BACKGROUND: Vorapaxar is a novel antagonist of protease-activated receptor (PAR)-1, the primary receptor for thrombin on human platelets that is also present on vascular endothelium and smooth muscle. Patients with peripheral artery disease (PAD) are at risk of systemic atherothrombotic events as well as acute and chronic limb ischemia and need for peripheral revascularization. METHODS AND RESULTS: The TRA2°P-TIMI 50 trial was a randomized, double-blind, placebo controlled trial of vorapaxar in 26,449 patients with stable atherosclerotic vascular disease (MI, stroke, or PAD). Patients with qualifying PAD (N= 3,787) had a history of claudication and ABI of <0.85 or prior revascularization for limb ischemia. The primary efficacy endpoint was cardiovascular death, MI, or stroke and the principal safety endpoint was GUSTO bleeding. In the PAD cohort, the primary endpoint did not differ significantly with vorapaxar (11.3% vs. 11.9%, HR 0.94, 95% CI 0.78-1.14, p=0.53). However, rates of hospitalization for acute limb ischemia (2.3% vs. 3.9%, HR 0.58, 95% CI 0.39-0.86, p=0.006) and peripheral artery revascularization (18.4% vs. 22.2%, HR 0.84, 95% CI 0.73-0.97, p=0.017) were significantly lower in patients randomized to vorapaxar. Bleeding occurred more frequently with vorapaxar compared with placebo (7.4% vs. 4.5%, HR 1.62, 95% CI 1.21-2.18, p=0.001). CONCLUSIONS: Vorapaxar did not reduce the risk of cardiovascular death, MI, or stroke in patients with PAD; however, vorapaxar significantly reduced acute limb ischemia and peripheral revascularization. The beneficial effects of PAR-1 antagonism on limb vascular events were accompanied by an increased risk of bleeding. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov; Identifier: NCT00526474.