title: Vorapaxar in the secondary prevention of atherothrombotic events.
abstract: BACKGROUND
  Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.
  
  
  METHODS
  We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.
  
  
  RESULTS
  At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).
  
  
  CONCLUSIONS
  Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).
authors.affiliation: Thrombolysis in Myocardial Infarction (TIMI) Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. dmorrow@partners.org
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.forename: Sebastian F
authors.initials: SF
authors.lastname: Ameriso
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Dalby
authors.forename: Mary Polly
authors.initials: MP
authors.lastname: Fish
authors.forename: Keith A A
authors.initials: KA
authors.lastname: Fox
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Lipka
authors.forename: Xuan
authors.initials: X
authors.lastname: Liu
authors.forename: José Carlos
authors.initials: JC
authors.lastname: Nicolau
authors.forename: A J Oude
authors.initials: AJ
authors.lastname: Ophuis
authors.forename: Ernesto
authors.initials: E
authors.lastname: Paolasso
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Scirica
authors.forename: Jindrich
authors.initials: J
authors.lastname: Spinar
authors.forename: Pierre
authors.initials: P
authors.lastname: Theroux
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Wiviott
authors.forename: John
authors.initials: J
authors.lastname: Strony
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
mesh_terms: D000368:Aged; D002545:Brain Ischemia / Q000188:drug therapy; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control*; D004311:Double-Blind Method; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D020300:Intracranial Hemorrhages / Q000139:chemically induced / Q000453:epidemiology; D053208:Kaplan-Meier Estimate; D007783:Lactones / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy; D058729:Peripheral Arterial Disease / Q000188:drug therapy; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D019233:Retreatment; D012306:Risk; D055502:Secondary Prevention; D020521:Stroke / Q000188:drug therapy
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C530299:vorapaxar