{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T15:58:38Z","timestamp":1779119918938,"version":"3.51.4"},"reference-count":21,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2021,12,28]],"date-time":"2021-12-28T00:00:00Z","timestamp":1640649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>In patients with atrial fibrillation (AF), peripheral artery disease (PAD) is associated with higher rates of stroke and bleeding. Both higher dose edoxaban (60\/30\u00a0mg) and lower dose edoxaban (30\/15\u00a0mg) were non-inferior to warfarin for stroke and systemic embolism (SSE) and significantly reduced major bleeding in AF patients in the global study to assess the safety and effectiveness of edoxaban vs standard practice of dosing with warfarin in patients with atrial fibrillation (ENGAGE AF-TIMI 48) trial. Whether the efficacy and safety of these dosing strategies vs. warfarin are consistent in patients with AF and PAD has not been described.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results<\/jats:title>\n                  <jats:p>Of 21\u2009105 patients with AF randomized to warfarin, edoxaban 60\/30\u00a0mg, or edoxaban 30\/15\u00a0mg, 841 were identified with PAD. Endpoints included major adverse cardiovascular events (MACEs), SSE, and major bleeding. Patients with PAD had higher risk of MACEs [adjusted hazard ratio (HRadj) 1.33, 95% confidence interval (CI) 1.12\u20131.57, P = 0.001] and cardiovascular (CV) death (HRadj 1.49, 95% CI 1.21\u20131.83, P &amp;lt; 0.001) than those without PAD, but not major bleeding. The efficacy of edoxaban 60\/30\u00a0mg vs. warfarin was consistent regardless of PAD (SSE HR; PAD 1.16, 95% CI 0.42\u20133.20; no-PAD 0.86, 95% CI 0.74\u20131.02, P-interaction 0.57) as was major bleeding (PAD 0.96, 95% CI 0.54\u20131.70; no-PAD 0.80, 95% CI 0.70\u20130.91, P-interaction 0.54). Edoxaban 30\/15\u00a0mg was inferior for SSE, with significant heterogeneity when stratified by PAD status (P-interaction 0.039).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Patients with AF and PAD are at heightened risk of MACEs and CV death vs. those without PAD. The efficacy and safety of edoxaban 60\/30\u00a0mg vs. warfarin in AF are consistent regardless of PAD; however, edoxaban 30\/15\u00a0mg is inferior for stroke prevention in AF patients with PAD.<\/jats:p>\n                  <jats:p>Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00781391<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/ehjcvp\/pvab089","type":"journal-article","created":{"date-parts":[[2021,12,27]],"date-time":"2021-12-27T04:06:13Z","timestamp":1640577973000},"page":"695-706","source":"Crossref","is-referenced-by-count":11,"title":["Ischaemic and bleeding risk in atrial fibrillation with and without peripheral artery disease and efficacy and safety of full- and half-dose edoxaban vs. warfarin: insights from ENGAGE AF-TIMI 48"],"prefix":"10.1093","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9860-3584","authenticated-orcid":false,"given":"Marc P","family":"Bonaca","sequence":"first","affiliation":[{"name":"TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA, USA"},{"name":"Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, MA, USA"},{"name":"CPC Clinical Research, University of Colorado School of Medicine , 13199 E. Montview Blvd., Suite 200, Aurora, CO 80045, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0808-9199","authenticated-orcid":false,"given":"Elliott M","family":"Antman","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA, USA"},{"name":"Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4481-7867","authenticated-orcid":false,"given":"Jonathan W","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen D","family":"Wiviott","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA, USA"},{"name":"Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabina A","family":"Murphy","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan L","family":"Halperin","sequence":"additional","affiliation":[{"name":"Cardiovascular Division, Department of Medicine, Icahn School of Medicine at Mount Sinai , New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey I","family":"Weitz","sequence":"additional","affiliation":[{"name":"Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute , Hamilton, ON, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael A","family":"Grosso","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Inc. , Basking Ridge, NJ, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans J","family":"Lanz","sequence":"additional","affiliation":[{"name":"Daiichi Sankyo Europe GmbH , Munich, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3472-626X","authenticated-orcid":false,"given":"Eugene","family":"Braunwald","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA, USA"},{"name":"Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4110-7675","authenticated-orcid":false,"given":"Robert P","family":"Giugliano","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA, USA"},{"name":"Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4712-3206","authenticated-orcid":false,"given":"Christian T","family":"Ruff","sequence":"additional","affiliation":[{"name":"TIMI Study Group, Cardiovascular Medicine, Brigham and Women's Hospital , Boston, MA, USA"},{"name":"Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,12,28]]},"reference":[{"key":"2022092908584477100_bib1","doi-asserted-by":"crossref","first-page":"e56","DOI":"10.1161\/CIR.0000000000000659","article-title":"Heart disease and stroke statistics\u20142019 update: a report from the American Heart Association","volume":"139","author":"Benjamin","year":"2019","journal-title":"Circulation"},{"key":"2022092908584477100_bib2","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1093\/eurheartj\/ehx095","article-title":"2017 ESC Guidelines on the diagnosis and treatment of peripheral arterial diseases, in collaboration with the European Society for Vascular Surgery (ESVS): document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries. 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