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

Study Questions:

What is the effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction (MI)?

Methods:

In TRA 2°P-TIMI 50—a randomized, placebo-controlled, parallel trial—the investigators 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 analyzing results were masked to treatment allocation. Patients with a qualifying MI within the previous 2 weeks to 12 months were analyzed as a predefined subgroup. The primary efficacy endpoint was cardiovascular death, MI, or stroke, analyzed by intention to treat. The authors analyzed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model.

Results:

A total of 17,779 of 26,449 patients had a qualifying MI and were assigned treatment (8,898 to vorapaxar and 8,881 to placebo). Median follow-up was 2.5 years (interquartile range [IQR], 2.0–2.9). Cardiovascular death, MI, or stroke occurred in 610 of 8,898 patients in the vorapaxar group and 750 of 8,881 in the placebo group (3-year Kaplan-Meier estimates, 8.1% vs. 9.7%; hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.72–0.89; p < 0.0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8,880 [3.4%, 3-year Kaplan-Meier estimate] vs. 151/8,849 [2.1%, 3-year Kaplan-Meier estimate]; HR, 1.61, 95% CI, 1.31–1.97; p < 0.0001). Intracranial hemorrhage occurred in 43 of 8,880 patients (0.6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8,849 (0.4%, 3-year Kaplan-Meier estimate) with placebo (p = 0.076). Other serious adverse events were equally distributed between groups.

Conclusions:

The authors concluded that for patients with a history of MI, vorapaxar reduces the risk of cardiovascular death or ischemic events when added to standard antiplatelet treatment, including aspirin, but increases the risk of moderate or severe bleeding.

Perspective:

This subgroup analysis of the TRA 2°P-TIMI 50 study reports that vorapaxar significantly reduced major cardiovascular thrombotic events in stable patients with a history of MI. This finding appears to suggest that protease-activated receptor-1 may potentially be a novel therapeutic target for long-term secondary prevention after MI. However, it is concerning that vorapaxar also increased the risk of moderate or severe bleeding. It will be important to identify patients for whom reduction of thrombotic events outweighs the risk of bleeding to guide treatment and define the future role of vorapaxar. Additional prospective studies are indicated to further define the role of vorapaxar and other novel antithrombotic drugs for extended antiplatelet treatment in addition to aspirin in patients with previous MI.

Clinical Topics: Prevention

Keywords: Myocardial Infarction, Stroke, Kaplan-Meier Estimate, Platelet Aggregation Inhibitors, Secondary Prevention


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