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. 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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

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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., V