title: 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.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Duke Clinical Research Institute, Durham NC. Electronic address: pierluigi.tricoci@duke.edu.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Tricoci
authors.affiliation: Duke Clinical Research Institute, Durham NC.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Lokhnygina
authors.affiliation: Duke Clinical Research Institute, Durham NC.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
authors.affiliation: University of Leuven, Leuven, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.affiliation: Medisch Centrum Alkmaar, Alkmaar, the Netherlands.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Cornel
authors.affiliation: Merck & Co, Inc, Whitehouse Station, NJ.
authors.forename: Edmond
authors.initials: E
authors.lastname: Chen
authors.affiliation: Department of Medical Sciences, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: Department of Medical Sciences, Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Held
authors.affiliation: SAHMRI, Flinders University and Medical Centre, Adelaide, Australia.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Aylward
authors.affiliation: Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, KY.
authors.forename: David J
authors.initials: DJ
authors.lastname: Moliterno
authors.affiliation: CirQuest Labs, LLC and University of Tennessee Health Science Center, Memphis, TN.
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Jennings
authors.affiliation: Green Lane Cardiovascular Service, Auckland City, Auckland, New Zealand.
authors.forename: Harvey D
authors.initials: HD
authors.lastname: White
authors.affiliation: University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.affiliation: Merck & Co, Inc, Whitehouse Station, NJ.
authors.forename: John
authors.initials: J
authors.lastname: Strony
authors.affiliation: Department of Medicine, Stanford University, Stanford, CA.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
mesh_terms: D054058:Acute Coronary Syndrome / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy; D000368:Aged; D000077144:Clopidogrel; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000379:methods; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000209:etiology / Q000517:prevention & control; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects; D055502:Secondary Prevention / Q000379:methods; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D016019:Survival Analysis; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D016896:Treatment Outcome
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; D000077144:Clopidogrel; D013988:Ticlopidine; C530299:vorapaxar