title: Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial.
abstract: BACKGROUND
  Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial.
  
  
  METHODS
  In TRA 2°P-TIMI 50--a randomised, placebo-controlled, parallel trial--we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2·5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2°P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474).
  
  
  RESULTS
  17,779 of 26,449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2·5 years (IQR 2·0-2·9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8·1%vs 9·7%, HR 0·80, 95% CI 0·72-0·89; p<0·0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3·4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2·1%, 3-year Kaplan-Meier estimate], HR 1·61, 95% CI 1·31-1·97; p<0·0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0·6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0·4%, 3-year Kaplan-Meier estimate) with placebo (p=0·076). Other serious adverse events were equally distributed between groups.
  
  
  CONCLUSIONS
  For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding.
  
  
  BACKGROUND
  Merck.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. bscirica@partners.org
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Scirica
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.forename: Gaetano M
authors.initials: GM
authors.lastname: De Ferrari
authors.forename: Daniel
authors.initials: D
authors.lastname: Isaza
authors.forename: Basil S
authors.initials: BS
authors.lastname: Lewis
authors.forename: Felix
authors.initials: F
authors.lastname: Mehrhof
authors.forename: Piera A
authors.initials: PA
authors.lastname: Merlini
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.forename: Marc S
authors.initials: MS
authors.lastname: Sabatine
authors.forename: Michal
authors.initials: M
authors.lastname: Tendera
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
authors.forename: Robert
authors.initials: R
authors.lastname: Wilcox
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000401:mortality; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007783:Lactones / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D055502:Secondary Prevention; D020521:Stroke / Q000209:etiology / Q000517:prevention & control; D013927:Thrombosis / Q000150:complications* / Q000209:etiology / Q000517:prevention & control*; D010975:Platelet Aggregation Inhibitors
chemical_list: D007783:Lactones; D011725:Pyridines; C530299:vorapaxar; D010975:Platelet Aggregation Inhibitors