{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T20:22:50Z","timestamp":1794601370753,"version":"4.9.1"},"reference-count":25,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T00:00:00Z","timestamp":1787961600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Daiichi Sankyo Europe Ludwig-Maximilians university hospital"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Med"],"published-print":{"date-parts":[[2026,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    The selection of the optimal antithrombotic regimen in patients with atrial fibrillation and acute coronary syndrome remains challenging. Previous trials have demonstrated that dual antithrombotic therapy (DAT), consisting of direct oral anticoagulants (DOACs) plus a P2Y12 inhibitor, reduces bleeding compared to a triple-therapy regimen using vitamin K antagonists. However, subsequent meta-analyses have suggested an increased risk of ischemic events with DAT, particularly within the first month of treatment. Clopidogrel has been the predominant P2Y12 inhibitor used across these studies, despite the risk of high on-treatment platelet reactivity when using this drug. In this study, we conducted an open-label, randomized controlled trial (EPIDAURUS) in patients with atrial fibrillation and acute coronary syndrome, designed to assess the efficacy and safety of a 1-month regimen of DOAC plus potent P2Y12 inhibitor (prasugrel or ticagrelor) compared to DOAC plus clopidogrel and in-hospital aspirin. The primary outcomes of the trial were an efficacy endpoint, recurrent ischemic events and safety endpoints, including death and major bleeding, which were evaluated 6\u2009weeks after randomization using separate win\u2212loss ratio analyses. The study was prematurely terminated after enrollment of 602 patients (154 female) of an expected 1,474 patients, owing to safety concerns raised by the Data and Safety Monitoring Board. Exploratory analyses of secondary safety endpoints, including bleeding type \u22652 and \u22653 according to the Bleeding Academic Research Consortium scale, revealed that, compared to clopidogrel and in-hospital aspirin, treatment with a potent P2Y12 inhibitor was associated with higher bleeding rates without a clear reduction in the risk of ischemic complications. These findings do not support the routine use of potent P2Y12 inhibitors in combination with DOACs in this patient population. 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S.S. declares speaker\/consulting honoraria from AstraZeneca, Novartis, Berlin-Chemie, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Bayer, Pfizer, Siemens Healthineers, Johnson & Johnson and Alnylam, all unrelated to this work. H.B. received speaker honoraria, travel support and\/or a fellowship grant from Abbott\/St. Jude, Biotronik, Boston Scientific, Cardio Focus, Medtronic, Shockwave, ZOLL, AstraZeneca, Bayer, Bristol Myers Squibb, Pfizer, Daiichi Sankyo and Novartis, all unrelated to this work. H.I. received speaker honoraria from Daiichi Sankyo, unrelated to this work. I.E. declares speaker honoraria from AstraZeneca, Abbott, Boston Scientific, Bristol Myers Squibb, Boehringer Ingelheim, Bayer, Cytogenetics, Corvia, Daiichi Sankyo, Meril, Novartis, Sanofi and Vifor. P.K. received research support for basic, translational and clinical research projects from the German Research Foundation, the European Union, the British Heart Foundation, the Leducq Foundation, the Else-Kr\u00f6ner-Fresenius Foundation, the Dutch Heart Foundation, the Accelerating Clinical Trials funding stream in Canada, the Medical Research Council (UK) and the German Center for Cardiovascular Research and from several drug and device companies active in atrial fibrillation. I.E. has also received honoraria from several such companies in the past but not in the last 5\u2009years. P.K. is listed as inventor on two issued patents held by the University of Hamburg (Atrial Fibrillation Therapy, WO 2015140571; Markers for Atrial Fibrillation, WO 2016012783). He volunteers as chairman of the Atrial Fibrillation Network (AFNET). J.S. received speaker honoraria from AstraZeneca and Johnson & Johnson and travel compensation from Medtronic, Meril and ShockWave, all unrelated to this work. D.S. received speaker fees and fees for advisory board activies from Bayer, Sanofi, Daiichi Sankyo and Werfen. N.F. reports speaker honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer. A.S. received lecture fees and honoraria from Abiomed, Amgen, AstraZeneca, Daiichi Sankyo, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Pfizer and ZOLL as well as research support from Abiomed and Daiichi Sankyo. All other authors declare no competing interests with respect to this study and to the products investigated in this study.","order":1,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Ethics"}}]}}