Vorapaxar in the secondary prevention of atherothrombotic events

David A. Morrow, Eugene Braunwald, Marc P. Bonaca, Sebastian F. Ameriso, Anthony J. Dalby, Mary Polly Fish, Keith A.A. Fox, Leslie J. Lipka, Xuan Liu, José Carlos Nicolau, A. J.Oude Ophuis, Ernesto Paolasso, Benjamin M. Scirica, Jindrich Spinar, Pierre Theroux, Stephen D. Wiviott, John Strony, Sabina A. Murphy, TRA 2P–TIMI 50 Steering Committee and Investigators, P. AylwardD. Chew

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    639 Citations (Scopus)

    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.)

    Original languageEnglish
    Pages (from-to)1404-1413
    Number of pages10
    JournalNew England Journal of Medicine
    Volume366
    Issue number15
    DOIs
    Publication statusPublished - 12 Apr 2012

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