{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:51:41Z","timestamp":1792788701719,"version":"4.5.0"},"reference-count":23,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"23","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,12,8]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71\u20131.01) with clopidogrel and 0.86 (95% CI, 0.73\u20131.01) without clopidogrel without statistical heterogeneity (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14\u20131.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22\u20131.01] without clopidogrel;\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              for interaction=0.71). With clopidogrel use &gt;30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44\u20137.13]) compared with shorter durations of clopidogrel (\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              for trend=0.06).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use &gt;30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (\u226430 days) associated with less bleeding.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Registration:<\/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=\"https:\/\/www.clinicaltrials.gov\">https:\/\/www.clinicaltrials.gov<\/jats:ext-link>\n              ; Unique identifier: NCT02504216.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.120.050465","type":"journal-article","created":{"date-parts":[[2020,11,3]],"date-time":"2020-11-03T10:00:20Z","timestamp":1604397620000},"page":"2219-2230","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":102,"title":["Rivaroxaban and Aspirin in Peripheral Artery Disease Lower Extremity Revascularization"],"prefix":"10.1161","volume":"142","clinical-trial-number":[{"clinical-trial-number":"nct02504216","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7571-7557","authenticated-orcid":true,"given":"William R.","family":"Hiatt","sequence":"first","affiliation":[{"name":"CPC Clinical Research, Aurora, CO (W.R.H., M.P.B., M.R.N., W.H.C., T.B., N.J., C.N.H.)."},{"name":"University of Colorado School of Medicine, Division of Cardiology, Anschutz Medical Campus, Aurora (W.R.H., M.P.B., C.N.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9860-3584","authenticated-orcid":true,"given":"Marc P.","family":"Bonaca","sequence":"additional","affiliation":[{"name":"CPC Clinical Research, Aurora, CO (W.R.H., M.P.B., M.R.N., W.H.C., T.B., N.J., C.N.H.)."},{"name":"University of Colorado School of Medicine, Division of Cardiology, Anschutz Medical Campus, Aurora (W.R.H., M.P.B., C.N.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manesh R.","family":"Patel","sequence":"additional","affiliation":[{"name":"Duke Clinical Research Institute, Division of Cardiology, Duke University Medical Center, Durham, NC (M.R.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Nehler","sequence":"additional","affiliation":[{"name":"CPC Clinical Research, Aurora, CO (W.R.H., M.P.B., M.R.N., W.H.C., T.B., N.J., C.N.H.)."},{"name":"Department of Surgery (M.R.N.), University of Colorado School of Medicine, Aurora."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eike Sebastian","family":"Debus","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Vascular Surgery\u2013Angiology\u2013Endovascular Therapy, University of Hamburg-Eppendorf, Hamburg, Germany (E.S.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3692-7441","authenticated-orcid":true,"given":"Sonia S.","family":"Anand","sequence":"additional","affiliation":[{"name":"Population Health Research Institute, Hamilton Health Sciences, McMaster University, ON, Canada (S.S.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren H.","family":"Capell","sequence":"additional","affiliation":[{"name":"CPC Clinical Research, Aurora, CO (W.R.H., M.P.B., M.R.N., W.H.C., T.B., N.J., C.N.H.)."},{"name":"Department of Medicine, Division of Endocrinology, University of Colorado Anschutz Medical Campus, Aurora (W.H.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Brackin","sequence":"additional","affiliation":[{"name":"CPC Clinical Research, Aurora, CO (W.R.H., M.P.B., M.R.N., W.H.C., T.B., N.J., C.N.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Jaeger","sequence":"additional","affiliation":[{"name":"CPC Clinical Research, Aurora, CO (W.R.H., M.P.B., M.R.N., W.H.C., T.B., N.J., C.N.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5830-0511","authenticated-orcid":true,"given":"Connie N.","family":"Hess","sequence":"additional","affiliation":[{"name":"CPC Clinical Research, Aurora, CO (W.R.H., M.P.B., M.R.N., W.H.C., T.B., N.J., C.N.H.)."},{"name":"University of Colorado School of Medicine, Division of Cardiology, Anschutz Medical Campus, Aurora (W.R.H., M.P.B., C.N.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2161-3151","authenticated-orcid":true,"given":"Akos F.","family":"Pap","sequence":"additional","affiliation":[{"name":"Bayer AG, Research &amp; Development, Wuppertal, Germany (A.F.P., E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9428-4408","authenticated-orcid":true,"given":"Scott D.","family":"Berkowitz","sequence":"additional","affiliation":[{"name":"Bayer US LLC, Whippany, NJ (S.D.B.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Muehlhofer","sequence":"additional","affiliation":[{"name":"Bayer AG, Research &amp; Development, Wuppertal, Germany (A.F.P., E.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lloyd","family":"Haskell","sequence":"additional","affiliation":[{"name":"Janssen Research and Development, Raritan, NJ (L.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Brasil","sequence":"additional","affiliation":[{"name":"FELUMA\u2013Faculdade de Ciencias Medicas de Minas Gerais School of Medicine, Belo Horizonte, Brazil 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