title: Vorapaxar in patients with peripheral artery disease: results from TRA2{degrees}P-TIMI 50.
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.
  
  
  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.
authors.affiliation: TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115, USA. mbonaca@partners.org
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Scirica
authors.forename: Mark A
authors.initials: MA
authors.lastname: Creager
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Olin
authors.forename: Henri
authors.initials: H
authors.lastname: Bounameaux
authors.forename: Mikael
authors.initials: M
authors.lastname: Dellborg
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Lamp
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
mesh_terms: D000368:Aged; D055109:Ankle Brachial Index; D015331:Cohort Studies; D015897:Comorbidity; D004311:Double-Blind Method; D005121:Extremities / Q000098:blood supply; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000139:chemically induced / Q000401:mortality; D006801:Humans; D007511:Ischemia / Q000188:drug therapy* / Q000401:mortality; D053208:Kaplan-Meier Estimate; D007783:Lactones / Q000008:administration & dosage* / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000401:mortality; D058729:Peripheral Arterial Disease / Q000188:drug therapy* / Q000401:mortality; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects*; D044463:Receptor, PAR-1 / Q000378:metabolism; D012307:Risk Factors; D020521:Stroke / Q000401:mortality; D013917:Thrombin / Q000378:metabolism; D016896:Treatment Outcome; D010975:Platelet Aggregation Inhibitors
chemical_list: D007783:Lactones; D011725:Pyridines; D044463:Receptor, PAR-1; D013917:Thrombin; C530299:vorapaxar; D010975:Platelet Aggregation Inhibitors