title: 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).
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.
authors.affiliation: Department of cardiology, Medisch Centrum Alkmaar, Alkmaar, the Netherlands. Electronic address: janhein.cornel@gmail.com.
authors.forename: Jan H
authors.initials: JH
authors.lastname: Cornel
authors.affiliation: Duke Clinical Research Institute, Durham, North Caroline.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Tricoci
authors.affiliation: Duke Clinical Research Institute, Durham, North Caroline.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Lokhnygina
authors.affiliation: Division of Cardiovascular Medicine, Gill Heart Institute, University of Kentucky, Lexington, Kentucky.
authors.forename: David J
authors.initials: DJ
authors.lastname: Moliterno
authors.affiliation: Department of Medical Sciences, Cardiology, and Uppsala Clinical Research Center, Uppsala, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Wallentin
authors.affiliation: Division of Cardiology, University of Alberta, Edmonton, Canada.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Armstrong
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: Duke Clinical Research Institute, Durham, North Caroline.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Clare
authors.affiliation: Global Clinical Development, Bayer HealthCare Pharmaceuticals Inc., Whippany, New Jersey.
authors.forename: Edmond
authors.initials: E
authors.lastname: Chen
authors.affiliation: Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Leonardi
authors.affiliation: Department of Cardiology, University of Leuven, Leuven, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.affiliation: Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand.
authors.forename: Harvey D
authors.initials: HD
authors.lastname: White
authors.affiliation: Department of Medical Sciences, Cardiology, and Uppsala Clinical Research Center, Uppsala, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Held
authors.affiliation: Merck & Co., Whitehouse Station, New Jersey.
authors.forename: John
authors.initials: J
authors.lastname: Strony
authors.affiliation: Department of Medicine, Stanford University, Stanford, California.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Mahaffey
authors.affiliation: Department of Medicine, Stanford University, Stanford, California.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
mesh_terms: D054058:Acute Coronary Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D000368:Aged; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007783:Lactones / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000008:administration & dosage*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011725:Pyridines; D018179:Receptors, Thrombin; C530299:vorapaxar