title: New ischemic stroke and outcomes with vorapaxar versus placebo: results from the TRA 2 °P-TIMI 50 trial.
abstract: BACKGROUND
  Vorapaxar, a novel antiplatelet therapy, reduces thrombotic events in patients with a history of myocardial infarction (MI) or peripheral artery disease (PAD); however, because of an increased risk of intracranial hemorrhage, it is contraindicated in patients with a history of stroke.
  
  
  OBJECTIVE
  The aim of this study was to investigate the incidence of new ischemic stroke and subsequent death or intracerebral hemorrhage in patients with MI or PAD and no cerebrovascular disease (CVD) treated with vorapaxar.
  
  
  METHODS
  The TRA 2 °P-TIMI 50 (Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis In Myocardial Infarction 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar 2.5 mg daily in 26,449 patients with atherosclerosis, stratified by qualifying disease (MI, PAD, or CVD). A total of 20,170 patients with MI/PAD, but no CVD, were enrolled.
  
  
  RESULTS
  In patients with MI/PAD and no prior stroke or transient ischemic attack, vorapaxar reduced first ischemic stroke (hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.43 to 0.75; p < 0.001). The risk of hemorrhagic conversion after stroke (HR: 1.19, 95% CI: 0.49 to 2.91; p = 0.70) or death (HR: 1.09, 95% CI: 0.57 to 2.07; p = 0.79) during follow-up was not significantly increased with vorapaxar in patients who had a new ischemic stroke (n = 204). Although hemorrhagic stroke was increased (HR: 2.79, 95% CI: 1.00 to 7.73; p = 0.049), overall stroke was significantly reduced (HR: 0.67, 95% CI: 0.52 to 0.87; p = 0.002).
  
  
  CONCLUSIONS
  Vorapaxar reduces ischemic stroke in patients with MI or PAD and no known CVD. There does not appear to be a significant increase in the risk of hemorrhagic conversion or death in patients who experienced a first ischemic stroke on vorapaxar. Although primary hemorrhagic stroke is increased, vorapaxar reduces the total incidence of stroke. (Trial to Assess the Effects of Vorapaxar (SCH 530348; MK-5348) in Preventing Heart Attack and Stroke in Patients With Atherosclerosis [TRA 2 °P-TIMI 50]; NCT00526474).
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. Electronic address: mbonaca@partners.org.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Scirica
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.affiliation: Department of Medicine (Cardiology), Tokai University School of Medicine, Institute of Medical Science, Isehara, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Goto
authors.affiliation: Department of Cardiology, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Nilsen
authors.affiliation: Department of Cardiology, Stavanger University Hospital, Stavanger, Norway; Department of Clinical Science, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway.
authors.forename: Vernon
authors.initials: V
authors.lastname: Bonarjee
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
mesh_terms: D000368:Aged; D050197:Atherosclerosis / Q000175:diagnosis / Q000188:drug therapy; D002545:Brain Ischemia / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007783:Lactones / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis / Q000188:drug therapy; D011725:Pyridines / Q000008:administration & dosage*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors; D020521:Stroke / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology*; D016896:Treatment Outcome
chemical_list: D007783:Lactones; D011725:Pyridines; D018179:Receptors, Thrombin; C530299:vorapaxar
keywords: PAR-1; antiplatelet therapy; intracranial hemorrhage; platelet aggregation inhibitors; secondary prevention; thrombin receptor