Fukui, K., Seki, K., Takenaka, T., Abe, M., Utsu, N., Oono, A., Mitsuo, K., Sueyoshi, A., Hirohata, A., Tsujimoto, M., Ueda, O., Takase, S., Suzuki, M., Sakuragi, S., Yamamoto, F., Fujimoto, N., Kakinoki, S., Sugiura, T., Sugino, H., Nakamura, T., Goto, S., Kadokami, T., Uehara, H., Ono, M., Yokoya, K., Koike, A., Komatsu, S., Sonoda, M., Ueno, H., Doi, T., Takagi, Y., Fujimoto, K., Eki, Y., Okubo, M., Sasaki, K., van Eck, M., Ronner, E., The, S., van de Wal, R., Nierop, P., de Nooijer, C., The, S., The, S., Werner, H., Westendorp, I., van der Zwaan, C., Crijns, H., Cornel, J. H., Strikwerda, S., Bos, R., de Melker, E., Kuijper, A., Louwerenburg, H., Plomp, J., Dantzig, J., Prins, F., van Kesteren, H., Willems, F., Amoroso, G., Carnero, G., Duronto, E., Besada, D., Chacon, C., Zangroniz, P., Solis, S., Liberman, A., Sernia, V., Alvarisqueta, A., Maffei, L., Vilamajo, O. G., Garcia, C., Sicer, M., Muntaner, J., Bordonava, A., Albisu, J., Zanini, A., Rista, L., Hominal, M., Estrada, J. N., Prado, A., Gosparini, D. M., Schiavi, B., Castillo, A. G., Ruiz, J. G., Martinez, G. R., Lopez, V. G., Rosas, E. L., Lopez, G. R., Cantu, E. G., de Los Rios Ibarra, M., Padilla, F. P., Carrasco, J. P., Carrillo, L. V., Garcia, J. D., Askar, A. N., Salinas, C. A., Gamba, M. A., Sanchez, C. G., Cantu, A. G., Sanchez, R. V., Madrigal, J. C., Urbano, R. H., Romo, A. I., Gonzalez Juanatey, J. R., Racugno, P., Fillat, A. C., de la Torre Hernandez, J. M., Pelaez, J. A., Cortada, J. B., Pavia, P. G., Navarro, M. J., Asenjo, R. M., Diaz, F. F., Peligero, E. B., Manterola, F. A., Ortiz, A. F., Mediavilla Garcia, J. D., Ortuno, F. M., Vera, T. R., Gonzalez, A. S., Vinas, J. A., Fernandez Portales, F. J., Mayordomo, P. S., Ojeda, F. B., Dominguez, A. R., Gonzalez, R. S., Guerrero, D. B., Ruiz Nodar, J. M., Marimon, X. G., Margaez, J. G., Aguilera, R. M., Diaz Fernandez, J. F., Zamorano Gomez, J. L., Gonzalez, V. B., Del Blanco, B. G., Perez, I. P., Moreno, M. R., Ereno, A. R., Garcia Lledo, J. A., Prieto, J., Villablanca, A., Raffo, C., Pincetti, C., Conejeros, C., Roman, O., Rodriguez, M., Varleta, P., Goldberg, C., Sandoval, J., Arriagada, G., Corbalan, R., Leon, L., Potthoff, S., Cobos, J., Figueroa, C., Makotoko, E., Fourie, N., Burgess, L., Nortje, H., Theron, R., Pillai, P., Ranjith, N., Trokis, J., Pillay, S., Reddy, J., Nunkoo, T., Kapp, C., Urbach, D., Distiller, L., Horak, A., van Zyl, L., Coetzee, K., Punt, Z., Bayat, J., Dawood, S., Mitha, I., Padayachee, T., Hoosen, F., Dalby, A., Prabhavathi, Gowdaiah, P., Mehta, V., Chag, M., Gadkari, M., Ramamurthee, K., Das, A., Sawhney, J. S., Banerjee, S., Sathe, P., Adhyapak, S., Nguyen, T., Pham, V., Do, H., Nguyen, A., Nguyen, H., Truong, B., Jamil-Copley, S., Lang, C., Pell, A., Zaman, A., Storey, R., Swanson, N., Smith, S., Sharman, D., Braganza, D., Hammond, P., Moriarty, A., Bain, S., Pye, M., Sharp, A., Blagden, M., Randeva, H., Myhill, T., Viswanathan, G., Keeling, P., Clifford, P., Saxena, M., Lyons, K., McMurray, J., Jaafar, F., Murphy, C., Cartwright, S., Abouglila, K., Antalik, L., Krajci, P., Urban, M., Fazekas, F., Pella, D., Koleny, D., Vykoukalova, T., Macek, V., Vinanska, D., Jamriskova, L., Such, S., Fulop, P., Farsky, S., Bugan, V., Strbova, J., Micko, K., Palka, J. J., Sivak, V., Kristensen, D., Refsgaard, J., Holmvang, L., Dixen, U., Nielsen, H., Egstrup, K., Jensen, L. O., Sykulski, R., Rasmussen, O., Andries, A., Luckow, A., Nielsen, G., Sorensen, T., Wongvipaporn, C., Chamnarnphol, N., Srimahachota, S., Sansanayudh, N., Kuanprasert, S., Tresukosol, D., Sookananchai, B., Kanadasi, M., Ozcan, T., Kucuk, M., Ongen, Z., Okuyan, E., Arat, A., Acikel, S., Yalcin, A., Guray, U., Ceyhan, C., Ozer, N., Arslan, S., Angeras, O., Johnston, N., Weiderman, A., Bandh, S., Hansen, O., Larnefeldt, H., Kusiak, D., Lindholm, C., Hedman, A., Erlinge, D., Curiac, D., Lundman, P., Zucconi-Mazzini, R., Aladellie, L., Jensen, J., Verwerft, J., Vrolix, M., Faes, D., Striekwold, H., Sinnaeve, P., Timmermans, P., Guedes, A., Delforge, M., Nimmegeers, J., Stammen, F., Buysschaert, I., Hoffer, E., Hollanders, G., Vervoort, G., Coussement, P., de Maeseneire, S., Janssens, L., Gravdal, S. A., Risberg, K., Gullestad, L., Hofseth, O. D., Nilsen, D., Lappegard, K. T., van den Heuvel, C., Gibbs, C., Khusrawi, A., Arora, S., Tomala, T., Kjarnli, T., Berg-Johansen, J., Hagemeier, R., Skjelvan, G., Colquhoun, D., Amerena, J., Morbey, C., Hammett, C., Dart, A., Lehman, R., Hamilton, A., Worthley, M., Purnell, P., Whelan, A., MacIsaac, R., Arya, K., Linjawi, S., Proietto, J., Prasad, L., Rodriguez, A., Godoy, A., Rodriguez, V., Berrospi, P., Chavez, C., Negron, S., Heredia, J., Medina, F., Manrique, H., Cabrera, W., Cordova, F., Quinteros, T., Haro, J. M., Regalado, S., Guitton, J., Arbanil, H., Pansieri, M., Decoulx, E., Goube, P., de Labriolle, A., Labeque, J. N., Range, G., Cottin, Y., Montalescot, G., Cayla, G., Danchin, N., Angoulvant, D., Ferrario, E., Elbaz, M., Dubreuil, O., Steg, P. G., Fontaine, C., Sorbets, E., Omer, H., Al-Saif, S., Al-Faleh, H., Al-Shehri, A., El-Amin, O., Alshehri, H., Bazari, R., Hei, P., Ying, M., Chan, M., Wong, M., Ma, R., Siu, S. C., Tsang, C. C., Ferrario, M., Assanelli, E., Senni, M., Piatti, P., Calabro, P., Urbinati, S., Michisanti, M., Varbella, F., de Cosmo, S., Trevisan, R., Bellotti, S., Di Pasquale, G., Bongo, A. S., Uguccioni, M., Mannucci, E., Mauro, C., Ragonese, M., Fresco, C., Turturo, M., Marcucci, R., Lievano Triana, M. J., Arana, C., Accini, J., Botero, R., Muzyk-Osikowicz, M., Dada, F. T., Vallejo, G. S., Manzur, F., Isaza, D., Molina, D., Mesa, J. G., Quintero, A., Nyman, K., Makela, J., Strand, J., Nieminen, S., Taurio, J., Kuusela, M., Valle, T., Pietila, M., Kekki, S., Strandberg, T., Klutstein, M., Greenberg, G., Rozenman, Y., Chorin, E., Roguin, A., Lewis, B., Bashkin, A., Tan, E., Prado, J. P., Ferrolino, A., Babilonia, N., Barbas, B., Matiga, G., Coching, R. M., Drexel, H., Brath, H., Schnack, C., Hanusch, U., FlieSSer-Gorzer, E., Paulweber, B., Ebenbichler, C., Prager, R., Huber, K., Wolzt, M., Auer, J., Berger, R., Schernthaner, G., Stanciulescu, G., Creteanu, M., Spiridon, M., Dobreanu, V., Vinereanu, D., Iosipescu, L. C., Istratoaie, O., Coman, I., Militaru, C., Cinteza, M., Bhatt, D. L., Fox, K., Harrington, R. A., Leiter, L. A., Mehta, S. R., Simon, T., Andersson, M., Himmelmann, A., Steg, P. G., Diaz, R., Amerena, J., Huber, K., Sinnaeve, P. R., Nicolau, J. C., Kerr Saraiva, J. F., Petrov, I., Leiter, L. A., Mehta, S. R., Corbalan, R., Ge, J., Zhao, Q., Botero, R., Widimsky, P., Kristensen, S. D., Hartikainen, J., Danchin, N., Darius, H., Tse, H. F., Kiss, R. G., Pais, P., Lev, E., de Luca, L., Goto, S., Ramos Lopez, G. A., Cornel, J. H., Kontny, F., Medina, F., Babilonia, N. A., Opolski, G., Vinereanu, D., Zateyshchikov, D. A., Ruda, M., Elamin, O., Kovar, F., Dalby, A. J., Jeong, M. H., Bueno, H., James, S. K., Chiang, C., Tresukosol, D., Ongen, Z., Ray, K. K., Parkhomenko, A., McGuire, D. K., Kosiborod, M. N., Nguyen, T. Q., Andersson, M., Chen, J., Himmelmann, A., Leonsson-Zachrisson, M., Ridderstrale, W. 2019

  Abstract

  BACKGROUND: Patients with stable coronary artery disease and diabetes with previous percutaneous coronary intervention (PCI), particularly those with previous stenting, are at high risk of ischaemic events. These patients are generally treated with aspirin. In this trial, we aimed to investigate if these patients would benefit from treatment with aspirin plus ticagrelor.METHODS: The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS) was a phase 3 randomised, double-blinded, placebo-controlled trial, done in 1315 sites in 42 countries. Patients were eligible if 50 years or older, with type 2 diabetes, receiving anti-hyperglycaemic drugs for at least 6 months, with stable coronary artery disease, and one of three other mutually non-exclusive criteria: a history of previous PCI or of coronary artery bypass grafting, or documentation of angiographic stenosis of 50% or more in at least one coronary artery. Eligible patients were randomly assigned (1:1) to either ticagrelor or placebo, by use of an interactive voice-response or web-response system. The THEMIS-PCI trial comprised a prespecified subgroup of patients with previous PCI. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke (measured in the intention-to-treat population).FINDINGS: Between Feb 17, 2014, and May 24, 2016, 11 154 patients (58% of the overall THEMIS trial) with a history of previous PCI were enrolled in the THEMIS-PCI trial. Median follow-up was 3·3 years (IQR 2·8-3·8). In the previous PCI group, fewer patients receiving ticagrelor had a primary efficacy outcome event than in the placebo group (404 [7·3%] of 5558 vs 480 [8·6%] of 5596; HR 0·85 [95% CI 0·74-0·97], p=0·013). The same effect was not observed in patients without PCI (p=0·76, pinteraction=0·16). The proportion of patients with cardiovascular death was similar in both treatment groups (174 [3·1%] with ticagrelor vs 183 (3·3%) with placebo; HR 0·96 [95% CI 0·78-1·18], p=0·68), as well as all-cause death (282 [5·1%] vs 323 [5·8%]; 0·88 [0·75-1·03], p=0·11). TIMI major bleeding occurred in 111 (2·0%) of 5536 patients receiving ticagrelor and 62 (1·1%) of 5564 patients receiving placebo (HR 2·03 [95% CI 1·48-2·76], p<0·0001), and fatal bleeding in 6 (0·1%) of 5536 patients with ticagrelor and 6 (0·1%) of 5564 with placebo (1·13 [0·36-3·50], p=0·83). Intracranial haemorrhage occurred in 33 (0·6%) and 31 (0·6%) patients (1·21 [0·74-1·97], p=0·45). Ticagrelor improved net clinical benefit: 519/5558 (9·3%) versus 617/5596 (11·0%), HR=0·85, 95% CI 0·75-0·95, p=0·005, in contrast to patients without PCI where it did not, pinteraction=0·012. Benefit was present irrespective of time from most recent PCI.INTERPRETATION: In patients with diabetes, stable coronary artery disease, and previous PCI, ticagrelor added to aspirin reduced cardiovascular death, myocardial infarction, and stroke, although with increased major bleeding. In that large, easily identified population, ticagrelor provided a favourable net clinical benefit (more than in patients without history of PCI). This effect shows that long-term therapy with ticagrelor in addition to aspirin should be considered in patients with diabetes and a history of PCI who have tolerated antiplatelet therapy, have high ischaemic risk, and low bleeding risk.FUNDING: AstraZeneca.

  View details for DOI 10.1016/S0140-6736(19)31887-2

  View details for PubMedID 31484629

• 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

• Trends in overall, cardiovascular and cancer-related mortality among individuals with diabetes reported on death certificates in the United States between 2007 and 2017 DIABETOLOGIA Kim, D., Li, A. A., Cholankeril, G., Kim, S. H., Ingelsson, E., Knowles, J. W., Harrington, R. A., Ahmed, A. 2019; 62 (7): 1185–94

  View details for DOI 10.1007/s00125-019-4870-9

  View details for Web of Science ID 000471176200009

• 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

  View details for DOI 10.1016/j.amepre.2007.01.016

  View details for Web of Science ID 000470823400022

• Stanford Cardiovascular Institute At the Forefront of Cardiovascular Research CIRCULATION RESEARCH Wu, J. C., Woo, Y., Mayerle, M., Harrington, R. A., Quertermous, T. 2019; 124 (10): 1420–24

  View details for DOI 10.1161/CIRCRESAHA.119.310761

  View details for Web of Science ID 000469344600007

• Anti-thrombotic options for secondary prevention in patients with chronic atherosclerotic vascular disease: what does COMPASS add? EUROPEAN HEART JOURNAL Fox, K. A., Eilcelboom, J. W., Anand, S. S., Bhatt, D. L., Bosch, J., Connolly, S. J., Harrington, R. A., Steg, P. G., Yusuf, S. 2019; 40 (18): 1466-+

  View details for DOI 10.1093/eurheartj/ehy347

  View details for Web of Science ID 000490014500015

• Comparison of Rates of Bleeding and Vascular Complications Before, During, and After Trial Enrollment in the SAFE-PCI Trial for Women CIRCULATION-CARDIOVASCULAR INTERVENTIONS Rymer, J. A., Kaltenbach, L. A., Kochar, A., Hess, C. N., Gilchrist, I. C., Messenger, J. C., Harrington, R. A., Jolly, S. S., Jacobs, A. K., Abbott, J., Wojdyla, D. M., Krucoff, M. W., Rao, S. V. 2019; 12 (5)

  View details for DOI 10.1161/CIRCINTERVENTIONS.118.007086

  View details for Web of Science ID 000472713100002

• Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study CLINICAL CARDIOLOGY Bhatt, D. L., Fox, K., Harrington, R. A., Leiter, L. A., Mehta, S. R., Simon, T., Andersson, M., Himmelmann, A., Ridderstrale, W., Held, C., Steg, P., Bhatt, D. L., Fox, K., Harrington, R. A., Leiter, L. A., Mehta, S. R., Simon, T., Andersson, M., Himmelmann, A., Steg, G., Diaz, R., Amerena, J., Huber, K., Sinnaeve, P., Nicolau, J., Kerr Saraiva, J., Petrov, I., Leiter, L. A., Mehta, S. R., Corbalan, R., Ge, J., Zhao, Q., Botero, R., Widimsky, P., Kristensen, S., Hartikainen, J., Danchin, N., Darius, H., Fat, T., Kiss, R., Pais, P., Lev, E., De Luca, L., Goto, S., Ramos Lopez, G., Cornel, J., Kontny, F., Medina, F., Babilonia, N., Opolski, G., Vinereanu, D., Zateyshchikov, D., Ruda, M., Elamin, O., Kovar, F., Dalby, A., Jeong, M., Bueno, H., James, S., Chiang, C., Tresukosol, D., Ongen, Z., Ray, K., Parkhomenko, A., McGuire, D., Kosiborod, M., Tuan Quang Nguyen, Wallentin, L., Fox, K. A., Eikelboom, J. W., Tuomilehto, J., Lee, K. L., Al-Khalidi, H. R., Ellis, S. J., Held, C., Hagstrom, E., Holmgren, P., Heldestad, U., Hallberg, T., Grausne, K., Alm, C., Palmquist, A., Svanberg, C., Capell, W. H., Nehler, M. R., Hiatt, W. R., Bonaca, M. P., Houser, S., Bachler, S., Jaeger, N., Andersson, M., Aunes, M., Brusehed, A., Chen, J., Dahlof, B., Dolezalova, J., Domzol, M., Findley, M., Himmelmann, A., Holmberg, N., Jahreskog, M., Knutsson, M., Kruszewski, J., Leonsson-Zachrisson, M., Ridderstrale, W., Stark, M., Winder, E., THEMIS Steering Comm 2019; 42 (5): 498–505

  View details for DOI 10.1002/clc.23164

  View details for Web of Science ID 000468080800001

• Trends in overall, cardiovascular and cancer-related mortality among individuals with diabetes reported on death certificates in the United States between 2007 and 2017. Diabetologia Kim, D., Li, A. A., Cholankeril, G., Kim, S. H., Ingelsson, E., Knowles, J. W., Harrington, R. A., Ahmed, A. 2019

  Abstract

  AIMS/HYPOTHESIS: The determination of diabetes as underlying cause of death by using the death certificate may result in inaccurate estimation of national mortality attributed to diabetes, because individuals who die with diabetes generally have other conditions that may contribute to their death. We investigated the trends in age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from cardiovascular disease (CVD), complications of diabetes and cancer among individuals with diabetes listed on death certificates in the USA from 2007 to 2017.METHODS: Using the US Census and national mortality database, we calculated age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality rates among adults over 20years with diabetes listed on death certificates. A total of 2,686,590 deaths where diabetes was underlying or contributing cause of death were analysed. We determined temporal mortality rate patterns by joinpoint regression analysis with estimates of annual percentage change (APC).RESULTS: Age-standardised diabetes mortality rates compared among underlying cause of death, contributing cause of death and all-cause mortality were 32.2 vs 75.7 vs 105.1 per 100,000 individuals during the study period. The age-standardised mortality rates due to diabetes as underlying or contributing cause of death declined from 112.2 per 100,000 individuals in 2007 to 104.3 per 100,000 individuals in 2017 with the most pronounced decline noted from 2007 to 2014 (APC -1.4%; 95% CI -1.9%, -1.0%) and stabilisation in decline from 2014 to 2017 (APC 1.1%; 95% CI -0.6%, 2.8%). In terms of cause-specific mortality among individuals with diabetes listed on death certificates, the age-standardised mortality rates for CVD declined at an annual rate of 1.2% with a marked decline of 2.3% between 2007 and 2014. Age-standardised diabetes-specific mortality rates as underlying cause of death decreased from 2007 to 2009 (APC -4.5%) and remained stable from 2009 to 2017. Age-standardised mortality rates for cancer steadily decreased with an average APC of -1.4% (95% CI -1.8%, -1.0%) during the 11-year period. Mortality in the subcategory of CVD demonstrated significant differences.CONCLUSIONS/INTERPRETATION: Current national estimates capture about 30% of all-cause mortality among individuals with diabetes listed as underlying or contributing cause of death on death certificates. The age-standardised mortality due to diabetes as underlying or contributing cause of death and cause-specific mortality from CVD in individuals with diabetes listed as underlying or contributing cause of death plateaued from 2014 onwards except for hypertensive heart disease and heart failure.

  View details for PubMedID 31011776

• Physical activity, sleep and cardiovascular health data for 50,000 individuals from the MyHeart Counts Study SCIENTIFIC DATA Hershman, S. G., Bot, B. M., Shcherbina, A., Doerr, M., Moayedi, Y., Pavlovic, A., Waggott, D., Cho, M. K., Rosenberger, M. E., Haskell, W. L., Myers, J., Champagne, M., Mignot, E., Salvi, D., Landray, M., Tarassenko, L., Harrington, R. A., Yeung, A. C., McConnell, M. V., Ashley, E. A. 2019; 6

  View details for DOI 10.1038/s41597-019-0016-7

  View details for Web of Science ID 000464198800001

• Physical activity, sleep and cardiovascular health data for 50,000 individuals from the MyHeart Counts Study. Scientific data Hershman, S. G., Bot, B. M., Shcherbina, A., Doerr, M., Moayedi, Y., Pavlovic, A., Waggott, D., Cho, M. K., Rosenberger, M. E., Haskell, W. L., Myers, J., Champagne, M. A., Mignot, E., Salvi, D., Landray, M., Tarassenko, L., Harrington, R. A., Yeung, A. C., McConnell, M. V., Ashley, E. A. 2019; 6 (1): 24

  Abstract

  Studies have established the importance of physical activity and fitness for long-term cardiovascular health, yet limited data exist on the association between objective, real-world large-scale physical activity patterns, fitness, sleep, and cardiovascular health primarily due to difficulties in collecting such datasets. We present data from the MyHeart Counts Cardiovascular Health Study, wherein participants contributed data via an iPhone application built using Apple's ResearchKit framework and consented to make this data available freely for further research applications. In this smartphone-based study of cardiovascular health, participants recorded daily physical activity, completed health questionnaires, and performed a 6-minute walk fitness test. Data from English-speaking participants aged 18 years or older with a US-registered iPhone who agreed to share their data broadly and who enrolled between the study's launch and the time of the data freeze for this data release (March 10 2015-October 28 2015) are now available for further research. It is anticipated that releasing this large-scale collection of real-world physical activity, fitness, sleep, and cardiovascular health data will enable the research community to work collaboratively towards improving our understanding of the relationship between cardiovascular indicators, lifestyle, and overall health, as well as inform mobile health research best practices.

  View details for PubMedID 30975992

• Sex Differences in the Pursuit of Interventional Cardiology as a Subspecialty Among Cardiovascular Fellows-in-Training (vol 12, pg 219, 2019) JACC-CARDIOVASCULAR INTERVENTIONS Yong, C. M., Abnousi, F., Rzeszut, A. K., Douglas, P. S., Harrington, R. A., Mehran, R., Grines, C., Altin, S. E., Duvernoy, C. S., ACC WIC, SCAI WIN 2019; 12 (7): 695

  View details for DOI 10.1016/j.jcin.2019.03.008

  View details for Web of Science ID 000462882900022

• Extended-duration betrixaban versus shorter-duration enoxaparin for venous thromboembolism prophylaxis in critically ill medical patients: an APEX trial substudy INTENSIVE CARE MEDICINE Chi, G., Gibson, C., Kalayci, A., Cohen, A. T., Hernandez, A. F., Hull, R. D., Kahe, F., Jafarizade, M., Sharfaei, S., Liu, Y., Harrington, R. A., Goldhaber, S. Z. 2019; 45 (4): 477–87

  View details for DOI 10.1007/s00134-019-05565-6

  View details for Web of Science ID 000463211400007

• It is time to learn from patients like mine. NPJ digital medicine Gombar, S., Callahan, A., Califf, R., Harrington, R., Shah, N. H. 2019; 2: 16

  Abstract

  Clinicians are often faced with situations where published treatment guidelines do not provide a clear recommendation. In such situations, evidence generated from similar patients' data captured in electronic health records (EHRs) can aid decision making. However, challenges in generating and making such evidence available have prevented its on-demand use to inform patient care. We propose that a specialty consultation service staffed by a team of medical and informatics experts can rapidly summarize 'what happened to patients like mine' using data from the EHR and other health data sources. By emulating a familiar physician workflow, and keeping experts in the loop, such a service can translate physician inquiries about situations with evidence gaps into actionable reports. The demand for and benefits gained from such a consult service will naturally vary by practice type and data robustness. However, we cannot afford to miss the opportunity to use the patient data captured every day via EHR systems to close the evidence gap between available clinical guidelines and realities of clinical practice. We have begun offering such a service to physicians at our academic medical center and believe that such a service should be core offering by clinical informatics professional throughout the country. Only if we launch such efforts broadly can we systematically study the utility of learning from the record of routine clinical practice.

  View details for DOI 10.1038/s41746-019-0091-3

  View details for PubMedID 31304364

  View details for PubMedCentralID PMC6550176

• It is time to learn from patients like mine NPJ DIGITAL MEDICINE Gombar, S., Callahan, A., Califf, R., Harrington, R., Shah, N. H. 2019; 2

  View details for DOI 10.1038/s41746-019-0091-3

  View details for Web of Science ID 000462452600001

• Patients with Recent Acute Coronary Syndrome and Polyvascular Disease Derive Large Absolute Benefit from Alirocumab: ODYSSEY OUTCOMES Trial. Journal of the American College of Cardiology Jukema, J. W., Szarek, M., Zijlstra, L. E., de Silva, H. A., 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. G., ODYSSEY OUTCOMES Committees and Investigators 2019

  Abstract

  BACKGROUND: Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACE) and death. The impact of lipid-lowering by proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibition in such patients is undetermined.OBJECTIVES: This pre-specified analysis from ODYSSEY OUTCOMES determined whether polyvascular disease (polyVD) influenced risks of MACE and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy.METHODS: Patients were randomized to alirocumab or placebo 1-12 months after ACS. The primary MACE endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint.RESULTS: Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyVD in two beds (coronary and peripheral artery or cerebrovascular), and 149 had polyVD in three beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACE by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, corresponding absolute risk reduction (ARR [95% confidence interval]) was 1.4% (0.6, 2.3), 1.9% (-2.4%, 6.2%), and 13.0% (-2.0, 28.0). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; ARR with alirocumab was 0.4% (-0.1, 1.0), 1.3% (-1.8%, 4.3%), and 16.2% (5.5, 26.8).CONCLUSIONS: In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyVD is associated with high risks of MACE and death. The large absolute reductions in those risks with alirocumab are a potential benefit for this population.

  View details for PubMedID 30898609

• Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial JAMA CARDIOLOGY Hochman, J. S., Reynolds, H. R., Bangalore, S., O'Brien, S. M., Alexander, K. P., Senior, R., Boden, W. E., Stone, G. W., Goodman, S. G., Lopes, R. D., Lopez-Sendon, J., White, H. D., Maggioni, A. P., Shaw, L. J., Min, J. K., Picard, M. H., Berman, D. S., Chaitman, B. R., Mark, D. B., Spertus, J. A., Cyr, D. D., Bhargava, B., Ruzyllo, W., Wander, G. S., Chernyavskiy, A. M., Rosenberg, Y. D., Maron, D. J., Mavromatis, K., Miller, T., Banerjee, S., Abdul-Nour, K., Stone, P. H., Jang, J. J., Weitz, S., Arnold, S., Shapiro, M. D., El-Hajjar, M., McFalls, E. O., Khouri, M., Goldberg, J. L., Goldweit, R., Cohen, R. A., Winchester, D. E., Kronenberg, M., Heitner, J. F., Dauber, I. M., Cannan, C., Sudarshan, S., Mehta, P. K., Hedgepeth, C. M., Sahul, Z., Booth, D., Setty, S., Barua, R. S., Hage, F., Dajani, K., El-Hajjar, M., Arif, I., Trejo (Gutierrez), J. F., Gemignani, A., Meadows, J. L., Call, J. T., Hannan, J., Martin, E. T., Vorobiof, G., Moorman, A., Kinlay, S., Rayos, G., Seedhom, A., Kumkumian, G., Sedlis, S. P., Tamis-Holland, J. E., Saba, S., Badami, U., Marzo, K., Robbins, I. H., Hamroff, G. S., Little, R. W., Lui, C. Y., Booth, D., Hu, B., Labovitz, A. J., Maron, D. J., Rodriguez, F., Deedwania, P., Sweeny, J., Spizzieri, C., Hochberg, C. P., Salerno, W. D., Wyman, R., Zarka, A., Haldis, T., Kohn, J. A., Girotra, S., Almousalli, O., Krishnam, M. S., Coram, R., Thomas, S., El Shahawy, M., Stafford, J., Abernethy, W. B., Zurick, A., Meyer, T. M., Rutkin, B., Bokhari, S., Sokol, S. I., Hamzeh, I., Turner, M. C., Good, A. P., Shammas, N. W., Chilton, R., Nguyen, P. K., Jezior, M., Gordon, P. C., Stenberg, R., Pedalino, R. P., Wiesel, J., Juang, G. J., Al-Amoodi, M., Wohns, D., Lader, E. W., Mumma, M., Dharmarajan, L., McGarvey, J. X., Downes, T. R., Cheong, B., Potluri, S., Mastouri, R. A., Li, D., Giedd, K., Old, W., Burt, F., Sokhon, K., Gopal, D., Valeti, U. S., Kobashigawa, J., Govindan, S., Manjunath, C., Pandit, N., Dwivedi, S. K., Wander, G. S., Bhargava, B., Mathew, A., Gadkari, M., Satheesh, S., Mathur, A., Christopher, J., Oomman, A., Naik, S., Christopher, J., Grant, P., Kachru, R., Kumar, A., Christopher, J., Kaul, U., Gamma, R., de Belder, M. A., Nageh, T., Lindsay, S. J., Hoye, A., Donnelly, P., Chauhan, A., Barr, C., Alfakih, K., Henriksen, P., Okane, P., de Silva, R., Conway, D. G., Sirker, A. A., Hoole, S. P., Witherow, F. N., Johnston, N., Luckie, M., Sobolewska, J., Jeetley, P., Travill, C., Braganza, D., Henderson, R., Berry, C., Moriarty, A. J., Glover, J. D., Mikhail, G., Gosselin, G., Diaz, A., Phaneuf, D., Garg, P., Chow, B. W., Bainey, K. R., Cheema, A. N., Cheema, A., Cha, J., Howarth, A. G., Wong, G., Uxa, A., Galiwango, P., Lam, A., Mehta, S., Udell, J., Genereux, P., Hameed, A., Daba, L., Hueb, W., Smanio, P., de Quadros, A., Vitola, J. V., Marin-Neto, J., Polanczyk, C. A., Carvalho, A., Alves Junior, A., Dracoulakis, M. A., Figueiredo, E., Caramori, P., Tumelero, R., Dall'Orto, F., Mesquita, C. T., Ribeiro da Silva, E., Saraiva, J., Costantini, C., Demkow, M., Mazurek, T., Drozdz, J., Szwed, H., Witkowski, A., Gajos, G., Pruszczyk, P., Loboz-Grudzien, K., Lesiak, M., Reczuch, K. W., Kalarus, Z., Musial, W. J., Bockeria, L., Chernyavskiy, A. M., Bershtein, L. L., Demchenko, E. A., Lopez-Sendon, J., Peteiro, J., Gonzalez Juanatey, J., Sionis, A., Miro, V., Ortuno, F., Blancas, M., Luena, J., Fernandez-Aviles, F., Chen, J., Wu, Y., Ma, Y., Ji, Z., Yang, X., Lin, W., Zeng, H., Fu, X., Yang, B., Wang, S., Cheng, G., Zhao, Y., Fang, X., Zeng, Q., Su, X., Li, Q., Nie, S., Yu, Q., Wang, J., Zhang, S., Perna, G., Provasoli, S., Monti, L., Di Chiara, A., Mortara, A., Galvani, M., Sicuro, M., Calabro, P., Tarantini, G., Racca, E., Briguori, C., Amati, R., Russo, A., Poh, K., Foo, D., Chua, T., Doerr, R., Sechtem, U., Schulze, P., Nickenig, G., Schuchlenz, H., Lang, I., Huber, K., Vertes, A., Varga, A., Fontos, G., Merkely, B., Kerecsen, G., Hinic, S., Beleslin, B. D., Cemerlic-Adjic, N., Davidovic, G., Dekleva, M., Stankovic, G., Apostolovic, S., Escobedo, J., Rosas, E., Selvanayagam, J. B., Thambar, S. T., Beltrame, J. F., Hillis, G. S., Thuaire, C., Steg, P., Slama, M. S., El Mahmoud, R., Nicollet, E., Barone-Rochette, G., Furber, A., Laucevicius, A., Kedhi, E., Riezebos, R. K., Suryapranata, H., Ramos, R., Pinto, F. J., Ferreira, N., Guzman, L., Figal, J., Alvarez, C., Courtis, J., Schiavi, L., Rubio, M., Devlin, G., Stewart, R., Kedev, S., Held, C., Aspberg, J., Sharir, T., Kerner, A., Fukuda, K., Yasuda, S., Nishimura, S., Goetschalckx, K., Hung, C., Ntsekhe, M., Moccetti, T., Abdelhamid, M., Pop, C., Popescu, B. A., Al-Mallah, M. H., Ramos, W., Kuanprasert, S., Yamwong, S., Khairuddin, A., O'Brien, S. M., Boden, W. E., Ferguson, B., Harrington, R., Stone, G. W., Williams, D., Berger, J., Newman, J., Sidhu, M., Mark, D. B., Shaw, L. J., Spertus, J. A., Berman, D. S., Chaitman, B. R., Doerr, R., Dzavik, V., Goodman, S. G., Gosselin, G., Held, C., Jiang, L., Keltai, M., Kohsaka, S., Lopes, R. D., Lopez-Sendon, J., Maggioni, A., Mancini, G., Merz, C., Min, J. K., Picard, M. H., Ruzyllo, W., Selvanayagam, J. B., Senior, R., Steg, P., Szwed, H., Weintraub, W., White, H. D., Ballantyne, C., Calfas, K. J., Davidson, M., Stone, P. H., Friedrich, M., Hachamovitch, R., Kwong, R., Harrell, F., Kullo, I., McManus, B., Cohen, D. J., Bugiardini, R., Celutkiene, J., Escobedo, J., Hoye, A., Lyubarova, R., Mattina, D., Peteiro, J., Nwosu, S., Broderick, S., Cyr, D., Rockhold, F., Anstrom, K., Jones, P., Phillips, L., Hayes, S. W., Friedman, J. D., Gerlach, R., Kwong, R. Y., Mongeon, F., Hung, J., Scherrer-Crosbie, M., Zeng, X., Ali, Z., Genereux, P., Arsanjani, R., Budoff, M., Leipsic, J., Nakanishi, R., Youn, T., Orso, F., Carvalho, A., Zhang, H., Zhang, L., Diaz, R., Van de Werf, F., Goetschalckx, K., Rosenberg, Y. D., Fleg, J., Kirby, R., Jeffries, N., ISCHEMIA Res Grp 2019; 4 (3): 273–86

  View details for DOI 10.1001/jamacardio.2019.0014

  View details for Web of Science ID 000461901600018

• What Is Needed Now to Improve Cardiovascular Clinical Registries in the Future JAMA CARDIOLOGY Hernandez, A. F., Harrington, R. A. 2019; 4 (3): 201-202

  View details for DOI 10.1001/jamacardio.2018.4946

  View details for Web of Science ID 000461901600004

• 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

• Baseline Characteristics and Risk Profiles of Participants in the ISCHEMIA Randomized Clinical Trial. JAMA cardiology Hochman, J. S., Reynolds, H. R., Bangalore, S., O'Brien, S. M., Alexander, K. P., Senior, R., Boden, W. E., Stone, G. W., Goodman, S. G., Lopes, R. D., Lopez-Sendon, J., White, H. D., Maggioni, A. P., Shaw, L. J., Min, J. K., Picard, M. H., Berman, D. S., Chaitman, B. R., Mark, D. B., Spertus, J. A., Cyr, D. D., Bhargava, B., Ruzyllo, W., Wander, G. S., Chernyavskiy, A. M., Rosenberg, Y. D., Maron, D. J., ISCHEMIA Research Group 2019

  Abstract

  Importance: It is unknown whether coronary revascularization, when added to optimal medical therapy, improves prognosis in patients with stable ischemic heart disease (SIHD) at increased risk of cardiovascular events owing to moderate or severe ischemia.Objective: To describe baseline characteristics of participants enrolled and randomized in the International Study of Comparative Health Effectiveness With Medical and Invasive Approaches (ISCHEMIA) trial and to evaluate whether qualification by stress imaging or nonimaging exercise tolerance test (ETT) influenced risk profiles.Design, Setting, and Participants: The ISCHEMIA trial recruited patients with SIHD with moderate or severe ischemia on stress testing. Blinded coronary computed tomography angiography was performed in most participants and reviewed by a core laboratory to exclude left main stenosis of at least 50% or no obstructive coronary artery disease (CAD) (<50% for imaging stress test and <70% for ETT). The study included 341 enrolling sites (320 randomizing) in 38 countries and patients with SIHD and moderate or severe ischemia on stress testing. Data presented were extracted on December 17, 2018.Main Outcomes and Measures: Enrolled, excluded, and randomized participants' baseline characteristics. No clinical outcomes are reported.Results: A total of 8518 patients were enrolled, and 5179 were randomized. Common reasons for exclusion were core laboratory determination of insufficient ischemia, unprotected left main stenosis of at least 50%, or no stenosis that met study obstructive CAD criteria on study coronary computed tomography angiography. Randomized participants had a median age of 64 years, with 1168 women (22.6%), 1726 nonwhite participants (33.7%), 748 Hispanic participants (15.5%), 2122 with diabetes (41.0%), and 4643 with a history of angina (89.7%). Among the 3909 participants randomized after stress imaging, core laboratory assessment of ischemia severity (in 3901 participants) was severe in 1748 (44.8%), moderate in 1600 (41.0%), mild in 317 (8.1%) and none or uninterpretable in 236 (6.0%), Among the 1270 participants who were randomized after nonimaging ETT, core laboratory determination of ischemia severity (in 1266 participants) was severe (an eligibility criterion) in 1051 (83.0%), moderate in 101 (8.0%), mild in 34 (2.7%) and none or uninterpretable in 80 (6.3%). Among the 3912 of 5179 randomized participants who underwent coronary computed tomography angiography, 79.0% had multivessel CAD (n=2679 of 3390) and 86.8% had left anterior descending (LAD) stenosis (n=3190 of 3677) (proximal in 46.8% [n=1749 of 3739]). Participants undergoing ETT had greater frequency of 3-vessel CAD, LAD, and proximal LAD stenosis than participants undergoing stress imaging.Conclusions and Relevance: The ISCHEMIA trial randomized an SIHD population with moderate or severe ischemia on stress testing, of whom most had multivessel CAD.Trial Registration: ClinicalTrials.gov Identifier: NCT01471522.

  View details for PubMedID 30810700

• Reduction of Cardiovascular Mortality and Ischemic Events in Acute Medically Ill Patients. Circulation Nafee, T., Gibson, C. M., Yee, M. K., Kerneis, M., Daaboul, Y., Korjian, S., Chi, G., Kalayci, A., Afzal, M. K., Kazmi, H., Datta, S., AlKhalfan, F., Hernandez, A. F., Hull, R. D., Harrington, R. A., Cohen, A. T., Goldhaber, S. Z. 2019; 139 (9): 1234–36

  View details for PubMedID 30802169

• Reduction of Cardiovascular Mortality and Ischemic Events in Acute Medically Ill Patients An APEX Substudy CIRCULATION Nafee, T., Gibson, C., Yee, M. K., Kerneis, M., Daaboul, Y., Korjian, S., Chi, G., Kalayci, A., Afzal, M., Kazmi, H., Datta, S., AlKhalfan, F., Hernandez, A. F., Hull, R. D., Harrington, R. A., Cohen, A. T., Goldhaber, S. Z. 2019; 139 (9): 1234-1236

  View details for DOI 10.1161/CIRCULATIONAHA.118.038654

  View details for Web of Science ID 000459676600015

• 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

• Rationale, Design, and Baseline Characteristics of THEMIS: Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study. Clinical cardiology Bhatt, D. L., Fox, K., Harrington, R. A., Leiter, L. A., Mehta, S. R., Simon, T., Andersson, M., Himmelmann, A., Ridderstrale, W., Held, C., Steg, P. G., THEMIS Steering Committee 2019

  Abstract

  In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor versus placebo, on top of low dose aspirin. Patients ≥ 50 years with type 2 diabetes receiving anti-diabetic medications for at least six months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of ≥ 50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19,220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice-daily dose, as the dose was lowered from 90 mg twice-daily part-way into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention. This article is protected by copyright. All rights reserved.

  View details for PubMedID 30788847

• What Is Needed Now to Improve Cardiovascular Clinical Registries in the Future. JAMA cardiology Hernandez, A. F., Harrington, R. A. 2019

  View details for PubMedID 30785599

• Association Between Female Corresponding Authors and Female Co-Authors in Top Contemporary Cardiovascular Medicine Journals. Circulation Ouyang, D., Harrington, R. A., Rodriguez, F. 2019; 139 (8): 1127–29

  View details for PubMedID 30779644

• Association Between Female Corresponding Authors and Female Co-Authors in Top Contemporary Cardiovascular Medicine Journals CIRCULATION Ouyang, D., Harrington, R. A., Rodriguez, F. 2019; 139 (8): 1127-1129

  View details for DOI 10.1161/CIRCULATIONAHA.118.037763

  View details for Web of Science ID 000458996100022

• Extended-duration betrixaban versus shorter-duration enoxaparin for venous thromboembolism prophylaxis in critically ill medical patients: an APEX trial substudy. Intensive care medicine Chi, G., Gibson, C. M., Kalayci, A., Cohen, A. T., Hernandez, A. F., Hull, R. D., Kahe, F., Jafarizade, M., Sharfaei, S., Liu, Y., Harrington, R. A., Goldhaber, S. Z. 2019

  Abstract

  PURPOSE: To assess the efficacy and safety of betrixaban for venous thromboembolism (VTE) prophylaxis among critically ill patients.METHODS: The APEX trial randomized 7513 acutely ill hospitalized patients to betrixaban for 35-42days or enoxaparin for 10±4days. Among those, 703 critically ill patients admitted to the intensive care unit were included in the analysis, and 547 patients who had no severe renal insufficiency or P-glycoprotein inhibitor use were included in the full-dose stratum. The risk of VTE, bleeding, net clinical benefit (composite of VTE and major bleeding), and mortality was compared at 35-42days and at 77days.RESULTS: At 35-42days, extended betrixaban reduced the risk of VTE (4.27% vs 7.95%, P=0.042) without causing excess major bleeding (1.14% vs 3.13%, P=0.07). Both VTE (3.32% vs 8.33%, P=0.013) and major bleeding (0.00% vs 3.26%, P=0.003) were decreased in the full-dose stratum. Patients who received betrixaban had more non-major bleeding than enoxaparin (overall population: 2.56% vs 0.28%, P=0.011; full-dose stratum: 3.32% vs 0.36%, P=0.010). Mortality was similar at the end of study (overall population: 13.39% vs 16.19%, P=0.30; full-dose stratum: 13.65% vs 16.30%, P=0.39).CONCLUSIONS: Compared with shorter-duration enoxaparin, critically ill medical patients who received extended-duration betrixaban had fewer VTE without more major bleeding events. The benefit of betrixaban was driven by preventing asymptomatic thrombosis and offset by an elevated risk of non-major bleeding. The APEX trial did not stratify by intensive care unit admission and the present study included a highly selected population of critically ill patients. These hypothesis-generating findings need to be validated in future studies.CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

  View details for PubMedID 30778649

• One Size Does Not Fit All: Improving Recruitment and Retention of Women in Cardiovascular Device-Related Clinical Trials. JACC. Cardiovascular interventions Rodriguez, F., Harrington, R. A. 2019; 12 (3): 309–11

  View details for PubMedID 30732737

• Sex Differences in the Pursuit of Interventional Cardiology as a Subspecialty Among Cardiovascular Fellows-in-Training JACC-CARDIOVASCULAR INTERVENTIONS Yong, C. M., Abnousi, F., Rzeszut, A. K., Douglas, P. S., Harrington, R. A., Mehran, R., Grines, C., Altin, S., Duvemoy, C. S., Amer Coll Cardiology Women, Cardiovasc Angiography 2019; 12 (3): 219-228

  View details for DOI 10.1016/j.jcin.2018.09.036

  View details for Web of Science ID 000457565300004

• One Size Does Not Fit All Improving Recruitment and Retention of Women in Cardiovascular Device-Related Clinical Trials JACC-CARDIOVASCULAR INTERVENTIONS Rodriguez, F., Harrington, R. A. 2019; 12 (3): 309-311

  View details for DOI 10.1016/j.jcin.2018.11.012

  View details for Web of Science ID 000457565300017

• 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

  View details for DOI 10.1016/j.jacc.2018.10.039

  View details for Web of Science ID 000456818200001

• Sex Differences in the Pursuit of Interventional Cardiology as a Subspecialty Among CardiovascularFellows-in-Training. JACC. Cardiovascular interventions Yong, C. M., Abnousi, F., Rzeszut, A. K., Douglas, P. S., Harrington, R. A., Mehran, R., Grines, C., Altin, S. E., Duvernoy, C. S., American College of Cardiology Women in Cardiology Leadership Council (ACC WIC), Society for Cardiovascular Angiography and Interventions Women in Innovations (SCAI WIN) 2019

  Abstract

  OBJECTIVES: The authors sought to determine the factors that influence fellows-in-training (FITs) to pursue a career in interventional cardiology (IC) and how these differ by sex.BACKGROUND: Despite increases in the proportion of women across numerous medical and surgical specialties over the last decade, IC still ranks at the bottom in terms of representation of women. It is unclear why this maldistribution persists.METHODS: An online survey of cardiovascular FITs was conducted under the direction of the American College of Cardiology Women in Cardiology Leadership Council to assess FIT perspectives regarding subspecialty choices.RESULTS: Of 574 respondents, 33% anticipated specializing in IC. Men were more likely to choose IC than women (39% men, 17% women, odds ratio: 3.98 [95% confidence interval: 2.38 to 6.68]; p< 0.001). Men were more likely to be married (p= 0.005) and have children (p= 0.002). Among married FITs, male IC FITs were more likely to have spouses who do not work (p= 0.003). Although men were more likely to be influenced by positive attributes to pursue IC, women were significantly more likely to be influenced negatively against pursuing the field by attributes including greater interest in another field (p= 0.001), little job flexibility (p= 0.02), physically demanding nature of job (p=0.004), radiation during childbearing (p< 0.001), "old boys' club" culture (p< 0.001), lack of female role models (p< 0.001), and sex discrimination (p< 0.001).CONCLUSIONS: Many factors uniquely dissuade women from pursuing IC compared with men, largely related to the culture of IC as a subspecialty. Targeted resolution of these specific factors may provide the most impact in reducing sex imbalances in the field.

  View details for PubMedID 30660463

• Stanford Cardiovascular Institute. Circulation research Wu, J. C., Woo, Y. J., Mayerle, M. n., Harrington, R. A., Quertermous, T. n. 2019; 124 (10): 1420–24

  View details for PubMedID 31070998

• Revisiting the Role of Aspirin for the Primary Prevention of Cardiovascular Disease. Circulation Marquis-Gravel, G. n., Roe, M. T., Harrington, R. A., Muñoz, D. n., Hernandez, A. F., Jones, W. S. 2019; 140 (13): 1115–24

  Abstract

  Aspirin is the cornerstone of the antithrombotic management of patients with established atherosclerotic cardiovascular disease, but major guidelines provide conflicting recommendations for its use in primary prevention. Findings from recent randomized trials totaling >47 000 patients called into question the net clinical benefits of aspirin in primary prevention for 3 key populations: patients with diabetes mellitus, community-dwelling elderly individuals, and patients without diabetes mellitus who are at intermediate risk for atherosclerotic events. In the context of increasing emphasis on the use of other treatments for primary prevention in patients with moderate-high future risk of developing atherosclerotic cardiovascular disease, the efficacy and safety of aspirin for primary prevention has become uncertain. Key unresolved questions regarding the role of aspirin in primary prevention include the optimal drug formulation, dosing schedule, weight-based dose selection, and interplay between sex and treatment response. In the current era, most patients without established atherosclerotic cardiovascular disease should not be prescribed aspirin. Rather, aggressive management of comorbidities tailored to the expected cardiovascular risk needs to be emphasized. In this context, informed shared decision making between clinicians and patients regarding the use of aspirin for primary prevention of cardiovascular events is a suitable and laudable approach. In this article, we revisit the role of aspirin for the primary prevention of cardiovascular diseases by critically reviewing the key scientific literature, highlight key areas of uncertainties for future research, and propose a decisional framework for clinicians to support prescription of aspirin in primary prevention.

  View details for DOI 10.1161/CIRCULATIONAHA.119.040205

  View details for PubMedID 31545683

• Inverse relationship of serum albumin to the risk of venous thromboembolism among acutely ill hospitalized patients: Analysis from the APEX trial AMERICAN JOURNAL OF HEMATOLOGY Chi, G., Gibson, C., Liu, Y., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. 2019; 94 (1): 21–28

  Abstract

  Hypoalbuminemia is a common finding and independent predictor for unfavorable prognosis. The prognostic value of albumin measurement for short-term VTE prediction in hospitalized patients remains unclear. In the APEX trial (ClinicalTrials.gov identifier: NCT01583218), medical inpatients were randomized to receive either extended-duration betrixaban or shorter-duration enoxaparin and followed for 77 days. Baseline albumin concentrations were obtained in 7266 subjects with evaluable VTE endpoints. The association of baseline albumin to VTE was assessed, with adjustment for patient characteristics, thromboprophylaxis, and biomarkers for fibrinolysis and inflammation (ie, D-dimer and C-reactive protein [CRP]). VTE risk refinement was evaluated by incorporation of albumin to well-validated risk assessment models. A stepwise increase in the risk of VTE (P < .0001) was observed with lower levels of albumin. Patients at the bottom albumin quartile (<35 g/L) had a two-fold greater odds for developing VTE compared with the top quartile (≥42 g/L) (OR = 2.119 [95% CI, 1.592-2.820]; adjusted OR = 2.079 [1.485-2.911]). The odds for VTE increased by 1.368 (95% CI, 1.240-1.509) times per SD decrement of albumin (5.24 g/L). Compared with the propensity score-matched pairs of patients with albumin ≥35 g/L, patients with albumin <35 g/L had a greater risk of VTE (OR = 1.623 [1.260-2.090]; adjusted OR = 1.658 [1.209-2.272]). Albumin measurement also refined VTE risk discrimination and reclassification after inclusion in the risk assessment models. In conclusion, acutely ill hospitalized patients with low serum albumin had an increased VTE risk through 77 days. VTE risk assessment models for medical inpatients should consider incorporation of baseline albumin measurement.

  View details for PubMedID 30252149

• Prehospital Phase of Acute Stroke Care: Guideline and Policy Considerations as Science and Evidence Rapidly Evolve. Stroke Harrington, R. A. 2019: STROKEAHA119025584

  View details for DOI 10.1161/STROKEAHA.119.025584

  View details for PubMedID 31104617

• Comparison of Rates of Bleeding and Vascular Complications Before, During, and After Trial Enrollment in the SAFE-PCI Trial for Women. Circulation. Cardiovascular interventions Rymer, J. A., Kaltenbach, L. A., Kochar, A. n., Hess, C. N., Gilchrist, I. C., Messenger, J. C., Harrington, R. A., Jolly, S. S., Jacobs, A. K., Abbott, J. D., Wojdyla, D. M., Krucoff, M. W., Rao, S. V. 2019; 12 (5): e007086

  Abstract

  SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women), a randomized controlled trial comparing radial and femoral access in women undergoing cardiac catheterization or percutaneous coronary intervention (PCI), was terminated early for lower than expected event rates. Whether this was because of patient selection or better access site practice among trial patients is unknown.SAFE-PCI was conducted within the National Cardiovascular Data Registry CathPCI registry. Using the National Cardiovascular Research Infrastructure Identification, PCI date, and age, patients enrolled in SAFE-PCI were compared with trial-eligible female CathPCI registry patients 1 year before, during, and 1 year after SAFE-PCI enrollment. Patient and procedure characteristics, predicted bleeding and mortality, and post-PCI bleeding were compared between groups. Enrolled SAFE-PCI patients and registry patients from the 3 time periods were linked to Centers for Medicare and Medicaid Services data to compare 30-day death and unplanned revascularization rates. At 54 SAFE-PCI sites, there were 496 SAFE-PCI trial patients with a PCI visit within the CathPCI registry. There were 24 958 registry patients from 1 year before and 1 year after SAFE-PCI enrollment and 15 904 trial-eligible registry patients during trial enrollment. Trial patients were younger, had lower predicted bleeding and mortality, and had lower rates of post-PCI bleeding within 72 hours compared with registry patients. Among 12 212 Centers for Medicare and Medicaid Services-linked patients, there were no significant differences in 30-day death and unplanned revascularization among the 4 groups.Lower predicted risk of bleeding and mortality among SAFE-PCI trial patients compared with registry patients suggests that lower-risk patients were selectively enrolled for the trial. These data demonstrate how registry-based randomized trials may offer methods for enrollment feedback to curb selection bias in recruitment.URL: https://www.clinicaltrials.gov . Unique identifier: NCT01406236.

  View details for PubMedID 31014090

• Effects of Alirocumab on Cardiovascular Events After Coronary Bypass Surgery. Journal of the American College of Cardiology Goodman, S. G., Aylward, P. E., Szarek, M. n., Chumburidze, V. n., Bhatt, D. L., Bittner, V. A., Diaz, R. n., Edelberg, J. M., Hanotin, C. n., Harrington, R. A., Jukema, J. W., Kedev, S. n., Letierce, A. n., Moryusef, A. n., Pordy, R. n., Ramos López, G. A., Roe, M. T., Viigimaa, M. n., White, H. D., Zeiher, A. M., Steg, P. G., Schwartz, G. G. 2019; 74 (9): 1177–86

  Abstract

  Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death.This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab).Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003).In each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]).Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

  View details for DOI 10.1016/j.jacc.2019.07.015

  View details for PubMedID 31466614

• A novel noninvasive method for remote heart failure monitoring: the EuleriAn video Magnification apPLications In heart Failure studY (AMPLIFY). NPJ digital medicine Abnousi, F., Kang, G., Giacomini, J., Yeung, A., Zarafshar, S., Vesom, N., Ashley, E., Harrington, R., Yong, C. 2019; 2: 80

  Abstract

  Current remote monitoring devices for heart failure have been shown to reduce hospitalizations but are invasive and costly; accurate non-invasive options remain limited. The EuleriAn Video Magnification ApPLications In Heart Failure StudY (AMPLIFY) pilot aimed to evaluate the accuracy of a novel noninvasive method that uses Eulerian video magnification. Video recordings were performed on the neck veins of 50 patients who were scheduled for right heart catheterization at the Palo Alto VA Medical Center. The recorded jugular venous pulsations were then enhanced by applying Eulerian phase-based motion magnification. Assessment of jugular venous pressure was compared across three categories: (1) physicians who performed bedside exams, (2) physicians who reviewed both the amplified and unamplified videos, and (3) direct invasive measurement of right atrial pressure from right heart catheterization. Motion magnification reduced inaccuracy of the clinician assessment of central venous pressure compared to the gold standard of right heart catheterization (mean discrepancy of -0.80cm H2O; 95% CI -2.189 to 0.612, p=0.27) when compared to both unamplified video (-1.84cm H2O; 95% CI -3.22 to -0.46, p=0.0096) and the bedside exam (-2.90cm H2O; 95% CI -4.33 to 1.40, p=0.0002). Major categorical disagreements with right heart catheterization were significantly reduced with motion magnification (12%) when compared to unamplified video (25%) or the bedside exam (27%). This novel method of assessing jugular venous pressure improves the accuracy of the clinical exam and may enable accurate remote monitoring of heart failure patients with minimal patient risk.

  View details for DOI 10.1038/s41746-019-0159-0

  View details for PubMedID 31453375

• 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

• Thrombophilia testing in the inpatient setting: impact of an educational intervention. BMC medical informatics and decision making Kwang, H. n., Mou, E. n., Richman, I. n., Kumar, A. n., Berube, C. n., Kaimal, R. n., Ahuja, N. n., Harman, S. n., Johnson, T. n., Shah, N. n., Witteles, R. n., Harrington, R. n., Shieh, L. n., Hom, J. n. 2019; 19 (1): 167

  Abstract

  Thrombophilia testing is frequently ordered in the inpatient setting despite its limited impact on clinical decision-making and unreliable results in the setting of acute thrombosis or ongoing anticoagulation. We sought to determine the effect of an educational intervention in reducing inappropriate thrombophilia testing for hospitalized patients.During the 2014 academic year, we implemented an educational intervention with a phase implementation design for Internal Medicine interns at Stanford University Hospital. The educational session covering epidemiology, appropriate thrombophilia evaluation and clinical rationale behind these recommendations. Their ordering behavior was compared with a contemporaneous control (non-medicine and private services) and a historical control (interns from prior academic year). From the analyzed data, we determined the proportion of inappropriate thrombophilia testing of each group. Logistic generalized estimating equations were used to estimate odds ratios for inappropriate thrombophilia testing associated with the intervention.Of 2151 orders included, 934 were deemed inappropriate (43.4%). The two intervention groups placed 147 orders. A pooled analysis of ordering practices by intervention groups revealed a trend toward reduction of inappropriate ordering (p = 0.053). By the end of the study, the intervention groups had significantly lower rates of inappropriate testing compared to historical or contemporaneous controls.A brief educational intervention was associated with a trend toward reduction in inappropriate thrombophilia testing. These findings suggest that focused education on thrombophilia testing can positively impact inpatient ordering practices.

  View details for DOI 10.1186/s12911-019-0889-6

  View details for PubMedID 31429747

• 10 Recommendations to Enhance Recruitment, Retention, and Career Advancement of Women Cardiologists. Journal of the American College of Cardiology Sharma, G. n., Sarma, A. A., Walsh, M. N., Hayes, S. N., Sahni, S. n., Brown, S. A., Singh, T. n., Harrington, R. A., Douglas, P. S., Duvernoy, C. S. 2019; 74 (14): 1839–42

  View details for DOI 10.1016/j.jacc.2019.08.016

  View details for PubMedID 31582144

• Translating Science Into Policy. Circulation Harrington, R. A., Churchwell, K. n., Whitsel, L. P. 2019; 140 (10): e545–e546

  View details for DOI 10.1161/CIRCULATIONAHA.119.042549

  View details for PubMedID 31479316

• 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

• 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

• Burnout and Career Satisfaction Among U.S. Cardiologists. Journal of the American College of Cardiology Mehta, L. S., Lewis, S. J., Duvernoy, C. S., Rzeszut, A. K., Walsh, M. N., Harrington, R. A., Poppas, A. n., Linzer, M. n., Binkley, P. F., Douglas, P. S. 2019; 73 (25): 3345–48

  View details for DOI 10.1016/j.jacc.2019.04.031

  View details for PubMedID 31248556

• Clinical consequences of bleeding among individuals with a recent acute coronary syndrome: Insights from the APPRAISE-2 trial. American heart journal Sharma, A. n., Hagström, E. n., Wojdyla, D. M., Neely, M. L., Harrington, R. A., Wallentin, L. n., Alexander, J. H., Goodman, S. G., Lopes, R. D. 2019; 215: 106–13

  Abstract

  Patients with a recent acute coronary syndrome (ACS) receiving oral antiplatelets and anticoagulants are at risk for bleeding and subsequent adverse non-bleeding-related events.In this post hoc analysis, we evaluated 7,392 high-risk patients (median follow-up 241 days) with a recent ACS randomized to apixaban or placebo in APPRAISE-2. Clinical events during a 30-day period after Thrombolysis in Myocardial Infarction (TIMI) major/minor bleeding were analyzed using unadjusted and adjusted Cox proportional-hazards models.In total, 153 (2.1%) patients experienced TIMI major/minor bleeding during follow-up. Bleeding risk for patients on triple therapy (apixaban, thienopyridine, and aspirin) was increased compared with those on dual therapy (apixaban plus aspirin: hazard ratio [HR] 2.02, 95% CI 1.08-3.79; thienopyridine plus aspirin: HR 1.99, 95% CI 1.41-2.83). Those receiving apixaban/aspirin had similar bleeding risk compared with those receiving thienopyridine/aspirin (HR 1.01, 95% CI 0.53-1.95). Patients who experienced TIMI major/minor bleeding had an increased risk of 30-day all-cause mortality (HR 24.7, 95% CI 15.34-39.66) and ischemic events (HR 6.7, 95% CI 3.14-14.14).In a contemporary cohort of high-risk patients after ACS, bleeding was associated with a significantly increased risk of subsequent ischemic events and mortality regardless of antithrombotic or anticoagulant strategy. Patients receiving apixaban plus aspirin had a similar bleeding risk compared with those receiving thienopyridine plus aspirin. Interventions to improve outcomes in patients after ACS should include strategies to optimize the reduction in ischemic events while minimizing the risk of bleeding.

  View details for DOI 10.1016/j.ahj.2019.05.004

  View details for PubMedID 31310855

• The Myheart Counts Cardiovascular Health Study: A Randomized Controlled Trial of Digital Health Coaching for Physical Activity Promotion Shcherbina, A., Hershman, S., King, A. C., Hekler, E., Pavlovic, A., Waggott, D., McConnell, M. V., Ashley, E. A., Harrington, R. A. LIPPINCOTT WILLIAMS & WILKINS. 2018: E767

  View details for Web of Science ID 000453713500032

• 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)

  View details for DOI 10.1161/JAHA.118.009609

  View details for Web of Science ID 000455184800006

• 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

  View details for Web of Science ID 000453713500005

• 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

  View details for Web of Science ID 000453713500041

• 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

• 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

• Promise and Perils of Big Data and Artificial Intelligence in Clinical Medicine and Biomedical Research CIRCULATION RESEARCH Rodriguez, F., Scheinker, D., Harrington, R. A. 2018; 123 (12): 1282-1284

  View details for DOI 10.1161/CIRCRESAHA.118.314119

  View details for Web of Science ID 000454198400012

• 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

  View details for DOI 10.1093/eurheartj/ehy562

  View details for Web of Science ID 000456853800015

• Sex Disparities in Authorship Order of Cardiology Scientific Publications Trends Over 40 Years CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Ouyang, D., Sing, D., Shah, S., Hu, J., Duvernoy, C., Harrington, R. A., Rodriguez, F. 2018; 11 (12)

  View details for DOI 10.1161/CIRCOUTCOMES.118.005040

  View details for Web of Science ID 000457567200012

• Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial THROMBOSIS AND HAEMOSTASIS Kalayci, A., Gibson, C., Chi, G., Yee, M. K., Korjian, S., Datta, S., Nafee, T., Gurin, M., Haroian, N., Qamar, I., Hull, R. D., Hernandez, A. F., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. 2018; 118 (12): 2046-2052

  View details for DOI 10.1055/s-0038-1675606

  View details for Web of Science ID 000451853100006

• 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

  View details for DOI 10.1056/NEJMoa1801174

  View details for Web of Science ID 000451402500005

• 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

• Asymptomatic Deep Vein Thrombosis is Associated with an Increased Risk of Death: Insights from the APEX Trial. Thrombosis and haemostasis Kalayci, A., Gibson, C. M., Chi, G., Yee, M. K., Korjian, S., Datta, S., Nafee, T., Gurin, M., Haroian, N., Qamar, I., Hull, R. D., Hernandez, A. F., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. 2018

  Abstract

  AIM: Asymptomatic deep vein thrombosis (DVT) diagnosed with compression ultrasound (CUS) is a common endpoint in trials assessing the efficacy of anticoagulants to prevent venous thromboembolism (VTE), but the relationship of asymptomatic thrombus to mortality remains uncertain.METHODS: In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35-42 days) or enoxaparin (10±4 days). Asymptomatic DVT was assessed once with CUS between day 32 and 47, and mortality was assessed through 77 days.RESULTS: A total of 309 asymptomatic DVTs were detected through CUS. Of these, 133 (4.27%) subjects were in the betrixaban group, and 176 (5.55%) subjects were in the enoxaparin group (relative risk=0.77, 95% confidence interval [CI]=0.62-0.97, p=0.025, number needed to treat=79). With respect to all-cause mortality due to cardiovascular diseases, non-cardiovascular diseases and unknown causes, the number of the deaths was 5 (1.67%), 4 (1.34%) and 1 (0.33%) in the asymptomatic DVT group and 25 (0.42%), 33 (0.56%) and 11 (0.19%) in the no DVT group, respectively. Subjects with an asymptomatic DVT had an almost threefold increase in the risk of all-cause mortality compared with subjects without DVT (hazard ratio=2.87, 95% CI=1.48-5.57, p=0.001). A positive linear trend was observed between greater thrombus burden and mortality during the follow-up (p=0.019).CONCLUSION: Asymptomatic DVT was associated with approximately threefold increased risk of short-term all-cause mortality in patients hospitalized with an acute medical illness within the prior 77 days. A positive linear trend was observed between greater thrombus burden and mortality during the follow-up.

  View details for PubMedID 30419597

• 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

• 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

  View details for Web of Science ID 000528619403200

• Betrixaban Reduced the Occurrence of Major Adverse Cardiovascular Events Among Acute Medically Ill Patients With a History of Myocardial Infarction or Stroke: Insights From the APEX Trial Nafee, T. O., Gibson, C. M., Yee, M. K., Kerneis, M., Travis, R., AlKhalfan, F., Chi, G., Hull, R. D., Hernandez, A. F., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619406178

• Prognostic Value of C-Reactive Protein as Inflammatory Marker for Venous Thromboembolism in Acutely Ill Hospitalized Patients: Analysis From the APEX Trial Chi, G., Gibson, M., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Liu, Y., Kalayci, A., Walia, S., Sharfaei, S., Pitliya, A., Kazmi, H. A., Datta, S., Kahe, F., Ghaffarpasand, E., Jafarizde, M., Yee, M. K., Travis, R. S., AlKhalfan, F., Nafee, T., Kerneis, M., Goldhaber, S. Z. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619406080

• Hypoalbuminemia and Its Association With Venous Thromboembolism in Acutely Ill Hospitalized Patients: Findings From the APEX Trial Chi, G., Gibson, M., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Liu, Y., Walia, S., Sharfaei, S., Pitliya, A., Kazmi, H. A., Datta, S., Kahe, F., Ghaffarpasand, E., Jafarizde, M., Kalayci, A., Nafee, T., Kerneis, M., AlKhalfan, F., Yee, M. K., Travis, R. S., Goldhaber, S. Z. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000528619406228

• 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

  View details for Web of Science ID 000528619400323

• 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

  View details for DOI 10.1016/j.ijcard.2018.06.034

  View details for Web of Science ID 000444609000023

• Cost implications of intraprocedural thrombotic events and bleeding in percutaneous coronary intervention: Results from the CHAMPION PHOENIX ECONOMICS Study CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Tamez, H., Genereux, P., Yeh, R. W., Amin, A. P., Fan, W., White, H. D., Kirtane, A. J., Stone, G. W., Gibson, C., Harrington, R. A., Bhatt, D. L., Pinto, D. S., CHAMPION PHOENIX ECONOMICS 2018; 92 (5): E348–E355

  Abstract

  Despite improvements in percutaneous coronary intervention (PCI), intraprocedural thrombotic events (IPTE) and bleeding complications occur and are prognostically important. These have not been included in prior economic studies.PHOENIX ECONOMICS was a substudy of the CHAMPION PHOENIX trial, evaluating cangrelor during PCI. Hospital bills were reviewed from 1,171 patients enrolled at 22 of 63 US sites. Costs were estimated using standard methods including resource-based accounting, hospital billing data, and the Medicare fee schedule. Bleeding and IPTE, defined as abrupt vessel closure (transient or sustained), new/suspected thrombus, new clot on wire/catheter, no reflow, side-branch occlusion, procedural stent thrombosis or urgent need for CABG were identified. Costs were calculated according to whether a complication occurred and type of event. Multivariate analyses were used to estimate the incremental costs of IPTE and postprocedural events.IPTE occurred in 4.3% and were associated with higher catheterization laboratory and overall index hospitalization costs by $2,734 (95%CI $1,117, $4,351; P = 0.001) and $6,354 (95% CI $4,122, $8,586; P < 0.001), respectively. IPTE were associated with MI (35.4% vs. 3.6%; P < 0.001), out-of-laboratory stent thrombosis (4.2% vs. 0.1%; 0 = 0.005), ischemia driven revascularization (12.5% vs. 0.3%; P < 0.001), but not mortality (2.1% vs. 0.2%; P = 0.12) vs. no procedural thrombotic complication. By comparison, ACUITY minor bleeding increased hospitalization cost by $1,416 (95%CI = 312, $2,519; P = 0.012). ACUITY major bleeding increased cost of hospitalization by $7,894 (95%CI $4,154, $11,635; P < 0.001).IPTE and bleeding complications, though infrequent, are associated with substantial increased cost. These complications should be collected in economic assessments of PCI.

  View details for PubMedID 29726596

• 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

• County-Level Hispanic Ethnic Density and Cardiovascular Disease Mortality. Journal of the American Heart Association Rodriguez, F., Hu, J., Kershaw, K., Hastings, K. G., Lopez, L., Cullen, M. R., Harrington, R. A., Palaniappan, L. P. 2018; 7 (19): e009107

  Abstract

  Background Hispanics are the fastest growing ethnic group in the United States, and little is known about how Hispanic ethnic population density impacts cardiovascular disease ( CVD ) mortality. Methods and Results We examined county-level deaths for Hispanics and non-Hispanic whites from 2003 to 2012 using data from the National Center for Health Statistics' Multiple Cause of Death mortality files. Counties with more than 20 Hispanic deaths (n=715) were included in the analyses. CVD deaths were identified using International Classification of Diseases, Tenth Revision (ICD-10), I00 to I78, and population estimates were calculated using linear interpolation from 2000 and 2010 census data. Multivariate linear regression was used to examine the association of Hispanic ethnic density with Hispanic and non-Hispanic white age-adjusted CVD mortality rates. County-level age-adjusted CVD mortality rates were adjusted for county-level demographic, socioeconomic, and healthcare factors. There were a total of 4769040 deaths among Hispanics (n=382416) and non-Hispanic whites (n=4386624). Overall, cardiovascular age-adjusted mortality rates were higher among non-Hispanic whites compared with Hispanics (244.8 versus 189.0 per 100000). Hispanic density ranged from 1% to 96% in each county. Counties in the highest compared with lowest category of Hispanic density had 60% higher Hispanic mortality (215.3 versus 134.2 per 100000 population). In linear regression models, after adjusting for county-level demographic, socioeconomic, and healthcare factors, increasing Hispanic ethnic density remained strongly associated with mortality for Hispanics but not for non-Hispanic whites. Conclusions CVD mortality is higher in counties with higher Hispanic ethnic density. County-level characteristics do not fully explain the higher CVD mortality among Hispanics in ethnically concentrated counties.

  View details for PubMedID 30371295

• Planning and Conducting the ISCHEMIA Trial: Setting the Record Straight CIRCULATION Maron, D. J., Harrington, R. A., Hochman, J. S. 2018; 138 (14): 1384–86

  View details for DOI 10.1161/CIRCULATIONAHA.118.036904

  View details for Web of Science ID 000446002500002

• Planning and Conducting the ISCHEMIA Trial. Circulation Maron, D. J., Harrington, R. A., Hochman, J. S. 2018; 138 (14): 1384-1386

  View details for DOI 10.1161/CIRCULATIONAHA.118.036904

  View details for PubMedID 30354348

  View details for PubMedCentralID PMC6205757

• County-Level Hispanic Ethnic Density and Cardiovascular Disease Mortality JOURNAL OF THE AMERICAN HEART ASSOCIATION Rodriguez, F., Hu, J., Kershaw, K., Hastings, K. G., Lopez, L., Cullen, M. R., Harrington, R. A., Palaniappan, L. P. 2018; 7 (19)

  View details for DOI 10.1161/JAHA.118.009107

  View details for Web of Science ID 000452823000013

• Variation in post-TAVR antiplatelet therapy utilization and associated outcomes: Insights from the STS/ACC TVT Registry AMERICAN HEART JOURNAL Sherwood, M. W., Vemulapalli, S., Harrison, J., Dai, D., Vora, A. N., Mack, M. J., Holmes, D. R., Rumsfeld, J. S., Cohen, D. J., Thourani, V. H., Kirtane, A., Peterson, E. D. 2018; 204: 9–16

  Abstract

  Dual antiplatelet therapy (DAPT) is recommended following transcatheter aortic valve replacement (TAVR); however, the optimal antiplatelet strategy is undefined, and little is known about practice patterns. We aimed to describe contemporary practice patterns of antiplatelet therapy and their relationship to outcomes post-TAVR.The population was derived from the National Cardiovascular Data Registry, Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry with Center for Medical Services linkage for 1-year outcomes from October 1, 2011 to June 30,2016. The primary outcome measured was DAPT use in patients without anticoagulation. Secondary outcomes included death, major bleeding, myocardial infarction (MI), and stroke at 1 year.Overall, 16,694 patients underwent transfemoral TAVR at 444 hospitals and were discharged without anticoagulation. Among these, 13,546 (81.1%) patients were discharged on DAPT, whereas 3,148 patients (18.9%) were discharged on monotherapy. Patients discharged on DAPT versus monotherapy were similar in age, sex, and most comorbid illnesses but had higher rates of coronary artery disease (64.6% vs 52.3%; P < .01) and peripheral artery disease (25.2% vs 22.3%; P < .01). Hospital prescribing patterns varied significantly (median frequency of DAPT 85.7%, interquartile range 94.1%-74.2%). DAPT (vs monotherapy) patients had a similar mortality risk at 1 year (adjusted hazard ratio 0.92, 95% CI 0.81-1.05), significantly higher risk for major bleeding (1.48, 1.10-1.99), and similar hazard for stroke (1.04, 0.83-1.31) and MI (1.00, 0.72-1.39).In the United States, most patients were discharged on DAPT following TAVR. Practice patterns varied significantly among hospitals. Patients discharged with DAPT had a similar adjusted risk of mortality, stroke, and MI compared to antiplatelet monotherapy, although risk for bleeding was significantly higher. Future investigation is needed to define the optimal antiplatelet therapy for patients undergoing TAVR.

  View details for DOI 10.1016/j.ahj.2018.06.006

  View details for Web of Science ID 000448664400002

  View details for PubMedID 30075326

• Heart Centers for Women: Historical Perspective on Formation and Future Strategies to Reduce Cardiovascular Disease CIRCULATION Lundberg, G. P., Mehta, L. S., Sanghani, R. M., Patel, H. N., Aggarwal, N. R., Aggarwal, N. T., Braun, L. T., Lewis, S. J., Mieres, J. H., Wood, M. J., Harrington, R. A., Volgman, A. S. 2018; 138 (11): 1155–65

  View details for DOI 10.1161/CIRCULATIONAHA.118.035351

  View details for Web of Science ID 000444083800013

• Heart Centers for Women. Circulation Lundberg, G. P., Mehta, L. S., Sanghani, R. M., Patel, H. N., Aggarwal, N. R., Aggarwal, N. T., Braun, L. T., Lewis, S. J., Mieres, J. H., Wood, M. J., Harrington, R. A., Volgman, A. S. 2018; 138 (11): 1155-1165

  Abstract

  Heart Centers for Women (HCW) developed as a response to the need for improved outcomes for women with cardiovascular disease (CVD). From 1984 until 2012, more women died of CVD every single year in comparison with men. Initially, there was limited awareness and sex-specific research regarding mortality or outcomes in women. HCW played an active role in addressing these disparities, provided focused care for women, and contributed to improvements in these gaps. In 2014 and 2015, death from CVD in women had declined below the level of death from CVD in comparison with men. Even though awareness of CVD in women has increased among the public and healthcare providers and both sex- and gender-specific research is currently required in all research trials, not all women have benefitted equally in mortality reduction. New strategies for HCW need to be developed to address these disparities and expand the current HCW model. The HCW care team needs to direct academic curricula on sex- and gender-specific research and care; expand to include other healthcare professionals and other subspecialties; provide new care models; address diversity; and include more male providers.

  View details for DOI 10.1161/CIRCULATIONAHA.118.035351

  View details for PubMedID 30354384

• Healthcare Service Utilization under a New Virtual Primary Care Delivery Model. Telemedicine journal and e-health : the official journal of the American Telemedicine Association Cheung, L., Leung, T. I., Ding, V. Y., Wang, J. X., Norden, J., Desai, M., Harrington, R. A., Desai, S. 2018

  Abstract

  BACKGROUND: Telemedicine holds great promise for changing healthcare delivery. While telemedicine has been used significantly in the direct-to-consumer setting, the use of telemedicine in a preventive primary care setting is not well studied.INTRODUCTION: ClickWell Care (CWC) is the first known implementation of a technology-enabled primary care model. We wanted to quantify healthcare utilization of primary care by patient characteristics and modality of care delivery.MATERIALS AND METHODS: Our study population included those who completed a visit to a CWC clinic between January 1, 2015 and September 30, 2015. We compared patients based on utilization of CWCs in-person and virtual visits across the following domains: patient demographics, distance from clinic, responses to a Health Risk Assessment, and top 10 conditions treated.RESULTS: Thousand two hundred seven patients completed a visit with a CWC physician in 2015. Nearly three-quarters of our patients were ≤40 years and sex was significantly different (p=0.015) between visit cohorts. The greatest representation of men (47%) was seen in the virtual-only cohort. Patients' proximity to the clinic was also significantly different across visit cohorts (p=0.018) with 44% of in-person-only and 34% of virtual-only patients living within 5 miles of Stanford Hospital.DISCUSSION: We found men were more likely to engage in virtual-only care. Young patients are willing to accept virtual care although many prefer to complete an in-person visit first.CONCLUSIONS: Our findings suggest that a "bricks-and-clicks" care model where telemedicine is supported by a brick-and-mortar location may be an effective way to leverage telemedicine to deliver primary care.

  View details for PubMedID 30192211

• Healthcare Service Utilization under a New Virtual Primary Care Delivery Model TELEMEDICINE AND E-HEALTH Cheung, L., Leung, T. I., Ding, V. Y., Wang, J. X., Norden, J., Desai, M., Harrington, R. A., Desai, S. 2018

  View details for DOI 10.1089/tmj.2018.0145

  View details for Web of Science ID 000444051000001

• 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

• Data Sharing-The Time Has (Not Yet?) Come JAMA CARDIOLOGY Yancy, C. W., Harrington, R. A., Bonow, R. O. 2018; 3 (9): 797–98

  View details for PubMedID 29971326

• Association of Anemia with Venous Thromboembolism in Acutely Ill Hospitalized Patients: An APEX Trial Substudy AMERICAN JOURNAL OF MEDICINE Chi, G., Gibson, C., Hernandez, A. F., Hull, R. D., Kazmi, S. A., Younes, A., Walia, S. S., Pitliya, A., Singh, A., Kahe, F., Kalayci, A., Nafee, T., Kerneis, M., AlKhalfan, F., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. 2018; 131 (8): 972.e1–972.e7

  Abstract

  Anemia is a common finding and independent predictor for adverse outcomes in hospitalized patients with medical illness. It remains unclear whether anemia is a risk factor for venous thromboembolism and whether the presence of anemia can refine risk assessment for prediction of venous thromboembolism, thereby adding incremental utility to a validated model.In the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban trial (APEX), 7513 hospitalized medical patients were randomized to receive either betrixaban or standard-of-care enoxaparin for thromboprophylaxis. Baseline hemoglobin concentrations were obtained in 6861 patients, with a follow-up of 77 days. Symptomatic venous thromboembolism events, including symptomatic deep vein thrombosis, pulmonary embolism, and venous thromboembolism-related mortality, were compared between low-hemoglobin and normal-hemoglobin groups (normal range: 12.5-17.0 g/dL for males and 11.0-15.5 g/dL for females). The relationship between anemia and venous thromboembolism events was assessed by fitting a univariable and multivariable logistic regression model composed of thromboprophylaxis and risk factors. Venous thromboembolism risk refinement by hemoglobin measurement was evaluated in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) risk assessment model.Low hemoglobin at baseline was associated with a greater risk of symptomatic venous thromboembolism (relative risk [RR] 1.94 [95% confidence interval, 1.27-2.98]; P = .002), symptomatic deep vein thrombosis (RR 2.29 [1.12-4.68]; P = .019), and nonfatal pulmonary embolism (RR 2.63 [1.22-5.65]; P = .010) but not venous thromboembolism-related mortality (RR 1.47 [0.71-3.04]; P = .30). After adjusting for thromboprophylaxis, history of previous venous thromboembolism, intensive or coronary unit admission, and D-dimer, low hemoglobin (as a categorical or continuous variable) remained associated with an increased likelihood of venous thromboembolism (adjusted odds ratio 1.71 [95% confidence interval, 1.09-2.69]; P = .020). Low hemoglobin also improved risk discrimination and reclassification after inclusion in the IMPROVE model.Anemia was independently associated with a greater risk of symptomatic venous thromboembolism among acutely ill medical patients despite the provision of thromboprophylaxis. Hemoglobin measurement also improved risk stratification by the IMPROVE venous thromboembolism risk score.

  View details for PubMedID 29660351

• Characterization of major and clinically relevant non-major bleeding in the APEX trial Nafee, T., Gibson, C. M., Yee, M. K., Travis, R., Kerneis, M., Chi, G., Alkhalfan, F., Daaboul, Y., Korjian, S., Bandman, O., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. OXFORD UNIV PRESS. 2018: 1264–65

  View details for Web of Science ID 000459824004003

• Performance of a machine learning model vs. IMPROVE score for VTE prediction in acute medically ill patients: insights from the APEX trial Nafee, T., Gibson, C. M., Travis, R., Kerneis, M., Yee, M. K., Alkhalfan, F., Chi, G., Kalayci, A., Mir, M., Alihashemi, M., Hull, R. D., Hernandez, A. F., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. OXFORD UNIV PRESS. 2018: 431

  View details for Web of Science ID 000459824001370

• Betrixaban versus enoxaparin for venous thromboembolism prophylaxis in critically ill patients: findings from the APEX trial Chi, G., Gibson, C. M., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Alkhalfan, F., Kalayci, A., Kerneis, M., Nafee, T., Goldhaber, S. Z., APEX Investigators OXFORD UNIV PRESS. 2018: 868

  View details for Web of Science ID 000459824002741

• Association of low hemoglobin with venous thromboembolism in acutely ill hospitalized medical patients: findings from the APEX trial Chi, G., Gibson, C. M., Hernandez, A. F., Hull, R. D., Kalayci, A., Kerneis, M., Alkhalfan, F., Nafee, T., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. OXFORD UNIV PRESS. 2018: 318

  View details for Web of Science ID 000459824001024

• Betrixaban compared to enoxaparin among obese acute medically ill subjects: an APEX trial subgroup analysis Yee, M. K., Gibson, C. M., Nafee, T., Kerneis, M., Travis, R., Alkhalfan, F., Chi, G., Datta, S., Jafarizade, M., Ghaffarpasand, E., Hull, R. D., Hernandez, A. F., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. OXFORD UNIV PRESS. 2018: 7–8

  View details for Web of Science ID 000459824000020

• Asymptomatic deep vein thrombosis in acutely ill medical patients: insights from the APEX trial Kalayci, A., Gibson, C. M., Chi, G., Yee, M., Korjian, S., Datta, S., Nafee, T., Gurin, M., Haroian, N., Hull, R. D., Hernandez, A. F., Cohen, A. T., Harrington, R. A., Goldhaber, S. Z. OXFORD UNIV PRESS. 2018: 31–32

  View details for Web of Science ID 000459824000087

• Men Versus Women. Circulation. Cardiovascular interventions Rodriguez, F., Harrington, R. A. 2018; 11 (8): e007016

  View details for DOI 10.1161/CIRCINTERVENTIONS.118.007016

  View details for PubMedID 30354789

• Evaluating Health Technology Through Pragmatic Trials Novel Approaches to Generate High-Quality Evidence JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Peterson, E. D., Harrington, R. A. 2018; 320 (2): 137–38

  View details for PubMedID 29998322

• 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

• International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design AMERICAN HEART JOURNAL Maron, D. J., Hochman, J. S., O'Brien, S. M., Reynolds, H. R., Boden, W. E., Stone, G. W., Bangalore, S., Spertus, J. A., Mark, D. B., Alexander, K. P., Shaw, L., Berger, J. S., Ferguson, T., Williams, D. O., Harrington, R. A., Rosenberg, Y., ISCHEMIA Trial Res Grp 2018; 201: 124-135

  View details for DOI 10.1016/j.ahj.2018.04.011

  View details for Web of Science ID 000436562100017

• Using Digital Health Technology to Better Generate Evidence and Deliver Evidence-Based Care JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Sharma, A., Harrington, R. A., McClellan, M. B., Turakhia, M. P., Eapen, Z. J., Steinhubl, S., Mault, J. R., Majmudar, M. D., Roessig, L., Chandross, K. J., Green, E. M., Patel, B., Hamer, A., Olgin, J., Rumsfeld, J. S., Roe, M. T., Peterson, E. D. 2018; 71 (23): 2680–90

  Abstract

  As we enter the information age of health care, digital health technologies offer significant opportunities to optimize both clinical care delivery and clinical research. Despite their potential, the use of such information technologies in clinical care and research faces major data quality, privacy, and regulatory concerns. In hopes of addressing both the promise and challenges facing digital health technologies in the transformation of health care, we convened a think tank meeting with academic, industry, and regulatory representatives in December 2016 in Washington, DC. In this paper, we summarize the proceedings of the think tank meeting and aim to delineate a framework for appropriately using digital health technologies in healthcare delivery and research.

  View details for PubMedID 29880129

• Mobile Health Advances in Physical Activity, Fitness, and Atrial Fibrillation Moving Hearts JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY McConnell, M. V., Turakhia, M. P., Harrington, R. A., King, A. C., Ashley, E. A. 2018; 71 (23): 2691–2701

  Abstract

  The growing recognition that "health" takes place outside of the hospital and clinic, plus recent advances in mobile and wearable devices, have propelled the field of mobile health (mHealth). Cardiovascular disease and prevention are major opportunities for mHealth, as mobile devices can monitor key physiological signals (e.g., physical activity, heart rate and rhythm) for promoting healthy behaviors, detecting disease, and aid in ongoing care. In this review, the authors provide an update on cardiovascular mHealth by highlighting recent progress and challenges with mobile and wearable devices for assessing and promoting physical activity and fitness, and for monitoring heart rate and rhythm for the detection and management of atrial fibrillation.

  View details for PubMedID 29880130

• 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

• Rediscovering the Orbit of Percutaneous Coronary Intervention After ORBITA CIRCULATION Bhatt, D. L., Gersh, B. J., Steg, P., Harrington, R. A., Windecker, S. 2018; 137 (23): 2427–29

  View details for PubMedID 29669787

• LP(A) AND CARDIOVASCULAR OUTCOMES: AN ANALYSIS FROM THE ODYSSEY OUTCOMES TRIAL Bittner, V., Szarek, M., Aylward, P. E., Bhatt, D. L., Diaz, R., Fras, Z., Goodman, S., Hanotin, C., Harrington, R., Jukema, J. W., Loizeau, V., Moriarty, P., Moryusef, A., Pordy, R., Roe, M. T., Sinnaeve, P., White, H. D., Zahger, D., Zeiher, A., Steg, P. G., Schwartz, G. ELSEVIER IRELAND LTD. 2018: 24–25

  View details for DOI 10.1016/j.atherosclerosissup.2018.04.072

  View details for Web of Science ID 000434628100070

• 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

• The TREAT Trial-Moving ST-Elevation Myocardial Infarction Care Forward, With More to Do JAMA CARDIOLOGY Yancy, C. W., Harrington, R. A. 2018; 3 (5): 399–400

  View details for PubMedID 29525820

• The efficacy of early versus delayed P2Y(12) inhibition in percutaneous coronary intervention for ST-elevation myocardial infarction: a systematic review and meta-analysis EUROINTERVENTION Bellemain-Appaix, A., Begue, C., Bhatt, D. L., Ducci, K., Harrington, R. A., Roe, M., Wiviott, S. D., Cucherat, M., Silvain, J., Collet, J., Bernasconi, F., Montalescot, G., ACTION Study Grp 2018; 14 (1): 78–85

  Abstract

  The aim of this meta-analysis was to compare the benefit of "early" vs. "delayed" P2Y12 inhibition in patients undergoing percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI).We conducted a meta-analysis including seven randomised controlled trials (RCTs) which compared early vs. delayed P2Y12inhibition in STEMI patients scheduled for PCI, providing data on major adverse cardiac events (MACE), all-cause death, and major bleeding. The primary endpoint was MACE. Secondary endpoints included stent thrombosis and the use of GP IIb/IIIa inhibitors (GPI). All endpoints were analysed at the shortest follow-up available. A total of 9,648 patients were included ("early"=4,792, "delayed"=4,856). "Early" P2Y12 inhibition was associated with a significant reduction in MACE rate (OR 0.73, 95% CI: 0.61-0.88, p=0.0008), myocardial infarction (OR 0.71, 95% CI: 0.57-0.90, p=0.004), bail-out GPI use (OR 0.87, 95% CI: 0.75-1.00, p=0.04) and improved coronary reperfusion before PCI (OR for Thrombolysis In Myocardial Infarction [TIMI] flow grade 2-3=1.12, 95% CI: 1.00-1.26, p=0.04). Major bleeding was not increased (OR 0.87, 95% CI: 0.62-1.21, p=0.41).A strategy of early effective P2Y12 inhibition in PCI of STEMI appears to improve coronary reperfusion before PCI, and reduce MACE, MI and bail-out GPI use without increase of major bleeding.

  View details for DOI 10.4244/EIJ-D-17-00852

  View details for Web of Science ID 000432908900013

  View details for PubMedID 29469030

• International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial: Rationale and design. American heart journal ISCHEMIA Trial Research Group, Maron, D. J., Hochman, J. S., O'Brien, S. M., Reynolds, H. R., Boden, W. E., Stone, G. W., Bangalore, S., Spertus, J. A., Mark, D. B., Alexander, K. P., Shaw, L., Berger, J. S., Ferguson, T. B., Williams, D. O., Harrington, R. A., Rosenberg, Y. 2018; 201: 124–35

  Abstract

  BACKGROUND: Prior trials comparing a strategy of optimal medical therapy with or without revascularization have not shown that revascularization reduces cardiovascular events in patients with stable ischemic heart disease (SIHD). However, those trials only included participants in whom coronary anatomy was known prior to randomization and did not include sufficient numbers of participants with significant ischemia. It remains unknown whether a routine invasive approach offers incremental value over a conservative approach with catheterization reserved for failure of medical therapy in patients with moderate or severe ischemia.METHODS: The ISCHEMIA trial is a National Heart, Lung, and Blood Institute supported trial, designed to compare an initial invasive or conservative treatment strategy for managing SIHD patients with moderate or severe ischemia on stress testing. Five thousand one-hundred seventy-nine participants have been randomized. Key exclusion criteria included estimated glomerular filtration rate (eGFR) <30 mL/min, recent myocardial infarction (MI), left ventricular ejection fraction <35%, left main stenosis >50%, or unacceptable angina at baseline. Most enrolled participants with normal renal function first underwent blinded coronary computed tomography angiography (CCTA) to exclude those with left main coronary artery disease (CAD) and without obstructive CAD. All randomized participants receive secondary prevention that includes lifestyle advice and pharmacologic interventions referred to as optimal medical therapy (OMT). Participants randomized to the invasive strategy underwent routine cardiac catheterization followed by revascularization with percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery, when feasible, as selected by the local Heart Team to achieve optimal revascularization. Participants randomized to the conservative strategy undergo cardiac catheterization only for failure of OMT. The primary endpoint is a composite of cardiovascular (CV) death, nonfatal myocardial infarction (MI), hospitalization for unstable angina, hospitalization for heart failure, or resuscitated cardiac arrest. Assuming the primary endpoint will occur in 16% of the conservative group within 4 years, estimated power exceeds 80% to detect an 18.5% reduction in the primary endpoint. Major secondary endpoints include the composite of CV death and nonfatal MI, net clinical benefit (primary and secondary endpoints combined with stroke), angina-related symptoms and disease-specific quality of life, as well as a cost-effectiveness assessment in North American participants. Ancillary studies of patients with advanced chronic kidney disease and those with documented ischemia and non-obstructive coronary artery disease are being conducted concurrently.CONCLUSIONS: ISCHEMIA will provide new scientific evidence regarding whether an invasive management strategy improves clinical outcomes when added to optimal medical therapy in patients with SIHD and moderate or severe ischemia.

  View details for PubMedID 29778671

• 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)

  View details for DOI 10.1161/CIRCINTERVENTIONS.117.005635

  View details for Web of Science ID 000435566700001

• 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

  View details for DOI 10.1177/2048872618761621

  View details for Web of Science ID 000430330900014

• Symptomatic event reduction with extended-duration betrixaban in acute medically ill hospitalized patients AMERICAN HEART JOURNAL Gibson, C., Nafee, T., Yee, M. K., Chi, G., Korjian, S., Daaboul, Y., AlKhalfan, F., Kerneis, M., Goldhaber, S. Z., Hull, R., Hernandez, A. F., Cohen, A. T., Harrington, R. A. 2018; 198: 84–90

  Abstract

  Approximately 15%-30% of patients in trials of medical thromboprophylaxis will have missing compression ultrasound (CUS) data. The goal of the present analysis was to perform analyses to minimize missing data.The APEX trial randomized 7,513 acutely medically ill hospitalized patients to thromboprophylaxis with either betrixaban for 35-42 days or enoxaparin for 6-14 days. A modified intent-to-treat (mITT) analysis was performed and included all subjects administered study drug, irrespective of CUS performance, and an analysis of symptomatic events which do not require performance of a CUS (symptomatic deep vein thrombosis, nonfatal pulmonary embolism, and venous thromboembolism (VTE)-related mortality).In the mITT population, betrixaban significantly reduced the primary end point (which included both symptomatic and CUS events) (165 [4.4%] vs 223 [6.0%]; relative risk = 0.75; 95% CI 0.61-0.91; P = .003; absolute risk reduction [ARR] = 1.6%; number needed to treat [NNT] = 63). Betrixaban also reduced symptomatic VTE through day 42 (35 [1.28%] vs 54 [1.88%], hazard ratio [HR] = 0.65; 95% CI 0.42-0.99; P = .044; ARR = 0.6%; NNT=167) as well as through day 77 (37 [1.02%] vs 67 [1.89%]; HR= 0.55; 95% CI 0.37-0.83; P = .003; ARR = 0.87%; NNT=115) as well as the individual end point of nonfatal pulmonary embolism (9 [0.25%] vs 20 [0.55%]; HR= 0.45; 95% CI 0.21-0.99; P = .041; ARR = 0.30%; NNT=334). On an "as-treated" basis, 80 mg of betrixaban reduced VTE-related mortality through day 77 (10 [0.34%] vs. 22 [0.79%]; HR=0.46; 95% CI 0.22-0.96; P = .035; ARR = 0.45%; NNT=223).In an mITT analysis of all patients administered study drug, extended-duration betrixaban reduced the primary end point as well as symptomatic events. In an as-treated analysis, 80 mg of betrixaban reduced VTE-related death.

  View details for PubMedID 29653652

• 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

  View details for DOI 10.1016/S0735-1097(18)30570-9

  View details for Web of Science ID 000429659700030

• Apixaban following acute coronary syndromes in patients with prior stroke: Insights from the APPRAISE-2 trial AMERICAN HEART JOURNAL Sherwood, M. W., Lopes, R. D., Sun, J., Liaw, D., Harrington, R. A., Wallentin, L., Laskowitz, D. T., James, S. K., Goodman, S. G., Darius, H., Lewis, B. S., Gibson, C., Pieper, K. S., Alexander, J. H. 2018; 197: 1–8

  Abstract

  Patients with prior stroke are at greater risk for recurrent cardiovascular events post-acute coronary syndromes (ACS) and may have a different risk/benefit profile with antithrombotic therapy than patients without prior stroke.We studied 7391 patients with ACS from APPRAISE-2, stratified by the presence or absence of prior stroke. Baseline characteristics and outcomes of cardiovascular death, myocardial infarction (MI), or stroke were compared between groups. Interactions between prior stroke, treatment assignment (apixaban vs placebo), and outcomes were tested before and after multivariable adjustment with Cox proportional hazards models.A total of 902 patients (12%) had prior stroke. Those with prior stroke were older (69 vs 67 years), had more hypertension (91% vs 77%), peripheral vascular disease (22% vs18%), and impaired renal function (38% vs 30%) but less diabetes (44% vs 48%) than those without prior stroke. Patients with prior stroke vs no prior stroke had higher unadjusted rates of cardiovascular death (4.8% vs 4.0%), MI (11.2% vs 7.1%), and ischemic stroke (3.2% vs 0.9%). Patients with prior stroke assigned to apixaban had similar rates of the composite of cardiovascular death, MI, or stroke compared with those assigned to placebo (HR 1.39; 95% CI 0.92-2.08). Patients without prior stroke assigned to apixaban had similar rates of cardiovascular death, MI, or ischemic stroke compared with those assigned to placebo (HR 0.87; 95% CI 0.73-1.04; P-interaction=.041). Median follow-up was 240 days.Patients with prior stroke are at higher risk for recurrent cardiovascular events post-ACS and had a differential risk/benefit profile with oral anticoagulation.

  View details for PubMedID 29447769

• 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

• 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

• Improving Heart Failure Therapeutics Development in the United States The Heart Failure Collaboratory JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY O'Connor, C. M., Psotka, M. A., Fiuzat, M., Lindenfeld, J., Abraham, W. T., Bristow, M. R., Canos, D., Harrington, R. A., Hillebrenner, M., Jessup, M., Malik, F. I., Solomon, S. D., Stockbridge, N., Tcheng, J. E., Unger, E. F., Whellan, D. J., Zuckerman, B., Califf, R. M. 2018; 71 (4): 443–53

  Abstract

  The current heart failure clinical trial environment is strained by increasing complexity and cost, regulatory requirements, competing demands on stakeholders, implementation challenges, and decreasing patient and investigator participation. To begin the process of developing potentially effective strategies and tactics, stakeholders including patients; investigators; academic leaders; pharmaceutical and device industry representatives; society representatives; third-party payers; and government representatives from the U.S. Food and Drug Administration, National Institutes of Health, and Centers for Medicare and Medicaid Services convened in March of 2017. This paper summarizes the discussions, outlines current challenges and actionable opportunities, and makes targeted recommendations to achieve the goals of improving efficiency in clinical trials and speeding the development of effective heart failure therapies, including the formation of an organized Heart Failure Collaboratory.

  View details for PubMedID 29389362

• Canakinumab for Atherosclerotic Disease NEW ENGLAND JOURNAL OF MEDICINE Nerlekar, N., Harper, R. W. 2018; 378 (2): 199

  View details for PubMedID 29320648

• Canakinumab for Atherosclerotic Disease REPLY NEW ENGLAND JOURNAL OF MEDICINE Harrington, R. A. 2018; 378 (2): 199–200

  View details for Web of Science ID 000419971600024

• What This Computer Needs Is a Physician Humanism and Artificial Intelligence JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Verghese, A., Shah, N. H., Harrington, R. 2018; 319 (1): 19–20

  View details for PubMedID 29261830

• Extended-Duration Betrixaban Reduces the Risk of Rehospitalization Associated With Venous Thromboembolism Among Acutely Ill Hospitalized Medical Patients Findings From the APEX Trial (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban Trial) CIRCULATION Chi, G., Yee, M. K., Amin, A. N., Goldhaber, S. Z., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Gibson, C. 2018; 137 (1): 91–94

  View details for PubMedID 29279341

• Increased benefit of betrixaban among patients with a history of venous thromboembolism: a post-hoc analysis of the APEX trial JOURNAL OF THROMBOSIS AND THROMBOLYSIS Yee, M. K., Nafee, T., Daaboul, Y., Korjian, S., AlKhalfan, F., Kerneis, M., Wiest, C., Goldhaber, S. Z., Hernandez, A. F., Hull, R. D., Cohen, A. T., Harrington, R. A., Gibson, C. 2018; 45 (1): 1–8

  Abstract

  Hospitalized acute medically ill patients with a history of venous thromboembolism (VTE) are at increased risk for recurrent VTE. We characterized the efficacy and safety of betrixaban for prevention of recurrent VTE in these high risk patients. The APEX trial randomized 7513 acutely ill hospitalized medical patients at risk for developing VTE to receive either betrixaban for 35-42 days or enoxaparin for 10 ± 4 days to prevent VTE. This exploratory post-hoc analysis assessed the efficacy and safety of betrixaban versus enoxaparin among subjects with and without prior VTE. Time-to-multiple symptomatic VTE events was also calculated. Approximately 8% of subjects in both arms had prior VTE, which was associated with a fourfold increase in adjusted risk of VTE [MV OR 4.03, 95% CI 3.06-5.30, p < 0.001]. Betrixaban reduced VTE compared with enoxaparin among subjects with prior VTE [32 (10.4%) vs. 55 (18.9%), RR 0.57, 95% CI 0.38-0.86, p = 0.006, ARR 8.5%, NNT 12] and without prior VTE [133 (3.9%) vs. 168 (4.9%), RR 0.79, 95% CI 0.64-0.99, p = 0.042, ARR 1.0%, NNT 100] (interaction p > 0.05). Additionally, four subjects in the enoxaparin arm and one subject in the betrixaban arm experienced a recurrent VTE. Compared with enoxaparin, betrixaban use was associated with reduction of recurrent VTE events through the active treatment period [36 vs. 57, HR 0.63, 95% CI 0.41-0.97, p = 0.045] and through the end of study [38 vs. 71, HR 0.54, 95% CI 0.36-0.81, p = 0.004]. Prior VTE is associated with a fourfold increase in the risk of VTE among hospitalized medically ill patients. Only 12 such patients would need to be treated with betrixaban versus enoxaparin to prevent an additional VTE endpoint. Betrixaban reduced not only the first but also all recurrent VTE events in a time-to-any-event analysis.http://www.clinicaltrials.gov , Unique identifier: NCT01583218.

  View details for PubMedID 29188425

• Promise and Perils of Big Data and Artificial Intelligence in Clinical Medicine and Biomedical Research. Circulation research Rodriguez, F. n., Scheinker, D. n., Harrington, R. A. 2018; 123 (12): 1282–84

  View details for PubMedID 30566055

• Sex Disparities in Authorship Order of Cardiology Scientific Publications. Circulation. Cardiovascular quality and outcomes Ouyang, D. n., Sing, D. n., Shah, S. n., Hu, J. n., Duvernoy, C. n., Harrington, R. A., Rodriguez, F. n. 2018; 11 (12): e005040

  Abstract

  Despite advances in the representation of women in medical training, women continue to be underrepresented in cardiology, academic medicine, and more specifically, in senior positions within academic medicine. Identifying disparities in research productivity and acknowledgment can highlight barriers to female representation in academic cardiology leadership, as well as in academic promotion.This bibliometric analysis included all authors of original research articles between 1980 and 2017 from 3 high-impact cardiology journals ( Journal of the American College of Cardiology, Circulation, and European Heart Journal). We identified 71 345 unique authors of 55 085 primary research articles during our study period. Female authors accounted for 33.1% of all authors; however, they represented only 26.7% of first authors and 19.7% of senior authors. Looking at the most prolific authors within this time period, female authors were not well represented, accounting for only 5% of the top 100 authors. Articles with a female senior author had more female middle authors than articles with a male senior author (mean 1.41 versus 0.97, P<0.001) and were more likely to have a female first author (0.37 versus 0.18, P<0.001). There was an increased representation of female authors as first and senior authors compared with the total number of articles with female authors over time ( P<0.001 for trend); however, female senior authorship rates continued to lag first authorship rates.Using a large database of published manuscripts, we found that female representation in published cardiology research has increased over the past 4 decades. However, women continue to be not well represented as first authors, senior authors, and in the number of publications. When women were senior authors, they published more articles with female first authors and had more female authors. In addition to recruiting more women into the field of cardiology, additional work is needed to identify and address barriers to academic advancement for female physician-scientists.

  View details for PubMedID 30562072

• Anti-thrombotic options for secondary prevention in patients with chronic atherosclerotic vascular disease: what does COMPASS add? European heart journal Fox, K. A., Eikelboom, J. W., Anand, S. S., Bhatt, D. L., Bosch, J. n., Connolly, S. J., Harrington, R. A., Steg, P. G., Yusuf, S. n. 2018

  View details for PubMedID 29945212

• Association of D-dimer Levels with Clinical Event Rates and the Efficacy of Betrixaban versus Enoxaparin in the APEX Trial. TH open : companion journal to thrombosis and haemostasis Gibson, C. M., Jennings, L. K., Chi, G. n., Yee, M. K., Halaby, R. n., Nafee, T. n., AlKhalfan, F. n., Kerneis, M. n., Korjian, S. n., Daaboul, Y. n., Goldhaber, S. Z., Hull, R. D., Hernandez, A. F., Cohen, A. T., Harrington, R. A. 2018; 2 (1): e16–e24

  Abstract

  Background  Elevated D-dimer concentrations are associated with an increased risk of venous thromboembolism (VTE). However, they may also provide prognostic value. The present analysis sought to study the association of D-dimer levels with VTE event rates and the efficacy of betrixaban versus enoxaparin in the APEX trial. Methods  Hospitalized acutely medically ill subjects ( n  = 7,513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35-42 days) or standard dose subcutaneous enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. D-dimer was assessed using a central core laboratory measurement. Results  For every 0.25 µg/mL increase in D-dimer concentration, there was a 2% increase in the relative risk of experiencing the primary efficacy endpoint (asymptomatic deep vein thrombosis [DVT], symptomatic DVT, nonfatal pulmonary embolism, or VTE-related death) in both the betrixaban ( p  < 0.001) and enoxaparin ( p  < 0.001) treatment arms. Among D-dimer-positive (≥ 2 × upper limit of normal; corresponding to ≥ 1.00 µg/mL) subjects, extended-duration betrixaban reduced the risk of experiencing the primary efficacy outcome (5.4% [ n  = 124] vs. 7.6% [ n  = 170]; odds ratio = 0.69; 95% confidence interval: 0.55-0.88; absolute risk reduction = 2.2%, number needed to treat = 46, p  = 0.003). There was no interaction between D-dimer and the treatment effect ( pint  = 0.53). Conclusion  Extended-duration betrixaban was superior to standard-duration enoxaparin, irrespective of D-dimer level at baseline. To prevent one VTE event, 46 D-dimer-positive patients would need to be treated with betrixaban.

  View details for DOI 10.1055/s-0037-1615288

  View details for PubMedID 31249924

  View details for PubMedCentralID PMC6524856

• 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

• Resuscitating Cardiovascular Drug Development JAMA CARDIOLOGY Helmy, K., Harrington, R. A., Kocher, B. 2017; 2 (12): 1295–96

  View details for DOI 10.1001/jamacardio.2017.3756

  View details for Web of Science ID 000418465600002

  View details for PubMedID 29117283

• Nativity Status and Cardiovascular Disease Mortality Among Hispanic Adults JOURNAL OF THE AMERICAN HEART ASSOCIATION Rodriguez, F., Hastings, K. G., Hu, J., Lopez, L., Cullen, M., Harrington, R. A., Palaniappan, L. P. 2017; 6 (12)

  View details for DOI 10.1161/JAHA.117.007207

  View details for Web of Science ID 000418951100050

• Thrombus Burden of Deep Vein Thrombosis and Its Association with Thromboprophylaxis and D-Dimer Measurement: Insights from the APEX Trial THROMBOSIS AND HAEMOSTASIS Chi, G., Goldhaber, S. Z., Hull, R. D., Hernandez, A. F., Kerneis, M., Al Khalfan, F., Cohen, A. T., Harrington, R. A., Gibson, C. 2017; 117 (12): 2389–95

  Abstract

  Background The aim of this study was to evaluate the effect of betrixaban on the occurrence of deep vein thrombosis (DVT) and also the extent of thrombus and to assess the association of baseline D-dimer with subsequent thrombus burden. Methods In the APEX trial (ClinicalTrials.gov: NCT01583218), 7,513 acutely ill hospitalized medical patients were randomly assigned to extended-duration betrixaban (35–42 days) or enoxaparin (10 ± 4 days). D-dimer concentration was measured at baseline, and mandatory lower-extremity compression ultrasonography (CUS) was performed at 35 to 42 days. The thrombus burden of DVT was assessed by the number of non-compressible vascular segments in six target proximal veins and compared between treatment groups and D-dimer categories (≥2 × upper limit of normal [ULN] versus <2 × ULN). Results Compared with enoxaparin, extended-duration betrixaban reduced the DVT risk at 35 to 42 days (any-dose: relative risk [RR] = 0.76 [95% confidence interval: 0.61–0.94]; p = 0.013; full-dose: RR = 0.70 [0.55–0.90]; p = 0.005). Patients who received betrixaban were more likely to have a lower thrombus burden (p = 0.012 for any-dose and p = 0.001 for full-dose). Elevated D-dimer at baseline was independently associated with a 2.12-fold increased risk of developing DVT (p < 0.001). A greater thrombus burden was also observed in those with D-dimer ≥ 2 × ULN compared with <2 × ULN (p < 0.0001). Conclusion Extended-duration betrixaban reduced the number of venous segments with thrombosis at 35 to 42 days compared with enoxaparin. A positive D-dimer was associated with a greater extent of thrombus burden among acutely ill medical patients who developed DVT despite receiving thromboprophylaxis.

  View details for PubMedID 29212126

• Cost-effectiveness of PCSK9 Inhibitors Proof in the Modeling JAMA CARDIOLOGY Bonow, R. O., Harrington, R. A., Yancy, C. W. 2017; 2 (12): 1298–99

  View details for PubMedID 29049827

• Competing risk analysis in a large cardiovascular clinical trial: An APEX substudy PHARMACEUTICAL STATISTICS Arbetter, D. F., Jain, P., Yee, M. K., Michalak, N., Hernandez, A. F., Hull, R. D., Goldhaber, S. Z., Harrington, R. A., Gold, A., Cohen, A. T., Gibson, C. 2017; 16 (6): 445–50

  Abstract

  Competing risk methods are time-to-event analyses that account for fatal and/or nonfatal events that may potentially alter or prevent a subject from experiencing the primary endpoint. Competing risk methods may provide a more accurate and less biased estimate of the incidence of an outcome but are rarely applied in cardiology trials. APEX investigated the efficacy of extended-duration betrixaban versus standard-duration enoxaparin to prevent a composite of symptomatic deep-vein thrombosis (proximal or distal), nonfatal pulmonary embolism, or venous thromboembolism (VTE)-related death in acute medically ill patients (n = 7513). The aim of the current analysis was to determine the efficacy of betrixaban vs standard-duration enoxaparin accounting for non-VTE-related deaths using the Fine and Gray method for competing risks. The proportion of non-VTE-related death was similar in both the betrixaban (133, 3.6%) and enoxaparin (136, 3.7%) arms, P = .85. Both the traditional Kaplan-Meier method and the Fine and Gray method accounting for non-VTE-related death as a competing risk showed equal reduction of VTE events when comparing betrixaban to enoxaparin (HR/SHR = 0.65, 95% 0.42-0.99, P = 0.046). Due to the similar proportion of non-VTE-related deaths in both treatment arms and the use of a univariate model, the Fine and Gray method provided identical results to the traditional Cox model. Using the Fine and Gray method in addition to the traditional Cox proportional hazards method can indicate whether the presence of a competing risk, which is dependent of the outcome, altered the risk estimate.

  View details for PubMedID 28840662

• 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

• 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

• Genetic variability in PAR4 platelet response in relation to bleeding and ischemic outcomes: a genetic substudy of the TRACER trial Tricoci, P., Neely, M., Whitley, M., Edelstein, L., Simon, L. M., Shaw, C., Moliterno, D. J., Armstrong, P. W., White, H. D., de Werf, F., Jennings, L. K., Wallentin, L., Harrington, R. A., Mahaffey, K. W., Bray, P. F. OXFORD UNIV PRESS. 2017: 646

  View details for Web of Science ID 000440509302477

• The efficacy of early versus delayed P2Y12 inhibition in percutaneous coronary intervention for ST-elevation myocardial infarction: a systematic review and meta-analysis Bellemain-Appaix, A., Begue, C., Bhatt, D. L., Ducci, K., Harrington, R. A., Roe, M. T., Wiviott, S. D., Cucherat, M., Silvain, J., Collet, J. P., Bernasconi, F., Montalescot, G., ACTION Study Grp OXFORD UNIV PRESS. 2017: 1263-1264

  View details for Web of Science ID 000440509305079

• N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with stroke among hospitalized medical patients: an APEX trial substudy Chi, G., Nafee, T., Korjian, S., Daaboul, Y., Harrington, R. A., Goldhaber, S. Z., Hull, R. D., Gold, A., Cohen, A. T., Gibson, C. M. OXFORD UNIV PRESS. 2017: 886

  View details for Web of Science ID 000440509303433

• D-dimer concentration is associated with increased risk for VTE and greater absolute benefit of extended prophylaxis with betrixaban in acutely III medical patients: insights from the APEX trial Gibson, C. M., Arbetter, D. F., Jain, P., Halaby, R., Chi, G., Nafee, T., Korjian, S., Daaboul, Y., Harrington, R. A., Goldhaber, S. Z., Hull, R. D., Gold, A., Cohen, A. T. OXFORD UNIV PRESS. 2017: 326

  View details for Web of Science ID 000440509301251

• Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis Chi, G., Nafee, T., Korjian, S., Daaboul, Y., Harrington, R. A., Goldhaber, S. Z., Hull, R. D., Gold, A., Cohen, A. T., Gibson, C. M. OXFORD UNIV PRESS. 2017: 1204–5

  View details for Web of Science ID 000440509304695

• Extended duration betrixaban in acutely ill medical patients is associated with reduction in fatal or irreversible ischemic or bleeding events compared with standard dose enoxaparin: an APEX substudy Gibson, C. M., Arbetter, D. F., Jain, P., Halaby, R., Chi, G., Nafee, T., Korjian, S., Daaboul, Y., Goldhaber, S. Z., Hull, R. D., Gold, A., Hernandez, A. F., Cohen, A. T., Harrington, R. A. OXFORD UNIV PRESS. 2017: 382

  View details for Web of Science ID 000440509301432

• History of venous thromboembolism is associated with higher risk for recurrent venous thromboembolism: insights from the APEX trial Yee, M. K., Chi, G., Nafee, T., Korjian, S., Daaboul, Y., Harrington, R. A., Goldhaber, S. Z., Hull, R. D., Gold, A., Cohen, A. T., Gibson, C. M. OXFORD UNIV PRESS. 2017: 1205

  View details for Web of Science ID 000440509304696

• Comparison of Fatal or Irreversible Events With Extended-Duration Betrixaban Versus Standard Dose Enoxaparin in Acutely III Medical Patients: An APEX Trial Substudy JOURNAL OF THE AMERICAN HEART ASSOCIATION Gibson, C., Korjian, S., Chi, G., Daaboul, Y., Jain, P., Arbetter, D., Goldhaber, S. Z., Hull, R., Hernandez, A. F., Lopes, R. D., Gold, A., Cohen, A. T., Harrington, R. A., APEX Investigators 2017; 6 (7)

  Abstract

  Extended-duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm.This was a post hoc analysis of the APEX trial-a multicenter, double-blind, randomized controlled trial comparing extended-duration betrixaban versus standard-of-care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time-to-first event analysis. In patients with positive D-dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [P=0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [P=0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [P=0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [P=0.002]).Among hospitalized medically ill patients, extended-duration betrixaban demonstrated an ≈30% reduction in fatal or irreversible ischemic or bleeding events compared with standard-duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin.URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01583218.

  View details for PubMedID 28698258

• 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

• 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

• 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

• Use of Antiplatelet Therapy/DAPT for Post-PCI Patients Undergoing Noncardiac Surgery JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Banerjee, S., Angiolillo, D. J., Boden, W. E., Murphy, J. G., Khalili, H., Hasan, A. A., Harrington, R. A., Rao, S. V. 2017; 69 (14): 1861-1870

  Abstract

  Dual antiplatelet therapy (DAPT) is prescribed to millions of patients worldwide following coronary stenting. DAPT is indicated to lower the risk of ischemic events, such as myocardial infarction, including stent thrombosis, ischemic stroke, or death from cardiovascular causes. A significant number of these patients undergo noncardiac surgery and may require DAPT interruption. This poses a significant clinical dilemma because DAPT interruption exposes patients to the potential risk of stent thrombosis, perioperative myocardial infarction, or both. Conversely, continuing DAPT may be associated with excess bleeding complications. Observational data in this area are conflicting, and there are no randomized clinical trials to guide practitioner decision making. On the basis of predominantly consensus recommendations, various strategies for managing DAPT during the perioperative period have been proposed. This review presents 3 commonly encountered clinical scenarios that lead into an evidence-based discussion of practical strategies for managing perioperative antiplatelet therapy in patients following percutaneous coronary intervention.

  View details for DOI 10.1016/j.jacc.2017.02.012

  View details for Web of Science ID 000398065100012

  View details for PubMedID 28385315

• 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

• New Delivery Model for Rising-Risk Patients: The Forgotten Lot? Telemedicine journal and e-health Cheung, L., Norden, J., Harrington, R. A., Desai, S. A. 2017

  Abstract

  Shared-risk models encourage providers to engage young patients early. Telemedicine may be well suited for younger, healthier patients although it is unclear how best to incorporate telemedicine into routine clinical care.We test the assumptions surrounding the use of telemedicine, younger and rising-risk patients, and primary care in ClickWell Care (CWC), a care model developed at our institution for our own accountable care organization.CWC's team of physicians and wellness coaches work together to provide comprehensive primary care through in-person, phone, and video visits. This study examines usage of the clinic over its initial year in operation.1,464 unique patients conducted a total of 3,907 visits. 2,294 (58.7%) visits were completed virtually (1,382 [35.4%] by phone and 912 [23.3%] by video). Patients were more inclined to see the physician in-person for a new visit (1,065 visits [70.5%] vs. 362 [24%] phone and 83 [6%] video) and more likely to see the physician virtually for a return visit (606 [43.2%] phone and 249 [17.7%] video vs. 548 [39.1%] in-person), a statistically significant difference (X(2) = 306.7, p < 0.00001).This new care model successfully engaged a younger population of patients. However, our data suggest young patients may not be inclined to establish care with a primary care physician virtually and, in fact, choose an initial in-person touch point, although many are willing to conduct return visits virtually. This new model of care could have a large impact on how care is delivered to low- and rising-risk patients.

  View details for DOI 10.1089/tmj.2016.0181

  View details for PubMedID 28375821

• Fasting glucose, NT-proBNP, treatment with eptifibatide, and outcomes in non-ST-segment elevation acute coronary syndromes: An analysis from EARLY ACS INTERNATIONAL JOURNAL OF CARDIOLOGY Farhan, S., Clare, R. M., Jarai, R., Giugliano, R. P., Lokhnygina, Y., Harrington, R. A., Newby, K., Huber, K. 2017; 232: 264–70

  Abstract

  Higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels have been linked to a more favorable glucometabolic profile. Little is known about the interaction of NT-proBNP and fasting glucose in non-ST-segment elevation acute coronary syndrome (NSTE ACS).Fasting glucose and NT-proBNP were measured in 2240 patients enrolled in the EARLY ACS trial. Multivariable Cox models were used to assess associations between fasting glucose and NT-proBNP and a 96-hour composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout; 30-day death or MI; and 1-year mortality.In adjusted Cox models, neither NT-proBNP nor fasting glucose was associated with the 96-hour endpoint (p=0.95 and p=0.87). NT-proBNP was associated with 30-day death or MI (hazard ratio [HR] 1.11, 95% confidence interval [CI] 1.02-1.22, p=0.02) and 1-year mortality (HR 1.63, 95% CI 1.42-1.89, p<0.0001), but fasting glucose was associated only with 1-year death (HR 1.53, 95% CI 1.08-2.16, p=0.02). NT-proBNP×glucose interaction terms were non-significant in all models. As fasting glucose levels increased, the risk of 96-hour and 30-day endpoints increased among patients who received early eptifibatide but not delayed, provisional use (pint=0.035 and pint=0.029). Higher NT-proBNP levels were associated with greater 30-day death or MI among patients who received early eptifibatide but not delayed, provisional use (pint=0.045).NT-proBNP and fasting glucose concentrations were associated with intermediate-term ischemic outcomes and may identify differential response to treatment with eptifibatide. CLINICALTRIALS.NCT00089895.

  View details for PubMedID 28089149

• Potent P2Y(12) Inhibitors in Men Versus Women A Collaborative Meta-Analysis of Randomized Trials JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Lau, E. S., Braunwald, E., Murphy, S. A., Wiviott, S. D., Bonaca, M. P., Husted, S., James, S. K., Wallentin, L., Clemmensen, P., Roe, M. T., Ohman, E. M., Harrington, R. A., Mega, J. L., Bhatt, D. L., Sabatine, M. S., O'Donoghue, M. L. 2017; 69 (12): 1549-1559

  Abstract

  Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain.The study investigated the efficacy and safety of the potent P2Y12 inhibitors in patients with coronary artery disease.A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y12 inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial.Potent P2Y12 inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p interaction = 0.93). Treatment reduced the risk of myocardial infarction by 13% in women (HR: 0.87; 95% CI: 0.78 to 0.96) and 16% in men (HR: 0.84; 95% CI: 0.77 to 0.91; p interaction = 0.65), and the risk of stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p interaction = 0.85). Directional consistency was seen for cardiovascular death in women (HR: 0.87; 95% CI: 0.76 to 1.01) and men (HR: 0.85; 95% CI: 0.77 to 0.95; p interaction = 0.86). The potent P2Y12 inhibitors increased major bleeding in women (HR: 1.28; 95% CI: 0.87 to 1.88) and men (HR: 1.52; 95% CI: 1.12 to 2.07; p interaction = 0.62).In randomized trials, the efficacy and safety of the potent P2Y12 inhibitors were comparable between men and women. Given these data, sex should not influence patient selection for the administration of potent P2Y12 inhibitors.

  View details for DOI 10.1016/j.jacc.2017.01.028

  View details for Web of Science ID 000396730200005

• Inhibitors in Men Versus Women: A Collaborative Meta-Analysis of Randomized Trials. Journal of the American College of Cardiology Lau, E. S., Braunwald, E., Murphy, S. A., Wiviott, S. D., Bonaca, M. P., Husted, S., James, S. K., Wallentin, L., Clemmensen, P., Roe, M. T., Ohman, E. M., Harrington, R. A., Mega, J. L., Bhatt, D. L., Sabatine, M. S., O'Donoghue, M. L. 2017; 69 (12): 1549-1559

  Abstract

  Sex-specific differences in response to antiplatelet therapies have been described. Whether women and men derive comparable benefit from intensification of antiplatelet therapy remains uncertain.The study investigated the efficacy and safety of the potent P2Y12 inhibitors in patients with coronary artery disease.A collaborative sex-specific meta-analysis was conducted of phase III or IV randomized trials of potent P2Y12 inhibitors, including prasugrel, ticagrelor, and intravenous cangrelor. Seven trials were included that enrolled a total of 24,494 women and 63,346 men. Major adverse cardiovascular events (MACE) were defined as the primary endpoint for each trial.Potent P2Y12 inhibitors significantly reduced the risk of MACE by 14% in women (hazard ratio [HR]: 0.86; 95% confidence interval [CI]: 0.78 to 0.94) and by 15% in men (HR: 0.85; 95% CI: 0.80 to 0.90; p interaction = 0.93). Treatment reduced the risk of myocardial infarction by 13% in women (HR: 0.87; 95% CI: 0.78 to 0.96) and 16% in men (HR: 0.84; 95% CI: 0.77 to 0.91; p interaction = 0.65), and the risk of stent thrombosis by 51% in women (HR: 0.49; 95% CI: 0.37 to 0.65) and 41% in men (HR: 0.59; 95% CI: 0.42 to 0.84; p interaction = 0.85). Directional consistency was seen for cardiovascular death in women (HR: 0.87; 95% CI: 0.76 to 1.01) and men (HR: 0.85; 95% CI: 0.77 to 0.95; p interaction = 0.86). The potent P2Y12 inhibitors increased major bleeding in women (HR: 1.28; 95% CI: 0.87 to 1.88) and men (HR: 1.52; 95% CI: 1.12 to 2.07; p interaction = 0.62).In randomized trials, the efficacy and safety of the potent P2Y12 inhibitors were comparable between men and women. Given these data, sex should not influence patient selection for the administration of potent P2Y12 inhibitors.

  View details for DOI 10.1016/j.jacc.2017.01.028

  View details for PubMedID 28335837

• NATIVITY STATUS AND CARDIOVASCULAR DISEASE MORTALITY AMONG HISPANICS Rodriguez, F., Hastings, K., Hu, J., Harrington, R., Palaniappan, L. ELSEVIER SCIENCE INC. 2017: 1753

  View details for Web of Science ID 000397342302475

• 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

  View details for Web of Science ID 000397342300008

• 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

  View details for Web of Science ID 000397342300113

• 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

  View details for Web of Science ID 000397342302067

• 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

• The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial. American heart journal Gibson, C. M., Halaby, R., Korjian, S., Daaboul, Y., Arbetter, D. F., Yee, M. K., Goldhaber, S. Z., Hull, R., Hernandez, A. F., Lu, S., Bandman, O., Leeds, J. M., Gold, A., Harrington, R. A., Cohen, A. T. 2017; 185: 93-100

  Abstract

  The APEX trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among hospitalized, acutely ill medical patients. The 80-mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein inhibitor.This analysis assessed the pharmacokinetics, efficacy, and safety of full- (80 mg) and reduced-dose (40 mg) betrixaban relative to enoxaparin in the APEX trial.The median concentration of betrixaban among subjects administered the 80-mg dose was higher than that of the 40-mg dose (19 ng/mL vs 11 ng/mL, P<.001). In the primary analysis cohort 1 (d-dimer ≥2× upper limit of normal), the primary efficacy outcome (asymptomatic proximal deep vein thrombosis, symptomatic proximal or distal deep vein thrombosis, symptomatic nonfatal pulmonary embolism, or venous thromboembolism-related death) was significantly reduced among subjects treated with 80 mg of extended-duration betrixaban versus enoxaparin (6.27% [95/1516] vs 8.39% [130/1549], relative risk reduction=0.26 [0.04-0.42], P=.023), and similarly in the entire primary efficacy outcome population (4.87% [122/2506] vs 7.06% [181/2562], relative risk reduction=0.30 [0.13-0.44], P=.001). There was no difference in the primary outcome for subjects treated with 40 mg betrixaban vs enoxaparin across cohorts. In addition, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin.The 80-mg betrixaban dose achieves higher plasma concentrations than the 40-mg dose and, in contrast to the 40-mg dose, is associated with improved efficacy across all cohorts relative to standard-dose enoxaparin without an excess risk of major bleeding in the management of medically ill subjects.

  View details for DOI 10.1016/j.ahj.2016.12.004

  View details for PubMedID 28267480

• Extended-Duration Betrixaban Reduces the Risk of Stroke Versus Standard-Dose Enoxaparin Among Hospitalized Medically Ill Patients: An APEX Trial Substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Circulation Gibson, C. M., Chi, G., Halaby, R., Korjian, S., Daaboul, Y., Jain, P., Arbetter, D., Goldhaber, S. Z., Hull, R., Hernandez, A. F., Gold, A., Bandman, O., Harrington, R. A., Cohen, A. T. 2017; 135 (7): 648-655

  Abstract

  Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban).Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35-42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee.The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32-0.96; P=0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30-0.94; P=0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26-0.90; P=0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24-0.87; P=0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin.Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01583218.

  View details for DOI 10.1161/CIRCULATIONAHA.116.025427

  View details for PubMedID 27881569

• Biomarkers and Coronary Lesions Predict Outcomes after Revascularization in Non-ST-Elevation Acute Coronary Syndrome CLINICAL CHEMISTRY Lindholm, D., James, S. K., Bertilsson, M., Becker, R. C., Cannon, C. P., Giannitsis, E., Harrington, R. A., Himmelmann, A., Kontny, F., Siegbahn, A., Steg, P. G., Storey, R. F., Velders, M. A., Weaver, W. D., Wallentin, L. 2017; 63 (2): 573-584

  Abstract

  Risk stratification in non-ST-elevation acute coronary syndrome (NSTE-ACS) is currently mainly based on clinical characteristics. With routine invasive management, angiography findings and biomarkers are available and may improve prognostication. We aimed to assess if adding biomarkers [high-sensitivity cardiac troponin T (cTnT-hs), N-terminal probrain-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15)] and extent of coronary artery disease (CAD) might improve prognostication in revascularized patients with NSTE-ACS.In the PLATO (Platelet Inhibition and Patient Outcomes) trial, 5174 NSTE-ACS patients underwent initial angiography and revascularization and had cTnT-hs, NT-proBNP, and GDF-15 measured. Cox models were developed adding extent of CAD and biomarker levels to established clinical risk variables for the composite of cardiovascular death (CVD)/spontaneous myocardial infarction (MI), and CVD alone. Models were compared using c-statistic and net reclassification improvement (NRI).For the composite end point and CVD, prognostication improved when adding extent of CAD, NT-proBNP, and GDF-15 to clinical variables (c-statistic 0.685 and 0.805, respectively, for full model vs 0.649 and 0.760 for clinical model). cTnT-hs did not contribute to prognostication. In the full model (clinical variables, extent of CAD, all biomarkers), hazard ratios (95% CI) per standard deviation increase were for cTnT-hs 0.93(0.81-1.05), NT-proBNP 1.32(1.13-1.53), GDF-15 1.20(1.07-1.36) for the composite end point, driven by prediction of CVD by NT-proBNP and GDF-15. For spontaneous MI, there was an association with NT-proBNP or GDF-15, but not with cTnT-hs.In revascularized patients with NSTE-ACS, the extent of CAD and concentrations of NT-proBNP and GDF-15 independently improve prognostication of CVD/spontaneous MI and CVD alone. This information may be useful for selection of patients who might benefit from more intense and/or prolonged antithrombotic treatment. ClinicalTrials.gov Identifier: NCT00391872.

  View details for DOI 10.1373/clinchem.2016.261271

  View details for Web of Science ID 000393360000020

  View details for PubMedID 27932413

• 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

• Disaggregation of Cause-Specific Cardiovascular Disease Mortality Among Hispanic Subgroups. JAMA cardiology Rodriguez, F., Hastings, K. G., Boothroyd, D. B., Echeverria, S., Lopez, L., Cullen, M., Harrington, R. A., Palaniappan, L. P. 2017

  Abstract

  Hispanics are the largest minority group in the United States and face a disproportionate burden of risk factors for cardiovascular disease (CVD) and low socioeconomic position. However, Hispanics paradoxically experience lower all-cause mortality rates compared with their non-Hispanic white (NHW) counterparts. This phenomenon has been largely observed in Mexicans, and whether this holds true for other Hispanic subgroups or whether these favorable trends persist over time remains unknown.To disaggregate a decade of national CVD mortality data for the 3 largest US Hispanic subgroups.Deaths from CVD for the 3 largest US Hispanic subgroups-Mexicans, Puerto Ricans, and Cubans-compared with NHWs were extracted from the US National Center for Health Statistics mortality records using the underlying cause of death based on coding from the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (I00-II69). Mortality data were evaluated from January 1, 2003, to December 31, 2012. Population estimates were calculated using linear interpolation from the 2000 and 2010 US Census reports. Data were analyzed from November 2015 to July 2016.Mortality due to CVD.Participants included 688 074 Mexican, 163 335 Puerto Rican, 130 397 Cuban, and 19 357 160 NHW individuals (49.0% men and 51.0% women; mean [SD] age, 75 [15] years). At the time of CVD death, Mexicans (age, 67 [18] years) and Puerto Ricans (age, 68 [17] years) were younger compared with NHWs (age, 76 [15] years). Mortality rates due to CVD decreased from a mean of 414.2 per 100 000 in 2003 to 303.3 per 100 000 in 2012. Estimated decreases in mortality rate for CVD from 2003 to 2012 ranged from 85 per 100 000 for all Hispanic women to 144 per 100 000 for Cuban men, but rate differences between groups vary substantially, with Puerto Ricans exhibiting similar mortality patterns to NHWs, and Mexicans experiencing lower mortality. Puerto Ricans experienced higher mortality rates for ischemic and hypertensive heart disease compared with other subgroups, whereas Mexicans experienced higher rates of cerebrovascular disease deaths.Significant differences in CVD mortality rates and changes over time were found among the 3 largest Hispanic subgroups in the United States. Findings suggest that the current aggregate classification of Hispanics masks heterogeneity in CVD mortality reporting, leading to an incomplete understanding of health risks and outcomes in this population.

  View details for DOI 10.1001/jamacardio.2016.4653

  View details for PubMedID 28114655

• 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

• The Systematic Evaluation of Identifying the Infarct Related Artery Utilizing Cardiac Magnetic Resonance in Patients Presenting with ST-Elevation Myocardial Infarction PLOS ONE Hamo, C. E., Klem, I., Rao, S. V., Songco, V., Najjar, S., Lakatta, E. G., Raman, S. V., Harrington, R. A., Heitner, J. F. 2017; 12 (1)

  Abstract

  Identification of the infarct-related artery (IRA) in patients with STEMI using coronary angiography (CA) is often based on the ECG and can be challenging in patients with severe multi-vessel disease. The current study aimed to determine how often percutaneous intervention (PCI) is performed in a coronary artery different from the artery supplying the territory of acute infarction on cardiac magnetic resonance imaging (CMR).We evaluated 113 patients from the Reduction of infarct Expansion and Ventricular remodeling with Erythropoetin After Large myocardial infarction (REVEAL) trial, who underwent CMR within 4±2 days of revascularization. Blinded reviewers interpreted CA to determine the IRA and CMR to determine the location of infarction on a 17-segment model. In patients with multiple infarcts on CMR, acuity was determined with T2-weighted imaging and/or evidence of microvascular obstruction.A total of 5 (4%) patients were found to have a mismatch between the IRA identified on CMR and CA. In 4/5 cases, there were multiple infarcts noted on CMR. Thirteen patients (11.5%) had multiple infarcts in separate territories on CMR with 4 patients (3.5%) having multiple acute infarcts and 9 patients (8%) having both acute and chronic infarcts.In this select population of patients, the identification of the IRA by CA was incorrect in 4% of patients presenting with STEMI. Four patients with a mismatch had an acute infarction in more than one coronary artery territory on CMR. The role of CMR in patients presenting with STEMI with multi-vessel disease on CA deserves further investigation.

  View details for DOI 10.1371/journal.pone.0169108

  View details for Web of Science ID 000391641500054

  View details for PubMedID 28060863

  View details for PubMedCentralID PMC5218460

• Nativity Status and Cardiovascular Disease Mortality Among Hispanic Adults. Journal of the American Heart Association Rodriguez, F. n., Hastings, K. G., Hu, J. n., Lopez, L. n., Cullen, M. n., Harrington, R. A., Palaniappan, L. P. 2017; 6 (12)

  Abstract

  Hispanic persons represent a heterogeneous and growing population of any race with origins in Mexico, the Caribbean, Central America, South America, or other Spanish-speaking countries. Previous studies have documented variation in cardiovascular risk and outcomes among Hispanic subgroups. Few studies have investigated whether these patterns vary by nativity status among Hispanic subgroups.We used the National Center for Health Statistics mortality file to compare deaths of Hispanic (n=1 258 229) and non-Hispanic white (n=18 149 774) adults (aged ≥25 years) from 2003 to 2012. We identified all deaths related to cardiovascular disease (CVD) and categorized them by subtype (all CVD, ischemic, or cerebrovascular) using the underlying cause of death (International Classification of Diseases, 10th Revision codes I00-I78, I20-I25, and I60-I69, respectively). Population estimates were calculated using linear interpolation from the 2000 and 2010 US censuses. CVD accounted for 31% of all deaths among Hispanic adults. Race/ethnicity and nativity status were recorded on death certificates by the funeral director using state guidelines. Nativity status was defined as foreign versus US born; 58% of Hispanic decedents were foreign born. Overall, Hispanic adults had lower age-adjusted CVD mortality rates than non-Hispanic white adults (296 versus 385 per 100 000). Foreign-born Cubans, Mexicans, and Puerto Ricans had higher CVD mortality than their US-born counterparts (rate ratio: 2.64 [95% confidence interval, 2.46-2.81], 1.17 [95% confidence interval, 1.15-1.21], and 1.91 [95% confidence interval, 1.83-1.99], respectively).Mortality rates for total cardiovascular, ischemic, and cerebrovascular disease are higher among foreign- than US-born Hispanic adults. These findings suggest the importance of disaggregating CVD mortality by disease subtype, Hispanic subgroup, and nativity status.

  View details for PubMedID 29237590

• The Academic Medical System: Reinvention to Survive the Revolution in Health Care. Journal of the American College of Cardiology Konstam, M. A., Hill, J. A., Kovacs, R. J., Harrington, R. A., Arrighi, J. A., Khera, A. n. 2017; 69 (10): 1305–12

  Abstract

  Academic medical centers (AMCs) are presently facing enormous challenges arising from a prospective decline in government funding for research and education, shifting payment models emphasizing efficiency and value, and increasing competition. Left unabated, these challenges will drive many AMCs to de-emphasize or forsake their core missions in an effort to survive. Stemming from a symposium held at the 2015 Scientific Sessions of the American College of Cardiology titled, "The Academic Medical Center of the Future," we propose a series of changes, including internal restructuring, system-wide partnership, and novel approaches to support research and education, that are designed to better position AMCs to compete and face their growing challenges in a manner that preserves their essential missions. In aggregate, these changes will facilitate establishing the academic medical system of the future.

  View details for PubMedID 28279297

• Bleeding and Mortality With Dual Antiplatelet Therapy: The Rashomon Effect. Journal of the American College of Cardiology Rao, S. V., Harrington, R. A. 2017; 69 (16): 2023–25

  View details for PubMedID 28427577

• When academic research organizations and clinical research organizations disagree: Processes to minimize discrepancies prior to unblinding of randomized trials. American heart journal Gibson, C. M., Goldhaber, S. Z., Cohen, A. T., Nafee, T. n., Hernandez, A. F., Hull, R. n., Korjian, S. n., Daaboul, Y. n., Chi, G. n., Yee, M. n., Harrington, R. A. 2017; 189: 1–8

  View details for PubMedID 28625365

• Unreliable Observations from a Confounded Analysis of a Skewed Database. The American journal of medicine Steg, P. G., Harrington, R. A., Himmelmann, A. n., James, S. K., Pieper, K. S., Wallentin, L. n. 2017; 130 (8): e355–e356

  View details for PubMedID 28734377

• Associations between tooth loss and prognostic biomarkers and the risk for cardiovascular events in patients with stable coronary heart disease. International journal of cardiology Vedin, O. n., Hagström, E. n., Östlund, O. n., Avezum, A. n., Budaj, A. n., Flather, M. D., Harrington, R. A., Koenig, W. n., Soffer, J. n., Siegbahn, A. n., Steg, P. G., Stewart, R. A., Wallentin, L. n., White, H. D., Held, C. n. 2017; 245: 271–76

  Abstract

  Underlying mechanisms behind the hypothesized relationship between periodontal disease (PD) and coronary heart disease (CHD) have been insufficiently explored. We evaluated associations between self-reported tooth loss- a marker of PD- and prognostic biomarkers in 15,456 (97%) patients with stable CHD in the global STABILITY trial.Baseline blood samples were obtained and patients reported their number of teeth according to the following tooth loss levels: "26-32 (All)" [lowest level], "20-25", "15-19", "1-14", and "No Teeth" [highest level]. Linear and Cox regression models assessed associations between tooth loss levels and biomarker levels, and the relationship between tooth loss levels and outcomes, respectively. After multivariable adjustment, the relative biomarker increase between the highest and the lowest tooth loss level was: high-sensitivity C-reactive protein 1.21 (95% confidence interval, 1.14-1.29), interleukin 6 1.14 (1.10-1.18), lipoprotein-associated phospholipase A2 activity 1.05 (1.03-1.06), growth differentiation factor 15 1.11 (1.08-1.14), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) 1.18 (1.11-1.25). No association was detected for high-sensitivity troponin T 1.02 (0.98-1.05). Some attenuation of the relationship between tooth loss and outcomes resulted from the addition of biomarkers to the multivariable analysis, of which NT-proBNP had the biggest impact.A graded and independent association between tooth loss and several prognostic biomarkers was observed, suggesting that tooth loss and its underlying mechanisms may be involved in multiple pathophysiological pathways also implicated in the development and prognosis of CHD. The association between tooth loss and cardiovascular death and stroke persisted despite comprehensive adjustment including prognostic biomarkers.www.clinicaltrials.gov; NCT00799903.

  View details for PubMedID 28735759

• N-terminal pro-B-type natriuretic peptide and the risk of stroke among patients hospitalized with acute heart failure: an APEX trial substudy. Journal of thrombosis and thrombolysis Chi, G. n., Januzzi, J. L., Korjian, S. n., Daaboul, Y. n., Goldhaber, S. Z., Hernandez, A. F., Hull, R. D., Gold, A. n., Cohen, A. T., Harrington, R. A., Gibson, C. M. 2017; 44 (4): 457–65

  Abstract

  Among patients hospitalized with acute heart failure (HF), the prognostic value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in short-term stroke prediction remains unclear.In the APEX trial, 7513 patients hospitalized for an acute medical illness were randomized to receive either extended-duration betrixaban (80 mg once daily for 35-42 days) or standard-of-care enoxaparin (40 mg once daily for 10 ± 4 days) for venous thromboprophylaxis. Baseline NT-proBNP concentrations were obtained in 3261 patients admitted for HF. Stroke events were adjudicated by an independent clinical events committee blinded to thromboprophylaxis allocation. The association of NT-proBNP level and other risk factors and biomarkers with stroke was assessed at 77 days after randomization.In univariate analysis, the risk of stroke at 77 days was associated with baseline NT-proBNP (HR 3.63 [95% CI 1.47-8.99]; P = 0.005), D-dimer (HR 2.73 [95% CI 1.03-7.20]; P = 0.043), and hsCRP (HR 3.03 [95% CI 1.36-6.75]; P = 0.007). In multivariable analysis adjusting for hsCRP and thromboprophylaxis, NT-proBNP was associated with the risk of stroke (adjusted HR 3.64 [95% CI 1.35-9.83]; P = 0.011). The interaction of NT-proBNP with the treatment effect was not significant (Pint = 0.30).Baseline NT-proBNP concentration was associated with short-term stroke among patients hospitalized with acute HF. Stroke risk assessment models should consider incorporation of NT-proBNP measurement.

  View details for PubMedID 28905172

• Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis. Journal of thrombosis and haemostasis : JTH Chi, G. n., Goldhaber, S. Z., Kittelson, J. M., Turpie, A. G., Hernandez, A. F., Hull, R. D., Gold, A. n., Curnutte, J. T., Cohen, A. T., Harrington, R. A., Gibson, C. M. 2017; 15 (10): 1913–22

  Abstract

  Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis.Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients.

  View details for PubMedID 28762617

• Targeting Inflammation in Coronary Artery Disease. The New England journal of medicine Harrington, R. A. 2017; 377 (12): 1197–98

  View details for PubMedID 28844177

• Author Relationships With Industry: Policies and Procedures for Authors and Editors of JAMA Cardiology. JAMA cardiology Yancy, C. W., Harrington, R. A., Bonow, R. O. 2017; 2 (11): 1181–82

  View details for PubMedID 28973086

• Feasibility of Obtaining Measures of Lifestyle From a Smartphone App: The MyHeart Counts Cardiovascular Health Study. JAMA cardiology McConnell, M. V., Shcherbina, A., Pavlovic, A., Homburger, J. R., Goldfeder, R. L., Waggot, D., Cho, M. K., Rosenberger, M. E., Haskell, W. L., Myers, J., Champagne, M. A., Mignot, E., Landray, M., Tarassenko, L., Harrington, R. A., Yeung, A. C., Ashley, E. A. 2017; 2 (1): 67-76

  Abstract

  Studies have established the importance of physical activity and fitness, yet limited data exist on the associations between objective, real-world physical activity patterns, fitness, sleep, and cardiovascular health.To assess the feasibility of obtaining measures of physical activity, fitness, and sleep from smartphones and to gain insights into activity patterns associated with life satisfaction and self-reported disease.The MyHeart Counts smartphone app was made available in March 2015, and prospective participants downloaded the free app between March and October 2015. In this smartphone-based study of cardiovascular health, participants recorded physical activity, filled out health questionnaires, and completed a 6-minute walk test. The app was available to download within the United States.The feasibility of consent and data collection entirely on a smartphone, the use of machine learning to cluster participants, and the associations between activity patterns, life satisfaction, and self-reported disease.From the launch to the time of the data freeze for this study (March to October 2015), the number of individuals (self-selected) who consented to participate was 48 968, representing all 50 states and the District of Columbia. Their median age was 36 years (interquartile range, 27-50 years), and 82.2% (30 338 male, 6556 female, 10 other, and 3115 unknown) were male. In total, 40 017 (81.7% of those who consented) uploaded data. Among those who consented, 20 345 individuals (41.5%) completed 4 of the 7 days of motion data collection, and 4552 individuals (9.3%) completed all 7 days. Among those who consented, 40 017 (81.7%) filled out some portion of the questionnaires, and 4990 (10.2%) completed the 6-minute walk test, made available only at the end of 7 days. The Heart Age Questionnaire, also available after 7 days, required entering lipid values and age 40 to 79 years (among 17 245 individuals, 43.1% of participants). Consequently, 1334 (2.7%) of those who consented completed all fields needed to compute heart age and a 10-year risk score. Physical activity was detected for a mean (SD) of 14.5% (8.0%) of individuals' total recorded time. Physical activity patterns were identified by cluster analysis. A pattern of lower overall activity but more frequent transitions between active and inactive states was associated with equivalent self-reported cardiovascular disease as a pattern of higher overall activity with fewer transitions. Individuals' perception of their activity and risk bore little relation to sensor-estimated activity or calculated cardiovascular risk.A smartphone-based study of cardiovascular health is feasible, and improvements in participant diversity and engagement will maximize yield from consented participants. Large-scale, real-world assessment of physical activity, fitness, and sleep using mobile devices may be a useful addition to future population health studies.

  View details for DOI 10.1001/jamacardio.2016.4395

  View details for PubMedID 27973671

• The IMPROVEDD VTE Risk Score: Incorporation of D-Dimer into the IMPROVE Score to Improve Venous Thromboembolism Risk Stratification. TH open : companion journal to thrombosis and haemostasis Gibson, C. M., Spyropoulos, A. C., Cohen, A. T., Hull, R. D., Goldhaber, S. Z., Yusen, R. D., Hernandez, A. F., Korjian, S. n., Daaboul, Y. n., Gold, A. n., Harrington, R. A., Chi, G. n. 2017; 1 (1): e56–e65

  Abstract

  Background  The IMPROVE score is a validated venous thromboembolism (VTE) assessment tool to risk stratify hospitalized, medically ill patients based on clinical variables. It was hypothesized that addition of D-dimer measurement to derive a new IMPROVEDD score would improve identification of at risk of VTE. Methods  The association of the IMPROVE score and D-dimer ≥ 2 × the upper limit of normal (ULN) with the risk of symptomatic deep vein thrombosis, nonfatal pulmonary embolism, or VTE-related death was evaluated in 7,441 hospitalized, medically ill patients randomized in the APEX trial. Based on the Cox regression analysis, the IMPROVEDD score was derived by adding two points to the IMPROVE score if the D-dimer was ≥ 2 × ULN. Results  Baseline D-dimer was independently associated with symptomatic VTE through 77 days (adjusted HR: 2.22 [95% CI: 1.38-1.58], p  = 0.001). Incorporation of D-dimer into the IMPROVE score improved VTE risk discrimination (ΔAUC: 0.06 [95% CI: 0.02-0.09], p  = 0.0006) and reclassification (continuous NRI: 0.34 [95% CI: 0.17-0.51], p  = 0.001; categorical NRI: 0.13 [95% CI: 0.03-0.23], p  = 0.0159). Patients with an IMPROVEDD score of ≥2 had a greater VTE risk compared with those with an IMPROVEDD score of 0 to 1 (HR: 2.73 [95% CI: 1.52-4.90], p  = 0.0007). Conclusion  Incorporation of D-dimer into the IMPROVE VTE risk assessment model further improves risk stratification in hospitalized, medically ill patients who received thromboprophylaxis. An IMPROVEDD score of ≥2 identifies hospitalized, medically ill patients with a heightened risk for VTE through 77 days.

  View details for DOI 10.1055/s-0037-1603929

  View details for PubMedID 31249911

  View details for PubMedCentralID PMC6524839

• 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

• The Safety and Tolerability of CSL112, a Reconstituted, Infusible, Human APOA-I, After Acute Myocardial Infarction - The APOA-I Event Reduction in Ischemic Syndromes I (AEGIS-I) Trial Gibson, C., Korjian, S., Tricoci, P., Daaboul, Y., Alexander, J. H., Steg, P. G., Lincoff, A. M., Kastelein, J. J., Mehran, R., D'Andrea, D., Merkely, B., Zarebinski, M., Ophius, T., Harrington, R. A. LIPPINCOTT WILLIAMS & WILKINS. 2016: E706

  View details for Web of Science ID 000390560100011

• Betrixaban in Acutely Ill Medical Patients Reply NEW ENGLAND JOURNAL OF MEDICINE Cohen, A. T., Harrington, R. A., Gibson, C. 2016; 375 (24)

  View details for Web of Science ID 000390036500032

• Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I) CIRCULATION Gibson, C. M., Korjian, S., Tricoci, P., Daaboul, Y., Yee, M., Jain, P., Alexander, J. H., Steg, P. G., Lincoff, A. M., Kastelein, J. J., Mehran, R., D'Andrea, D. M., Deckelbaum, L. I., Merkely, B., Zarebinski, M., Ophuis, T. O., Harrington, R. A. 2016; 134 (24): 1918-?

  Abstract

  Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction.The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy).A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar.Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial.URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.

  View details for DOI 10.1161/CIRCULATIONAHA.116.025687

  View details for Web of Science ID 000390558300003

  View details for PubMedCentralID PMC5147036

• Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I). Circulation Michael Gibson, C., Korjian, S., Tricoci, P., Daaboul, Y., Yee, M., Jain, P., Alexander, J. H., Steg, P. G., Lincoff, A. M., Kastelein, J. J., Mehran, R., D'Andrea, D. M., Deckelbaum, L. I., Merkely, B., Zarebinski, M., Ophuis, T. O., Harrington, R. A. 2016; 134 (24): 1918-1930

  Abstract

  Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein-mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction.The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy).A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar.Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial.URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.

  View details for DOI 10.1161/CIRCULATIONAHA.116.025687

  View details for PubMedID 27881559

  View details for PubMedCentralID PMC5147036

• The Safety and Efficacy of Full Versus Reduced Dose Betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) Trial Cohen, A. T., Halaby, R., Korjian, S., Daaboul, Y., Szlosek, D., Arbetter, D., Goldhaber, S. Z., Hull, R., Hernandez, A., Gold, A., Wiens, B., Harrington, R., Gibson, C. AMER SOC HEMATOLOGY. 2016

  View details for DOI 10.1182/blood.V128.22.3824.3824

  View details for Web of Science ID 000394452302017

• Levosimendan in patients with left ventricular systolic dysfunction undergoing cardiac surgery on cardiopulmonary bypass: Rationale and study design of the Levosimendan in Patients with Left Ventricular Systolic Dysfunction Undergoing Cardiac Surgery Requiring Cardiopulmonary Bypass (LEVO-CTS) trial AMERICAN HEART JOURNAL Mehta, R. H., van Diepen, S., Meza, J., Bokesch, P., Leimberger, J. D., Tourt-Uhlig, S., Swartz, M., Parrotta, J., Jankowich, R., Hay, D., Harrison, R. W., Fremes, S., Goodman, S. G., Luber, J., Toller, W., Heringlake, M., Anstrom, K. J., Levy, J. H., Harrington, R. A., Alexander, J. H. 2016; 182: 62-71

  Abstract

  Low cardiac output syndrome is associated with increased mortality and occurs in 3% to 14% of patients undergoing cardiac surgery on cardiopulmonary bypass (CPB). Levosimendan, a novel calcium sensitizer and KATP channel activator with inotropic, vasodilatory, and cardioprotective properties, has shown significant promise in reducing the incidence of low cardiac output syndrome and related adverse outcomes in patients undergoing cardiac surgery on CPB.LEVO-CTS is a phase 3 randomized, controlled, multicenter study evaluating the efficacy, safety, and cost-effectiveness of levosimendan in reducing morbidity and mortality in high-risk patients with reduced left ventricular ejection fraction (≤35%) undergoing cardiac surgery on CPB. Patients will be randomly assigned to receive either intravenous levosimendan (0.2 μg kg(-1) min(-1) for the first hour followed by 0.1 μg/kg for 23hours) or matching placebo initiated within 8hours of surgery. The co-primary end points are (1) the composite of death or renal replacement therapy through day 30 or perioperative myocardial infarction, or mechanical assist device use through day 5 (quad end point tested at α<.01), and (2) the composite of death through postoperative day 30 or mechanical assist device use through day 5 (dual end point tested at α<.04). Safety end points include new atrial fibrillation and death through 90days. In addition, an economic analysis will address the cost-effectiveness of levosimendan compared with placebo in high-risk patients undergoing cardiac surgery on CPB. Approximately 880 patients will be enrolled at approximately 60 sites in the United States and Canada between July 2014 and September 2016, with results anticipated in January 2017.LEVO-CTS, a large randomized multicenter clinical trial, will evaluate the efficacy, safety, and cost-effectiveness of levosimendan in reducing adverse outcomes in high-risk patients undergoing cardiac surgery on CPB.ClinicalTrials.gov (NCT02025621).

  View details for DOI 10.1016/j.ahj.2016.09.001

  View details for PubMedID 27914501

• The State of Medical Student Performance Evaluations: Improved Transparency or Continued Obfuscation? Academic medicine Hom, J., Richman, I., Hall, P., Ahuja, N., Harman, S., Harrington, R., Witteles, R. 2016; 91 (11): 1534-1539

  Abstract

  The medical student performance evaluation (MSPE), a letter summarizing academic performance, is included in each medical student's residency application. The extent to which medical schools follow Association of American Medical Colleges (AAMC) recommendations for comparative and transparent data is not known. This study's purpose was to describe the content, interpretability, and transparency of MSPEs.This cross-sectional study examined one randomly selected MSPE from every Liaison Committee on Medical Education-accredited U.S. medical school from which at least one student applied to the Stanford University internal medical residency program during the 2013-2014 application cycle. The authors described the number, distribution, and range of key words and clerkship grades used in the MSPEs and the proportions of schools with missing or incomplete data.The sample included MSPEs from 117 (89%) of 131 medical schools. Sixty schools (51%) provided complete information about clerkship grade and key word distributions. Ninety-six (82%) provided comparative data for clerkship grades, and 71 (61%) provided complete key word data. Key words describing overall performance were extremely heterogeneous, with a total of 72 used and great variation in the assignment of the top designation (median: 24% of students; range: 1%-60%). There was also great variation in the proportion of students awarded the top internal medicine clerkship grade (median: 29%; range: 2%-90%).The MSPE is a critical component of residency applications, yet data contained within MSPEs are incomplete and variable. Approximately half of U.S. medical schools do not follow AAMC guidelines for MSPEs.

  View details for PubMedID 26703411

• The State of Medical Student Performance Evaluations: Improved Transparency or Continued Obfuscation? ACADEMIC MEDICINE Hom, J., Richman, I., Hall, P., Ahuja, N., Harman, S., Harrington, R., Witteles, R. 2016; 91 (11): 1534–39

  View details for DOI 10.1097/ACM.0000000000001034

  View details for Web of Science ID 000387208300024

• Radial access in patients with acute coronary syndrome without persistent ST-segment elevation: Systematic review, collaborative meta-analysis, and meta-regression INTERNATIONAL JOURNAL OF CARDIOLOGY Ando, G., Porto, I., Montalescot, G., Bolognese, L., Trani, C., Oreto, G., Harrington, R. A., Bhatt, D. L. 2016; 222: 1031-1039

  Abstract

  Consistent evidence of benefit exists for radial access (RA) in ST-elevation acute myocardial infarction (STEMI). Patients with non ST-elevation acute coronary syndrome (NSTE-ACS) have a more varied ischemic and bleeding profile. No randomized trial of vascular access ever focused on NSTE-ACS and landmark studies did not provide conclusive results in this heterogeneous subset of patients.We assessed in a meta-analysis whether RA is associated with improved outcomes in NSTE-ACS patients. Included studies had to meet the following criteria: 1) enrolling patients with NSTE-ACS undergoing invasive management; 2) reporting outcomes with respect to RA as compared with femoral access (FA); 3) reporting short-term (procedural, in-hospital and up to 30-day) or long-term clinical outcomes. Studies were pooled with fixed and random effects models and heterogeneity was investigated by weighted meta-regression.Eleven studies were included encompassing 131.339 patients, 46.451 receiving RA and 84.888 receiving FA. Thirty-day mortality and MACE were lower with RA (p<0.001 with fixed effects, p=NS with random effects model), but these results depended on one large observational database. Major bleeding was consistently reduced by RA (p<0.001), albeit an inverse relationship with the proportion of patients in each study receiving FA and experiencing major bleeding was evident. The association of RA with reduced long-term mortality was of borderline significance (p=0.054 with random-effects, p=0.001 with fixed-effect model) and also depended on major bleeding in FA patients.RA is associated with better outcomes as compared with FA in NSTE-ACS, although this observation is influenced by nonrandomized comparisons. Large heterogeneity exists among studies.This study is registered in the PROSPERO database (CRD42015029459).

  View details for DOI 10.1016/j.ijcard.2016.07.228

  View details for PubMedID 27537543

• The Changing Landscape of Randomized Clinical Trials in Cardiovascular Disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Jones, W. S., Roe, M. T., Antman, E. M., Pletcher, M. J., Harrington, R. A., Rothman, R. L., Oetgen, W. J., Rao, S. V., Krucoff, M. W., Curtis, L. H., Hernandez, A. F., Masoudi, F. A. 2016; 68 (17): 1898-1907

  Abstract

  Large randomized clinical trials in cardiovascular disease have proliferated over the past 3 decades, with results that have influenced every aspect of cardiology practice. Despite these advances, there remains a substantial need for more high-quality evidence to inform cardiovascular clinical practice, given the increasing prevalence of cardiovascular disease around the world. Traditional clinical trials are increasingly challenging due to rising costs, increasing complexity and length, and burdensome institutional and regulatory requirements. This review will examine the current landscape of cardiovascular clinical trials in the United States, highlight recently conducted registry-based clinical trials, and discuss the potential attributes of the recently launched pragmatic clinical trial by the Patient-Centered Outcomes Research Institute's National Patient-Centered Clinical Research Network, called the ADAPTABLE (Aspirin Dosing: A Patient-centric Trial Assessing the Benefits and Long-term Effectiveness) trial.

  View details for DOI 10.1016/j.jacc.2016.07.781

  View details for Web of Science ID 000386826700011

  View details for PubMedID 27765193

• Rationale and design of Apo-I Event Reduction in Ischemic Syndromes I (AEGIS-I): A phase 2b, randomized, placebo-controlled, dose-ranging trial to investigate the safety and tolerability of CSL112, a reconstituted, infusible, human apoA-I, after acute myocardial infarction AMERICAN HEART JOURNAL Gibson, C. M., Korjian, S., Tricoci, P., Daaboul, Y., Alexander, J. H., Steg, P. G., Lincoff, A. M., Kastelein, J. J., Mehran, R., D'Andrea, D., Merkely, B., Zarebinski, M., Ophius, T. O., Harrington, R. A. 2016; 180: 22-28

  Abstract

  Despite aggressive pharmacotherapy and stenting, there is a residual risk of major adverse cardiovascular events among patients with acute coronary syndrome. High-density lipoprotein (HDL) has been a major target for secondary acute coronary syndrome prevention; however, a better understanding of the physiologic function of HDL has demonstrated that a high cholesterol efflux capacity, rather than high HDL concentrations alone, may be critical to improving outcomes. CSL112, a reconstituted, infusible human apolipoprotein A-I, has been demonstrated to increase cholesterol efflux capacity and to have a protective effect in experimental models of atherosclerotic cardiovascular disease.The AEGIS-I trial (ClinicalTrials.govNCT02108262) is a phase 2b, multicenter, randomized, placebo-controlled, dose-ranging clinical trial to evaluate the hepatic and renal safety of multiple administrations of 2 doses of CSL112 among subjects with acute myocardial infarction (AMI). Approximately 1,200 subjects (400 per treatment group) with either normal renal function or mild renal impairment will be enrolled up to 7 days after an AMI and will be stratified by renal function and randomized in a 1:1:1 ratio to either 1 of 2 doses of CSL112 (either 2 g or 6 g) or placebo as a weekly 2-hour infusion over the course of 4 consecutive weeks. The coprimary safety endpoints will be the incidence of hepatic and renal toxicity, defined as either confirmed ALT >3 × ULN, total bilirubin >2 × ULN, serum creatinine ≥1.5×baseline value, or a new requirement for renal replacement therapy through the end of the active treatment period.The AEGIS-I trial will characterize the safety profile of CSL112, a reconstituted formulation of apolipoprotein A-I, and will assess if administration to patients with a recent AMI is associated with a clinically significant alteration in either liver or kidney function when compared with placebo.

  View details for DOI 10.1016/j.ahj.2016.06.017

  View details for Web of Science ID 000384157800003

  View details for PubMedID 27659879

• The Outlook of Digital Health for Cardiovascular Medicine: Challenges but Also Extraordinary Opportunities. JAMA cardiology Turakhia, M. P., Desai, S. A., Harrington, R. A. 2016; 1 (7): 743-744

  View details for DOI 10.1001/jamacardio.2016.2661

  View details for PubMedID 27580275

• 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

• A resident-created hospitalist curriculum for internal medicine housestaff. Journal of hospital medicine Kumar, A., Smeraglio, A., Witteles, R., Harman, S., Nallamshetty, S., Rogers, A., Harrington, R., Ahuja, N. 2016; 11 (9): 646-649

  Abstract

  The growth of hospital medicine has led to new challenges, and recent graduates may feel unprepared to meet the expanding clinical duties expected of hospitalists. At our institution, we created a resident-inspired hospitalist curriculum to address the training needs for the next generation of hospitalists. Our program provided 3 tiers of training: (1) clinical excellence through improved training in underemphasized areas of hospital medicine, (2) academic development through required research, quality improvement, and medical student teaching, and (3) career mentorship. In this article, we describe the genesis of our program, our final product, and the challenges of creating a curriculum while being internal medicine residents. Journal of Hospital Medicine 2016. © 2016 Society of Hospital Medicine.

  View details for DOI 10.1002/jhm.2590

  View details for PubMedID 27079160

• Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. New England journal of medicine Cohen, A. T., Harrington, R. A., Goldhaber, S. Z., Hull, R. D., Wiens, B. L., Gold, A., Hernandez, A. F., Gibson, C. M. 2016; 375 (6): 534-544

  Abstract

  Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown.Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding.A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55).Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.).

  View details for DOI 10.1056/NEJMoa1601747

  View details for PubMedID 27232649

• 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

• 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

• Does a clinical history of gout influence the relationship of serum uric acid levels and cardiovascular outcomes among patients with acute coronary syndromes? Pagidipati, N., Hess, C. N., Clare, R. M., Akerblom, A., Tricoci, P., Wojdyla, D., Keenan, R., James, S., Held, C., Mahaffey, K., Harrington, R., Klein, A. B., Wallentin, L., Roe, M. T. OXFORD UNIV PRESS. 2016: 458

  View details for Web of Science ID 000383869502194

• Radial access in patients with acute coronary syndromes without persistent ST-segment elevation: meta-analysis, and meta-regression Porto, I., Ando, G., Montalescot, G., Bolognese, L., Trani, C., Harrington, R. A., Bhatt, D. L. OXFORD UNIV PRESS. 2016: 579

  View details for Web of Science ID 000383869502591

• Bleeding events and subsequent 30-day and 1-year mortality after percutaneous coronary intervention: a contemporary pooled patient-level analysis from the CHAMPION trials Vaduganathan, M., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Deliargyris, E. N., Prats, J., Elkin, S., Mahaffey, K. W., White, H. D., Bhatt, D. L., CHAMPION Investigators OXFORD UNIV PRESS. 2016: 614

  View details for Web of Science ID 000383869503046

• Off hours versus on hours presentation in ST-segment elevation myocardial infarction: findings from CHAMPION PHOENIX Selvaraj, S., Bhatt, D. L., Stone, G. W., Gibson, C. M., Steg, P. G., Hamm, C. W., Price, M. J., Deliargyris, E. N., Prats, J., Mahaffey, K. W., White, H. D., Harrington, R. A., CHAMPION PHOENIX OXFORD UNIV PRESS. 2016: 1175-1176

  View details for Web of Science ID 000383869505618

• Cangrelor compared with clopidogrel in patients with prior myocardial infarction - Insights from the CHAMPION trials Eisen, A., 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., CHAMPION PHOENIX Investigators OXFORD UNIV PRESS. 2016: 1233

  View details for Web of Science ID 000383869506132

• 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

• Defining a Mobile Health Roadmap for Cardiovascular Health and Disease. Journal of the American Heart Association Eapen, Z. J., Turakhia, M. P., McConnell, M. V., Graham, G., Dunn, P., Tiner, C., Rich, C., Harrington, R. A., Peterson, E. D., Wayte, P. 2016; 5 (7)

  View details for DOI 10.1161/JAHA.115.003119

  View details for PubMedID 27405809

• Impact of glycoprotein IIb/IIIa inhibitors on the efficacy and safety of ticagrelor compared with clopidogrel in patients with acute coronary syndromes: Analysis from the Platelet Inhibition and Patient Outcomes (PLATO) Trial AMERICAN HEART JOURNAL Shimada, Y. J., Bansilal, S., Wiviott, S. D., Becker, R. C., Harrington, R. A., Himmelmann, A., Neely, B., Husted, S., James, S. K., Katus, H. A., Lopes, R. D., Steg, P. G., Storey, R. F., Wallentin, L., Cannon, C. P. 2016; 177: 1-8

  Abstract

  Ticagrelor reduced cardiovascular events compared with clopidogrel in PLATO without increasing overall major bleeding. We evaluated whether the use of glycoprotein IIb/IIIa inhibitor (GPI) impacts the relative efficacy and safety of ticagrelor compared with clopidogrel.PLATO randomized 18,624 subjects with acute coronary syndrome to ticagrelor versus clopidogrel. The primary efficacy end point was cardiovascular death/myocardial infarction/stroke, and the primary safety end point was major bleeding. The use of GPI was at the physician's discretion and open-label. We evaluated outcomes at 30 days stratified by GPI use in the subgroup of 9,983 patients who underwent percutaneous coronary intervention (PCI) within 72 hours.A total of 4,020 (40%) received a GPI. Those receiving a GPI were more likely to be younger, be male, and undergo multivessel PCI. There was no interaction between treatment and GPI use for the primary efficacy and safety end points. Patients treated without GPI had a lower rate of definite stent thrombosis and higher rate of minor/major bleeding with ticagrelor compared with clopidogrel (P < .05), whereas there was no such difference with GPI (P interaction < .05).In patients with acute coronary syndrome undergoing early PCI, the efficacy and safety of ticagrelor as compared with clopidogrel were not modified by GPI use according to the primary efficacy and safety end point of the trial, although there were indications of greater benefit on definite stent thrombosis and more major or minor bleeding with ticagrelor in patients without (vs with) GPI treatment.

  View details for DOI 10.1016/j.ahj.2016.03.015

  View details for Web of Science ID 000377473100002

  View details for PubMedID 27297843

• 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

• Lipoprotein-Associated Phospholipase A(2) Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease JOURNAL OF THE AMERICAN HEART ASSOCIATION Wallentin, L., Held, C., Armstrong, P. W., Cannon, C. P., Davies, R. Y., Granger, C. B., Hagstrom, E., Harrington, R. A., Hochman, J. S., Koenig, W., Krug-Gourley, S., Mohler, E. R., Siegbahn, A., Tarka, E., Steg, P. G., Stewart, R. A., Weiss, R., Ostlund, O., White, H. D. 2016; 5 (6)

  Abstract

  We evaluated lipoprotein-associated phospholipase A2 (Lp-PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp-PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial.Plasma Lp-PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp-PLA2 activity levels and outcomes. At baseline, the median Lp-PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1-204.2 μmol/min per liter). Comparing the highest and lowest Lp-PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23-1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29-2.93) for hospitalization for heart failure, 1.42 (1.07-1.89) for cardiovascular death, and 1.37 (1.03-1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp-PLA2 activity. There were no associations between on-treatment Lp-PLA2 activity or changes of Lp-PLA2 activity and outcomes, and there were no significant interactions between baseline and on-treatment Lp-PLA2 activity or changes in Lp-PLA2 activity levels and the effects of darapladib on outcomes.Although high Lp-PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp-PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp-PLA2 activity.URL: https://www.clinicaltrials.gov. Unique identifier: NCT00799903.

  View details for DOI 10.1161/JAHA.116.003407

  View details for Web of Science ID 000386712700045

  View details for PubMedID 27329448

  View details for PubMedCentralID PMC4937279

• 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

• VTE Prevention in Acutely Ill Medical Patients with Extended Duration Betrixaban - A Multicenter, Randomized, Active-Controlled Efficacy and Safety Study Comparing Extended Duration Betrixaban with Standard of Care Enoxaparin Gibson, C. M., Harrington, R. A., Goldhaber, S. Z., Hernandez, A. F., Hull, R. D., Wiens, B. L., Gold, A., Cohen, A. T. WILEY-BLACKWELL. 2016: 8–9

  View details for Web of Science ID 000379164000023

• Extended-Duration Thromboprophylaxis Among Acute Medically Ill Patients: An Unmet Need JOURNAL OF CARDIOVASCULAR PHARMACOLOGY AND THERAPEUTICS Korjian, S., Daaboul, Y., Halaby, R., Goldhaber, S. Z., Cohen, A. T., Singh, K., Susheela, A. T., Harrington, R. A., Hull, R. D., Hernandez, A. F., Gibson, C. M. 2016; 21 (3): 227-232

  Abstract

  Acute medical illnesses are associated with a prolonged elevation in inflammatory markers that predisposes patients to thrombosis beyond the duration of their hospital stay. In parallel, both observational and randomized data have demonstrated a rate of postdischarge venous thromboembolic events that often exceeds that observed in the hospital setting. Despite this significant residual risk of venous thromboembolic events following discharge among acute medically ill patients, no therapeutic strategies have been recommended to address this unmet need. Available randomized trials have demonstrated the efficacy of extending the duration of thromboprophylaxis with available anticoagulants; however, the efficacy is offset, at least in part, by an increase in bleeding events. Identification of the optimal therapeutic strategies, treatment duration, and risk assessment tools that reconcile both efficacy and safety of extended-duration thromboprophylaxis among acute medically ill patients is an area of ongoing investigation.

  View details for DOI 10.1177/1074248415601894

  View details for Web of Science ID 000373751000001

  View details for PubMedID 26341120

• Tooth loss is independently associated with poor outcomes in stable coronary heart disease EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY Vedin, O., Hagstrom, E., Budaj, A., Denchev, S., Harrington, R. A., Koenig, W., Soffer, J., Sritara, P., Stebbins, A., Stewart, R. H., Swart, H. P., Viigimaa, M., Vinereanu, D., Wallentin, L., White, H. D., Held, C. 2016; 23 (8): 839-846

  Abstract

  We investigated associations between self-reported tooth loss and cardiovascular outcomes in a global stable coronary heart disease cohort.We examined 15,456 patients from 39 countries with stable coronary heart disease (prior myocardial infarction, prior revascularisation or multivessel coronary heart disease) in the STABILITY trial. At baseline, patients reported number of teeth (26-32 (all), 20-25, 15-19, 1-14 and no teeth) and were followed for 3.7 years. Cox regression models adjusted for cardiovascular risk factors and socioeconomic status, determined associations between tooth loss level (26-32 teeth: lowest level; no teeth: highest level) and cardiovascular outcomes.After adjustment, every increase in tooth loss level was associated with an increased risk of the primary outcome, the composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke (hazard ratio 1.06; 95% confidence interval 1.02-1.10), cardiovascular death (1.17; 1.10-1.24), all-cause death (1.16; 1.11-1.22) and non-fatal or fatal stroke (1.14; 1.04-1.24), but not with non-fatal or fatal myocardial infarction (0.99; 0.94-1.05). Having no teeth, compared to 26-32 teeth, entailed a significantly higher risk of the primary outcome (1.27 (1.08, 1.49)), cardiovascular death (1.85 (1.45, 2.37), all-cause death (1.81 (1.50, 2.20)) and stroke (1.67 (1.15, 2.39)).In this large global cohort of patients with coronary heart disease, self-reported tooth loss predicted adverse cardiovascular outcomes and all-cause death independent of cardiovascular risk factors and socioeconomic status.

  View details for DOI 10.1177/2047487315621978

  View details for Web of Science ID 000374971500007

  View details for PubMedID 26672609

• 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

  View details for DOI 10.1016/S0735-1097(16)30453-3

  View details for Web of Science ID 000375188701296

• Safety and efficacy of ticagrelor and clopidogrel in primary percutaneous coronary intervention HEART Velders, M. A., Abtan, J., Angiolillo, D. J., Ardissino, D., Harrington, R. A., Hellkamp, A., Himmelmann, A., Husted, S., Katus, H. A., Meier, B., Schulte, P. J., Storey, R. F., Wallentin, L., Steg, P. G., James, S. K. 2016; 102 (8): 617-625

  Abstract

  The effects of ticagrelor in the subpopulation of patients with ST-elevation myocardial infarction (STEMI) were consistent with those observed in the overall Platelet Inhibition and Patient Outcomes (PLATO) study. However, this subgroup included patients initially or ultimately treated conservatively. The aim of this study is to compare treatment using ticagrelor with treatment using clopidogrel in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).This post-hoc subgroup analysis compared ticagrelor with clopidogrel in 4949 PLATO patients with STEMI that were treated with primary PCI within 12 h of admission. The primary endpoint was cardiovascular death, myocardial infarction or stroke. The safety endpoint consisted of any major bleeding. Secondary endpoints included stent thrombosis. The analysis was not adequately powered to establish significance of any treatment effects.During a median of 286 days, the primary endpoint occurred in 7.9% of ticagrelor-treated patients versus 8.6% of clopidogrel-treated patients (HR 0.91, 95% CI 0.75 to 1.12, p=0.38). Major bleeding occurred in 6.7% in ticagrelor-treated patients versus 6.8% of clopidogrel-treated patients (HR 0.97, 95% CI 0.77 to 1.22, p=0.79). No interactions were observed for the treatment effect of ticagrelor versus clopidogrel on the primary efficacy (p=0.40) and primary safety endpoints (p=0.15) as compared with the full PLATO population. Treatment with ticagrelor versus clopidogrel reduced the occurrence of definite stent thrombosis (HR 0.58, 95% CI 0.37 to 0.89, p=0.013).In the subset of patients with STEMI treated with primary PCI, ticagrelor compared with clopidogrel was safe, and efficacy outcomes were consistent with the overall PLATO trial.NCT00391872; Results.

  View details for DOI 10.1136/heartjnl-2015-308963

  View details for Web of Science ID 000373308700011

• Safety and efficacy of ticagrelor and clopidogrel in primary percutaneous coronary intervention. Heart (British Cardiac Society) Velders, M. A., Abtan, J., Angiolillo, D. J., Ardissino, D., Harrington, R. A., Hellkamp, A., Himmelmann, A., Husted, S., Katus, H. A., Meier, B., Schulte, P. J., Storey, R. F., Wallentin, L., Gabriel Steg, P., James, S. K. 2016; 102 (8): 617-25

  Abstract

  The effects of ticagrelor in the subpopulation of patients with ST-elevation myocardial infarction (STEMI) were consistent with those observed in the overall Platelet Inhibition and Patient Outcomes (PLATO) study. However, this subgroup included patients initially or ultimately treated conservatively. The aim of this study is to compare treatment using ticagrelor with treatment using clopidogrel in patients with STEMI undergoing primary percutaneous coronary intervention (PCI).This post-hoc subgroup analysis compared ticagrelor with clopidogrel in 4949 PLATO patients with STEMI that were treated with primary PCI within 12 h of admission. The primary endpoint was cardiovascular death, myocardial infarction or stroke. The safety endpoint consisted of any major bleeding. Secondary endpoints included stent thrombosis. The analysis was not adequately powered to establish significance of any treatment effects.During a median of 286 days, the primary endpoint occurred in 7.9% of ticagrelor-treated patients versus 8.6% of clopidogrel-treated patients (HR 0.91, 95% CI 0.75 to 1.12, p=0.38). Major bleeding occurred in 6.7% in ticagrelor-treated patients versus 6.8% of clopidogrel-treated patients (HR 0.97, 95% CI 0.77 to 1.22, p=0.79). No interactions were observed for the treatment effect of ticagrelor versus clopidogrel on the primary efficacy (p=0.40) and primary safety endpoints (p=0.15) as compared with the full PLATO population. Treatment with ticagrelor versus clopidogrel reduced the occurrence of definite stent thrombosis (HR 0.58, 95% CI 0.37 to 0.89, p=0.013).In the subset of patients with STEMI treated with primary PCI, ticagrelor compared with clopidogrel was safe, and efficacy outcomes were consistent with the overall PLATO trial.NCT00391872; Results.

  View details for DOI 10.1136/heartjnl-2015-308963

  View details for PubMedID 26848185

• 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

• Coronary Artery Bypass Surgery Is Not Underutilized! CIRCULATION Fearon, W. F., Harrington, R. A. 2016; 133 (10): 1027–35

  View details for PubMedID 26951822

• 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

• 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

• Frequency, clinical and angiographic characteristics, and outcomes of high-risk non-ST-segment elevation acute coronary syndromes patients with left circumflex culprit lesions INTERNATIONAL JOURNAL OF CARDIOLOGY Halim, S. A., Clare, R. M., Newby, L. K., Lokhnygina, Y., Schweiger, M. J., Hof, A. W., Hochman, J. S., James, S. K., White, H. D., Widimsky, P., Betriu, A., Bode, C., Giugliano, R. P., Harrington, R. A., Zeymer, U. 2016; 203: 708-713

  Abstract

  The relationship between culprit vessel, infarct size, and outcomes in non-ST-segment elevation acute coronary syndromes (NSTE ACS) is unclear. In some reports, the left circumflex artery (LCX) was more often the culprit at angiography than the right coronary artery (RCA) or left anterior descending artery (LAD), and infarcts were larger with LCX culprits.We determined culprit vessel frequency and initial patency (TIMI flow grade), median fold elevation of peak troponin above the upper limit of normal, and outcomes (30-day death or myocardial infarction [MI] and 1-year mortality) by culprit vessel in high-risk NSTE ACS patients in the EARLY ACS trial.Of 9406 patients, 2066 (22.0%) had angiographic core laboratory data. We evaluated 1774 patients for whom the culprit artery was not the left main, a bypass graft, or branch vessel. The culprit was the LCX in 560 (31.6%), LAD in 653 (36.8%), and RCA in 561 (31.6%) patients. There were fewer women (24.1%) and more prior MI (25.5%) among patients with a culprit LCX compared with those with a culprit LAD or RCA. Patients with LCX (21.2%) and RCA (27.5%) culprits more often had an occluded artery (TIMI 0/1) than did those with LAD (11.3%). Peak troponin elevation was significantly higher for LCX than RCA or LAD culprits. LCX culprit vessels were not associated with worse 30-day or 1-year outcomes in adjusted models.Among patients with NSTE ACS, the frequencies of LCX, LAD, and RCA culprits were similar. Although LCX lesions were associated with higher peak troponin levels, there was no difference in short- or intermediate-term outcomes by culprit artery.

  View details for DOI 10.1016/j.ijcard.2015.11.036

  View details for PubMedID 26587725

• Frequency and Predictors of Internal Mammary Artery Graft Failure and Subsequent Clinical Outcomes Insights From the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial CIRCULATION Harskamp, R. E., Alexander, J. H., Ferguson, T. B., Hager, R., Mack, M. J., Englum, B., Wojdyla, D., Schulte, P. J., Kouchoukos, N. T., de Winter, R. J., Gibson, C. M., Peterson, E. D., Harrington, R. A., Smith, P. K., Lopes, R. D. 2016; 133 (2): 131-138

  Abstract

  The internal mammary artery (IMA) is the preferred conduit for bypassing the left anterior descending (LAD) artery in patients undergoing coronary artery bypass grafting. Systematic evaluation of the frequency and predictors of IMA failure and long-term outcomes is lacking.The Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV trial participants who underwent IMA-LAD revascularization and had 12- to 18-month angiographic follow-up (n=1539) were included. Logistic regression with fast false selection rate methods was used to identify characteristics associated with IMA failure (≥75% stenosis). The relationship between IMA failure and long-term outcomes, including death, myocardial infarction, and repeat revascularization, was assessed with Cox regression. IMA failure occurred in 132 participants (8.6%). Predictors of IMA graft failure were LAD stenosis <75% (odds ratio, 1.76; 95% confidence interval, 1.19-2.59), additional bypass graft to diagonal branch (odds ratio, 1.92; 95% confidence interval, 1.33-2.76), and not having diabetes mellitus (odds ratio, 1.82; 95% confidence interval, 1.20-2.78). LAD stenosis and additional diagonal graft remained predictive of IMA failure in an alternative model that included angiographic failure or death before angiography as the outcome. IMA failure was associated with a significantly higher incidence of subsequent acute (<14 days of angiography) clinical events, mostly as a result of a higher rate of repeat revascularization.IMA failure was common and associated with higher rates of repeat revascularization, and patients with intermediate LAD stenosis or with an additional bypass graft to the diagonal branch had increased risk for IMA failure. These findings raise concerns about competitive flow and the benefit of coronary artery bypass grafting in intermediate LAD stenosis without functional evidence of ischemia.URL: http:/www.clinicaltrials.gov. Unique identifier: NCT00042081.

  View details for DOI 10.1161/CIRCULATIONAHA.115.015549

  View details for Web of Science ID 000367922700005

  View details for PubMedCentralID PMC4814323

• Frequency and Predictors of Internal Mammary Artery Graft Failure and Subsequent Clinical Outcomes: Insights From the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial. Circulation Harskamp, R. E., Alexander, J. H., Ferguson, T. B., Hager, R., Mack, M. J., Englum, B., Wojdyla, D., Schulte, P. J., Kouchoukos, N. T., de Winter, R. J., Gibson, C. M., Peterson, E. D., Harrington, R. A., Smith, P. K., Lopes, R. D. 2016; 133 (2): 131-8

  Abstract

  The internal mammary artery (IMA) is the preferred conduit for bypassing the left anterior descending (LAD) artery in patients undergoing coronary artery bypass grafting. Systematic evaluation of the frequency and predictors of IMA failure and long-term outcomes is lacking.The Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV trial participants who underwent IMA-LAD revascularization and had 12- to 18-month angiographic follow-up (n=1539) were included. Logistic regression with fast false selection rate methods was used to identify characteristics associated with IMA failure (≥75% stenosis). The relationship between IMA failure and long-term outcomes, including death, myocardial infarction, and repeat revascularization, was assessed with Cox regression. IMA failure occurred in 132 participants (8.6%). Predictors of IMA graft failure were LAD stenosis <75% (odds ratio, 1.76; 95% confidence interval, 1.19-2.59), additional bypass graft to diagonal branch (odds ratio, 1.92; 95% confidence interval, 1.33-2.76), and not having diabetes mellitus (odds ratio, 1.82; 95% confidence interval, 1.20-2.78). LAD stenosis and additional diagonal graft remained predictive of IMA failure in an alternative model that included angiographic failure or death before angiography as the outcome. IMA failure was associated with a significantly higher incidence of subsequent acute (<14 days of angiography) clinical events, mostly as a result of a higher rate of repeat revascularization.IMA failure was common and associated with higher rates of repeat revascularization, and patients with intermediate LAD stenosis or with an additional bypass graft to the diagonal branch had increased risk for IMA failure. These findings raise concerns about competitive flow and the benefit of coronary artery bypass grafting in intermediate LAD stenosis without functional evidence of ischemia.URL: http:/www.clinicaltrials.gov. Unique identifier: NCT00042081.

  View details for DOI 10.1161/CIRCULATIONAHA.115.015549

  View details for PubMedID 26647082

  View details for PubMedCentralID PMC4814323

• Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia The Case for Community Equipoise JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Stone, G. W., Hochman, J. S., Williams, D. O., Boden, W. E., Ferguson, T. B., Harrington, R. A., Maron, D. J. 2016; 67 (1): 81-99

  Abstract

  All patients with stable ischemic heart disease (SIHD) should be managed with guideline-directed medical therapy (GDMT), which reduces progression of atherosclerosis and prevents coronary thrombosis. Revascularization is also indicated in patients with SIHD and progressive or refractory symptoms, despite medical management. Whether a strategy of routine revascularization (with percutaneous coronary intervention or coronary artery bypass graft surgery as appropriate) plus GDMT reduces rates of death or myocardial infarction, or improves quality of life compared to an initial approach of GDMT alone in patients with substantial ischemia is uncertain. Opinions run strongly on both sides, and evidence may be used to support either approach. Careful review of the data demonstrates the limitations of our current knowledge, resulting in a state of community equipoise. The ongoing ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) is being performed to determine the optimal approach to managing patients with SIHD, moderate-to-severe ischemia, and symptoms that can be controlled medically. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

  View details for DOI 10.1016/j.jacc.2015.09.056

  View details for Web of Science ID 000367520500013

  View details for PubMedCentralID PMC5545795

• Medical Therapy With Versus Without Revascularization in Stable Patients With Moderate and Severe Ischemia: The Case for Community Equipoise. Journal of the American College of Cardiology Stone, G. W., Hochman, J. S., Williams, D. O., Boden, W. E., Ferguson, T. B., Harrington, R. A., Maron, D. J. 2016; 67 (1): 81-99

  Abstract

  All patients with stable ischemic heart disease (SIHD) should be managed with guideline-directed medical therapy (GDMT), which reduces progression of atherosclerosis and prevents coronary thrombosis. Revascularization is also indicated in patients with SIHD and progressive or refractory symptoms, despite medical management. Whether a strategy of routine revascularization (with percutaneous coronary intervention or coronary artery bypass graft surgery as appropriate) plus GDMT reduces rates of death or myocardial infarction, or improves quality of life compared to an initial approach of GDMT alone in patients with substantial ischemia is uncertain. Opinions run strongly on both sides, and evidence may be used to support either approach. Careful review of the data demonstrates the limitations of our current knowledge, resulting in a state of community equipoise. The ongoing ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) is being performed to determine the optimal approach to managing patients with SIHD, moderate-to-severe ischemia, and symptoms that can be controlled medically. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

  View details for DOI 10.1016/j.jacc.2015.09.056

  View details for PubMedID 26616030

  View details for PubMedCentralID PMC5545795

• Autologous CD34(+) Cell Therapy for Refractory Angina: 2-Year Outcomes From the ACT34-CMI Study CELL TRANSPLANTATION Henry, T. D., Schaer, G. L., Traverse, J. H., Povsic, T. J., Davidson, C., Lee, J. S., Costa, M. A., Bass, T., Mendelsohn, F., Fortuin, F. D., Pepine, C. J., Patel, A. N., Riedel, N., Junge, C., Hunt, A., Kereiakes, D. J., White, C., Harrington, R. A., Schatz, R. A., Losordo, D. W. 2016; 25 (9): 1701-1711

  Abstract

  An increasing number of patients have refractory angina despite optimal medical therapy and are without further revascularization options. Preclinical studies indicate that human CD34(+) stem cells can stimulate new blood vessel formation in ischemic myocardium, improving perfusion and function. In ACT34-CMI (N = 167), patients treated with autologous CD34(+) stem cells had improvements in angina and exercise time at 6 and 12 months compared to placebo; however, the longer-term effects of this treatment are unknown. ACT34 was a phase II randomized, double-blind, placebo-controlled clinical trial comparing placebo, low dose (1 × 10(5) CD34/kg body weight), and high dose (5 × 10(5) CD34/kg) using intramyocardial delivery into the ischemic zone following NOGA(®) mapping. To obtain longer-term safety and efficacy in these patients, we compiled data of major adverse cardiac events (MACE; death, myocardial infarction, acute coronary syndrome, or heart failure hospitalization) up to 24 months as well as angina and quality of life assessments in patients who consented for 24-month follow-up. A total of 167 patients with class III-IV refractory angina were randomized and completed the injection procedure. The low-dose-treated patients had a significant reduction in angina frequency (p = 0.02, 0.035) and improvements in exercise tolerance testing (ETT) time (p = 0.014, 0.017) compared to the placebo group at 6 and 12 months. At 24 months, patients treated with both low-and high-dose CD34(+) cells had significant reduction in angina frequency (p = 0.03). At 24 months, there were a total of seven deaths (12.5%) in the control group versus one (1.8%) in the low-dose and two (3.6%) in the high-dose (p = 0.08) groups. At 2 years, MACE occurred at a rate of 33.9%, 21.8%, and 16.2% in control, low-, and high-dose patients, respectively (p = 0.08). Autologous CD34(+) cell therapy was associated with persistent improvement in angina at 2 years and a trend for reduction in mortality in no-option patients with refractory angina.

  View details for DOI 10.3727/096368916X691484

  View details for Web of Science ID 000382800300011

  View details for PubMedID 27151378

• The Role of Peer Support in Attaining Ideal Cardiovascular Health: Peer Pressure and Prevention. Journal of the American College of Cardiology Rodriguez, F. n., Harrington, R. A. 2016; 67 (5): 486–87

  View details for PubMedID 26562045

• Response to Letters Regarding Article, "Frequency and Predictors of Internal Mammary Artery Graft Failure and Subsequent Clinical Outcomes: Insights From the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial". Circulation Harskamp, R. E., Alexander, J. H., Ferguson, T. B., Hager, R. n., Mack, M. J., Englum, B. n., Wojdyla, D. n., Schulte, P. J., Kouchoukos, N. T., de Winter, R. J., Gibson, C. M., Peterson, E. D., Harrington, R. A., Smith, P. K., Lopes, R. D. 2016; 133 (21): e665

  View details for PubMedID 27217439

• Betrixaban in Acutely Ill Medical Patients. The New England journal of medicine Cohen, A. T., Harrington, R. A., Gibson, C. M. 2016; 375 (24): e50

  View details for PubMedID 27974029

• Cholesterol, Cardiovascular Risk, Statins, PCSK9 Inhibitors, and the Future of LDL-C Lowering. JAMA Rodriguez, F. n., Harrington, R. A. 2016; 316 (19): 1967–68

  View details for PubMedID 27838727

• 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

• Acquisition, Analysis, and Sharing of Data in 2015 and Beyond: A Survey of the Landscape A Conference Report From the American Heart Association Data Summit 2015 JOURNAL OF THE AMERICAN HEART ASSOCIATION Antman, E. M., Benjamin, E. J., Harrington, R. A., Houser, S. R., Peterson, E. D., Bauman, M. A., Brown, N., Bufalino, V., Califf, R. M., Creager, M. A., Daugherty, A., DeMets, D. L., Dennis, B. P., Ebadollahi, S., Jessup, M., Lauer, M. S., Lo, B., MacRae, C. A., McConnell, M. V., McCray, A. T., Mello, M. M., Mueller, E., Newburger, J. W., Okun, S., Packer, M., Philippakis, A., Ping, P., Prasoon, P., Roger, V. L., Singer, S., Temple, R., Turner, M. B., Vigilante, K., Warner, J., Wayte, P. 2015; 4 (11)

  Abstract

  A 1.5-day interactive forum was convened to discuss critical issues in the acquisition, analysis, and sharing of data in the field of cardiovascular and stroke science. The discussion will serve as the foundation for the American Heart Association's (AHA's) near-term and future strategies in the Big Data area. The concepts evolving from this forum may also inform other fields of medicine and science.A total of 47 participants representing stakeholders from 7 domains (patients, basic scientists, clinical investigators, population researchers, clinicians and healthcare system administrators, industry, and regulatory authorities) participated in the conference. Presentation topics included updates on data as viewed from conventional medical and nonmedical sources, building and using Big Data repositories, articulation of the goals of data sharing, and principles of responsible data sharing. Facilitated breakout sessions were conducted to examine what each of the 7 stakeholder domains wants from Big Data under ideal circumstances and the possible roles that the AHA might play in meeting their needs. Important areas that are high priorities for further study regarding Big Data include a description of the methodology of how to acquire and analyze findings, validation of the veracity of discoveries from such research, and integration into investigative and clinical care aspects of future cardiovascular and stroke medicine. Potential roles that the AHA might consider include facilitating a standards discussion (eg, tools, methodology, and appropriate data use), providing education (eg, healthcare providers, patients, investigators), and helping build an interoperable digital ecosystem in cardiovascular and stroke science.There was a consensus across stakeholder domains that Big Data holds great promise for revolutionizing the way cardiovascular and stroke research is conducted and clinical care is delivered; however, there is a clear need for the creation of a vision of how to use it to achieve the desired goals. Potential roles for the AHA center around facilitating a discussion of standards, providing education, and helping establish a cardiovascular digital ecosystem. This ecosystem should be interoperable and needs to interface with the rapidly growing digital object environment of the modern-day healthcare system.

  View details for DOI 10.1161/JAHA.115.002810

  View details for Web of Science ID 000366615600032

  View details for PubMedID 26541391

  View details for PubMedCentralID PMC4845234

• Association of spontaneous and procedure-related bleeds with short- and long-term mortality after acute coronary syndromes: an analysis from the PLATO trial EUROINTERVENTION Ducroq, G., Schulte, P. J., Becker, R. C., Cannon, C. P., Hanington, R. A., Held, C., Himmelmann, A., Lassila, R., Storey, R. F., Sorbets, E., Wallentin, L., Steg, P. 2015; 11 (7): 737-745

  Abstract

  We sought to describe the differential effect of bleeding events in acute coronary syndromes (ACS) on short- and long-term mortality according to their type and severity.The PLATO trial randomised 18,624 ACS patients to clopidogrel or ticagrelor. Post-randomisation bleeding events were captured according to bleeding type (spontaneous or procedure-related), with PLATO, TIMI, and GUSTO definitions. The association of bleeding events with subsequent short-term (<30 days) and long-term (>30 days) all-cause mortality was assessed using time-dependent Cox proportional hazard models. A model was fitted to compare major and minor bleeding for mortality prediction. Of 18,624 patients, 2,189 (11.8%) had at least one PLATO major bleed (mean follow-up 272.2±123.5 days). Major bleeding was associated with higher short-term mortality (adjusted hazard ratio [HR] 9.28; 95% confidence interval [CI]: 7.50-11.48) but not with long-term mortality (adjusted HR 1.28; 95% CI: 0.93-1.75). Spontaneous bleeding was associated with short-term (adjusted HR 14.59; 95% CI: 11.14-19.11) and long-term (adjusted HR 3.38; 95% CI: 2.26-5.05) mortality. Procedure-related bleeding was associated with short-term mortality (adjusted HR 5.29; 95% CI: 4.06-6.87): CABG-related and non-coronary-procedure-related bleeding were associated with a higher short-term mortality, whereas PCI or angiography-related bleeding was not associated with either short- or long-term mortality. Similar results were obtained using the GUSTO and TIMI bleeding definitions.Major bleeding is associated with high subsequent mortality in ACS. However, this association is much stronger in the first 30 days and is strongest for spontaneous (vs. procedure-related) bleeding.

  View details for DOI 10.4244/EIJY14M09_11

  View details for Web of Science ID 000368214100005

  View details for PubMedID 25254357

• Team-Based Care and Quality A Move Toward Evidence-Based Policy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Harrington, R. A., Heidenreich, P. A. 2015; 66 (16): 1813–15

  View details for PubMedID 26483106

• 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

  View details for DOI 10.1016/j.jacc.2015.08.122

  View details for Web of Science ID 000363329000080

• 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

  View details for DOI 10.1016/j.jacc.2015.08.118

  View details for Web of Science ID 000363329000076

• 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

• Clinician Innovator: A Novel Career Path in Academic Medicine A Presidentially Commissioned Article From the American Heart Association JOURNAL OF THE AMERICAN HEART ASSOCIATION Majmudar, M. D., Harrington, R. A., Brown, N. J., Graham, G., McConnell, M. V. 2015; 4 (10)

  View details for DOI 10.1161/JAHA.115.001990

  View details for PubMedID 26450117

• Characterising and predicting bleeding in high-risk patients with an acute coronary syndrome HEART Khan, R., Lopes, R. D., Neely, M. L., Stevens, S. R., Harrington, R. A., Diaz, R., Cools, F., Jansky, P., Montalescot, G., Atar, D., Lopez-Sendon, J., Flather, M., Liaw, D., Wallentin, L., Alexander, J. H., Goodman, S. G. 2015; 101 (18): 1475-1484

  Abstract

  In the Apixaban for Prevention of Acute Ischemic Events (APPRAISE-2) trial, the use of apixaban, when compared with placebo, in high-risk patients with a recent acute coronary syndrome (ACS) resulted in a significant increase in bleeding without a reduction in ischaemic events. The aim of this analysis was to provide further description of these bleeding events and to determine the baseline characteristics associated with bleeding in high-risk post-ACS patients.APPRAISE-2 was a multinational clinical trial including 7392 high-risk patients with a recent ACS randomised to apixaban (5 mg twice daily) or placebo. Bleeding including Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding, International Society on Thrombosis and Haemostasis (ISTH) major or clinically relevant non-major (CRNM) bleeding, and any bleeding were analysed using an on-treatment analysis. Kaplan-Meier curves were plotted to describe the timing of bleeding, and a Cox proportional hazards model was used to identify predictors of ISTH major or CRNM bleeding and any bleeding. Median follow-up was 241 days.The proportion of patients who experienced TIMI major or minor, ISTH major or CRNM, and any bleeding was 1.5%, 2.2% and 13.3%, respectively. The incidence of bleeding was highest in the immediate post-ACS period (0.11 in the first 30 days vs 0.03 after 30 days events per 1 patient-year); however, >60% of major bleeding events occurred >30 days after the end of the index hospitalisation. Gastrointestinal bleeding was the most common cause of major bleeding, accounting for 45.9% of TIMI major or minor and 39.5% of ISTH major or CRNM bleeding events. Independent predictors of ISTH major or CRNM bleeding events included older age, renal dysfunction, dual oral antiplatelet therapy, smoking history, increased white cell count and coronary revascularisation.When compared with placebo, the use of apixaban is associated with an important short-term and long-term risk of bleeding in high-risk post-ACS patients, with gastrointestinal bleeding being the most common source of major bleeding. The baseline predictors of major bleeding appear to be consistent with those identified in lower-risk ACS populations with shorter-term follow-up.NCT00831441.

  View details for DOI 10.1136/heartjnl-2014-307346

  View details for Web of Science ID 000360307600012

• Comparison of quality-of-life measures after radial versus femoral artery access for cardiac catheterization in women: Results of the Study of Access Site for Enhancement of Percutaneous Coronary Intervention for Women quality-of-life substudy AMERICAN HEART JOURNAL Hess, C. N., Krucoff, M. W., Sheng, S., Anstrom, K. J., Barham, W. B., Gilchrist, I. C., Harrington, R. A., Jacobs, A. K., Mehran, R., Messenger, J. C., Mark, D. B., Rao, S. V. 2015; 170 (2): 371-379

  Abstract

  In the SAFE-PCI for Women trial, patient preference for radial access for future procedures was greater than for femoral access. We sought to assess whether radial or femoral access impacts formal measures of quality-of-life (QOL) among women undergoing cardiac catheterization.We assessed QOL using European quality of life-5 dimensions (EQ-5D) and EQ visual analog scale (EQ-VAS) scores among 304 women randomized to radial or femoral arteriotomy in the SAFE-PCI for Women trial at sites with QOL substudy approval. Patient surveys were administered at baseline, hospital discharge, and 30 days (for percutaneous coronary intervention patients).Women randomized to both treatments had similar EQ-5D index and EQ-VAS scores at baseline, hospital discharge, and 30-day follow-up. After adjustment for baseline scores, there was no effect of assigned treatment on EQ-5D (discharge 0.004; 95% CI -0.03 to 0.04; 30 days -0.03; 95% CI -0.09 to 0.02) or EQ-VAS (discharge -1.31; 95% CI -4.74 to 2.12; 30 days -2.10; 95% CI -8.92 to 4.71) scores. At discharge, 60.5% versus 63.5% (P = .60) of patients in radial and femoral groups were free from access site pain; at 30 days, rates were 85.7% versus 77.6% (P = .30), respectively. Patient preference for the same access strategy for repeat procedures was greater in the radial versus femoral group (77.2% vs 26.8%; P < .0001).Using established QOL instruments, we did not measure any difference in QOL or functional status according to access site strategy in women undergoing cardiac catheterization, yet patient preference for the radial approach was significantly greater. Other factors influencing patient choice for radial access should be investigated.

  View details for DOI 10.1016/j.ahj.2015.04.024

  View details for Web of Science ID 000360360100026

• Characteristics of dyspnoea and associated clinical outcomes in the CHAMPION PHOENIX study Storey, R. F., Bhatt, D. L., Steg, P. G., Stone, G. W., White, H. D., Gibson, C. M., Hamm, C. W., Prats, J., Mahaffey, K. W., Harrington, R. A., CHAMPION PHOENIX Investigators OXFORD UNIV PRESS. 2015: 237

  View details for Web of Science ID 000361205102272

• The effect of cangrelor and access site on ischemic and bleeding events: insights from CHAMPION-PHOENIX Gutierrez, J. A., Harrington, R. A., Stone, G. W., Steg, P. G., Gibson, C. M., Hamm, C. W., Price, M. J., Mahaffey, K. W., White, H. D., Bhatt, D. L. OXFORD UNIV PRESS. 2015: 681

  View details for Web of Science ID 000361205104636

• Implications of different criteria for percutaneous coronary intervention-related myocardial infarction on study results of three large phase III clinical trials: the CHAMPION experience Leonardi, S., Lopes, R. D., Abnousi, F., Mangum, S., Prats, J., Wilson, M., Todd, M., Harrington, R. A., Bhatt, D. L., Mahaffey, K. W. OXFORD UNIV PRESS. 2015: 698

  View details for Web of Science ID 000361205105060

• Living alone and depressive symptoms are associated with major cardiovascular events in patients with chronic coronary heart disease Hagstrom, E., Nordlund, F., Harrington, R. A., Lopez-Sendon, J., Soffer, J., Stebbins, A., Stewart, R. H., Wallentin, L., White, H. D., Held, C. OXFORD UNIV PRESS. 2015: 1144

  View details for Web of Science ID 000361205107455

• Comparison of quality-of-life measures after radial versus femoral artery access for cardiac catheterization in women: Results of the Study of Access Site for Enhancement of Percutaneous Coronary Intervention for Women quality-of-life substudy. American heart journal Hess, C. N., Krucoff, M. W., Sheng, S., Anstrom, K. J., Barham, W. B., Gilchrist, I. C., Harrington, R. A., Jacobs, A. K., Mehran, R., Messenger, J. C., Mark, D. B., Rao, S. V. 2015; 170 (2): 371-379

  Abstract

  In the SAFE-PCI for Women trial, patient preference for radial access for future procedures was greater than for femoral access. We sought to assess whether radial or femoral access impacts formal measures of quality-of-life (QOL) among women undergoing cardiac catheterization.We assessed QOL using European quality of life-5 dimensions (EQ-5D) and EQ visual analog scale (EQ-VAS) scores among 304 women randomized to radial or femoral arteriotomy in the SAFE-PCI for Women trial at sites with QOL substudy approval. Patient surveys were administered at baseline, hospital discharge, and 30 days (for percutaneous coronary intervention patients).Women randomized to both treatments had similar EQ-5D index and EQ-VAS scores at baseline, hospital discharge, and 30-day follow-up. After adjustment for baseline scores, there was no effect of assigned treatment on EQ-5D (discharge 0.004; 95% CI -0.03 to 0.04; 30 days -0.03; 95% CI -0.09 to 0.02) or EQ-VAS (discharge -1.31; 95% CI -4.74 to 2.12; 30 days -2.10; 95% CI -8.92 to 4.71) scores. At discharge, 60.5% versus 63.5% (P = .60) of patients in radial and femoral groups were free from access site pain; at 30 days, rates were 85.7% versus 77.6% (P = .30), respectively. Patient preference for the same access strategy for repeat procedures was greater in the radial versus femoral group (77.2% vs 26.8%; P < .0001).Using established QOL instruments, we did not measure any difference in QOL or functional status according to access site strategy in women undergoing cardiac catheterization, yet patient preference for the radial approach was significantly greater. Other factors influencing patient choice for radial access should be investigated.

  View details for DOI 10.1016/j.ahj.2015.04.024

  View details for PubMedID 26299236

• 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

• 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

• Organizational Change, Leadership, and the Transformation of Continuing Professional Development: Lessons Learned From the American College of Cardiology JOURNAL OF CONTINUING EDUCATION IN THE HEALTH PROFESSIONS Beliveau, M. E., Warnes, C. A., Harrington, R. A., Nishimura, R. A., O'Gara, P. T., Sibley, J. B., Oetgen, W. J. 2015; 35 (3): 201-210

  Abstract

  There is a need for a transformational change in clinical education. In postgraduate medical education we have traditionally had a faculty-centric model. That is, faculty knew what needed to be taught and who were the best teachers to teach it. They built the agenda, and worked with staff to follow Accreditation Council for Continuing Medical Education (ACCME) accreditation criteria and manage logistics. Changes in the health care marketplace now demand a learner-centric model-one that embraces needs assessments, identification of practice gaps relative to competency, development of learning objectives, contemporary adult learning theory, novel delivery systems, and measurable outcomes. This article provides a case study of one medical specialty society's efforts to respond to this demand.

  View details for DOI 10.1002/chp.21301

  View details for Web of Science ID 000363878600007

  View details for PubMedID 26378426

• 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

• 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

• 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

• 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

• COCATS 4 Task Force 15: Training in Cardiovascular Research and Scholarly Activity JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Harrington, R. A., Barac, A., Brush, J. E., Hill, J. A., Krumholz, H. M., Lauer, M. S., Sivaram, C. A., Taubman, M. B., Williams, J. L. 2015; 65 (17): 1899-1906

  View details for DOI 10.1016/j.jacc.2015.03.032

  View details for Web of Science ID 000353644200017

  View details for PubMedID 25777645

• Anticoagulant therapy and outcomes in patients with prior or acute heart failure and acute coronary syndromes: Insights from the APixaban for PRevention of Acute ISchemic Events 2 trial AMERICAN HEART JOURNAL Cornel, J. H., Lopes, R. D., James, S., Stevens, S. R., Neely, M. L., Liaw, D., Miller, J., Mohan, P., Amerena, J., Raev, D., Huo, Y., Urina-Triana, M., Cazorla, A. G., Vinereanu, D., Fridrich, V., Harrington, R. A., Wallentin, L., Alexander, J. H. 2015; 169 (4): 531-538

  Abstract

  Clinical outcomes and the effects of oral anticoagulants among patients with acute coronary syndrome (ACS) and either a history of or acute heart failure (HF) are largely unknown. We aimed to assess the relationship between prior HF or acute HF complicating an index ACS event and subsequent clinical outcomes and the efficacy and safety of apixaban compared with placebo in these populations.High-risk patients were randomly assigned post-ACS to apixaban 5.0 mg or placebo twice daily. Median follow-up was 8 (4-12) months. The primary outcome was cardiovascular death, myocardial infarction, or stroke. The main safety outcome was thrombolysis in myocardial infarction major bleeding.Heart failure was reported in 2,995 patients (41%), either as prior HF (2,076 [28%]) or acute HF (2,028 [27%]). Patients with HF had a very high baseline risk and were more often managed medically. Heart failure was associated with a higher rate of the primary outcome (prior HF: adjusted hazard ratio [HR] 1.73, 95% CI 1.42-2.10, P < .0001, acute HF: adjusted HR 1.65, 95% CI 1.35-2.01, P < .0001) and cardiovascular death (prior HF: HR 2.54, 95% CI 1.82-3.54, acute HF: adjusted HR 2.52, 95% CI 1.82-3.50). Patients with acute HF also had significantly higher rates of thrombolysis in myocardial infarction major bleeding (prior HF: adjusted HR 1.22, 95% CI 0.65-2.27, P = .54, acute HF: adjusted HR 1.78, 95% CI 1.03-3.08, P = .04). There was no statistical evidence of a differential effect of apixaban on clinical events or bleeding in patients with or without prior HF; however, among patients with acute HF, there were numerically fewer events with apixaban than placebo (14.8 vs 19.3, HR 0.76, 95% CI 0.57-1.01, interaction P = .13), a trend that was not seen in patients with prior HF or no HF.In high-risk patients post-ACS, both prior and acute HFs are associated with an increased risk of subsequent clinical events. Apixaban did not significantly reduce clinical events and increased bleeding in patients with and without HF; however, there was a tendency toward fewer clinical events with apixaban in patients with acute HF.

  View details for DOI 10.1016/j.ahj.2014.12.022

  View details for Web of Science ID 000351949500016

• Anticoagulant therapy and outcomes in patients with prior or acute heart failure and acute coronary syndromes: Insights from the APixaban for PRevention of Acute ISchemic Events 2 trial. American heart journal Cornel, J. H., Lopes, R. D., James, S., Stevens, S. R., Neely, M. L., Liaw, D., Miller, J., Mohan, P., Amerena, J., Raev, D., Huo, Y., Urina-Triana, M., Gallegos Cazorla, A., Vinereanu, D., Fridrich, V., Harrington, R. A., Wallentin, L., Alexander, J. H. 2015; 169 (4): 531-538

  Abstract

  Clinical outcomes and the effects of oral anticoagulants among patients with acute coronary syndrome (ACS) and either a history of or acute heart failure (HF) are largely unknown. We aimed to assess the relationship between prior HF or acute HF complicating an index ACS event and subsequent clinical outcomes and the efficacy and safety of apixaban compared with placebo in these populations.High-risk patients were randomly assigned post-ACS to apixaban 5.0 mg or placebo twice daily. Median follow-up was 8 (4-12) months. The primary outcome was cardiovascular death, myocardial infarction, or stroke. The main safety outcome was thrombolysis in myocardial infarction major bleeding.Heart failure was reported in 2,995 patients (41%), either as prior HF (2,076 [28%]) or acute HF (2,028 [27%]). Patients with HF had a very high baseline risk and were more often managed medically. Heart failure was associated with a higher rate of the primary outcome (prior HF: adjusted hazard ratio [HR] 1.73, 95% CI 1.42-2.10, P < .0001, acute HF: adjusted HR 1.65, 95% CI 1.35-2.01, P < .0001) and cardiovascular death (prior HF: HR 2.54, 95% CI 1.82-3.54, acute HF: adjusted HR 2.52, 95% CI 1.82-3.50). Patients with acute HF also had significantly higher rates of thrombolysis in myocardial infarction major bleeding (prior HF: adjusted HR 1.22, 95% CI 0.65-2.27, P = .54, acute HF: adjusted HR 1.78, 95% CI 1.03-3.08, P = .04). There was no statistical evidence of a differential effect of apixaban on clinical events or bleeding in patients with or without prior HF; however, among patients with acute HF, there were numerically fewer events with apixaban than placebo (14.8 vs 19.3, HR 0.76, 95% CI 0.57-1.01, interaction P = .13), a trend that was not seen in patients with prior HF or no HF.In high-risk patients post-ACS, both prior and acute HFs are associated with an increased risk of subsequent clinical events. Apixaban did not significantly reduce clinical events and increased bleeding in patients with and without HF; however, there was a tendency toward fewer clinical events with apixaban in patients with acute HF.

  View details for DOI 10.1016/j.ahj.2014.12.022

  View details for PubMedID 25819860

• 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

• Economic Analysis of Ticagrelor Therapy From a US Perspective JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Cowper, P. A., Pan, W., Anstrom, K. J., Kaul, P., Wallentin, L., Davidson-Ray, L., Nikolic, E., Janzon, M., Levin, L., Cannon, C. P., Harrington, R. A., Mark, D. B. 2015; 65 (5): 465-476

  Abstract

  Based on results of the PLATO (Platelet Inhibition and Patient Outcomes) trial comparing ticagrelor with clopidogrel therapy, the U.S. Food and Drug Administration approved ticagrelor in 2011 for reducing thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) with the proviso that it be taken with low-dose aspirin.This study sought to assess the cost and cost effectiveness of ticagrelor therapy relative to clopidogrel in treating ACS patients from the perspective of the U.S. health care system.We estimated within-trial resource use and costs using U.S. low-dose aspirin patients in PLATO (n = 547). Quality-adjusted life expectancy was estimated using the total PLATO population (n = 18,624), combined with baseline risk and long-term survival data from an external ACS patient cohort. Study drugs were valued at current costs. Cost effectiveness was assessed, as was the sensitivity of results to sampling and methodological uncertainties.One year of ticagrelor therapy, relative to that of generic clopidogrel, cost $29,665/quality-adjusted life-year gained, with 99% of bootstrap estimates falling under a $100,000 willingness-to-pay threshold. Results were robust to extensive sensitivity analyses, including variations in clopidogrel cost, exclusion of costs in extended years of life, and a recalibrated estimate of survival reflecting a lower underlying mortality risk in the United States.For PLATO-eligible ACS patients, a U.S. perspective comparison of the current standard of dual antiplatelet therapy of aspirin with clopidogrel versus aspirin plus ticagrelor showed that the ticagrelor regimen increased life expectancy at an incremental cost well within accepted benchmarks of good value for money. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

  View details for DOI 10.1016/j.jacc.2014.11.034

  View details for Web of Science ID 000348667000012

• Economic analysis of ticagrelor therapy from a U.S. perspective: results from the PLATO study. Journal of the American College of Cardiology Cowper, P. A., Pan, W., Anstrom, K. J., Kaul, P., Wallentin, L., Davidson-Ray, L., Nikolic, E., Janzon, M., Levin, L. Å., Cannon, C. P., Harrington, R. A., Mark, D. B. 2015; 65 (5): 465-76

  Abstract

  Based on results of the PLATO (Platelet Inhibition and Patient Outcomes) trial comparing ticagrelor with clopidogrel therapy, the U.S. Food and Drug Administration approved ticagrelor in 2011 for reducing thrombotic cardiovascular events in patients with acute coronary syndrome (ACS) with the proviso that it be taken with low-dose aspirin.This study sought to assess the cost and cost effectiveness of ticagrelor therapy relative to clopidogrel in treating ACS patients from the perspective of the U.S. health care system.We estimated within-trial resource use and costs using U.S. low-dose aspirin patients in PLATO (n = 547). Quality-adjusted life expectancy was estimated using the total PLATO population (n = 18,624), combined with baseline risk and long-term survival data from an external ACS patient cohort. Study drugs were valued at current costs. Cost effectiveness was assessed, as was the sensitivity of results to sampling and methodological uncertainties.One year of ticagrelor therapy, relative to that of generic clopidogrel, cost $29,665/quality-adjusted life-year gained, with 99% of bootstrap estimates falling under a $100,000 willingness-to-pay threshold. Results were robust to extensive sensitivity analyses, including variations in clopidogrel cost, exclusion of costs in extended years of life, and a recalibrated estimate of survival reflecting a lower underlying mortality risk in the United States.For PLATO-eligible ACS patients, a U.S. perspective comparison of the current standard of dual antiplatelet therapy of aspirin with clopidogrel versus aspirin plus ticagrelor showed that the ticagrelor regimen increased life expectancy at an incremental cost well within accepted benchmarks of good value for money. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

  View details for DOI 10.1016/j.jacc.2014.11.034

  View details for PubMedID 25660925

• More Than 10 Million Steps in the Right Direction: Results From the First American Heart Association Scientific Sessions Walking Challenge PROGRESS IN CARDIOVASCULAR DISEASES Harrington, R. A., Arena, R., Despres, J., Ciarochi, A., Croll, E., Bloch, K. D. 2015; 57 (4): 296-298

  Abstract

  In 2013, the Global Congress theme at the American Heart Association (AHA) Annual Scientific Sessions was Physical Activity (PA). As a key component of the Congress, iHealth working in collaboration with AHA provided a Bluetooth-enabled wireless PA and sleep tracker to up to 2,000 Scientific Sessions attendees. Approximately 1850 Scientific Sessions attendees registered for, received a PA tracker and participated in the Walking Challenge. More than 10 million steps were walked by participants (10,703,504) during the 2.5 days of the Walking Challenge. This translates into almost 6000 miles walked (5976.3 miles) and 656,716 calories burned by participants during the Challenge. The Global Congress of PA held at Scientific Sessions 2013 not only extensively reviewed the science of PA as a powerful/independent and, most importantly, modifiable cardiovascular risk factor, but it also provided evidence from a fun and entertaining challenge that PA as a risk behavior can be assessed and targeted. We just took 10 million steps in the right direction. Join us and make your steps count!

  View details for DOI 10.1016/j.pcad.2014.09.009

  View details for Web of Science ID 000348003900002

  View details for PubMedID 25269063

• Recognition of biomarker identified high-risk patients in the acute medically ill venous thromboembolism prevention with extended duration betrixaban study resulting in a protocol amendment. American heart journal Cohen, A. T., Harrington, R., Goldhaber, S. Z., Hull, R., Gibson, C. M., Hernandez, A. F., Gold, A. 2015; 169 (1): 186-187

  View details for DOI 10.1016/j.ahj.2014.09.004

  View details for PubMedID 25497265

• Selecting revascularization strategies in patients with coronary disease. The New England journal of medicine Harrington, R. A. 2015; 372 (13): 1261–63

  View details for PubMedID 25774977

• Appropriate Use Criteria for Coronary Revascularization and the Learning Health System: A Good Start. JAMA Harrington, R. A. 2015; 314 (19): 2029–31

  View details for PubMedID 26550932

• 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

• D-Dimer elevation and adverse outcomes JOURNAL OF THROMBOSIS AND THROMBOLYSIS Halaby, R., Popma, C. J., Cohen, A., Chi, G., Zacarkim, M. R., Romero, G., Goldhaber, S. Z., Hull, R., Hernandez, A., Mentz, R., Harrington, R., Lip, G., Peacock, F., Welker, J., Martin-Loeches, I., Daaboul, Y., Korjian, S., Gibson, C. M. 2015; 39 (1): 55-59

  Abstract

  D-Dimer is a biomarker of fibrin formation and degradation. While a D-dimer within normal limits is used to rule out the diagnosis of deep venous thrombosis and pulmonary embolism among patients with a low clinical probability of venous thromboembolism (VTE), the prognostic association of an elevated D-dimer with adverse outcomes has received far less emphasis. An elevated D-dimer is independently associated with an increased risk for incident VTE, recurrent VTE, and mortality. An elevated D-dimer is an independent correlate of increased mortality and subsequent VTE across a broad variety of disease states. Therefore, medically ill subjects in whom the D-dimer is elevated constitute a high risk subgroup in which the prospective evaluation of the efficacy and safety of antithrombotic therapy is warranted.

  View details for DOI 10.1007/s11239-014-1101-6

  View details for Web of Science ID 000348660300008

  View details for PubMedID 25006010

  View details for PubMedCentralID PMC4300425

• 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

• 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

• Predictors of contemporary coronary artery bypass grafting outcomes JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Weisel, R. D., Nussmeier, N., Newman, M. F., Pearl, R. G., Wechsler, A. S., Ambrosio, G., Pitt, B., Clare, R. M., Pieper, K. S., Mongero, L., Reece, T. L., Yau, T. M., Fremes, S., Menasche, P., Lira, A., Harrington, R. A., Ferguson, T. B. 2014; 148 (6): 2720-U1368

  Abstract

  The study objective was to identify the predictors of outcomes in a contemporary cohort of patients from the Reduction in cardiovascular Events by acaDesine in patients undergoing CABG (RED-CABG) trial. Despite the increasing risk profile of patients who undergo coronary artery bypass grafting, morbidity and mortality have remained low, and identification of the current predictors of adverse outcomes may permit new treatments to further improve outcomes.The RED-CABG trial was a multicenter, randomized, double-blind, placebo-controlled study that determined that acadesine did not reduce adverse events in moderately high-risk patients undergoing nonemergency coronary artery bypass grafting. The primary efficacy end point was a composite of all-cause death, nonfatal stroke, or the need for mechanical support for severe left ventricular dysfunction through postoperative day 28. Logistic regression modeling with stepwise variable selection identified which prespecified baseline characteristics were associated with the primary outcome. A second logistic model included intraoperative variables as potential covariates.The 4 independent preoperative risk factors predictive of the composite end point were (1) a history of heart failure (odds ratio, 2.9); (2) increasing age (odds ratio, 1.033 per decade); (3) a history of peripheral vascular disease (odds ratio, 1.6); and (4) receiving aspirin before coronary artery bypass grafting (odds ratio, 0.5), which was protective. The duration of the cardiopulmonary bypass (odds ratio, 1.8) was the only intraoperative variable that contributed to adverse outcomes.Patients who had heart failure and preserved systolic function had a similar high risk of adverse outcomes as those with low ejection fractions, and new approaches may mitigate this risk. Recognition of patients with excessive atherosclerotic burden may permit perioperative interventions to improve their outcomes. The contemporary risks of coronary artery bypass grafting have changed, and their identification may permit new methods to improve outcomes.

  View details for DOI 10.1016/j.jtcvs.2014.08.018

  View details for Web of Science ID 000345686100064

  View details for PubMedID 25218533

• Extent, Location, and Clinical Significance ? of Non-Infarct-Related Coronary Artery Disease Among Patimts With ST-Elevation Myocardial Infarction JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Park, D., Clare, R. M., Schulte, P. J., Pieper, K. S., Shaw, L. K., Califf, R. M., Ohman, E. M., Van de Werf, F., Hirji, S., Harrington, R. A., Armstrong, P. W., Granger, C. B., Jeong, M., Patel, M. R. 2014; 312 (19): 2019-2027

  Abstract

  Little information exists about the anatomical characteristics and clinical relevance of non-infarct-related artery (IRA) disease among patients with ST-segment elevation myocardial infarction (STEMI).To investigate the incidence, extent, and location of obstructive non-IRA disease and compare 30-day mortality according to the presence of non-IRA disease in patients with STEMI.Retrospective study of patients pooled from a convenience sample of 8 independent, international, randomized STEMI clinical trials published between 1993 and 2007. Follow-up varied from 1 month to 1 year. Among 68,765 patients enrolled in the trials, 28,282 patients with valid angiographic information were included in this analysis. Obstructive coronary artery disease was defined as stenosis of 50% or more of the diameter of a major epicardial artery. To assess the generalizability of trial-based results, external validation was performed using observational data for patients with STEMI from the Korea Acute Myocardial Infarction Registry (KAMIR) (between November 1, 2005, and December 31, 2013; n = 18,217) and the Duke Cardiovascular Databank (between January 1, 2005, and December 31, 2012; n = 1812).Thirty-day mortality following STEMI.Overall, 52.8% (14,929 patients) had obstructive non-IRA disease; 29.6% involved 1 vessel and 18.8% involved 2 vessels. There was no substantial difference in the extent and distribution of non-IRA disease according to the IRA territory. Unadjusted and adjusted rates of 30-day mortality were significantly higher in patients with non-IRA disease than in those without non-IRA disease (unadjusted, 4.3% vs 1.7%, respectively; risk difference, 2.7% [95% CI, 2.3% to 3.0%], P < .001; and adjusted, 3.3% vs 1.9%, respectively; risk difference, 1.4% [95% CI, 1.0% to 1.8%], P < .001). The overall prevalence and association of non-IRA disease with 30-day mortality was consistent with findings from the KAMIR registry (adjusted, 3.6% for patients with non-IRA disease vs 2.5% in those without it; risk difference, 1.1% [95% CI, 0.6% to 1.7%]; P < .001), but not with the Duke database (adjusted, 4.7% with non-IRA disease vs 4.3% without it; risk difference, 0.4% [95% CI, -1.4% to 2.2%], P = .65).In a retrospective pooled analysis of 8 clinical trials, obstructive non-IRA disease was common among patients presenting with STEMI, and was associated with a modest statistically significant increase in 30-day mortality. These findings require confirmation in prospectively designed studies, but raise questions about the appropriateness and timing of non-IRA revascularization in patients with STEMI.

  View details for DOI 10.1001/jama.2014.15095

  View details for Web of Science ID 000345450500016

• Extent, location, and clinical significance of non-infarct-related coronary artery disease among patients with ST-elevation myocardial infarction. JAMA Park, D. W., Clare, R. M., Schulte, P. J., Pieper, K. S., Shaw, L. K., Califf, R. M., Ohman, E. M., Van de Werf, F., Hirji, S., Harrington, R. A., Armstrong, P. W., Granger, C. B., Jeong, M. H., Patel, M. R. 2014; 312 (19): 2019-27

  Abstract

  Little information exists about the anatomical characteristics and clinical relevance of non-infarct-related artery (IRA) disease among patients with ST-segment elevation myocardial infarction (STEMI).To investigate the incidence, extent, and location of obstructive non-IRA disease and compare 30-day mortality according to the presence of non-IRA disease in patients with STEMI.Retrospective study of patients pooled from a convenience sample of 8 independent, international, randomized STEMI clinical trials published between 1993 and 2007. Follow-up varied from 1 month to 1 year. Among 68,765 patients enrolled in the trials, 28,282 patients with valid angiographic information were included in this analysis. Obstructive coronary artery disease was defined as stenosis of 50% or more of the diameter of a major epicardial artery. To assess the generalizability of trial-based results, external validation was performed using observational data for patients with STEMI from the Korea Acute Myocardial Infarction Registry (KAMIR) (between November 1, 2005, and December 31, 2013; n = 18,217) and the Duke Cardiovascular Databank (between January 1, 2005, and December 31, 2012; n = 1812).Thirty-day mortality following STEMI.Overall, 52.8% (14,929 patients) had obstructive non-IRA disease; 29.6% involved 1 vessel and 18.8% involved 2 vessels. There was no substantial difference in the extent and distribution of non-IRA disease according to the IRA territory. Unadjusted and adjusted rates of 30-day mortality were significantly higher in patients with non-IRA disease than in those without non-IRA disease (unadjusted, 4.3% vs 1.7%, respectively; risk difference, 2.7% [95% CI, 2.3% to 3.0%], P < .001; and adjusted, 3.3% vs 1.9%, respectively; risk difference, 1.4% [95% CI, 1.0% to 1.8%], P < .001). The overall prevalence and association of non-IRA disease with 30-day mortality was consistent with findings from the KAMIR registry (adjusted, 3.6% for patients with non-IRA disease vs 2.5% in those without it; risk difference, 1.1% [95% CI, 0.6% to 1.7%]; P < .001), but not with the Duke database (adjusted, 4.7% with non-IRA disease vs 4.3% without it; risk difference, 0.4% [95% CI, -1.4% to 2.2%], P = .65).In a retrospective pooled analysis of 8 clinical trials, obstructive non-IRA disease was common among patients presenting with STEMI, and was associated with a modest statistically significant increase in 30-day mortality. These findings require confirmation in prospectively designed studies, but raise questions about the appropriateness and timing of non-IRA revascularization in patients with STEMI.

  View details for DOI 10.1001/jama.2014.15095

  View details for PubMedID 25399277

• 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

• 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

• 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

• 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

  View details for DOI 10.1016/j.jacc.2014.07.537

  View details for Web of Science ID 000359649700476

• 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

• Prognostic implications of major bleeding on mortality in ACS patients. An analysis of the PLATO trial Ducrocq, G., Schulte, P. J., Cannon, C. P., Becker, R. C., Harrington, R. A., Held, C., Himmelmann, A., Sorbets, E., Wallentin, L., Steg, P. G. OXFORD UNIV PRESS. 2014: 724

  View details for Web of Science ID 000343001304274

• 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

• Early benefit of cangrelor in patients undergoing PCI in CHAMPION PHOENIX Cavender, M., Harrington, R., Stone, G., Mahaffey, K., Skerjanec, S., Prats, J., Liu, T., Day, J., Deliargyris, E., Bhatt, D. OXFORD UNIV PRESS. 2014: 136

  View details for Web of Science ID 000343001300505

• Cangrelor reduces large, prognostically important, myocardial infarctions in patients undergoing PCI: findings from CHAMPION-PHOENIX Cavender, M., Bhatt, D., Stone, G., White, H., Leonardi, S., Prats, J., Liu, T., Day, J., Mahaffey, K., Harrington, R. OXFORD UNIV PRESS. 2014: 1031

  View details for Web of Science ID 000343001306231

• 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

• Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial EUROPEAN HEART JOURNAL Lindholm, D., Varenhorst, C., Cannon, C. P., Harrington, R. A., Himmelmann, A., Maya, J., Husted, S., Steg, P. G., Cornel, J. H., Storey, R. F., Stevens, S. R., Wallentin, L., James, S. K. 2014; 35 (31): 2083-2093

  Abstract

  The optimal platelet inhibition strategy for ACS patients managed without revascularization is unknown. We aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non-ST-elevation acute coronary syndrome (NSTE-ACS) subgroup of the PLATO trial, in the total cohort, and in the subgroups managed with and without revascularization within 10 days of randomization.We performed a retrospective analysis of the primary endpoint of cardiovascular death/myocardial infarction/stroke. Among 18 624 PLATO patients, 11 080 (59%) were categorized as NSTE-ACS at randomization. During the initial 10 days, 74% had angiography, 46% PCI, and 5% CABG. In NSTE-ACS patients, the primary endpoint was reduced with ticagrelor vs. clopidogrel [10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% confidence interval (CI) = 0.74-0.93], as was myocardial infarction (6.6 vs. 7.7%; HR 0.86; 95% CI = 0.74-0.99), cardiovascular death (3.7 vs. 4.9%; HR 0.77; 95% CI = 0.64-0.93), and all-cause death (4.3 vs. 5.8%; HR 0.76; 95% CI = 0.64-0.90). Major bleeding rate was similar between treatment groups (13.4 vs. 12.6%; HR 1.07; 95% CI = 0.95-1.19), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs. 3.8%; HR 1.28; 95% CI = 1.05-1.56). Within the first 10 days, 5366 (48.4%) patients were managed without revascularization. Regardless of revascularization or not, ticagrelor consistently reduced the primary outcome (HR 0.86 vs. 0.85, interaction P = 0.93), and all-cause death (HR 0.75 vs. 0.73, interaction P = 0.89) with no significant increase in overall major bleeding.In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall PLATO trial, independent of actually performed revascularization during the initial 10 days.

  View details for DOI 10.1093/eurheartj/ehu160

  View details for Web of Science ID 000342232600013

  View details for PubMedID 24727884

  View details for PubMedCentralID PMC4132637

• Vein Graft Preservation Solutions, Patency, and Outcomes After Coronary Artery Bypass Graft Surgery Follow-up From PREVENT IV Randomized Clinical Trail JAMA SURGERY Harskamp, R. E., Alexander, J. H., Schulte, P. J., Brophy, C. M., Mack, M. J., Peterson, E. D., Williams, J. B., Gibson, C. M., Califf, R. M., Kouchoukos, N. T., Harrington, R. A., Ferguson, T. B., Lopes, R. D. 2014; 149 (8): 798-805

  Abstract

  In vitro and animal model data suggest that intraoperative preservation solutions may influence endothelial function and vein graft failure (VGF) after coronary artery bypass graft (CABG) surgery. Clinical studies to validate these findings are lacking.To evaluate the effect of vein graft preservation solutions on VGF and clinical outcomes in patients undergoing CABG surgery.Data from the Project of Ex-Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) study, a phase 3, multicenter, randomized, double-blind, placebo-controlled trial that enrolled 3014 patients at 107 US sites from August 1, 2002, through October 22, 2003, were used. Eligibility criteria for the trial included CABG surgery for coronary artery disease with at least 2 planned vein grafts.Preservation of vein grafts in saline, blood, or buffered saline solutions.One-year angiographic VGF and 5-year rates of death, myocardial infarction, and subsequent revascularization.Most patients had grafts preserved in saline (1339 [44.4%]), followed by blood (971 [32.2%]) and buffered saline (507 [16.8%]). Baseline characteristics were similar among groups. One-year VGF rates were much lower in the buffered saline group than in the saline group (patient-level odds ratio [OR], 0.59 [95% CI, 0.45-0.78; P < .001]; graft-level OR, 0.63 [95% CI, 0.49-0.79; P < .001]) or the blood group (patient-level OR, 0.62 [95% CI, 0.46-0.83; P = .001]; graft-level OR, 0.63 [95% CI, 0.48-0.81; P < .001]). Use of buffered saline solution also tended to be associated with a lower 5-year risk for death, myocardial infarction, or subsequent revascularization compared with saline (hazard ratio, 0.81 [95% CI, 0.64-1.02; P = .08]) and blood (0.81 [0.63-1.03; P = .09]) solutions.Patients undergoing CABG whose vein grafts were preserved in a buffered saline solution had lower VGF rates and trends toward better long-term clinical outcomes compared with patients whose grafts were preserved in saline- or blood-based solutions.clinicaltrials.gov Identifier: NCT00042081.

  View details for DOI 10.1001/jamasurg.2014.87

  View details for PubMedID 25073921

• A Registry-Based Randomized Trial Comparing Radial and Femoral Approaches in Women Undergoing Percutaneous Coronary Intervention The SAFE-PCI for Women (Study of Access Site for Enhancement of PCI for Women) Trial JACC-CARDIOVASCULAR INTERVENTIONS Rao, S. V., Hess, C. N., Barham, B., Aberle, L. H., Anstrom, K. J., Patel, T. B., Jorgensen, J. P., Mazzaferri, E. L., Jolly, S. S., Jacobs, A., Newby, L. K., Gibson, C. M., Kong, D. F., Mehran, R., Waksman, R., Gilchrist, I. C., McCourt, B. J., Messenger, J. C., Peterson, E. D., Harrington, R. A., Krucoff, M. W. 2014; 7 (8): 857-867

  Abstract

  This study sought to determine the effect of radial access on outcomes in women undergoing percutaneous coronary intervention (PCI) using a registry-based randomized trial.Women are at increased risk of bleeding and vascular complications after PCI. The role of radial access in women is unclear.Women undergoing cardiac catheterization or PCI were randomized to radial or femoral arterial access. Data from the CathPCI Registry and trial-specific data were merged into a final study database. The primary efficacy endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding or vascular complications requiring intervention. The primary feasibility endpoint was access site crossover. The primary analysis cohort was the subgroup undergoing PCI; sensitivity analyses were conducted in the total randomized population.The trial was stopped early for a lower than expected event rate. A total of 1,787 women (691 undergoing PCI) were randomized at 60 sites. There was no significant difference in the primary efficacy endpoint between radial or femoral access among women undergoing PCI (radial 1.2% vs. 2.9% femoral, odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.12 to 1.27); among women undergoing cardiac catheterization or PCI, radial access significantly reduced bleeding and vascular complications (0.6% vs. 1.7%; OR: 0.32; 95% CI: 0.12 to 0.90). Access site crossover was significantly higher among women assigned to radial access (PCI cohort: 6.1% vs. 1.7%; OR: 3.65; 95% CI: 1.45 to 9.17); total randomized cohort: (6.7% vs. 1.9%; OR: 3.70; 95% CI: 2.14 to 6.40). More women preferred radial access.In this pragmatic trial, which was terminated early, the radial approach did not significantly reduce bleeding or vascular complications in women undergoing PCI. Access site crossover occurred more often in women assigned to radial access. (SAFE-PCI for Women; NCT01406236).

  View details for DOI 10.1016/j.jcin.2014.04.007

  View details for Web of Science ID 000340894700012

  View details for PubMedID 25147030

• Association of metabolic syndrome and its individual components with outcomes among patients with high-risk non-ST-segment elevation acute coronary syndromes AMERICAN HEART JOURNAL Mehta, R. H., Westerhout, C. M., Zheng, Y., Giugliano, R. P., Huber, K., Prabhakaran, D., Harrington, R. A., Newby, K. L., Armstrong, P. W. 2014; 168 (2): 182-?

  Abstract

  The relationship of metabolic syndrome and its individual components (obesity, hypertension, glucose intolerance, high triglycerides, and low high-density lipoprotein cholesterol) with 1-year mortality in non-ST-segment elevation acute coronary syndromes (NSTE ACS) patients is not known.The association of metabolic syndrome (and its individual components) with all-cause mortality within 1 year was assessed in NSTE ACS patients enrolled in the EARLY ACS trial. Adjusted hazard ratio (HR) and 95% CIs are reported.Of 9,406 patients, 2,596 (27.6%) had metabolic syndrome. Compared with those without metabolic syndrome, patients with this syndrome were younger, were more often female, and had a higher prevalence of comorbid conditions and higher-risk presenting features. Metabolic syndrome was not associated with increased 1-year mortality (HR 1.20, 95% CI 0.97-1.47; P = .09). The risk of 1-year mortality varied across the individual components: high-density lipoprotein <40 mg/dL (men)/<50 mg/dL (women; or dyslipidemia) was associated with higher risk (HR 1.52, 95% CI 1.15-2.02), and triglycerides >150 mg/dL (or dyslipidemia) was associated with lower risk (HR 0.66, 95% CI 0.54-0.81), whereas the other components (ie, body mass index >30 kg/m(2), fasting plasma glucose >100 mg/dL or diabetes, systolic blood pressure >130 mm Hg or diastolic >85 mm Hg [or hypertension]) were associated with neutral risk of this event.The individual components of metabolic syndrome had varying associations with 1-year mortality, and as an integrated diagnosis, metabolic syndrome was not significantly associated with 1-year mortality. Thus, patient case-mix of the studied NSTE ACS population may influence the observed relationship of metabolic syndrome with subsequent cardiovascular events.

  View details for DOI 10.1016/j.ahj.2014.04.009

  View details for Web of Science ID 000340207700012

  View details for PubMedID 25066557

• A 'green button' for using aggregate patient data at the point of care. Health affairs Longhurst, C. A., Harrington, R. A., Shah, N. H. 2014; 33 (7): 1229-1235

  Abstract

  Randomized controlled trials have traditionally been the gold standard against which all other sources of clinical evidence are measured. However, the cost of conducting these trials can be prohibitive. In addition, evidence from the trials frequently rests on narrow patient-inclusion criteria and thus may not generalize well to real clinical situations. Given the increasing availability of comprehensive clinical data in electronic health records (EHRs), some health system leaders are now advocating for a shift away from traditional trials and toward large-scale retrospective studies, which can use practice-based evidence that is generated as a by-product of clinical processes. Other thought leaders in clinical research suggest that EHRs should be used to lower the cost of trials by integrating point-of-care randomization and data capture into clinical processes. We believe that a successful learning health care system will require both approaches, and we suggest a model that resolves this escalating tension: a "green button" function within EHRs to help clinicians leverage aggregate patient data for decision making at the point of care. Giving clinicians such a tool would support patient care decisions in the absence of gold-standard evidence and would help prioritize clinical questions for which EHR-enabled randomization should be carried out. The privacy rule in the Health Insurance Portability and Accountability Act (HIPAA) of 1996 may require revision to support this novel use of patient data.

  View details for DOI 10.1377/hlthaff.2014.0099

  View details for PubMedID 25006150

• Utilisation of novel anti-platelet agents: evidence, guidelines and proven patients' value THROMBOSIS AND HAEMOSTASIS Wallentin, L., Himmelmann, A., Storey, R. F., Steg, P., Harrington, R. A., PLATO Publications Comm 2014; 112 (1): 12-14

  View details for DOI 10.1160/TH14-04-0328

  View details for Web of Science ID 000338820300004

  View details for PubMedID 24816949

• Antiplatelet and Anticoagulation Therapy for Acute Coronary Syndromes CIRCULATION RESEARCH Bhatt, D. L., Hulot, J., Moliterno, D. J., Harrington, R. A. 2014; 114 (12): 1929-1943

  Abstract

  The past 2 decades have witnessed the introduction and demise of several different antithrombotic medications for acute coronary syndromes. Part of the assessment of these compounds has been their effect on thrombotic events relative to the degree of increase in bleeding events. This review will outline the data supporting various antiplatelet and anticoagulant therapies and their combinations in patients with acute coronary syndromes and related disorders in both the acute and chronic phases of therapy.

  View details for DOI 10.1161/CIRCRESAHA.114.302737

  View details for Web of Science ID 000337707200008

  View details for PubMedID 24902976

• 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

• 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

• 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

  View details for DOI 10.1161/CIRCULATIONAHA.114.009353

  View details for Web of Science ID 000335638500004

  View details for PubMedID 24821832

• 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

  View details for DOI 10.1160/TH13-07-0624

  View details for Web of Science ID 000335541500013

• 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

• Angiographic Outcomes With Early Eptifibatide Therapy in Non-ST-Segment Elevation Acute Coronary Syndrome (from the EARLY ACS Trial) AMERICAN JOURNAL OF CARDIOLOGY Kunadian, V., Giugliano, R. P., Newby, L. K., Zorkun, C., Guo, J., Bagai, A., Montalescot, G., Braunwald, E., Califf, R. M., Van de Werf, F., Armstrong, P. W., Harrington, R., Gibson, C. M. 2014; 113 (8): 1297-1305

  Abstract

  Early administration of glycoprotein IIbIIIa inhibitors results in improved angiographic parameters, including thrombolysis in myocardial infarction (TIMI) flow grade, corrected TIMI frame count, and TIMI myocardial perfusion grade (TMPG) among patients with ST-segment elevation myocardial infarction. Whether the same is true in the setting of non-ST-segment elevation acute coronary syndrome is unknown. The goal of the early glycoprotein IIbIIIa inhibition in non-ST-segment elevation acute coronary syndrome (EARLY ACS) angiographic substudy was to compare angiographic outcomes among patients with non-ST-segment elevation acute coronary syndrome who were administered early routine versus delayed provisional eptifibatide. Of 9,406 patients in the EARLY ACS trial, 2,066 patients were included in the angiographic substudy (early routine eptifibatide [n=1,042] or early placebo [n=1,024] with delayed provisional eptifibatide after angiography and before percutaneous coronary intervention [PCI]). The angiographic substudy primary end point was the incidence of TMPG 3 before and after PCI. TMPG 3 before (43.7% vs 44.9%, p=0.58) and after PCI (52.4% vs 50.1%, p=0.73) was similar for early routine versus delayed provisional eptifibatide, respectively. Angiographic procedural complications consisting of a composite of loss of side branch, abrupt vessel closure, distal embolization, and no reflow occurred less frequently in early routine group versus delayed provisional group (9.3% vs 13.6%, respectively, p=0.01). In the EARLY ACS angiographic substudy, the use of early routine eptifibatide resulted in fewer angiographic procedural complications. These data provide support for the use of eptifibatide in the catheterization laboratory during high-risk cases merely to prevent angiographic procedural complications.

  View details for DOI 10.1016/j.amjcard.2014.01.404

  View details for Web of Science ID 000334648000006

  View details for PubMedID 24607027

• Ferric carboxymaltose in patients with iron-deficiency anemia and impaired renal function: the REPAIR-IDA trial NEPHROLOGY DIALYSIS TRANSPLANTATION Onken, J. E., Bregman, D. B., Harrington, R. A., Morris, D., Buerkert, J., Hamerski, D., Iftikhar, H., Mangoo-Karim, R., Martin, E. R., Martinez, C. O., Newman, G. E., Qunibi, W. Y., Ross, D. L., Singh, B., Smith, M. T., Butcher, A., Koch, T. A., Goodnough, L. T. 2014; 29 (4): 833-842

  Abstract

  Iron-deficiency anemia in non-dialysis-dependent chronic kidney disease (NDD-CKD) frequently requires parenteral iron replacement, but existing therapies often require multiple administrations. We evaluated the efficacy and cardiovascular safety of ferric carboxymaltose (FCM), a non-dextran parenteral iron permitting large single-dose infusions, versus iron sucrose in patients with iron-deficiency anemia and NDD-CKD.A total of 2584 participants were randomized to two doses of FCM 750 mg in one week, or iron sucrose 200 mg administered in up to five infusions in 14 days. The primary efficacy endpoint was the mean change to highest hemoglobin from baseline to Day 56. The primary composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, congestive heart failure, arrhythmias and hyper- and hypotensive events.The mean hemoglobin increase was 1.13 g/dL in the FCM group and 0.92 g/dL in the iron sucrose group (95% CI, 0.13-0.28). Similar results were observed across all subgroups, except Stage 2 CKD. More subjects in the FCM group achieved a hemoglobin increase of ≥ 1.0 g/dL between baseline and Day 56 (48.6 versus 41.0%; 95% CI, 3.6-11.6%). There was no significant difference between FCM and iron sucrose recipients with respect to the primary composite safety endpoint, including the major adverse cardiac events of death, myocardial infarction, or stroke. A significant difference in the number of protocol-defined, predominantly transient hypertensive episodes was observed in the FCM group.Two 750-mg infusions of FCM are a safe and effective alternative to multiple lower dose iron sucrose infusions in NDD-CKD patients with iron-deficiency anemia.

  View details for DOI 10.1093/ndt/gft251

  View details for Web of Science ID 000336093700020

  View details for PubMedID 23963731

• 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

  View details for DOI 10.1016/S0735-1097(14)60036-X

  View details for Web of Science ID 000359579100037

• 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

• The design and rationale for the Acute Medically Ill Venous Thromboembolism Prevention with Extended Duration Betrixaban (APEX) study. American heart journal Cohen, A. T., Harrington, R., Goldhaber, S. Z., Hull, R., Gibson, C. M., Hernandez, A. F., Kitt, M. M., Lorenz, T. J. 2014; 167 (3): 335-341

  Abstract

  Randomized clinical trials have identified a population of acute medically ill patients who remain at risk for venous thromboembolism (VTE) beyond the standard duration of therapy and hospital discharge. The aim of the APEX study is to determine whether extended administration of oral betrixaban (35-42 days) is superior to a standard short course of prophylaxis with subcutaneous enoxaparin (10 ± 4 days followed by placebo) in patients with known risk factors for post-discharge VTE. Patients initially are randomized to receive either betrixaban or enoxaparin (and matching placebo) in a double dummy design. Following a standard duration period of enoxaparin treatment (with placebo tablets) or betrixaban (with placebo injections), patients receive only betrixaban (or alternative matching placebo). Patients are considered for enrollment if they are older than 40 years, have a specified medical illness, and restricted mobility. They must also meet the APEX criteria for increased VTE risk (aged ≥75 years, baseline D-Dimer ≥2× upper the limit of "normal", or 2 additional ancillary risk factors for VTE). The primary efficacy end point is the composite of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, non-fatal (pulmonary embolus) pulmonary embolism, or VTE-related death through day 35. The primary safety outcome is the occurrence of major bleeding. We hypothesize that extended duration betrixaban VTE prophylaxis will be safe and more effective than standard short duration enoxaparin in preventing VTE in acute medically ill patients with known risk factors for post hospital discharge VTE.

  View details for DOI 10.1016/j.ahj.2013.11.006

  View details for PubMedID 24576517

• Outcomes among non-ST-segment elevation acute coronary syndromes patients with no angiographically obstructive coronary artery disease: observations from 37,101 patients EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE De Ferrari, G. M., Fox, K. A., White, J. A., Giugliano, R. P., Tricoci, P., Reynolds, H. R., Hochman, J. S., Gibson, C., Theroux, P., Harrington, R. A., Van de Werf, F., White, H. D., Califf, R. M., Newby, L. 2014; 3 (1): 37-45

  Abstract

  Limited data exist concerning outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) with no angiographically obstructive coronary artery disease (non-obstructive CAD). We assessed the frequency of clinical outcomes among patients with non-obstructive CAD compared with obstructive CAD.We pooled data from eight NSTE ACS randomized clinical trials from 1994 to 2008, including 37,101 patients who underwent coronary angiography. The primary outcome was 30-day death or myocardial infarction (MI). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day death or MI for non-obstructive versus obstructive CAD were generated for each trial. Summary ORs (95% CIs) across trials were generated using random effects models. Overall, 3550 patients (9.6%) had non-obstructive CAD. They were younger, more were female, and fewer had diabetes mellitus, previous MI or prior percutaneous coronary intervention than patients with obstructive CAD. Thirty-day death or MI was less frequent among patients with non-obstructive CAD (2.2%) versus obstructive CAD (13.3%) (OR(adj) 0.15; 95% CI, 0.11-0.20); 30-day death or spontaneous MI and six-month mortality were also less frequent among patients with non-obstructive CAD (OR(adj) 0.19 (0.14-0.25) and 0.37 (0.28-0.49), respectively).Among patients with NSTE ACS, one in 10 had non-obstructive CAD. Death or MI occurred in 2.2% of these patients by 30 days. Compared with patients with obstructive CAD, the rate of major cardiac events was lower in patients with non-obstructive CAD but was not negligible, prompting the need to better understand management strategies for this group.

  View details for DOI 10.1177/2048872613489315

  View details for Web of Science ID 000420080100005

  View details for PubMedID 24562802

  View details for PubMedCentralID PMC3932771

• 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

• A multicenter, randomized, active-controlled study to investigate the efficacy and safety of intravenous ferric carboxymaltose in patients with iron deficiency anemia TRANSFUSION Onken, J. E., Bregman, D. B., Harrington, R. A., Morris, D., Acs, P., Akright, B., Barish, C., Bhaskar, B. S., Smith-Nguyen, G. N., Butcher, A., Koch, T. A., Goodnough, L. T. 2014; 54 (2): 306-315

  Abstract

  BACKGROUND: Many patients receiving oral iron for iron deficiency anemia (IDA) cannot tolerate or fail to respond to therapy, and existing intravenous (IV) iron formulations often require repeated administrations. Ferric carboxymaltose (FCM), a nondextran IV formulation, permits larger single doses. STUDY DESIGN AND METHODS: We evaluated FCM versus oral iron in IDA patients. After 14 days of oral iron, 507 participants responding inadequately to oral iron (hemoglobin [Hb] increase <1 g/dL; Cohort 1) were assigned to Group A (two doses of FCM, 750 mg, 1 week apart) or Group B (oral iron, 325 mg, 3 × day for 14 additional days). Also, 504 subjects not appropriate for oral iron (Cohort 2) were assigned to Group C (FCM as above) or Group D (standard-of-care IV iron). The primary efficacy endpoint was change to highest observed Hb from baseline to Day 35. The composite safety endpoint included all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, unstable angina, heart failure, arrhythmias, and hyper- or hypotensive events. RESULTS: Mean (± standard deviation [SD]) Hb increase was significantly greater in Group A-FCM than Group B-oral iron: 1.57 (±1.19) g/dL versus 0.80 (±0.80) g/dL (p = 0.001). Post hoc comparison of Group C-FCM and Group D-IV standard of care also demonstrated significant mean (±SD) increase in Hb from baseline to highest value by Day 35 in Group C versus Group D: 2.90 (±1.64) g/dL versus 2.16 (±1.25) g/dL (p = 0.001). Safety endpoints occurred in 17 of 499 (3.4%) participants receiving FCM versus 16 of 498 (3.2%) in comparator groups. CONCLUSION: Two 750-mg FCM infusions are safe and superior to oral iron in increasing Hb levels in IDA patients with inadequate oral iron response.

  View details for DOI 10.1111/trf.12289

  View details for PubMedID 23772856

• 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

• 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

• Advances in understanding percutaneous coronary intervention pharmacology: ischemia, bleeding, the ISAR research group, and a commitment to progress. Coronary artery disease Harrington, R. A., Popma, C. J., Gibson, C. M. 2014; 25 (6): 453–55

  View details for PubMedID 25072657

• From abstract to peer-reviewed publication: country matters. International journal of cardiology Østergaard, L. n., Fosbøl, P. L., Harrington, R. A., Eapen, Z. J., Peterson, E. D., Fosbøl, E. L. 2014; 174 (3): 830–32

  View details for PubMedID 24794059

• Calculating risks and benefits to help guide revascularization decisions: turning all available data into useful information. Journal of the American College of Cardiology Harrington, R. A. 2014; 64 (5): 433–35

  View details for PubMedID 25082574

• A message from modern-day healthcare to physical activity and fitness: welcome home! Progress in cardiovascular diseases Arena, R. n., Harrington, R. A., Després, J. P. 2014; 57 (4): 293–95

  View details for PubMedID 25446552

• 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

• 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

  View details for Web of Science ID 000332162907142

• Preservation Solutions, Patency, and Outcomes After Coronary Bypass Surgery Harskamp, R. E., Alexander, J. H., Schulte, P. J., Brophy, C. M., Mack, M. I., Peterson, E. D., Williams, J. B., Gibson, C., Califf, R. M., Kouchoukos, N. T., Harrington, R. A., Ferguson, T. B., Lopes, R. D. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000332162903480

• Fasting Glucose, NT-proBNP, Treatment With Glycoprotein IIb/IIIa Inhibitors, and Outcomes in Non-ST-Segment Elevation Acute Coronary Syndromes: An Analysis From EARLY ACS Farhan, S., Clare, R. M., Jarai, R., Newby, L., Morrow, D., Giugliano, R. P., Lokhnygina, Y., Califf, R. M., Harrington, R. A., Huber, K. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000332162904146

• 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

  View details for Web of Science ID 000332162900452

• 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

  View details for Web of Science ID 000332162901202

• 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

  View details for Web of Science ID 000332162903040

• 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

  View details for Web of Science ID 000332162903408

• 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

  View details for Web of Science ID 000332162905212

• 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

  View details for Web of Science ID 000332162907012

• Relationship between postoperative clopidogrel use and subsequent angiographic and clinical outcomes following coronary artery bypass grafting JOURNAL OF THROMBOSIS AND THROMBOLYSIS Williams, J. B., Lopes, R. D., Hafley, G. E., Ferguson, T. B., Mack, M. J., Gibson, C. M., Harrington, R. A., Peterson, E. D., Smith, P. K., Mehta, R. H., Alexander, J. H. 2013; 36 (4): 384-393

  Abstract

  Dual antiplatelet therapy with both aspirin and clopidogrel is increasingly used after coronary artery bypass grafting (CABG); however, little is known about the safety or efficacy. We sought to determine the relationship between postoperative clopidogrel and clinical and angiographic outcomes following CABG. We evaluated 3,014 patients from PREVENT IV who underwent CABG at 107 US sites. Postoperative antiplatelet therapy was left to physician discretion. Risk-adjusted angiographic and clinical outcomes were compared in patients taking and not taking clopidogrel 30 days post-CABG. At 30 days, 633 (21 %) patients were taking clopidogrel. Clopidogrel users were more likely to have peripheral vascular (15 vs. 11 %) and cerebrovascular disease (17 vs. 11 %), prior myocardial infarction (MI) (46 vs. 41 %), and off-pump surgery (33 vs. 18 %). Clopidogrel use was associated with statistically insignificant higher graft failure (adjusted odds ratio 1.3; 95 % confidence interval [CI] [1.0, 1.7]; P = 0.05). At 5-year follow-up, clopidogrel use was associated with similar composite rates of death, MI, or revascularization (27 vs. 24 %; adjusted hazard ratio 1.1; 95 % CI [0.9, 1.4]; P = 0.38) compared with those not using clopidogrel. There was an interaction between use of cardiopulmonary bypass and clopidogrel with a trend toward lower 5-year clinical events with clopidogrel in patients undergoing off-pump CABG. In this observational analysis, clopidogrel use was not associated with better 5-year outcomes following CABG. There may be better outcomes with clopidogrel among patients having off-pump surgery. Adequately powered randomized clinical trials are needed to determine the role of dual antiplatelet therapy after CABG.

  View details for DOI 10.1007/s11239-013-0904-1

  View details for Web of Science ID 000326802500004

• Association between bleeding and mortality among women and men with high-risk acute coronary syndromes: Insights from the Early versus Delayed, Provisional Eptifibatide in Acute Coronary Syndromes (EARLY ACS) trial AMERICAN HEART JOURNAL Kaul, P., Tanguay, J., Newby, L. K., Hochman, J. S., Westerhout, C. M., Califf, R. M., Tricoci, P., Gibson, C. M., Giugliano, R. P., Harrington, R. A., Van de Werf, F., Armstrong, P. W. 2013; 166 (4): 723-728

  Abstract

  Female sex is an established risk factor for bleeding, which is an important safety end point in patients presenting with non-ST-segment elevation acute coronary syndromes (NSTE ACS). However, it is unknown whether the association between bleeding and mortality is modulated by sex in this patient population.We examined the interaction between sex and bleeding and 30-day mortality outcomes among 2,975 women and 6,431 men with high-risk NSTE ACS enrolled in the EARLY ACS trial. The Global Utilization of Strategies to Open Occluded Arteries (GUSTO) criteria were used to identify moderate or severe bleeds.Women were older and had more comorbid disease compared with men. Bleeding rates were higher among women (8.2%) than among men (5.5%; P < .01). However, the association of bleeding and 30-day mortality was stronger among men (odds ratio 5.8, 95% CI 3.9-8.8) than among women (odds ratio 1.5, 95% CI 0.8-2.9; sex * bleeding interaction P < .01). Sex differences in the association of bleeding and mortality persisted in a landmark analysis of 120-hour survivors.In a contemporary high-risk NSTE ACS cohort, women had higher bleeding rates than did men. Paradoxically, the association between bleeding and mortality was worse among men than among women.

  View details for DOI 10.1016/j.ahj.2013.07.014

  View details for Web of Science ID 000325092300027

  View details for PubMedID 24093853

• Outcomes with ticagrelor versus clopidogrel in relation to high sensitivity troponin-T in non-ST-elevation acute coronary syndrome patients managed with early invasive or non-invasive treatment - a substudy from the prospective randomized PLATelet inhibit Wallentin, L., James, S., Giannitsis, E., Katus, H., Becker, R. C., Cannon, C. P., Horrow, J., Husted, S., Siegbahn, A., Steg, G. P., Storey, R. F., Wernroth, L., Harrington, R. WILEY-BLACKWELL. 2013: E189

  View details for Web of Science ID 000325360100052

• Age, treatment, and outcomes in high-risk non-ST-segment elevation acute coronary syndrome patients: Insights from the EARLY ACS trial INTERNATIONAL JOURNAL OF CARDIOLOGY Lopes, R. D., White, J. A., Tricoci, P., White, H. D., Armstrong, P. W., Braunwald, E., Giugliano, R. P., Harrington, R. A., Lewis, B. S., Brogan, G. X., Gibson, C. M., Califf, R. M., Newby, L. K. 2013; 167 (6): 2580-2587

  Abstract

  BACKGROUND: Elderly patients with acute coronary syndromes (ACS) are at high risk for death and recurrent thrombotic events. We evaluated the efficacy and safety of intensive treatment with glycoprotein IIb/IIIa inhibitors in an elderly population, and the relationships between age, timing of administration, and clinical outcomes. METHODS: We used data from high-risk non-ST-segment elevation ACS patients randomized to early eptifibatide vs. delayed provisional use at percutaneous coronary intervention. In multivariable models, we included age×treatment interaction terms to assess whether treatment effect varied by age after adjusting for confounders. RESULTS: Of 9406 patients, 13.9% were aged <55years; 27.6%, 55-64years; 33.2%, 65-74years; and 25.3%, ≥75years. For each 10-year age increase, the adjusted odds ratio (OR) (95% confidence interval [CI]) for 96-hour death, myocardial infarction (MI), recurrent ischemia requiring urgent revascularization, or thrombotic bailout was 1.13 (1.04-1.23) and for 30-day death or MI was 1.13 (1.04-1.22). Increasing age was also associated with greater 1-year mortality (adjusted hazard ratio per 10years: 1.44, 95% CI 1.30-1.60). There was no interaction between age and treatment (p interaction=0.99, 0.54, and 0.87, respectively). Increasing age was associated with more non-coronary artery bypass grafting-related TIMI major bleeding (adjusted OR and 95% CI per 10years: 1.54 [1.24-1.92]), GUSTO moderate/severe bleeding (1.52 [1.33-1.75]), and transfusion (1.25 [1.07-1.45]). The amount by which TIMI major bleeding was increased with early vs. delayed provisional eptifibatide use was significantly greater with increasing age (p interaction=0.02), but the age×treatment interactions were not significant for GUSTO moderate/severe bleeding or transfusion (p interaction=0.33 and 0.54, respectively). CONCLUSION: Increasing age was associated with greater risk for ischemic events and more bleeding. Despite higher baseline ischemic risk in older patients, there was no preferential benefit of early vs. delayed provisional eptifibatide use for ischemic outcomes as age increased, but the incremental bleeding risk was amplified.

  View details for DOI 10.1016/j.ijcard.2012.06.053

  View details for Web of Science ID 000324478400046

  View details for PubMedID 22795720

• 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

• Duration of eptifibatide infusion after percutaneous coronary intervention and outcomes among high-risk patients with non-ST-segment elevation acute coronary syndrome: insights from EARLY ACS EUROPEAN HEART JOURNAL-ACUTE CARDIOVASCULAR CARE Hess, C. N., Schulte, P. J., Newby, L., Steg, P., Dalby, A. J., Schweiger, M. J., Lewis, B. S., Armstrong, P. W., Califf, R. M., van de Werf, F., Harrington, R. A. 2013; 2 (3): 246-255

  Abstract

  Eptifibatide is indicated during percutaneous coronary intervention (PCI) with continuation for 18-24 hours post procedure but is associated with bleeding. We examined the efficacy and safety of shorter post-PCI eptifibatide infusions in high-risk non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients.EARLY ACS patients treated with PCI and eptifibatide were grouped by post-procedure infusion duration: <10, 10-13, 13-17, and 17-25 (per protocol) hours. Adjusted estimated event rates for 96-hour death/myocardial infarction (MI)/recurrent ischaemia requiring urgent revascularization (RIUR), 30-day death/MI, post-PCI packed red blood cell (PRBC) transfusion, and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) moderate/severe bleeding were obtained using inverse-propensity weighting to account for informative censoring of infusions.Among 3271 eptifibatide-treated PCI patients, there were 66 96-hour death/MI/RIUR events, 94 30-day death/MI events, 127 PRBC transfusions, and 115 GUSTO moderate/severe bleeds. Compared with per protocol, patients receiving post-PCI infusions <10 hours had similar adjusted estimated rates of 96-hour death/MI/RIUR (absolute difference 0.021 higher; 0.040 vs. 0.019, 95% CI -0.023 to 0.064; p=0.35) and 30-day death/MI (0.020 higher; 0.046 vs. 0.026, 95% CI -0.021 to 0.062; p=0.34). There were also no differences in ischaemic outcomes between infusions of 10-17 hours and per-protocol infusions. Adjusted estimated rates of PRBC transfusion were higher for the <10-hour infusion group compared with per protocol (0.048 higher; 0.079 vs. 0.031, 95% CI 0.005 to 0.091, p=0.03) but were similar for other groups. Adjusted GUSTO moderate/severe bleeding rates were similar to per-protocol rates for all groups.In high-risk NSTE ACS patients, post-PCI eptifibatide infusions <18 hours were not associated with worse ischaemic outcomes. Shorter eptifibatide infusions in this population may be feasible.

  View details for DOI 10.1177/2048872612474922

  View details for Web of Science ID 000420079000007

  View details for PubMedID 24222836

  View details for PubMedCentralID PMC3821813

• Routine early eptifibatide versus delayed provisional use at percutaneous coronary intervention in high-risk non-ST-segment elevation acute coronary syndromes patients: An analysis from the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome trial AMERICAN HEART JOURNAL Bagai, A., White, J. A., Lokhnygina, Y., Giugliano, R. P., Van de Werf, F., Montalescot, G., Armstrong, P. W., Tricoci, P., Gibson, C. M., Califf, R. M., Harrington, R. A., Newby, L. K. 2013; 166 (3): 466-?

  Abstract

  In the EARLY ACS trial, routine early eptifibatide was not superior to delayed provisional use at percutaneous coronary intervention (PCI); however, among PCI-treated patients, numerically fewer ischemic end points occurred in the upstream eptifibatide group. We sought to further explore this finding using methods for examination of treatment effect in this postrandomization subgroup.Of 9,406 patients in the EARLY ACS primary analysis cohort, 9,166 (97.4%) underwent coronary angiography. We used Cox proportional hazards regression modeling, with PCI as a time-dependent covariate, to examine the effect of routine early versus delayed provisional eptifibatide among 5,541 patients undergoing PCI and to explore the interaction between treatment with PCI and randomized treatment strategy. After multivariable adjustment, compared with delayed provisional use, routine early eptifibatide was associated with lower rate of 30-day death or myocardial infarction (MI) after PCI (hazard ratio [HR] 0.80, 95% CI 0.68-0.95) but not with medical management (HR 0.97, 95% CI 0.74-1.29); PCI × randomized treatment interaction term P = .24. Excluding PCI-related MI, the adjusted HR for 30-day death or MI for routine early eptifibatide versus delayed provisional use was 0.80 (95% CI 0.60-1.08) for post-PCI treatment and 1.01 (95% CI 0.79-1.34) for medical management; PCI × randomized treatment interaction term P = .28.Consistent with previous literature, upstream treatment with eptifibatide was associated with improved outcomes in high-risk non-ST-segment elevation acute coronary syndrome patients treated with PCI; however, a nonsignificant interaction term precludes a definite conclusion.

  View details for DOI 10.1016/j.ahj.2013.05.019

  View details for Web of Science ID 000324163600020

  View details for PubMedID 24016495

• Quantitative ST-depression in Acute Coronary Syndromes: the PLATO Electrocardiographic Substudy AMERICAN JOURNAL OF MEDICINE Armstrong, P. W., Westerhout, C. M., Fu, Y., Harrington, R. A., Storey, R. F., Katus, H., James, S., Wallentin, L. 2013; 126 (8): 723-?

  Abstract

  We evaluated whether electrocardiogram (ECG) characteristics were aligned with clinical outcomes and the effect of ticagrelor within the diverse spectrum of non-ST-elevation acute coronary syndrome patients enrolled in the PLATelet inhibition and patient Outcomes (PLATO) trial.There were 8884 PLATO patients who had baseline ECGs assessed by a core laboratory; of these, 4935 had an ECG at hospital discharge that also was assessed. Associations with study treatment on vascular death or myocardial infarction within 1 year were examined.At baseline, most patients had either no or ≤0.5 mm of ST-segment depression (57%); 26% had 1.0 mm, and 17% had more extensive depression (>1.0 mm). Across the baseline ST-segment depression strata, there was a consistent treatment benefit with ticagrelor versus clopidogrel on vascular death/myocardial infarction. The extent of residual ST-segment depression at discharge was similar in the treatment groups, and the treatment effect did not differ by the extent of discharge ST-segment depression. There was a progressive increase in vascular death/myocardial infarction with increasing extent of baseline ST-segment depression (1.0 mm [vs no/0.5 mm]: hazard ratio [HR] 1.22; 95% confidence interval [CI], 1.03-1.45; >1.0 mm: HR 1.49; 95% CI, 1.24-1.78; P <.001) and at discharge (HR 1.28; 95% CI, 1.02-1.61; HR 2.13; 95% CI, 1.54-2.95; P <.001).The treatment effect of ticagrelor among non-ST-segment-elevation acute coronary syndrome patients was consistently expressed across all baseline ST-segment depression strata. There was no indication of an anti-ischemic benefit of ticagrelor as reflected on the discharge ECG. Our data affirm the independent prognostic relationship of both baseline and hospital discharge ST-segment depression on outcomes within 1 year in non-ST-segment-elevation acute coronary syndrome patients.

  View details for DOI 10.1016/j.amjmed.2013.01.038

  View details for Web of Science ID 000322827200027

  View details for PubMedID 23795897

• Intracranial hemorrhage in acute coronary syndrome: incidence, predictors, and outcomes from APPRAISE-2, PLATO, and TRACER Mahaffey, K. W., Horton, J., Alexander, J. H., Tricoci, P., Harrington, R. A., Wallentin, L. OXFORD UNIV PRESS. 2013: 23

  View details for Web of Science ID 000327744600074

• From abstract to peer-reviewed publication: country matters Fosbol, E., Fosbol, P. L., Eapen, Z. J., Harrington, R. A., Peterson, E. D. OXFORD UNIV PRESS. 2013: 476

  View details for Web of Science ID 000327744602662

• International variation in management and outcomes in high-risk patients following acute coronary syndromes: results from the APPRAISE-2 trial Hess, C. N., Alexander, J. H., Neely, M. L., James, S., Liaw, D., Amerena, J., Parkhomenko, A., Harrington, R. A., Lopes, R. D. OXFORD UNIV PRESS. 2013: 885

  View details for Web of Science ID 000327744605299

• Relationship between diabetes, race, obesity and outcomes in patients with acute coronary syndrome: a pool analysis from randomized trials Koshizaka, M., Lopes, R. D., Newby, L. K., Schulte, P. J., Clare, R. M., Tricoci, P., Mahaffey, K. W., Ogawa, H., Harrington, R. A., Alexander, J. H. OXFORD UNIV PRESS. 2013: 787

  View details for Web of Science ID 000327744604625

• 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

• Platelet inhibition with cangrelor during PCI. The New England journal of medicine Bhatt, D. L., Harrington, R. A. 2013; 369 (4): 393-4

  View details for DOI 10.1056/NEJMc1305978

  View details for PubMedID 23883387

• 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

• Angiographic Outcomes in the PLATO Trial (Platelet Inhibition and Patient Outcomes) JACC-CARDIOVASCULAR INTERVENTIONS Kunadian, V., James, S. K., Wojdyla, D. M., Zorkun, C., Wu, J., Storey, R. F., Steg, P. G., Katus, H., Emanuelsson, H., Horrow, J., Maya, J., Wallentin, L., Harrington, R. A., Gibson, M. 2013; 6 (7): 671-683

  Abstract

  The PLATO (Platelet Inhibition and Patient Outcomes) angiographic substudy sought to compare the efficacy of ticagrelor versus clopidogrel with respect to angiographic outcomes before and after PCI in the setting of acute coronary syndrome.Greater platelet inhibition has been associated with improved angiographic outcomes before and after percutaneous coronary intervention (PCI). Therefore, it was hypothesized that treatment with ticagrelor, which achieves more rapid, higher, and more consistent platelet inhibition, would be associated with improved angiographic outcomes when compared with those of clopidogrel treatment.The angiographic cohort consists of 2,616 patients drawn from the 18,624-patient PLATO trial. Clopidogrel naïve or pre-treated patients were randomized to 180 mg of ticagrelor or 300 mg of clopidogrel (75 mg for clopidogrel pre-treated patients). PCI patients were administered, as per treatment group: 1) an additional 90 mg of ticagrelor if >24 h following the initial loading dose; or 2) an optional further 300 mg of clopidogrel or placebo (total 600 mg) prior to PCI. The substudy primary endpoint was the incidence of post-PCI TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 (TMPG 3) among patients who received a study drug prior to PCI.In total, 21.3% of patients were pretreated with clopidogrel prior to randomization. There was a short time interval between randomization and PCI (median: 0.68 [interquartile range (IQR): 0.30 to 2.21] h) among all patients. Post-PCI TMPG 3 was similar between the ticagrelor and clopidogrel groups (47.1% vs. 46.9%; p = 0.96). Likewise, the following pre-PCI outcomes were similar in the ticagrelor and clopidogrel groups, respectively: TMPG 3 (30.5% vs. 31.2%), TIMI flow grade 3 (37.1% vs. 39.3%), corrected TIMI frame count (median: 100 vs. 71 frames), TIMI thrombus grade 0 (24.1% vs. 27.6%), minimum lumen diameter (median: 0.3 [IQR: 0.0 to 0.6] vs. 0.3 [IQR: 0.0 to 0.6] mm) and percentage of diameter stenosis (median: 89 [IQR: 78 to 100] vs. 89 [IQR: 77 to 100]).Neither coronary flow nor myocardial perfusion, evaluated on coronary angiograms performed before or following PCI procedures within a few hours after the start of oral antiplatelet treatment in the setting of acute coronary syndromes, demonstrated a difference with ticagrelor versus clopidogrel. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

  View details for DOI 10.1016/j.jcin.2013.03.014

  View details for Web of Science ID 000322129400007

  View details for PubMedID 23866179

• Assessing Research Results in the Medical Literature Trust but Verify JAMA INTERNAL MEDICINE Califf, R. M., McCall, J., Harrington, R. A. 2013; 173 (12): 1053-1055

  View details for DOI 10.1001/jamainternmed.2013.829

  View details for Web of Science ID 000320861700004

  View details for PubMedID 23609490

• 2013 ACCF/AHA Key Data Elements and Definitions for Measuring the Clinical Management and Outcomes of Patients With Acute Coronary Syndromes and Coronary Artery Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). Critical pathways in cardiology Cannon, C. P., Brindis, R. G., Chaitman, B. R., Cohen, D. J., Cross, J. T., Drozda, J. P., Fesmire, F. M., Fintel, D. J., Fonarow, G. C., Fox, K. A., Gray, D. T., Harrington, R. A., Hicks, K. A., Hollander, J. E., Krumholz, H., Labarthe, D. R., Long, J. B., Mascette, A. M., Meyer, C., Peterson, E. D., Radford, M. J., Roe, M. T., Richmann, J. B., Selker, H. P., Shahian, D. M., Shaw, R. E., Sprenger, S., Swor, R., Underberg, J. A., Van de Werf, F., Weiner, B. H., Weintraub, W. S. 2013; 12 (2): 65-105

  View details for DOI 10.1097/HPC.0b013e3182846e16

  View details for PubMedID 23680811

• 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

• 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

• Rescuing clinical trials in the United States and beyond: A call for action AMERICAN HEART JOURNAL Eapen, Z. J., Vavalle, J. P., Granger, C. B., Harrington, R. A., Peterson, E. D., Califf, R. M. 2013; 165 (6): 837-847

  Abstract

  Numerous challenges-financial, regulatory, and cultural-are hindering US participation and performance in multinational clinical trials. Consequently, it is increasingly unclear how the results of these trials should be applied to American patients, practice patterns, and systems of care. Both incremental and transformative changes are needed to revitalize US participation as well as the broader clinical trial enterprise. To promote consensus around the solutions needed to address the adverse trends in clinical research, the Duke Clinical Research Institute convenedstakeholders from academia, industry, and government. article summarizes the proceedings of this meeting and addresses: (1) adverse trends in the United States and multinational clinical trials, (2) the key issues that underlie these adverse trends, and (3) potential solutions to these problems.

  View details for DOI 10.1016/j.ahj.2013.02.003

  View details for Web of Science ID 000319439900004

  View details for PubMedID 23708153

• A phase 3, randomized, double-blinded, active-controlled, unblinded standard of care study assessing the efficacy and safety of intramyocardial autologous CD34+ cell administration in patients with refractory angina: Design of the RENEW study AMERICAN HEART JOURNAL Povsic, T. J., Junge, C., Nada, A., Schatz, R. A., Harrington, R. A., Davidson, C. J., Fortuin, F. D., Kereiakes, D. J., Mendelsohn, F. O., Sherman, W., Schaer, G. L., White, C. J., Stewart, D., Story, K., Losordo, D. W., Henry, T. D. 2013; 165 (6): 854-?

  Abstract

  Preclinical trials indicate that CD34+ cells represent an effective angiogenic stem cell component. Early-phase clinical trials suggest that intramyocardial administration of autologous CD34+ cells may improve functional capacity and symptoms of angina. RENEW is a pivotal phase 3 trial designed to determine the efficacy of granulocyte colony-stimulating factor (G-CSF)-mobilized CD34+ stem cells for the treatment for patients with refractory angina and chronic myocardial ischemia. Patients (n = 444) receiving maximally tolerated antianginal therapies and lacking conventional revascularization options with Canadian Cardiovascular Society class III or IV angina and ischemia on stress testing will be randomized 2:1:1 to cell therapy (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5) autologous CD34(+) cells/kg), active control (G-CSF-mediated stem cell mobilization, apheresis, and intramyocardial placebo injection), or open-label standard of care. The primary efficacy end point is change in exercise treadmill time in the treated vs active control patients, with 90% power to detect a 60-second difference in exercise time between cell-treated (n = 200) and active control (n = 100) patients. Key secondary end points include total number of anginal episodes per week and the incidence of independently adjudicated major adverse cardiac events and serious adverse events. RENEW will be the first adequately powered study aimed at definitively determining the efficacy of a cell therapy (intramyocardially delivered autologous CD34+ cells) for improvement of functional capacity in patients with refractory angina.

  View details for DOI 10.1016/j.ahj.2013.03.003

  View details for Web of Science ID 000319439900006

  View details for PubMedID 23708155

• Prevalence and clinical outcomes of undiagnosed diabetes mellitus and prediabetes among patients with high-risk non-ST-segment elevation acute coronary syndrome AMERICAN HEART JOURNAL Giraldez, R. R., Clare, R. M., Lopes, R. D., Dalby, A. J., Prabhakaran, D., Brogan, G. X., Giugliano, R. P., James, S. K., Tanguay, J., Pollack, C. V., Harrington, R. A., Braunwald, E., Newby, L. K. 2013; 165 (6): 918-?

  Abstract

  We examined the prevalence of undiagnosed diabetes or prediabetes and associations with ischemic outcomes among non-ST-segment elevation acute coronary syndrome (ACS) patients.We categorized 8795 EARLY ACS trial patients into one of the following groups: "known diabetes" (n = 2860 [32.5%]; reported on the case report form), "undiagnosed diabetes" (n = 1069 [12.2%]; no diabetes history and fasting glucose ≥126 mg/dL or hemoglobin A1c ≥6.5%), "prediabetes" (n = 947 [10.8%]; fasting glucose ≥110 to <126 mg/dL, or "normal" (n = 3919 [44.5%]). Adjusted associations of known diabetes, undiagnosed diabetes, and prediabetes (versus normal) with 30-day and 1-year outcomes were determined.Undiagnosed diabetes was associated with greater 30-day death or myocardial infarction (MI) (ORadj 1.28, 95% CI 1.05-1.57), driven primarily by greater 30-day mortality (ORadj 1.65, 95% CI 1.09-2.48). Known diabetic patients had 30-day death or MI outcomes similar to those of normal patients, but 30-day mortality was higher (ORadj 1.40, 95% CI 1.01-1.93). Prediabetic patients had 30-day death or MI outcomes similar to those of normal patients. One-year mortality was greater among known diabetic patients (HRadj 1.38, 95% CI 1.13-1.67) but not among those with undiagnosed diabetes or prediabetes.Undiagnosed diabetes and prediabetes were common among high-risk non-ST-segment elevation ACS patients. Routine screening for undiagnosed diabetes may be useful since these patients seem to have worse short-term outcomes and deserve consideration of alternative management strategies.

  View details for DOI 10.1016/j.ahj.2013.01.005

  View details for Web of Science ID 000319439900013

  View details for PubMedID 23708162

• 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

• Response to letter regarding article, “sustained ventricular tachycardia and ventricular fibrillation complicating non–ST-segment elevation acute coronary syndromes”. Circulation Piccini, J. P., White, J. A., Mehta, R. H., Lokhnygina, Y., Al-Khatib, S. M., Tricoci, P., Califf, R. M., Harrington, R. A., Newby, L. K., Pollack, C. V., Montalescot, G., Van de Werf, F., Gibson, C. M., Giugliano, R. P. 2013; 127 (20): e634

  View details for PubMedID 23833786

• Ticagrelor in Patients With Acute Coronary Syndromes and Stroke Interpretation of Subgroups in Clinical Trials STROKE James, S. K., Pieper, K. S., Cannon, C. P., Storey, R. F., Becker, R. C., Steg, P., Wallentin, L., Harrington, R. A., PLATO Study Grp 2013; 44 (5): 1477-1479

  View details for DOI 10.1161/STROKEAHA.111.000514

  View details for Web of Science ID 000318030000064

  View details for PubMedID 23572474

• 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

• Relationship between postoperative clopidogrel use and subsequent angiographic and clinical outcomes following coronary artery bypass grafting. Journal of thrombosis and thrombolysis Williams, J. B., Lopes, R. D., Hafley, G. E., Bruce Ferguson, T., Mack, M. J., Michael Gibson, C., Harrington, R. A., Peterson, E. D., Smith, P. K., Mehta, R. H., Alexander, J. H. 2013

  Abstract

  Dual antiplatelet therapy with both aspirin and clopidogrel is increasingly used after coronary artery bypass grafting (CABG); however, little is known about the safety or efficacy. We sought to determine the relationship between postoperative clopidogrel and clinical and angiographic outcomes following CABG. We evaluated 3,014 patients from PREVENT IV who underwent CABG at 107 US sites. Postoperative antiplatelet therapy was left to physician discretion. Risk-adjusted angiographic and clinical outcomes were compared in patients taking and not taking clopidogrel 30 days post-CABG. At 30 days, 633 (21 %) patients were taking clopidogrel. Clopidogrel users were more likely to have peripheral vascular (15 vs. 11 %) and cerebrovascular disease (17 vs. 11 %), prior myocardial infarction (MI) (46 vs. 41 %), and off-pump surgery (33 vs. 18 %). Clopidogrel use was associated with statistically insignificant higher graft failure (adjusted odds ratio 1.3; 95 % confidence interval [CI] [1.0, 1.7]; P = 0.05). At 5-year follow-up, clopidogrel use was associated with similar composite rates of death, MI, or revascularization (27 vs. 24 %; adjusted hazard ratio 1.1; 95 % CI [0.9, 1.4]; P = 0.38) compared with those not using clopidogrel. There was an interaction between use of cardiopulmonary bypass and clopidogrel with a trend toward lower 5-year clinical events with clopidogrel in patients undergoing off-pump CABG. In this observational analysis, clopidogrel use was not associated with better 5-year outcomes following CABG. There may be better outcomes with clopidogrel among patients having off-pump surgery. Adequately powered randomized clinical trials are needed to determine the role of dual antiplatelet therapy after CABG.

  View details for DOI 10.1007/s11239-013-0904-1

  View details for PubMedID 23543398

• Radial versus femoral access, bleeding and ischemic events in patients with non-ST-segment elevation acute coronary syndrome managed with an invasive strategy AMERICAN HEART JOURNAL Klutstein, M. W., Westerhout, C. M., Armstrong, P. W., Giugliano, R. P., Lewis, B. S., Gibson, C. M., Lutchmedial, S., Widimsky, P., Steg, P. G., Dalby, A., Zeymer, U., Van de Werf, F., Harrington, R. A., Newby, L. K., Rao, S. V. 2013; 165 (4): 583-?

  Abstract

  Bleeding is a major limitation of antithrombotic therapy among invasively managed non-ST-segment elevation acute coronary syndromes (NSTE-ACS) patients; therefore, we examined the use of radial access and its association with outcomes among NSTE-ACS patients.Clinical characteristics and geographic variation in radial access were examined, as well as its association with bleeding, red blood cell transfusion and ischemic outcomes (96-hour death/myocardial infarction/recurrent ischemic/thrombotic bailout; 30-day death/myocardial infarction; 1-year death) in the EARLY versus delayed, provisional eptifibatide in acute coronary syndromes trial.Of 9126 patients, 13.5% underwent radial-access catheterization. Female sex, age, weight, and prior revascularization were inversely associated with radial access, and its use varied widely by country (2%-97%). There were fewer GUSTO severe/moderate bleeds and red blood cell transfusions in the radial access group; however, it was attenuated after adjustment (odds ratio 0.73, 95% confidence intervals [CI] [0.50-1.06], P = .094 and 1.00 [0.71-1.40] P = .991). Ischemic outcomes did not differ by access site.In this post hoc analysis of a large clinical trial, there was significant international variation in use of radial access for NSTE-ACS patients undergoing invasive management, and it was preferentially used in those at lower risk for bleeding. Radial approach was not associated with a significant reduction in either bleeding or ischemic outcomes. Further study is needed to determine whether wider application of radial approach to acute coronary syndrome patients at high risk for bleeding improves overall outcomes.

  View details for DOI 10.1016/j.ahj.2013.01.009

  View details for Web of Science ID 000317184300021

  View details for PubMedID 23537976

• Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? Proceedings of an Ad Hoc Working Group Meeting JOURNAL OF THROMBOSIS AND HAEMOSTASIS Berger, J., Eikelboom, J. W., Quinlan, D. J., Guyatt, G., Buller, H. R., Sobieraj-Teague, M., Harrington, R. A., Hirsh, J. 2013; 11 (4): 778-782

  View details for DOI 10.1111/jth.4900

  View details for Web of Science ID 000317615500027

  View details for PubMedID 23578178

• ACP Journal Club. PCI using drug-eluting stents had higher mortality than CABG in diabetes and multivessel CAD. Annals of internal medicine Harrington, R. A. 2013; 158 (6): JC8-?

  View details for DOI 10.7326/0003-4819-158-6-201303190-02008

  View details for PubMedID 23552875

• 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards). Circulation Cannon, C. P., Brindis, R. G., Chaitman, B. R., Cohen, D. J., Cross, J. T., Drozda, J. P., Fesmire, F. M., Fintel, D. J., Fonarow, G. C., Fox, K. A., Gray, D. T., Harrington, R. A., Hicks, K. A., Hollander, J. E., Krumholz, H., Labarthe, D. R., Long, J. B., Mascette, A. M., Meyer, C., Peterson, E. D., Radford, M. J., Roe, M. T., Richmann, J. B., Selker, H. P., Shahian, D. M., Shaw, R. E., Sprenger, S., Swor, R., Underberg, J. A., Van de Werf, F., Weiner, B. H., Weintraub, W. S. 2013; 127 (9): 1052-1089

  View details for DOI 10.1161/CIR.0b013e3182831a11

  View details for PubMedID 23357718

• 2013 ACCF/AHA key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes and coronary artery disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on clinical data standards (writing committee to develop acute coronary syndromes and coronary artery disease clinical data standards). Journal of the American College of Cardiology Cannon, C. P., Brindis, R. G., Chaitman, B. R., Cohen, D. J., Cross, J. T., Drozda, J. P., Fesmire, F. M., Fintel, D. J., Fonarow, G. C., Fox, K. A., Gray, D. T., Harrington, R. A., Hicks, K. A., Hollander, J. E., Krumholz, H., Labarthe, D. R., Long, J. B., Mascette, A. M., Meyer, C., Peterson, E. D., Radford, M. J., Roe, M. T., Richmann, J. B., Selker, H. P., Shahian, D. M., Shaw, R. E., Sprenger, S., Swor, R., Underberg, J. A., Van de Werf, F., Weiner, B. H., Weintraub, W. S. 2013; 61 (9): 992-1025

  View details for DOI 10.1016/j.jacc.2012.10.005

  View details for PubMedID 23369353

• Response to letter regarding article, "ticagrelor in patients with acute coronary syndromes and stroke: interpretation of subgroups in clinical trials". Stroke; a journal of cerebral circulation James, S. K., Storey, R. F., Pieper, K. S., Cannon, C. P., Becker, R. C., Steg, P. G., Wallentin, L. n., Harrington, R. A. 2013; 44 (8): e95–6

  View details for DOI 10.1161/STROKEAHA.113.002069

  View details for PubMedID 23800556

• ACP Journal Club. Intraaortic balloon counterpulsation did not reduce mortality in acute MI with cardiogenic shock. Annals of internal medicine Harrington, R. A. 2012; 157 (12): JC6-11

  View details for DOI 10.7326/0003-4819-157-12-201212180-02011

  View details for PubMedID 23247960

• Conversion of Cardiovascular Conference Abstracts to Publications CIRCULATION Fosbol, E. L., Fosbol, P. L., Harrington, R. A., Eapen, Z. J., Peterson, E. D. 2012; 126 (24): 2819-?

  Abstract

  The transition of scientific knowledge from discovery into practice is less than ideal. A key step in this translation occurs when presentations from major meetings are published in peer-reviewed literature, yet the completeness and speed of this process are not known. We performed a systematic and automated evaluation of rates, timing, and correlates of publication from scientific abstracts presented at 3 major cardiovascular conferences.Using an automated computer algorithm, we searched the ISI Web of Science to identify peer-reviewed publications of abstracts presented at the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC) scientific sessions from 2006 to 2008. We compared abstract publication rates and journal impact factor between the 3 meetings using multivariable logistic regression modeling. From 2006 to 2008, 11 365, 5005, and 10 838 abstracts were presented at the AHA, ACC, and ESC meetings, respectively. Overall, 30.6% of presented abstracts were published within 2 years of the conference; ranging from 34.5% for AHA to 29.5% for ACC to 27.0% for ESC (P<0.0001). Five years after conference presentation in 2005, these rates had risen slightly to 49.7% for AHA, 42.6% for ACC, and 37.6% for ESC (P<0.0001). After adjustment for abstract characteristics and contributing countries, abstracts presented at the AHA meeting remained more likely for publication relative to the ESC (adjusted odds ratio, 1.24; 95% confidence interval, 1.16-1.34) and the ACC (adjusted odds ratio, 1.20; 95% confidence interval, 1.11-1.29). Median impact factors for subsequent publications varied from 4.8 (interquartile range, 3.8-10.1) for AHA to 4.0 (interquartile range, 3.1-7.5) for ACC and 3.9 (quartile 1-3, 2.5-5.8) for ESC (P for difference between groups <0.01). Clinical science and population science were less likely to be published compared with basic science.One third of abstracts were translated into publications by 2 years after presentation and less than one half by 5 years after presentation. Our findings suggest that efforts to understand the barriers to publication and to facilitate the rapid dissemination of new knowledge are needed to speed up the transition of scientific discovery into clinical practice.

  View details for DOI 10.1161/CIRCULATIONAHA.112.120535

  View details for Web of Science ID 000312275600010

  View details for PubMedID 23124031

• Are Central Institutional Review Boards the Solution? The National Heart, Lung, and Blood Institute Working Group's Report on Optimizing the IRB Process ACADEMIC MEDICINE Mascette, A. M., Bernard, G. R., DiMichele, D., Goldner, J. A., Harrington, R., Harris, P. A., Leeds, H. S., Pearson, T. A., Ramsey, B., Wagner, T. H. 2012; 87 (12): 1710-1714

  Abstract

  The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health convened a working group in June 2011 to examine alternative institutional review board (IRB) models. The working group was held in response to proposed changes in the regulations for government-supported research and the proliferation of multicenter clinical trials where multiple individual reviews may be inefficient. Group members included experts in heart, lung, and blood research, research oversight, bioethics, health economics, regulations, and information technology (IT). The group discussed alternative IRB models, ethical concerns, metrics for evaluating IRBs, IT needs, and economic considerations. Participants noted research gaps in IRB best practices and in metrics. The group arrived at recommendations for process changes, such as defining specific IRB performance requirements in funding announcements, requiring funded researchers to use more efficient alternative IRB models, and developing IT systems to facilitate information sharing and collaboration among IRBs. Despite the success of the National Cancer Institute's central IRB (CIRB), the working group, concerned about the creation costs and unknown cost-efficiency of a new CIRB, and about the risk of shifting the burden of dealing with multiple IRBs from sponsors to research institutions, did not recommend the creation of an NHLBI-funded CIRB.

  View details for DOI 10.1097/ACM.0b013e3182720859

  View details for Web of Science ID 000311836800021

  View details for PubMedID 23095928

• EPC Mobilization After Erythropoietin Treatment in Acute St-elevation Myocardial Infarction: The Reveal EPC Substudy Povsic, T. J., Rao, S. V., Najjar, S. S., Melton, L. G., Prather, K., Zhou, J., Adams, S. D., Zavodni, K. L., Kelly, F., Hasselblad, V., Heitner, J. F., Raman, S. V., Barsness, G. W., Patel, M. R., Kim, R. J., Lakatta, E. G., Harrington, R. A. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000208885002002

• Cardiac Biomarker Elevation during Stem Cell Mobilisation, Apheresis and Intramyocardial Delivery is Common but does not Impact Incidence of Long-Term MACE: An Analysis from ACT34-CMI Povsic, T. J., Losordo, D. W., Story, K., Junge, C. E., Schatz, R. A., Harrington, R. A., Henry, T. D. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000208885001426

• A Phase 3, Randomized, Partially Blinded, Active-Controlled, Study Assessing the Efficacy and Safety of Intramyocardial Autologous CD34+Cell Administration in Patients with Refractory Angina: Design of the RENEW Study Povsic, T. I., Losordo, D. W., Story, K., Junge, C. E., Schatz, R. A., Harrington, R. A., Davidson, C. J., Fortuin, D. F., Kereiakes, D. J., Mendelsohn, F. O., Sherman, W., Henry, T. D. LIPPINCOTT WILLIAMS & WILKINS. 2012

  View details for Web of Science ID 000208885002001

• Transforming Clinical Trials in Cardiovascular Disease Mission Critical for Health and Economic Well-being JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Antman, E. M., Harrington, R. A. 2012; 308 (17): 1743-1744

  View details for Web of Science ID 000310726500017

  View details for PubMedID 23117771

• Incidence and clinical significance of cardiac biomarker elevation during stem cell mobilization, apheresis, and intramyocardial delivery: An analysis from ACT34-CMI AMERICAN HEART JOURNAL Povsic, T. J., Losordo, D. W., Story, K., Junge, C. E., Schatz, R. A., Harrington, R. A., Henry, T. D. 2012; 164 (5): 689-U86

  Abstract

  Cell therapy is a promising therapeutic for a variety of cardiovascular conditions including refractory angina. Elevation of cardiac biomarkers during cell delivery has been frequently described, but the clinical implications have never been studied.ACT34-CMI was a randomized double-blind study assessing the use of intramyocardial delivery of autologous CD34(+) cells for the treatment of refractory angina. Patients (n = 167) underwent G-CSF-mediated (5 μg/[kg day] × 5 days) stem cell mobilization, apheresis, and intramyocardial injection of 1 × 10(5)/kg or 5 × 10(5)/kg CD34(+) cells or placebo. Troponin and creatinine kinase MB were assessed at baseline (n = 161), after cell mobilization and apheresis (n = 153 and 143, respectively), and post-intramyocardial injection (n = 155 and 141, respectively). Major adverse cardiac events (MACE) included death, myocardial infarction, acute congestive heart failure, urgent revascularization, or sustained ventricular arrhythmia.Seven (4.3%) subjects had troponin above the upper limits of normal (ULN) at baseline. Thirty-four (22.2%) and 11 (7.2%) subjects had troponin levels > ULN or >3× ULN after cell mobilization and apheresis, whereas 72 (46.1%) and 39 (25.2%) subjects had troponin elevations > ULN or >3× ULN, respectively, after intramyocardial injections. Age, but no other preprocedural factors, was predictive of troponin elevation. Periprocedural troponin elevation was not associated with an increased risk of MACE during 1 year, especially in cell therapy-treated patients.Troponin elevation is common during stem cell harvesting and intramyocardial administration, is usually asymptomatic, and does not appear to be associated with long-term MACE in subjects undergoing stem cell mobilization and intramyocardial injection.

  View details for DOI 10.1016/j.ahj.2012.06.022

  View details for Web of Science ID 000310783100011

  View details for PubMedID 23137499

• Road mapping ATLAS ACS 2: are we there yet? EUROPEAN HEART JOURNAL Armstrong, P. W., Harrington, R. A. 2012; 33 (20): 2510-2512

  View details for DOI 10.1093/eurheartj/ehs015

  View details for Web of Science ID 000310167200007

  View details for PubMedID 22297122

• Association Between Angiographic Complications and Clinical Outcomes Among Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention An EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) Angiographic Substudy JACC-CARDIOVASCULAR INTERVENTIONS Pride, Y. B., Mohanavelu, S., Zorkun, C., Kunadian, V., Giugliano, R. P., Newby, L. K., Braunwald, E., Califf, R. M., Harrington, R. A., Gibson, C. M. 2012; 5 (9): 927-935

  Abstract

  The goal of this analysis was to determine the association between intraprocedural complications and clinical outcomes among patients with high-risk non-ST-segment elevation acute coronary syndrome (NSTEACS) undergoing percutaneous coronary intervention (PCI).Among patients undergoing PCI for NSTEACS, the relationship between intraprocedural complications and clinical outcomes, independent of epicardial and myocardial perfusion, has not been well characterized.The EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) trial enrolled 9,406 patients with high-risk NSTEACS undergoing an early invasive strategy. Of these, 1,452 underwent angiographic assessment in an independent core laboratory and did not have a myocardial infarction (MI) between enrollment and angiography. We assessed the relationship between abrupt closure, loss of side branch(es), distal embolization, and no-reflow phenomenon and 30-day clinical outcomes in these patients.Of the patients, 166 (11.4%) experienced an intraprocedural complication. Baseline clinical characteristics were similar between patients who did and did not have complications. The 30-day composite of death or MI was significantly higher among patients with an intraprocedural complication (28.3% vs. 7.8%, odds ratio [OR]: 4.68, 95% confidence interval [CI]: 3.2 to 7.0, p < 0.001). Individually, both mortality (3.0% vs. 0.9%, OR: 3.60, 95% CI: 1.2 to 10.5, p = 0.019) and MI (27.1% vs. 7.4%, OR: 4.66, 95% CI: 3.1 to 7.0, p < 0.001) were significantly increased. After adjusting for differences in post-PCI epicardial and myocardial perfusion, the association with 30-day death or MI remained significant.Among high-risk NSTEACS patients undergoing an invasive strategy, the incidence of intraprocedural complications is high, and the occurrence of these complications is associated with worse clinical outcomes independent of epicardial and myocardial perfusion. (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-segment Elevation Acute Coronary Syndrome [EARLY ACS]; NCT00089895).

  View details for DOI 10.1016/j.jcin.2012.05.007

  View details for Web of Science ID 000309351600007

  View details for PubMedID 22995880

• 2012 American College of Cardiology Foundation/Society for Cardiovascular Angiography and Interventions expert consensus document on cardiac catheterization laboratory standards update: American College of Cardiology Foundation Task Force on expert consensus documents Society of Thoracic Surgeons Society for Vascular Medicine. Catheterization and cardiovascular interventions Bashore, T. M., Balter, S., Barac, A., Byrne, J. G., Cavendish, J. J., Chambers, C. E., Hermiller, J. B., Kinlay, S., Landzberg, J. S., Laskey, W. K., McKay, C. R., Miller, J. M., Moliterno, D. J., Moore, J. W., Oliver-McNeil, S. M., Popma, J. J., Gardner 2012; 80 (3): E37-49

  View details for DOI 10.1002/ccd.24466

  View details for PubMedID 22570114

• Edifoligide and long-term outcomes after coronary artery bypass grafting: PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT IV) 5-year results AMERICAN HEART JOURNAL Lopes, R. D., Williams, J. B., Mehta, R. H., Reyes, E. M., Hafley, G. E., Allen, K. B., Mack, M. J., Peterson, E. D., Harrington, R. A., Gibson, C. M., Califf, R. M., Kouchoukos, N. T., Ferguson, T. B., Lorenz, T. J., Alexander, J. H. 2012; 164 (3): 379-U284

  Abstract

  Edifoligide, an E2F transcription factor decoy, does not prevent vein graft failure or adverse clinical outcomes at 1 year in patients undergoing coronary artery bypass grafting (CABG). We compared the 5-year clinical outcomes of patients in PREVENT IV treated with edifoligide and placebo to identify predictors of long-term clinical outcomes.A total of 3,014 patients undergoing CABG with at least 2 planned vein grafts were enrolled. Kaplan-Meier curves were generated to compare the long-term effects of edifoligide and placebo. A Cox proportional hazards model was constructed to identify factors associated with 5-year post-CABG outcomes. The main outcome measures were death, myocardial infarction (MI), repeat revascularization, and rehospitalization through 5 years.Five-year follow-up was complete in 2,865 patients (95.1%). At 5 years, patients randomized to edifoligide and placebo had similar rates of death (11.7% and 10.7%, respectively), MI (2.3% and 3.2%), revascularization (14.1% and 13.9%), and rehospitalization (61.6% and 62.5%). The composite outcome of death, MI, or revascularization occurred at similar frequency in patients assigned to edifoligide and placebo (26.3% and 25.5%, respectively; hazard ratio 1.03 [95% CI 0.89-1.18], P = .721). Factors associated with death, MI, or revascularization at 5 years included peripheral and/or cerebrovascular disease, time on cardiopulmonary bypass, lung disease, diabetes mellitus, and congestive heart failure.Up to a quarter of patients undergoing CABG will have a major cardiac event or repeat revascularization procedure within 5 years of surgery. Edifoligide does not affect outcomes after CABG; however, common identifiable baseline and procedural risk factors are associated with long-term outcomes after CABG.

  View details for DOI 10.1016/j.ahj.2012.05.019

  View details for Web of Science ID 000308690100015

  View details for PubMedID 22980305

• Prior smoking status, clinical outcomes, and the comparison of ticagrelor with clopidogrel in acute coronary syndromes-Insights from the PLATelet inhibition and patient Outcomes (PLATO) trial AMERICAN HEART JOURNAL Cornel, J. H., Becker, R. C., Goodman, S. G., Husted, S., Katus, H., Santoso, A., Steg, G., Storey, R. F., Vintila, M., Sun, J. L., Horrow, J., Wallentin, L., Harrington, R., James, S. 2012; 164 (3): 334-U239

  Abstract

  Habitual smoking has been associated with increased platelet reactivity, increased risk of thrombotic complications and greater efficacy of clopidogrel therapy over placebo. In the PLATO trial, ticagrelor compared to clopidogrel in patients with acute coronary syndromes (ACS) reduced the primary composite end point of vascular death, myocardial infarction and stroke, without increasing overall rates of major bleeding. We evaluated the results in relation to smoking habits.Interactions between habitual smokers (n = 6678) and in ex/nonsmokers (n = 11,932) and the effects of randomized treatments on ischemic and bleeding outcomes were evaluated by Cox regression analyses.Habitual smokers had an overall lower risk profile and more often ST-elevation ACS. After adjustment for baseline imbalances, habitual smoking was associated with a higher incidence of definite stent thrombosis (adjusted HR, 1.44 [95% CI, 1.07-1.94]); there were no significant associations with other ischemic or bleeding end points. The effects of ticagrelor compared to clopidogrel were consistent for all outcomes regardless of smoking status. Thus, there was a similar reduction in the primary composite end point for habitual smokers (adjusted HR, 0.83 [95% CI, 0.68-1.00]) and ex/nonsmokers (adjusted HR, 0.89 [95% CI, 0.79-1.00]) (interaction P = .50), and in definite stent thrombosis for habitual smokers (adjusted HR, 0.59 [0.39-0.91]) and ex/nonsmokers (adjusted HR, 0.69 [95% CI, 0.45-1.07]) (interaction P = .61).In patients hospitalized with ACS, habitual smoking is associated with a greater risk of subsequent stent thrombosis. The reduction of vascular death, myocardial infarction, stroke, and stent thrombosis by ticagrelor compared to clopidogrel is consistent regardless of smoking habits.

  View details for DOI 10.1016/j.ahj.2012.06.005

  View details for Web of Science ID 000308690100009

  View details for PubMedID 22980299

• 2012 ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement: developed in collabration with the American Heart Association, American Society of Echocardiography, European Association for Cardio-Thoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. journal of thoracic and cardiovascular surgery Holmes, D. R., Mack, M. J., Kaul, S., Agnihotri, A., Alexander, K. P., Bailey, S. R., Calhoon, J. H., Carabello, B. A., Desai, M. Y., Edwards, F. H., Francis, G. S., Gardner, T. J., Kappetein, A. P., Linderbaum, J. A., Mukherjee, C., Mukherjee, D., Otto, C. M., Ruiz, C. E., Sacco, R. L., Smith, D., Thomas, J. D., Harrington, R. A., Bhatt, D. L., Ferrari, V. A., Fisher, J. D., Garcia, M. J., Gardner, T. J., Gentile, F., Gilson, M. F., Hernandez, A. F., Jacobs, A. K., Kaul, S., Linderbaum, J. A., Moliterno, D. J., Weitz, H. H. 2012; 144 (3): e29-84

  View details for DOI 10.1016/j.jtcvs.2012.03.001

  View details for PubMedID 22898522

• Venous thromboembolism prophylaxis: do trial results enable clinicians and patients to evaluate whether the benefits justify the risk? proceedings of an ad hoc working group meeting. Journal of thrombosis and haemostasis : JTH Berger, J., Eikelboom, J. W., Quinlan, D. J., Guyatt, G., Büller, H. R., Sobieraj-Teague, M., Harrington, R. A., Hirsh, J. 2012

  Abstract

  Physicians and patients consider the balance between benefits and risks of treatment when making decisions about the use of anticoagulants for the prevention of venous thromboembolism (VTE). The results of early trials demonstrating the efficacy of heparin compared with placebo or no thromboprophylaxis for the prevention of fatal pulmonary embolism (PE) led to adoption of routine anticoagulant prophylaxis in patients considered to be at increased risk of VTE. More recent trials comparing new anticoagulants with heparin have most commonly used the composite outcome, asymptomatic (or "silent") deep vein thrombosis (DVT), detected by screening venography, and symptomatic (or "patient-important") VTE, as the primary measure of efficacy [1-3]. © 2012 International Society on Thrombosis and Haemostasis.

  View details for DOI 10.1111/j.1538-7836.2012.04900.x

  View details for PubMedID 22906159

• Lecture Halls without Lectures NEW ENGLAND JOURNAL OF MEDICINE Eapen, Z. J., Vavalle, J. P., Harrington, R. A. 2012; 367 (7): 678-678

  View details for Web of Science ID 000307496600025

  View details for PubMedID 22894591

• Effect of Adenosine-Regulating Agent Acadesine on Morbidity and Mortality Associated With Coronary Artery Bypass Grafting The RED-CABG Randomized Controlled Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Newman, M. F., Ferguson, T. B., White, J. A., Ambrosio, G., Koglin, J., Nussmeier, N. A., Pearl, R. G., Pitt, B., Wechsler, A. S., Weisel, R. D., Reece, T. L., Lira, A., Harrington, R. A. 2012; 308 (2): 157-164

  Abstract

  Ischemia/reperfusion injury remains an important cause of morbidity and mortality after coronary artery bypass graft (CABG) surgery. In a meta-analysis of randomized controlled trials, perioperative and postoperative infusion of acadesine, a first-in-class adenosine-regulating agent, was associated with a reduction in early cardiac death, myocardial infarction, and combined adverse cardiac outcomes in participants undergoing on-pump CABG surgery.To assess the efficacy and safety of acadesine administered in the perioperative period in reducing all-cause mortality, nonfatal stroke, and severe left ventricular dysfunction (SLVD) through 28 days.The Reduction in Cardiovascular Events by Acadesine in Patients Undergoing CABG (RED-CABG) trial, a randomized, double-blind, placebo-controlled, parallel-group evaluation of intermediate- to high-risk patients (median age, 66 years) undergoing nonemergency, on-pump CABG surgery at 300 sites in 7 countries. Enrollment occurred from May 6, 2009, to July 30, 2010.Eligible participants were randomized 1:1 to receive acadesine (0.1 mg/kg per minute for 7 hours) or placebo (both also added to cardioplegic solutions) beginning just before anesthesia induction.Composite of all-cause mortality, nonfatal stroke, or need for mechanical support for SLVD during and following CABG surgery through postoperative day 28.Because results of a prespecified futility analysis indicated a very low likelihood of a statistically significant efficacious outcome, the trial was stopped after 3080 of the originally projected 7500 study participants were randomized. The primary outcome occurred in 75 of 1493 participants (5.0%) in the placebo group and 76 of 1493 (5.1%) in the acadesine group (odds ratio, 1.01 [95% CI, 0.73-1.41]). There were no differences in key secondary end points measured.In this population of intermediate- to high-risk patients undergoing CABG surgery, acadesine did not reduce the composite of all-cause mortality, nonfatal stroke, or SLVD.clinicaltrials.gov Identifier: NCT00872001.

  View details for Web of Science ID 000306219500029

  View details for PubMedID 22782417

• Usefulness of Medical Conferences JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Antman, E. M., Harrington, R., Tomaselli, G. 2012; 308 (1): 31-32

  View details for DOI 10.1001/jama.2012.6368

  View details for Web of Science ID 000306183000015

  View details for PubMedID 22760283

• Sustained Ventricular Tachycardia and Ventricular Fibrillation Complicating Non-ST-Segment-Elevation Acute Coronary Syndromes CIRCULATION Piccini, J. P., White, J. A., Mehta, R. H., Lokhnygina, Y., Al-Khatib, S. M., Tricoci, P., Pollack, C. V., Montalescot, G., Van de Werf, F., Gibson, C. M., Giugliano, R. P., Califf, R. M., Harrington, R. A., Newby, L. K. 2012; 126 (1): 41-49

  Abstract

  Ventricular arrhythmias remain a lethal complication of acute coronary syndromes (ACS). However, the incidence and prognosis of sustained ventricular tachycardia/ventricular fibrillation (VT/VF) in contemporary non-ST-segment-elevation (NSTE) ACS populations are not well described.We examined the incidence of VT/VF and subsequent survival among 9211 patients enrolled in the Early Glycoprotein IIb/IIIa Inhibition in NSTE ACS (EARLY ACS) trial. The cumulative incidence of VT/VF was 1.5% (n=141); 0.6% (n=55) had VT/VF ≤48 hours after enrollment, and 0.9% (n=86) had VT/VF >48 hours after enrollment. Patients with VT/VF more frequently had prior heart failure, an ejection fraction <30%, and triple-vessel coronary artery disease. Predictors of sustained VT/VF were similar regardless of the timing of VT/VF (≤48 versus >48 hours). Patients with VT/VF ≤48 hours after enrollment had higher 30-day mortality than those who did not have VT/VF ≤48 hours (13.0% versus 2.2%; adjusted odds ratio, 6.73; 95% confidence interval, 2.68-16.9). The increased risk of death associated with VT/VF ≤48 hours persisted at 1 year. The risk of mortality, relative to patients without VT/VF, was greater for patients with VT/VF >48 hours (hazard ratio, 20.70; 95% confidence interval, 15.39-27.85) than for those with earlier VT/VF (hazard ratio, 7.45; 95% confidence interval, 4.60-12.08; P=0.0003). The frequency of arrhythmic death was higher in patients with VT/VF than in those without VT/VF (26.4% versus 6.9%).Sustained VT/VF is infrequent after NSTE ACS but is as likely to occur after 48 hours as within the first 48 hours. The marked increase in all-cause death among NSTE ACS patients with both early and late sustained VT/VF raises important considerations for aggressive monitoring beyond 48 hours and interventions to prevent arrhythmic death in these patients.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00089895.

  View details for DOI 10.1161/CIRCULATIONAHA.111.071860

  View details for Web of Science ID 000306977100022

  View details for PubMedID 22645292

• Highlights from the IV International Symposium of Thrombosis and Anticoagulation (ISTA), October 20-21, 2011, Salvador, Bahia, Brazil JOURNAL OF THROMBOSIS AND THROMBOLYSIS Lopes, R. D., Becker, R. C., Newby, L. K., Peterson, E. D., Hylek, E. M., Granger, C. B., Crowther, M., Wang, T., Carvalho, A. C., Berwanger, O., Giraldez, R. R., Feitosa, G. S., Ribeiro, J. P., Darze, E., Kalil, R. A., Andrande, M., Boas, F. V., Andrade, J., Rocha, A. T., Harrington, R. A., Lopes, A. C., Garcia, D. A. 2012; 34 (1): 143-163

  Abstract

  To discuss and share knowledge about advances in the care of patients with thrombotic disorders, the Fourth International Symposium of Thrombosis and Anticoagulation was held in Salvador, Bahia, Brazil, from October 20-21, 2011. 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/s11239-012-0700-3

  View details for Web of Science ID 000305523300023

  View details for PubMedID 22427055

• Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials JOURNAL OF THROMBOSIS AND THROMBOLYSIS Angiolillo, D. J., Schneider, D. J., Bhatt, D. L., French, W. J., Price, M. J., Saucedo, J. F., Shaburishvili, T., Huber, K., Prats, J., Liu, T., Harrington, R. A., Becker, R. C. 2012; 34 (1): 44-55

  Abstract

  Cangrelor is an intravenous antagonist of the P2Y(12) receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 μmol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: -1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower in patients treated with cangrelor. A rapid platelet inhibitory effect was achieved during cangrelor infusion and a rapid offset of action after treatment discontinuation. This CHAMPION platelet function substudy represents the largest pharmacodynamic experience with cangrelor, demonstrating its potent P2Y(12) receptor inhibitory effects, and rapid onset/offset of action. Although there was no significant pharmacodynamic interaction when transitioning to clopidogrel therapy, further studies are warranted given that enrollment in this study was limited due to premature interruption of the main trial.

  View details for DOI 10.1007/s11239-012-0737-3

  View details for Web of Science ID 000305523300007

  View details for PubMedID 22569899

• Pharmacokinetic and Pharmacodynamic Effects of Elinogrel Results of the Platelet Function Substudy From the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention Patients (INNOVATE-PCI) Trial CIRCULATION-CARDIOVASCULAR INTERVENTIONS Angiolillo, D. J., Welsh, R. C., Trenk, D., Neumann, F., Conley, P. B., McClure, M. W., Stephens, G., Kochman, J., Jennings, L. K., Gurbel, P. A., Wojcik, J., Dabrowski, M., Saucedo, J. F., Stumpf, J., Buerke, M., Broderick, S., Harrington, R. A., Rao, S. V. 2012; 5 (3): 347-356

  Abstract

  Elinogrel is the only selective, competitive and reversible platelet P2Y(12) inhibitor available in both intravenous (IV) and oral formulations.This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300-600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of the peri-PCI period. During chronic therapy, elinogrel achieved similar levels of platelet reactivity compared with clopidogrel before the next oral dose and, although platelet reactivity was lower with elinogrel up to 6 hours after daily oral maintenance dosing, these differences were not statistically significant. These pharmacodynamic effects matched the pharmacokinetic profile of elinogrel. There were no differences in pharmacodynamic and pharmacokinetic effects between the two elinogrel dosing regimens.Compared with clopidogrel, the combination of IV and oral elinogrel achieves more rapid and enhanced antiplatelet effects that were sustained through the transition to oral elinogrel in the peri-PCI period, but these were not significant during chronic dosing in this pilot investigation.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

  View details for DOI 10.1161/CIRCINTERVENTIONS.111.965608

  View details for Web of Science ID 000311707000012

  View details for PubMedID 22619259

• A Randomized, Double-Blind, Active-Controlled Phase 2 Trial to Evaluate a Novel Selective and Reversible Intravenous and Oral P2Y(12) Inhibitor Elinogrel Versus Clopidogrel in Patients Undergoing Nonurgent Percutaneous Coronary Intervention The INNOVATE-PCI Trial CIRCULATION-CARDIOVASCULAR INTERVENTIONS Welsh, R. C., Rao, S. V., Zeymer, U., Thompson, V. P., Huber, K., Kochman, J., McClure, M. W., Gretler, D. D., Bhatt, D. L., Gibson, C. M., Angiolillo, D. J., Gurbel, P. A., Berdan, L. G., Paynter, G., Leonardi, S., Madan, M., French, W. J., Harrington, R. A. 2012; 5 (3): 336-346

  Abstract

  We evaluated the safety, efficacy, and tolerability of elinogrel, a competitive, reversible intravenous and oral P2Y(12) inhibitor that does not require metabolic activation, in patients undergoing nonurgent percutaneous coronary intervention.In a randomized, double-blind, dose-ranging phase 2b trial, 652 patients received either 300 or 600 mg of clopidogrel pre-percutaneous coronary intervention followed by 75 mg daily or 80 or 120 mg of IV elinogrel followed by 50, 100, or 150 mg oral elinogrel twice daily. Numerous exploratory safety and efficacy end points were assessed and, as such, had no prespecified primary end point, and the study was not powered to conclusively evaluate its objectives. Thrombolysis in myocardial infarction combined bleeding was increased with elinogrel (hazard ratio, 1.98; 95% confidence interval, 1.10 to 3.57), related largely to increased bleeding requiring medical attention (elinogrel 47/408 [11.5%] versus clopidogrel 13/208 [6.3%]) and occurring primarily at the percutaneous coronary intervention access site. Efficacy end points and postprocedure cardiac enzyme were similar, but there was a nonsignificant higher frequency of periprocedural myocardial infarctions in the elinogrel arms (OR, 1.59; 95% confidence interval, 0.79 to 3.48). There was an increased incidence of dyspnea (elinogrel 50/408 [12.3%] versus clopidogrel 8/208 [3.8%]) and transaminase elevation (alanine transferase/aspartate transferase >3× the upper limit of normal; elinogrel 18/408 [4.4%] versus clopidogrel 2/208 [1.0%]) in the elinogrel arms, but there were no cases of heart block, bradycardia, hypotension, or liver failure.In patients undergoing nonurgent percutaneous coronary intervention and in comparison with clopidogrel, intravenous and oral elinogrel therapy did not significantly increase thrombolysis in myocardial infarction major or minor bleeding, although bleeding requiring medical attention was more common. The significance of these findings will need to be more definitively determined in future Phase 3 studies.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

  View details for DOI 10.1161/CIRCINTERVENTIONS.111.964197

  View details for Web of Science ID 000311707000011

  View details for PubMedID 22647518

• 2012 ACCF/AATS/SCAI/STS Expert Consensus Document on Transcatheter Aortic Valve Replacement Developed in collaboration with the American Heart Association, American Society of Echocardiography, European Association for CardioThoracic Surgery, Heart Failure Society of America, Mended Hearts, Society of Cardiovascular Anesthesiologists, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Holmes, D. R., Mack, M. J., Kaul, S., Agnihotri, A., Alexander, K. P., Bailey, S. R., Calhoon, J. H., Carabello, B. A., Desai, M. Y., Edwards, F. H., Francis, G. S., Gardner, T. J., Kappetein, A. P., Linderbaum, J. A., Mukherjee, C., Mukherjee, D., Otto, C. M., Ruiz, C. E., Sacco, R. L., Smith, D., Thomas, J. D., Harrington, R. A., Bhatt, D. L., Ferrari, V. A., Fisher, J. D., Garcia, M. J., Gardner, T. J., Gentile, F., Gilson, M. F., Hernandez, A. F., Jacobs, A. K., Kaul, S., Linderbaum, J. A., Moliterno, D. J., Weitz, H. H. 2012; 79 (7): 1023-1082

  View details for DOI 10.1002/ccd.24351

  View details for Web of Science ID 000304753500001

  View details for PubMedID 22294439

• 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

• Regional Patterns of Use of a Medical Management Strategy for Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Insights From the EARLY ACS Trial CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Roe, M. T., White, J. A., Kaul, P., Tricoci, P., Lokhnygina, Y., Miller, C. D., Van'T Hof, A. W., Montalescot, G., James, S. K., Saucedo, J., Ohman, E. M., Pollack, C. V., Hochman, J. S., Armstrong, P. W., Giugliano, R. P., Harrington, R. A., Van de Werf, F., Califf, R. M., Newby, L. K. 2012; 5 (2): 205-213

  Abstract

  Regional differences in the profile and prognosis of non-ST-segment elevation acute coronary syndrome (NSTE ACS) patients treated with medical management after angiography remain uncertain.Using data from the Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndromes (EARLY ACS) trial, we examined regional variations in the use of an in-hospital medical management strategy in NSTE ACS patients who had significant coronary artery disease (CAD) identified during angiography, factors associated with the use of a medical management strategy, and 1-year mortality rates. Of 9406 patients, 8387 (89%) underwent angiography and had significant CAD; thereafter, 1766 (21%) were treated solely with a medical management strategy (range: 18% to 23% across 4 major geographic regions). Factors most strongly associated with a medical management strategy were negative baseline troponin values, prior coronary artery bypass grafting, lower baseline hemoglobin values, and greater number of diseased vessels; region was not a significant factor. One-year mortality was higher among patients treated with a medical management strategy compared with those who underwent revascularization (7.8% versus 3.6%; adjusted hazard ratio, 1.46; 95% CI, 1.21-1.76), with no significant interaction by region (interaction probability value=0.42).Approximately 20% of NSTE ACS patients with significant CAD in an international trial were treated solely with an in-hospital medical management strategy after early angiography, with no regional differences in factors associated with medical management or the risk of 1-year mortality. These findings have important implications for the conduct of future clinical trials, and highlight global similarities in the profile and prognosis of medically managed NSTE ACS patients.

  View details for DOI 10.1161/CIRCOUTCOMES.111.962332

  View details for Web of Science ID 000302120300014

  View details for PubMedID 22373905

• 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

• Relationship Between Vein Graft Failure and Subsequent Clinical Outcomes After Coronary Artery Bypass Surgery CIRCULATION Lopes, R. D., Mehta, R. H., Hafley, G. E., Williams, J. B., Mack, M. J., Peterson, E. D., Allen, K. B., Harrington, R. A., Gibson, C. M., Califf, R. M., Kouchoukos, N. T., Ferguson, T. B., Alexander, J. H. 2012; 125 (6): 749-756

  Abstract

  Vein graft failure (VGF) is common after coronary artery bypass graft surgery, but its relationship with long-term clinical outcomes is unknown. In this retrospective analysis, we examined the relationship between VGF, assessed by coronary angiography 12 to 18 months after coronary artery bypass graft surgery, and subsequent clinical outcomes.Using the Project of Ex Vivo Vein Graft Engineering via Transfection IV (PREVENT IV) trial database, we studied data from 1829 patients who underwent coronary artery bypass graft surgery and had an angiogram performed up to 18 months after surgery. The main outcome measure was death, myocardial infarction, and repeat revascularization through 4 years after angiography. VGF occurred in 787 of 1829 patients (43%). Clinical follow-up was completed in 97% of patients with angiographic follow-up. The composite of death, myocardial infarction, or revascularization occurred more frequently among patients who had any VGF compared with those who had none (adjusted hazard ratio, 1.58; 95% confidence interval, 1.21-2.06; P=0.008). This was due mainly to more frequent revascularization with no differences in death (adjusted hazard ratio, 1.04; 95% confidence interval, 0.71-1.52; P=0.85) or death or myocardial infarction (adjusted hazard ratio, 1.08; 95% confidence interval, 0.77-1.53; P=0.65).VGF is common after coronary artery bypass graft surgery and is associated with repeat revascularization but not with death and/or myocardial infarction. Further investigations are needed to evaluate therapies and strategies for decreasing VGF to improve outcomes in patients undergoing coronary artery bypass graft surgery.

  View details for DOI 10.1161/CIRCULATIONAHA.111.040311

  View details for Web of Science ID 000300605200012

  View details for PubMedID 22238227

• 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

• ST-Elevation Acute Coronary Syndromes in the Platelet Inhibition and Patient Outcomes (PLATO) Trial Insights From the ECG Substudy CIRCULATION Armstrong, P. W., Siha, H., Fu, Y., Westerhout, C. M., Steg, P. G., James, S. K., Storey, R. F., Horrow, J., Katus, H., Clemmensen, P., Harrington, R. A., Wallentin, L. 2012; 125 (3): 514-U131

  Abstract

  Ticagrelor, when compared with clopidogrel, reduced the 12-month risk of vascular death/myocardial infarction and stroke in patients with ST-elevation acute coronary syndromes intended to undergo primary percutaneous coronary intervention in the PLATelet inhibition and patient Outcomes (PLATO) trial. This prespecified ECG substudy explored whether ticagrelor's association with vascular death and myocardial infarction within 1 year would be amplified by (1) the extent of baseline ST shift and (2) subsequently associated with fewer residual ST changes at hospital discharge.ECGs were evaluated centrally in a core laboratory in 3122 ticagrelor- and 3084 clopidogrel-assigned patients having at least 1 mm ST-elevation in 2 contiguous leads as identified by site investigators on the qualifying ECG. Patients with greater ST-segment shift at baseline had higher rates of vascular death/myocardial infarction within 1 year. Among those who also had an ECG at hospital discharge (n=4798), patients with ≥50% ΣST-deviation (ΣST-dev) resolution had higher event-free survival than those with incomplete resolution (6.4% versus 8.8%, adjusted hazard ratio 0.69 (0.54-0.88), P=0.003). The extent of ΣST-dev resolution was similar irrespective of treatment assignment. The benefit of ticagrelor versus clopidogrel on clinical events was consistent irrespective of the extent of baseline ΣST-dev (P(interaction)=0.728). When stratified according to conventional times from symptom onset, ie, ≤3 hours, 3 to 6 hours, >6 hours, the extent of baseline ΣST-dev declined progressively over time. As time from symptom onset increased beyond 3 hours, the benefit of ticagrelor appeared to be more pronounced; however, the interaction between time and treatment was not significant (P=0.175).Ticagrelor did not modify ΣST-dev resolution at discharge nor was its benefit affected by the extent of baseline ΣST-dev. These hypothesis-generating observations suggest that the main effects of ticagrelor may not relate to the rapidity or the completeness of acute reperfusion, but rather the prevention of recurrent vascular events by more powerful platelet inhibition or other mechanisms.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

  View details for DOI 10.1161/CIRCULATIONAHA.111.047530

  View details for Web of Science ID 000300252800019

  View details for PubMedID 22179530

• 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

• Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes EUROPEAN HEART JOURNAL Storey, R. F., Becker, R. C., Harrington, R. A., Husted, S., James, S. K., Cools, F., Steg, P. G., Khurmi, N. S., Emanuelsson, H., Cooper, A., Cairns, R., Cannon, C. P., Wallentin, L. 2011; 32 (23): 2945-2953

  Abstract

  AIMS To describe the incidence of dyspnoea and its associations with demographic characteristics and clinical outcomes in patients with acute coronary syndromes (ACS) treated with ticagrelor or clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) study. METHODS AND RESULTS In the PLATO study, 18 624 patients were randomized to receive either clopidogrel [300-600 mg loading dose (LD), 75 mg daily] or ticagrelor (180 mg LD, 90 mg b.i.d.). The occurrence of reported dyspnoea adverse events (AEs) was analysed in the 18 421 patients who received at least one dose of study medication in relation to demographic characteristics, clinical outcomes and other associations of patients with and without dyspnoea. A total of 1339 ticagrelor-treated patients (14.5%) and 798 clopidogrel-treated patients (8.7%) had a dyspnoea AE following randomization, with respectively 39 (0.4%) and 24 (0.3%) classified as severe in intensity. Excluding dyspnoea AEs occurring after the secondary endpoint of myocardial infarction (MI), the yearly rates of the efficacy endpoints in dyspnoea AE patients in the ticagrelor and clopidogrel groups were: for the primary composite of CV death, MI, and stroke, 8.8 and 10.4% (unadjusted P = 0.25; adjusted P = 0.54); for CV death, 3.1 and 4.8% (unadjusted P = 0.024; adjusted P = 0.18); and for total death 3.7 and 6.2% (unadjusted P = 0.004; adjusted P = 0.06), respectively. CONCLUSIONS Ticagrelor-related dyspnoea is usually mild or moderate in intensity and does not appear to be associated with differences concerning any efficacy or safety outcomes with ticagrelor compared with clopidogrel therapy in ACS patients.

  View details for DOI 10.1093/eurheartj/ehr231

  View details for Web of Science ID 000297647400009

  View details for PubMedID 21804104

• Pulmonary Function in Patients With Acute Coronary Syndrome Treated With Ticagrelor or Clopidogrel (from the Platelet Inhibition and Patient Outcomes [PLATO] Pulmonary Function Substudy) AMERICAN JOURNAL OF CARDIOLOGY Storey, R. F., Becker, R. C., Harrington, R. A., Husted, S., James, S. K., Cools, F., Steg, P. G., Khurmi, N. S., Emanuelsson, H., Lim, S. T., Cannon, C. P., Katus, H. A., Wallentin, L. 2011; 108 (11): 1542-1546

  Abstract

  The Platelet Inhibition and Patient Outcomes (PLATO) trial showed that ticagrelor reduced the risk for cardiovascular events in patients with acute coronary syndromes compared to clopidogrel but was associated with increased incidence of dyspnea. This substudy assessed whether ticagrelor affects pulmonary function in patients with acute coronary syndromes: 199 patients enrolled in the PLATO trial and receiving randomized treatment with ticagrelor 90 mg twice daily (n = 101) or clopidogrel 75 mg/day (n = 98) took part in the pulmonary function substudy. Patients with advanced lung disease, congestive heart failure, or coronary artery bypass graft surgery after the index event were excluded. Pulse oximetry (blood oxygen saturation), spirometry (forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow between 25% and 75% of forced vital capacity before and 20 minutes after inhalation of a β(2) agonist), lung volumes (total lung capacity, functional residual capacity, residual volume), and diffusion capacity were performed after patients received study medication for 30 to 40 days. Tests were then repeated <10 days before and approximately 30 days after the discontinuation of study medication. After a mean treatment duration of 31 days, there were no differences between the groups for any of the pulmonary function parameters. At the end of treatment (mean 211 days) and after the discontinuation of study medication (mean 32 days after the last dose), there was also no evidence of a change in pulmonary function in either group. For example, forced expiratory volume in 1 second values before β(2) agonist inhalation in the ticagrelor and clopidogrel groups were 2.81 ± 0.73 and 2.70 ± 0.84 L, respectively, at the first visit and did not change significantly at subsequent visits. In conclusion, no effect of ticagrelor on pulmonary function was seen in this cohort of patients with acute coronary syndromes compared to clopidogrel.

  View details for DOI 10.1016/j.amjcard.2011.07.015

  View details for Web of Science ID 000297880000004

  View details for PubMedID 21890085

• 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

• Safety and efficacy of adjusted-dose eptifibatide in patients with acute coronary syndromes and reduced renal function AMERICAN HEART JOURNAL Melloni, C., James, S. K., White, J. A., Giugliano, R. P., Harrington, R. A., Huber, K., Tricoci, P., Armstrong, P. W., Van de Werf, F., Montalescot, G., Califf, R. M., Newby, L. K. 2011; 162 (5)

  Abstract

  Dose adjustment of renally excreted antithrombotic drugs is recommended for patients with reduced renal function. We examined the influence of dose modification on bleeding and efficacy.Based on initial study drug infusion rate, Early GP IIb/IIIa Inhibition in non-ST-segment elevation acute coronary syndromes (EARLY ACS) patients were categorized into groups: standard dose (2 μg/kg/min; estimated creatinine clearance [eCrCl] ≥50 ml/min), adjusted dose (1 μg/kg/min; eCrCl <50 ml/min, per protocol), excess dose (2 μg/kg/min; eCrCl <50 ml/min). We explored relationships among initial dosing, randomized treatment assignment, and bleeding and ischemic end points (96-h composite of death, myocardial infarction [MI], recurrent ischemia requiring urgent revascularization or thrombotic bailout, and 30-d death or MI).Of 8,708 patients with eCrCl and dosing data, 19% had eCrCl <50 ml/min. Of these, 13% received adjusted dose eptifibatide and 6% received an excess dose. Across all dosing groups, no significant reductions were found in ischemic end points between early versus delayed provisional eptifibatide (OR 1.14, 95% CI 0.80-1.65; OR 1.13, 95% CI 0.81-1.56, respectively, for 96-h and 30-d composite end points). Bleeding risk was not significantly increased in the early versus delayed provisional treatment group in either the adjusted (OR 1.50, 95% CI 0.95-2.39) or excess dose group (OR 1.67, 95% CI 0.85-3.39). There were no significant interactions between dose group and treatment strategy on bleeding or efficacy.Similar to observations in practice, despite guidelines recommendations and protocol guidance, 34% of EARLY ACS patients with reduced renal function failed to receive an appropriately adjusted study drug infusion. Use of an appropriately adjusted eptifibatide infusion was not associated with expected reductions in bleeding among patients with renal insufficiency.

  View details for DOI 10.1016/j.ahj.2011.08.020

  View details for Web of Science ID 000297247800014

  View details for PubMedID 22093205

• Apixaban with Antiplatelet Therapy after Acute Coronary Syndrome NEW ENGLAND JOURNAL OF MEDICINE Alexander, J. H., Lopes, R. D., James, S., Kilaru, R., He, Y., Mohan, P., Bhatt, D. L., Goodman, S., Verheugt, F. W., Flather, M., Huber, K., Liaw, D., Husted, S. E., Lopez-Sendon, J., De Caterina, R., Jansky, P., Darius, H., Vinereanu, D., Cornel, J. H., Cools, F., Atar, D., Luis Leiva-Pons, J., Keltai, M., Ogawa, H., Pais, P., Parkhomenko, A., Ruzyllo, W., Diaz, R., White, H., Ruda, M., Geraldes, M., Lawrence, J., Harrington, R. A., Wallentin, L. 2011; 365 (8): 699-708

  Abstract

  Apixaban, an oral, direct factor Xa inhibitor, may reduce the risk of recurrent ischemic events when added to antiplatelet therapy after an acute coronary syndrome.We conducted a randomized, double-blind, placebo-controlled clinical trial comparing apixaban, at a dose of 5 mg twice daily, with placebo, in addition to standard antiplatelet therapy, in patients with a recent acute coronary syndrome and at least two additional risk factors for recurrent ischemic events.The trial was terminated prematurely after recruitment of 7392 patients because of an increase in major bleeding events with apixaban in the absence of a counterbalancing reduction in recurrent ischemic events. With a median follow-up of 241 days, the primary outcome of cardiovascular death, myocardial infarction, or ischemic stroke occurred in 279 of the 3705 patients (7.5%) assigned to apixaban (13.2 events per 100 patient-years) and in 293 of the 3687 patients (7.9%) assigned to placebo (14.0 events per 100 patient-years) (hazard ratio with apixaban, 0.95; 95% confidence interval [CI], 0.80 to 1.11; P=0.51). The primary safety outcome of major bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) definition occurred in 46 of the 3673 patients (1.3%) who received at least one dose of apixaban (2.4 events per 100 patient-years) and in 18 of the 3642 patients (0.5%) who received at least one dose of placebo (0.9 events per 100 patient-years) (hazard ratio with apixaban, 2.59; 95% CI, 1.50 to 4.46; P=0.001). A greater number of intracranial and fatal bleeding events occurred with apixaban than with placebo.The addition of apixaban, at a dose of 5 mg twice daily, to antiplatelet therapy in high-risk patients after an acute coronary syndrome increased the number of major bleeding events without a significant reduction in recurrent ischemic events. (Funded by Bristol-Myers Squibb and Pfizer; APPRAISE-2 ClinicalTrials.gov number, NCT00831441.).

  View details for DOI 10.1056/NEJMoa1105819

  View details for Web of Science ID 000294205300005

  View details for PubMedID 21780946

• Biomedical Innovation: A Risky Business at Risk SCIENCE TRANSLATIONAL MEDICINE Stack, R. S., Harrington, R. A. 2011; 3 (96)

  Abstract

  Regulatory and financial challenges conspire to stall the development and market approval of breakthrough medical products. Inconsistent parameters are used to assess the safety and efficacy of drugs, biologics, and devices; this glitch in the system introduces uncertainty, slows or blocks product approvals, and increases the costs of product development. Here, we consider how to balance the benefits and risks to the public in the assessment of innovative medical products. We also discuss the Institute of Medicine's recent report on the medical device approval process.

  View details for DOI 10.1126/scitranslmed.3002459

  View details for Web of Science ID 000293953100002

  View details for PubMedID 21849662

• American Industry and the U.S. Cardiovascular Clinical Research Enterprise An Appropriate Analogy? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Califf, R. M., Harrington, R. A. 2011; 58 (7): 677-680

  View details for DOI 10.1016/j.jacc.2011.03.048

  View details for Web of Science ID 000293455300004

  View details for PubMedID 21816302

• Intramyocardial, Autologous CD34+Cell Therapy for Refractory Angina CIRCULATION RESEARCH Losordo, D. W., Henry, T. D., Davidson, C., Lee, J. S., Costa, M. A., Bass, T., Mendelsohn, F., Fortuin, F. D., Pepine, C. J., Traverse, J. H., Amrani, D., Ewenstein, B. M., Riedel, N., Story, K., Barker, K., Povsic, T. J., Harrington, R. A., Schatz, R. A. 2011; 109 (4): 428-U235

  Abstract

  A growing number of patients with coronary disease have refractory angina. Preclinical and early-phase clinical data suggest that intramyocardial injection of autologous CD34+ cells can improve myocardial perfusion and function.Evaluate the safety and bioactivity of intramyocardial injections of autologous CD34+ cells in patients with refractory angina who have exhausted all other treatment options.In this prospective, double-blind, randomized, phase II study (ClinicalTrials.gov identifier: NCT00300053), 167 patients with refractory angina received 1 of 2 doses (1×10(5) or 5×10(5) cells/kg) of mobilized autologous CD34+ cells or an equal volume of diluent (placebo). Treatment was distributed into 10 sites of ischemic, viable myocardium with a NOGA mapping injection catheter. The primary outcome measure was weekly angina frequency 6 months after treatment. Weekly angina frequency was significantly lower in the low-dose group than in placebo-treated patients at both 6 months (6.8±1.1 versus 10.9±1.2, P=0.020) and 12 months (6.3±1.2 versus 11.0±1.2, P=0.035); measurements in the high-dose group were also lower, but not significantly. Similarly, improvement in exercise tolerance was significantly greater in low-dose patients than in placebo-treated patients (6 months: 139±151 versus 69±122 seconds, P=0.014; 12 months: 140±171 versus 58±146 seconds, P=0.017) and greater, but not significantly, in the high-dose group. During cell mobilization and collection, 4.6% of patients had cardiac enzyme elevations consistent with non-ST segment elevation myocardial infarction. Mortality at 12 months was 5.4% in the placebo-treatment group with no deaths among cell-treated patients.Patients with refractory angina who received intramyocardial injections of autologous CD34+ cells (10(5) cells/kg) experienced significant improvements in angina frequency and exercise tolerance. The cell-mobilization and -collection procedures were associated with cardiac enzyme elevations, which will be addressed in future studies.

  View details for DOI 10.1161/CIRCRESAHA.111.245993

  View details for Web of Science ID 000293504100011

  View details for PubMedID 21737787

• 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

• Saphenous Vein Grafts With Multiple Versus Single Distal Targets in Patients Undergoing Coronary Artery Bypass Surgery One-Year Graft Failure and Five-Year Outcomes From the Project of Ex-Vivo Vein Graft Engineering via Transfection (PREVENT) IV Trial CIRCULATION Mehta, R. H., Ferguson, T. B., Lopes, R. D., Hafley, G. E., Mack, M. J., Kouchoukos, N. T., Gibson, C. M., Harrington, R. A., Califf, R. M., Peterson, E. D., Alexander, J. H. 2011; 124 (3): 280-288

  Abstract

  Limited information exists on the intermediate-term graft patency and 5-year clinical outcomes of patients receiving saphenous vein grafts with multiple (m-SVG) versus single distal targets (s-SVG) during coronary artery bypass graft (CABG) surgery in the current era.We studied the association of the use of m-SVG versus s-SVG conduits with 1-year SVG failure (defined as ≥75% angiographic stenosis) and 5-year clinical events (death; death or myocardial infarction [MI]; and death, MI, or revascularization) in 3014 patients undergoing their first CABG surgery enrolled in the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV. Of 3014 patients enrolled in PREVENT IV, 1045 (34.7%) had ≥1 m-SVGs during CABG. Vein graft failure at 1-year was higher for m-SVG compared with s-SVG (adjusted odds ratio 1.24, 95% confidence interval 1.03 to 1.48). At 5 years, the adjusted composite of death, MI (including perioperative MI), or revascularization (hazard ratio 1.15, 95% confidence interval 1.00 to 1.31) and death or MI (hazard ratio 1.21, 95% confidence interval 1.03 to 1.43) were significantly higher in patients receiving m-SVGs.In patients undergoing first CABG surgery, the use of m-SVG was associated with a higher 1-year vein graft failure rate and trends toward worse clinical outcomes. Additional studies are needed to better understand the most appropriate conduit to improve long-term graft patency and clinical outcomes of patients undergoing CABG surgery. In the meantime, these data should encourage the use of s-SVG over m-SVG when feasible.

  View details for DOI 10.1161/CIRCULATIONAHA.110.991299

  View details for Web of Science ID 000292819300010

  View details for PubMedID 21709060

• ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents Developed in Collaboration With the American Academy of Neurology, American Geriatrics Society, American Society for Preventive Cardiology, American Society of Hypertension, American Society of Nephrology, Association of Black Cardiologists, and European Society of Hypertension JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION Aronow, W. S., Fleg, J. L., Pepine, C. J., Artinian, N. T., Bakris, G., Brown, A. S., Ferdinand, K. C., Forciea, M. A., Frishman, W. H., Jaigobin, C., Kostis, J. B., Mancia, G., Oparil, S., Ortiz, E., Reisin, E., Rich, M. W., Schocken, D. D., Weber, M. A., Wesley, D. J., Harrington, R. A., Bates, E. R., Bhatt, D. L., Bridges, C. R., Eisenberg, M. J., Ferrari, V. A., Fisher, J. D., Gardner, T. J., Gentile, F., Gilson, M. F., Hlatky, M. A., Jacobs, A. K., Kaul, S., Moliterno, D. J., Mukherjee, D., Rosenson, R. S., Stein, J. H., Weitz, H. H., Wesley, D. J. 2011; 5 (4): 259-352

  View details for DOI 10.1016/j.jash.2011.06.001

  View details for Web of Science ID 000293866000007

  View details for PubMedID 21771565

• Upstream Use of Small-Molecule Glycoprotein IIb/IIIa Inhibitors in Patients With Non-ST-Segment Elevation Acute Coronary Syndromes A Systematic Overview of Randomized Clinical Trials CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Tricoci, P., Newby, L. K., Hasselblad, V., Kong, D. F., Giugliano, R. P., White, H. D., Theroux, P., Stone, G. W., Moliterno, D. J., Van de Werf, F., Armstrong, P. W., Prabhakaran, D., Rasoul, S., Bolognese, L., durand, e., Braunwald, E., Califf, R. M., Harrington, R. A. 2011; 4 (4): 448-458

  Abstract

  The use of upstream small-molecule glycoprotein (GP) IIb/IIIa inhibitors in non-ST-segment elevation acute coronary syndromes (NSTE ACS) has been studied in multiple randomized clinical trials. We systematically reviewed the effect of upstream GP IIb/IIIa inhibitor use in NSTE ACS as reported in published clinical trials.Randomized clinical trials of upstream small-molecule GP IIb/IIIa inhibitors in NSTE ACS were identified through a PubMed and EMBASE search and were included if they contained 30-day outcome data. Odds ratios were generated from the published data and pooled by means of random effects modeling. The primary outcome measures were 30-day death and 30-day death or myocardial infarction. Primary safety measures were major bleeding and transfusion during the index hospitalization. Twelve clinical trials were included, evaluating tirofiban, eptifibatide, and lamifiban. Of these, 7 evaluated upstream GP IIb/IIIa inhibitors versus placebo (n=24 031) and 5 evaluated a strategy of upstream GP IIb/IIIa inhibitors versus upstream placebo with later provisional use at the time of percutaneous coronary intervention (n=19 643). Overall, upstream GP IIb/IIIa inhibitor use was associated with an 11% reduction in 30-day death/myocardial infarction (odds ratio [OR], 0.89; 95% confidence interval [CI], 0.83 to 0.95) but no significant mortality effect (OR, 0.93; 95% CI, 0.83 to 1.05). The risk of major bleeding was 23% higher in patients treated with upstream GP IIb/IIIa inhibitors (OR, 1.23; 95% CI, 1.02 to 1.48). Results were similar when only trials comparing upstream GP IIb/IIIa inhibitors versus placebo were considered: 30-day death/myocardial infarction (OR, 0.88; 95% CI, 0.81 to 0.95); 30-day death (OR, 0.89; 95% CI, 0.76 to 1.03); and major bleeding (OR, 1.17; 95% CI, 0.88 to 1.54). Upstream versus selective use at percutaneous coronary intervention trended toward lower 30-day death/myocardial infarction (OR, 0.91; 95% CI, 0.82 to 1.01) but had no effect on mortality (OR, 1.00; 95% CI, 0.81 to 1.23) and increased major bleeding risk by 34% (OR, 1.34; 95% CI, 1.10 to 1.63).In NSTE ACS, treatment with upstream small-molecule GP IIb/IIIa inhibitors provides a significant but modest ischemic benefit when compared with initial placebo. Compared with delayed, selective use at percutaneous coronary intervention, early upstream use is associated with a trend toward fewer ischemic events. However, these modest benefits are associated with an increased risk of bleeding.

  View details for DOI 10.1161/CIRCOUTCOMES.110.960294

  View details for Web of Science ID 000292872500012

  View details for PubMedID 21712522

• Dueling Registries? An Alternative Perspective and the Case for Competitive Collaboration CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Harrington, R. A. 2011; 4 (4): 486-487

  View details for DOI 10.1161/CIRCOUTCOMES.111.961250

  View details for Web of Science ID 000292872500017

  View details for PubMedID 21772006

• Dose Selection for a Direct and Selective Factor IXa Inhibitor and its Complementary Reversal Agent: Translating Pharmacokinetic and Pharmacodynamic Properties of the REG1 System to Clinical Trial Design JOURNAL OF THROMBOSIS AND THROMBOLYSIS Povsic, T. J., Cohen, M. G., Chan, M. Y., Zelenkofske, S. L., WARGIN, W. A., Harrington, R. A., Alexander, J. H., Rusconi, C. P., Becker, R. C. 2011; 32 (1): 21-31

  Abstract

  We performed detailed pharmacokinetic and pharmacodynamic modeling of REG1, an anticoagulation system composed of the direct factor IXa (FIXa) inhibitor pegnivacogin (RB006) and its matched active control agent anivamersen (RB007), with a focus on level of target inhibition to translate phase 1 results to phase 2 dose selection. We modeled early-phase clinical data relating weight-adjusted pegnivacogin dose and plasma concentration to prolongation of the activated partial thromboplastin time (aPTT). Using an in vitro calibration curve, percent FIXa inhibition was determined and related to aPTT prolongation and pegnivacogin dose and concentration. Similar methods were applied to relate anivamersen dose and level of reversal of pegnivacogin anticoagulation. Combined early-phase data suggested that ≥0.75 mg/kg pegnivacogin was associated with >99% inhibition of FIX activity and prolongation of plasma aPTT values ≈2.5 times above baseline, leading to selection of a 1 mg/kg dose for a phase 2a elective percutaneous coronary intervention study to achieve a high intensity of anticoagulation and minimize intersubject variability. Phase 2 validated our predictions, demonstrating 1 mg/kg pegnivacogin yielded plasma concentrations ≈25 μg/ml and >99% inhibition of FIX activity. The relationship between the anivamersen to pegnivacogin dose ratio and degree of pegnivacogin reversal was also validated. Our approach decreased the need for extensive dose-response studies, reducing the duration, complexity and cost of clinical development. The 1 mg/kg pegnivacogin dose and a range of anivamersen dose ratios are being tested in the phase 2b RADAR study (NCT00932100).

  View details for DOI 10.1007/s11239-011-0588-3

  View details for Web of Science ID 000292832800003

  View details for PubMedID 21503856

• Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial BRITISH MEDICAL JOURNAL James, S. K., Roe, M. T., Cannon, C. P., Cornel, J. H., Horrow, J., Husted, S., Katus, H., Morais, J., Steg, P. G., Storey, R. F., Stevens, S., Wallentin, L., Harrington, R. A. 2011; 342

  Abstract

  To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy.Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial.862 centres in 43 countries.5216 (28%) of 18,624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management.Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615).Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year.2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel.In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy.Clinical trials NCT00391872.

  View details for DOI 10.1136/bmj.d3527

  View details for Web of Science ID 000291933200003

  View details for PubMedID 21685437

• ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents CIRCULATION Aronow, W. S., Fleg, J. L., Pepine, C. J., Artinian, N. T., Bakris, G., Brown, A. S., Ferdinand, K. C., Forciea, M. A., Frishman, W. H., Jaigobin, C., Kostis, J. B., Mancia, G., Oparil, S., Ortiz, E., Reisin, E., Rich, M. W., Schocken, D. D., Weber, M. A., Wesley, D. J., Harrington, R. A., Bates, E. R., Bhatt, D. L., Bridges, C. R., Eisenberg, M. J., Ferrari, V. A., Fisher, J. D., Gardner, T. J., Gentile, F., Gilson, M. F., Hlatky, M. A., Jacobs, A. K., Kaul, S., Moliterno, D. J., Mukherjee, D., Rosenson, R. S., Stein, J. H., Weitz, H. H., Wesley, D. J. 2011; 123 (21): 2434-2506

  View details for DOI 10.1161/CIR.0b013e31821daaf6

  View details for Web of Science ID 000291104000018

• Intravenous Erythropoietin in Patients With ST-Segment Elevation Myocardial Infarction REVEAL: A Randomized Controlled Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Najjar, S. S., Rao, S. V., Melloni, C., Raman, S. V., Povsic, T. J., Melton, L., Barsness, G. W., Prather, K., Heitner, J. F., Kilaru, R., Gruberg, L., Hasselblad, V., Greenbaum, A. B., Patel, M., Kim, R. J., Talan, M., Ferrucci, L., Longo, D. L., Lakatta, E. G., Harrington, R. A. 2011; 305 (18): 1863-1872

  Abstract

  Acute ST-segment elevation myocardial infarction (STEMI) is a leading cause of morbidity and mortality. In experimental models of MI, erythropoietin reduces infarct size and improves left ventricular (LV) function.To evaluate the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI.A prospective, randomized, double-blind, placebo-controlled trial with a dose-escalation safety phase and a single dose (60,000 U of epoetin alfa) efficacy phase; the Reduction of Infarct Expansion and Ventricular Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial was conducted at 28 US sites between October 2006 and February 2010, and included 222 patients with STEMI who underwent successful percutaneous coronary intervention (PCI) as a primary or rescue reperfusion strategy.Participants were randomly assigned to treatment with intravenous epoetin alfa or matching saline placebo administered within 4 hours of reperfusion.Infarct size, expressed as percentage of LV mass, assessed by cardiac magnetic resonance (CMR) imaging performed 2 to 6 days after study medication administration (first CMR) and again 12 ± 2 weeks later (second CMR).In the efficacy cohort, the infarct size did not differ between groups on either the first CMR scan (n = 136; 15.8% LV mass [95% confidence interval {CI}, 13.3-18.2% LV mass] for the epoetin alfa group vs 15.0% LV mass [95% CI, 12.6-17.3% LV mass] for the placebo group; P = .67) or on the second CMR scan (n = 124; 10.6% LV mass [95% CI, 8.4-12.8% LV mass] vs 10.4% LV mass [95% CI, 8.5-12.3% LV mass], respectively; P = .89). In a prespecified analysis of patients aged 70 years or older (n = 21), the mean infarct size within the first week (first CMR) was larger in the epoetin alfa group (19.9% LV mass; 95% CI, 14.0-25.7% LV mass) than in the placebo group (11.7% LV mass; 95% CI, 7.2-16.1% LV mass) (P = .03). In the safety cohort, of the 125 patients who received epoetin alfa, the composite outcome of death, MI, stroke, or stent thrombosis occurred in 5 (4.0%; 95% CI, 1.31%-9.09%) but in none of the 97 who received placebo (P = .04).In patients with STEMI who had successful reperfusion with primary or rescue PCI, a single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Subgroup analyses raised concerns about an increase in infarct size among older patients.clinicaltrials.gov Identifier: NCT00378352.

  View details for Web of Science ID 000290438800023

  View details for PubMedID 21558517

• The Incidence of Bradyarrhythmias and Clinical Bradyarrhythmic Events in Patients With Acute Coronary Syndromes Treated With Ticagrelor or Clopidogrel in the PLATO (Platelet Inhibition and Patient Outcomes) Trial Results of the Continuous Electrocardiographic Assessment Substudy JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Scirica, B. M., Cannon, C. P., Emanuelsson, H., Michelson, E. L., Harrington, R. A., Husted, S., James, S., Katus, H., Pais, P., Raev, D., Spinar, J., Steg, P. G., Storey, R. F., Wallentin, L. 2011; 57 (19): 1908-1916

  Abstract

  The aim of this study was to determine whether ticagrelor increased the risk of ventricular pauses compared with clopidogrel and whether these pauses were associated with any clinical bradycardic events in patients presenting with acute coronary syndromes.Ticagrelor, an oral reversibly binding P2Y(12) inhibitor, provides more potent and consistent inhibition of platelet aggregation than clopidogrel but in a phase II study was associated with increased risk for ventricular pauses. A prospective continuous electrocardiographic (cECG) assessment was therefore performed within the PLATO (Platelet Inhibition and Patient Outcomes) study comparing ticagrelor and clopidogrel in patients hospitalized with acute coronary syndromes.Patients in the cECG assessment had planned 7-day cECG recording initiated at the time of randomization (week 1), which was within 24 h of symptom onset, and then repeated at 1 month after randomization during the convalescent phase. The principal safety endpoint was the incidence of ventricular pauses lasting at least 3 s. Investigators also reported symptomatic bradycardic adverse events during the entire study duration (median 277 days).A total of 2,908 patients were included in the cECG assessment, of whom 2,866 (98.5%) had week 1 recordings, 1,991 (68.4%) had 1-month recordings, and 1,949 (67.0%) had both. During the first week after randomization, ventricular pauses ≥3 s occurred more frequently in patients receiving ticagrelor than clopidogrel (84 [5.8%] vs. 51 [3.6%]; relative risk: 1.61; p = 0.006). At 1 month, pauses ≥3 s occurred overall less frequently and were similar between treatments (2.1% vs. 1.7%). Most were ventricular pauses, and the greatest excess associated with ticagrelor were asymptomatic, sinoatrial nodal in origin (66%), and nocturnal. There were no differences between ticagrelor and clopidogrel in the incidence of clinically reported bradycardic adverse events, including syncope, pacemaker placement, and cardiac arrest.In the PLATO cECG assessment, more patients treated with ticagrelor compared with clopidogrel had ventricular pauses, which were predominantly asymptomatic, sinoatrial nodal in origin, and nocturnal and occurred most frequently in the acute phase of acute coronary syndromes. There were no apparent clinical consequences related to the excess in ventricular pauses in patients assigned to ticagrelor. (A Comparison of AZD6140 and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

  View details for DOI 10.1016/j.jacc.2010.11.056

  View details for Web of Science ID 000290210100010

  View details for PubMedID 21545948

• The PLATO trial reveals further opportunities to improve outcomes in patients with acute coronary syndrome. Editorial on Serebruany. "Viewpoint: Paradoxical excess mortality in the PLATO trial should be independently verified" (Thromb Haemost 2011; 105.5). Thrombosis and haemostasis Wallentin, L., Becker, R. C., James, S. K., Harrington, R. A. 2011; 105 (5): 760-762

  View details for DOI 10.1160/TH11-03-0162

  View details for PubMedID 21394383

• Upstream Clopidogrel Use and the Efficacy and Safety of Early Eptifibatide Treatment in Patients With Acute Coronary Syndrome An Analysis From the Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) Trial CIRCULATION Wang, T. Y., White, J. A., Tricoci, P., Giugliano, R. P., Zeymer, U., Harrington, R. A., Montalescot, G., James, S. K., Van de Werf, F., Armstrong, P. W., Braunwald, E., Califf, R. M., Newby, L. K. 2011; 123 (7): 722-730

  Abstract

  In the Early Glycoprotein IIb/IIIa Inhibition in Patients with Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial, routine preangiography eptifibatide use was not superior to delayed provisional use but led to more bleeding. This analysis examines efficacy and safety of early eptifibatide in the setting of concurrent upstream clopidogrel use.In EARLY-ACS, clopidogrel use and timing were determined by treating physicians, but randomization to early eptifibatide versus placebo was stratified by the intent to use upstream clopidogrel. Among 9166 non-ST-elevation acute coronary syndrome patients who underwent coronary angiography, intent to use upstream clopidogrel was declared in 6895 (75%), and 7068 (77%) received upstream clopidogrel. After multivariable adjustment, intended upstream clopidogrel use did not differentially influence the effect of early eptifibatide on the primary end point of 96-hour death/myocardial infarction/recurrent ischemia requiring urgent revascularization/thrombotic bailout (interaction P=0.988). Early eptifibatide use reduced 30-day death/myocardial infarction among patients with intended upstream clopidogrel (adjusted odds ratio 0.85; 95% confidence interval 0.73 to 0.99) but not among those without intended upstream clopidogrel use (adjusted odds ratio 1.02; 95% confidence interval 0.80 to 1.30). However, the clopidogrel by randomized treatment interaction term was not significant (P=0.23). Thrombolysis in Myocardial Infarction major bleeding risk was increased with early eptifibatide in the setting of upstream clopidogrel use. Results were similar using actual clopidogrel treatment strata.Routine early eptifibatide use, compared with delayed provisional use, may be associated with lower 30-day ischemic risk in non-ST-elevation acute coronary syndrome patients also treated with clopidogrel before angiography. The benefit-risk ratio of intensive platelet inhibition with combined early use of antiplatelet agents needs further evaluation in prospective randomized trials.

  View details for DOI 10.1161/CIRCULATIONAHA.110.958041

  View details for Web of Science ID 000287588000011

  View details for PubMedID 21300952

• 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

• Impact of Recovery of Renal Function on Long-Term Mortality After Coronary Artery Bypass Grafting AMERICAN JOURNAL OF CARDIOLOGY Mehta, R. H., Honeycutt, E., Patel, U. D., Lopes, R. D., Shaw, L. K., Glower, D. D., Harrington, R. A., Califf, R. M., Sketch, M. H. 2010; 106 (12): 1728-1734

  Abstract

  Whether prognosis differs in acute renal failure (ARF) after coronary artery bypass grafting (CABG) in patients with and without recovery of renal function is not known. We studied patients who had CABG at Duke University Medical Center (1995 to 2008). ARF was defined as an increase in peak creatinine ≥50% after CABG or ≥0.7 mg/dl above baseline or need for new dialysis. Patients were categorized into 3 groups: (1) no ARF after CABG, (2) ARF after CABG and completely recovered renal function at day 7 (return of creatinine to no higher than baseline and no dialysis), or (3) ARF after CABG with no recovery of renal function at day 7 (creatinine no higher than baseline or new dialysis). Main outcome measurement was risk-adjusted long-term mortality (excluding death ≤7 days). ARF after CABG occurred in 2,083 of 10,415 patients (20%) and completely recovered in 703 (33.7%). Risk-adjusted mortality was highest in patients with ARF without recovery of renal function (hazard ratios 1.47, 95% confidence interval 1.34 to 1.62) and intermediate in those with ARF but completely recovered renal function (hazard ratios 1.21, 95% confidence interval 1.07 to 1.37, referent no-ARF group). Mortality was lower in patients with ARF compared to those without complete recovery of renal function (p = 0.0083). In conclusion, in patients with ARF after CABG, complete recovery of renal function was associated with significantly lower long-term mortality compared to those without such recovery, although this was significantly higher than in those without ARF. Thus, major emphasis should be on prevention of ARF in patients undergoing CABG.

  View details for DOI 10.1016/j.amjcard.2010.07.045

  View details for Web of Science ID 000285735000010

  View details for PubMedID 21126617

• 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

• Randomized, Double-Blind, Placebo-Controlled Trial of Autologous CD34+Cell Therapy for Refractory Angina: 2-Year Safety Analysis Losordo, D. W., Henry, T. D., Schatz, R. A., Lee, J. S., Costa, M., Bass, T., Schaer, G. L., Mendelsohn, F., Davidson, C., Waksman, R., Soukas, P. A., Simon, D., Chronos, N., Fortuin, F. D., Huang, P. P., Weintraub, N., Yeung, A., Rosenfield, K., Wong, S. C., Taussig, A., Raval, A. N., Sherman, W., Kereiakes, D., Strumpf, R. K., Port, S., Pieper, K., Ewenstein, B., Story, K. O., Barker, K. B., Harrington, R. A. LIPPINCOTT WILLIAMS & WILKINS. 2010

  View details for Web of Science ID 000208231601899

• ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 appropriate use criteria for cardiac computed tomography. A report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular Computed Tomography, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the American Society of Nuclear Cardiology, the North American Society for Cardiovascular Imaging, the Society for Cardiovascular Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. Journal of the American College of Cardiology Taylor, A. J., Cerqueira, M., Hodgson, J. M., Mark, D., Min, J., O'Gara, P., Rubin, G. D., Kramer, C. M., Berman, D., Brown, A., Chaudhry, F. A., Cury, R. C., Desai, M. Y., Einstein, A. J., Gomes, A. S., Harrington, R., Hoffmann, U., Khare, R., Lesser, J., McGann, C., Rosenberg, A., Schwartz, R., Shelton, M., Smetana, G. W., Smith, S. C. 2010; 56 (22): 1864-1894

  Abstract

  The American College of Cardiology Foundation (ACCF), along with key specialty and subspecialty societies, conducted an appropriate use review of common clinical scenarios where cardiac computed tomography (CCT) is frequently considered. The present document is an update to the original CCT/cardiac magnetic resonance (CMR) appropriateness criteria published in 2006, written to reflect changes in test utilization, to incorporate new clinical data, and to clarify CCT use where omissions or lack of clarity existed in the original criteria (1). The indications for this review were drawn from common applications or anticipated uses, as well as from current clinical practice guidelines. Ninety-three clinical scenarios were developed by a writing group and scored by a separate technical panel on a scale of 1 to 9 to designate appropriate use, inappropriate use, or uncertain use. In general, use of CCT angiography for diagnosis and risk assessment in patients with low or intermediate risk or pretest probability for coronary artery disease (CAD) was viewed favorably, whereas testing in high-risk patients, routine repeat testing, and general screening in certain clinical scenarios were viewed less favorably. Use of noncontrast computed tomography (CT) for calcium scoring was rated as appropriate within intermediate- and selected low-risk patients. Appropriate applications of CCT are also within the category of cardiac structural and functional evaluation. It is anticipated that these results will have an impact on physician decision making, performance, and reimbursement policy, and that they will help guide future research.

  View details for DOI 10.1016/j.jacc.2010.07.005

  View details for PubMedID 21087721

• Ticagrelor Versus Clopidogrel in Patients With ST-Elevation Acute Coronary Syndromes Intended for Reperfusion With Primary Percutaneous Coronary Intervention A Platelet Inhibition and Patient Outcomes (PLATO) Trial Subgroup Analysis CIRCULATION Steg, P. G., James, S., Harrington, R. A., Ardissino, D., Becker, R. C., Cannon, C. P., Emanuelsson, H., Finkelstein, A., Husted, S., Katus, H., Kilhamn, J., Olofsson, S., Storey, R. F., Weaver, D., Wallentin, L. 2010; 122 (21): 2131-2141

  Abstract

  Aspirin and clopidogrel are recommended for patients with acute coronary syndromes (ACS) or undergoing coronary stenting. Ticagrelor, a reversible oral P2Y12-receptor antagonist, provides faster, greater, and more consistent platelet inhibition than clopidogrel and may be useful for patients with acute ST-segment elevation (STE) ACS and planned primary percutaneous coronary intervention.Platelet Inhibition and Patient Outcomes (PLATO), a randomized, double-blind trial, compared ticagrelor with clopidogrel for the prevention of vascular events in 18 624 ACS patients. This report concerns the 7544 ACS patients with STE or left bundle-branch block allocated to either ticagrelor 180-mg loading dose followed by 90 mg twice daily or clopidogrel 300-mg loading dose (with provision for 300 mg clopidogrel at percutaneous coronary intervention) followed by 75 mg daily for 6 to 12 months. The reduction of the primary end point (myocardial infarction, stroke, or cardiovascular death) with ticagrelor versus clopidogrel (10.8% versus 9.4%; hazard ratio [HR], 0.87; 95% confidence interval, 0.75 to 1.01; P=0.07) was consistent with the overall PLATO results. There was no interaction between presentation with STE/left bundle-branch block and randomized treatment (interaction P=0.29). Ticagrelor reduced several secondary end points, including myocardial infarction alone (HR, 0.80; P=0.03), total mortality (HR, 0.82; P=0.05), and definite stent thrombosis (HR, 0.66; P=0.03). The risk of stroke, low in both groups, was higher with ticagrelor (1.7% versus 1.0%; HR,1.63; 95% confidence interval, 1.07 to 2.48; P=0.02). Ticagrelor did not affect major bleeding (HR, 0.98; P=0.76).In patients with STE-ACS and planned primary percutaneous coronary intervention, the effects of ticagrelor were consistent with those observed in the overall PLATO trial.URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00391872.

  View details for DOI 10.1161/CIRCULATIONAHA.109.927582

  View details for Web of Science ID 000284471800013

  View details for PubMedID 21060072

• Design and rationale of the Reduction of Infarct Expansion and Ventricular Remodeling with Erythropoietin after Large Myocardial Infarction (REVEAL) trial AMERICAN HEART JOURNAL Melloni, C., Rao, S. V., Povsic, T. J., Melton, L., Kim, R. J., Kilaru, R., Patel, M. R., Talan, M., Ferrucci, L., Longo, D. L., Lakatta, E. G., Najjar, S. S., Harrington, R. A. 2010; 160 (5): 795-U39

  Abstract

  Acute myocardial infarction (MI) remains a leading cause of death despite advances in pharmacologic and percutaneous therapies. Animal models of ischemia/reperfusion have demonstrated that single-dose erythropoietin may reduce infarct size, decrease apoptosis, and increase neovascularization, possibly through mobilization of endothelial progenitor cells.REVEAL is a randomized, double-blind, placebo-controlled, multicenter trial evaluating the effects of epoetin α on infarct size and left ventricular remodeling in patients with large MIs. The trial comprises a dose-escalation safety phase and a single-dose efficacy phase using the highest acceptable epoetin α dose up to 60,000 IU. Up to 250 ST-segment elevation myocardial infarction patients undergoing primary or rescue percutaneous coronary intervention will be randomized to intravenous epoetin α or placebo within 4 hours of successful reperfusion. The primary study end point is infarct size expressed as a percentage of left ventricular mass, as measured by cardiac magnetic resonance imaging 2 to 6 days post study medication administration. Secondary end points will assess changes in endothelial progenitor cell numbers and changes in indices of ventricular remodeling.The REVEAL trial will evaluate the safety and efficacy of the highest tolerated single dose of epoetin α in patients who have undergone successful rescue or primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction.

  View details for DOI 10.1016/j.ahj.2010.09.007

  View details for Web of Science ID 000284458700004

  View details for PubMedID 21095264

• Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome THROMBOSIS AND HAEMOSTASIS Becker, R. C., Alexander, J. H., Newby, L. K., Yang, H., Barrett, Y., Mohan, P., Wang, J., Harrington, R. A., Wallentin, L. C. 2010; 104 (5): 976-983

  Abstract

  Apixaban is an oral, direct factor Xa inhibitor under development for secondary prevention in acute coronary syndrome (ACS). Apixaban's effect on D-dimer and prothrombin fragment 1.2 (F1.2) (coagulation activity biomarkers ) was determined in a randomised, double-blinded, placebo-controlled, phase 2 study. Patients (n=1,715) with either ST- segment elevation or non-ST-segment elevation ACS received either placebo or apixaban 2.5 mg twice daily, 10 mg once daily, 10 mg twice daily or 20 mg once daily for six months. Samples were obtained at baseline (before study drug administration), week 3 and week 26. Apixaban plasma concentrations were measured directly by liquid chromatography/mass spectometry, and anti-Xa activity was determined using apixaban as a reference standard. D-dimer and F 1.2 were measured using ELISA-based methods. Most patients had elevated D-dimer and F1.2 levels at baseline. Both coagulation activity biomarkers decreased by week 3 in all treatment groups, but to a greater degree with apixaban than placebo (p<0.001). In a multivariable analysis, apixaban was independently associated with a change in biomarkers over time (p<0.0001). While the overall decrease did not differ significantly among the three highest apixaban doses, F1.2 was suppressed more rapidly by the 10 mg once daily than the 2.5 mg twice daily dose (p<0.05). There was a strong and direct relationship between apixaban plasma concentrations and anti-Xa-apixaban levels, and an inverse relationship for both measures with coagulation activity biomarkers. In conclusion, the oral direct factor Xa inhibitor apixaban significantly reduced coagulation activity biomarkers among patients with ACS. The 10 mg once daily dose reduced thrombin generation (F 1.2) and fibrin formation (D-dimer) more rapidly and robustly than the 2.5 mg twice daily dose. The effect on both D-dimer and F 1.2 was apixaban concentration-and factor Xa inhibition dependent, durable and provided general guidance for dose selection in phase 3 investigation.

  View details for DOI 10.1160/TH10.04.0247

  View details for Web of Science ID 000284522600016

  View details for PubMedID 20806117

• Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease AMERICAN HEART JOURNAL White, H., Held, C., Stewart, R., Watson, D., Harrington, R., Budaj, A., Steg, P. G., Cannon, C. P., Krug-Gourley, S., Wittes, J., Trivedi, T., Tarka, E., Wallentin, L. 2010; 160 (4): 655-U289

  Abstract

  Elevated plasma levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with increased risk of cardiovascular (CV) events. Direct inhibition of this proinflammatory enzyme with darapladib may benefit CV patients when given as an adjunct to standard of care, including lipid-lowering and antiplatelet therapies.STABILITY is a randomized, placebo-controlled, double-blind, international, multicenter, event-driven trial. The study has randomized 15,828 patients with chronic coronary heart disease (CHD) receiving standard of care to darapladib enteric-coated (EC) tablets, 160 mg or placebo.The primary end point is the composite of major adverse cardiovascular events (MACE): CV death, nonfatal myocardial infarction, and nonfatal stroke. The key secondary end points will include major coronary events, total coronary events, individual components of MACE, and all-cause mortality. Prespecified substudies include 24-hour ambulatory blood pressure monitoring, albuminuria progression, changes in cognitive function, and pharmacokinetic and biomarker analyses. Health economic outcomes and characterization of baseline lifestyle risk factors also will be assessed. The study will continue until 1,500 primary end points have occurred to achieve 90% power to detect a 15.5% reduction in the primary end point. The median treatment duration is anticipated to be 2.75 years.STABILITY will assess whether direct inhibition of Lp-PLA(2) with darapladib added to the standard of care confers clinical benefit to patients with CHD.

  View details for DOI 10.1016/j.ahj.2010.07.006

  View details for Web of Science ID 000282677300015

  View details for PubMedID 20934559

• 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

• Ticagrelor Versus Clopidogrel in Acute Coronary Syndromes in Relation to Renal Function Results From the Platelet Inhibition and Patient Outcomes (PLATO) Trial CIRCULATION James, S., Budaj, A., Aylward, P., Buck, K. K., Cannon, C. P., Cornel, J. H., Harrington, R. A., Horrow, J., Katus, H., Keltai, M., Lewis, B. S., Parikh, K., Storey, R. F., Szummer, K., Wojdyla, D., Wallentin, L. 2010; 122 (11): 1056-1067

  Abstract

  Reduced renal function is associated with a poorer prognosis and increased bleeding risk in patients with acute coronary syndromes and may therefore alter the risk-benefit ratio with antiplatelet therapies. In the Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor compared with clopidogrel reduced the primary composite end point of cardiovascular death, myocardial infarction, and stroke at 12 months but with similar major bleeding rates.Central laboratory serum creatinine levels were available in 15 202 (81.9%) acute coronary syndrome patients at baseline, and creatinine clearance, estimated by the Cockcroft Gault equation, was calculated. In patients with chronic kidney disease (creatinine clearance <60 mL/min; n=3237), ticagrelor versus clopidogrel significantly reduced the primary end point to 17.3% from 22.0% (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.65 to 0.90) with an absolute risk reduction greater than that of patients with normal renal function (n=11 965): 7.9% versus 8.9% (HR, 0.90; 95% CI, 0.79 to 1.02). In patients with chronic kidney disease, ticagrelor reduced total mortality (10.0% versus 14.0%; HR, 0.72; 95% CI, 0.58 to 0.89). Major bleeding rates, fatal bleedings, and non-coronary bypass-related major bleedings were not significantly different between the 2 randomized groups (15.1% versus 14.3%; HR, 1.07; 95% CI, 0.88 to 1.30; 0.34% versus 0.77%; HR, 0.48; 95% CI, 0.15 to 1.54; and 8.5% versus 7.3%; HR, 1.28; 95% CI, 0.97 to 1.68). The interactions between creatinine clearance and randomized treatment on any of the outcome variables were nonsignificant.In acute coronary syndrome patients with chronic kidney disease, ticagrelor compared with clopidogrel significantly reduces ischemic end points and mortality without a significant increase in major bleeding but with numerically more non-procedure-related bleeding.URL:http://www.clinicatrials.gov. Unique identifier: NCT00391872.

  View details for DOI 10.1161/CIRCULATIONAHA.109.933796

  View details for Web of Science ID 000281877800002

  View details for PubMedID 20805430

• President's page: the ACC reconfirms commitment to transparent relationships with industry. Journal of the American College of Cardiology Brindis, R., Harrington, R. 2010; 56 (11): 900-902

  View details for DOI 10.1016/j.jacc.2010.08.001

  View details for PubMedID 20813288

• First Clinical Application of an Actively Reversible Direct Factor IXa Inhibitor as an Anticoagulation Strategy in Patients Undergoing Percutaneous Coronary Intervention CIRCULATION Cohen, M. G., Purdy, D. A., Rossi, J. S., Grinfeld, L. R., Myles, S. K., Aberle, L. H., Greenbaum, A. B., Fry, E., Chan, M. Y., Tonkens, R. M., Zelenkofske, S., Alexander, J. H., Harrington, R. A., Rusconi, C. P., Becker, R. C. 2010; 122 (6): 614-622

  Abstract

  The ideal anticoagulant should prevent ischemic complications without increasing the risk of bleeding. Controlled anticoagulation is possible with the REG1 system, an RNA aptamer pair comprising the direct factor IXa inhibitor RB006 and its active control agent RB007.This phase 2a study included a roll-in group (n=2) treated with REG1 plus glycoprotein IIb/IIIa inhibitors followed by 2 groups randomized 5:1 to REG1 or unfractionated heparin. In group 1 (n=12), RB006 was partially reversed with RB007 after percutaneous coronary intervention and fully reversed 4 hours later. In group 2 (n=12), RB006 was fully reversed with RB007 immediately after percutaneous coronary intervention. Femoral sheaths were removed after complete reversal. Patients were pretreated with aspirin and clopidogrel. End points included major bleeding within 48 hours; composite of death, myocardial infarction, or urgent target vessel revascularization within 14 days; and pharmacodynamic measures. All cases were successful, with final Thrombolysis in Myocardial Infarction grade 3 flow and no angiographic thrombotic complications. There were 2 ischemic end points in the REG1 group and 1 in the unfractionated heparin group, with 1 major bleed in the unfractionated heparin group. Median activated clotting time values rose from 151 to 236 seconds after RB006. Administration of the partial RB007 dose reversed anticoagulation to an intermediate activated clotting time value of 186 seconds. Complete reversal with RB007 returned the median activated clotting time value to 144 seconds. Both reversal strategies enabled scheduled femoral sheath removal.This study demonstrates the clinical translation of a novel platform of anticoagulation targeting factor IXa and its active reversal to percutaneous coronary intervention and provides the basis for further investigation.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00715455.

  View details for DOI 10.1161/CIRCULATIONAHA.109.927756

  View details for Web of Science ID 000280757300008

  View details for PubMedID 20660806

• Randomized Evaluation of efficacy and safety of ferric carboxymaltose in Patients with iron deficiency Anaemia and Impaired Renal function (REPAIR-IDA): rationale and study design NEPHROLOGY DIALYSIS TRANSPLANTATION Szczech, L. A., Bregman, D. B., Harrington, R. A., Morris, D., Butcher, A., Koch, T. A., Goodnough, L. T., Wolf, M., Onken, J. E. 2010; 25 (7): 2368-2375

  Abstract

  Patients with iron deficiency anaemia (IDA) in the setting of non-dialysis-dependent chronic kidney disease (NDD-CKD) may benefit from treatment with intravenous (IV) iron. Ferric carboxymaltose (FCM) is a novel IV iron formulation designed to permit larger infusions compared to currently available IV standards such as Venofer(R) (iron sucrose).The primary objective of REPAIR-IDA is to estimate the cardiovascular safety and efficacy of FCM (two doses at 15 mg/kg to a maximum of 750 mg per dose) compared to Venofer(R) (1000 mg administered as five infusions of 200 mg) in subjects who have IDA and NDD-CKD. REPAIR-IDA is a multi-centre, randomized, active-controlled, open-label study. Eligible patients must have haemoglobin (Hgb) < or = 11.5 g/dL and CKD defined as (1) GFR < 60 mL/min/1.73 m(2) on two occasions or (2) GFR < 90 mL/min/1.73 m(2) and either evidence of renal injury by urinalysis or elevated Framingham cardiovascular risk score. Two thousand and five hundred patients will be randomized to FCM or Venofer(R) in a 1:1 ratio. The primary efficacy endpoint is mean change in Hgb from baseline to the highest observed Hgb between baseline and Day 56. The primary safety endpoint is the proportion of subjects experiencing at least one of the following events: death due to any cause, non-fatal myocardial infarction, non-fatal stroke, unstable angina requiring hospitalization, congestive heart failure requiring hospitalization or medical intervention, arrhythmias, hypertension or hypotension during the 120 days following randomization.REPAIR-IDA will assess the efficacy and safety of two 750-mg infusions of FCM compared to an FDA-approved IV iron regimen in patients with NDD-CKD at increased risk for cardiovascular disease.

  View details for DOI 10.1093/ndt/gfq218

  View details for Web of Science ID 000279189400051

  View details for PubMedID 20466657

• Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI) AMERICAN HEART JOURNAL Leonardi, S., Rao, S. V., Harrington, R. A., Bhatt, D. L., Gibson, C. M., Roe, M. T., Kochman, J., Huber, K., Zeymer, U., Madan, M., Gretler, D. D., McClure, M. W., Paynter, G. E., Thompson, V., Welsh, R. C. 2010; 160 (1): 65-72

  Abstract

  Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y(12) receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y(12) inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI.

  View details for DOI 10.1016/j.ahj.2010.04.008

  View details for Web of Science ID 000279440400011

  View details for PubMedID 20598974

• There Is a Role for Industry-Sponsored Education in Cardiology CIRCULATION Harrington, R. A., Califf, R. M. 2010; 121 (20): 2221-2227

  View details for DOI 10.1161/CIRCULATIONAHA.109.868026

  View details for Web of Science ID 000278018500010

  View details for PubMedID 20497985

• An update on the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) design AMERICAN HEART JOURNAL Califf, R. M., Lokhnygina, Y., Cannon, C. P., Stepanavage, M. E., McCabe, C. H., Musliner, T. A., Pasternak, R. C., Blazing, M. A., Giugliano, R. P., Harrington, R. A., Braunwald, E. 2010; 159 (5): 705-709

  View details for DOI 10.1016/j.ahj.2010.03.004

  View details for Web of Science ID 000277243300001

  View details for PubMedID 20435175

• Changes in Inflammatory Biomarkers in Patients Treated With Ticagrelor or Clopidogrel CLINICAL CARDIOLOGY Husted, S., Storey, R. F., Harrington, R. A., Emanuelsson, H., Cannon, C. P. 2010; 33 (4): 206-212

  Abstract

  Inflammation is a key factor in the development of atherosclerotic disease and acute coronary syndromes (ACS). The P2Y(12) receptor antagonists ticagrelor (AZD6140) and clopidogrel may have anti-inflammatory effects. The objective of this analysis from the Dose Confirmation Study Assessing Anti-Platelet Effects of AZD6140 vs Clopidogrel in NSTEMI 2 (DISPERSE 2) trial was to compare ticagrelor and clopidogrel for effects on the inflammatory biomarkers C-reactive protein (CRP), interleukin 6 (IL-6), myeloperoxidase (MPO), and soluble CD40 ligand (sCD40L).Ticagrelor inhibits the P2Y(12) receptor and inflammation to a greater extent than clopidogrel in nonST-segment elevation ACS (NSTE-ACS) patients.In a double-blind, double-dummy, multicenter trial, 990 patients who had been hospitalized within the previous 48 hours with NSTE-ACS were randomized to receive ticagrelor 90 mg twice daily, ticagrelor 180 mg twice daily, or clopidogrel 300 mg initially and then 75 mg once daily. Within the ticagrelor groups, patients were also randomized to receive or not receive a loading dose of ticagrelor 270 mg initially. All patients received standard treatment for ACS, which included 325 mg aspirin initially and 75 to 100 mg aspirin each day subsequently. Inflammatory biomarkers were measured at baseline, upon hospital discharge, and after 4 weeks.Inflammatory biomarker measurements were not significantly different among treatment groups at baseline, discharge, and 4 weeks.Ticagrelor and clopidogrel appeared not to differ in this study with respect to the inflammatory biomarkers CRP, IL-6, MPO, and sCD40L in patients with NSTE-ACS.

  View details for DOI 10.1002/clc.20732

  View details for Web of Science ID 000277113300004

  View details for PubMedID 20394040

• Towards a new order in cardiovascular medicine: re-engineering through global collaboration EUROPEAN HEART JOURNAL Califf, R. M., Armstrong, P. W., Granger, C. B., Harrington, R. A., Lee, K., Simess, R. J., Van de Werf, F., Wallentin, L., White, H. D. 2010; 31 (8): 911-917

  View details for DOI 10.1093/eurheartj/ehp550

  View details for Web of Science ID 000277278900010

  View details for PubMedID 20130014

• Metabolic Syndrome Is Not Associated With Increased Mortality or Cardiovascular Risk in Nondiabetic Patients With a New Diagnosis of Coronary Artery Disease CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES Petersen, J. L., Yow, E., Aljaroudi, W., Shaw, L. K., Goyal, A., McGuire, D. K., Peterson, E. D., Harrington, R. A. 2010; 3 (2): 165-172

  Abstract

  Metabolic syndrome (MetSyn) is associated with increased cardiovascular risk in the general population. Its prognostic implications are less well defined in patients with coronary artery disease.We analyzed patients in the Duke Database for Cardiovascular Disease with a diagnosis of incident obstructive coronary artery disease. Diabetes mellitus (DM) was classified as a clinical history of DM, use of hypoglycemic drugs, or fasting glucose of >or=126 mg/dL. MetSyn was defined as having 3 of 5 characteristics: fasting glucose >or=100 and <126 mg/dL, low high-density lipoprotein cholesterol (men, <40 mg/dL; women, <50 mg/dL), triglycerides >150 mg/dL, blood pressure >or=130/85 mm Hg, or use of antihypertensive therapy, or body mass index >or=27. Death, myocardial infarction, or stroke was assessed at 6 months, 1 year, then annually. Cox proportional hazards models were generated to compare mortality and cardiovascular events between groups. The primary cohort consisted of 5744 patients; 1831 (31.9%) had DM, 2491 (43.4%) had MetSyn, and 1422 (24.7%) had no DM/MetSyn. Median follow-up was 5 years. Compared with no DM/MetSyn patients, DM patients had a higher adjusted risk for mortality (hazard ratio, 1.47; 95% CI, 1.28 to 1.69) but MetSyn patients did not (hazard ratio, 0.94; 95% CI, 0.81 to 1.08). Similar results were found for the combined end points of death or myocardial infarction, and death, myocardial infarction, or stroke.In a population of consecutive patients with a new diagnosis of coronary artery disease by angiography, MetSyn without DM was not an independent predictor of mortality or cardiovascular events.

  View details for DOI 10.1161/CIRCOUTCOMES.109.864447

  View details for Web of Science ID 000276080200010

  View details for PubMedID 20179266

• 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

• Comparison of ticagrelor with clopidogrel in patients with planned invasive strategy for acute coronary syndromes (PLATO): a randomised double-blind study LANCET Cannon, C. P., Harrington, R. A., James, S., Ardissino, D., Becker, R. C., Emanuelsson, H., Husted, S., Katus, H., Keltai, M., Khurmi, N. S., Kontny, F., Lewis, B. S., Steg, P. G., Storey, R. F., Wojdyla, D., Wallentin, L. 2010; 375 (9711): 283-293

  Abstract

  Variation in and irreversibility of platelet inhibition with clopidogrel has led to controversy about its optimum dose and timing of administration in patients with acute coronary syndromes. We compared ticagrelor, a more potent reversible P2Y12 inhibitor with clopidogrel in such patients.At randomisation, an invasive strategy was planned for 13 408 (72.0%) of 18 624 patients hospitalised for acute coronary syndromes (with or without ST elevation). In a double-blind, double-dummy study, patients were randomly assigned in a one-to-one ratio to ticagrelor and placebo (180 mg loading dose followed by 90 mg twice a day), or to clopidogrel and placebo (300-600 mg loading dose or continuation with maintenance dose followed by 75 mg per day) for 6-12 months. All patients were given aspirin. The primary composite endpoint was cardiovascular death, myocardial infarction, or stroke. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00391872.6732 patients were assigned to ticagrelor and 6676 to clopidogrel. The primary composite endpoint occurred in fewer patients in the ticagrelor group than in the clopidogrel group (569 [event rate at 360 days 9.0%] vs 668 [10.7%], hazard ratio 0.84, 95% CI 0.75-0.94; p=0.0025). There was no difference between clopidogrel and ticagrelor groups in the rates of total major bleeding (691 [11.6%] vs 689 [11.5%], 0.99 [0.89-1.10]; p=0.8803) or severe bleeding, as defined according to the Global Use of Strategies To Open occluded coronary arteries, (198 [3.2%] vs 185 [2.9%], 0.91 [0.74-1.12]; p=0.3785).Ticagrelor seems to be a better option than clopidogrel for patients with acute coronary syndromes for whom an early invasive strategy is planned.

  View details for DOI 10.1016/S0140-6736(09)62191-7

  View details for Web of Science ID 000274069300029

  View details for PubMedID 20079528

• 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

• 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

• Safety and feasibility of adjunctive antiplatelet therapy with intravenous elinogrel, a direct-acting and reversible P2Y12 ADP-receptor antagonist, before primary percutaneous intervention in patients with ST-elevation myocardial infarction: The Early Rapid ReversAl of Platelet ThromboSis with Intravenous Elinogrel before PCI to Optimize REperfusion in Acute Myocardial Infarction (ERASE MI) pilot trial AMERICAN HEART JOURNAL Berger, J. S., Roe, M. T., Gibson, C. M., Kilaru, R., Green, C. L., Melton, L., Blankenship, J. D., Metzger, D. C., Granger, C. B., Gretler, D. D., Grines, C. L., Huber, K., Zeymer, U., Buszman, P., Harrington, R. A., Armstrong, P. W. 2009; 158 (6): 998-U145

  Abstract

  Inhibition of the P2Y12 ADP-receptor with oral antiplatelet agents given to patients undergoing primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) is associated with improved outcomes, but this strategy is limited by the time required for maximal antiplatelet effect after administration. We examined the safety and tolerability of a novel, direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, versus placebo when administered to STEMI patients before primary PCI.The ERASE MI trial was a pilot, phase IIA, randomized, double-blind, placebo-controlled, dose-escalation study designed to evaluate the safety and tolerability of escalating doses (10, 20, 40, and 60 mg) of elinogrel administered as a single intravenous bolus before the start of the diagnostic angiogram preceding primary PCI. Patients were randomly assigned in a 1:1 manner to either elinogrel or placebo within each dosing group; and all patients received a 600-mg clopidogrel loading dose, followed by a second 300-mg clopidogrel loading dose 4 hours after PCI. The major outcome, in-hospital bleeding, was assessed with the Thrombolysis in Myocardial Infarction and Global Strategies to Open Occluded Coronary Arteries bleeding scales. Pre-PCI corrected Thrombolysis in Myocardial Infarction frame count and ST-segment resolution were also evaluated.Seventy patients were randomized in the dose-escalation study, but the dose-confirmation phase was not started because the trial was prematurely terminated for administrative reasons. The incidence of bleeding events was infrequent and appeared to be similar in patients treated with all doses of elinogrel versus placebo. No differences in serious adverse events, laboratory values, corrected Thrombolysis in Myocardial Infarction frame count, or ST resolution were demonstrated between elinogrel and placebo.With the limitations of a small study sample size, this pilot study provided preliminary data on the feasibility and tolerability of escalating doses of a direct-acting, reversible, intravenous P2Y12 ADP-receptor antagonist, elinogrel, as an adjunctive therapy for primary PCI for STEMI.

  View details for DOI 10.1016/j.ahj.2009.10.010

  View details for Web of Science ID 000273051100016

  View details for PubMedID 19958867

• Standardized reporting of bleeding complications for clinical investigations in acute coronary syndromes: A proposal from the Academic Bleeding Consensus (ABC) Multidisciplinary Working Group AMERICAN HEART JOURNAL Rao, S. V., Eikelboom, J., Steg, P. G., Lincoff, A. M., Weintraub, W. S., Bassand, J., Rao, A. K., Gibson, C. M., Petersen, J. L., Mehran, R., Manoukian, S. V., Charnigo, R., Lee, K. L., Moscucci, M., Harrington, R. A. 2009; 158 (6): 881-U16

  Abstract

  Clinical trials of antithrombotic agents for the treatment of ACS routinely assess bleeding as a safety endpoint, but variation in bleeding definitions makes comparison of the relative safety of these agents difficult.The ABC Multidisciplinary Working Group, an informal working group comprising clinical researchers and representatives from the US Food and Drug Administration, the National Institutes of Health, and the pharmaceutical industry, sought to develop a consensus approach to measuring the incidence and severity of bleeding complications during clinical trials of acute coronary syndromes (ACS). A meeting of the ABC was convened in April 2008 in Washington, DC, with the goal of developing a consensus approach to measuring the incidence and severity of hemorrhagic complications during clinical trials of ACS. Relevant literature on bleeding was reviewed through a series of short lectures and intensive group discussion.Using existing evidence on bleeding and outcomes as well as clinical judgment, criteria for the assessment of bleeding were developed through expert consensus. This consensus statement divides bleeding-related data elements into three categories: essential, recommended, and optional.The ABC Group recommendations for collection and reporting of bleeding complications provide a framework for consistency in the collection of information on hemorrhagic complications in trials of ACS. Widespread adoption of the statement recommendations will facilitate understanding of the mechanisms of adverse outcomes after bleeding and comparisons of the relative safety of antithrombotic agents, as well as the interpretation of safety results from future studies.

  View details for DOI 10.1016/j.ahj.2009.10.008

  View details for Web of Science ID 000273051100001

  View details for PubMedID 19958852

• 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

• Autologous CD34+Cell Therapy for Refractory Angina: 12 Month Results of the Phase II ACT34-CMI Study 82nd National Conference and Exhibitions and Scientific Sessions of the American-Heart-Association Losordo, D. W., Henry, T., Schatz, R. A., Lee, J. S., Costa, M., Bass, T., Schaer, G., Niederman, A., Mendelsohn, F., Davidson, C., Waksman, R., Soukas, P. A., Simon, D., Chronos, N., Fortuin, F. D., Huang, P. P., Weintraub, N., Yeung, A., Rosenfield, K., Wong, S. C., Taussig, A., Rava, A. N., Sherman, W., Kereiakes, D., Strumpf, R. K., Port, S., Pieper, K., Adams, P. X., Harrington, R. LIPPINCOTT WILLIAMS & WILKINS. 2009: S1132–S1132

  View details for Web of Science ID 000271831504167

• Enoxaparin Versus Unfractionated Heparin in Elective Percutaneous Coronary Intervention 1-Year Results From the STEEPLE (SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation) Trial JACC-CARDIOVASCULAR INTERVENTIONS Montalescot, G., Gallo, R., White, H. D., Cohen, M., Steg, G., Aylward, P. E., Bode, C., Chiariello, M., King, S. B., Harrington, R. A., Desmet, W. J., Macaya, C., Steinhubl, S. R. 2009; 2 (11): 1083-1091

  Abstract

  Our purpose was to evaluate long-term mortality and identify factors associated with 1-year mortality in patients who underwent elective percutaneous coronary intervention (PCI).While long-term outcomes in PCI patients have been reported previously, limited data are currently available regarding the comparative long-term outcomes in PCI patients who receive enoxaparin versus intravenous unfractionated heparin (UFH).We conducted a follow-up analysis of clinical outcomes at 1 year in patients enrolled in the STEEPLE (SafeTy and Efficacy of Enoxaparin in Percutaneous coronary intervention patients, an internationaL randomized Evaluation) trial of 3,528 patients undergoing elective PCI. Patients were randomized to receive either intravenous 0.50-mg/kg or 0.75-mg/kg enoxaparin or intravenous UFH during elective PCI procedures. All-cause mortality at 1 year after index PCI was the main outcome measure.Mortality rates were 1.4%, 2.0%, and 1.5% from 1 month to 1 year, and 2.3%, 2.2%, and 1.9% from randomization to 1 year, after index PCI in patients receiving 0.50 mg/kg enoxaparin, 0.75 mg/kg enoxaparin, and UFH, respectively. Multivariate analysis identified nonfatal myocardial infarction and/or urgent target vessel revascularization up to 30 days after index PCI (hazard ratio: 3.5, 95% confidence interval: 1.7 to 7.3; p < 0.001), and major bleeding within 48 h (hazard ratio: 3.0, 95% confidence interval: 1.1 to 8.5; p = 0.04) as the strongest independent risk factors for 1-year mortality.The 1-year mortality rates were low and comparable between patients receiving enoxaparin and UFH during elective PCI. Periprocedural ischemic or bleeding events were the strongest independent predictors of 1-year mortality. (The STEEPLE Trial; NCT00077844).

  View details for DOI 10.1016/j.jcin.2009.08.016

  View details for Web of Science ID 000275913800008

  View details for PubMedID 19926048

• Patterns of management of atrial fibrillation complicating coronary artery bypass grafting: Results from the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT-IV) Trial AMERICAN HEART JOURNAL Al-Khatib, S. M., Hafley, G., Harrington, R. A., Mack, M. J., Ferguson, T. B., Peterson, E. D., Califf, R. M., Kouchoukos, N. T., Alexander, J. H. 2009; 158 (5): 792-798

  Abstract

  Current practice related to the management of atrial fibrillation (AF) complicating coronary artery bypass grafting (CABG) is uncertain.We examined management of post-CABG AF in the PREVENT-IV trial, and we explored patterns of use of postoperative rhythm versus rate control and anticoagulation for AF by geographic region and type of site. We also compared outcomes of patients who developed post-CABG AF (663) with those who did not (2,131).The incidence of AF was 24%. Post-CABG AF was treated with a rhythm control strategy in 81% of patients and with warfarin in 23% of patients. Although there were significant variations across sites in the management of post-CABG AF, patterns of use of postoperative rhythm versus rate control and anticoagulation did not differ by geographic region or by whether or not the enrolling site was an academic institution. Mortality was higher in patients with post-CABG AF than patients without AF at 30 days (1.5% vs 0.7%, P = .01) but not at 3 years (6.9% vs 4.9%, P = .41). There was a trend toward a higher risk of mortality or stroke at 30 days in patients with AF (2.4% vs 1.9%, P = .08).Although a rhythm control strategy was used in most of the patients in this trial and the overall rate of use of warfarin was low, the significance of these findings is uncertain because of the lack of data from randomized clinical trials. The substantial variations in the management of post-CABG AF across sites are likely because of definitive data on the most effective therapies, highlighting the need for clinical trials on rate versus rhythm control and on anticoagulation for AF in this setting.

  View details for DOI 10.1016/j.ahj.2009.09.003

  View details for Web of Science ID 000271275400016

  View details for PubMedID 19853700

• Catheter thrombosis and percutaneous coronary intervention: fundamental perspectives on blood, artificial surfaces and antithrombotic drugs JOURNAL OF THROMBOSIS AND THROMBOLYSIS Chan, M. Y., Weitz, J. I., Merhi, Y., Harrington, R. A., Becker, R. C. 2009; 28 (3): 366-380

  Abstract

  Recent reports of catheter thrombosis among patients undergoing percutaneous coronary intervention (PCI) have had a significant impact on the development of new antithrombotic therapies. The overall incidence of this complication is unknown, mainly because of underreporting in contemporary clinical trials of coronary intervention. The etiology and pathophysiology of catheter thrombosis is also poorly understood. Introduction of a catheter or guidewire may not provoke the intense thrombotic response that follows angioplasty or stenting, but factors such as catheter materials and device size, equipment surface properties, flow conditions, procedural time and complexity, as well as the antiplatelet and anticoagulant drugs administered during the procedure influence the likelihood, rate and clinical impact of thrombosis. The crucial role of cellular interactions involving tissue-factor bearing cells and platelets in the process of thrombosis also needs to be critically explored when considering blood contact with an exogenous material. Focusing on the inherently prothrombotic environment of percutaneous coronary intervention, we review the physiologic underpinnings of catheter and guidewire thrombosis, and explore the effect of antithrombotic drugs at the interface between blood and material surfaces. We also propose a clinical classification for the diagnosis and investigation of catheter thrombosis in clinical trials of anticoagulant therapy and PCI.

  View details for DOI 10.1007/s11239-009-0375-6

  View details for Web of Science ID 000269860600021

  View details for PubMedID 19597766

• 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

• Antithrombotics in Acute Coronary Syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Bonaca, M. P., Steg, P. G., Feldman, L. J., Canales, J. F., Ferguson, J. J., Wallentin, L., Califf, R. M., Harrington, R. A., Giugliano, R. P. 2009; 54 (11): 969-984

  Abstract

  Antithrombotic agents are an integral component of the medical regimens and interventional strategies currently recommended to reduce thrombotic complications in patients with acute coronary syndromes (ACS). Despite great advances with these therapies, associated high risks for thrombosis and hemorrhage remain as the result of complex interactions involving patient comorbidities, drug combinations, multifaceted dosing adjustments, and the intricacies of the care environment. As such, the optimal combinations of antithrombotic therapies, their timing, and appropriate targeted subgroups remain the focus of intense research. During the last several years a number of new antithrombotic treatments have been introduced, and new data regarding established therapies have come to light. Although treatment guidelines include the most current available data, subsequent findings can be challenging to integrate. This challenge is compounded by the complexity associated with different efficacy and safety measures and the variability in study populations, presenting syndromes, physician, and patient preferences. In this work we review recent data regarding clinically available antiplatelet and anticoagulation agents used in the treatment of patients with ACS. We address issues including relative efficacy, safety, and timing of therapies with respect to conservative and invasive treatment strategies. In specific cases we will highlight remaining questions and controversies and ongoing trials, which will hopefully shed light in these areas. In addition to reviewing existing agents, we take a look forward at the most promising new antithrombotics currently in late-stage clinical development and their potential role in the context of ACS management.

  View details for DOI 10.1016/j.jacc.2009.03.083

  View details for Web of Science ID 000269477500001

  View details for PubMedID 19729112

• 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

• Sex Differences in Mortality Following Acute Coronary Syndromes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Berger, J. S., Elliott, L., Gallup, D., Roe, M., Granger, C. B., Armstrong, P. W., Simes, R. J., White, H. D., Van de Werf, F., Topol, E. J., Hochman, J. S., Newby, L. K., Harrington, R. A., Califf, R. M., Becker, R. C., Douglas, P. S. 2009; 302 (8): 874-882

  Abstract

  Conflicting information exists about whether sex differences modulate short-term mortality following acute coronary syndromes (ACS).To investigate the relationship between sex and 30-day mortality in ACS, and to determine whether this relationship was modified by clinical syndrome or coronary anatomy using a large database across the spectrum of ACS and adjusting for potentially confounding clinical covariates.A convenience sample of patients pooled from 11 independent, international, randomized ACS clinical trials between 1993 and 2006 whose databases are maintained at the Duke Clinical Research Institute, Durham, North Carolina. Of 136 247 patients, 38 048 (28%) were women; 102 004 (26% women) with ST-segment elevation myocardial infarction (STEMI), 14 466 (29% women) with non-STEMI (NSTEMI), and 19 777 (40% women) with unstable angina.Thirty-day mortality following ACS.Thirty-day mortality was 9.6% in women and 5.3% in men (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.83-2.00). After multivariable adjustment, mortality was not significantly different between women and men (adjusted OR, 1.06; 95% CI, 0.99-1.15). A significant sex by type of ACS interaction was demonstrated (P < .001). In STEMI, 30-day mortality was higher among women (adjusted OR, 1.15; 95% CI, 1.06-1.24), whereas in NSTEMI (adjusted OR, 0.77; 95% CI, 0.63-0.95) and unstable angina, mortality was lower among women (adjusted OR, 0.55; 95% CI, 0.43-0.70). In a cohort of 35 128 patients with angiographic data, women more often had nonobstructive (15% vs 8%) and less often had 2-vessel (25% vs 28%) and 3-vessel (23% vs 26%) coronary disease, regardless of ACS type. After additional adjustment for angiographic disease severity, 30-day mortality among women was not significantly different than men, regardless of ACS type. The relationship between sex and 30-day mortality was similar across the levels of angiographic disease severity (P for interaction = .70).Sex-based differences existed in 30-day mortality among patients with ACS and vary depending on clinical presentation. However, these differences appear to be largely explained by clinical differences at presentation and severity of angiographically documented disease.

  View details for Web of Science ID 000269260100021

  View details for PubMedID 19706861

• Premature Release of Data from Clinical Trials of Ezetimibe NEW ENGLAND JOURNAL OF MEDICINE Califf, R. M., Harrington, R. A., Blazing, M. A. 2009; 361 (7): 712-717

  View details for Web of Science ID 000268884100015

  View details for PubMedID 19675335

• Endoscopic versus Open Vein-Graft Harvesting in Coronary-Artery Bypass Surgery NEW ENGLAND JOURNAL OF MEDICINE Lopes, R. D., Hafley, G. E., Allen, K. B., Ferguson, T. B., Peterson, E. D., Harrington, R. A., Mehta, R. H., Gibson, C. M., Mack, M. J., Kouchoukos, N. T., Califf, R. M., Alexander, J. H. 2009; 361 (3): 235-244

  Abstract

  Vein-graft harvesting with the use of endoscopy (endoscopic harvesting) is a technique that is widely used to reduce postoperative wound complications after coronary-artery bypass grafting (CABG), but the long-term effects on the rate of vein-graft failure and on clinical outcomes are unknown.We studied the outcomes in patients who underwent endoscopic harvesting (1753 patients) as compared with those who underwent graft harvesting under direct vision, termed open harvesting (1247 patients), in a secondary analysis of 3000 patients undergoing CABG. The method of graft harvesting was determined by the surgeon. Vein-graft failure was defined as stenosis of at least 75% of the diameter of the graft on angiography 12 to 18 months after surgery (data were available in an angiographic subgroup of 1817 patients and 4290 grafts). Clinical outcomes included death, myocardial infarction, and repeat revascularization. Generalized estimating equations were used to adjust for baseline covariates associated with vein-graft failure and to account for the potential correlation between grafts within a patient. Cox proportional-hazards modeling was used to assess long-term clinical outcomes.The baseline characteristics were similar between patients who underwent endoscopic harvesting and those who underwent open harvesting. Patients who underwent endoscopic harvesting had higher rates of vein-graft failure at 12 to 18 months than patients who underwent open harvesting (46.7% vs. 38.0%, P<0.001). At 3 years, endoscopic harvesting was also associated with higher rates of death, myocardial infarction, or repeat revascularization (20.2% vs. 17.4%; adjusted hazard ratio, 1.22; 95% confidence interval [CI], 1.01 to 1.47; P=0.04), death or myocardial infarction (9.3% vs. 7.6%; adjusted hazard ratio, 1.38; 95% CI, 1.07 to 1.77; P=0.01), and death (7.4% vs. 5.8%; adjusted hazard ratio, 1.52; 95% CI, 1.13 to 2.04; P=0.005).Endoscopic vein-graft harvesting is independently associated with vein-graft failure and adverse clinical outcomes. Randomized clinical trials are needed to further evaluate the safety and effectiveness of this harvesting technique.

  View details for Web of Science ID 000267976100004

  View details for PubMedID 19605828

• A new generation of antiplatelet agents CURRENT OPINION IN CARDIOLOGY Sellers, M. B., Tricoci, P., Harrington, R. A. 2009; 24 (4): 307-312

  Abstract

  Since the development and market entry of clopidogrel, a platelet ADP blocker, physicians have had few new antiplatelet options available to them for the treatment of acute and chronic coronary disease, specifically in the setting of acute coronary syndromes, percutaneous coronary intervention, and chronic stent management. Over the years, limitations of current antiplatelet regimens have emerged, establishing a need for novel antiplatelet drugs. This article discusses potential new targets for platelet inhibition and reviews innovative antiplatelet therapies under investigation.There are five main categories of antiplatelet therapies currently undergoing clinical study, consisting of the thienopyridines (P2Y12 receptor antagonists), cyclopentyltriazolopyrimidines (P2Y12 receptor antagonists), anti-von Willebrand factor aptamers, thrombin receptor (protease-activated receptor-1) antagonists, and thromboxane receptor antagonists. Early studies of these agents are discussed.Each of these new antiplatelet therapies has a unique profile that is aimed at improving clinical response with hopes of incremental efficacy and decreased complications, specifically bleeding.

  View details for DOI 10.1097/HCO.0b013e32832e2b44

  View details for Web of Science ID 000267279500006

  View details for PubMedID 19509485

• Apixaban, an Oral, Direct, Selective Factor Xa Inhibitor, in Combination With Antiplatelet Therapy After Acute Coronary Syndrome Results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) Trial CIRCULATION Alexander, J. H., Becker, R. C., Bhatt, D. L., Cools, F., Crea, F., Dellborg, M., Fox, K. A., Goodman, S. G., Harrington, R. A., Huber, K., Husted, S., Lewis, B. S., Lopez-Sendon, J., Mohan, P., Montalescot, G., Ruda, M., Ruzyllo, W., Verheugt, F., Wallentin, L., Darius, H., Simoons, M., Boersma, E., DeLemos, J., Spencer, F. 2009; 119 (22): 2877-U39

  Abstract

  After an acute coronary syndrome, patients remain at risk of recurrent events. Apixaban, an oral direct factor Xa inhibitor, is a novel anticoagulant that may reduce these events but also poses a risk of bleeding.Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) was a phase 2, double-blind, placebo-controlled, dose-ranging study. Patients (n=1715) with recent ST-elevation or non-ST-elevation acute coronary syndrome were randomized to 6 months of placebo (n=611) or 1 of 4 doses of apixaban: 2.5 mg twice daily (n=317), 10 mg once daily (n=318), 10 mg twice daily (n=248), or 20 mg once daily (n=221). Nearly all patients received aspirin; 76% received clopidogrel. The primary outcome was International Society of Thrombosis and Hemostasis major or clinically relevant nonmajor bleeding. A secondary outcome was cardiovascular death, myocardial infarction, severe recurrent ischemia, or ischemic stroke. At the recommendation of the Data Monitoring Committee, the 2 higher-dose apixaban arms were discontinued because of excess total bleeding. Compared with placebo, apixaban 2.5 mg twice daily (hazard ratio, 1.78; 95% confidence interval, 0.91 to 3.48; P=0.09) and 10 mg once daily (hazard ratio, 2.45; 95% confidence interval, 1.31 to 4.61; P=0.005) resulted in a dose-dependent increase in major or clinically relevant nonmajor bleeding. Apixaban 2.5 mg twice daily (hazard ratio, 0.73; 95% confidence interval, 0.44 to 1.19; P=0.21) and 10 mg once daily (hazard ratio, 0.61; 95% confidence interval, 0.35 to 1.04; P=0.07) resulted in lower rates of ischemic events compared with placebo. The increase in bleeding was more pronounced and the reduction in ischemic events was less evident in patients taking aspirin plus clopidogrel than in those taking aspirin alone.We observed a dose-related increase in bleeding and a trend toward a reduction in ischemic events with the addition of apixaban to antiplatelet therapy in patients with recent acute coronary syndrome. The safety and efficacy of apixaban may vary depending on background antiplatelet therapy. Further testing of apixaban in patients at risk of recurrent ischemic events is warranted.

  View details for DOI 10.1161/CIRCULATIONAHA.108.832139

  View details for Web of Science ID 000266777900004

  View details for PubMedID 19470889

• Careers for Clinician Investigators CIRCULATION Harrington, R. A., Califf, R. M., Hodgson, P. K., Peterson, E. D., Roe, M. T., Mark, D. B. 2009; 119 (22): 2945-2950

  View details for DOI 10.1161/CIRCULATIONAHA.107.752717

  View details for Web of Science ID 000266777900012

  View details for PubMedID 19506126

• Early versus Delayed, Provisional Eptifibatide in Acute Coronary Syndromes NEW ENGLAND JOURNAL OF MEDICINE Giugliano, R. P., White, J. A., Bode, C., Armstrong, P. W., Montalescot, G., Lewis, B. S., van't Hof, A., Berdan, L. G., Lee, K. L., Strony, J. T., Hildemann, S., Veltri, E., Van de Werf, F., Braunwald, E., Harrington, R. A., Califf, R. M., Newby, L. K. 2009; 360 (21): 2176-2190

  Abstract

  Glycoprotein IIb/IIIa inhibitors are indicated in patients with acute coronary syndromes who are undergoing an invasive procedure. The optimal timing of the initiation of such therapy is unknown.We compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in 9492 patients who had acute coronary syndromes without ST-segment elevation and who were assigned to an invasive strategy. Patients were randomly assigned to receive either early eptifibatide (two boluses, each containing 180 microg per kilogram of body weight, administered 10 minutes apart, and a standard infusion > or = 12 hours before angiography) or a matching placebo infusion with provisional use of eptifibatide after angiography (delayed eptifibatide). The primary efficacy end point was a composite of death, myocardial infarction, recurrent ischemia requiring urgent revascularization, or the occurrence of a thrombotic complication during percutaneous coronary intervention that required bolus therapy opposite to the initial study-group assignment ("thrombotic bailout") at 96 hours. The key secondary end point was a composite of death or myocardial infarction within the first 30 days. Key safety end points were bleeding and the need for transfusion within the first 120 hours after randomization.The primary end point occurred in 9.3% of patients in the early-eptifibatide group and in 10.0% in the delayed-eptifibatide group (odds ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P=0.23). At 30 days, the rate of death or myocardial infarction was 11.2% in the early-eptifibatide group, as compared with 12.3% in the delayed-eptifibatide group (odds ratio, 0.89; 95% CI, 0.79 to 1.01; P=0.08). Patients in the early-eptifibatide group had significantly higher rates of bleeding and red-cell transfusion. There was no significant difference between the two groups in rates of severe bleeding or nonhemorrhagic serious adverse events.In patients who had acute coronary syndromes without ST-segment elevation, the use of eptifibatide 12 hours or more before angiography was not superior to the provisional use of eptifibatide after angiography. The early use of eptifibatide was associated with an increased risk of non-life-threatening bleeding and need for transfusion. (ClinicalTrials.gov number, NCT00089895.)

  View details for DOI 10.1056/NEJMoa0901316

  View details for Web of Science ID 000266206000005

  View details for PubMedID 19332455

• Prior polyvascular disease: risk factor for adverse ischaemic outcomes in acute coronary syndromes EUROPEAN HEART JOURNAL Bhatt, D. L., Peterson, E. D., Harrington, R. A., Ou, F., Cannon, C. P., Gibson, C. M., Kleiman, N. S., Brindis, R. G., Peacock, W. F., Brener, S. J., Menon, V., Smith, S. C., Pollack, C. V., Gibler, W. B., Ohman, E. M., Roe, M. T. 2009; 30 (10): 1195-1202

  Abstract

  The presence of peripheral arterial disease (PAD) or cerebrovascular disease (CVD) is associated with higher likelihood of significant coronary artery disease (CAD). We sought to assess the prevalence of PAD, CVD, prior CAD, or pre-existent disease in multiple arterial territories ('polyvascular' disease) in patients presenting with non-ST-segment elevation acute coronary syndrome and its impact on adverse events.Data from 95 749 patients enrolled from February 2003 to September 2006 at 484 sites in the CRUSADE registry were analysed. Patients were categorized as having prior 0, 1, 2, or 3 affected arterial beds. The rates of in-hospital mortality, myocardial infarction, stroke, and congestive heart failure were analysed, as were the rates of non-bypass surgery-related red blood cell transfusion and major bleeding. On presentation, 11,345 (11.9%) patients had established PAD, 9973 (10.4%) had documented CVD, and 41,404 (43.2%) had prior CAD. In this cohort, 0, 1, 2, and 3 arterial bed disease before presentation was present in 46 814 (48.9%, 95% CI 48.6-49.2%), 36 704 (38.3%, 95% CI 37.8-39.0%), 10 675 (11.2%, 95% CI 10.9-11.9%), and 1556 (1.6%, 95% CI 1.5-1.8%) patients, respectively. The rates of ischaemic events increased with the number of affected vascular beds. The adjusted odds ratio for the composite of in-hospital ischaemic events for pre-existent disease in 1, 2, or 3 arterial beds (compared with 0 arterial bed involvement) increased from 1.07 to 1.26 to 1.31 (P < 0.001). Similarly, the adjusted odds ratio for transfusion increased with greater disease burden from 1.11 to 1.28 to 1.30 (P < 0.001), although the adjusted rates of protocol-defined non-bypass surgery-related major bleeding did not.Prior polyvascular disease increases the risk of in-hospital adverse events, including mortality. Identification of these patients in clinical trial and real world populations may provide an opportunity to reduce their excess risk with intensive secondary prevention efforts.

  View details for DOI 10.1093/eurheartj/ehp099

  View details for Web of Science ID 000266115200009

  View details for PubMedID 19339264

• Incidence, distribution, and prognostic impact of occluded culprit arteries among patients with non-ST-elevation acute coronary syndromes undergoing diagnostic angiography AMERICAN HEART JOURNAL Wang, T. Y., Zhang, M., Fu, Y., Armstrong, P. W., Newby, L. K., Gibson, C. M., Moliterno, D. J., de Werf, F. V., White, H. D., Harrington, R. A., Roe, M. T. 2009; 157 (4): 716-723

  Abstract

  Because acute occlusion of coronary arteries supplying the inferolateral myocardium frequently eludes standard 12-lead electrocardiogram (ECG) diagnosis, these patients may present as non-ST-segment elevation acute coronary syndromes (NSTE-ACS).We examined culprit artery occlusion among 1,957 NSTE-ACS patients in the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network trial who underwent diagnostic coronary angiography. We compared baseline characteristics, electrocardiographic findings, in-hospital treatment, and long-term outcomes between patients with and without occluded culprit arteries.The culprit artery was occluded in 528 (27%) patients. Culprit lesions were more frequently identified in the inferolateral territory among patients with an occluded culprit artery (63%) compared with those with a nonoccluded artery (45%, P < .0001). Patients with an occluded culprit artery were younger, more often male, and more likely to have had a prior myocardial infarction. Despite similar in-hospital treatment, patients with an occluded culprit artery had larger infarcts (median peak creatine kinase-MB 4.3 vs 2.1 x upper limit of normal, P < .0001) and higher risk-adjusted 6-month mortality (hazard ratio 1.72, 95% CI 1.07-2.79).More than 25% of NSTE-ACS patients had an occluded culprit artery on angiography. These patients may represent ST-segment elevation myocardial infarction equivalents; thus, improved early risk stratification techniques would help more rapidly triage these high-risk patients to an early invasive management strategy.

  View details for DOI 10.1016/j.ahj.2009.01.004

  View details for Web of Science ID 000265110100020

  View details for PubMedID 19332201

• Comparison of ticagrelor, the first reversible oral P2Y(12) receptor antagonist, with clopidogrel in patients with acute coronary syndromes: Rationale, design, and baseline characteristics of the PLATelet inhibition and patient Outcomes (PLATO) trial AMERICAN HEART JOURNAL James, S., Akerblom, A., Cannon, C. P., Emanuelsson, H., Husted, S., Katus, H., Skene, A., Steg, P. G., Storey, R. F., Harrington, R., Becker, R., Wallentin, L. 2009; 157 (4): 599-605

  Abstract

  Antiplatelet therapy is essential treatment for acute coronary syndromes (ACS). Current therapies, however, have important limitations affecting their clinical success. Ticagrelor, the first reversible oral P2Y(12) receptor antagonist, provides faster, greater, and more consistent adenosine diphosphate-receptor inhibition than clopidogrel. The phase III PLATelet inhibition and patient Outcomes (PLATO) trial is designed to test the hypothesis that ticagrelor compared with clopidogrel will result in a lower risk of recurrent thrombotic events in a broad patient population with ACS.PLATO is an international, randomized, double-blind, event-driven trial involving >18,000 patients hospitalized for ST-elevation ACS with scheduled primary percutaneous coronary intervention or for non-ST-elevation ACS. After loading doses of ticagrelor 180 mg or clopidogrel 300 mg in a double-blind, double-dummy fashion (with provision for additional 300 mg clopidogrel at percutaneous coronary intervention), patients will receive ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 6 to 12 months on top of acetylsalicylic acid. The primary efficacy end point is time to first occurrence of death from vascular causes, myocardial infarction, or stroke. The primary safety variable is PLATO-defined major bleeding. An extensive substudy program will explore the pathophysiology of ACS, indicators of prognosis and response to treatment, mechanisms of effect and safety of the study medications, health economics, and quality of life.The PLATO study will provide a pivotal comparison of the efficacy and safety of ticagrelor with those of clopidogrel in ACS patients, together with extensive information on treatment outcomes in different subsets of ACS in a broad patient population.

  View details for DOI 10.1016/j.ahj.2009.01.003

  View details for Web of Science ID 000265110100002

  View details for PubMedID 19332184

• Bleeding risk with AZD6140, a reversible P2Y(12) receptor antagonist, vs. clopidogrel in patients undergoing coronary artery bypass grafting in the DISPERSE2 trial INTERNATIONAL JOURNAL OF CLINICAL PRACTICE Husted, S., Harrington, R. A., Cannon, C. P., Storey, R. F., Mitchell, P., Emanuelsson, H. 2009; 63 (4): 667-670

  Abstract

  AZD6140, the first reversible oral P2Y(12) receptor antagonist, exhibits greater and more consistent inhibition of platelet aggregation than the irreversible thienopyridine clopidogrel. As a result of its reversible effect, AZD6140 may pose less risk for bleeding when antiplatelet treatment cannot be stopped at least 5 days before coronary artery bypass graft (CABG) surgery or other invasive procedures. The Dose conflrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in NSTEMI (DISPERSE2) trial showed overall comparable bleeding rates with antiplatelet treatment with AZD6140 90 mg twice daily or 180 mg twice daily vs. clopidogrel 75 mg once daily in 984 patients with non-ST-elevation acute coronary syndromes. A post hoc exploratory analysis of bleeding outcomes in the subset of 84 patients undergoing CABG in DISPERSE2 suggests reduced risk for total bleeding (41% and 58% vs. 62%), all major bleeding (38% and 50% vs. 62%), and life-threatening bleeding (22% and 38% vs. 54%) with AZD6140 90 mg (n = 32) and 180 mg (n = 26) vs. clopidogrel (n = 26) respectively. Trends suggested that major bleeding rates were reduced with AZD6140 (combined groups) vs. clopidogrel when treatment was stopped < or = 5 days prior to surgery (39% vs. 63%, p = 0.15) but not when treatment was stopped > 5 days before surgery (50% vs. 60%). This observation is consistent with the reversible binding of AZD6140 to the P2Y(12) receptor. Further prospective studies are planned to assess the relationship between this potential clinical benefit of AZD6140 and the reversibility of its antiplatelet effects.

  View details for DOI 10.1111/j.1742-1241.2009.02030.x

  View details for Web of Science ID 000264241100020

  View details for PubMedID 19335707

• 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

• Relation Between Aspirin Dose, All-Cause Mortality, and Bleeding in Patients With Recent Cerebrovascular or Coronary Ischemic Events (from the BRAVO Trial) AMERICAN JOURNAL OF CARDIOLOGY Aronow, H. D., Califf, R. M., Harrington, R. A., Vallee, M., Graffagnino, C., Shuaib, A., Fitzgerald, D. J., Easton, J. D., Van de Werf, F., Diener, H., Ferguson, J., Koudstaal, P. J., Amarenco, P., Theroux, P., Davis, S., Topol, E. J. 2008; 102 (10): 1285-1290

  Abstract

  Despite aspirin's established role in the treatment of atherosclerotic vascular disease, considerable controversy exists regarding its most effective dosing strategy. In a retrospective observational study, we examined the relation between prescribed aspirin dose (<162 mg vs > or =162 mg/day aspirin) and clinical outcome in 4,589 placebo-treated patients enrolled in the Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial over a median follow-up of 366 days. Standard Cox regression analysis was employed because propensity analysis was not feasible. Compared with lower aspirin doses, higher doses were associated with lower unadjusted all-cause mortality (2.9 vs 1.6%, respectively; log rank chi-square 8.6, p = 0.0034). Higher aspirin dose remained independently predictive of lower all-cause mortality in a multivariable Cox proportional hazards model (hazard ratio 0.64, 95% confidence interval 0.42 to 0.97, p = 0.037). However, there was no significant difference in the incidence of the composite endpoint death, nonfatal myocardial infarction, or nonfatal stroke (6.1% vs 6.2%, p = 0.74). Higher aspirin dose was a significant independent predictor of any (hazard ratio 1.32, 95% confidence interval 1.12 to 1.55, p = 0.001) but not serious bleeding. In conclusion, our findings suggest that aspirin doses of > or =162 mg/day may be more beneficial than those <162 mg/day at preventing death.

  View details for DOI 10.1016/j.amjcard.2008.07.019

  View details for Web of Science ID 000261194000001

  View details for PubMedID 18993142

• Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): Comparison of ezetimbe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes AMERICAN HEART JOURNAL Cannon, C. P., Giugliano, R. P., Blazing, M. A., Harrington, R. A., Peterson, J. L., Sisk, C. M., Strony, J., Musliner, T. A., McCabe, C. H., Veltri, E., Braunwald, E., Califf, R. M. 2008; 156 (5): 826-832

  Abstract

  Reduction in low-density lipoprotein cholesterol (LDL-C) improves clinical outcomes in patients with chronic coronary artery disease and acute coronary syndromes (ACSs). The combination of ezetimibe/simvastatin produces greater reductions in LDL-C compared to simvastatin monotherapy. The IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) is a multicenter, randomized, double-blind, active-control trial designed to test the hypothesis that the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, will translate into increased clinical benefit on cardiovascular outcomes relative to simvastatin monotherapy in patients with ACS.The study will recruit up to 18,000 moderate- to high-risk patients stabilized after ACS. Patients are randomized in a 1:1 ratio to once-daily doses of either ezetimibe/simvastatin 10/40 mg or simvastatin monotherapy 40 mg. Follow-up visits are at 1 and 4 months, and every 4 months thereafter. If consecutive measures of LDL-C are >79 mg/dL at follow-up visits, the simvastatin dose will be increased to 80 mg in a double-blind manner. The primary end point is the first occurrence of cardiovascular death, nonfatal myocardial infarction, rehospitalization for unstable angina, coronary revascularization (occurring at least 30 days after randomization), or stroke. Patients will be followed for a minimum of 2.5 years and until at least 5,250 patients experience a primary end point.IMPROVE-IT will determine whether the addition of ezetimibe to statin therapy, using ezetimibe/simvastatin, improves cardiovascular outcomes compared with simvastatin monotherapy in patients after ACS. In addition, the difference in achieved LDL-C levels between the groups will provide data on whether the target for LDL-C lowering should be reduced further.

  View details for DOI 10.1016/j.ahj.2008.07.023

  View details for Web of Science ID 000260700100007

  View details for PubMedID 19061694

• Relation Between Previous Lipid-Lowering Therapy and Infaret Size (Creatine Kinase-MB Level) in Patients Presenting With Acute Myocardial Infarction AMERICAN JOURNAL OF CARDIOLOGY Aronow, H. D., Lincoff, A. M., Quinn, M. J., McRae, A. T., Gurm, H. S., Houghtaling, P. L., Granger, C. B., Harrington, R. A., de Werf, F. V., Topol, E. J., Lauer, M. S. 2008; 102 (9): 1119-1124

  Abstract

  Animal experimental data have shown that lipid-lowering agents reduce myocardial infarct size. This association has not been well studied in humans. We compared infarct size in 10,548 patients in the GUSTO IIb and PURSUIT trials who were (n = 1,028) or were not (n = 9,520) on lipid-lowering therapy before an enrolling myocardial infarction (MI). Patients using lipid-lowering agents before their index MI had smaller infarcts than those who were not using these agents (median peak creatine kinase [CK]-MB 4.2 vs 5.2 times the upper limit of normal [ULN]; p <0.0001). Similarly, in an unadjusted model, patients on previous lipid-lowering therapy were less likely to have a peak CK-MB >3 times the ULN (620 of 1,028 [60.3%] vs 6,486 of 9,520 patients [68.1%]; p <0.001; relative risk 0.88, 95% confidence interval 0.84 to 0.93, p <0.0001). In a covariate- and propensity-adjusted multivariable model, the association between pretreatment with lipid-lowering agents and smaller infarct size persisted (relative risk for CK-MB >3 times the ULN 0.94, 95% confidence interval 0.88 to 0.99, p = 0.04). In conclusion, patients on lipid-lowering agents before an MI had significantly smaller infarcts. These findings suggest that lipid-lowering therapy may exert additional salutary effects in the setting of acute coronary syndromes.

  View details for DOI 10.1016/j.amjcard.2008.06.032

  View details for Web of Science ID 000261007500001

  View details for PubMedID 18940276

• Influence of preoperative renal dysfunction on one-year bypass graft patency and two-year outcomes in patients undergoing coronary artery bypass surgery JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Mehta, R. H., Hafley, G. E., Gibson, M., Harrington, R. A., Peterson, E. D., Mack, M. J., Kouchoukos, N. T., Califf, R. M., Ferguson, T. B., Alexander, J. H. 2008; 136 (5): 1149-1155

  Abstract

  Limited information exists on the impact of preoperative renal dysfunction on internal thoracic artery and saphenous vein graft failure and 2-year clinical outcomes in patients undergoing coronary artery bypass surgery.We studied the impact of preoperative renal dysfunction (creatinine clearance < 60 mL/min) on 1-year internal thoracic artery and saphenous vein graft failure (defined as > or = 75% angiographic stenosis) and 2-year clinical events (death; death or myocardial infarction; and death, myocardial infarction, or revascularization) in 3014 patients undergoing coronary artery bypass surgery enrolled in the Project of Ex-vivo Vein Graft Engineering via Transfection-IV study.Of 2973 patients (98.6%) with preoperative measurement of renal function, 440 (14.8%) had renal dysfunction. Most baseline comorbidities were higher in these patients. Two-year clinical events were higher in patients with preoperative renal dysfunction (adjusted death, myocardial infarction, or revascularization, hazard ratio 1.21, 95% confidence interval 0.97-1.50; adjusted death or myocardial infarction, hazard ratio 1.35, 95% confidence interval 1.05-1.74; adjusted death, hazard ratio 1.47, 95% confidence interval 0.98-2.21). However, saphenous vein graft (odds ratio 1.02, 95% confidence interval 0.79-1.33) and internal thoracic artery (odds ratio 0.76, 95% confidence interval 0.40-1.44) failure were similar in the 2 groups.Although the risk of adverse clinical events is higher in patients with preoperative renal dysfunction, that of internal thoracic artery and saphenous vein graft failure is not. This suggests that factors other than graft failure account for the worse clinical outcomes in this high-risk cohort. Further studies are needed to identify other mechanisms of these worse outcomes so that appropriate measures can be developed to improve long-term outcomes in patients with renal dysfunction undergoing coronary artery bypass surgery.

  View details for DOI 10.1016/j.jtcvs.2008.02.085

  View details for Web of Science ID 000261162400006

  View details for PubMedID 19026795

• 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

• 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

• Phase 1b randomized study of antidote-controlled modulation of factor IXa activity in patients with stable coronary artery disease CIRCULATION Chan, M. Y., Cohen, M. G., Dyke, C. K., Myles, S. K., Aberle, L. G., Lin, M., Walder, J., Steinhubl, S. R., Gilchrist, I. C., Kleiman, N. S., Vorchheimer, D. A., Chronos, N., Melloni, C., Alexander, J. H., Harrington, R. A., Tonkens, R. M., Becker, R. C., Rusconi, C. P. 2008; 117 (22): 2865-2874

  Abstract

  Whether selective factor IXa inhibition produces an appropriate anticoagulant effect when combined with platelet-directed therapy in patients with stable coronary artery disease is unknown. REG1 consists of RB006 (drug), an injectable RNA aptamer that specifically binds and inhibits factor IXa, and RB007 (antidote), the complementary oligonucleotide that neutralizes its anti-IXa activity.We evaluated the safety, tolerability, and pharmacodynamic profile of REG1 in a randomized, double-blind, placebo-controlled study, assigning 50 subjects with coronary artery disease taking aspirin and/or clopidogrel to 4 dose levels of RB006 (15, 30, 50, and 75 mg) and RB007 (30, 60, 100, and 150 mg). The median age was 61 years (25th and 75th percentiles, 56 and 68 years), and 80% of patients were male. RB006 increased the activated partial thromboplastin time dose dependently; the median activated partial thromboplastin time at 10 minutes after a single intravenous bolus of 15, 30, 50, and 75 mg RB006 was 29.2 seconds (25th and 75th percentiles, 28.1 and 29.8 seconds), 34.6 seconds (25th and 75th percentiles, 30.9 and 40.0 seconds), 46.9 seconds (25th and 75th percentiles, 40.3 and 51.1 seconds), and 52.2 seconds (25th and 75th percentiles, 46.3 and 58.6) (P<0.0001; normal 25th and 75th percentiles, 27 and 40 seconds). RB007 reversed the activated partial thromboplastin time to baseline levels within a median of 1 minute (25th and 75th percentiles, 1 and 2 minutes) with no rebound increase through 7 days. No major bleeding or other serious adverse events occurred.This is the first experience of an RNA aptamer drug-antidote pair achieving inhibition and active restoration of factor IXa activity in combination with platelet-directed therapy in stable coronary artery disease. The preliminary clinical safety and predictable pharmacodynamic effects form the basis for ongoing studies in patients undergoing elective revascularization procedures.

  View details for DOI 10.1161/CIRCULATIONAHA.107.745687

  View details for Web of Science ID 000256376200005

  View details for PubMedID 18506005

• Acute pharmacological conversion of atrial fibrillation to sinus rhythm - Is short-term symptomatic therapy worth it? A report from the December 2007 meeting of the Cardiovascular and Renal Drugs Advisory Committee of the Food and Drug Administration CIRCULATION Hiatt, W. R., Lincoff, A. M., Harrington, R. A. 2008; 117 (22): 2956-2957

  View details for DOI 10.1161/CIRCULATIONAHA.108.780155

  View details for Web of Science ID 000256376200015

  View details for PubMedID 18519863

• Executive summary: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest Hirsh, J., Guyatt, G., Albers, G. W., Harrington, R., Schünemann, H. J. 2008; 133 (6): 71S-109S

  View details for DOI 10.1378/chest.08-0693

  View details for PubMedID 18574259

• Antithrombotic and thrombolytic therapy CHEST Hirsh, J., Guyatt, G., Albers, G. W., Harrington, R., Schunemann, H. J. 2008; 133 (6): 110S-112S

  Abstract

  Since publication of the seventh American College of Chest Physicians (ACCP) supplement on antithrombotic and thrombolytic therapy, the results of clinical trials have provided important new information on the management of thromboembolic disorders, and the science of developing recommendations has advanced. In the accompanying supplement, we provide the new and updated recommendations and review several important changes that we have made in our guideline development process. We again made a conscious effort to increase the participation of female authors and contributors from outside North America, the latter reflecting the widespread use and dissemination of these guidelines internationally. The grading system for the recommendations was adopted in 2006 by the ACCP for all its guidelines, is similar to the increasingly widely used Grades of Recommendation, Assessment, Development, and Evaluation approach, and is described in detail in one of the introductory chapters. While most of the evidence on which recommendations are made remains low quality in fields of pediatric thrombosis, thrombosis in pregnancy, and thrombosis in valvular heart disease, rigorous studies in other fields have resulted in new and strong evidence-based recommendations for many indications.

  View details for DOI 10.1378/chest.08-0652

  View details for Web of Science ID 000257151800002

• American College of Chest Physicians evidence-based clinical practice guidelines (8th edition) CHEST Hirsh, J., Guyatt, G., Albers, G. W., Harrington, R., Schunemann, H. J. 2008; 133 (6): 71S-109S

  View details for DOI 10.1378/chest.08-0693

  View details for Web of Science ID 000257151800001

• Acute ST-segment elevation myocardial infarction CHEST Goodman, S. G., Menon, V., Cannon, C. P., Steg, G., Ohman, E. M., Harrington, R. A. 2008; 133 (6): 708S-775S

  Abstract

  This chapter about fibrinolytic, antiplatelet, and antithrombin treatment for acute ST-segment elevation (STE) myocardial infarction (MI) is part of the American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following: for patients with ischemic symptoms characteristic of acute MI of < or = 12 h in duration and persistent STE, we recommend that all undergo rapid evaluation for reperfusion (primary percutaneous coronary intervention [PCI] or fibrinolytic) therapy and have a reperfusion strategy implemented promptly after contact with the health-care system (Grade 1A). For patients with ischemic symptoms characteristic of acute MI of < or = 12 h in duration and persistent STE, we recommend administration of streptokinase, anistreplase, alteplase, reteplase, or tenecteplase over no fibrinolytic therapy (all Grade 1A). For patients with symptom duration < or = 6 h, we recommend the administration of alteplase or tenecteplase over streptokinase (both Grade 1A). We recommend aspirin over no aspirin therapy followed by indefinite therapy (Grade 1A); we also recommend clopidogrel in addition to aspirin for up to 28 days (Grade 1A). In addition to aspirin and other antiplatelet therapies, we recommend the use of antithrombin therapy (eg, unfractionated heparin (UFH), enoxaparin, or fondaparinux) over no antithrombin therapy (Grade 1A), including for those patients receiving fibrinolysis (and regardless of which lytic agent is administered), primary PCI, or patients not receiving reperfusion therapy.

  View details for DOI 10.1378/chest.08-0665

  View details for Web of Science ID 000257151800019

  View details for PubMedID 18574277

• The primary and secondary prevention of coronary artery disease CHEST Becker, R. C., Meade, T. W., Berger, P. B., Ezekowitz, M., O'Connor, C. M., Vorchheimer, D. A., Guyatt, G. H., Mark, D. B., Harrington, R. A. 2008; 133 (6): 776S-814S

  Abstract

  The following chapter devoted to antithrombotic therapy for chronic coronary artery disease (CAD) is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs. Grade 2 suggests that individual patient values may lead to different choices (for a full understanding of the grading see the "Grades of Recommendation" chapter by Guyatt et al in this supplement, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations in this chapter are the following: for patients with non-ST-segment elevation (NSTE)-acute coronary syndrome (ACS) we recommend daily oral aspirin (75-100 mg) [Grade 1A]. For patients with an aspirin allergy, we recommend clopidogrel, 75 mg/d (Grade 1A). For patients who have received clopidogrel and are scheduled for coronary bypass surgery, we suggest discontinuing clopidogrel for 5 days prior to the scheduled surgery (Grade 2A). For patients after myocardial infarction, after ACS, and those with stable CAD and patients after percutaneous coronary intervention (PCI), we recommend daily aspirin (75-100 mg) as indefinite therapy (Grade 1A). We recommend clopidogrel in combination with aspirin for patients experiencing ST-segment elevation (STE) and NSTE-ACS (Grade 1A). For patients with contraindications to aspirin, we recommend clopidogrel as monotherapy (Grade 1A). For long-term treatment after PCI in patients who receive antithrombotic agents such as clopidogrel or warfarin, we recommend aspirin (75 to 100 mg/d) [Grade 1B]. For patients who undergo bare metal stent placement, we recommend the combination of aspirin and clopidogrel for at least 4 weeks (Grade 1A). We recommend that patients receiving drug-eluting stents (DES) receive aspirin (325 mg/d for 3 months followed by 75-100 mg/d) and clopidogrel 75 mg/d for a minimum of 12 months (Grade 2B). For primary prevention in patients with moderate risk for a coronary event, we recommend aspirin, 75-100 mg/d, over either no antithrombotic therapy or vitamin K antagonist (Grade 1A).

  View details for DOI 10.1378/chest.08-0685

  View details for Web of Science ID 000257151800020

  View details for PubMedID 18574278

• Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes CHEST Harrington, R. A., Becker, R. C., Cannon, C. P., Gutterman, D., Lincoff, A. M., Popma, J. J., Steg, G., Guyatt, G. H., Goodman, S. G. 2008; 133 (6): 670S-707S

  Abstract

  This chapter about antithrombotic therapy for coronary artery disease is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicans Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggestions are weaker as there is uncertainty regarding the benefits, risks and costs such that individual patients' values may lead to different choices (for a full understanding of the grading see the "Grades of Recommendation for Antithrombotic Agents" chapter by Guyatt et al, CHEST 2008; 133[suppl]:123S-131S). Among the key recommendations are the following: for all patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS), without a clear allergy to aspirin, we recommend immediate aspirin (162 to 325 mg po) and then daily oral aspirin (75 to 100 mg) [Grade 1A]. For NSTE ACS patients who are at at least moderate risk for an ischemic event and who will undergo an early invasive management strategy, we recommend "upstream" treatment either with clopidogrel (300 mg po bolus, followed by 75 mg/d) or a small-molecule IV glycoprotein (GP) IIb/IIIa inhibitor (eptifibatide or tirofiban) [Grade 1A]. For NSTE ACS patients who are at least moderate risk for an ischemic event and for whom an early conservative or a delayed invasive strategy of management is to be used, we recommend "upstream" treatment with clopidogrel (300 mg oral bolus, followed by 75 mg/d) [Grade 1A]. For NSTE ACS patients who undergo PCI, we recommend treatment with both clopidogrel and an IV GP IIb/IIIa inhibitor (Grade 1A). We recommend a loading dose of 600 mg of clopidogrel given at least 2 h prior to planned PCI followed by 75 mg/d (Grade 1B). For all patients presenting with NSTE ACS, we recommend anticoagulation with UFH or LMWH or bivalirudin or fondaparinux over no anticoagulation (Grade 1A). For NSTE ACS patients who will undergo an early invasive strategy of management, we recommend UFH (with a GP IIb/IIIa inhibitor) over either LMWH or fondaparinux (Grade 1B). For NSTE ACS patients in whom an early conservative or a delayed invasive strategy of management is to be used, we recommend fondaparinux over enoxaparin (Grade 1A) and LMWH over UFH (Grade 1B). We recommend continuing LMWH during PCI treatment of patients with NSTE ACS when it has been started as the "upstream" anticoagulant (Grade 1B). In low- to moderate-risk patients with NSTE ACS undergoing PCI, we recommend either bivalirudin with provisional ("bail-out") GP IIb/IIIa inhibitors or UFH plus a GP IIb/IIIa inhibitor over alternative antithrombotic regimens (Grade 1B).

  View details for DOI 10.1378/chest.08-0691

  View details for Web of Science ID 000257151800018

  View details for PubMedID 18574276

• Antithrombotic and thrombolytic therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest Hirsh, J., Guyatt, G., Albers, G. W., Harrington, R., Schünemann, H. J., American College of Chest Physician 2008; 133 (6): 110S-112S

  Abstract

  Since publication of the seventh American College of Chest Physicians (ACCP) supplement on antithrombotic and thrombolytic therapy, the results of clinical trials have provided important new information on the management of thromboembolic disorders, and the science of developing recommendations has advanced. In the accompanying supplement, we provide the new and updated recommendations and review several important changes that we have made in our guideline development process. We again made a conscious effort to increase the participation of female authors and contributors from outside North America, the latter reflecting the widespread use and dissemination of these guidelines internationally. The grading system for the recommendations was adopted in 2006 by the ACCP for all its guidelines, is similar to the increasingly widely used Grades of Recommendation, Assessment, Development, and Evaluation approach, and is described in detail in one of the introductory chapters. While most of the evidence on which recommendations are made remains low quality in fields of pediatric thrombosis, thrombosis in pregnancy, and thrombosis in valvular heart disease, rigorous studies in other fields have resulted in new and strong evidence-based recommendations for many indications.

  View details for DOI 10.1378/chest.08-0652

  View details for PubMedID 18574260

• Cockcroft-Gault versus Modification of Diet in Renal Disease - Importance of glomerular filtration rate formula for classification of chronic kidney disease in patients with Non-ST-Segment elevation acute coronary syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Mellord, C., Peterson, E. D., Chen, A. Y., Szczech, L. A., Newby, L. K., Harrington, R. A., Gibler, W. B., Ohman, E. M., Spinler, S. A., Roe, M. T., Alexander, K. P. 2008; 51 (10): 991-996

  Abstract

  Our purpose was to compare formulae for estimating glomerular filtration rate (GFR) in non-ST-segment elevation acute coronary syndromes (NSTE ACS) patients.Assessment of GFR is important for antithrombotic dose adjustment in NSTE ACS patients.We assessed estimated glomerular filtration rate (eGFR) with Cockcroft-Gault (C-G) and Modification of Diet in Renal Disease (MDRD) formulae in 46,942 NSTE ACS patients from 408 CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association Guidelines) hospitals. Formula agreement was shown continuously and by chronic kidney disease (CKD) stages. We determined in-hospital outcomes and the association between antithrombotic dose adjustment and bleeding for moderate CKD as determined by each formula.The median (interquartile range [IQR]) eGFR was 53.2 ml/min (34.7, 75.1 ml/min) by C-G and 65.8 ml/min (47.6, 83.5 ml/min) by MDRD. The mean eGFR was higher with MDRD (approximately 9.1 ml/min), but this difference was greater in age, weight, and gender subgroups. Chronic kidney disease classification differed in 20% of the population and altered when antithrombotic dose adjustment was required by C-G versus MDRD (eptifibatide: 45.7% vs. 27.3%; enoxaparin: 19.0% vs. 9.6%).Important CKD disagreements occur in approximately 20% of acute coronary syndrome patients, affecting dosing adjustments in those already susceptible to bleeding. Dosing based on C-G formula is preferable, particularly in the small, female, or elderly patient.

  View details for DOI 10.1016/j.jacc.2007.11.045

  View details for Web of Science ID 000253997000003

  View details for PubMedID 18325437

• Prognostic value of troponins in patients with non-ST-segment elevation acute coronary syndromes and chronic kidney disease CLINICAL CARDIOLOGY Metioni, C., Alexander, K. P., Milford-Beland, S., Newby, L. K., Szczech, L. A., Pollack, C. V., Kirk, J. D., Christenson, R. H., Harrington, R. A., Gibter, W. B., Ohman, E. M., Peterson, E. D., Roe, M. T. 2008; 31 (3): 125-129

  Abstract

  The prognostic value of cardiac troponins (cTn) in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) and chronic kidney disease (CKD) is debated.We tested the performance of cTnI and cTnT for risk stratification in patients with CKD and evaluated the prognostic significance of cTnI and cTnT elevations by their magnitude across the range of CKD severity.We examined correlations among cTn elevation, CKD, and in-hospital mortality in 31,586 high-risk patients with NSTE ACS included in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the American College of Cardiology/American Heart Association Guidelines initiative (CRUSADE). Cardiac tropinins I and T levels were categorized as ratios of each site's upper limit of normal (ULN) for myocardial necrosis: normal (cTn ratio < or =1 x ULN), mild (cTn ratio > 1-3 x ULN), and major (cTn ratio > 3 x ULN) elevation. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease equation. Stages of CKD were categorized as normal to mild (eGFR > 60 mL/min), moderate (eGFR 30-60 mL/min), or severe (eGFR < 30 mL/min).Mortality increased more steeply across CKD stages (2.0%-12.9%) than across cTn ratio categories (2.7%-5.4%). In normal or mild CKD, mortality was low regardless of cTn elevations. In moderate CKD, mortality increased incrementally with cTnI (3.3% versus 5.4% versus 7.4%) and cTnT (3.7% versus 5.3% versus 7.3%) elevation. Among severe CKD patients, only major cTn elevations further distinguished risk (cTnI: 10.1% versus 9.7% versus 14.6%; cTnT: 7.0% versus 5.7% versus 14.0%).In patients with CKD, cTnI and cTnT perform equally in differentiating short-term prognosis following NSTE ACS; however, the prognostic impact of cTn is dependent upon the degree of CKD severity.

  View details for DOI 10.1002/clc.20210

  View details for Web of Science ID 000254128600006

  View details for PubMedID 18383049

• Meta-analysis comparing reported frequency of atrial fibrillation after acute coronary syndromes in Asians versus whites AMERICAN JOURNAL OF CARDIOLOGY Novaro, G. M., Asher, C. R., Bhatt, D. L., Moliterno, D. J., Harrington, R. A., Lincoff, A. M., Newby, L. K., Tcheng, J. E., Hsu, A. P., Pinski, S. L. 2008; 101 (4): 506-509

  Abstract

  The development of atrial fibrillation (AF) in cardiac patients is multifactorial, including not well defined genetic factors. To determine if Asian ethnicity is associated with the development of AF in patients with coronary disease, a meta-analysis was conducted of patient-level data from 7 prospective randomized clinical trials that prospectively collected information on the development of AF: 3 trials in patients with ST-elevation myocardial infarction (Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO] I, GUSTO III, and GUSTO V), 3 trials in patients with non-ST-elevation acute coronary syndromes (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy [PURSUIT], Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II [IMPACT II], and Platelet IIb/IIIa Antagonist for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network [PARAGON A]), and 1 trial in patients with both conditions (GUSTO IIb). A total of 94,785 patients were identified (93,050 white, 1,735 Asian). At baseline, Asian patients were younger; had lower body mass indexes; had a lower prevalence of female gender, previous angioplasty, and previous coronary artery bypass grafting; and had a greater prevalence of diabetes compared with white patients. The development of AF was lower in Asian than in white patients (4.7% vs 7.6%, p <0.001), while rates of ventricular tachycardia and fibrillation were similar in the 2 groups. In multivariate logistic regression analysis, Asian ethnicity was associated with significantly lower rates of AF (odds ratio 0.65, 95% confidence interval 0.50 to 0.84, p = 0.001) compared with white ethnicity. In conclusion, similar to previous studies showing a lower incidence of AF in non-Caucasian populations, Asians experiencing acute ischemic syndromes have a significantly lower frequency of AF compared with whites. Further study is needed to investigate the mechanisms and potential genetic underpinnings behind this association.

  View details for DOI 10.1016/j.amjcard.2007.09.098

  View details for Web of Science ID 000253173900018

  View details for PubMedID 18312767

• Coronary artery bypass graft failure after on-pump and off-pump coronary artery bypass: findings from PREVENT IV 53rd Annual Meeting of the Southern-Thoracic-Surgical-Association Magee, M. J., Alexander, J. H., Hafley, G., Ferguson, T. B., Gibson, C. M., Harrington, R. A., Peterson, E. D., Califf, R. M., Kouchoukos, N. T., Herbert, M. A., Mack, M. J. ELSEVIER SCIENCE INC. 2008: 494–500

  Abstract

  This analysis compares 1-year vein graft patency and major adverse cardiac and cerebral events (MACCE [death, myocardial infarction, or stroke]) in on-pump and off-pump patients enrolled in PREVENT IV (the PRoject of Ex-vivo Vein graft ENgineering via Transfection IV).The PREVENT IV was a multicenter (107 sites) randomized trial of edifoligide to prevent vein graft failure from neointimal hyperplasia in 3,014 patients undergoing primary, isolated coronary artery bypass grafting (CABG) with at least two vein grafts. One-year angiographic follow-up was completed on 1,920 patients (4,736 grafts) with MACCE follow-up on 99.4% of enrolled patients.In all, 2,377 procedures (78.9%) were on pump and 637 (21.1%) were off pump. On-pump patients had more chronic lung disease (17% versus 11%; p < 0.001), congestive heart failure (10% versus 7%; p = 0.03), lower mean ejection fraction (50% versus 55%; p < 0.001), and worse target artery quality (good 63.8% versus 68.1%; fair 26.4% versus 22.7%; poor 9.8% versus 9.2%; p < 0.001). Vein graft failure (more than 75% graft stenosis) in on- versus off-pump patients was 25.3% versus 25.7% (p = 0.62). After adjusting for differences in significant predictors of vein graft failure (target artery quality, surgery time, endoscopic vein harvest, more than 1 distal anastomosis/graft, and patient weight), the odds of vein graft failure was 0.82 (95% confidence interval: 0.67 to 1.00; p = 0.05) for on-pump versus off-pump patients. One-year mortality for on- versus off-pump patients was 3.3% versus 2.5% (p = 0.30); and MACCE was 15.4% versus 11.3% (p = 0.01). The adjusted hazard ratio for 1-year MACCE was 1.31 (95% confidence interval: 1.01-1.69; p = 0.01) for on pump versus off pump.Observed saphenous vein failure rate was 25% in both groups. One-year clinical outcomes (MACCE) were better with off-pump than with on-pump CABG, suggesting benefits not related to vein graft patency.

  View details for DOI 10.1016/j.athoracsur.2007.10.008

  View details for Web of Science ID 000252664900023

  View details for PubMedID 18222251

• Impact of saphenous vein graft radiographic markers on clinical events and angiographic parameters ANNALS OF THORACIC SURGERY Olenchock, S. A., Karmpaliotis, D., Gibson, W. J., Murphy, S. A., Southard, M. C., Ciaglo, L., Buros, J., Mack, M. J., Alexander, J. H., Harrington, R. A., Califf, R. M., Kouchoukos, N. T., Ferguson, T. B., Gibson, C. M. 2008; 85 (2): 520-524

  Abstract

  Use of saphenous vein graft (SVG) radiographic markers has been associated with shorter cardiac catheterization procedure times and reduced contrast agent volume for postoperative coronary artery bypass graft (CABG) catheterizations. Use of such markers is varied and often operator-dependent, as the effect of SVG markers has not been fully evaluated. The goal of the present analysis was to evaluate the association of SVG markers with clinical outcomes and graft patency.Data were drawn from the Project of Ex-vivo Vein Graft Engineering via Transfection (PREVENT) IV trial of patients undergoing CABG at 107 hospitals across the United States. Repeat angiography was performed within 12 to 18 months after CABG. The SVG markers were used at the discretion of the surgeon and were identified on the follow-up angiogram as any device used to mark the ostium, regardless of shape.The SVG markers were present in 51.2% of evaluable patients (910 of 1,778) and 52.3% of SVGs (2,228 of 4,240). Among patients with totally occluded SVGs (n = 911), visual identification of the SVG was obtained more frequently in those with an SVG marker (90.7% vs 72.1%, p < 0.001). The SVG stenosis 70% or greater at follow-up did not differ by use of markers (25.8% with marker vs 24.4% without marker, p = not significant). These findings were also consistent in ostial lesions (n = 942). Long-term death or myocardial infarction (MI) was similar by use of marker. The perioperative CABG MI was higher in patients with SVG markers (10.1% vs 5.5%, odds ratio adjusted 1.86, p = 0.021).Saphenous vein graft radiographic markers were associated with higher rates of direct visualization of totally occluded SVGs without an adverse effect on graft patency or long-term clinical outcomes, but the association of SVG markers with increased perioperative CABG MI warrants further examination.

  View details for DOI 10.1016/j.athoracsur.2007.10.061

  View details for Web of Science ID 000252664900027

  View details for PubMedID 18222256

• Initial aspirin dose and outcome among ST-elevation myocardial infarction patients treated with fibrinolytic therapy CIRCULATION Berger, J. S., Stebbins, A., Granger, C. B., Ohman, E. M., Armstrong, P. W., de Werf, F. V., White, H. D., Simes, R. J., Harrington, R. A., Califf, R. M., Peterson, E. D. 2008; 117 (2): 192-199

  Abstract

  Although treatment with immediate aspirin reduces morbidity and mortality in ST-elevation myocardial infarction, the optimal dose is unclear. We therefore compared the acute mortality and bleeding risks associated with the initial use of 162 versus 325 mg aspirin in fibrinolytic-treated ST-elevation myocardial infarction patients.Using combined data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) trials (n=48 422 ST-elevation myocardial infarction patients), we compared the association between initial aspirin dose of 162 versus 325 mg and 24-hour and 7-day mortality, as well as rates of in-hospital moderate/severe bleeding. Results were adjusted for previously identified mortality and bleeding risk factors. Overall, 24.4% of patients (n=11 828) received an initial aspirin dose of 325 mg, and 75.6% (n=36 594) received 162 mg. The 24-hour mortality rates were 2.9% versus 2.8% (P=0.894) for those receiving an initial aspirin dose of 325 versus 162 mg. Mortality rates at 7 and 30 days were 5.2% versus 4.9% (P=0.118) and 7.1% versus 6.5% (P=0.017) among patients receiving the 325 versus 162 mg aspirin. After adjustment, aspirin dose was not associated with 24-hour (odds ratio [OR], 1.01; 95% CI, 0.82 to 1.25), 7-day (OR, 1.00; 95% CI, 0.87 to 1.17), or 30-day (OR, 0.99; 95% CI, 0.87 to 1.12) mortality rates. No significant difference was noted for myocardial infarction or the composite of death or myocardial infarction between groups. In-hospital moderate/severe bleeding occurred in 9.3% of those treated with 325 mg versus 12.2% among those receiving 162 mg (P<0.001). After adjustment, 325 mg was associated with a significant increase in moderate/severe bleeding (OR, 1.14; 95% CI, 1.05 to 1.24; P=0.003).These data suggest that an initial dose of 162 mg aspirin may be as effective as and perhaps safer than 325 mg for the acute treatment of ST-elevation myocardial infarction.

  View details for DOI 10.1161/CIRCULATIONAHA.107.729558

  View details for Web of Science ID 000252601400016

  View details for PubMedID 18086929

• International variation in the use of blood transfusion in patients with non-ST-segment elevation acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Rao, S. V., Chiswell, K., Sun, J., Granger, C. B., Newby, L. K., de Werf, F. V., White, H. D., Armstong, P. W., Califf, R. A., Harrington, R. A. 2008; 101 (1): 25-29

  Abstract

  The purpose of this study was to determine international patterns of blood transfusion in patients with acute coronary syndrome (ACS). Previous studies showed geographic heterogeneity in some aspects of ACS care. Data for variability in the use of blood transfusion in ACS management are limited. Pooled data from 3 international randomized trials of patients with non-ST-segment elevation ACS (n = 23,906) were analyzed to determine the association between non-United States (US) location and blood transfusion after stratifying by the use of invasive procedures. The analysis adjusted for differences in patient characteristics and was repeated using a 2-stage mixed-model approach and in patients who underwent in-hospital coronary artery bypass grafting. Compared with US patients, both unadjusted and adjusted hazards for blood transfusion were significantly lower in non-US patients who did not undergo invasive procedures (unadjusted hazard ratio [HR] 0.23, 95% confidence interval [CI] 0.17 to 0.33; adjusted HR 0.20, 95% CI 0.14 to 0.28). This was also true in non-US patients who underwent invasive procedures (unadjusted HR 0.34, 95% CI 0.27 to 0.44; adjusted HR 0.31, 95% CI 0.23 to 0.42). Results were similar in both validation analyses. In conclusion, there was substantial international variation in blood transfusion use in patients with ACS. These results, along with the controversy regarding the appropriate use of transfusion in patients with coronary heart disease, emphasize the need for understanding the role of blood transfusion in the management of patients with ACS and factors that influence transfusion decisions.

  View details for DOI 10.1016/j.amjcard.2007.07.042

  View details for Web of Science ID 000252136400005

  View details for PubMedID 18157960

• 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

• Clinical and angiographic correlates of short- and long-term mortality in patients undergoing coronary artery bypass grafting AMERICAN JOURNAL OF CARDIOLOGY Mehta, R. H., Honeycutt, E., Shaw, L. K., Milano, C. A., Smith, P. K., Harrington, R. A., Sketch, M. H. 2007; 100 (10): 1538-1542

  Abstract

  Differences in the clinical and angiographic factors associated with short- and long-term outcomes in patients undergoing coronary artery bypass grafting (CABG) are less known. Accordingly, differences were examined in clinical and angiographic correlates of short- and long-term mortality after CABG in 8,229 patients undergoing initial CABG enrolled in the Duke Cardiovascular Disease Database (1995 to 2002). Logistic regression and Cox proportional hazard modeling were performed to determine independent correlates of 30-day and long-term mortality. Death occurred in 2.4% at 30 days and 17.6% beyond 30 days at a median follow-up of 6 years in patients who underwent CABG. Multivariable models identified older age, lower left ventricular ejection fraction, lower or higher body mass index, cerebrovascular disease, lack of internal mammary artery use, and lower cholesterol to be associated with increased risk of both events. Although hemodynamic status (preoperative myocardial infarction, New York Heart Association class, and cardiogenic shock), female gender, and minority race were associated with 30-day death; co-morbid conditions (serum creatinine, chronic lung disease, diabetes, previous heart failure, peripheral vascular disease, and left main disease) were associated with increased long-term (beyond 30 days) death (c indexes 0.76 and 0.79 for the short- and long-term mortality models, respectively). In conclusion, our study suggested that correlates of acute and long-term death were different in patients undergoing CABG. These differences should be kept in context when counseling patients undergoing CABG and may help facilitate targeted strategies to improve short- and long-term mortality risks after CABG.

  View details for DOI 10.1016/j.amjcard.2007.06.053

  View details for Web of Science ID 000251294500008

  View details for PubMedID 17996515

• Safety, tolerability, and initial efficacy of AZD6140, the first reversivle oral adenosine diphosphate receptor antagonist, compared with clopidigrel, in patients with non-ST-segment elevation acute coronary syndrome - Primary results of the DISPERSE-2 trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Cannon, C. P., Husted, S., Harrington, R. A., Scirica, B. M., Emanuelsson, H., Storey, R. F. 2007; 50 (19): 1844-1851

  View details for DOI 10.1016/j.jacc.2007.07.053

  View details for Web of Science ID 000250788300005

• Inhibition of platelet aggregation by AZD6140, A reversible oral P2Y(12) receptor antagonist, compared with clopidogral in patients with acute coronary syndrome JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Storey, R. F., Husted, S., Harrington, R. A., Heptinstall, S., Wilcox, R. G., Peters, G., Wickens, M., Emanuelsson, H., Gurbel, P., Grande, P., Cannon, C. P. 2007; 50 (19): 1852-1856

  Abstract

  In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel-pretreated patients.Clopidogrel, in combination with aspirin, reduces cardiovascular events in patients with acute coronary syndromes (ACS). However, patients with poor inhibition of platelet aggregation with clopidogrel may be less well protected. AZD6140 is a reversible oral P2Y(12) receptor antagonist that has been studied in ACS patients in comparison with clopidogrel (DISPERSE-2 study).Patients were randomized to receive either AZD6140 90 mg twice a day, AZD6140 180 mg twice a day, or clopidogrel 75 mg once a day for up to 12 weeks in a double-blind, double-dummy design. One-half the patients allocated AZD6140 received a 270-mg loading dose. Patients randomized to receive clopidogrel were given a 300-mg loading dose unless they had already been treated with clopidogrel. Adenosine diphosphate-induced platelet aggregation was assessed by optical aggregometry on day 1 and at 4-week intervals.AZD6140 inhibited platelet aggregation in a dose-dependent fashion and both doses achieved greater levels of inhibition than clopidogrel (e.g., 4 weeks, 4-h postdose [mean (+/-SD)]: clopidogrel 64% [+/-22%], AZD6140 90 mg 79% [+/-22%], AZD6140 180 mg 95% [+/-8%]. AZD6140 also produced further suppression of platelet aggregation in patients previously treated with clopidogrel.AZD6140 exhibited greater mean inhibition of platelet aggregation than a standard regimen of clopidogrel in ACS patients. In addition, AZD6140 further suppressed platelet aggregation in clopidogrel pretreated patients.

  View details for DOI 10.1016/j.jacc.2007.07.058

  View details for Web of Science ID 000250788300006

  View details for PubMedID 17980251

• Complementary effects of thienopyridine pretreatment and platelet glycoprotein IIb/IIIa integrin blockade with eptifibatide in coronary stent intervention; Results from the ESPRIT trial CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS Dery, J., Campbell, M. E., Mathias, J., Pieper, K. S., Harrington, R. A., Madan, M., Gibson, C. M., Tolleson, T. R., O'Shea, J. C., Tcheng, J. E. 2007; 70 (1): 43-50

  Abstract

  This analysis sought to investigate the complementary effect of thienopyridine pretreatment and platelet glycoprotein (GP) IIb/IIIa integrin blockade in coronary stent intervention.Definitive evidence supporting combined antiplatelet therapy consisting of thienopyridine pretreatment and GP IIb/IIIa receptor blockade in patients undergoing percutaneous coronary intervention (PCI) with stent implantation is limited.We retrospectively analyzed clinical outcomes by thienopyridine use in the 2,040 patients randomized to eptifibatide or placebo who underwent PCI in the ESPRIT trial.A total of 901 patients received a loading dose of thienopyridine before PCI (group 1), 123 received thienopyridine pretreatment without a loading dose (group 2), and 1,016 were not treated with thienopyridine before PCI (group 3). The composite incidence of death or myocardial infarction at 30 days was significantly lower in group 1 than in groups 2 and 3 combined (OR, 0.71 [95%CI, 0.52-0.99]; P = 0.0417). A similar trend was seen for the composite of death, myocardial infarction, or urgent target vessel revascularization (unadjusted OR, 0.77 [0.57-1.05]; P = 0.1025). After adjusting for baseline characteristics, these differences were no longer significant. No interactions were identified with eptifibatide assignment for any of the group comparisons.Pretreatment with a loading dose of thienopyridine lowers the rate of ischemic complications regardless of treatment with a GP IIb/IIIa inhibitor. Conversely, the efficacy of eptifibatide is maintained whether or not a loading dose of a thienopyridine is administered. Optimal outcomes are achieved in patients receiving thienopyridine pretreatment along with platelet GP IIb/IIIa inhibitor therapy.

  View details for DOI 10.1002/ccd.21059

  View details for Web of Science ID 000247812400008

  View details for PubMedID 17203469

• Timing of glycoprotein IIb/IIIa inhibitor use and outcomes among patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (Results from CRUSADE) AMERICAN JOURNAL OF CARDIOLOGY Tricoci, P., Peterson, E. D., Chen, A. Y., Newby, L. K., Harrington, R. A., Greenbaum, A. B., Cannon, C. P., Gibson, C. M., Hoekstra, J. W., Pollack, C. V., Ohman, E. M., Gibler, W. B., Roe, M. T. 2007; 99 (10): 1389-1393

  Abstract

  Although glycoprotein (GP) IIb/IIIa inhibitors are recommended for patients with unstable angina and non-ST-segment elevation myocardial infarction who undergo percutaneous coronary intervention (PCI), the American College of Cardiology/American Heart Association guidelines do not specify optimal timing for their initiation. We compared patient characteristics and clinical outcomes in 30,830 patients with non-ST-segment elevation myocardial infarction included in the CRUSADE initiative (January 2001 to December 2004) who underwent PCI with upstream (>1 hour before PCI) or periprocedural use of GP IIb/IIIa inhibitors. GP IIb/IIIa inhibitors were administered upstream in 43% of patients versus periprocedurally in 57%. Time from arrival to PCI was longer for patients who received GP IIb/IIIa inhibitors upstream (median 25.6 hours) compared with periprocedurally (18.2 hours). Unadjusted incidence of in-hospital death or reinfarction was lower with upstream GP IIb/IIIa inhibitor use (3.8% vs 4.3%, p = 0.046), but after adjusting for patient and hospital characteristics, this difference was not statistically significant. Treatment with upstream GP IIb/IIIa inhibitors was associated with a lower incidence of unadjusted death or reinfarction in patients who underwent PCI <12 hours from hospital arrival. In conclusion, in this observational analysis, overall ischemic outcomes were similar between the 2 groups, but clinical trials are needed to solve the controversy over optional timing of GP IIb/IIIa inhibitor use.

  View details for DOI 10.1016/j.amjcard.2006.12.066

  View details for Web of Science ID 000246715900009

  View details for PubMedID 17493466

• Bleeding and blood transfusion issues in patients with non-ST-segment elevation acute coronary syndromes EUROPEAN HEART JOURNAL Rao, S. V., Eikelboom, J. A., Granger, C. B., Harrington, R. A., Califf, R. M., Bassand, J. 2007; 28 (10): 1193-1204

  Abstract

  Antithrombotic therapy and invasive risk stratification in selected high-risk patients have improved outcomes from non-ST-segment elevation acute coronary syndromes (NSTE-ACS), but carry a risk of bleeding and blood transfusion. Although the true incidence of bleeding depends on the population studied (i.e. clinical trial vs. registry), the definition used, and the use of invasive procedures, it is becoming clear that bleeding is associated with an increased risk for adverse outcomes including myocardial infarction and death. Blood transfusion itself may carry a risk for ischaemic outcomes that is independent of bleeding. Therefore, therapies that provide an adequate level of anticoagulation to reduce ischaemia while simultaneously minimizing the risk of bleeding and transfusion have the potential to improve outcomes among patients with NSTE-ACS. Anticoagulants studied in recent clinical trials that have focused on bleeding reduction include fondaparinux and bivalirudin. In this review, we discuss the clinical trial evidence for these agents, the association between bleeding and clinical outcomes, the biology of blood transfusion and potential mechanisms underlying its association with adverse outcomes, and propose strategies to deal with bleeding complications. Future directions for research and clinical practice are also discussed.

  View details for DOI 10.1093/eurheartj/ehm019

  View details for Web of Science ID 000247430000011

  View details for PubMedID 17456480

• Effect of nitric oxide synthase inhibition on haemodynamics and outcome of patients with persistent cardiogenic shock complicating acute myocardial infarction: a phase II dose-ranging study EUROPEAN HEART JOURNAL Dzavik, V., Cotter, G., Reynolds, H. R., Alexander, J. H., Ramanathan, K., Stebbins, A. L., Hathaway, D., Farkouh, M. E., Ohman, E. M., Baran, D. A., Prondzinsky, R., Panza, J. A., Cantor, W. J., Vered, Z., Buller, C. E., Kleiman, N. S., Webb, J. G., Holmes, D. R., Parrilo, J. E., Hazen, S. L., Gross, S. S., Harrington, R. A., Hochman, J. S. 2007; 28 (9): 1109-1116

  Abstract

  Previous studies suggested haemodynamic benefits and, possibly, mortality reduction with the use of nitric oxide synthase (NOS) inhibition in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS). We assessed preliminary efficacy and safety of four doses of l-n-monomethyl-arginine (l-NMMA), a non-selective NOS inhibitor, in patients with AMI complicated by CS despite an open infarct-related artery.Patients (n = 79) were randomly assigned to a bolus and 5 h infusion of placebo or 0.15, 0.5, 1.0, or 1.5 mg/kg of l-NMMA. The primary outcome measure was absolute change in mean arterial pressure (MAP) at 2 h. Fifteen minutes after study drug initiation, mean change in MAP was -4.0 mmHg in the placebo group and 5.8 (P = 0.02), 4.8 (P = 0.02), 5.1 (P = 0.07), and 11.6 (P < 0.001) mmHg in the four l-NMMA groups, respectively (all vs. placebo). Mean change in MAP at 2 h was -0.4, 4.4, 1.8, -4.1, and 6.8 mmHg in the placebo and four l-NMMA groups, respectively (all P = NS).l-NMMA resulted in modest increases in MAP at 15 min compared with placebo but there were no differences at 2 h.

  View details for DOI 10.1093/eurheartj/ehm075

  View details for Web of Science ID 000247071200017

  View details for PubMedID 17459901

• Changes in patterns of coronary revascularization strategies for patients with acute coronary syndromes (from the CRUSADE Quality Improvement Initiative) AMERICAN JOURNAL OF CARDIOLOGY Gogo, P. B., Dauerman, H. L., Mulgund, J., Ohman, E. M., Patel, M. R., Cohen, D. J., Saucedo, J. F., Harrington, R. A., Gibler, W. B., Smith, S. C., Peterson, E. D., Roe, M. T. 2007; 99 (9): 1222-1226

  Abstract

  Since the introduction of drug-eluting stents (DESs), patterns of revascularization strategies for patients with non-ST-segment elevation acute coronary syndromes have not been assessed. We studied 82,924 patients from the CRUSADE Initiative who presented with non-ST-segment elevation acute coronary syndromes and underwent coronary angiography at 365 United States hospitals that had capabilities for surgical (coronary artery bypass grafting [CABG]) and percutaneous (percutaneous coronary intervention [PCI]) revascularization from January 2002 to June 2005. Temporal trends in the use of PCI, CABG, and medical management without revascularization were analyzed with respect to the introduction of DESs. In total, 73,577 patients (89%) had >50% stenosis in > or =1 coronary artery, and there was a significant increase in the use of PCI (vs CABG or medical management without revascularization) during the study period (38.3% vs 52.5%). By quarter 2 of 2005, 80% of patients who underwent PCI received a DES. In total, 18,462 of 25,068 patients (73.6%) with 3-vessel disease (3VD) underwent revascularization and use of CABG decreased for these patients (48.9% to 39.9%, p <0.001), whereas use of PCI increased (51.1% to 60.1%, p <0.001). Factors significantly associated with use of PCI for patients with 3VD who underwent any revascularization included previous PCI, previous CABG, cardiology inpatient care, care at an academic hospital, renal insufficiency, and previous congestive heart failure. In conclusion, coinciding with the introduction of DESs, there has been a significant increase in the use of PCI and, in those patients with 3VD, a decrease in the use of CABG with a shift toward increasing use of PCI. Long-term implications of this shift remain uncertain, especially in patients with 3VD.

  View details for DOI 10.1016/j.amjcard.2006.12.037

  View details for Web of Science ID 000246168600010

  View details for PubMedID 17478146

• Effect of tilarginine acetate in patients with acute myocardial infarction and cardiogenic shock - The TRIUMPH randomized controlled trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Hochman, J. S., Alexander, J. H., Reynolds, H. R., Stebbins, A. L., Dzavik, V., Harrington, R. A., de Werf, F. V. 2007; 297 (15): 1657-1666

  Abstract

  Cardiogenic shock complicating acute myocardial infarction (MI) remains a common and lethal disorder despite aggressive use of early revascularization. Systemic inflammation, including expression of inducible nitric oxide synthase (NOS) and generation of excess nitric oxide, is believed to contribute to the pathogenesis and inappropriate vasodilatation of persistent cardiogenic shock. Preliminary, single-center studies suggested a beneficial effect of NOS inhibition on hemodynamics, renal function, and survival in patients with cardiogenic shock.To examine the effects of an isoform-nonselective NOS inhibitor in patients with MI and refractory cardiogenic shock despite establishment of an open infarct artery.International, multicenter, randomized, double-blind, placebo-controlled trial (Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock [TRIUMPH]) with planned enrollment of 658 patients at 130 centers. Participants were enrolled between January 2005 and August 2006 when the study was terminated early.Tilarginine (L-N(G)-monomethylarginine [L-NMMA]), 1-mg/kg bolus and 1-mg/kg per hour 5-hour infusion, vs matching placebo.The primary outcome was 30-day all-cause mortality among patients who received study medication. Secondary outcomes included shock resolution and duration, New York Heart Association (NYHA) functional class at 30 days, and 6-month mortality.Enrollment was terminated at 398 patients based on a prespecified futility analysis. Six-month follow-up was completed in February 2007. There was no difference in 30-day all-cause mortality between patients who received tilarginine (97/201 [48%]) vs placebo (76/180 [42%]) (risk ratio, 1.14; 95% confidence interval, 0.92-1.41; P = .24). Resolution of shock (133/201 [66%] tilarginine vs 110/180 [61%] placebo; P = .31) and duration of shock (median, 156 [interquartile range, 78-759] hours tilarginine vs 190 [100-759] placebo; P = .16) were similar. At 30 days a similar percentage of patients had heart failure (48% tilarginine vs 51% placebo; P = .51) with a similar percentage of those patients in NYHA class I/II (73% tilarginine vs 75% placebo; P = .27). After 6 months mortality rates were similar in the 2 groups (58% tilarginine vs 59% placebo; hazard ratio, 1.04; 95% confidence interval, 0.79-1.36; P = .80).Tilarginine, 1-mg/kg bolus and 5-hour infusion, did not reduce mortality rates in patients with refractory cardiogenic shock complicating MI despite an open infarct artery. Early mortality rates in this patient group are high. Further research is needed to develop effective therapies for patients with cardiogenic shock following acute MI.clinicaltrials.gov Identifier: NCT00112281

  View details for Web of Science ID 000245747400019

  View details for PubMedID 17387132

• Outcomes associated with the use of secondary prevention medications after coronary artery bypass graft surgery ANNALS OF THORACIC SURGERY Goyal, A., Alexander, J. H., Hafley, G. E., Graham, S. H., Mehta, R. H., Mack, M. J., Wolf, R. K., Cohn, L. H., Kouchoukos, N. T., Harrington, R. A., Gennevois, D., Gibson, C. M., Califf, R. M., Ferguson, T. B., Peterson, E. D. 2007; 83 (3): 993-1001

  Abstract

  Secondary prevention medications are beneficial after acute coronary syndromes, but these benefits are less clear after coronary artery bypass graft surgery. We investigated whether greater use of secondary prevention medications after coronary artery bypass graft surgery is associated with improved clinical outcomes.Patients undergoing coronary artery bypass graft surgery in the PREVENT IV trial (n = 2970) were surveyed for use of antiplatelet agents, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and lipid-lowering agents after hospital discharge and at 1 year. Patients were categorized based on their percentage use of indicated medications after hospital discharge. Cox modeling was used to determine the association between medication use categories and rates of death or myocardial infarction through 2 years after adjustment for clinical factors, the number of indicated medications, and treatment propensity.Rates of use of antiplatelet agents and lipid-lowering agents were high at discharge and at 1 year, but use of beta-blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was suboptimal. There was a stepwise association between medication use at discharge and patient outcomes (p for trend = 0.014). Patients taking 50% or less of indicated medications at discharge had a significantly higher 2-year rate of death or myocardial infarction (8.0% versus 4.2%; adjusted hazard ratio, 1.69; 95% confidence interval, 1.12 to 2.55; p = 0.013) than those taking all indicated medications.Greater use of indicated secondary prevention medications after coronary artery bypass graft surgery is associated with a lower 2-year rate of death or myocardial infarction. These data underscore the importance of appropriate secondary prevention measures to improve long-term clinical outcomes after coronary artery bypass graft surgery.

  View details for DOI 10.1016/j.athoracsur.2006.10.046

  View details for Web of Science ID 000244648100016

  View details for PubMedID 17307447

• 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

• 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

• A comparison of acute coronary syndrome care at academic and nonacademic hospitals AMERICAN JOURNAL OF MEDICINE Patel, M. R., Chen, A. Y., Roe, M. T., Ohman, E. M., Newby, L. K., Harrington, R. A., Smith, S. C., Gibler, W. B., Calvin, J. E., Peterson, E. D. 2007; 120 (1): 40-46

  Abstract

  Although adherence to guidelines recommendations is assumed to be more difficult for nonacademic community hospitals, patterns of adherence have not been evaluated by hospital type. We sought to identify hospital characteristics associated with high levels of adherence in order to gain insight into successful processes of care.From January 2001 through March 2004, we analyzed data from 86,042 patients in the CRUSADE Initiative with high-risk non-ST-segment elevation acute coronary syndromes (NSTE ACS) defined by positive cardiac markers or ischemic ST-segment changes. Academic sites were defined by Council of Teaching Hospital affiliation in the American Hospital Association database. Adherence was determined for each hospital based on guidelines recommendations for the use of 4 acute (<24 hrs) and 5 discharge therapies in patients without contraindications. Multivariable modeling was used to standardize hospital estimates for patient characteristics and control for clustering within centers.A total of 60,285 patients were admitted to nonacademic hospitals (n=355), and 25,757 were admitted to academic hospitals (n=125). Academic hospitals were larger (median 500 vs 268 beds, P <.001) and more often had bypass services (88% vs 60%, P <.001). Composite adherence to recommended therapies was slightly higher at academic vs. nonacademic hospitals (median 77.8% vs 73.7%, P <0.01), and variance in individual hospital performance was greater among nonacademic sites. Nonacademic hospitals accounted for 15 of the 20 highest performing sites and 19 of the 20 lowest performing sites. In-hospital clinical outcomes, including cardiogenic shock, stroke, and death were similar for patients admitted to both types of hospital.Adherence to American College of Cardiology and American Heart Association (ACC/AHA) guidelines for NSTE ACS care at academic hospitals is slightly higher than at nonacademic hospitals; however there is significant room for improvement within both systems. The larger performance variation in care among nonacademic hospitals highlights the need for continued emphasis on consistent care processes.

  View details for DOI 10.1016/j.amjmed.2006.10.008

  View details for Web of Science ID 000243309000010

  View details for PubMedID 17208078

• First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology - A phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity 79th Annual Scientific Session of the American-Heart-Association Dyke, C. K., Steinhubl, S. R., Kleiman, N. S., Cannon, R. O., Aberle, L. G., Lin, M., Myles, S. K., Melloni, C., Harrington, R. A., Alexander, J. H., Becker, R. C., Rusconi, C. P. LIPPINCOTT WILLIAMS & WILKINS. 2006: 2490–97

  Abstract

  Selectivity, titratability, rapidity of onset, and active reversibility are desirable pharmacological properties of anticoagulant therapy administered for acute indications and collectively represent an attractive platform to maximize patient safety. A novel anticoagulation system (REG1, Regado Biosciences), developed using a protein-binding oligonucleotide to factor IXa (drug, RB006) and its complementary oligonucleotide antidote (RB007), was evaluated in healthy volunteers. The primary objective was to determine the safety profile and to characterize the pharmacodynamic responses in this first-in-human study.Regado 1a was a subject-blinded, dose-escalation, placebo-controlled study that randomized 85 healthy volunteers to receive a bolus of drug or placebo followed 3 hours later by a bolus of antidote or placebo. Pharmacodynamic samples were collected serially. Subject characteristics were the following: median age, 32 years (interquartile range, 23 to 39 years); female gender, 35%; and median weight, 79 kg (interquartile range, 70 to 87 kg). No significant differences were found in median hemoglobin, platelet, creatinine, or liver function studies. There were no significant bleeding signals associated with RB006, and overall, both drug and antidote were well tolerated. One serious adverse event, an episode of transient encephalopathy, occurred in a subject receiving the low intermediate dose of RB006. The subject's symptoms resolved rapidly, and no further sequelae occurred. A predictable dose-pharmacodynamic response, reflected in activated partial thromboplastin time measurements, was seen after administration of the bolus of drug, with a clear correlation between the peak posttreatment activated partial thromboplastin time and post hoc weight-adjusted dose of drug (correlation coefficient, 0.725; P<0.001). In subjects treated with drug, antidote administration reversed the pharmacological activity of the drug, with a rapid (mean time, 1 to 5 minutes across all dose levels) and sustained return of activated partial thromboplastin time to within the normal range. The activated clotting time followed a similar anticoagulant response and reversal pattern. As anticipated, prothrombin time remained unchanged compared with baseline.These observations represent a first-in-human experience of an RNA aptamer and its complementary oligonucleotide antidote used as an anticoagulant system. The findings contribute to an emerging platform of selective, actively reversible anticoagulant drugs for use among patients with thrombotic disorders of the venous and arterial circulations.

  View details for DOI 10.1161/CIRUCLATIONAHA.106.668434

  View details for Web of Science ID 000243477500013

  View details for PubMedID 17101847

• 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

• The influence of peripheral arterial disease on outcomes - A pooled analysis of mortality in eight large randomized percutaneous coronary intervention trials JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Saw, J., Bhatt, D. L., Moliterno, D. J., Brener, S. J., Steinhubl, S. R., Lincoff, A. M., Tcheng, J. E., Harrington, R. A., Simoons, M., Hu, T., Sheikh, M. A., Kereiakes, D. J., Topol, E. J. 2006; 48 (8): 1567-1572

  Abstract

  We aimed to evaluate clinical outcomes among peripheral arterial disease (PAD) patients following percutaneous coronary intervention (PCI).A significant proportion of patients with coronary artery disease undergoing PCI have concomitant PAD, which may be associated with worse outcomes.We performed a pooled analysis of 8 randomized PCI trials. We included multicenter PCI trials that compared antiplatelet therapies (EPIC, EPILOG, EPISTENT, RAPPORT, CAPTURE, IMPACT-II, TARGET, and CREDO) and had baseline PAD status recorded. Multivariable analyses were performed with stepwise logistic regression for 7- and 30-day outcomes and Cox regression for 6-month and 1-year events.In our pooled analysis of 19,867 patients undergoing PCI, 1,602 (8.1%) were previously diagnosed with PAD. Patients with PAD had higher incidences of 7-day death (1.0% vs. 0.4%; p < 0.001) or myocardial infarction (MI) (6.8% vs. 5.6%; p = 0.047), 30-day death (1.7% vs. 0.7%; p < 0.001) or MI (7.4% vs. 6.1%; p = 0.05), 6-month death (4.2% vs. 1.5%; p < 0.001) or MI (9.1%, vs. 7.7%; p = 0.048), and 1-year death (5.0% vs. 2.1%; p < 0.001). There was a trend toward higher major bleeding risk with PAD (4.8% vs. 3.9%; p = 0.06). With multivariable analyses, PAD remains a significant predictor of mortality at 30 days (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.03 to 2.70; p = 0.039), 6 months (HR 1.76, 95% CI 1.31 to 2.37; p < 0.001), and 1 year (HR 1.46, 95% CI 1.08 to 1.96; p = 0.013).The presence of PAD is associated with higher rates of post-PCI death and MI, and is an independent predictor of short- and long-term mortality.

  View details for DOI 10.1016/j.jacc.2006.03.067

  View details for Web of Science ID 000241414600007

  View details for PubMedID 17045889

• Recent trends in the care of patients with non- ST-segment elevation acute coronary syndromes - Insights from the CRUSADE initiative ARCHIVES OF INTERNAL MEDICINE Mehta, R. H., Roe, M. T., Chen, A. Y., Lytle, B. L., Pollack, C. V., Brindis, R. G., Smith, S. C., Harrington, R. A., Fintel, D., Fraulo, E. S., Califf, R. M., Gibler, W. B., Ohman, E. M., Peterson, E. D. 2006; 166 (18): 2027-2034

  Abstract

  The extent to which national health quality improvement initiatives have altered reported treatment gaps among patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) is unknown. We sought to determine recent trends in adherence to guideline-based therapies for NSTE ACS.We evaluated the treatment of patients with high-risk (positive cardiac markers and/or ischemic ST-segment changes) NSTE ACS enrolled in the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA (American College of Cardiology/American Heart Association) Guidelines (CRUSADE) Quality Improvement Initiative from 2002 through 2004 (a total of 113 595 patients over 11 calendar quarters). We analyzed adherence to guideline-recommended therapies, including medications used in the acute care period (<24 hours after presentation), invasive procedures, in-hospital outcomes, and discharge therapies and interventions.The use of each class I guideline recommendation, as well as overall adherence to the guidelines, improved significantly (P<.001) during the study period. In the acute care setting, the use of antiplatelet agents increased by 5% and beta-blockers by 12%; at hospital discharge, the use of antiplatelet agents increased by 3% and beta-blockers by 8%. Heparin use in the acute care period increased by 6%, largely owing to a 9% increase in the use of low-molecular-weight heparin. Use of glycoprotein IIb/IIIa inhibitors in the acute care period also increased by more than 13%. At discharge, clopidogrel use increased by 22%, lipid-lowering agents by 11%, and angiotensin-converting enzyme inhibitors by 5%. While adherence improved, many patients still failed to receive 100% indicated treatments at the end of the study period.During the 4 years since the initial release of the ACC/AHA guidelines for NSTE ACS, adherence to class I recommendations has significantly improved among hospitals participating in CRUSADE. Still, further improvements are needed for optimal implementation of the these guidelines.

  View details for Web of Science ID 000241057300015

  View details for PubMedID 17030838

• Prevalence, predictors, and outcomes of patients with non-ST-segment elevation myocardial infarction and insignificant coronary artery disease: Results from the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) initiative AMERICAN HEART JOURNAL Patel, M. R., Chen, A. Y., Peterson, E. D., Newby, L. K., Pollack, C. V., Brindis, R. G., Gibson, C. M., Kleiman, N. S., Saucedo, J. F., Bhatt, D. L., Gibler, W. B., Ohman, E. M., Harrington, R. A., Roe, M. T. 2006; 152 (4): 641-647

  Abstract

  Unlike ST-segment elevation myocardial infarction, the degree of stenosis and physiology of ischemia varies in patients with non-ST-segment elevation myocardial infarction (NSTEMI). The prevalence, predictors, and outcomes of patients with NSTEMI who lack significant epicardial coronary artery disease (CAD) in routine clinical practice remain poorly characterized. We sought to determine the prevalence, predictors, and outcomes of patients with NSTEMI and insignificant CAD.We analyzed 38301 patients with NSTEMI in the CRUSADE quality improvement initiative who underwent cardiac catheterization to determine the prevalence and factors associated with insignificant CAD (all coronary stenoses <50%) and inhospital outcomes for patients with and without CAD. A multivariable model was used to determine the factors associated with insignificant CAD.A total of 3306 (8.6%) of 38301 patients had insignificant CAD. The strongest multivariable predictors of insignificant CAD were female sex (odds ratio 2.8, 95% CI 2.6-3.1), younger age (odds ratio per 10-year decrease 1.5, 95% CI 1.5-1.6), and lack of current/recent smoking (odds ratio 1.9, 95% CI 1.7-2.0). Inhospital rates of death were 0.65% for patients with insignificant CAD compared with 2.36% for patients with CAD (P < .0001).Insignificant CAD is present in 9% of patients with NSTEMI and is associated with a low incidence of adverse outcomes. The strongest predictors of insignificant CAD are female sex and younger age. These findings underscore the need for research to understand the pathophysiology of myocardial infarction in this population.

  View details for DOI 10.1016/j.ahj.2006.02.035

  View details for Web of Science ID 000241719300007

  View details for PubMedID 16996828

• Clinical correlates of long-term mortality after percutaneous interventions of saphenous vein grafts AMERICAN HEART JOURNAL Mehta, R. H., Honeycutt, E., Shaw, L. K., Glower, D., Harrington, R. A., Sketch, M. H. 2006; 152 (4): 801-806

  Abstract

  Increasing number of patients undergo percutaneous intervention of saphenous vein grafts (SVGs). However, the clinical factors associated with long-term mortality after SVG interventions are currently less known. Accordingly, the goal of present study was to evaluate clinical correlates of long-term mortality and to develop a simple bedside tool for risk stratification in patients undergoing SVG interventions.We analyzed 1019 patients undergoing SVG interventions from the Duke Cardiovascular Disease Database (1986-2003). Cox proportional hazards model was used to identify baseline variables associated with long-term mortality, and the model variables were then used to construct a nomogram for survival probability at 4 years.At a median follow-up of 4 years, 24% of those undergoing SVG interventions died (interquartile range 2-7 years). Independent correlates of death at follow-up on multivariable analysis included presenting heart rate (hazard ratio [HR] 1.02, 95% CI 1.01-1.03), diabetes (HR 1.73, 95% CI 1.37-2.18), presenting heart failure (HR 1.62, 95% CI 1.27-2.06), age (per 10-year increase, HR 1.29, 95% CI 1.13-1.46), peripheral vascular disease (HR 1.59, 95% CI 1.23-2.04), renal insufficiency (HR 2.01, 95% CI 1.36-2.97), patent internal mammary graft (HR 0.67, 95% CI 0.53-0.86), body mass index < or = 25 kg/m2 (HR 0.91, 95% CI 0.85-0.97), carotid bruit (HR 1.44, 95% CI 1.12-1.85), S3 ventricular gallop (HR 1.83, 95% CI 1.11-3.03), and hypertension (HR 1.38, 95% CI 1.04-1.83) (c-index 0.83). Bootstrap validation confirmed excellent internal validity of the model (mean c-index 0.84, 95% CI 0.80-0.85).Long-term survival after SVG intervention is poor, with one fourth of patients dying at median follow-up of 4 years. The nomogram developed using the model variables provides a method for clinicians to advise patients undergoing SVG interventions regarding their long-term prognosis, thereby enhancing discharge and long-term follow-up planning and setting up of realistic expectations.

  View details for DOI 10.1016/j.ahj.2006.06.004

  View details for Web of Science ID 000241719300041

  View details for PubMedID 16996861

• Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention NEW ENGLAND JOURNAL OF MEDICINE Montalescot, G., White, H. D., Gallo, R., Cohen, M., Steg, P. G., Aylward, P. E., Bode, C., Chiariello, M., King, S. B., Harrington, R. A., Desmet, W. J., Macaya, C., Steinhubl, S. R. 2006; 355 (10): 1006-1017

  Abstract

  Despite its limitations, unfractionated heparin has been the standard anticoagulant used during percutaneous coronary intervention (PCI). Several small studies have suggested that intravenous enoxaparin may be a safe and effective alternative. Our primary aim was to assess the safety of enoxaparin as compared with that of unfractionated heparin in elective PCI.In this prospective, open-label, multicenter, randomized trial, we randomly assigned 3528 patients with PCI to receive enoxaparin (0.5 or 0.75 mg per kilogram of body weight) or unfractionated heparin adjusted for activated clotting time, stratified according to the use or nonuse of glycoprotein IIb/IIIa inhibitors. The primary end point was the incidence of major or minor bleeding that was not related to coronary-artery bypass grafting. The main secondary end point was the percentage of patients in whom the target anticoagulation levels were reached.Enoxaparin at a dose of 0.5 mg per kilogram was associated with a significant reduction in the rate of non-CABG-related bleeding in the first 48 hours, as compared with unfractionated heparin (5.9% vs. 8.5%; absolute difference, -2.6; 95% confidence interval [CI], -4.7 to -0.6; P=0.01), but the higher enoxaparin dose was not (6.5% vs. 8.5%; absolute difference, -2.0; 95% CI, -4.0 to 0.0; P=0.051). The incidence of major bleeding was significantly reduced in both enoxaparin groups, as compared with the unfractionated heparin group. Target anticoagulation levels were reached in significantly more patients who received enoxaparin (0.5-mg-per-kilogram dose, 79%; 0.75-mg-per-kilogram dose, 92%) than who received unfractionated heparin (20%, P<0.001).In elective PCI, a single intravenous bolus of 0.5 mg of enoxaparin per kilogram is associated with reduced rates of bleeding, and a dose of 0.75 mg per kilogram yields rates similar to those for unfractionated heparin, with more predictable anticoagulation levels. The trial was not large enough to provide a definitive comparison of efficacy in the prevention of ischemic events. (ClinicalTrials.gov number, NCT00077844 [ClinicalTrials.gov].).

  View details for Web of Science ID 000240273300006

  View details for PubMedID 16957147

• Challenges in predicting the need for coronary artery bypass grafting at presentation in patients with non-ST-segment elevation acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Mehta, R. H., Chen, A. Y., Pollack, C. V., Roe, M. T., Zalenski, R. J., Clements, E. A., Gibler, W. B., Ohman, E. M., Harrington, R. A., Peterson, E. D. 2006; 98 (5): 624-627

  Abstract

  In the case of non-ST-segment elevation acute coronary syndromes (NSTE-ACSs), the acute use of certain antiplatelet agents is complicated by concerns about perioperative bleeding risks in patients requiring coronary artery bypass grafting (CABG) during the index hospitalization. As a result, clinicians often withhold potentially useful agents, such as clopidogrel, before determining patients' coronary anatomy. An accurate predictive model could allow for a better balance of this safety concern with the demonstrated benefits of agents such as clopidogrel. To create an accurate decision-making tool that would assess, at hospital presentation, the need for CABG in patients with NSTE-ACSs, we studied 61,974 high-risk patients with NSTE-ACS admitted to 311 CABG-capable hospitals participating in Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) from 2001 to 2003. A total of 8,395 patients (14%) underwent CABG during their initial hospital stay. A multivariate model was developed and identified 13 presenting clinical characteristics significantly associated with the likelihood of CABG (previous CABG, male gender, previous heart failure, diabetes, hyperlipidemia, renal insufficiency, ST depression and transient ST elevation, age > or = 75 years, previous percutaneous coronary intervention, family history of coronary artery disease, hypertension, trends in CABG rates, and previous stroke). This model had only modest predictive accuracy and calibration (c-index = 0.67). In conclusion, although certain presenting clinical features are associated with an increased likelihood of CABG in patients with NSTE-ACSs during the index hospitalization, it remains difficult to reliably identify, before diagnostic angiography, those who will subsequently undergo surgical revascularization.

  View details for DOI 10.1016/j.amjcard.2006.03.040

  View details for Web of Science ID 000240324300012

  View details for PubMedID 16923449

• Impact of internal mammary artery conduit on long-term outcomes after percutaneous intervention of saphenous vein graft 78th Annual Scientific Session of the American-Heart-Association Mehta, R. H., Honeycutt, E., Peterson, E. D., Granger, C. B., Halabi, A. R., Shaw, L. K., Smith, P. K., Califf, R. M., Harrington, R. A., Sketch, M. H. LIPPINCOTT WILLIAMS & WILKINS. 2006: I396–I401

  Abstract

  The influence of an internal mammary artery (IMA) graft on long-term outcomes after percutaneous saphenous vein graft (SVG) intervention is currently unknown.To examine the impact of IMA on outcomes in patients undergoing SVG interventions, we analyzed 2119 patients from the Duke Cardiovascular Disease Database (1986-2003) with prior coronary artery bypass surgery undergoing cardiac catheterization who had at least 1 SVG graft. Patients were categorized into 4 groups: group I, SVG intervention and patent IMA; group II, no SVG intervention and patent IMA; group III, SVG intervention without patent IMA; and group IV, no SVG intervention without patent IMA. At a median follow-up of 4.8 years (interquartile range, 2.1 to 8.8 years), adjusted survival rates in groups I, II, III, and IV were 72.8%, 72.3%, 64.5%, and 58.9%, respectively. Multivariate Cox proportional hazards modeling showed similar survival for groups I and II (P=0.63) and for groups III and IV (P=0.33). The presence of IMA graft was related to lower long-term mortality (adjusted hazard ratio [HR], 0.69; 95% CI, 0.58 to 0.82), whereas SVG intervention was not associated with long-term mortality (adjusted HR, 0.94; 95% CI, 0.81 to 1.10). In contrast, the adjusted event-free rates for nonfatal myocardial infarction were lower in the SVG intervention groups (groups I and III) than in the non-SVG intervention groups (groups II and IV) (HR for SVG intervention versus no SVG intervention, 3.19; 95% CI, 2.18 to 4.66), with the presence of patent IMA conferring no significant benefit on this outcome (HR, 1.37; 95% CI, 0.91 to 2.08).In patients undergoing SVG interventions, survival, but not nonfatal myocardial infarction, is favorably influenced by the presence of patent IMA. In contrast, SVG intervention had no measurable survival benefit but was associated with an increased risk of nonfatal myocardial infarction.

  View details for DOI 10.1161/CIRCULATIONAHA.105.000349

  View details for Web of Science ID 000238688200064

  View details for PubMedID 16820607

• Provisional glycoprotein IIb/IIIa blockade in a randomized investigation of bivalirudin versus heparin plus planned glycoprotein IIb/IIIa inhibition during percutaneous coronary intervention: Predictors and outcome in the Randomized Evaluation in Percutaneous coronary intervention Linking Angiomax to reduced Clinical Events (REPLACE)-2 trial AMERICAN HEART JOURNAL Exaire, J. E., Butman, S. M., Ebrahimi, R., Kleiman, N. S., Harrington, R. A., Schweiger, M. J., Bittl, J. A., Wolski, K., Topol, E. J., Lincoff, A. M. 2006; 152 (1): 157-162

  Abstract

  The REPLACE-2 trial demonstrated the noninferiority of bivalirudin with provisional glycoprotein IIb/IIIa (GPIIb/IIIa) blockade as compared with heparin plus planned GPIIb/IIIa blockade among patients undergoing percutaneous coronary revascularization. Provisional drug was used in 374 (6%) of the 6010 patients. We sought to analyze the predictors for provisional drug use and to assess the outcomes in this cohort.Outcome among the 5.2% of patients in the heparin plus GPIIb/IIIa blockade group and the 7.2% of patients in the bivalirudin group who received provisional placebo or GPIIb/IIIa inhibitor, respectively, was compared against patients without provisional drug use and between randomized arms. Multivariate models identified predictors of provisional drug use and outcome at 30 days, 6 months, and 1 year.Myocardial infarction, repeat revascularization, and bleeding events occurred more frequently among patients who required provisional drug than those who did not, but there were no differences in 1-year mortality. Ischemic and hemorrhagic end points occurred at similar rates among patients receiving provisional drug in either the heparin plus GPIIb/IIIa group compared with the bivalirudin group. Independent predictors of provisional drug use were randomization to bivalirudin, recent infarction, multilesion intervention, impaired pretreatment coronary flow, and lesion complexity. Provisional drug use, but not randomization to bivalirudin, independently predicted 30-day and 6-month ischemic events.Provisional administration of a GPIIb/IIIa inhibitor is associated with more frequent ischemic and bleeding events, reflecting the procedural complications that led to the use of provisional drug. The proportion of bivalirudin-treated patients who will require provisional GPIIb/IIIa blockade, however, is not large enough to have a significant deleterious impact on the overall incidence of ischemic end points or to invalidate the strategy of bivalirudin plus provisional GPIIb/IIIa blockade.

  View details for DOI 10.1016/j.ahj.2005.09.004

  View details for Web of Science ID 000239060200026

  View details for PubMedID 16824849

• The influence of risk status on guideline adherence for patients with non-ST-segment elevation acute coronary syndromes AMERICAN HEART JOURNAL Roe, M. T., Peterson, E. D., Newby, L. K., Chen, A. Y., Pollack, C. V., Brindis, R. G., Harrington, R. A., Christenson, R. H., Smith, S. C., Califf, R. M., Braunwald, E., Gibler, W. B., Ohman, E. M. 2006; 151 (6): 1205-1213

  Abstract

  Practice guidelines for patients with non-ST-segment elevation (NSTE) acute coronary syndromes (ACS) recommend targeting evidence-based therapies for the highest-risk patients. We characterized guideline adherence for NSTE ACS by risk status.We analyzed inhospital treatments and outcomes for 77760 patients with NSTE ACS (ischemic ST-segment changes and/or positive cardiac markers) included in the CRUSADE initiative from January 2001 to September 2003 at 457 US hospitals. Compliance with the American College of Cardiology/American Heart Association Class guideline recommendations for NSTE ACS was evaluated in subgroups of eligible patients without listed contraindications at increased risk for mortality and among risk categories designated by an adapted version of the PURSUIT risk model designed to predict inhospital mortality.Inhospital mortality was increased in patients with diabetes mellitus (5.8% vs 4.3%), renal insufficiency (10.0% vs 3.9%), signs of congestive heart failure on presentation (10.6% vs 3.1%), and age > or = 75 years (8.6% vs 2.7%), compared with patients without these features. Use of guideline-recommended acute medications, invasive cardiac procedures, and discharge medications and interventions was significantly lower in patients with these high-risk features. Patients designated as high-risk for inhospital mortality were less likely to be treated with guideline-recommended therapies compared with low-risk and moderate-risk patients.Patients with NSTE ACS with the highest risk of mortality are less likely to receive guideline-recommended therapies and interventions. These findings highlight the need to clarify guideline recommendations for high-risk patients and to develop novel quality improvement approaches that target undertreated subgroups of patients with NSTE ACS.

  View details for DOI 10.1016/j.ahj.2005.08.006

  View details for Web of Science ID 000238614600010

  View details for PubMedID 16781220

• 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

• 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

• Association between hospital process performance and outcomes among patients with acute coronary syndromes JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Peterson, E. D., Roe, M. T., Mulgund, J., DeLong, E. R., Lytle, B. L., Brindis, R. G., Smith, S. C., Pollack, C. V., Newby, L. K., Harrington, R. A., Gibler, W. B., Ohman, E. M. 2006; 295 (16): 1912-1920

  Abstract

  Selected care processes are increasingly being used to measure hospital quality; however, data regarding the association between hospital process performance and outcomes are limited.To evaluate contemporary care practices consistent with the American College of Cardiology/American Heart Association (ACC/AHA) guideline recommendations, to examine how hospital performance varied among centers, to identify characteristics predictive of higher guideline adherence, and to assess whether hospitals' overall composite guideline adherence was associated with observed and risk-adjusted in-hospital mortality rates.An observational analysis of hospital care in 350 academic and nonacademic US centers of 64,775 patients enrolled in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) National Quality Improvement Initiative between January 1, 2001, and September 30, 2003, presenting with chest pain and positive electrocardiographic changes or cardiac biomarkers consistent with non-ST-segment elevation acute coronary syndrome (ACS).Use of 9 ACC/AHA class I guideline-recommended treatments and the correlation among hospitals' use of individual care processes as well as overall composite adherence rates.Overall, the 9 ACC/AHA guideline-recommended treatments were adhered to in 74% of eligible instances. There was modest correlation in hospital performance among the individual ACS process metrics. However, composite adherence performance varied widely (median [interquartile range] composite adherence scores from lowest to highest hospital quartiles, 63% [59%-66%] vs 82% [80%-84%]). Composite guideline adherence rate was significantly associated with in-hospital mortality, with observed mortality rates decreasing from 6.31% for the lowest adherence quartile to 4.15% for the highest adherence quartile (P<.001). After risk adjustment, every 10% increase in composite adherence at a hospital was associated with an analogous 10% decrease in its patients' likelihood of in-hospital mortality (adjusted odds ratio, 0.90; 95% confidence interval, 0.84-0.97; P<.001).A significant association between care process and outcomes was found, supporting the use of broad, guideline-based performance metrics as a means of assessing and helping improve hospital quality.

  View details for Web of Science ID 000237059200026

  View details for PubMedID 16639050

• Clopidogrel to treat patients with non-ST-segment elevation acute coronary syndromes after hospital discharge ARCHIVES OF INTERNAL MEDICINE Tricoci, P., Roe, M. T., Mulgund, J., Newby, L. K., Smith, S. C., Pollack, C. V., Fintel, D. J., Cannon, C. P., Bhatt, D. L., Gibler, W. B., Ohman, E. M., Peterson, E. D., Harrington, R. A. 2006; 166 (7): 806-811

  Abstract

  Clopidogrel added to aspirin improved outcomes after hospitalization in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, regardless of in-hospital treatment approach. The American College of Cardiology/American Heart Association (ACC/AHA) Guidelines for treating NSTE ACS thus recommend prescribing clopidogrel plus aspirin at discharge for all patients, not just for those undergoing percutaneous coronary intervention (PCI).We studied 61 052 patients with high-risk NSTE ACS (defined as the presence of positive cardiac markers and/or ischemic ST-segment changes) from January 2002 through December 2003 at 461 US hospitals participating in the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Quality Improvement Initiative. We evaluated temporal trends of clopidogrel use at discharge since the ACC/AHA 2002 Guidelines update and examined variables associated with clopidogrel use in patients who did not undergo PCI.A total of 34 319 patients (56.2%) received clopidogrel when they were discharged from the hospital. Among patients who did not undergo PCI, variables associated with receiving clopidogrel at discharge included prior PCI, coronary artery bypass grafting (CABG), stroke, or myocardial infarction; hypercholesterolemia; elevated cardiac markers; and cardiology inpatient care. By late 2003, 96.3% of patients who underwent PCI received clopidogrel at discharge, compared with 42.8% of patients who did not undergo cardiac catheterization and 23.5% of the patients who underwent CABG, although clopidogrel prescription at discharge increased in each of these treatment groups from 2002 to 2003.Since release of the ACC/AHA Guidelines recommendations for treatment of NSTE ACS, prescription of clopidogrel at hospital discharge in patients with NSTE ACS who are treated with medical therapy alone and in those who undergo CABG has increased, but most of these patients still do not receive clopidogrel at discharge.

  View details for Web of Science ID 000236679800015

  View details for PubMedID 16606819

• Initial experience with an intravenous P2Y(12) platelet receptor antagonist in patients undergoing percutaneous coronary intervention: Results from a 2-part, phase II, multicenter, randomized, placebo- and active-controlled trial AMERICAN HEART JOURNAL Greenbaum, A. B., Grines, C. L., Bittl, J. A., Becker, R. C., Kereiakes, D. J., Gilchrist, I. C., Clegg, J., Stankowski, J. E., Grogan, D. R., Harrington, R. A., Emanuelsson, H., Weaver, W. D. 2006; 151 (3)

  Abstract

  Platelet-initiated acute thrombosis and coronary embolization are fundamental in the pathophysiology of complications during percutaneous coronary intervention (PCI). Cangrelor (formerly AR-C69931MX) is a novel, rapidly acting, intravenous, specific antagonist of platelet aggregation via binding to the adenosine diphosphate (ADP) P2Y12 receptor subtype. The primary aims of this study were to assess the initial safety and pharmacodynamics of cangrelor in patients undergoing PCI.In part 1, patients undergoing PCI were randomized to an 18- to 24-hour of either placebo, 1-, 2-, or 4-microg/kg per minute cangrelor in addition to aspirin and heparin beginning before PCI. In part 2, patients were randomized to receive either cangrelor (4 microg/kg per minute) or abciximab before PCI. The primary end point was the composite incidence of major and minor bleeding through 7 days. Secondary end points included the occurrence of major adverse coronary events (death, MI, and unplanned repeat coronary intervention) through 30 days plus ex vivo platelet aggregation and bleeding times.Two hundred patients (3 dosage groups and placebo) were studied in part 1, and 199 additional patients were then randomized in the second part, comparing 1 dose of cangrelor and abciximab. Combined major and minor bleeding occurred in 13% of those receiving cangrelor and in 8% in those randomized to placebo (P = non significant [NS]) during part 1 and in 7% receiving cangrelor compared with 10% randomized to abciximab (P = NS), during part 2. The 30-day composite incidence of adverse cardiac events was similar between those receiving cangrelor and those receiving abciximab during part 2 (7.6% vs 5.3%, respectively, P = NS). Mean inhibition of ex vivo platelet aggregation in response to 3 micromol/L ADP at steady state was 100% for both cangrelor 4 microg/kg per minute and abciximab groups in part 2. After termination of infusion, platelet aggregation returned to baseline response more rapidly with cangrelor compared with abciximab. There was a trend toward longer bleeding time prolongation and lower platelet count with abciximab compared with cangrelor.This initial experience with intravenous cangrelor during PCI suggests an acceptable risk of bleeding and adverse cardiac events while achieving rapid, reversible inhibition of platelet aggregation via competitive binding to the ADP P2Y12 platelet receptor with less prolongation of bleeding time then the glycoprotein IIb/IIIa receptor antagonist abciximab.

  View details for DOI 10.1016/j.ahj.2005.11.014

  View details for Web of Science ID 000236353900020

  View details for PubMedID 16504633

• Outcomes of patients in clinical trials with ST-segment elevation myocardial infarction among countries with different gross national incomes EUROPEAN HEART JOURNAL Orlandini, A., Diaz, R., Wojdyla, D., Pieper, K., Van de Werf, F., Granger, C. B., Harrington, R. A., Boersma, E., Califf, R. M., ARMSTRONG, P., White, H., Simes, J., PAOLASSO, E. 2006; 27 (5): 527-533

  Abstract

  To evaluate whether there is an association between 30-day mortality in patients with ST-segment elevation myocardial infarction (STEMI) included in clinical trials and country gross national income (GNI).A retrospective analysis of the databases of five randomized trials including 50 310 patients with STEMI (COBALT 7169, GIK-2 2931, HERO-2 17,089, ASSENT-2 17,005, and ASSENT-3 6116 patients) from 53 countries was performed. Countries were divided into three groups according to their GNI based on the World Bank data: low (less than 2900 US dollars), medium (between 2900 US dollars and 9000 US dollars), and high GNI (more than 9000 US dollars per capita). Baseline characteristics, in-hospital management variables, and 30-day outcomes were evaluated. A previously defined logistic regression model was used to adjust for differences in baseline characteristics and to predict mortality. The observed mortality was higher than the predicted mortality in the low (12.1 vs. 11.8%) and in the medium income groups (9.4 vs. 7.9%), whereas it was lower in the high income group (4.9 vs. 5.6%).An inverse relationship between mortality and GNI was observed in STEMI clinical trials. Most of the variability in mortality can be explained by differences in baseline characteristics; however, after adjustment, lower income countries have higher mortality than the expected.

  View details for DOI 10.1093/eurheartj/ehi701

  View details for Web of Science ID 000235605100008

  View details for PubMedID 16410369

• 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

• Cardiac tamponade in the fibrinolytic era: Analysis of > 100000 patients with ST-segment elevation myocardial infarction AMERICAN HEART JOURNAL Patel, M. R., Meine, T. J., Lindblad, L., Griffin, J., Granger, C. B., Becker, R. C., Van de Werf, F., White, H., Califf, R. M., Harrington, R. A. 2006; 151 (2): 316-322

  Abstract

  Cardiac tamponade is a life-threatening complication of acute myocardial infarction (MI). Data on the incidence, risk factors, and outcome of tamponade in patients with acute MI in the fibrinolytic era are limited.Data from a combined clinical trials database of ST-segment elevation MI were used to evaluate the incidence of cardiac tamponade, baseline characteristics, and outcomes in patients with and without tamponade. Univariable and multivariable analyses assessed the relationship between patient characteristics and tamponade development, and the influence of tamponade on mortality.Of 102,060 patients, 865 (0.85%) developed isolated cardiac tamponade during initial hospitalization. Patients with tamponade were older (median 71.9 vs 61.6 years, P < .001), were more likely to be female (54.0% vs 25.1%, P < .001), were more likely to have an anterior MI (61.9% vs 41.5%, P < .001), and had a longer time from symptom onset to reperfusion (median 3.5 vs 2.8 hours, P < .001) than those without tamponade. Multivariable analyses identified increasing age, anterior MI location, female sex, and increased time from symptom onset to treatment as significant independent predictors of tamponade. Patients with tamponade had an increased death rate at 30 days (hazard ratio 7.9, 95% CI 4.7-13.5).Cardiac tamponade occurs in < 1% of patients with fibrinolytic-treated acute MI and is associated with increased 30-day mortality. Time from symptom onset to treatment strongly predicted the development of tamponade, underscoring the need for continued efforts to increase speed to treatment in acute MI.

  View details for DOI 10.1016/j.ahj.2005.04.014

  View details for Web of Science ID 000235521100008

  View details for PubMedID 16442893

• Frequency and clinical implications of discordant creatine kinase-MB and troponin measurements in acute coronary syndromes JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Newby, L. K., Roe, M. T., Chen, A. Y., Ohman, E. M., Christenson, R. H., Pollack, C. V., Hoekstra, J. W., Peacock, W. F., Harrington, R. A., Jesse, R. L., Gibler, W. B., Peterson, E. D. 2006; 47 (2): 312-318

  Abstract

  We sought to evaluate the association between discordant cardiac marker results and in-hospital mortality and treatment patterns in patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS).Creatine kinase-MB (CK-MB) and cardiac troponins (cTn) are often measured concurrently in patients with NSTE ACS. The significance of discordant CK-MB and cTn results is unknown.Among 29,357 ACS patients in the CRUSADE initiative who had both CK-MB and cTn measured during the first 36 hours, we examined relationships of four marker combinations (CK-MB-/cTn-, CK-MB+/cTn-, CK-MB-/cTn+, and CK-MB+/cTn+) with mortality and American College of Cardiology/American Heart Association guidelines-recommended acute care.The CK-MB and cTn results were discordant in 28% of patients (CK-MB+/cTn-, 10%; CK-MB-/cTn+, 18%). In-hospital mortality was 2.7% among CK-MB-/cTn- patients; 3.0%, CK-MB+/cTn-; 4.5%, CK-MB-/cTn+; and 5.9%, CK-MB+/cTn+. After adjustment for other presenting risk factors, patients with CK-MB+/cTn- had a mortality odds ratio (OR) of 1.02 (95% confidence interval [CI] 0.75 to 1.38), those with CK-MB-/cTn+ had an OR of 1.15 (95% CI 0.86 to 1.54), and those with CK-MB+/cTn+ had an OR of 1.53 (95% CI 1.18 to 1.98). Despite variable risk, patients with CK-MB+/cTn- and CK-MB-/cTn+ were treated similarly with early antithrombotic agents and catheter-based interventions.Among patients with NSTE ACS, an elevated troponin level identifies patients at increased acute risk regardless of CK-MB status, but an isolated CK-MB+ status has limited prognostic value. Recognition of these risk differences may contribute to more appropriate early use of antithrombotic therapy and invasive management for all cTn+ patients.

  View details for DOI 10.1016/j.jacc.2005.08.062

  View details for Web of Science ID 000234667100007

  View details for PubMedID 16412853

• 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

• Efficacy and safety of edifoligide, an E2F transcription factor decoy, for prevention of vein graft failure following coronary artery bypass graft surgery - PREVENT IV: A randomized controlled trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Alexander, J. H., Hafley, G., Harrington, R., Peterson, E. D., Ferguson, T. B., Lorenz, T. J., Goyal, A., Gibson, M., Mack, M. J., Gennevois, D., Califf, R. M., Kouchoukos, N. T. 2005; 294 (19): 2446-2454

  Abstract

  Coronary artery bypass graft (CABG) surgery with autologous vein grafting is commonly performed. Progressive neointimal hyperplasia, however, contributes to considerable vein graft failure. Edifoligide is an oligonucleotide decoy that binds to and inhibits E2F transcription factors and thus may prevent neointimal hyperplasia and vein graft failure.To assess the efficacy and safety of pretreating vein grafts with edifoligide for patients undergoing CABG surgery.A phase 3 randomized, double-blind, placebo-controlled trial of 3014 patients undergoing primary CABG surgery with at least 2 planned saphenous vein grafts and without concomitant valve surgery, who were enrolled between August 2002 and October 2003 at 107 US sites.Vein grafts were treated ex vivo with either edifoligide or placebo in a pressure-mediated delivery system. The first 2400 patients enrolled were scheduled for 12- to 18-month follow-up angiography.The primary efficacy end point was angiographic vein graft failure (> or =75% vein graft stenosis) occurring 12 to 18 months after CABG surgery. Other end points included other angiographic variables, adverse events through 30 days, and major adverse cardiac events.A total of 1920 patients (80%) either died (n = 91) or underwent follow-up angiography (n = 1829). Edifoligide had no effect on the primary end point of per patient vein graft failure (436 [45.2%] of 965 patients in the edifoligide group vs 442 [46.3%] of 955 patients in the placebo group; odds ratio, 0.96 [95% confidence interval {CI}, 0.80-1.14]; P = .66), on any secondary angiographic end point, or on the incidence of major adverse cardiac events at 1 year (101 [6.7%] of 1508 patients in the edifoligide group vs 121 [8.1%] of 1506 patients in the placebo group; hazard ratio, 0.83 [95% CI, 0.64-1.08]; P = .16).Failure of at least 1 vein graft is quite common within 12 to 18 months after CABG surgery. Edifoligide is no more effective than placebo in preventing these events. Longer-term follow-up and additional research are needed to determine whether edifoligide has delayed beneficial effects, to understand the mechanisms and clinical consequences of vein graft failure, and to improve the durability of CABG surgery. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00042081.

  View details for Web of Science ID 000233277400023

  View details for PubMedID 16287955

• Relation of early saphenous vein graft failure to outcomes following coronary artery bypass surgery AMERICAN JOURNAL OF CARDIOLOGY Halabi, A. R., Alexander, J. H., Shaw, L. K., Lorenz, T. J., Liao, L., Kong, D. F., Milano, C. A., Harrington, R. A., Smith, P. K. 2005; 96 (9): 1254-1259

  Abstract

  Up to 20% of saphenous vein grafts (SVGs) fail within 2 years of coronary artery bypass grafting (CABG). The long-term effects of early SVG failure on major clinical events remain undefined in contemporary patient populations. We sought to examine the relation between early SVG failure and long-term outcomes after CABG. Using the Duke Cardiovascular Databank, we examined baseline clinical and angiographic characteristics and clinical outcomes among patients who underwent catheterization 1 to 18 months after their first CABG from 1986 to 2004. Patients were classified on the basis of their worst SVG stenosis as having no (<25%), noncritical (25% to 74%), critical (75% to 99%), or occlusive (100%) SVG disease. Our primary outcome measure was the composite of death, myocardial infarction, or repeat revascularization after catheterization. Of 1,243 patients included in the analysis, 27.9% had no, 11.9% had noncritical, 20.8% had critical, and 39.3% had occlusive SVG disease. At 10 years, the corresponding adjusted composite event rates were 41.2%, 56.2%, 81.2%, and 67.1%, respectively (p <0.0001). Most events occurred immediately after catheterization in patients with critical and occlusive SVG disease and were primarily repeat revascularization. On multivariate analysis, critical, nonocclusive SVG disease was the strongest predictor of the composite outcome (hazard ratio 2.36, 95% confidence interval 2.00 to 2.79, p <0.0001). In conclusion, in contemporary clinical practice, early SVG failure is associated with worse long-term outcomes after CABG.

  View details for DOI 10.1016/j.amjcard.2005.06.067

  View details for Web of Science ID 000233343500016

  View details for PubMedID 16253593

• 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

• The PRoject of ex-vivo vein graft ENgineering via Transfection IV (PREVENT IV) trial: Study rationale, design, and baseline patient characteristics AMERICAN HEART JOURNAL Alexander, J. H., Ferguson, T. B., Joseph, D. M., Mack, M. J., Wolf, R. K., Gibson, M., Gennevois, D., Lorenz, T. J., Harrington, R. A., Peterson, E. D., Lee, K. L., Califf, R. M., Kouchoukos, N. T. 2005; 150 (4): 643-649

  Abstract

  Coronary artery bypass graft (CABG) surgery with autologous vein graft (VG) conduit is one of the most frequently performed operations in the United States. Unfortunately, many VGs become occluded during long-term follow-up largely because of neointimal hyperplasia. A novel approach to preventing neointimal hyperplasia is with the double-stranded oligonucleotide edifoligide (Corgentech Inc, South San Francisco, Calif). Edifoligide inhibits E2F, a transcription factor that activates cell-cycle genes responsible for neointimal hyperplasia.PREVENT IV is a phase-III, multicenter, randomized double-blind placebo-controlled trial of ex vivo treatment of autologous VGs with edifoligide in patients undergoing initial CABG surgery. The primary end point is VG failure, defined as death or > or =75% stenosis in a treated VG at 12- to 18-month angiographic follow-up. Secondary end points include major adverse cardiac events through at least 5 years and adverse events through 30 days.Enrollment of 3014 patients from 107 sites was completed on October 22, 2003. The baseline and procedural characteristics of the PREVENT IV population are generally well matched to a contemporary population of patients undergoing initial CABG from the Society of Thoracic Surgeons National Database. Angiographic follow-up is ongoing and scheduled to be completed in March 2005.The PREVENT IV data will establish whether VG pretreatment with an E2F transcription factor decoy, edifoligide, can improve graft patency and reduce the long-term morbidity and mortality of patients undergoing CABG surgery.

  View details for DOI 10.1016/j.ahj.2005.05.021

  View details for Web of Science ID 000232953300004

  View details for PubMedID 16209958

• Renal function, concomitant medication use and outcomes following acute coronary syndromes NEPHROLOGY DIALYSIS TRANSPLANTATION Reddan, D. N., Szczech, L., Bhapkar, M. V., Moliterno, D. J., Califf, R. M., Ohman, E. M., Berger, P. B., Hochman, J. S., Van de Werf, F., Harrington, R. A., Newby, L. K. 2005; 20 (10): 2105-2112

  Abstract

  Chronic kidney disease (CKD) is highly prevalent in patients with cardiovascular disease. We explored the associations of CKD with outcomes using combined data from two large acute coronary syndrome (ACS) trials. We also explored the associations of CKD with prescription patterns for common cardiovascular medications and the association of these prescription patterns with clinical outcomes.Patients were stratified by CKD stage using creatinine clearance (CrCl, ml/min) estimated by the modified MDRD equation using baseline core laboratory creatinine measures. Serum creatinine > or =1.5 mg/dl was an exclusion criterion for the SYMPHONY trials. Baseline characteristics and outcomes across CKD categories were compared and Cox proportional hazards regression was used to assess the relationship of renal insufficiency with clinical outcomes after adjusting for previously identified outcome predictors. Interactions between the use of specific medications and calculated CrCl were tested in the final Cox proportional hazards model predicting time to mortality.Of 13 707 patients analysed, 6840 had CKD stage I (CrCl > or =90 ml/min), 5909 stage II (CrCl 60-89 ml/min), 955 stage III (CrCl 30-59 ml/min) and three stage IV (CrCl <30 ml/min). Patients with more advanced CKD (III) were older, more often female, non-smokers and more likely to have co-morbid diseases including diabetes mellitus, hypertension and congestive heart failure. Cardiovascular medications were used less frequently in patients with CKD. Unadjusted survival was poorer in patients with CKD stages > or =II. In adjusted analyses, for those with CrCl < or =91, each 10 ml/min increase in CrCl was associated with a significantly decreased risk of mortality (hazards ratio 0.897, 95% confidence interval 0.815-0.986) (P = 0.024). The interaction between use of angiotensin-converting enzyme (ACE) inhibitors and CrCl was significantly associated with outcomes; the benefit of drug therapy was greater among patients with CKD.CKD is an independent predictor of risk among ACS patients, and is associated with less frequent use of proven medical therapies. More aggressive use of conventional cardiovascular therapies in patients with CKD and ACS may be warranted.

  View details for DOI 10.1093/ndt/gfh981

  View details for Web of Science ID 000232102800015

  View details for PubMedID 16030030

• Frequency, predictors, and outcomes of drug-eluting stent utilization in patients with high-risk non-ST-segment elevation acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Kandzari, D. E., Roe, M. T., Ohman, E. M., Milford-Beland, S., Chen, A. Y., Lytle, B. L., Cohen, D. J., Smith, S. C., Harrington, R. A., Gibler, W. B., Peterson, E. D. 2005; 96 (6): 750-755

  Abstract

  Despite the established benefit of drug-eluting stents (DESs) in improving clinical and angiographic outcomes in pivotal, randomized trials, relatively little is known regarding the frequency and patterns of DES use in clinical practice. To characterize DES use in a broad, unselected high-risk non-ST-segment elevation acute coronary syndrome population, we evaluated the frequency, patterns, and predictors of DES use among patients in the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the American College of Cardiology/American Heart Association Guidelines (CRUSADE) Quality Improvement Initiative who were selected to undergo percutaneous coronary intervention. Of 8,852 patients with high-risk non-ST-segment elevation acute coronary syndromes who underwent percutaneous revascularization at 262 hospitals between October 2003 and June 2004, 5,858 (66.2%) were treated with DESs and 2,994 (33.8%) were not. During a 9-month period, DES use increased considerably from 52.6% of cases in October 2003 to 78.5% in June 2004. Compared with the bare metal stent cohort, patients receiving DESs were more likely to be women and to have private insurance, but were less likely to present with positive cardiac markers or ST-segment depression. In adjusted analysis, death and recurrent infarction were significantly lower among the patients with a DES, yet early revascularization and treatment with guideline-recommended therapies were less frequent. In a multivariate model, significant (p <0.05) predictors of DES use included hyperlipidemia, elevated systolic blood pressure, private insurance, and treatment at a larger hospital. In conclusion, these findings not only identified differences in the selection and treatment of patients receiving bare metal stents versus DESs, but also demonstrated the increasing use of DESs in higher risk patients who have previously been excluded from randomized, pivotal trials.

  View details for DOI 10.1016/j.amjcard.2005.05.015

  View details for Web of Science ID 000232096700003

  View details for PubMedID 16169352

• Facilitated percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: Results from the prematurely terminated ADdressing the Value of facilitated ANgioplasty after Combination therapy or Eptifibatide, monotherapy in acute Myocardial Infarction (ADVANCE MI) trial AMERICAN HEART JOURNAL Adgey, J., Ardissino, D., ARMSTRONG, P., Berger, P., Betriu, A., Beyar, R., Bode, C., Braunwald, E., Brindis, R., Brogan, G., Buller, C., Califf, R., CASTERELLA, P., Gibler, W. B., Giugliano, R., Goldstein, P., Granger, C., Guetta, V., Harrington, R., Herrmann, H., Hochman, J., Hoekstra, J., Kleiman, N., Labinaz, M., Langer, A., Montalescot, G., Ohman, E. M., O'Neill, W., Pollack, C., Roe, M., Satler, L., Schweiger, M., Simoons, M., Steg, G., Tanguay, J. F., Van de Werf, F., Wallentin, L., Zeymer, U. 2005; 150 (1): 116-122

  Abstract

  Facilitated percutaneous coronary intervention (PCI)--simultaneous administration of glycoprotein IIb/IIIa inhibitors and reduced-dose fibrinolytics before primary PCI for ST-segment elevation myocardial infarction (STEMI)--may be a promising reperfusion strategy.The ADVANCE MI trial was intended to evaluate facilitated PCI in 5640 STEMI patients but was prematurely terminated as a result of slow recruitment over 12 months at 30 centers in the United States. Patients with STEMI with planned primary PCI were randomly assigned to receive eptifibatide + 50% of standard-dose tenecteplase (which equated to 0.25 mg/kg intravenous bolus) or eptifibatide + placebo before PCI and randomized in a 2 x 2 factorial design to unfractionated heparin or enoxaparin.A total of 148 patients were randomized (74 patients in each treatment arm) and formed the "as-randomized" intention-to-treat population. However, only 69 patients actually received eptifibatide + tenecteplase, and 77 actually received eptifibatide + placebo (2 patients did not receive eptifibatide and 4 patients randomized to tenecteplase did not receive this therapy)--these 146 patients formed the "as-treated" population. Among both populations, epicardial infarct artery patency and myocardial tissue perfusion on pre-PCI angiography were improved in the tenecteplase group, but ST-segment resolution at 60 minutes was similar. The frequency of the primary end point of death or new/worsening severe heart failure at 30 days was higher among patients treated with eptifibatide + tenecteplase in the "as-treated" (10% vs 3%, P = .09) and the "as-randomized" (11% vs 1%, P = .02) populations. Bleeding complications were 2-fold higher with eptifibatide + tenecteplase. Analysis of the results by treatment with unfractionated heparin versus enoxaparin demonstrated similar findings.Although definitive conclusions cannot be made as a result of the small sample size and premature study termination, facilitated PCI with eptifibatide + reduced-dose tenecteplase was associated with improved angiographic flow patterns, increases in adverse clinical outcomes, and higher bleeding rates compared with eptifibatide + placebo administered before primary PCI for STEMI.

  View details for DOI 10.1016/j.ahj.2005.04.005

  View details for Web of Science ID 000232219900018

  View details for PubMedID 16084157

• Use of bivalirudin during percutaneous coronary intervention in patients with diabetes mellitus - An analysis from the randomized evaluation in percutaneous coronary intervention linking angiomax to reduced clinical events (REPLACE)-2 trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Gurm, H. S., Sarembock, I. J., Kereiakes, D. J., Young, J. J., Harrington, R. A., Kleiman, N., Feit, F., Wolski, K., Bittl, J. A., Wilcox, R., Topol, E. J., Lincoff, A. M. 2005; 45 (12): 1932-1938

  Abstract

  The objective of this study was to confirm that the efficacy and safety of percutaneous coronary intervention (PCI) in diabetic patients are not compromised by a bivalirudin-based antithrombotic strategy.Previous studies have shown a survival benefit with use of platelet glycoprotein (GP) IIb/IIIa inhibitors in diabetic patients undergoing PCI. The Randomized Evaluation in Percutaneous Coronary Intervention Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial showed the non-inferiority of a strategy of bivalirudin with provisional GP IIb/IIIa inhibition compared with routine GP IIb/IIIa inhibition. The relative efficacy of these two strategies in diabetic patients has not been studied.We evaluated the diabetic patients enrolled in the REPLACE-2 trial to assess the impact of these antithrombotic strategies on the short- and long-term outcome after PCI.The REPLACE-2 trial enrolled 1,624 diabetic patients and 4,368 non-diabetic patients. Compared with non-diabetic patients, diabetic patients had similar short-term outcome but higher mortality at 1 year (3.06% vs. 1.85%, p = 0.004). There was no difference in short-term or long-term ischemic events among the diabetic patients randomized to the two arms. Specifically, the 1-year mortality rate was non-significantly lower in the bivalirudin arm, suggesting no differential survival impact of the two strategies (2.3% vs. 3.9%). There was less minor bleeding in the bivalirudin arm in diabetic patients (12.6% vs. 24.4%, p < 0.001), whereas no difference was seen in the incidence of major bleeding (3.0% vs. 3.3%, p = 0.69).Compared with routine GP IIb/IIIa inhibition, the use of bivalirudin with provisional GP IIb/IIIa inhibitors in diabetic patients is associated with no differences in clinical outcomes at 30 days, a trend toward lesser mortality at 1 year, and a reduction in minor bleeding.

  View details for DOI 10.1016/j.jacc.2005.02.074

  View details for Web of Science ID 000229848500004

  View details for PubMedID 15963389

• 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

• The Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY ACS) trial: A randomized placebo-controlled trial evaluating the clinical benefits of early front-loaded-eptifibatide in the treatment of patients with non-ST-segment elevation acute coronary syndrome - Study design and rationale AMERICAN HEART JOURNAL Giugliano, R. P., Newby, L. K., Harrington, R. A., Gibson, C. M., Van de Werf, F., ARMSTRONG, P., Montalescot, G., Gilbert, J., Strony, J. T., Califf, R. M., Braunwald, E. 2005; 149 (6): 994-1002

  Abstract

  The recent North American and European practice guidelines in patients with non-ST-segment elevation acute coronary syndrome (nSTE ACS) recommend glycoprotein IIb/IIIa (GpIIb-IIIa) inhibition in patients undergoing an early invasive treatment strategy. However, the guidelines are not explicit regarding the timing of initiation of GpIIb-IIIa antagonists, and there is marked variation in clinical practice regarding their use.The EARLY ACS trial will enroll 10,500 patients in a prospective, randomized, double blind, international, multicenter investigation of early eptifibatide compared with placebo (with provisional eptifibatide in the catheterization laboratory) in patients with high-risk nSTE ACS in whom an invasive strategy is planned no sooner than the next calendar day. The primary efficacy end point is the 96-hour composite of all-cause mortality, nonfatal myocardial infarction, recurrent ischemia requiring urgent revascularization, or need for thrombotic bailout with GpIIb-IIIa inhibitor during percutaneous coronary intervention. The key secondary end point is the composite of death or nonfatal myocardial infarction within 30 days of enrollment.The EARLY ACS trial will be the largest study to date to evaluate the utility of early GpIIb-IIIa inhibition in patients with nSTE ACS in whom an invasive approach is planned. This trial will provide important evidence regarding the benefit of initiating eptifibatide early after presentation with high-risk ACS versus delayed provisional use after coronary angiography. Furthermore, it will explore the ability of biomarkers to identify high-risk patients who may benefit from such an early aggressive approach.

  View details for DOI 10.1016/j.ahj.2005.03.029

  View details for Web of Science ID 000230622100012

  View details for PubMedID 15976780

• Should we routinely supplement coronary patients with folate therapy to prevent in-stent restenosis? AMERICAN HEART JOURNAL Halabi, A. R., Harrington, R. A. 2005; 149 (6): 1035-1036

  View details for DOI 10.1016/j.ahj.2005.03.014

  View details for Web of Science ID 000230622100024

  View details for PubMedID 15976784

• Early glycoprotein IIb/IIIa inhibitor use for non-ST-segment elevation acute coronary syndrome: Patient selection and associated treatment patterns ACADEMIC EMERGENCY MEDICINE Hoekstra, J. W., Roe, M. T., Peterson, E. D., Menon, V., Mulgund, J., Pollack, C. V., Miller, C., Palabrica, T., Harrington, R. A., Ohman, E. M., Gibler, B. 2005; 12 (5): 431-438

  Abstract

  The authors analyzed contemporary use of glycoprotein (GP) IIb/IIIa inhibitors in patients with non-ST-segment elevation acute coronary syndrome (NSTE ACS) to determine patient selection patterns with early (<24 hours) GP IIb/IIIa inhibitor use and the relationship between GP IIb/IIIa inhibitor therapy and use of other guidelines-recommended therapies for NSTE ACS.Using the CRUSADE Quality Improvement Initiative database, patient characteristics, in-hospital treatments, and outcomes for 65,424 patients with ischemic chest pain of <24 hours' duration and either positive cardiac markers or ischemic electrocardiographic changes were analyzed. Data were collected from 443 U.S. hospitals from January 2001 to June 2003.Only 35% of eligible patients received GP IIb/IIIa inhibitors <24 hours after hospital admission. Approximately one third of patients received GP IIb/IIIa inhibitors in the emergency department, one third in the coronary care unit, and one third in the catheterization laboratory. Admission to a cardiologist's care was the most significant associated factor with early GP IIb/IIIa inhibitor use, along with elevated cardiac markers or ST-segment deviation. Patients at high risk for adverse cardiac events due to advanced age, congestive heart failure, or female gender were less likely to receive early GP IIb/IIIa inhibitor therapy. Patients who received early GP IIb/IIIa inhibitor therapy were more likely to receive other guidelines-recommended therapies.Despite the American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommendations, early GP IIb/IIIa inhibitor therapy remains underutilized in patients with NSTE ACS and administration of early GP IIb/IIIa inhibitors is directed toward lower-risk patients. Early GP IIb/IIIa inhibitor therapy is associated with improved overall adherence to the ACC/AHA guidelines.

  View details for DOI 10.1197/j.aem.2004.11.029

  View details for Web of Science ID 000228817100008

  View details for PubMedID 15863399

• Comparison of ST-segment resolution with combined fibrinolytic and glycoprotein IIb/IIIa inhibitor therapy versus fibrinolytic alone (data from four clinical trials) AMERICAN JOURNAL OF CARDIOLOGY Rebeiz, A. G., Johanson, P., Green, C. L., Crater, S. W., Roe, M. T., Langer, A., Giugliano, R. P., Lincoff, A. M., Newby, L. K., Harrington, R. A., Topol, E. J., Califf, R. M., Wagner, G. S., Krucoff, M. W. 2005; 95 (5): 611-614

  Abstract

  We compared combination fibrinolytic plus glycoprotein IIb/IIIa inhibitor therapy with stand-alone fibrinolysis with respect to speed and stability of reperfusion in patients who had acute ST-segment elevation myocardial infarction; data were obtained from 654 patients in 4 trials (Integrilin to Manage Platelet Aggregation to Combat Thrombosis in Acute Myocardial Infarction, Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction, Integrilin and Tenecteplase in Acute Myocardial Infarction, and the Fifth Global Use of Strategies to Open Occluded Coronary Arteries) that compared thrombolytics plus lamifiban, eptifibatide, or abciximab with standard thrombolysis. We found significantly faster and more stable ST-segment recovery with combination therapy starting at 60 minutes (56.7% vs 48.0% with >/=50% ST-segment resolution, p = 0.03) and sustained over 180 minutes after drug administration; this transient benefit may suggest a time frame when more optimal percutaneous coronary intervention can be performed.

  View details for DOI 10.1016/j.amjcard.2004.10.038

  View details for Web of Science ID 000227156400012

  View details for PubMedID 15721101

• Outcomes, Health Policy, and Managed Care - Influence of clinical trial enrollment on the quality of care and outcomes for patients with non-ST-segment elevation acute coronary syndromes AMERICAN HEART JOURNAL Kandzari, D. E., Roe, M. T., Chen, A. Y., Lytle, B. L., Pollack, C. V., Harrington, R. A., Ohman, E. M., Gibler, W. B., Peterson, E. D. 2005; 149 (3): 474-?

  View details for DOI 10.1016/j.ahj.2004.11.014

  View details for Web of Science ID 000228487800015

• First experience with direct, selective factor Xa inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XaNADU-ACS trial JOURNAL OF THROMBOSIS AND HAEMOSTASIS Alexander, J. H., Yang, H., Becker, R. C., Kodama, K., Goodman, S., Dyke, C. K., Kleiman, N. S., Hochman, J. S., Berger, P. B., Cohen, E. A., Lincoff, A. M., Burton, J. R., Bovill, E. G., Kawai, C., Armstrong, P. W., Harrington, R. A. 2005; 3 (3): 439-447

  Abstract

  Unfractionated heparin is widely used in patients with non-ST-elevation acute coronary syndromes but has important limitations. Anticoagulants with predictable kinetics and anticoagulant effects, better efficacy, and greater safety are needed.To investigate the efficacy and safety of a direct, selective factor Xa inhibitor, DX-9065a (Daiichi Pharmaceuticals LTD, Inc.) compared with heparin, in patients with non-ST-elevation acute coronary syndromes.Patients (n = 402) from the USA, Canada, and Japan were randomized to blinded, weight-adjusted heparin, low-dose DX-9065a, or high-dose DX-9065a.The primary efficacy endpoint of death, myocardial infarction, urgent revascularization, or ischemia on continuous ST-segment monitoring occurred in 33.6%, 34.3%, and 31.3% of patients assigned to heparin, low-dose DX-9065a, and high-dose DX-9065a (P = 0.91 for heparin vs. combined DX-9065a). The composite of death, myocardial infarction, or urgent revascularization occurred in 19.5%, 19.3%, and 11.9% (P = 0.125 for heparin vs. high-dose DX-9065a) of patients; major or minor bleeding occurred in 7.7%, 4.2%, and 7.0% of patients; and major bleeding in 3.3%, 0.8%, and 0.9% of patients. Higher concentrations of DX-9065a were associated with a lower likelihood of ischemic events (P = 0.03) and a non-significant tendency toward a higher likelihood of major bleeding (P = 0.32).In this small phase II trial, there was a non-significant tendency toward a reduction in ischemic events and bleeding with DX-9065a compared with heparin in patients with acute coronary syndromes. The absence of an effect on ST-monitor ischemia warrants further investigation. These data provide the rationale for adequately powered studies of DX-9065a in acute coronary syndromes or percutaneous intervention.

  View details for Web of Science ID 000227685500006

  View details for PubMedID 15748230

• Angiographic and clinical outcomes associated with direct versus conventional stenting among patients treated with fibrinolytic therapy for ST-elevation acute myocardial infarction AMERICAN JOURNAL OF CARDIOLOGY Ly, H. Q., Kirtane, A. J., Buros, J., Giugliano, R. P., Popma, J. J., Antman, E. M., Harrington, R. A., Ohman, E. M., Gibson, C. M. 2005; 95 (3): 383-386

  Abstract

  The present study reports outcomes of direct stenting versus conventional stenting, which was performed during adjunctive/rescue percutaneous coronary intervention (n = 556) in the Integrilin and Tenecteplase in Acute Myocardial Infarction trial, the Enoxaparin as Adjunctive Antithrombin Therapy for ST-Elevation Myocardial Infarction-Thrombolysis in Myocardial Infarction 23 trial, and the Fibrinolytic and Aggrastat ST-Elevation Resolution trial of fibrinolytic therapy in ST-elevation myocardial infarction. Direct stenting was associated with a lower rate of death, myocardial infarction, or congestive heart failure during hospitalization and at 30 days and was independently associated with improved in-hospital outcomes (odds ratio 0.44, 95% confidence interval 0.23 to 0.85, p = 0.014).

  View details for DOI 10.1016/j.amjcard.2004.09.038

  View details for Web of Science ID 000226679800014

  View details for PubMedID 15670549

• Outcomes of patients with acute coronary syndromes and prior percutaneous coronary intervention: a pooled analysis of three randomized clinical trials EUROPEAN HEART JOURNAL Labinaz, M., Mathias, J., Pieper, K., Granger, C. B., Lincoff, A. M., Moliterno, D. J., Van de Werf, F., Simes, J., White, H. D., Simoons, M. L., Califf, R. M., Topol, E. J., Armstrong, P. W., Harrington, R. A. 2005; 26 (2): 128-136

  Abstract

  We sought to characterize the outcomes of patients with a prior percutaneous coronary intervention (PCI) who presented with a non-ST-segment elevation acute coronary syndrome (ACS).We analysed the 30 and 180 day outcomes of 3012 patients with prior PCI and 21 154 patients without prior PCI enrolled in three randomized ACS trials (GUSTO IIb, PURSUIT, and PARAGON-B). The median (25th, 75th percentile) interval between the prior PCI and randomization was 647 (123, 1585) days. Patients with prior PCI had significantly more adverse baseline clinical characteristics, left ventricular dysfunction, and multi-vessel coronary artery disease. After adjusting for baseline characteristics and treatment, we found that patients with prior PCI had a significantly lower mortality rate at 30 days [hazard ratio (HR), 0.60; 95% confidence interval (CI), 0.45-0.80; P=0.0006] and 180 days (HR, 0.81; 95% CI, 0.66-0.98; P=0.029). However, no difference was observed in the composite of death or myocardial infarction (MI) at 30 days (HR, 0.95; 95% CI, 0.83-1.08; P=0.42) or 180 days (HR, 1.01; 95% CI, 0.90-1.13; P=0.90). Patients with prior PCI had a higher rate of MI at 180 days (13.3 vs. 12.0%; P=0.045). Prior-PCI patients had lower incidences of in-hospital cardiogenic shock, congestive heart failure (CHF), and atrial fibrillation.Patients with prior PCI who present with non-ST-segment elevation ACS have a lower mortality rate than those without prior PCI.

  View details for DOI 10.1093/eurheartj/ehi061

  View details for Web of Science ID 000228892000007

  View details for PubMedID 15618068

• Vascular endothelial tissue factor pathway inhibitor kinetics in culture following exposure to DX-9065a - A selective and direct factor Xa inhibitor JOURNAL OF THROMBOSIS AND THROMBOLYSIS Becker, R. C., Alexander, J. H., Li, Y. F., Robertson, T., Kunitada, S., Spencer, F. A., Yang, H. Q., Harrington, R. A. 2005; 18 (3): 193-197

  View details for DOI 10.1007/s11239-005-0345-6

  View details for Web of Science ID 000228277300005

• Utilization of early invasive management strategies for high-risk patients with non-ST-segment elevation acute coronary syndromes - Results from the CRUSADE quality improvement initiative JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Bhatt, D. L., Roe, M. T., Peterson, E. D., Li, Y., Chen, A. Y., Harrington, R. A., Greenbaum, A. B., Berger, P. B., Cannon, C. P., Cohen, D. J., Gibson, C. M., Saucedo, J. F., Kleiman, N. S., Hochman, J. S., Boden, W. E., Brindis, R. G., Peacock, W. F., Smith, S. C., Pollack, C. V., Gibler, W. B., Ohman, E. M. 2004; 292 (17): 2096-2104

  Abstract

  The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of non-ST-segment elevation acute coronary syndromes (NSTE ACS) recommend early invasive management for high-risk patients, given the benefits with this approach demonstrated in randomized clinical trials.To determine the use and predictors of early invasive management strategies (cardiac catheterization <48 hours following presentation) in high-risk patients with NSTE ACS and to examine the association of early invasive management with mortality.The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) Quality Improvement Initiative evaluated care patterns and outcomes for 17,926 high-risk NSTE ACS patients (positive cardiac markers and/or ischemic electrocardiographic changes) based on ACC/AHA guidelines recommendations at 248 US hospitals with catheterization and revascularization facilities between March 2000 and September 2002.Use of early invasive management within 48 hours of presentation, predictors of early invasive management, and in-hospital mortality. Results Of the 17,926 patients analyzed, 8037 (44.8%) underwent early cardiac catheterization less than 48 hours following presentation. Predictors of early invasive management included cardiology care, younger age, lack of prior or current congestive heart failure, lack of renal insufficiency, ischemic electrocardiographic changes, positive cardiac markers, white race, and male sex. Patients treated with early invasive management were more likely to be treated with medications and interventions recommended by the ACC/AHA guidelines and had a lower risk of in-hospital mortality after adjusting for differences in clinical characteristics and after comparing propensity-matched pairs (2.5% vs 3.7%, P<.001). Conclusions An early invasive management strategy is not utilized in the majority of high-risk patients with NSTE ACS. This strategy appears to be reserved for patients without significant comorbidities and those cared for by cardiologists and is associated with a lower risk of in-hospital mortality.

  View details for Web of Science ID 000224921900022

  View details for PubMedID 15523070

• Care of non-ST-segment elevation patients: Insights from the CRUSADE national quality improvement initiative 1st International Quality Improvement Summit on Acute Coronary Syndromes Ohman, E. M., Roe, M. T., Smith, S. C., Brindis, R. G., Christenson, R. H., Harrington, R. A., Gibler, W. B., Peterson, E. D. MOSBY-ELSEVIER. 2004: S34–S39

  Abstract

  Acute coronary syndromes (ACS), including non-ST-segment elevation (NSTE) ACS, represent a significant source of morbidity and mortality in the United States. To address this widespread, serious health problem, the American College of Cardiology and the American Heart Association (ACC/AHA) published guidelines for the treatment of NSTE ACS, which include unstable angina (UA) and NSTE myocardial infarction (NSTEMI). These ACC/AHA guidelines are intended to help physicians make appropriate decisions when diagnosing and treating patients with NSTE ACS.

  View details for DOI 10.1016/j.ahj.2004.09.013

  View details for Web of Science ID 000225160900003

  View details for PubMedID 15514632

• Antithrombotic therapy during percutaneous coronary intervention - The seventh ACCP Conference on antithrombotic and thrombolytic therapy CHEST Popma, J. J., Berger, P., Ohman, E. M., Harrington, R. A., Grines, C., Weitz, J. I. 2004; 126 (3): 576S-599S

  Abstract

  This chapter about antithrombotic therapy during percutaneous coronary intervention (PCI) is part of the seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients' values may lead to different choices (for a full understanding of the grading, see Guyatt et al, CHEST 2004;126:179S-187S). Among the key recommendations in this chapter are the following: For patients undergoing PCI, we recommend pretreatment with aspirin, 75 to 325 mg (Grade 1A). For long-term treatment after PCI, we recommend aspirin, 75 to 162 mg/d (Grade 1A). For long-term treatment after PCI in patients who receive antithrombotic agents such as clopidogrel or warfarin, we recommend lower-dose aspirin, 75 to 100 mg/d (Grade 1C+). For patients who undergo stent placement, we recommend the combination of aspirin and a thienopyridine derivative (ticlopidine or clopidogrel) over systemic anticoagulation therapy (Grade 1A). We recommend clopidogrel over ticlopidine (Grade 1A). For all patients undergoing PCI, particularly those undergoing primary PCI, or those with refractory unstable angina or other high-risk features, we recommend use of a glycoprotein (GP) IIb-IIIa antagonist (abciximab or eptifibatide) [Grade 1A]. In patients undergoing PCI for ST-segment elevation MI, we recommend abciximab over eptifibatide (Grade 1B). In patients undergoing PCI, we recommend against the use of tirofiban as an alternative to abciximab (Grade 1A). In patients after uncomplicated PCI, we recommend against routine postprocedural infusion of heparin (Grade 1A). For patients undergoing PCI who are not treated with a GP IIb-IIIa antagonist, we recommend bivalirudin over heparin during PCI (Grade 1A). In PCI patients who are at low risk for complications, we recommend bivalirudin as an alternative to heparin as an adjunct to GP IIb-IIIa antagonists (Grade 1B). In PCI patients who are at high risk for bleeding, we recommend that bivalirudin over heparin as an adjunct to GP IIb-IIIa antagonists (Grade 1B). In patients who undergo PCI with no other indication for systemic anticoagulation therapy, we recommend against routine use of vitamin K antagonists after PCI (Grade 1A).

  View details for Web of Science ID 000224298900017

  View details for PubMedID 15383485

• Antithrombotic therapy for coronary artery disease CHEST Harrington, R. A., Becker, R. C., Ezekowitz, A., Meade, T. W., O'Connor, C. M., Vorchheimer, D. A., Guyatt, G. H. 2004; 126 (3): 513S-548S

  View details for Web of Science ID 000224298900015

• Thrombolysis and adjunctive therapy in acute myocardial infarction CHEST Menon, V., Harrington, R. A., Hochman, J. S., Cannon, C. P., Goodman, S. D., Wilcox, R. G., Schunemann, H. J., Ohman, E. M. 2004; 126 (3): 549S-575S

  View details for Web of Science ID 000224298900016

• Highlights of the 53rd Annual Scientific Session of the American College of Cardiology - March 7-10, 2004 JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kushwaha, S. S., Bashore, T. M., Khandheria, B., Harrington, R. A., Ferguson, J. J., Hammill, S. C., Lavie, C. J., Murphy, D. J. 2004; 44 (2): 1A-1A

  View details for DOI 10.1016/j.jacc.2004.06.016

  View details for Web of Science ID 000222914200001

• 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

• Dynamic prognostication in non-ST-elevation acute coronary syndromes: Insights from GUSTO-llb and PURSUIT AMERICAN HEART JOURNAL Chang, W. C., Boersma, E., Granger, C. B., Harrington, R. A., Califf, R. M., Simoons, M. L., Kleiman, N. S., Armstrong, P. W. 2004; 148 (1): 62-71

  Abstract

  Risk assessment in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS) traditionally focuses on and is limited to admission findings. The objective of the current study was to develop an approach to predicting outcome in NSTE-ACS that could account for the changing nature of risk.In 7294 of 8010 patients with NSTE-ACS and complete electrocardiographic data in the GUSTO-IIb trial, we predicted the mortality probability at days 0-2, 0-30, 3-30, 5-30, and 7-30 using multiple logistic regression. Resulting risk estimates were incorporated into a composite, dynamic model to estimate the effects of changing probabilities over time. These models were validated against an independent sample of 9461 patients from the PURSUIT trial.As time passed after admission, the risk of 30-day death declined in stable patients. This risk, which was 3.72% at baseline, declined to 1.92% in 6-day survivors, and the risk reduction was greatest for those with the highest baseline risk. Importantly, however, the development of inhospital complications modified these trends. The use of dynamic models not only allowed us to estimate early (<48 h) mortality with a high degree of accuracy (C-index of 0.87), but also to continuously update the longer-term prognosis with increasing accuracy: the C-index increased from 0.75 for the day 0-30 model to 0.81 and 0.82 for the composite and day 7-30 models, respectively.Dynamic risk assessment is feasible and reliable. This approach can improve risk assessment and provide valuable guidance for management of patients with NSTE-ACS.

  View details for DOI 10.1016/j.ahj.2003.05.004

  View details for Web of Science ID 000222357700010

  View details for PubMedID 15215793

• Combined assessment of thrombolysis in myocardial infarction flow grade, myocardial perfusion grade, and st-segment resolution to evaluate epicardial and myocardial reperfusion AMERICAN JOURNAL OF CARDIOLOGY Giugliano, R. P., Sabatine, M. S., Gibson, C. M., Roe, M. T., Harrington, R. A., Murphy, S. A., Morrow, D. A., Antman, E. M., Braunwald, E. 2004; 93 (11): 1362-1367

  Abstract

  The restoration of epicardial and myocardial flow remains the primary goal of reperfusion therapy in patients with ST-segment elevation myocardial infarction, but the optimal method to assess this goal has not been defined. Thrombolysis In Myocardial Infarction flow grade (TFG), myocardial perfusion grade (MPG), and ST-segment resolution (STRes) were combined to formulate a new measure of successful reperfusion in 649 patients who received pharmacologic reperfusion therapy in 3 recent phase II clinical trials of ST-segment elevation myocardial infarction. Coronary angiograms and electrocardiograms were analyzed at 60 minutes (before any intervention) after the initiation of reperfusion therapy. The complete restoration of perfusion, or the "trifecta," defined as the presence of TFG 3, MPG 3, and complete (> or =70%) STRes, occurred in 117 patients (18%). The achievement of this trifecta was associated with low rates of 30-day mortality (0% vs 3.9%, p = 0.02), congestive heart failure (CHF) (0.9% vs 7.1%, p = 0.01), and the combination of death or CHF (0.9% vs 10.7%, p = 0.001). When the results were stratified with respect to subsequent percutaneous coronary intervention (PCI) from 60 to 120 minutes, attainment of the trifecta at 60 minutes remained a strong predictor of better clinical outcomes, particularly in those patients who underwent early PCI. The achievement of TFG 3, MPG 3, and complete STRes at 60 minutes after fibrinolytic therapy and before PCI occurred in only 18% of patients but was associated with very low rates of death and CHF at 30 days. This new end point is proposed to evaluate the success of reperfusion therapy in patients who undergo early angiography.

  View details for DOI 10.1016/j.amjcard.2004.02.031

  View details for Web of Science ID 000221815100006

  View details for PubMedID 15165915

• Six-month outcomes of percutaneous coronary balloon angioplasty in acute coronary syndromes: Results from the PURSUIT trial CANADIAN JOURNAL OF CARDIOLOGY Labinaz, M., Kaul, P., Harrington, R. A., Chang, W. C., Kleiman, N. S., Simoons, M. L., Boersma, E., Akkerhuis, M., Califf, R. M., Armstrong, P. W. 2004; 20 (8): 773-778

  Abstract

  Potent inhibition of the platelet glycoprotein IIb/IIIa receptor has improved the acute outcome of patients presenting with acute coronary syndromes (ACS). For patients with ACS undergoing percutaneous balloon angioplasty without coronary stenting in the era of platelet glycoprotein IIb/IIIa blockade, the long-term prognosis is less clear.To examine the six-month outcome of patients who received eptifibatide within a randomized clinical trial and subsequently underwent balloon angioplasty.Patients included in this substudy were enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, a randomized study evaluating the efficacy of eptifibatide in reducing the incidence of death or nonfatal myocardial infarction (MI) in non-ST segment elevation ACS. During the index hospitalization, 1151 (12.2%) of the PURSUIT patients underwent percutaneous balloon angioplasty without coronary stenting.Eptifibatide was associated with a significant reduction in the adjudicated composite end point of death or MI at six months after randomization in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) (P=0.037). A trend toward a beneficial effect was evident before the procedure (4.7% versus 6.9%; P=0.13) and at 30 days (12.1% versus 15.3%; P=0.12). The incidence of repeat revascularization was relatively low for patients undergoing PTCA, with no difference observed between the eptifibatide and placebo groups (16.3% versus 14.8%; P=0.51).Eptifibatide was associated with a sustained beneficial effect to six months in patients with ACS undergoing PTCA. It reduced the incidence of preprocedural MI. The rate of repeat revascularization at six months was low and was not significantly altered by eptifibatide.

  View details for Web of Science ID 000222287100005

  View details for PubMedID 15229770

• Comparison of Bivalirudin versus heparin during percutaneous coronary intervention (the randomized evaluation of PCI linking angiomax to reduced clinical events [REPLACE]-1 trial) AMERICAN JOURNAL OF CARDIOLOGY Lincoff, A. M., Bittl, J. A., Kleiman, N. S., Sarembock, I. J., Jackman, J. D., Mehta, S., Tannenbaum, M. A., Niederman, A. L., Bachinsky, W. B., Tift-Mann, J., Parker, H. G., Kereiakes, D. J., Harrington, R. A., Feit, F., Maierson, E. S., Chew, D. P., Topol, E. J. 2004; 93 (9): 1092-1096

  Abstract

  To assess the efficacy of the direct thrombin inhibitor bivalirudin relative to heparin during contemporary coronary intervention, 1,056 patients who underwent elective or urgent revascularization were randomized in a large-scale pilot study to receive heparin (70 U/kg initial bolus) or bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/hour infusion during the procedure). All patients received aspirin; pretreatment with clopidogrel was encouraged, and glycoprotein (GP) IIb/IIIa blockade was at the physician's discretion. Stents were placed in 85% of patients; 72% received a GP IIb/IIIa inhibitor, and 56% were pretreated with clopidogrel. Activated clotting times were higher among patients randomized to bivalirudin than among those given heparin before device activation (median 359 vs 293 seconds, p <0.001). The composite efficacy end point of death, myocardial infarction, or repeat revascularization before hospital discharge or within 48 hours occurred in 5.6% and 6.9% of patients in the bivalirudin and heparin groups, respectively (p = 0.40). Major bleeding occurred in 2.1% versus 2.7% of patients randomized to bivalirudin or heparin, respectively (p = 0.52). This trial represents the largest prospective dataset of bivalirudin administered concomitantly with planned GP IIb/IIIa blockade and provides evidence of the safety and efficacy of this combined antithrombotic approach.

  View details for DOI 10.1016/j.amjcard.2004.01.033

  View details for Web of Science ID 000221140100003

  View details for PubMedID 15110198

• Association of the timing of ST-segment resolution with TIMI myocardial perfusion grade in acute myocardial infarction AMERICAN HEART JOURNAL Gibson, C. M., Karha, J., Giugliano, R. P., Roe, M. T., Murphy, S. A., Harrington, R. A., Green, C. L., Schweiger, M. J., Miklin, J. S., Baran, K. W., Palmeri, S., Braunwald, E., Krucoff, M. W. 2004; 147 (5): 847-852

  Abstract

  More complete ST-segment resolution (ST res) in acute myocardial infarction (MI) has been associated with better epicardial and myocardial reperfusion as assessed with the Thrombolysis in Myocardial Infarction (TIMI) flow grade (TFG) and the TIMI myocardial perfusion grade (TMPG), respectively. However, no data exist comparing the speed of ST resolution on continuous electrocardiogram (ECG) monitoring with the TMPG on coronary angiography. We hypothesized that delayed ST res is associated with impaired TMPGs.Continuous 12-lead ECG recordings and 60-minute angiographic data were analyzed in 120 patients with acute MI who received tenectaplase monotherapy or combination therapy with low-dose tenectaplase and eptifibatide in the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial.More rapid ST res on continuous ECG monitoring was associated with improved TMPGs on coronary angiography performed 60 minutes after study drug administration. For TMPG 3, the median time to ST resolution was 53 minutes. For TMPG 2, 1, and 0, the corresponding times were 64 minutes, 80 minutes, and 106 minutes, respectively (P =.01 for trend). Likewise, more rapid ST res was also associated with faster epicardial flow. For TFG 3, the median time to ST resolution was 46 minutes, compared with 109 minutes for TIMI flow grades 0 to 2 (P =.001). The corresponding times for a corrected TIMI frame count < or =40 versus >40 were 52 minutes and 112 minutes, respectively (P <.001).Although the static ECG has been associated with epicardial and myocardial blood flow in the past, this study extends these observations to demonstrate that more rapid ST res on continuous ECG monitoring is associated with improved myocardial perfusion after thrombolytic administration.

  View details for DOI 10.1016/j.ahj.2003.11.015

  View details for Web of Science ID 000221479100022

  View details for PubMedID 15131541

• Association of a pulsatile blood flow pattern on coronary arteriography and short-term clinical outcomes in acute myocardial infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Gibson, C. M., Karha, J., Murphy, S. A., de Lemos, J. A., Morrow, D. A., Giugliano, R. P., Roe, M. T., Harrington, R. A., Cannon, C. P., Antman, E. M., Califf, R. M., Braunwald, E. 2004; 43 (7): 1170-1176

  Abstract

  We hypothesized that recognition of systolic flow reversal (pulsatile flow) after thrombolytic administration on coronary angiography is associated with angiographic and electrocardiogram findings reflecting impaired myocardial perfusion, as well as poorer clinical outcomes.Reversal of systolic flow on Doppler velocity wire recordings has been associated with impaired tissue perfusion on myocardial contrast echocardiography in the setting of myocardial infarction (MI).Patients (n = 1,062) with a patent infarct-related artery were drawn from the Thrombolysis In Myocardial Infarction (TIMI) 10, TIMI 14, and Integrillin and Tenecteplase acute MI trials.Pulsatile flow (systolic flow reversal with cessation of antegrade contrast-dye motion or frank reversal of contrast-dye motion during systole) at 60 min after fibrinolytic administration was present in 11.0% of patients. Pulsatile flow was associated with higher corrected TIMI frame counts (slower epicardial flow) (median 40.1 frames, IQ 30 of 63 vs. 30 frames, interquartile 22 of 42, p < 0.0001), a closed microvasculature (TIMI myocardial perfusion grades 0 of 1, 57.1% vs. 37.8%, p = 0.03) and less complete (> or =70%) ST-segment resolution (23.5% vs. 58.9%, p = 0.008). Patients with pulsatile flow had a higher risk of death or reinfarction at 30 days (10.3% vs. 5.0%, p = 0.019). After controlling for age, pulse, blood pressure, anterior MI location, epicardial flow, and creatine kinase, pulsatile flow remained associated with an increased risk of death/MI (odds ratio 3.1, p = 0.006).A pulsatile pattern of flow is associated with impaired myocardial perfusion and poorer clinical outcomes independent of the velocity of antegrade flow in the epicardial artery. This simple and easily identifiable angiographic flow pattern may be useful in clinical risk stratification.

  View details for DOI 10.1016/j.jacc.2003.11.035

  View details for Web of Science ID 000220640400007

  View details for PubMedID 15063425

• Aspirin dose and six-month outcome after an acute coronary syndrome JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Quinn, M. J., Aronow, H. D., Calif, R. M., Bhatt, D. L., Sapp, S., Kleiman, N. S., Harrington, R. A., Kong, D. F., Kandzari, D. E., Topol, E. J. 2004; 43 (6): 972-978

  Abstract

  This study was designed to compare the efficacy of low and intermediate aspirin doses in acute coronary syndromes.Little is known of the comparative efficacy of low and intermediate aspirin doses in this setting.We compared six-month death, myocardial infarction (MI), and stroke in patients with unstable angina or acute MI discharged while receiving low (<150 mg) or intermediate (> or =150 mg) aspirin therapy in the GUSTO IIb and PURSUIT trials (n = 20,521). We used multivariable analysis and performed a propensity analysis in order to adjust for baseline imbalances between the groups.Aspirin doses <150 mg were prescribed to 29.9% (6,128) of patients. By six months, 6.4% of the patients (1,310 of 20,521) had a primary event, 6.2% of the patients receiving <150 mg and 6.6% of the patients receiving aspirin doses > or =150 mg (hazard ratio [HR] 1.06 [95% confidence interval (CI) 0.94 to 1.19], p = 0.35). After adjusting for baseline imbalances and the propensity score for discharge aspirin dose, there was no effect of aspirin dose on the composite end point at six months (HR 0.92 [95% CI 0.79 to 1.07], p = 0.28). However, the higher aspirin dose was associated with a reduction in six-month MI (HR 0.79 [95% CI 0.64 to 0.98], p = 0.03). The outcome was similar when patients were matched on the basis of the propensity score for aspirin dose (HR for death/MI/stroke 0.94 [95% CI 0.80 to 1.12], p = 0.51), although stroke occurred significantly more frequently among patients receiving the higher aspirin dose (HR 1.74 [95% CI 1.01 to 3.02] p = 0.05) and the effect on MI was no longer apparent.Although these data are non-randomized, they suggest that the aspirin dose upon discharge may influence the clinical course after unstable angina or acute MI.

  View details for DOI 10.1016/j.jacc.2003.09.059

  View details for Web of Science ID 000220212400007

  View details for PubMedID 15028352

• Improved clinical outcomes with abciximab therapy in acute myocardial infarction: A systematic overview of randomized clinical trials AMERICAN HEART JOURNAL Kandzari, D. E., Hasselblad, V., Tcheng, J. E., Stone, G. W., Califf, R. M., Kastrati, A., Neumann, F. J., Brener, S. J., Montalescot, G., Kong, D. F., Harrington, R. A. 2004; 147 (3): 457-462

  Abstract

  Investigations of glycoprotein (GP) IIb/IIIa inhibition in primary percutaneous coronary intervention (PCI) have suggested the efficacy of abciximab in improving clinical and angiographic outcomes, but sample-size limitations and variability in trial design preclude the ability to generalize these results to a broader patient population.Meta-analytic techniques were used to evaluate clinical outcomes from randomized trials comparing GP IIb/IIIa inhibition with placebo or control therapy in primary PCI for acute myocardial infarction (MI).In 3266 patients, treatment with abciximab significantly reduced the 30-day composite end point of death, reinfarction, or ischemic or urgent target-vessel revascularization (TVR; odds ratio [OR], 0.54; 95% CI, 0.40-0.72), with trends toward reduced 30-day death and death or reinfarction. Abciximab resulted in an increased likelihood of major bleeding (OR, 1.74; 95% CI, 1.11-2.72). By 6 months, abciximab significantly reduced the occurrence of death, reinfarction, or any TVR (OR, 0.80; 95% CI, 0.67-0.97), and there were positive trends favoring a decrease in mortality alone and the composite of death or reinfarction.Treatment with abciximab significantly reduces early adverse ischemic events, a clinical benefit that is maintained at 6-month follow-up. These findings support the use of adjunctive GP IIb/IIIa inhibition in primary PCI.

  View details for DOI 10.1016/j.ahj.2003.08.011

  View details for Web of Science ID 000220539400017

  View details for PubMedID 14999194

• Economic impact of drug-eluting stents on hospital systems: A disease-state model AMERICAN HEART JOURNAL Kong, D. F., Eisenstein, E. L., Sketch, M. H., Zidar, J. P., RYAN, T. J., Harrington, R. A., Newman, M. F., Smith, P. K., Mark, D. B., Califf, R. M. 2004; 147 (3): 449-456

  Abstract

  Drug-eluting intracoronary stents decrease restenosis and later revascularization. The US Department of Health and Human Services (HHS), recognizing the financial and clinical impact of this technology, recently proposed accelerated reimbursement to hospitals.A disease state-transition computer model simulated the clinical and economic consequences to hospitals of drug-eluting stents over 5 years. Model parameters combined information from a longitudinal clinical database, a hospital cost-accounting system, and a survey instrument. Simulations were repeated 1000 times for each set of parameters. With 85% of stent procedures shifted to drug-eluting stents in the first year of availability, the mean number of repeat revascularizations dropped by 60.4% at year 5. With no changes in reimbursement policy, a hospital with a catheterization laboratory volume of 3112 patients yearly converted from a 2.01 million dollars (M) annual profit to an 8.10 M dollars loss in the first year (95% CI 8.09 M dollars to 8.12 M dollars) and 8.7 M dollars annual losses in later years. This represented an overall change in cash flow of 55.71 M dollars (95% CI 55.66 M dollars to 55.76 M dollars) away from the hospital over 5 years. The incremental reimbursement proposed by HHS reduced this loss to 4.75 M dollars in the first year and to 5.6 M dollars annually thereafter. In sensitivity analyses, the conversion of patients from bypass surgery to drug-eluting stents was the largest driver of overall cash flow shifts.Although Medicare has proposed to increase reimbursement to ease the impact of drug-eluting stents on hospitals, this increase will not totally offset the costs.

  View details for DOI 10.1016/j.ahj.2003.11.005

  View details for Web of Science ID 000220539400016

  View details for PubMedID 14999193

• Feasibility of endovascular cooling as an adjunct to primary percutaneous coronary intervention (results of the LOWTEMP pilot study) AMERICAN JOURNAL OF CARDIOLOGY Kandzari, D. E., Chu, A., Brodie, B. R., Stuckey, T. A., Hermiller, J. B., Vetrovec, G. W., Hannan, K. L., Krucoff, M. W., Christenson, R. H., Gibbons, R. J., Sigmon, K. N., Garg, J., Hasselblad, V., Collins, K., Harrington, R. A., Berger, P. B., Chronos, N. A., Hochman, J. S., Califf, R. M. 2004; 93 (5): 636-639

  Abstract

  In a nonrandomized feasibility study of therapeutic hypothermia in acute myocardial infarction, 18 patients were treated with endovascular cooling (Alsius, Irvine, California) as adjunctive therapy to primary percutaneous coronary intervention to assess measures of infarct size (area under the curve creatinine kinase-MB and technetium-99m single-photon emission computed tomography sestamibi) and the quality of myocardial perfusion (continuous ST-segment monitoring). Periprocedural endovascular cooling successfully decreased core body temperature (median 33.5 degrees C) and was well tolerated, which supports the evaluation of adjunctive hypothermia in pivotal trials to limit infarct size and decrease reperfusion injury.

  View details for DOI 10.1016/j.amjcard.2003.11.038

  View details for Web of Science ID 000220075800027

  View details for PubMedID 14996598

• Improved speed and stability of ST-segment recovery with reduced-dose tenecteplase and eptifibatide compared with full-dose tenecteplase for acute ST-segment elevation myocardial infarction JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Roe, M. T., Green, C. L., Giugliano, R. P., Gibson, C. M., Baran, K., Greenberg, M., Palmeri, S. T., Crater, S., Trollinger, K., Hannan, K., Harrington, R. A., Krucoff, M. W. 2004; 43 (4): 549-556

  Abstract

  This sub-study of the Integrilin and Tenecteplase in Acute Myocardial Infarction (INTEGRITI) trial evaluated of the impact of combination reperfusion therapy with reduced-dose tenecteplase plus eptifibatide on continuous ST-segment recovery and angiographic results.Combination therapy with reduced-dose fibrinolytics and glycoprotein IIb/IIIa inhibitors for ST-segment elevation myocardial infarction improves biomarkers of reperfusion success but has not reduced mortality when compared with full-dose fibrinolytics.We evaluated 140 patients enrolled in the INTEGRITI trial with 24-h continuous 12-lead ST-segment monitoring and angiography at 60 min. The dose-combination regimen of 50% of standard-dose tenecteplase (0.27 microg/kg) plus high-dose eptifibatide (2 boluses of 180 microg/kg separated by 10 min, 2.0 microg/kg/min infusion) was compared with full-dose tenecteplase (0.53 microg/kg).The dose-confirmation regimen of reduced-dose tenecteplase plus high-dose eptifibatide was associated with a faster median time to stable ST-segment recovery (55 vs. 98 min, p = 0.06), improved stable ST-segment recovery by 2 h (89.6% vs. 67.7%, p = 0.02), and less recurrent ischemia (34.0% vs. 57.1%, p = 0.05) when compared with full-dose tenecteplase. Continuously updated ST-segment recovery analyses demonstrated a modest trend toward greater ST-segment recovery at 30 min (57.7% vs. 40.6%, p = 0.13) and 60 min (82.7% vs. 65.6%, p = 0.08) with this regimen. These findings correlated with improved angiographic results at 60 min.Combination therapy with reduced-dose tenecteplase and eptifibatide leads to faster, more stable ST-segment recovery and improved angiographic flow patterns, compared with full-dose tenecteplase. These findings question the relationship between biomarkers of reperfusion success and clinical outcomes.

  View details for DOI 10.1016/j.jacc.2003.09.039

  View details for Web of Science ID 000188944600008

  View details for PubMedID 14975462

• Differential treatment benefit of platelet glycoprotein IIb/IIIa inhibition with percutaneous coronary intervention versus medical therapy for acute coronary syndromes - Exploration of methods CIRCULATION Pieper, K. S., Tsiatis, A. A., Davidian, M., Hasselblad, V., Kleiman, N. S., Boersma, E., Chang, W. C., Griffin, J., Armstrong, P. W., Califf, R. M., Harrington, R. A. 2004; 109 (5): 641-646

  Abstract

  Although many believe that platelet glycoprotein IIb/IIIa inhibitors should be used only in acute coronary syndrome patients undergoing percutaneous coronary intervention, supporting data from randomized clinical trials are tenuous. The assumption that these agents are useful only in conjunction with percutaneous coronary intervention is based primarily on inappropriate subgroup analyses performed across the glycoprotein IIb/IIIa inhibitor trials.We describe the problems with these analytical techniques and demonstrate that different approaches to the question can result in opposing answers.Clinical-practice decisions and practice guidelines should be based on overall trial results and not analyses of post-randomization subgroups.

  View details for DOI 10.1161/01.CIR.0000112570.97220.89

  View details for Web of Science ID 000188836600016

  View details for PubMedID 14769687

• 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

• Conflict of interest AMERICAN HEART JOURNAL Holmes, D. R., Firth, B. G., James, A., Winslow, R., Hodgson, P. K., Gamble, G. L., Popp, R. L., Harrington, R. A. 2004; 147 (2): 228-237

  Abstract

  The clinical research enterprise is increasingly scrutinized, in part because of the issue of conflict of interest. The issue is broad and its implications touch on a wide range of concerns, from the safety of patient care to the viability of a large industry. Numerous constituencies are affected by conflict of interest, and representatives of all of them convened in November 2002 for a one-and-a-half day discussion of the issues as well as possible solutions to both the perception and the actuality of such conflict. Participants included medical journal editors, news reporters, physician investigators, representatives of institutional conflict-of-interest oversight committees, representatives of the medical products industry, and Federal regulators. The resulting manuscript provides a review of the issues as well as desirable ways for each of the players to monitor themselves; each section thus contains provocative recommendations for eliminating conflict of interest to ensure that our vibrant health care system continues to foster exciting new advances to improve patient care.

  View details for DOI 10.1016/j.ahj.2003.12.001

  View details for Web of Science ID 000220253900011

  View details for PubMedID 14760318

• Initial experience with factor-Xa inhibition in percutaneous coronary intervention: the XaNADU-PCI pilot JOURNAL OF THROMBOSIS AND HAEMOSTASIS Alexander, J. H., Dyke, C. K., Yang, H., Becker, R. C., Hasselblad, V., Zillman, L. A., Kleiman, N. S., Hochman, J. S., Berger, P. B., Cohen, E. A., Lincoff, A. M., Saint-Jacques, H., Chetcuti, S., Burton, J. R., Buergler, J. M., Spence, F. P., Shimoto, Y., Robertson, T. L., Kunitada, S., Bovill, E. G., Armstrong, P. W., Harrington, R. A. 2004; 2 (2): 234-241

  Abstract

  Direct factor (F)Xa inhibition is an attractive method to limit thrombotic complications during percutaneous coronary intervention (PCI).To investigate drug levels achieved, effect on coagulation markers, and preliminary efficacy and safety of several doses of DX-9065a, an intravenous, small molecule, direct, reversible FXa inhibitor during PCI.Patients undergoing elective, native-vessel PCI (n = 175) were randomized 4 : 1 to open-label DX-9065a or heparin in one of four sequential stages. DX-9065a regimens in stages I-III were designed to achieve concentrations of > 100 ng mL-1, > 75 ng mL-1, and > 150 ng mL-1. Stage IV used the stage III regimen but included patients recently given heparin.At 15 min median (minimum) DX-9065a plasma levels were 192 (176), 122 (117), 334 (221), and 429 (231) ng mL-1 in stages I-IV, respectively. Median whole-blood international normalized ratios (INRs) were 2.6 (interquartile range 2.5, 2.7), 1.9 (1.8, 2.0), 3.2 (3.0, 4.1), and 3.8 (3.4, 4.6), and anti-FXa levels were 0.36 (0.32, 0.38), 0.33 (0.26, 0.39), 0.45 (0.41, 0.51), and 0.62 (0.52, 0.65) U mL-1, respectively. Stage II enrollment was stopped (n = 7) after one serious thrombotic event. Ischemic and bleeding events were rare and, in this small population, showed no clear relation to DX-9065a dose.Elective PCI is feasible using a direct FXa inhibitor for anticoagulation. Predictable plasma drug levels can be rapidly obtained with double-bolus and infusion DX-9065a dosing. Monitoring of DX-9065a may be possible using whole-blood INR. Direct FXa inhibition is a novel and potentially promising approach to anticoagulation during PCI that deserves further study.

  View details for Web of Science ID 000189249200006

  View details for PubMedID 14995984

• 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

• GP IIb/IIIa blockade in elective percutaneous coronary intervention CURRENT PHARMACEUTICAL DESIGN Dery, J. P., Harrington, R. A., Tcheng, J. E. 2004; 10 (4): 387-398

  Abstract

  Cumulative scientific evidence gathered over the past ten years has confirmed the role of platelet GP IIb/IIIa inhibitors in reducing ischemic complications of patients undergoing percutaneous coronary intervention (PCI). Recently, mortality data available on more than 20,000 patients enrolled in randomized clinical trials suggest that GP IIb/IIIa blockade also improves short and long-term survival after PCI. Despite convincing arguments, GP IIb/IIIa inhibitors are still inconsistently administered in patients undergoing coronary intervention. The following review will discuss the scientific grounds and the principal controversies surrounding the use of these compounds in patients undergoing elective percutaneous coronary intervention.

  View details for Web of Science ID 000188439200007

  View details for PubMedID 14965200

• Evaluating the benefits of glycoprotein, IIb/IIIa inhibitors in heart failure at baseline in acute coronary syndromes AMERICAN HEART JOURNAL Srichai, M. B., Jaber, W. A., Prior, D. L., Marso, S. P., Houghtaling, P. L., Menon, V., Simoons, M. L., Harrington, R. A., Hochman, J. S. 2004; 147 (1): 84-90

  Abstract

  We evaluated whether the use of glycoprotein IIb/IIIa receptor inhibitors, in addition to heparin and aspirin, imparts an incremental benefit in a subgroup of patients with acute coronary syndromes (ACS) who had congestive heart failure (CHF) symptoms at presentation.We analyzed patients enrolled in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, a randomized, double-blind, placebo-controlled study evaluating the use of eptifibatide versus placebo for patients with ACS without persistent ST-elevation. We compared the clinical characteristics and 30-day outcomes for 861 patients who had Killip class II or III CHF symptoms with those of 8558 patients who had no CHF symptoms.Odds ratios for the primary end point, 30-day death or non-fatal myocardial infarction, in the placebo group versus the eptifibatide group were similar for patients with and without CHF (odds ratio, 1.11; 95% CI, 0.8-1.5; odds ratio, 1.13; 95% CI, 1.0-1.3). However, adverse events were almost twice as frequent for patients with CHF compared with patients with no CHF (24.5% vs 14%).Although patients with non-ST-segment elevation ACS who have CHF have markedly worse outcomes than patients without CHF symptoms, we did not find an incremental benefit from the use of eptifibatide in this seriously ill subgroup.

  View details for DOI 10.1016/S0002-8703(03)00530-1

  View details for Web of Science ID 000220253800016

  View details for PubMedID 14691424

• Changing the model of care for patients with acute coronary syndromes AMERICAN HEART JOURNAL Roe, M. T., Ohman, E. M., Pollack, C. V., Peterson, E. D., Brindis, R. G., Harrington, R. A., Christenson, R. H., Smith, S. C., Califf, R. M., Gibler, W. B. 2003; 146 (4): 605-612

  Abstract

  Acute coronary syndromes (ACS) represent a major cause of morbidity and mortality for patients with cardiovascular disease, but evidence-based therapies shown to improve outcomes for ACS are often underused in clinically eligible patients. Although clinical practice guidelines have been developed to provide standards for the diagnosis and treatment of patients with ACS and to provide physicians with a framework for clinical decision-making, multiple obstacles have hindered their implementation and questions remain about the applicability of guidelines for diverse clinical situations. Systematic reviews of quality-improvement studies have shown that multifaceted approaches using targeted educational interventions, creation of quality standards, and regular performance feedback are needed to ensure sustained improvements in care. Approaches to quality improvement thus are being redirected to focus on multidisciplinary collaborations designed to improve the entire process of care for patients with ACS. Multiple large observational registries and quality-improvement initiatives now are capturing data regarding adherence to practice guidelines and contemporary patterns of care for ACS. This comprehensive evaluation of ACS treatment will help guide efforts designed to promote evidence-based care and ultimately determine the effect of widespread implementation of practice guidelines on clinical outcomes. The shifting model of care for ACS therefore suggests that quality improvement and monitoring of adherence to practice guidelines should be considered components of optimal clinical practice.

  View details for DOI 10.1016/S0002-8703(03)00388-0

  View details for Web of Science ID 000186019200009

  View details for PubMedID 14564312

• Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions AMERICAN JOURNAL OF CARDIOLOGY Kong, D. F., Hasselblad, V., Harrington, R. A., White, H. D., Tcheng, J. E., Kandzari, D. E., Topol, E. J., Califf, R. M. 2003; 92 (6): 651-655

  Abstract

  We performed a cumulative meta-analysis of available studies to evaluate the effect of intravenous platelet glycoprotein (GP) IIb/IIIa antagonists on survival at 30 days and 6 months after percutaneous coronary intervention (PCI). Compounds that block the GP IIb/IIIa receptor substantially reduce myocardial infarctions (MIs) and repeat revascularization. We included 12 trials, which enrolled 20,186 patients in all, in the analysis. Overall, 30-day mortality was significantly reduced with GP IIb/IIIa inhibition (odds ratio 0.73, 95% confidence interval 0.55 to 0.96, p = 0.024). Although 10 of the 12 trials showed a beneficial effect of GP IIb/IIIa inhibitor treatment on mortality, no individual trial detected a statistically significant mortality benefit. The 30-day mortality benefit became significant at the p <0.05 level with addition of the ADMIRAL trial and was further enhanced by the CADILLAC trial. No significant heterogeneity was detected in the collection of trials. At 6 months, the odds ratio was 0.84 (95% confidence interval 0.69 to 1.03, p = 0.087). This survival benefit amounts to preventing approximately 1 of every 3 deaths that occur within 30 days after PCI, saving 2.8 lives/1,000 patients treated (number needed to treat, 357). Thus, patients who undergo PCI can expect significantly lower 30-day mortality, in addition to known reductions in nonfatal MI and repeat procedures, with GP IIb/IIa inhibition. There also is increasing evidence that mortality reductions are preserved at 6 months.

  View details for DOI 10.1016/S002-9149(03)00816-6

  View details for Web of Science ID 000185330800001

  View details for PubMedID 12972100

• Reduction of myocardial ischemic injury following coronary intervention (The MC-1 to eliminate necrosis and damage trial) AMERICAN JOURNAL OF CARDIOLOGY Kandzari, D. E., Labinaz, M., Cantor, W. J., Madan, M., Gallup, D. S., Hasselblad, V., Joseph, D., Allen, A., Green, C., Hidinger, K. G., Krucoff, M. W., Christenson, R. H., Harrington, R. A., Tcheng, J. E. 2003; 92 (6): 660-664

  Abstract

  Myocardial ischemic injury complicating acute myocardial infarction (AMI) and coronary revascularization procedures remains an unresolved clinical dilemma. In preclinical studies, treatment with pyridoxal-5'-phosphate monohydrate (MC-1), a vitamin B6 metabolite, has demonstrated cardioprotective effects. Sixty patients scheduled for elective percutaneous coronary intervention (PCI) who had clinically high-risk characteristics for ischemic complications were randomized to treatment with MC-1 or placebo in a 2:1 double-blinded fashion. The primary end point was defined as infarct size as measured by area under the curve creatine kinase MB (CK-MB) enzymes. Secondary end points included periprocedural ischemia as assessed by continuous electrocardiographic monitoring, 30-day major adverse cardiac events, and net clinical safety, which included liver function testing. The primary end point, median periprocedural CK-MB area under the curve, was reduced from 32.9 ng/ml in the placebo group to 18.6 ng/ml with MC-1 treatment (p = 0.038), reflecting a shift in the distribution of CK-MB. By categorical classification, the occurrence of 30-day nonfatal AMI did not differ between groups. There were no deaths, and 30-day composite adverse event rates were similar (17.9% MC-1 vs 15.0% placebo, p = 1.0). There were no significant differences in ischemia parameters per continuous electrocardiographic monitoring, and no safety issues were identified. In this phase II pilot study, treatment of high-risk patients who underwent PCI with MC-1 was associated with a decrease in the total amount of CK-MB released after PCI. These results support the evaluation of MC-1 in pivotal trials of patients at risk for developing myocardial ischemia, infarction, or reperfusion injury.

  View details for DOI 10.1016/S0002-91-9149(03)00818-X

  View details for Web of Science ID 000185330800003

  View details for PubMedID 12972102

• Association between admission white blood cell count and one-year mortality in patients with acute coronary syndromes AMERICAN JOURNAL OF MEDICINE Yen, M. H., Bhatt, D. L., Chew, D. P., Harrington, R. A., Newby, L. K., Ardissino, D., Van de Werf, F., White, J. A., Moliterno, D. J., Topol, E. J. 2003; 115 (4): 318-321

  View details for DOI 10.1016/S0002-9343(03)00358-9

  View details for Web of Science ID 000185332100009

  View details for PubMedID 12967697

• Frequency of stent thrombosis after acute coronary syndromes (from the SYMPHONY and 2nd SYMPHONY trials) AMERICAN JOURNAL OF CARDIOLOGY Tolleson, T. R., Newby, L. K., Harrington, R. A., Bhapkar, M. V., Verheught, F. W., Berger, P. B., Moliterno, D. J., White, H. D., Ohman, E. M., Van de Werf, F., Topol, E. J., Califf, R. M. 2003; 92 (3): 330-333

  Abstract

  We studied stent thrombosis in 4,607 patients with acute coronary syndromes who received a coronary stent as part of routine care during 2 trials of aspirin versus sibrafiban for secondary prevention. In these patients, stent thrombosis occurred more often than in previous patients who underwent elective percutaneous coronary intervention. These patients and their outcomes may be more representative of patients with typical acute coronary syndromes undergoing stenting in clinical practice.

  View details for DOI 10.1016/s0002-9149(03)00641-6

  View details for Web of Science ID 000184503800024

  View details for PubMedID 12888148

• Randomized, double-blind, placebo-controlled, international trial of the oral IIb/IIIa antagonist lotrafiban in coronary and cerebrovascular disease CIRCULATION Topol, E. J., Easton, D., Harrington, R. A., Amarenco, P., Califf, R. M., Graffagnino, C., Davis, S., Diener, H. C., Ferguson, J., Fitzgerald, D., Granett, J., Shuaib, A., Koudstaal, P. J., Theroux, P., Van de Werf, F., Sigmon, K., Pieper, K., Vallee, M., Willerson, J. T. 2003; 108 (4): 399-406

  Abstract

  This is the primary report of the large-scale evaluation of lotrafiban, an orally administered IIb/IIIa receptor antagonist, a unique trial with respect to the platelet antagonist, protocol design, and inclusion of cerebrovascular disease in a significant proportion of patients.Patients with vascular disease were randomized to lotrafiban 30 or 50 mg BID on the basis of age and predicted creatinine clearance or placebo in addition to aspirin at a dose ranging from 75 to 325 mg/d at the discretion of the physician-investigator. Follow-up was for up to 2 years. The primary end point was the composite of all-cause mortality, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, and urgent revascularization. Of 9190 patients enrolled from 23 countries and 690 hospitals, 41% had cerebrovascular disease at the time of entry, and 59% had coronary artery disease. Death occurred in 2.3% of placebo-assigned patients and 3.0% of lotrafiban-group patients (hazard ratio 1.33, 95% CI 1.03 to 1.72, P=0.026), and the cause of excess death was vascular related. There was no significant difference in the primary end point (17.5% compared with 16.4%, respectively; hazard ratio 0.94, 95% CI 0.85 to 1.03, P=0.19). Serious bleeding was more frequent in the lotrafiban group (8.0% compared with 2.8%; P<0.001). Serious bleeding was more common among patients who received higher doses of aspirin (>162 mg/d), with or without lotrafiban.Lotrafiban, an orally administered platelet glycoprotein IIb/IIIa blocker, induced a 33% increase in death rate, which was vascular in origin and not affected by the type of atherosclerotic involvement at entry to the trial. Although the dose of aspirin was not randomly assigned, the finding of increased bleeding with doses >162 mg/d is noteworthy.

  View details for DOI 10.1161/01.CIR.0000084501.48570.F6

  View details for Web of Science ID 000184409300009

  View details for PubMedID 12874182

• Effect of revascularization on mortality associated with an elevated white blood cell count in acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Bhatt, D. L., Chew, D. P., Lincoff, A. M., Simoons, M. L., Harrington, R. A., Ommen, S. R., Jia, G., Topol, E. J. 2003; 92 (2): 136-140

  Abstract

  Inflammation is increasingly recognized as having an important role in patients with acute coronary syndromes. We sought to determine whether an elevated white blood cell (WBC) count would predict subsequent mortality and whether revascularization would have a protective effect. We analyzed data from 10,480 patients with acute coronary syndromes enrolled in the PURSUIT trial who had a WBC count measured on admission. WBC count values were stratified by quartiles, and death rates at 6 months were examined in univariate and multivariate analyses. Propensity analysis was performed to assess the effect of revascularization on the relation between WBC count and mortality. In the lowest quartile of WBC count, mortality was 4.0%; it was 5.8% in the second quartile, 6.7% in the third quartile, and 8.0% in the fourth quartile (p <0.001). In a multivariable model incorporating baseline demographic and clinical variables, an increasing WBC count was a significant predictor of death, with a hazard ratio of 1.07 per 1,000/microl increment in WBC count (p <0.001). Furthermore, the interaction term between mortality due to an elevated WBC count and benefit of in-hospital revascularization was significant (hazard ratio 0.94, p = 0.032), suggesting that the excess risk due to an elevated WBC count was attenuated by revascularization. An elevated WBC count at hospital admission, although only a crude index of inflammation, nevertheless is an independent predictor of death at 6 months in patients with acute coronary syndromes. This finding supports a pivotal role for inflammation in acute coronary syndromes. Importantly, this study suggests that in-hospital revascularization may mitigate some of the excess risk due to inflammation.

  View details for DOI 10.1016/S0002-9149(03)00527-7

  View details for Web of Science ID 000184163000004

  View details for PubMedID 12860213

• Distance from the coronary ostium to the culprit lesion in acute ST-elevation myocardial infarction and its implications regarding the potential prevention of proximal plaque rupture JOURNAL OF THROMBOSIS AND THROMBOLYSIS Gibson, C. M., Kirtane, A. J., Murphy, S. A., Karha, J., Cannon, C. P., Giugliano, R. P., Roe, M. T., Harrington, R. A., Ohman, E. M., Antman, E. M. 2003; 15 (3): 189-196

  Abstract

  Shorter distances from the coronary ostia to culprit lesions have been associated with a higher incidence of adverse outcomes in ST elevation acute myocardial infarction (STEMI). As drug-eluting stents are associated with low rates of restenosis and formation of a stable intima, we sought to develop a mathematical model to estimate how far down the coronary artery a drug-eluting stent would have to be placed to theoretically mitigate the risk of proximal plaque rupture.Distances from the ostia to the end of the culprit lesions were planimetered in 1,914 patients from the TIMI 14, INTEGRITI, FASTER and ENTIRE/TIMI 23 trials.The first 60 mm of the coronary artery contained 75% of STEMI culprit lesions. The median distance from the vessel ostium to the end of the culprit lesion was 43 mm (mean 50 +/- 34) and the relative distance from the vessel ostium to the end of the lesion was 29% (mean 33 +/- 17%) of the total culprit artery length. Diabetes was the only baseline clinical characteristic associated with a longer absolute distance to the end of the culprit lesion (46 mm vs. 43 mm, p = 0.03) as well as relative to total artery length (31% vs. 29%, p = 0.04). Median distances from the artery ostium to the end of the culprit lesion were shortest among the left anterior descending culprits (40 mm), followed by circumflex lesions (43 mm) and then right coronary artery lesions (47 mm, 3-way p < 0.0001).The majority of culprit lesions in STEMI are contained within the proximal 30% of the major epicardial coronary arteries, but the distance varies depending upon which epicardial artery is involved. Cumulative distribution functions are presented to allow estimation of the percent of culprit lesions lying proximal to any given distance from the ostium to model the feasibility of prophylactic drug-eluting stenting to minimize the risk of subsequent proximal plaque rupture.

  View details for Web of Science ID 000187940500007

  View details for PubMedID 14739628

• Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction - Results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) phase II angiographic trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Giugliano, R. P., Roe, M. T., Harrington, R. A., Gibson, M., Zeymer, U., Van de Werf, F., Baran, K. W., Hobbach, H. P., Woodlief, L. H., Hannan, K. L., Greenberg, S., Miller, J., Kitt, M. M., Strony, J., McCabe, C. H., Braunwald, E., Califf, R. M. 2003; 41 (8): 1251-1260

  Abstract

  The goal of this study was to evaluate combinations of eptifibatide with reduced-dose tenecteplase (TNK) in ST-elevation myocardial infarction (STEMI).Glycoprotein IIb/IIIa inhibitors enhance thrombolysis. The role of combination therapy in clinical practice remains to be established.Patients (n = 438) with STEMI <6 h were enrolled. In dose-finding, 189 patients were randomized to different combinations of double-bolus eptifibatide and reduced-dose TNK. In dose-confirmation, 249 patients were randomized 1:1 to eptifibatide 180 microg/kg bolus, 2 microg/kg/min infusion, and 180 microg/kg bolus 10 min later (180/2/180) plus half-dose TNK (0.27 mg/kg) or standard-dose (0.53 mg/kg) TNK monotherapy. All patients received aspirin and unfractionated heparin (60 U/kg bolus; infusion 7 U/kg/h [combination], 12 U/kg/h [monotherapy]). The primary end point was Thrombolysis In Myocardial Infarction (TIMI) grade 3 epicardial flow at 60 min.In dose-finding, TIMI grade 3 flow rates were similar across groups (64% to 68%). Arterial patency was highest for eptifibatide 180/2/180 plus half-dose TNK (96%, p = 0.02 vs. eptifibatide 180/2/90 plus half-dose TNK). In dose-confirmation, this combination, compared with TNK monotherapy, tended to achieve more TIMI 3 flow (59% vs. 49%, p = 0.15), arterial patency (85% vs. 77%, p = 0.17), and ST-segment resolution (median 71% vs. 61%, p = 0.08) but was associated with more major hemorrhage (7.6% vs. 2.5%, p = 0.14) and transfusions (13.4% vs. 4.2%, p = 0.02). Intracranial hemorrhage occurred in 1.0%, 0.6%, and 1.7% of patients treated with any combination, eptifibatide 180/2/180 and half-dose TNK, and TNK monotherapy, respectively.Double-bolus eptifibatide (180/2/180) plus half-dose TNK tended to improve angiographic flow and ST-segment resolution compared with TNK monotherapy but was associated with more transfusions and non-cerebral bleeding. Further study is needed before this combination can be recommended for general use.

  View details for DOI 10.1016/S0735-1097(03)00123-2

  View details for Web of Science ID 000182177300003

  View details for PubMedID 12706917

• 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

  View details for DOI 10.1016/S0195-668X(02)00525-0

  View details for Web of Science ID 000181813300009

• Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention - REPLACE-2 Randomized Trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Lincoff, A. M., Bittl, J. A., Harrington, R. A., Feit, F., Kleiman, N. S., Jackman, J. D., Sarembock, I. J., Cohen, D. J., Spriggs, D., Ebrahimi, R., Keren, G., Carr, J., Cohen, E. A., Betriu, A., Desmet, W., Kereiakes, D. J., Rutsch, W., Wilcox, R. G., de Feyter, P. J., Vahanian, A., Topol, E. J. 2003; 289 (7): 853-863

  Abstract

  The direct thrombin inhibitor bivalirudin has been associated with better efficacy and less bleeding than heparin during coronary balloon angioplasty but has not been widely tested during contemporary percutaneous coronary intervention (PCI).To determine the efficacy of bivalirudin, with glycoprotein IIb/IIIa (Gp IIb/IIIa) inhibition on a provisional basis for complications during PCI, compared with heparin plus planned Gp IIb/IIIa blockade with regard to protection from periprocedural ischemic and hemorrhagic complications.The Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE)-2 trial, a randomized, double-blind, active-controlled trial conducted among 6010 patients undergoing urgent or elective PCI at 233 community or referral hospitals in 9 countries from October 2001 through August 2002.Patients were randomly assigned to receive intravenous bivalirudin (0.75-mg/kg bolus plus 1.75 mg/kg per hour for the duration of PCI), with provisional Gp IIb/IIIa inhibition (n = 2999), or heparin (65-U/kg bolus) with planned Gp IIb/IIIa inhibition (abciximab or eptifibatide) (n = 3011). Both groups received daily aspirin and a thienopyridine for at least 30 days after PCI.The primary composite end point was 30-day incidence of death, myocardial infarction, urgent repeat revascularization, or in-hospital major bleeding; the secondary composite end point was 30-day incidence of death, myocardial infarction, or urgent repeat revascularization.Provisional Gp IIb/IIIa blockade was administered to 7.2% of patients in the bivalirudin group. By 30 days, the primary composite end point had occurred among 9.2% of patients in the bivalirudin group vs 10.0% of patients in the heparin-plus-Gp IIb/IIIa group (odds ratio, 0.92; 95% confidence interval, 0.77-1.09; P =.32). The secondary composite end point occurred in 7.6% of patients in the bivalirudin vs 7.1% of patients in the heparin-plus-Gp IIb/IIIa groups (odds ratio, 1.09; 95% confidence interval 0.90-1.32; P =.40). Prespecified statistical criteria for noninferiority to heparin plus Gp IIb/IIIa were satisfied for both end points. In-hospital major bleeding rates were significantly reduced by bivalirudin (2.4% vs 4.1%; P<.001).Bivalirudin with provisional Gp IIb/IIIa blockade is statistically not inferior to heparin plus planned Gp IIb/IIIa blockade during contemporary PCI with regard to suppression of acute ischemic end points and is associated with less bleeding.

  View details for Web of Science ID 000181072200029

  View details for PubMedID 12588269

• 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

• Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention - Observations from the ESPRIT trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Tolleson, T. R., O'Shea, J. C., Bittl, J. A., Hillegass, W. B., Williams, K. A., Levine, G., Harrington, R. A., Tcheng, J. E. 2003; 41 (3): 386-393

  Abstract

  We evaluated the relationship between the degree of heparin anticoagulation and clinical efficacy and bleeding in patients undergoing contemporary percutaneous coronary intervention (PCI) with stent implantation.Despite universal acceptance of heparin anticoagulation as a standard of care in PCI, considerable controversy still exists regarding the appropriate dosing of heparin.The study population (n = 2,064) comprised all patients enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial. The index activated clotting time (ACT) was defined as the ACT measured after the last heparin dose and before first device activation and was correlated with outcome and bleeding events.No association was observed between decreasing ACT levels and the rate of ischemic events in the treatment or placebo arms. The incidence of the primary composite end point (death, myocardial infarction, urgent target vessel revascularization, and thrombotic bailout glycoprotein IIb/IIIa inhibitor therapy at 48 h) was actually lowest in the lowest ACT tertile for both the placebo (10.0%) and treatment groups (6.1%). When analyzed by tertile, major bleeding rates did not increase in the lowest ACT tertile in patients given placebo (0.6%) versus those receiving eptifibatide (0.7%). Major bleeding rates increased as the ACT increased in the eptifibatide-treated patients.Ischemic end points in patients undergoing contemporary PCI with stent placement do not increase by decreasing ACT levels, at least to a level of 200 s. Bleeding events do increase with increasing ACT levels and are enhanced with eptifibatide treatment. An ACT of 200 to 250 s is reasonable in terms of efficacy and safety with the use of contemporary technology and pharmacotherapy.

  View details for DOI 10.1016/S0735-1097(02)02767-5

  View details for Web of Science ID 000180759800005

  View details for PubMedID 12575964

• Improving the care of patients with non-ST-elevation acute coronary syndromes in the emergency department: The CRUSADE initiative ACADEMIC EMERGENCY MEDICINE Hoekstra, J. W., Pollack, C. V., Roe, M. T., Peterson, E. D., Brindis, R., Harrington, R. A., Christenson, R. H., Smith, S. C., Ohman, M., Gibler, W. B. 2002; 9 (11): 1146-1155

  Abstract

  Although acute coronary syndromes (ACS) represent a well-recognized source of morbidity and mortality for patients with cardiovascular disease, evidence-based therapies shown to improve outcomes for ACS are frequently underused in appropriate patients, especially in the emergency department (ED). Despite dissemination of expert recommendations from the American College of Cardiology/American Heart Association (ACC/AHA) and ED-focused recapitulation of them in the emergency medicine literature, significant barriers continue to limit the adoption of guidelines in clinical practice and appear to hinder the use of beneficial therapies and interventions in the ED. Unique and creative approaches are therefore needed to stimulate better adherence to practice guidelines and improve the quality of care for patients with non-ST-elevation myocardial infarction (NSTE) ACS. The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines) quality improvement and educational initiative provides an innovative and multifaceted approach to the education of emergency physicians and cardiologists in the care of patients with NSTE ACS. The CRUSADE initiative is a multidisciplinary cooperative effort involving over 400 EDs and medical centers. It includes an ACS registry designed to characterize demographic patterns and risk stratification results in patients who meet diagnostic criteria for high-risk NSTE ACS. It also measures the use of ED treatment modalities including aspirin, heparin, beta-blockers, and platelet inhibitors as recommended in the ACC/AHA guidelines. The results of a given institution's treatment patterns will be reported back to the practitioners, with comparisons with national norms. These reports can be used as quality improvement tools to improve care at participating institutions. Beyond a static registry, these reports are coupled with educational efforts by the CRUSADE steering committee, scientific publications of risk stratification practice and success, as well as ED patterns of care, and tailored educational interventions, to reinforce compliance with the ACC/AHA guidelines. This initiative represents a truly innovative approach to improving care for ACS patients in the ED as well as on the cardiology service. This article describes the CRUSADE initiative and its implications for the practicing emergency physician. It is the intent of CRUSADE to improve patient care in the ED by tracking and encouraging compliance with evidence-based guidelines for the evaluation and management of NSTE ACS.

  View details for Web of Science ID 000179203100014

  View details for PubMedID 12414463

• Randomized COMparison of platelet inhibition with abciximab, TiRofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes - The COMPARE trial CIRCULATION Batchelor, W. B., Tolleson, T. R., Huang, Y., Larsen, R. L., Mantell, R. M., Dillard, P., Davidian, M., Zhang, D. W., Cantor, W. J., Sketch, M. H., Ohman, E. M., Zidar, J. P., Gretler, D., DiBattiste, P. M., Tcheng, J. E., Califf, R. M., Harrington, R. A. 2002; 106 (12): 1470-1476

  View details for DOI 10.1161/01.CIR.0000029744.01096.1F

  View details for Web of Science ID 000178122500011

• Sustained ventricular arrhythmias among patients with acute coronary syndromes with no ST-segment elevation - Incidence, predictors, and outcomes CIRCULATION Al-Khatib, S. M., Granger, C. B., Huang, Y., Lee, K. L., Califf, R. M., Simoons, M. L., Armstrong, P. W., Van de Werf, F., White, H. D., Simes, R. J., Moliterno, D. J., Topol, E. J., Harrington, R. A. 2002; 106 (3): 309-312

  Abstract

  The prognosis of ventricular arrhythmias among patients with non-ST-elevation acute coronary syndromes is unknown. We studied the incidence, predictors, and outcomes of sustained ventricular arrhythmias in 4 large randomized trials of such patients.We pooled the datasets of the Global Use of Streptokinase and tPA for Occluded Arteries (GUSTO)-IIb, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON)-A, and PARAGON-B trials (n=26 416). We identified independent predictors of ventricular fibrillation (VF) and ventricular tachycardia (VT) and compared the 30-day and 6-month mortality rates of patients who did (n=552) and did not (n=25 864) develop these arrhythmias during the index hospitalization. Independent predictors of in-hospital VF included prior hypertension, chronic obstructive pulmonary disease, prior myocardial infarction, and ST-segment changes at presentation. Except for hypertension, these variables also independently predicted in-hospital VT. In Cox proportional-hazards modeling, in-hospital VF and VT were independently associated with 30-day mortality (hazard ratio [HR], 23.2 [95% CI, 18.1 to 29.8] for VF and HR, 7.6 [95% CI, 5.5 to 10.4] for VT) and 6-month mortality (HR, 14.8 [95% CI, 12.1 to 18.3] for VF and HR, 5.0 [95% CI, 3.8 to 6.5] for VT). These differences remained significant after excluding patients with heart failure or cardiogenic shock and those who died <24 hours after enrollment.Despite the use of effective therapies for non-ST-elevation acute coronary syndromes, ventricular arrhythmias in this setting are associated with increased 30-day and 6-month mortality. More effective therapies are needed to improve the survival of patients with these arrhythmias.

  View details for DOI 10.1161/01.CIR.0000022692.49934.E3

  View details for Web of Science ID 000176944300009

  View details for PubMedID 12119245

• Early angioplasty in acute coronary syndromes without persistent ST-segment elevation improves outcome but increases the need for six-month repeat revascularization - An analysis of the PURSUIT trial JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Ronner, E., Boersma, E., Laarman, G. J., Somsen, G. A., Harrington, R. A., Deckers, J. W., Topol, E. J., Califf, R. M., Simoons, M. L. 2002; 39 (12): 1924-1929

  View details for Web of Science ID 000176266900006

• First experience with direct factor Xa inhibition in patients with stable coronary disease - A pharmacokinetic and pharmacodynamic evaluation CIRCULATION Dyke, C. K., Becker, R. C., Kleiman, N. S., Hochman, J. S., Bovill, E. G., Lincoff, A. M., Gerstenblith, G., Dzavik, V., Gardner, L. H., Hasselblad, V., Zillman, L. A., Shimoto, Y., Robertson, T. L., Kunitada, S., Armstrong, P. W., Harrington, R. A. 2002; 105 (20): 2385-2391

  Abstract

  Thrombin generation is critical to the formation of an arterial thrombus after rupture of an atherosclerotic plaque. In patients with stable coronary disease receiving standard medical therapy, we evaluated the pharmacokinetics, pharmacodynamics, and safety profile of DX-9065a, a novel small-molecule anticoagulant that directly, selectively, and reversibly inhibits factor Xa.In a double-blind trial, 73 patients (median age, 63 years; 29% women) were randomly assigned to receive a fixed-dose intravenous bolus, followed by a 72-hour infusion of placebo or 1 of 4 weight-adjusted regimens of DX-9065a. Plasma samples were collected during infusion and a 24-hour elimination period. Only minor bleeding occurred, predominantly ecchymoses at infusion sites, and its incidence did not differ significantly among the groups, including placebo. Median hemoglobin, platelet count, serum creatinine level, and liver function tests did not change significantly from baseline during infusion or elimination. Significant predictors of pharmacokinetic response included infusion dose and weight. At 60 hours into the DX-9065a infusion, plasma drug levels correlated strongly with anti-factor Xa activity (r=0.97), prothrombin time (r=0.77), and international normalized ratio (r=0.72) but less so with activated partial thromboplastin time (r=0.56; all P<0.001).This is the first study of a selective, reversible, and direct small-molecule factor Xa inhibitor in patients with stable coronary disease. These data lay the foundation for further investigation of factor Xa inhibitors in the treatment of patients with coronary atherothrombosis.

  View details for DOI 10.1161/01.CIR.0000016351.12759.52

  View details for Web of Science ID 000175853600012

  View details for PubMedID 12021225

• Minor myocardial damage and prognosis - Are spontaneous and percutaneous coronary intervention-related events different? CIRCULATION Akkerhuis, K. M., Alexander, J. H., Tardiff, B. E., Boersma, E., Harrington, R. A., Lincoff, A. M., Simoons, M. L. 2002; 105 (5): 554-556

  Abstract

  The relevance of the adverse prognostic implications of CK-MB elevation after percutaneous coronary intervention (PCI) remains controversial. Therefore, we compared the relationship between the level of postprocedural CK-MB elevation and 6-month mortality in patients undergoing PCI with the relationship between the level of spontaneous, non-PCI-related CK-MB elevation and 6-month mortality in patients with acute coronary syndromes (ACS) treated medically.In the PURSUIT trial, 5583 of 9461 patients who presented with a non-ST-elevation ACS did not undergo PCI or CABG and had at least 1 CK-MB sample collected during index-hospitalization. There was a gradual increase in 6-month mortality with higher CK-MB levels: 4.1%, 8.6%, 9.0%, 14.3%, 15.5% for CK-MB ratios 0 to 1, >1 to 3, >3 to 5, >5 to 10, and >10 times the upper limit of normal. A combined analysis in 8838 patients undergoing PCI in 5 large, clinical trials revealed a proportional relationship between postprocedural CK-MB levels (1 to 3, >3 to 5, >5 to 10, and >10, the risk of death was 1.3%, 2.0%, 2.3%, 4.3%, and 7.4%, respectively. The absolute mortality rates were lower after procedure-related infarcts compared with spontaneous infarcts. Yet, the relative increase in 6-month mortality with each increase in peak CK-MB level was similar for PCI-related myocardial necrosis and spontaneous myocardial necrosis, as all tests for heterogeneity of the odds ratios were nonsignificant.The present analysis indicates that the adverse prognostic implications of periprocedural myocardial necrosis should be considered similar to the adverse consequences of spontaneous myocardial necrosis.

  View details for Web of Science ID 000173735400019

  View details for PubMedID 11827918

• 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

  View details for DOI 10.1067/mhj.2002.120145

  View details for Web of Science ID 000173890800010

• Outcomes of patients with acute coronary syndromes and prior coronary artery bypass grafting - Results from the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial CIRCULATION Labinaz, M., Kilaru, R., Pieper, K., Marso, S. P., Kitt, M. M., Simoons, M. L., Califf, R. M., Topol, E. J., Armstrong, P. W., Harrington, R. A. 2002; 105 (3): 322-327

  Abstract

  Patients with prior CABG with a subsequent non-ST-segment elevation acute coronary syndrome (ACS) pose an increasingly important clinical problem. Although GP IIb/IIIa inhibitors have improved the outcome of patients with ACS, their efficacy in patients with prior CABG has not been previously evaluated. Methods and Results- We analyzed the 30- and 180-day outcomes of patients with prior CABG enrolled in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. In this trial, which evaluated the efficacy of eptifibatide in patients with ACS, 1134 patients (12%) with prior CABG and 8321 without prior CABG were enrolled. After adjusting for differences in baseline characteristics and treatment, patients with prior CABG had a significantly higher mortality rates at 30 days (hazard ratio [HR], 1.45 [95% CI, 1.06 to 1.98]; P=0.019) and at 180 days (HR, 1.32 [95% CI, 1.04 to 1.67]; P=0.021). At 30 days, there was a similar effect on the primary end point of death or myocardial infarction in the eptifibatide group versus the placebo group in prior CABG patients (unadjusted HR, 0.90 [95% CI, 0.67 to 1.20]) and in patients without a history of CABG (unadjusted HR, 0.89 [95% CI, 0.80 to 0.99]).Patients with prior CABG with non-ST-segment elevation ACS have a significantly worse prognosis than do patients without a history of CABG. The treatment effect of eptifibatide in the prior CABG group was similar to the effect seen in patients without prior CABG.

  View details for Web of Science ID 000173466100015

  View details for PubMedID 11804987

• Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials LANCET Boersma, E., Harrington, R. A., Moliterno, D. J., White, H., Theroux, P., Van de Werf, F., De Torbal, A., Armstrong, P. W., Wallentin, L. C., Wilcox, R. G., Simes, J., Califf, R. M., Topol, E. J., Simoons, M. L. 2002; 359 (9302): 189-198

  Abstract

  Platelet glycoprotein IIb/IIIa inhibitors have been shown to reduce cardiac complications in patients undergoing percutaneous coronary intervention. The clinical efficacy of these drugs in acute coronary syndromes, however, is still unclear. We did a meta-analysis of all large randomised trials designed to study the clinical efficacy and safety of glycoprotein IIb/IIIa inhibitors in patients with acute coronary syndromes who were not routinely scheduled to undergo early coronary revascularisation.Inclusion criteria were: randomisation of patients with acute coronary syndromes but without persistent ST elevation; comparison of a glycoprotein IIb/IIIa inhibitor with placebo or control therapy; non-recommendation of early coronary revascularisation during study-drug infusion; and enrollment of at least 1000 patients. Data on individual patients were obtained from all participants in these trials.Six trials, enrolling 31402 patients, fulfilled the inclusion criteria. 30 days after randomisation, 3530 (11.2%) patients died or developed a myocardial infarction. At 30 days, a 9% reduction in the odds of death or myocardial infarction was seen with glycoprotein IIb/IIIa inhibitors compared with placebo or control (10.8% [1980/18297] vs 11.8% [1550/13105] events; odds ratio 0.91 [95% CI 0.84-0.98]; p=0.015). The relative treatment benefit was similar in subgroups of patients according to important clinical baseline characteristics; hence, the absolute treatment benefit was largest in high-risk patients. An unexpected and significant interaction was seen between sex and allocated treatment, with a treatment benefit in men (0.81 [0.75-0.89] but not in women (1.15 [1.01-1.30]). However, once patients were stratified according to troponin concentration, there was no evidence of a sex difference in treatment response, and a risk reduction was seen in men and women with raised troponin concentrations. Major bleeding complications were increased by glycoprotein IIb/IIIa inhibitors (2.4% [445/18297] vs 1.4% [180/13105]; p<0.0001), but intracranial bleeding was not (16 [0.09%] vs 8 [0.06%]; p=0.40).Glycoprotein IIb/IIIa inhibitors reduce the occurrence of death or myocardial infarction in patients with acute coronary syndromes not routinely scheduled for early revascularisation. The event reduction is greatest in patients at high risk of thrombotic complications. Treatment with a glycoprotein IIb/IIIa inhibitor might therefore be considered especially in such patients early after admission, and continued until a decision about early coronary revascularisation has been made.

  View details for Web of Science ID 000173350800008

  View details for PubMedID 11812552

• Comparison of two aspirin doses on ischemic stroke in post-myocardial infarction patients in the warfarin (Coumadin) Aspirin Reinfarction Study (CARS) AMERICAN JOURNAL OF CARDIOLOGY O'Connor, C. M., Gattis, W. A., Hellkamp, A. S., Langer, A., Larsen, R. L., Harrington, R. A., Berkowitz, S. D., O'Gara, P. T., Kopecky, S. L., Gheorghiade, M., DALY, R., Califf, R. M., Fuster, V. 2001; 88 (5): 541-546

  Abstract

  The Coumadin Aspirin Reinfarction Study demonstrated that combination treatment with fixed dose warfarin (1 or 3 mg) + aspirin 80 mg was not superior to aspirin 160 mg alone after myocardial infarction for reducing nonfatal reinfarction, nonfatal stroke, and cardiovascular death. In this analysis, we examined the importance of aspirin dose in the protection against the secondary end point of ischemic stroke. The comparison arms for this analysis were warfarin 1 mg + aspirin 80 mg versus aspirin 160 mg. In the Coumadin Aspirin Reinfarction Study, 2,028 patients were randomized to aspirin 80 mg plus warfarin 1 mg, and 3,393 were randomized to aspirin 160 mg alone. A predictive model for ischemic stroke was developed using the Cox proportional-hazards model. A reduced Cox proportional-hazards model was developed to test for the effect of aspirin dose on ischemic stroke in predefined subgroups. The incidence of ischemic stroke was lower in patients treated with aspirin 160 mg than in patients treated with aspirin 80 mg + warfarin 1 mg (0.6% vs 1.1%; p = 0.0534). Age, previous stroke or transient ischemic attack, and aspirin dose were independent predictors of ischemic stroke. In addition, the highest risk patients, those with Q-wave myocardial infarction and male patients, appeared to receive greater benefit from aspirin 160 mg than from aspirin 80 mg + warfarin 1 mg. The results of this secondary analysis suggest that aspirin 160 mg is more effective than aspirin 80 mg + warfarin 1 mg in preventing ischemic stroke in post-myocardial infarction patients.

  View details for Web of Science ID 000170652400015

  View details for PubMedID 11524065

• Initiation of hormone replacement therapy after acute myocardial infarction is associated with more cardiac events during follow-up JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Alexander, K. P., Newby, L. K., Hellkamp, A. S., Harrington, R. A., Peterson, E. D., Kopecky, S., Langer, A., O'Gara, P., O'Connor, C. M., Daly, R. N., Califf, R. M., Khan, S., Fuster, V. 2001; 38 (1): 1-7

  Abstract

  This study explored the association between the initiation of hormone replacement therapy (HRT) and early cardiac events (<1 year) in women with a recent myocardial infarction (MI).Observational studies have linked postmenopausal hormone use with a reduced risk of death from heart disease. However, a recent randomized trial of HRT found no long-term benefit, primarily due to an increase in cardiac events in the first year.The Coumadin Aspirin Reinfarction Study (CARS) database contains information on HRT use and menopausal status for women with a recent MI. We classified the 1,857 postmenopausal women in CARS as prior/current HRT users if they took HRT before enrollment, new users if they began HRT during the study period or never users. We assessed the incidence of cardiac events (death, MI, unstable angina [UA]) during follow-up.In our cohort, 28% (n = 524) used HRT at some point. Of these, 21% (n = 111) began HRT after their MI. New users had a higher incidence of death/MI/UA (41% vs. 28%, p = 0.001) during follow-up than never users, largely due to a higher incidence of UA (39% vs. 20%, p = 0.001). After adjustment, new users still had a significantly higher risk of death/MI/UA than never users during follow-up (relative risk [RR] = 1.44 [1.05-1.99]). Prior/current users had no excess risk of the composite end point after adjustment. Users of estrogen/progestin had a lower incidence of death/MI/UA during follow-up than users of estrogen only (RR = 0.56 [0.37-0.85]).Postmenopausal women who initiated HRT after a recent MI had an increased risk of cardiac events largely due to excess UA during follow-up.

  View details for Web of Science ID 000169625400001

  View details for PubMedID 11451256

• 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

  View details for Web of Science ID 000169532500017

• Prognostic value of ST segment depression in acute coronary syndromes: Insights from PARAGON-A applied to GUSTO-IIb JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kaul, P., Fu, Y. L., Chang, W. C., Harrington, R. A., Wagner, G. S., Goodman, S. G., Granger, C. B., Moliterno, D. J., Van de Werf, F., Califf, R. N., Topol, E. J., Armstrong, P. W. 2001; 38 (1): 64-71

  Abstract

  Our objectives were to develop a risk-stratification model addressing the importance of the magnitude and distribution of ST segment depression in predicting long-term outcomes and to validate the model in an analogous patient population.Although patients without ST segment elevation presenting with acute coronary syndromes represent an increasingly frequent population admitted to coronary care units, little attention has been paid to quantifying their ST segment abnormalities.ST segment depression was categorized into three groups: 1) no ST segment depression; 2) 1-mm ST segment depression in two contiguous leads; and 3) ST segment depression > or =2 mm in two contiguous leads. A logistic regression model was developed using Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON-A) data to assess the prognostic value of the extent and distribution of ST segment depression in predicting one-year mortality. The model was validated using the non-ST segment elevation population in Global Use of Strategies To Open occluded arteries in acute coronary syndromes (GUSTO-IIb).ST segment depression was the strongest predictor of one-year mortality, accounting for 35% of the model's predictive power. Patients with ST segment depression > or =2 mm were approximately 6 times (odds ratio [OR] 5.73, 95% confidence interval [CI] 2.8 to 11.6) more likely to die within one year than patients with no ST segment depression. On validation, the model showed good discriminatory power (c-index = 0.75). Patients with ST segment depression > or =2 mm in more than one region were almost 10 times more likely to die within one year than patients with no ST segment depression.These data provide new evidence supporting the powerful prognostic value of the baseline electrocardiogram and, in particular, the magnitude and distribution of ST segment depression in predicting unfavorable events.

  View details for Web of Science ID 000169625400010

  View details for PubMedID 11451297

• Effect of lipid-lowering therapy on early mortality after acute coronary syndromes: an observational study LANCET Aronow, H. D., Topol, E. J., Roe, M. T., Houghtaling, P. L., Wolski, K. E., Lincoff, A. M., Harrington, R. A., Califf, R. M., Ohman, E. M., Kleiman, N. S., Keltai, M., Wilcox, R. G., Vahanian, A., Armstrong, P. W., Lauer, M. S. 2001; 357 (9262): 1063-1068

  Abstract

  Lipid-lowering agents are known to reduce long-term mortality in patients with stable coronary disease or significant risk factors. However, the effect of lipid-lowering therapy on short-term mortality immediately after an acute coronary syndrome has not been determined. We did an observational study using data from two randomised trials to investigate this issue.We used data from the GUSTO IIb and PURSUIT trials to compare all-cause mortality among patients with acute coronary syndromes who were discharged on lipid-lowering agents (n=3653) with those who were not (n=17,156). A propensity analysis was done to adjust for presumed selection biases in the prescription of lipid-lowering agents.Lipid-lowering therapy was associated with a smaller proportion of deaths at 30 days (17 [0.5%] vs 179 [1.0%], hazard ratio 0.44 [95% CI 0.27-0.73], p=0.001) and at 6 months (63 [1.7%] vs 605 [3.5%], 0.48 [0.37-0.63], p<0.0001). After adjustment for the propensity to be prescribed lipid-lowering agents and other potential confounders, prescription of a lipid-lowering agent at discharge remained associated with a reduced risk of death at 6 months (0.67 [0.48-0.95], p=0.023).Prescription of a lipid-lowering drug at hospital discharge was independently associated with reduced short-term mortality among patients after an acute coronary syndrome.

  View details for Web of Science ID 000167996200007

  View details for PubMedID 11297956

• Variation in patient management and outcomes for acute coronary syndromes in Latin America and North America: Results from the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial AMERICAN HEART JOURNAL Cohen, M. G., Pacchiana, C. M., Corbalan, R., Perez, J. E., Ponte, C. I., Oropeza, E. S., Diaz, R., PAOLASSO, E., Izasa, D., Rodas, M. A., Urrutia, C. E., Harrington, R. A., Topol, E. J., Califf, R. M. 2001; 141 (3): 391-401

  Abstract

  Although more than 9500 patients have been enrolled in major clinical trials in Latin America, practice patterns in this region have rarely been examined. We sought to compare characteristics, resource utilization, and outcomes of patients treated for acute coronary syndromes in Latin America with those in North America.The Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Theraphy Trial (PURSUIT) enrolled 10,948 patients with non-ST-segment elevation acute coronary syndromes, including 585 in Latin America and 4358 in North America. We analyzed regional differences in patient groups, treatment patterns, and outcomes and used logistic regression analysis to identify association of enrollment region and survival.For patients in Latin America, the length of hospital stay was significantly longer (10 [7, 15] days vs 6 [4, 9], P <.001). Angiograms, angioplasty, and bypass surgery were significantly less common in Latin America (46.2%, 17.6%, and 11.3% vs 79.4%, 33.6%, and 19.4%, P <.001). Thirty-day death/myocardial infarction was not significantly higher, although mortality alone was significantly higher (6.8% vs 3.1%, P <.001). After adjustment for baseline characteristics, enrollment in Latin America remained an independent predictor for death at 30 days (odds ratio [OR] [95% confidence interval (CI)] 2.42 [1.60-3.67]) and persisted at 6 months (OR [95% CI] 2.5 [1.8-3.4]).Latin American patients treated for acute coronary syndromes were managed less invasively and were twice as likely as their North American counterparts to die within 6 months. This mortality difference was not explained by imbalances in baseline risk.

  View details for DOI 10.1067/mhj.2001.113216

  View details for Web of Science ID 000167321600015

  View details for PubMedID 11231436

• Prognostic importance of concomitant heparin with eptifibatide in acute coronary syndromes AMERICAN JOURNAL OF CARDIOLOGY Peterson, J. G., Topol, E. J., Roe, M. T., Sapp, S. K., Lincoff, A. M., Deckers, J. W., Blackstone, E. H., Harrington, R. A., Califf, R. M., Lauer, M. S. 2001; 87 (5): 532-536

  Abstract

  Platelet glycoprotein IIb/IIIa inhibitors have been extensively studied in the treatment of patients with ischemic heart disease. Data regarding the use of these agents in the absence of concomitant intravenous heparin have been conflicting. We sought to determine, using propensity analysis, whether the benefit of eptifibatide, a IIb/IIIa inhibitor, in the treatment of acute coronary syndromes is affected by the concurrent administration of heparin. By trial design, patients were randomized to either eptifibatide or placebo, whereas use of intravenous heparin was left to the discretion of treating physicians. The effect of eptifibatide on the 30-day composite end point of death or myocardial infarction was studied in patients who received heparin and those who did not. Propensity analysis methods were used to control for confounding and presumed selection biases. Among 5,576 patients who were receiving heparin when the bolus dose of the study drug was administered, eptifibatide was associated with a reduced composite end point rate (13%) compared with that of placebo (14.5% vs 16.6%, p = 0.03). In contrast, among 1,441 patients who were not receiving heparin, there was no difference in 30-day event rates with eptifibatide compared with placebo (13.7% vs 13.1%, p > 0.7). After a propensity score for use of heparin was developed, however, use of heparin did not affect the reduced risk associated with eptifibatide (adjusted relative risk [RR] for heparin-eptifibatide interaction term 0.90, 95% confidence interval [CI] 0.61 to 1.32, p > 0.5), but the propensity for heparin use was a strong predictor of events (adjusted RR 1.76, 95% CI 1.42 to 2.17, p < 0.001). The use of eptifibatide independently predicted a lower risk of events (adjusted RR 0.31, 95% CI 0.10 to 0.93, p = 0.04). Thus, the apparent positive impact of heparin on the benefits of eptifibatide therapy was largely due to confounding and bias.

  View details for Web of Science ID 000167218000006

  View details for PubMedID 11230834

• 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

  View details for Web of Science ID 000173941300006

• 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

  View details for Web of Science ID 000173941300007

• Antithrombotic therapy in patients undergoing percutaneous coronary intervention CHEST Popma, J. J., Ohman, E. M., Weitz, J., Lincoff, M., Harrington, R. A., Berger, P. 2001; 119 (1): 321S-336S

  View details for Web of Science ID 000166812000020

  View details for PubMedID 11157657

• 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

• Enhanced efficacy of eptifibatide administration in patients with acute coronary syndrome requiring in-hospital coronary artery bypass grafting CIRCULATION Marso, S. P., Bhatt, D. L., Roe, M. T., Houghtaling, P. L., Labinaz, M., Kleiman, N. S., Dyke, C., Simmoons, M. L., Califf, R. M., Harrington, R. A., Topol, E. J. 2000; 102 (24): 2952-2958

  Abstract

  Patients with a recent episode of non-ST-segment elevation acute coronary syndrome before CABG have higher rates of operative morbidity and mortality than patients with stable coronary syndromes. The efficacy of administering eptifibatide to these patients undergoing in-hospital CABG is unknown.The Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial randomized 10 948 patients to receive either eptifibatide or placebo. There were 1558 study participants who underwent in-hospital CABG: 692 received placebo, and 866 received eptifibatide. The main substudy analysis end point was death or myocardial infarction (MI) rates at the 6-month follow-up. The 30-day death or MI rates were 30. 8% and 26.1% for the placebo and eptifibatide groups, respectively (P:=0.041). The benefit of eptifibatide administration persisted through 6-months of follow-up (32.7% versus 27.6% for placebo versus eptifibatide, respectively; P:=0.029). There was a greater reduction in the 6-month death or MI rate for patients who received eptifibatide within 72 hours of CABG (33.6% versus 23.8%; P:=0.002) compared with the >72-hour group (31.6% versus 32%; P:=1.0). The incidence of major bleeding was 56.6% for placebo-treated patients versus 58.2% for eptifibatide-treated patients (P:=0.7).Eptifibatide administration in patients undergoing in-hospital CABG with a recent episode of a non-ST-segment elevation acute coronary syndrome results in a significant reduction in death or MI that is evident at 7 days and persists through the 6-month follow-up without a significant increase in perioperative bleeding rates.

  View details for Web of Science ID 000165813600015

  View details for PubMedID 11113045

• Management of patients with acute coronary syndromes in the United States by platelet glycoprotein IIb/IIIa inhibition - Insights from the platelet glycoprotein IIb/IIIa in unstable angina: Receptor suppression using integrilin therapy (PURSUIT) trial CIRCULATION Lincoff, A. M., Harrington, R. A., Califf, R. M., Hochman, J. S., Guerci, A. D., Ohman, E. M., Pepine, C. J., Kopecky, S. L., Kleiman, N. S., Pacchiana, C. M., Berdan, L. G., Kitt, M. M., Simoons, M. L., Topol, E. J. 2000; 102 (10): 1093-1100

  Abstract

  A multinational, randomized, placebo-controlled trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy, PURSUIT) demonstrated that the platelet glycoprotein IIb/IIIa receptor antagonist eptifibatide reduced the incidence of death or myocardial infarction among patients with acute ischemic syndromes without ST-segment elevation. Because of expected differences in practice patterns, a prospectively planned analysis of outcomes as a function of regions of the world was performed. The current study provides a detailed assessment of eptifibatide among the subgroup of patients enrolled within the United States.Patients presenting with chest pain within the previous 24 hours and ischemic ECG changes or creatine kinase-MB elevation were eligible for enrollment. Of the 10 948 patients randomized worldwide, 4035 were enrolled within the United States. Patients were allocated to placebo or eptifibatide infusion for up to 72 to 96 hours. Other medical therapies and revascularization strategies were at the discretion of the treating physician. Eptifibatide reduced the rate of the primary end point of death or myocardial infarction by 30 days from 15.4% to 11.9% (P=0.003) among patients in the United States. The treatment effect was achieved early and maintained over a period of 6 months (18.9% versus 15.2%; P=0.004). Bleeding events were more common in patients receiving eptifibatide but were predominantly associated with invasive procedures. The magnitude of clinical benefit from eptifibatide was greater among patients in the United States than elsewhere in the world.Platelet glycoprotein IIb/IIIa receptor blockade with eptifibatide reduces the incidence of death or myocardial infarction among patients treated for acute ischemic syndromes without ST-segment elevation within the United States.

  View details for Web of Science ID 000089157400006

  View details for PubMedID 10973836

• Immediate coronary artery bypass surgery after platelet inhibition with eptifibatide: Results from PURSUIT 36th Annual Meeting of the Society-of-Thoracic-Surgeons Dyke, C. M., Bhatia, D., Lorenz, T. J., Marso, S. P., Tardiff, B. E., Hogeboom, C., Harrington, R. A. ELSEVIER SCIENCE INC. 2000: 866–71

  Abstract

  The platelet GP IIb/IIIa inhibitor eptifibatide improves outcomes in patients with acute coronary syndromes. Patients requiring emergent coronary artery bypass grafting, however, may be at increased risk for bleeding if exposed to eptifibatide. Data from the PURSUIT trial were reviewed to assess this risk in patients undergoing coronary surgery immediately after exposure to eptifibatide.In PURSUIT, 10,948 patients who presented with non-ST segment elevation acute coronary syndromes were prospectively randomized to receive eptifibatide (180 microg/kg bolus plus 2 microg/kg/min infusion) or placebo. A total of 78 patients underwent immediate coronary artery bypass surgery within 2 hours of cessation of study drug (placebo, n = 46; eptifibatide, n = 32). Clinical outcome, bleeding, and transfusion requirements within this subset were examined.Major bleeding was not different between groups, occurring in 64% of patients receiving placebo and 63% of patients receiving eptifibatide. The incidence of blood transfusion was similar as well (57% vs 59%). Postoperative thrombocytopenia occurred less often after eptifibatide exposure. Perioperative myocardial infarction was significantly reduced in patients who received eptifibatide (46% vs 22%, p < 0.05). There was no difference in perioperative stroke (2.2% vs 6.3%) or mortality (6.3% vs 6.5%).Patients may safely undergo coronary artery bypass surgery within 2 hours of discontinuation of eptifibatide. Eptifibatide infusion in the immediate preoperative period had no adverse clinical effects, but did significantly decrease the incidence of perioperative myocardial infarction. Additionally, platelet counts after surgery were higher in the group of patients who received eptifibatide, perhaps indicative of a platelet-sparing effect during cardiopulmonary bypass.

  View details for Web of Science ID 000089447400046

  View details for PubMedID 11016325

• Dose-finding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease 71st Scientific Session of the American-Heart-Association Harrington, R. A., Armstrong, P. W., Graffagnino, C., Van de Werf, F., Kereiakes, D. J., Sigmon, K. N., Card, T., Joseph, D. M., Samuels, R., Granett, J., Chan, R., Califf, R. M., Topol, E. J. LIPPINCOTT WILLIAMS & WILKINS. 2000: 728–35

  Abstract

  Antiplatelet therapy is the mainstay of the treatment and secondary prevention of cardiovascular and cerebrovascular ischemic events. We assessed the safety, tolerability, and pharmacodynamics of lotrafiban, an oral platelet glycoprotein IIb/IIIa inhibitor, as a secondary prevention strategy in patients with cerebrovascular or cardiovascular disease.Overall, 451 patients with a recent cardiovascular or cerebrovascular acute ischemic event were randomized in a double-blind fashion to 1 of 5 dosing regimens for 12 weeks: placebo or 5, 20, 50, or 100 mg lotrafiban, both twice daily with 300 to 325 mg/d aspirin. The primary end point was the incidence and tolerability of major and minor bleeding during treatment. Secondary end points included inhibition of platelet aggregation and clinical events. The placebo and lotrafiban 5-mg groups had similarly low rates of minor and major bleeding, but the 100-mg arm was terminated early because of excess major bleeding. Protocol-defined thrombocytopenia (<100 000 platelets/microL) occurred in 5 lotrafiban-treated patients (1.4%, 95% CI 0.2% to 2.7%) and 1 placebo patient (1.1%, 95% CI 0% to 3.1%). Three lotrafiban-treated patients had a nadir platelet count <20 000/microL (0.9%, 95% CI 0% to 1.8%). Lotrafiban produced dose-dependent inhibition of platelet aggregation; 5 mg lotrafiban did not differ significantly from placebo, whereas 100 mg inhibited aggregation by nearly 100%.-Lotrafiban provides dose-dependent platelet inhibition when administered to a range of patients with atherosclerosis. The level of platelet inhibition appears to correlate with bleeding risk and drug tolerability.

  View details for Web of Science ID 000088748100003

  View details for PubMedID 10942739

• Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation results from an international trial of 9461 patients CIRCULATION Boersma, E., Pieper, K. S., Steyerberg, E. W., Wilcox, R. G., Chang, W. C., Lee, K. L., Akkerhuis, K. M., Harrington, R. A., Deckers, J. W., Armstrong, P. W., Lincoff, A. M., Califf, R. M., Topol, E. J., Simoons, M. L. 2000; 101 (22): 2557-2567

  Abstract

  Appropriate treatment policies should include an accurate estimate of a patient's baseline risk. Risk modeling to date has been underutilized in patients with acute coronary syndromes without persistent ST-segment elevation.We analyzed the relation between baseline characteristics and the 30-day incidence of death and the composite of death or myocardial (re)infarction in 9461 patients with acute coronary syndromes without persistent ST-segment elevation enrolled in the PURSUIT trial [Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin (eptifibatide) Therapy]. Variables examined included demographics, history, hemodynamic condition, and symptom duration. Risk models were created with multivariable logistic regression and validated by bootstrapping techniques. There was a 3.6% mortality rate and 11.4% infarction rate by 30 days. More than 20 significant predictors for mortality and for the composite end point were identified. The most important baseline determinants of death were age (adjusted chi(2)=95), heart rate (chi(2)=32), systolic blood pressure (chi(2)=20), ST-segment depression (chi(2)=20), signs of heart failure (chi(2)=18), and cardiac enzymes (chi(2)=15). Determinants of mortality were generally also predictive of death or myocardial (re)infarction. Differences were observed, however, in the relative prognostic importance of predictive variables for mortality alone or the composite end point; for example, sex was a more important determinant of the composite end point (chi(2)=21) than of death alone (chi(2)=10). The accuracy of the prediction of the composite end point was less than that of mortality (C-index 0.67 versus 0.81).The occurrence of adverse events after presentation with acute coronary syndromes is affected by multiple factors. These factors should be considered in the clinical decision-making process.

  View details for Web of Science ID 000087431100004

  View details for PubMedID 10840005

• Design of the blockade of the glycoprotein IIb/IIIa receptor to avoid vascular occlusion (BRAVO) trial AMERICAN HEART JOURNAL Topol, E. J., Easton, J. D., Amarenco, P., Califf, R., Harrington, R., Graffagnino, C., Davis, S., Diener, H. C., Ferguson, J., Fitzgerald, D., Shuaib, A., Koudstaal, P. J., Theroux, P., Van de Werf, F., Willerson, J. T., Chan, R., Samuels, R., Ilson, B., Granett, J. 2000; 139 (6): 927-933

  Abstract

  Platelets play a key role in the pathogenesis of atherosclerosis, thrombosis, and acute coronary and cerebrovascular syndromes. Inhibition of platelet function by acetylsalicylic acid (aspirin) has been shown to reduce the incidence atherothrombotic events in patients with coronary, cerebrovascular, or peripheral vascular disease. Thienopyridine agents, however, including ticlopidine and clopidogrel, inhibit the adenosine diphosphate receptor and have modestly superior effects compared with aspirin on reduction of death, myocardial infarction, and stroke among a broad group of patients with vascular disease. More effective antithrombotic agents are still required to treat patients at high risk for recurrent vascular events.Lotrafiban, a selective, nonpeptide antagonist of the human platelet fibrinogen receptor (glycoprotein [GP] IIb/IIIa [alphaIIb/beta3 integrin]), blocks the binding of fibrinogen to the GP IIb/IIIa receptor, which is the final common pathway of platelet aggregation. Lotrafiban at doses of up to 50 mg twice daily was well-tolerated in a 12-week, double-blind, placebo-controlled, dose-ranging study in patients with recent myocardial infarction, unstable angina, transient ischemic attack, or stroke when added to aspirin therapy. On the basis of these results, a dosing regimen was selected for the phase III Blockage of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occlusion (BRAVO) trial based on pharmacodynamics and drug tolerability. In the pivotal BRAVO study, lotrafiban therapy is being evaluated in patients who have had a recent myocardial infarction, unstable angina, transient ischemic attack, or ischemic stroke, or who present at any time after a diagnosis of peripheral vascular disease combined with either cardiovascular or cerebrovascular disease.The efficacy evaluation will be based on a composite end point of clinical events (death by any cause, myocardial infarction, stroke, recurrent ischemia requiring hospitalization, or urgent ischemia-driven revascularization). The target enrollment is 9200 patients worldwide. Approximately 700 centers will participate and will be distributed within 30 countries across North America, Europe, Australia, and Asia.

  View details for Web of Science ID 000087467600001

  View details for PubMedID 10827369

• Age and outcome after acute coronary syndromes without persistent ST-segment elevation AMERICAN HEART JOURNAL Hasdai, D., Holmes, D. R., Criger, D. A., Topol, E. J., Califf, R. M., Harrington, R. A. 2000; 139 (5): 858-866

  Abstract

  Although age is the most important variable associated with death among patients with persistent ST-segment elevation, its impact on outcome among patients without persistent ST-segment elevation remains unknown. Moreover, the impact of age on the efficacy of antiplatelet therapy with eptifibatide is unknown.We analyzed the impact of increased age on outcome (death or [re]infarction) among patients enrolled in PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina Receptor Suppression Using Integrilin Therapy), a prospective, randomized study comparing placebo versus eptifibatide therapy in acute coronary syndromes without persistent ST-segment elevation. The 9461 patients were divided into 10-year age groups: <50, 50-59, 60-69, 70-79, and >/=80. In addition, we examined whether age had an impact on the efficacy of eptifibatide therapy.Eptifibatide improved outcome at 30 days (P =.04). There was no interaction among age and treatment (placebo vs eptifibatide) and adjusted outcome (P =.16 for death or [re]infarction at 30 days). Despite their worse clinical profile, older patients were less likely to undergo coronary angiography at 30 days: 936 (71%), 1489 (68%), 1969 (65%), 1357 (57%), and 193 (38%) in the respective age groups. Death or (re)infarction at 30 days occurred in 121 (9%), 255 (12%), 447 (15%), 460 (19%), and 134 (26%) in the respective age groups, and at 6 months in 149 (11%), 301 (14%), 547 (18%), 575 (24%), and 162 (32%). For a 10-year difference in age group, the adjusted odds for death or (re)infarction were greater by 33% within 30 days and by 34% within 6 months. These trends persisted for patients with or without myocardial infarction on presentation.Age did not significantly affect the efficacy of eptifibatide. Older age among patients with acute coronary syndromes was associated with worse baseline characteristics, fewer invasive procedures, and worse outcome.

  View details for Web of Science ID 000086970400019

  View details for PubMedID 10783220

• 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

• Cigarette smoking status and outcome among patients with acute coronary syndromes without persistent ST-segment elevation: Effect of inhibition of platelet glycoprotein IIb/IIIa with eptifibatide AMERICAN HEART JOURNAL Hasdai, D., Holmes, D. R., Criger, D. A., Topol, E. J., Califf, R. M., Wilcox, R. G., PAOLASSO, E., Simoons, M., Deckers, J., Harrington, R. A. 2000; 139 (3): 454-460

  Abstract

  Studies have shown that cigarette smokers constitute a substantial proportion of patients with acute coronary syndromes (ACS) and have platelet-rich coronary thrombi. We characterized the influence of smoking status on outcome of patients with ACS without persistent ST-segment elevation and tested the hypothesis that selective inhibition of the platelet glycoprotein IIb/IIIa receptor with eptifibatide would improve outcomes among cigarette smokers.The study population included patients enrolled in the PURSUIT trial (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy) with known smoking status presenting with ischemic chest pain

  View details for Web of Science ID 000085761900014

  View details for PubMedID 10689260

• 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

• Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial LANCET Topol, C. E., Califf, R. M., Simes, R. J., Van de Werf, F., Diaz, R., PAOLASSO, E., Aylward, P. E., KEECH, A., Klein, W., Piegas, L., Tomov, I., Armstrong, P. W., Widimsky, P., Grande, P., Halinen, M., Vahanian, A., Neuhaus, K., Dimas, A. P., Preda, I., Kristinsson, A., Tzivoni, D., Ardissino, D., White, H. D., Madsen, S., Sugrue, D., Sadowski, Z., Seabra-Gomes, R., Apetrei, E., Dalby, A., Betriu, A., Pfisterer, M., Verheugt, F., Fox, K., Bates, E. R., Gibler, W. B., Granger, C. B., Harrington, R. A., Hochman, J. S., Holmes, D. R., Kleiman, N. S., Lee, K. L., Moliterno, D. J., Newby, L. K., Ohman, E. M., Califf, R., Newby, K., Zillman, L., Lee, K., Lemons, P., McCourt, B., Campbell, C., Tardiff, B., Snapp, J., Bassett, K., Hodgson, P., Hannan, K., Kandzari, L., Hawkins, S., Hinman-Smith, E., McDougal, M., Raffetto, K., Thompson, D., Wehrle, T., Ange, C., Brown, R., Grissom, G., Heuckel, M., McCall, J., Pennachi, W., Spychala, M., Veasey, S., Pullium, M., Journey, T., Quintero, K., Mark, D., Davidson-Ray, L., Diner, L., Nelson, C., Sowers, C., Webb, G., Young, M., Bhapkar, M., Pacchiana, C., Sparapani, R., Tuttle, R., Weaver, D., Borzak, S., Douthat, L., Topol, E., Moliterno, D., Konczos, L., Baishnab, R., Baishnab, R., Bakos, A., Blashford, L., Bratsch, J., BROWN, K., Cadorini, E., Carlson, J., Clemmons, P., DELVALLE, M., Drabik, M., Fu, G., Gates, K., Gibson, Y., Heil, L., Hill, N., Klancar, R., McHale, B., Montague, E., Pasca, N., Pergi, L., Randall, R., Rosso, R., Sankovich, K., Smith, D., Wisniewski, L., Witkowski, M., Zovkic, V., Alexander, K., Bhatt, D., Brener, S., Campbell, L., Cho, L., COLE, C., Deedy, M., Foody, J., Gassler, J., Ghaffari, S., Haas, G., Kapadia, S., Lauer, M., Lauer, M. S., Lincoff, M., Lutton, S., Marso, S., Mukherjee, D., Patel, V., Penn, M., Robbins, M., Roe, M., Sila, C., Thamilarasan, M., Wagner, G., ARMSTRONG, P., Bestilny, S., Van de Werf, F., Budts, W., Graux, S., Luyten, A., Simes, J., KEECH, A., Kava, M., Bower, T., Chan, S., Crampton, L., Monro, C., Nayak, M., Parente, G., Riley, V., Wilton, D., Aylward, P., Dolan, S., Thomas, C., White, H., Scott, M., Frye, R., Alpert, J., Bertrand, M., Ryan, T., Fisher, L., Asarch, L., Smith, M., Lim, L., Bokslag, M., Chiu, P., Chung, J., Collins, S., Dougherty, C., Guimaraes, D., Hakim, Z., Mathieson, J., Montgomery, L., Novotny, B., Steiner, B., Wittke, B. 2000; 355 (9201): 337-345

  View details for Web of Science ID 000085122100008

• 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

• Redefining medical treatment in the management of unstable angina AMERICAN JOURNAL OF MEDICINE Braunwald, E., Califf, R. M., Cannon, C. P., Fox, K. A., Fuster, V., Gibler, W. B., Harrington, R. A., King, S. B., Kleiman, N. S., Theroux, P., Topol, E. J., Van de Werf, F., White, H. D., Willerson, J. T. 2000; 108 (1): 41-53

  Abstract

  In 1994, the Agency for Health Care Policy and Research sponsored the development of guidelines for diagnosing and managing patients with unstable angina. Since their publication, several important developments have occurred. The prognostic value of biochemical assays for cardiac-specific troponins T and I have been shown in many studies. The possible role for C-reactive protein in determining prognosis deserves further investigation. Substantial clinical benefits have been obtained with intravenous inhibitors of the platelet glycoprotein (GP) IIb-IIIa receptor (abciximab, eptifibatide, tirofiban) and with one of the low-molecular-weight heparins (enoxaparin). The therapeutic potential of other low-molecular-weight heparins, direct thrombin inhibitors, and oral GP IIb-IIIa inhibitors remains to be clarified. On the basis of this evidence, consideration should be given to measuring serum levels of a cardiac troponin (either T or I) and using intravenous GP IIb-IIIa inhibitors and low-molecular-weight heparin in the standard management of patients with unstable angina.

  View details for Web of Science ID 000084710800008

  View details for PubMedID 11059440

• Recent clinical trials in acute coronary syndromes without persistent ST elevation CURRENT OPINION IN CARDIOLOGY Tolleson, T. R., Harrington, R. A. 1999; 14 (5): 403-411

  Abstract

  Acute coronary occlusion is a serious manifestation of coronary artery disease leading to significant short- and long-term morbidity and mortality. Traditionally classified as Q-wave myocardial infarction, non-Q-wave myocardial infarction, and unstable angina, these events are more appropriately termed acute coronary syndromes with and without ST-segment elevation, reflecting the diagnostic criteria used by clinicians to guide initial treatment strategies. Standard therapy with aspirin and heparin has been expanded with the low molecular weight heparin enoxaparin and the intravenous glycoprotein IIb/IIIa inhibitors eptifibatide and tirofiban. Debate continues as to whether a strategy of early intervention or initial conservative management is most appropriate. Continued clinical trials will help define optimal treatment strategies in this high-risk group of patients.

  View details for Web of Science ID 000082197900008

  View details for PubMedID 10500902

• Clinical significance of thrombocytopenia during a non-ST-elevation acute coronary syndrome - The platelet glycoprotein IIb IIIa in unstable angina: Receptor suppression using integrilin therapy (PURSUIT) trial experience CIRCULATION McClure, M. W., Berkowitz, S. D., Sparapani, R., Tuttle, R., Kleiman, N. S., Berdan, L. G., Lincoff, A. M., Deckers, J., Diaz, R., Karsch, K. R., Gretler, D., Kitt, M., Simoons, M., Topol, E. J., Califf, R. M., Harrington, R. A. 1999; 99 (22): 2892-2900

  Abstract

  The significance of thrombocytopenia in patients experiencing an acute coronary syndrome (ACS) has not been examined systematically. We evaluated this condition in a large non-ST-elevation ACS clinical trial, with particular interest paid to its correlation with clinical outcomes.Patients presenting without persistent ST elevation during an ACS were randomized to receive a double-blind infusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor eptifibatide or placebo in addition to other standard therapies including heparin and aspirin. The primary end point was death/nonfatal myocardial infarction (MI) at 30 days, whereas bleeding and stroke were the main safety outcomes. Thrombocytopenia (nadir platelet count <100x10(9)/L or <50% of baseline) occurred in 7.0% of enrolled patients. The time to onset was a median of 4 days in both treatment arms. Patients with thrombocytopenia were older, weighed less, were more likely nonwhite, and had more cardiac risk factors. These patients experienced significantly more bleeding events: they were more than twice as likely to experience moderate/severe bleeding after adjustment for confounders. Univariably, ischemic events (stroke, MI, and death) occurred significantly (P<0.001) more frequently in patients with thrombocytopenia; multivariable regression modeling preserved this association with death/nonfatal MI at 30 days. Neither the use of heparin or eptifibatide was found to independently increase thrombocytopenic risk.Although causality between thrombocytopenia and adverse clinical events could not be established definitively, thrombocytopenia was highly correlated with both bleeding and ischemic events, and the presence of this condition identified a more-at-risk patient population.

  View details for Web of Science ID 000080662900010

  View details for PubMedID 10359733

• Use of glycoprotein IIb IIIa inhibition plus fibrinolysis in acute myocardial infarction JOURNAL OF THROMBOSIS AND THROMBOLYSIS Hudson, M. P., Greenbaum, A. B., Harrington, R. A., Ohman, E. M. 1999; 7 (3): 241-245

  Abstract

  Pharmacological reperfusion therapy for acute myocardial infarction with intravenous fibrinolytic agents improves survival yet fails to achieve early and complete coronary blood flow in nearly half of treated patients. In principle, glycoprotein (GP) IIb/IIIa inhibitors, potent antiplatelet agents, might improve the efficacy and clinical outcomes associated with fibrinolysis. Preclinical research suggests more rapid and effective reperfusion with combined platelet GP IIb/IIIa inhibition and fibrinolysis. Early clinical studies confirm improved early patency and more rapid electrocardiographic resolution, but increased bleeding complications, with the addition of GP IIb/IIIa antagonists to conventional fibrinolysis. Future studies may combine reduced-dose fibrinolytic therapy with GP IIb/IIIa inhibition to optimize efficacy and safety.

  View details for Web of Science ID 000081163600003

  View details for PubMedID 10373717

• Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease CIRCULATION Kong, D. F., Califf, R. M., Miller, D. P., Moliterno, D. J., White, H. D., Harrington, R. A., Tcheng, J. E., Lincoff, A. M., Hasselblad, V., Topol, E. J. 1998; 98 (25): 2829-2835

  Abstract

  Several platelet glycoprotein (GP) IIb/IIIa receptor antagonists have been evaluated in clinical trials. We conducted a systematic overview (meta-analysis) to assess the effect of these compounds on death, myocardial infarction (MI), and revascularization.ORs were calculated for 16 randomized, controlled trials of GP IIb/IIIa inhibitors. An empirical Bayesian random-effects model combined the outcomes of 32 135 patients. There was a significant mortality reduction by GP IIb/IIIa inhibitors at 48 to 96 hours, with an OR of 0.70 (95% CI, 0. 51 to 0.96; P<0.03), equivalent to a reduction of 1 death per 1000 patients treated. Mortality benefits at 30 days (OR, 0.87; 95% CI, 0. 74 to 1.02; P=0.08) and 6 months (OR, 0.97; 95% CI, 0.86 to 1.10; P=0.67) were not statistically significant. For the combined end point of death or MI, there was a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors at each time point. The 30-day OR was 0.76 (95% CI, 0.66 to 0.87), or 20 fewer events per 1000 patients treated. For the composite end point of death, MI, or revascularization, there was also a highly significant (P<0.001) benefit for GP IIb/IIIa inhibitors. At 30 days, the OR was 0.77 (95% CI, 0.68 to 0.86), or 30 fewer events per 1000 patients treated. The risk differences for death, death or MI, and composite outcomes were similar at 6 months, indicating a sustained absolute improvement. Similar benefit was seen when trials were subgrouped by therapeutic indication (percutaneous intervention versus acute coronary syndromes).Application of this new therapeutic class to clinical practice promises substantial benefit for both indications.

  View details for Web of Science ID 000077606900009

  View details for PubMedID 9860783

• Prognostic value of congestive heart failure history in patients undergoing percutaneous coronary interventions 45th Annual Scientific Session of the American-College-of-Cardiology Anderson, R. D., Ohman, E. M., Holmes, D. R., Harrington, R. A., Barsness, G. W., Wildermann, N. M., Phillips, H. R., Topol, E. J., Califf, R. M. ELSEVIER SCIENCE INC. 1998: 936–41

  Abstract

  We sought to determine the prognostic significance of a history of congestive heart failure above that provided by baseline ejection fraction in patients undergoing percutaneous coronary interventions.Left ventricular function is a known predictor of survival in patients with coronary artery disease, as is a history of congestive heart failure. The contribution of heart failure history independent of left ventricular function is unknown.Data were pooled from four interventional trials and the Duke University database. The combined dataset included 5,260 patients undergoing percutaneous interventions, 334 with and 4,926 without a history of heart failure. Patients were defined by the treating physician as having a clinical history of heart failure at the time of enrollment.The 30-day and 6-month mortality were higher in patients with a clinical history of congestive heart failure than in those without such a history (2% vs. <1%, p=0.002 at 30 days, 5% vs. 1%, p=0.001 at 6 months). Heart failure history did not influence the incidence of myocardial infarction, use of angioplasty or the use of bypass surgery during follow-up. Multivariable analysis revealed that heart failure history added significantly to ejection fraction in predicting intermediate-term (6-month) mortality (p=0.01). Stepwise logistic regression also revealed heart failure history to be an independent predictor of 6-month mortality (odds risk 1.9, 95% confidence interval 1.1 to 3.5).A clinical history of congestive heart failure is associated with increased early and intermediate-term mortality in patients undergoing percutaneous revascularization. Congestive heart failure history appears to provide prognostic information independent of that available from a patient's left ventricular function. These findings suggest that patients with a clinical history of congestive heart failure who undergo a percutaneous intervention should be closely monitored, especially those with the lowest ejection fractions.

  View details for Web of Science ID 000076214000011

  View details for PubMedID 9768714

• Relation between inhibition of platelet aggregation and clinical outcomes Symposium on Role and Significance of Coagulation Markers in Understanding and Treating Acute Coronary Syndromes Harrington, R. A., Kleiman, N. S., Granger, C. B., Ohman, E. M., Berkowitz, S. D. MOSBY-ELSEVIER. 1998: S43–S50

  Abstract

  Despite a clinical trials experience in excess of 30,000 randomized patients, there is no definitive answer or agreement as to the relation between the level of inhibition of platelet aggregation and clinical outcome. Work with abciximab in the setting of percutaneous intervention would suggest that a level of platelet inhibition in excess of 80% provides the most favorable clinical benefit. Whether this applies to the small molecule inhibitors such as eptifibatide, tirofiban, and lamifiban is unknown and will require testing of the hypothesis in large-scale clinical trials. In the acute coronary syndromes, only the peptide and nonpeptide inhibitors have been studied independent of a need for percutaneous intervention. The level of platelet inhibition required to achieve maximal clinical benefit is unknown and awaits data from the large-scale unstable angina and myocardial infarction trials. Issues of combining heparin with GP IIb/IIIa inhibition and the platelet-altering effects of thrombolysis must be considered when examining what might be the optimal level of platelet inhibition that provides maximal efficacy while maintaining safety. Long-term therapy with the oral platelet inhibitors poses a particular challenge in determining an optimal level of treatment that renders clinical effectiveness while preserving safety. Large, ongoing clinical trials with these agents should provide insight into this question. Finally, given the complexity of using such potent therapies in any individual patient, there is a need for improved monitoring of the platelet inhibitory effect. Standard platelet aggregometry has its problems and limitations, as described, and is not a test that has wide-scale applicability. Whole blood aggregometry and other methods of rapidly assessing platelet function at the point of care have promise in this arena. In a clinical trial, such technology might allow better delineation of the population's pharmacodynamic response to an agent because it could be more widely applied and therefore more patients would be studied. In clinical practice, patients could be dosed individually so that a range of platelet inhibition could be achieved that was believed to provide optimal benefit and safety.

  View details for Web of Science ID 000076408000005

  View details for PubMedID 9778087

• Glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: Pathophysiologic foundation and clinical findings Symposium on Role and Significance of Coagulation Markers in Understanding and Treating Acute Coronary Syndromes Kleiman, N. S., Lincoff, A. M., Ohman, E. M., Harrington, R. A. MOSBY-ELSEVIER. 1998: S32–S42

  Abstract

  The pathophysiologic basis for potent platelet inhibition in the acute coronary syndromes has been established. In the setting of PTCA for unstable angina and non-Q-wave myocardial infarction, there are clear data for a benefit of GP IIb/IIIa inhibition, whereas for primary PTCA in evolving myocardial infarction, preliminary data are very encouraging and a large-scale clinical trial is nearly completed. Glycoprotein IIb/IIIa inhibition as an adjunct to medical therapy for unstable angina is also the subject of encouraging preliminary data, and 3 large-scale clinical trials have just been completed. Preliminary data have also been accrued for GP IIb/IIIa inhibition as conjunctive therapy with thrombolytic agents, and large clinical trials are now commencing.

  View details for Web of Science ID 000076408000004

  View details for PubMedID 9778086

• Occurrence and clinical significance of thrombocytopenia in a population undergoing high-risk percutaneous coronary revascularization 45th Annual Scientific Session of the American-College-of-Cardiology Berkowitz, S. D., Sane, D. C., Sigmon, K. N., Shavender, J. H., Harrington, R. A., Tcheng, J. E., Topol, E. J., Califf, R. M. ELSEVIER SCIENCE INC. 1998: 311–19

  Abstract

  This study sought to determine the frequency of thrombocytopenia and its relation with clinical outcomes in high risk patients undergoing percutaneous coronary revascularization who received either the platelet glycoprotein (GP) IIb/IIIa receptor antagonist abciximab (ReoPro, c7E3 Fab) or conventional therapy.The development of thrombocytopenia on exposure to GPIIb/IIIa antagonists threatens the utility and economic viability of this drug class for patients with vascular disease.We analyzed data from the Evaluation of c7E3 for the Prevention of Ischemic Complications trial (EPIC), a 2,099-patient, randomized trial of placebo, abciximab bolus or abciximab bolus plus a 12-h infusion during high-risk coronary revascularization.Thrombocytopenia (nadir platelet count <100 x 10(9)/ liter) developed in 81 patients (3.9%) during their hospital stay, with 19 (0.9%) developing severe (<50 x 10(9)/liter) thrombocytopenia. Both thrombocytopenia and severe thrombocytopenia were more frequent in the bolus-plus-infusion arm (5.2% and 1.6%, respectively) than in the bolus-only and placebo arms combined (p = 0.020 and p = 0.025, respectively). Acute profound thrombocytopenia developed in two patients in the bolus-plus-infusion arm. Patients with thrombocytopenia experienced more unfavorable clinical outcomes than those who did not develop thrombocytopenia, regardless of treatment assignment, but those with thrombocytopenia who received abciximab had fewer worse outcomes at 30 days. Multivariable logistic modeling revealed a lower baseline platelet count, older age and lighter weight to be important predictors of thrombocytopenia. In a logistic regression model, bolus-plus-infusion treatment was a significant predictor of thrombocytopenia (p = 0.016) and remained so after adjustment for procedures and baseline risk factors (p = 0.0077).Thrombocytopenia was associated with adverse clinical outcomes and excessive bleeding, but patients receiving abciximab fared better than those receiving placebo.

  View details for Web of Science ID 000075273200003

  View details for PubMedID 9708455

• Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade LANCET Topol, E. J., Lincoff, A. M., Califf, R. M., Tcheng, J. E., Kleiman, N. S., Adelman, A. G., Burton, J. R., Talley, J. D., Ivanhoe, R. J., Ducas, C., Cheung, P. K., Schick, U., Badard, D., Kramer, J., Leary, J., Snyder, H., Wilson, R., Dearen, M., Caramori, P., Webber, S., Taylor, J., Ferrando, T., Cohen, E., Balleza, L., Rouse, C., Hogg, N., Kelly, T., Alston, S., Webb, J., Buller, E., Ricci, D. R., Mockman, S., Tanguay, J. F., Poitras, A. M., Timis, G., Davey, D., Coleman, P., Herrold-Runge, P., O'Neill, B. J., Foshey, K., Fitzgerald, N., Almond, D., Kostuk, W., WHITE, J., Oskalns, R., Gottlieb, R., Koren, P., Palazzo, D., Azrin, M., Barry, M. B., Blankenship, J., Demko, S. L., Kraft, P., Dvorak, L., Brown, R., Colclough, M., Stevens, K., Sarembock, I., Snyder, L., Sayre, S., Browne, K., Roy, M., Reen, B., Short, R., Thompson, M., Chiodo, V., Hoffman, D., Bass, T. A., Zenni, M., Rohman, G., Marquis, J. F., Labinaz, M., Jelley, J., French, W., Goldberg, S., Wang, S., Gradman, A., Boltey, L., Collins, J., Worley, S., Hollywood, L., Frey, L., Yakubov, S., Gilliland, C., Rodriguez, A., Potter, K., Taylor, M., Aji, J., Cleary, E., Tannenbaum, M., Hartz, A., Rund, M., Smigley, R., Lopez, J., Kunny, P., Hochman, J., Slater, J., Termey, D., Bates, E., Fox-Bruenger, P., Gonzalez, M., Jopperri, L., Runyon, J. P., Higby, N., Krucoft, M., Booth, T., Aguirre, F., Bach, R., Mechem, C., Azrin, M., Murphy, D., Cummins, F. E., Nonweiler, J., Sanz, M., COLE, C., Weston, M. W., Anderson, H. V., Weigelt, L., Larkin, T., JACKSON, B. J., Rosenberg, M. J., Tully, S., Hartman, C., Lunow, S., Lucore, C., Mishkel, G., McShane, K., Muhlestein, B., Jerman, J., Sander, G., Stevens, A., Chisholm, R., Del Core, M., Stengel, L., Cannata, R., Castle, V., DeLuca, S., Balog, C., Knuth, T., McCollough, T., Godfrey, N., Melton, J., Miller, D., Pulliam, M., Sapp, S., Sigmon, K. N., Templin, M., Montague, E., Carlson, J., Heil, L., Zovkic, V., Malone, K., Rodkey, S., Haas, G., Harrington, R., Kapadis, S., Campbell, L., Mukherjee, D., Deedy, M., Augostini, R., Alexander, J., Whellan, D., Bajzer, C., Rabbani, R., Clemons, P., Baishnab, R., Randall, R., Underwood, D., Lauer, M. A., Lauer, M. S., Roe, M., Farhy, R., Schweikert, R., Grady, T., Ellis, S., Moliterno, D., Debowey, D., Ivanc, T., Ols, L., Poliszcuk, R., Balazs, E., Witherspoon, B., Anderson, K. M., Barnathan, E., Cabot, C. F., Stoner, G. L., Weisman, H. F. 1998; 352 (9122): 87-92

  Abstract

  Coronary stenting with use of heparin, aspirin, and ticlopidine for thromboprophylaxis is performed in more than 500,000 patients per year worldwide. We did a randomised controlled trial to assess the role of platelet glycoprotein-IIb/IIIa blockade for use in elective stenting.At 63 hospitals in the USA and Canada, 2399 patients with ischaemic heart disease and suitable coronary-artery lesions were randomly assigned stenting plus placebo (n=809), stenting plus abciximab, a IIb/IIIa inhibitor (n=794), or balloon angioplasty plus abciximab (n=796). The primary endpoint was a combination of death, myocardial infarction, or need for urgent revascularisation in the first 30 days. All patients received heparin, aspirin, and standard pharmacological therapy.The primary endpoint occurred in 87 (10.8%) of 809 patients in the stent plus placebo group, 42 (5.3%) of 794 in the stent plus abciximab group (hazard ratio 0.48 [95% CI 0.33-0.69] p<0.001), and 55 (6.9%) of 796 in the balloon plus abciximab group (0.63 [0.45-0.88] p=0.007). The main outcomes that occurred less with abciximab were death and large myocardial infarction--7.8% in the placebo group, 3.0% for stent plus abciximab (p<0.001), and 4.7% for balloon angioplasty plus abciximab (p=0.01). Major bleeding complications occurred in 2.2% of patients assigned stent plus placebo, 1.5% assigned stent plus abciximab, and 1.4% assigned balloon angioplasty plus abciximab (p=0.38).Platelet glycoprotein-IIb/IIIa blockade with abciximab substantially improves the safety of coronary-stenting procedures. Balloon angioplasty with abciximab is safer than stenting without abciximab.

  View details for Web of Science ID 000074775100010

  View details for PubMedID 9672272

• 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

• IMMEDIATE AND REVERSIBLE PLATELET INHIBITION AFTER INTRAVENOUS ADMINISTRATION OF A PEPTIDE GLYCOPROTEIN IIB/IIIA INHIBITOR DURING PERCUTANEOUS CORONARY INTERVENTION AMERICAN JOURNAL OF CARDIOLOGY Harrington, R. A., Kleiman, N. S., KOTTKEMARCHANT, K., Lincoff, A. M., Tcheng, J. E., Sigmon, K. N., Joseph, D., Rios, G., Trainor, K., Rose, D., Greenberg, C. S., Kitt, M. M., Topol, E. J., Califf, R. M. 1995; 76 (17): 1222-1227

  Abstract

  We studied the pharmacokinetic and pharmacodynamic properties of integrelin, a novel platelet glycoprotein IIb/IIIa receptor inhibitor, in patients undergoing elective percutaneous coronary intervention. Patients were randomized to placebo (n = 19) or to 1 of 4 integrelin dosing regimens (total n = 54) that were studied sequentially. All patients received aspirin and heparin. Patients were followed until discharge for the occurrence of adverse clinical events: death, myocardial infarction, coronary artery bypass surgery, repeat intervention, or recurrent ischemia. Bleeding was the primary safety end point. Frequent blood sampling was performed for adenosine diphosphate-induced platelet aggregations. Simplate bleeding times were performed. Adverse clinical events occurred less often in the integrelin-treated patients, although the overall numbers were too small to make a definitive statement as to clinical efficacy. There was no significant increase in serious bleeding among integrelin-treated patients. The 2 highest integrelin boluses (180 and 135 micrograms/kg) immediately (15 minutes after the bolus) provided > 80% inhibition of adenosine diphosphate-induced platelet aggregation in > 75% of treated patients. A constant integrelin infusion of 0.75 micrograms/kg/min maintained this marked antiplatelet effect, whereas an infusion of 0.50 micrograms/kg/min allowed gradual recovery of platelet function. Elective coronary intervention was performed safely and with no significant increase in serious bleeding events using integrelin with aspirin and heparin as an antithrombotic regimen. Integrelin provided rapid, intense, and persistent ex vivo platelet inhibition during coronary intervention. This new antiplatelet agent may be beneficial in reducing platelet-mediated ischemic complications of percutaneous coronary intervention.

  View details for Web of Science ID A1995TK15100003

  View details for PubMedID 7503000

• Early clinical experience with integrelin, an inhibitor of the platelet glycoprotein IIb/IIIa integrin receptor Symposium on Prevention and Management of Thrombotic Complications during Coronary Interventions Ohman, E. M., Harrington, R. A., Lincoff, A. M., Kitt, M. M., Kleiman, N. S., Tcheng, J. E. OXFORD UNIV PRESS. 1995: 50–55

  Abstract

  Aggregation of platelets leading to thrombosis is one of the hallmarks of unstable angina, acute myocardial infarction, and ischaemic complications following coronary angioplasty. Activated platelets bind to fibrinogen through the glycoprotein IIb/IIIa integrin receptor. New agents have been developed to bind this receptor and thus prevent aggregation of platelets. One such compound (integrelin) is a cyclical peptide that has been shown to be a potent inhibitor of the glycoprotein IIb/IIIa receptor in man. A number of phase I and phase II clinical trials have been completed to evaluate this agent for the indications of unstable angina, acute myocardial infarction, as well as an adjunct to coronary angioplasty. This article will focus on the clinical investigation of integrelin with particular emphasis on its use during angioplasty. It has been consistently shown across different trials that integrelin can inhibit between 70% and 95% of platelet aggregation responses to 20 mumols of ADP at a variety of dosages used in the phase II trials. Preliminaray data also suggest that a more clinically unstable patient may require a higher dose of integrelin to cause a near complete inhibition of the platelet aggregation response to ADP. Future studies will need to explore more definitely the relationship between dose of glycoprotein IIb/IIIa receptor blockers and clinical instability.

  View details for Web of Science ID A1995TR85500010

  View details for PubMedID 8869019

• MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF THE PLATELET INTEGRIN GLYCOPROTEIN IIB/IIIA BLOCKER INTEGRELIN IN ELECTIVE CORONARY INTERVENTION CIRCULATION Tcheng, J. E., Harrington, R. A., KOTTKEMARCHANT, K., Kleiman, N. S., Ellis, S. G., Kereiakes, D. J., MICK, M. J., Navetta, F. I., Smith, J. E., Worley, S. J., Miller, J. A., Joseph, D. M., Sigmon, K. N., Kitt, M. M., DUMEE, C. P., Califf, R. M., Topol, E. J. 1995; 91 (8): 2151-2157

  View details for Web of Science ID A1995QR28500009