Vorapaxar in the Secondary Prevention of Atherothrombotic Events

Study Questions:

What is the role of vorapaxar, a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of protease-activated receptor (PAR-1), for secondary prevention of atherothrombotic events?

Methods:

The investigators 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 endpoint 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 endpoint had occurred in 1,028 patients (9.3%) in the vorapaxar group and in 1,176 patients (10.5%) in the placebo group (hazard ratio in the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80-0.94; p < 0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1,259 patients (11.2%) in the vorapaxar group and 1,417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82-0.95; 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, 1.43-1.93; 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:

The authors concluded that vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy.

Perspective:

This study suggests that 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. Any clinical use of vorapaxar would have to be based on an appropriate selection of patients, with the risk of bleeding balanced against that of recurrent thrombotic events, and the future role of this drug remains uncertain.

Clinical Topics: Dyslipidemia, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Novel Agents

Keywords: Stroke, Myocardial Infarction, Thrombin, Platelet Aggregation Inhibitors, Receptors, Proteinase-Activated, Clinical Trials Data Monitoring Committees, Pyridines, Peripheral Arterial Disease, Receptors, Thrombin, Intracranial Hemorrhages, Secondary Prevention, Lactones, Confidence Intervals


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