• Benjamin M Scirica, Marc P Bonaca, Eugene Braunwald, Gaetano M De Ferrari, Daniel Isaza, Basil S Lewis, Felix Mehrhof, Piera A Merlini, Sabina A Murphy, Marc S Sabatine, Michal Tendera, Frans Van de Werf, Robert Wilcox, David A Morrow, and TRA 2°P-TIMI 50 Steering Committee Investigators.
• Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. bscirica@partners.org
• Lancet. 2012 Oct 13; 380 (9850): 131713241317-24.

BackgroundVorapaxar 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.MethodsIn 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).Findings17,779 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.InterpretationFor 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.FundingMerck.Copyright © 2012 Elsevier Ltd. All rights reserved.

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