title: Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease: Results From the Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50).
abstract: BACKGROUND
  Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a morbid event that may result in limb loss. We investigated the causes, sequelae, and predictors of ALI in a contemporary population with symptomatic PAD and whether protease-activated receptor 1 antagonism with vorapaxar reduced ALI overall and by type.
  
  
  RESULTS
  The Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis-Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in stable patients, including 3787 with symptomatic PAD. ALI was a prespecified adjudicated end point using a formal definition. A total of 150 ALI events occurred in 108 patients during follow-up (placebo 3-year rate, 3.9%; 1.3% annualized). For patients with symptomatic PAD, previous peripheral revascularization, smoking, and the ankle-brachial index were predictive of ALI. The majority of ALI events occurred as a result of surgical graft thrombosis (56%), followed by native vessel in situ thrombosis (27%). Stent thrombosis and thromboembolism caused ALI in 13% and 5%, respectively. Amputation occurred in 17.6% presenting with ALI. Vorapaxar reduced first ALI events by 41% (hazard ratio, 0.58; 95% confidence interval, 0.39-0.86; P=0.006) and total ALI events by 41% (94 versus 56 events; risk ratio, 0.59; 95% confidence interval, 0.38-0.93; P=0.022). The efficacy of vorapaxar was consistent across types of ALI.
  
  
  CONCLUSIONS
  In selected patients with symptomatic PAD and without atrial fibrillation, ALI occurs at a rate of 1.3%/y, is most frequently caused by acute bypass graft thrombosis or in situ thrombosis of a diseased vessel, and often results in limb loss. Vorapaxar reduces ALI in patients with symptomatic PAD with consistency across type, including PAD resulting from surgical graft thrombosis and in-situ thrombosis.
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT00526474.
authors.affiliation: From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA(M.P.B., J.A.G., B.M.S., S.A.H., E.B., D.A.M.); Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH(M.A.C.); and Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY (J.O.). mbonaca@partners.org.
authors.forename: Marc P
authors.initials: MP
authors.lastname: Bonaca
authors.affiliation: From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA(M.P.B., J.A.G., B.M.S., S.A.H., E.B., D.A.M.); Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH(M.A.C.); and Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY (J.O.).
authors.forename: J Antonio
authors.initials: JA
authors.lastname: Gutierrez
authors.affiliation: From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA(M.P.B., J.A.G., B.M.S., S.A.H., E.B., D.A.M.); Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH(M.A.C.); and Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY (J.O.).
authors.forename: Mark A
authors.initials: MA
authors.lastname: Creager
authors.affiliation: From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA(M.P.B., J.A.G., B.M.S., S.A.H., E.B., D.A.M.); Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH(M.A.C.); and Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY (J.O.).
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Scirica
authors.affiliation: From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA(M.P.B., J.A.G., B.M.S., S.A.H., E.B., D.A.M.); Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH(M.A.C.); and Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY (J.O.).
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Olin
authors.affiliation: From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA(M.P.B., J.A.G., B.M.S., S.A.H., E.B., D.A.M.); Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH(M.A.C.); and Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY (J.O.).
authors.forename: Sabina A
authors.initials: SA
authors.lastname: Murphy
authors.affiliation: From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA(M.P.B., J.A.G., B.M.S., S.A.H., E.B., D.A.M.); Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH(M.A.C.); and Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY (J.O.).
authors.forename: Eugene
authors.initials: E
authors.lastname: Braunwald
authors.affiliation: From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA(M.P.B., J.A.G., B.M.S., S.A.H., E.B., D.A.M.); Dartmouth-Hitchcock Heart and Vascular Center, Geisel School of Medicine at Dartmouth, Lebanon, NH(M.A.C.); and Wiener Cardiovascular Institute and Marie-Jose and Henry R. Kravis Center for Cardiovascular Health, Mount Sinai School of Medicine, New York, NY (J.O.).
authors.forename: David A
authors.initials: DA
authors.lastname: Morrow
mesh_terms: D000208:Acute Disease; D000368:Aged; D050197:Atherosclerosis / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D001026:Coronary Artery Bypass / Q000009:adverse effects; D004311:Double-Blind Method; D005121:Extremities / Q000098:blood supply; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007511:Ischemia / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D007783:Lactones / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control*; D058729:Peripheral Arterial Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D011446:Prospective Studies; D011725:Pyridines / Q000627:therapeutic use*; D020521:Stroke / Q000175:diagnosis / Q000453:epidemiology / Q000517:prevention & control*; D015912:Thrombolytic Therapy / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D007783:Lactones; D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C530299:vorapaxar
keywords: limb; limb ischemia; peripheral artery disease; peripheral vascular diseases; thrombosis