Safety and efficacy of protease-activated receptor-1 antagonists in patients with coronary artery disease: A meta-analysis of randomized clinical trials

Background: Thrombin receptor antagonists blocking protease-activated receptor-1 (PAR-1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. Objectives: We investigated the safety and efficacy of PAR-1 antagonists in patients with coronary artery disease (CAD). Patients/Methods: Randomized, placebo-controlled trials of the PAR-1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. Results: A total of 41647 patients from eight trials were included. PAR-1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39-1.57, P<0.001), major (OR 1.46, 95% CI 1.28-1.67, P<0.001) and minor (OR 1.67, 95% CI 1.40-2.00, P<0.001) bleeding than placebo in the fixed-effects model. PAR-1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81-0.92, P<0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78-0.92, P<0.001). Conversely, PAR-1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90-1.09, P=0.81) or stroke (OR 0.96, 95% CI 0.84-1.10, P=0.59). Conclusions: PAR-1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.