Vorapaxar in Patients With Peripheral Artery Disease

Abstract

Background— Vorapaxar is a novel antagonist of protease-activated receptor-1, the primary receptor for thrombin on human platelets that is also present on vascular endothelium and smooth muscle. Patients with peripheral artery disease are at risk of systemic atherothrombotic events, as well as acute and chronic limb ischemia and the need for peripheral revascularization. Methods and Results— The Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26 449 patients with stable atherosclerotic vascular disease (myocardial infarction, stroke, or peripheral artery disease). Patients with qualifying peripheral artery disease (n=3787) had a history of claudication and an ankle-brachial index of <0.85 or prior revascularization for limb ischemia. The primary efficacy end point was cardiovascular death, myocardial infarction, or stroke, and the principal safety end point was Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) bleeding. In the peripheral artery disease cohort, the primary end point did not differ significantly with vorapaxar (11.3% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.78–1.14; P =0.53). However, rates of hospitalization for acute limb ischemia (2.3% versus 3.9%; hazard ratio, 0.58; 95% confidence interval, 0.39–0.86; P =0.006) and peripheral artery revascularization (18.4% versus 22.2%; hazard ratio, 0.84; 95% confidence interval, 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% versus 4.5%; hazard ratio, 1.62; 95% confidence interval, 1.21–2.18; P =0.001). Conclusions— Vorapaxar did not reduce the risk of cardiovascular death, myocardial infarction, or stroke in patients with peripheral artery disease; however, vorapaxar significantly reduced acute limb ischemia and peripheral revascularization. The beneficial effects of protease-activated receptor-1 antagonism on limb vascular events were accompanied by an increased risk of bleeding. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00526474.

Targeting PAR1: Now What?

“…In patients from TRA 2°P with peripheral vascular disease, vorapaxar reduced hospitalization as a result of acute limb ischemia (2.3% with vorapaxar, 3.9% with placebo, P=0.006) and peripheral artery revascularization (18.4% with vorapaxar, 22.2% with placebo, P=0.017). Bleeding was more frequent in patients taking vorapaxar (7.4% with vorapaxar, 4.5% with placebo, P=0.001) [73]. Diabetics participating in the TRA 2°P trial demonstrated additional benefit with regard to the primary endpoint of cardiovascular death, MI, or cerebrovascular accident (12.6% with vorapaxar, 15.7% with placebo, P=0.004).…”

Platelets: Small in Size But Essential in the Regulation of Vascular Homeostasis – Translation From Basic Science to Clinical Medicine –

“…Role of Platelets PAR-1 inhibitors; that is, patients with prior MI. 119 Even in prior MI patients, those with diabetes were shown to be the most appropriate patient population for vorapaxar. 59 The clinical development of vorapaxar and the assessment of the data by the US regulatory authority 120 give us a clue to the selection of suitable small populations of patients for new drug interventions within the database of large-scale global trials in the future.…”

Unmet needs in the management of acute myocardial infarction: role of novel protease-activated receptor-1 antagonist vorapaxar

“…In an analysis excluding such patients (n=14,909), known as a low-bleeding-risk cohort, the primary combined ischemic end point was significantly reduced with vorapaxar compared with placebo (6.8% versus 8.6%, HR 0.75, 95% CI 0.66–0.85; P <0.0001), and there was also a significant reduction in cardiovascular death (1.5% versus 2.0%, HR 0.73, 95% CI 0.56–0.95; P =0.02). GUSTO moderate or severe bleeding was lower than in the overall trial, although still higher with vorapaxar than placebo (2.7% versus 1.8%) 59. Overall, this analysis conducted among patients who were randomized in the TRA 2°P trial indicates that among appropriately selected patients, prolonged treatment with vorapaxar when added to aspirin with or without a thienopyridine may be beneficial for long-term secondary prevention in patients with prior MI.…”

“…Vorapaxar failed to reduce the primary efficacy end point compared with placebo (11.3% versus 11.9%, HR 0.94, 95% CI 0.78–1.14; P =0.53) 59. However, vorapaxar did reduce the rate of hospitalization for acute limb ischemia (2.3% versus 3.9%, HR 0.58, 95% CI 0.39–0.86; P =0.006) and peripheral artery revascularization (18.4% versus 22.2%, HR 0.84, 95% CI 0.73–0.97; P =0.017).…”