David J Whellan1, Pierluigi Tricoci2, Edmond Chen3, Zhen Huang2, David Leibowitz4, Pascal Vranckx5, Gregary D Marhefka6, Claes Held7, Jose C Nicolau8, Robert F Storey9, Witold Ruzyllo10, Kurt Huber11, Peter Sinnaeve12, A Teddy Weiss4, Jean-Pierre Dery13, David J Moliterno14, Frans Van de Werf12, Philip E Aylward15, Harvey D White16, Paul W Armstrong17, Lars Wallentin7, John Strony3, Robert A Harrington18, Kenneth W Mahaffey18. 1. Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. Electronic address: djw150@jefferson.edu. 2. Duke Clinical Research Institute, Durham, North Carolina. 3. Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey. 4. Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. 5. Thoraxcentre, Rotterdam, the Netherlands. 6. Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. 7. Department of Medical Sciences, Uppsala Clinical Research Center, Uppsala, Sweden. 8. Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil. 9. Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom. 10. Department of Coronary Artery Disease and Cardiac Catheterization Laboratory, Institute of Cardiology, Warsaw, Poland. 11. 3rd Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria. 12. Department of Cardiology, University of Leuven, Leuven, Belgium. 13. Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Québec, Canada. 14. Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky. 15. South Australian Health and Medical Research Institute, Flinders University and Medical Centre, Adelaide, Australia. 16. Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand. 17. Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada. 18. Department of Medicine, Stanford University, Stanford, California.
Abstract
OBJECTIVES: 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 coronarysyndromes undergoing coronary artery bypass grafting (CABG). BACKGROUND: 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. METHODS: 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. RESULTS: 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 placeboCABG 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%). CONCLUSIONS: 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).
RCT Entities:
OBJECTIVES: 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). BACKGROUND: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: In non-ST-segment elevation acute coronary syndromepatients 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).
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