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

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 degrees P)-TIMI 50 trial.

Methods In TRA 2 degrees 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 degrees P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474).

Findings 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.

Interpretation 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.