{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T03:40:05Z","timestamp":1781754005146,"version":"3.54.5"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2016,3,8]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              The Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis\u2013Thrombolysis in Myocardial Infarction 50 (TRA2\u00b0P-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\u20130.86;\n              <jats:italic>P<\/jats:italic>\n              =0.006) and total ALI events by 41% (94 versus 56 events; risk ratio, 0.59; 95% confidence interval, 0.38\u20130.93;\n              <jats:italic>P<\/jats:italic>\n              =0.022). The efficacy of vorapaxar was consistent across types of ALI.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Clinical Trial Registration\u2014<\/jats:title>\n            <jats:p>\n              URL:\n              <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.clinicaltrials.gov\">http:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              . Unique identifier: NCT00526474.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.115.019355","type":"journal-article","created":{"date-parts":[[2016,1,30]],"date-time":"2016-01-30T03:54:07Z","timestamp":1454126047000},"page":"997-1005","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":180,"title":["Acute Limb Ischemia and Outcomes With Vorapaxar in Patients With Peripheral Artery Disease"],"prefix":"10.1161","volume":"133","author":[{"given":"Marc P.","family":"Bonaca","sequence":"first","affiliation":[{"name":"From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Antonio","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Creager","sequence":"additional","affiliation":[{"name":"From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin M.","family":"Scirica","sequence":"additional","affiliation":[{"name":"From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Olin","sequence":"additional","affiliation":[{"name":"From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina A.","family":"Murphy","sequence":"additional","affiliation":[{"name":"From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Braunwald","sequence":"additional","affiliation":[{"name":"From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s 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.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Morrow","sequence":"additional","affiliation":[{"name":"From TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women\u2019s 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. 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