title: 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).
abstract: BACKGROUND
  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.
  
  
  METHODS
  TRACER was a double-blind, randomized trial comparing vorapaxar with placebo in 12,944 patients with NSTE ACS.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC. Electronic address: schuyler.jones@dm.duke.edu.
authors.forename: William Schuyler
authors.initials: WS
authors.lastname: Jones
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Tricoci
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Huang
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: Department of Medicine, Stanford University, Stanford, CA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Harrington
authors.affiliation: Department of Cardiology, University of Leuven, Leuven, Belgium.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Sinnaeve
authors.affiliation: Merck & Co, Whitehouse Station, NJ.
authors.forename: John
authors.initials: J
authors.lastname: Strony
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: Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Held
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: Global Clinical Development, Bayer HealthCare Pharmaceuticals Inc, Whippany, NJ.
authors.forename: Edmond
authors.initials: E
authors.lastname: Chen
authors.affiliation: Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
authors.forename: Manesh R
authors.initials: MR
authors.lastname: Patel
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 / Q000188:drug therapy* / Q000601:surgery; D000368:Aged; D000671:Amputation, Surgical / Q000706:statistics & numerical data*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007783:Lactones / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009204:Myocardial Revascularization / Q000706:statistics & numerical data*; D058729:Peripheral Arterial Disease / Q000150:complications / Q000188:drug therapy* / Q000601:surgery; D011725:Pyridines / Q000008:administration & dosage*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D007783:Lactones; D011725:Pyridines; D018179:Receptors, Thrombin; C530299:vorapaxar