title: 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).
abstract: OBJECTIVE
  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 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).
authors.affiliation: Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania. Electronic address: djw150@jefferson.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Whellan
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Tricoci
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey.
authors.forename: Edmond
authors.initials: E
authors.lastname: Chen
authors.affiliation: Duke Clinical Research Institute, Durham, North Carolina.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Leibowitz
authors.affiliation: Thoraxcentre, Rotterdam, the Netherlands.
authors.forename: Pascal
authors.initials: P
authors.lastname: Vranckx
authors.affiliation: Division of Cardiology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania.
authors.forename: Gregary D
authors.initials: GD
authors.lastname: Marhefka
authors.affiliation: Department of Medical Sciences, Uppsala Clinical Research Center, Uppsala, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Held
authors.affiliation: Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Nicolau
authors.affiliation: Department of Cardiovascular Science, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.affiliation: Department of Coronary Artery Disease and Cardiac Catheterization Laboratory, Institute of Cardiology, Warsaw, Poland.
authors.forename: Witold
authors.initials: W
authors.lastname: Ruzyllo
authors.affiliation: 3rd Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria.
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.affiliation: Department of Cardiology, University of Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Sinnaeve
authors.affiliation: Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: A Teddy
authors.initials: AT
authors.lastname: Weiss
authors.affiliation: Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Québec, Canada.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Dery
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky.
authors.forename: David J
authors.initials: DJ
authors.lastname: Moliterno
authors.affiliation: Department of Cardiology, University of Leuven, Leuven, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.affiliation: South Australian Health and Medical Research Institute, Flinders University and Medical Centre, Adelaide, Australia.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Aylward
authors.affiliation: Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Harvey D
authors.initials: HD
authors.lastname: White
authors.affiliation: Division of Cardiology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
authors.affiliation: Department of Medical Sciences, Uppsala Clinical Research Center, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: Merck Sharp & Dohme Corp., Whitehouse Station, New Jersey.
authors.forename: John
authors.initials: J
authors.lastname: Strony
authors.affiliation: Department of Medicine, Stanford University, Stanford, California.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.affiliation: Department of Medicine, Stanford University, Stanford, California.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
mesh_terms: D054058:Acute Coronary Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality* / Q000601:surgery; D000368:Aged; D016001:Confidence Intervals; D001026:Coronary Artery Bypass / Q000009:adverse effects / Q000379:methods*; D004562:Electrocardiography / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D017052:Hospital Mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D007783:Lactones / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000517:prevention & control; D011183:Postoperative Complications / Q000517:prevention & control; D019106:Postoperative Hemorrhage / Q000517:prevention & control; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011725:Pyridines / Q000008:administration & dosage*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors; D012016:Reference Values; D018570:Risk Assessment; D012720:Severity of Illness Index; D020521:Stroke / Q000517:prevention & control; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D007783:Lactones; D011725:Pyridines; D018179:Receptors, Thrombin; C530299:vorapaxar
keywords: bypass; coronary disease; myocardial infarction; platelets; thrombin