Net Benefit of Early Anticoagulation for Stroke With Atrial Fibrillation
Authors: Alexandros A. Polymeris, Mattia Branca, P. N. Sylaja, Else Charlotte Sandset, Diana Aguiar de Sousa, Götz Thomalla, Maurizio Paciaroni, Thomas Gattringer, Daniel Strbian, Sven Trelle, Patrik Michel, Krassen Nedeltchev, Leo H. Bonati, George Ntaios, Masatoshi Koga, Zuzana Gdovinova, Robin Lemmens, Natan M. Bornstein, Peter Kelly, Martina B. Goeldlin, Stefanie Abend, Magdy Selim, Mira Katan, Thomas Horvath, Jesse Dawson, Urs Fischer, Adedolapo Kamaldee Adeyemi, Adhiyaman Vedamurthy, Adrian Scutelnic, Akiyama Hisanao, Alastair Wilson, Alexander Pichler, Alexander Salerno, Alexander Vanhoorne, Ami Wilkinson, Ana Paiva Nunes, Anastasia Adamou, André Peeters, Andrea M. Humm, Andrea Zini, Aneesh Dhasan, Angelika Alonso, Anna Fischer, Anna Maija Saukkonen, Anna Müller, Anne Berberich, Anne Falcou, Annemie Devroye, Arne Hostens, Arsany Hakim, Arthur Liesz, Arunkumar Annamalai, Arvind Vijaysharan Sharma, Asterios Paliantonis, Aumugam Nallasivan, Azmil Abdul-Rahim, Beata Rezny-Kasprzak, Ben Grimshaw, Bernd Kallmünzer, Biljana Rodic, Brian Clarke, Brian Menezes, Bruno J. Weder, Carla Ciobanu, Carlo W. Cereda, Caroline Loos, Caterina Kulyk, Catia Gonçalves Martins, Cecilia Ferrari, Christian Fung, Christina Caporale, Christine McAlpine, Christoph Globas, Christoph Gumbinger, Christophe Bonvin, Christos Krogias, Clare  Whyte, Claudio Bassetti, Dan Ryan, Daniel Charissé, Daniel Richter, Daniel Schrammel, Daria Giudici, Darius G. Nabavi, David Bradley, David Orion, David J. Seiffge, David Werring, Davide Strambo, Derek Esson, Dheeraj Khurana , Diana Melancia, Dimitre Staykov, Dimitri Hemelsoet, Dominik Michalski, Eckhard Schlemm, Efstathia Karagkiozi, Elisabeth Olbert, Espen Saxhaug Kristoffersen, Evelyn Marcelis, Fiona Wright, François Delvoye, Friedrich Medlin, Fukano Takayuki , Gaia Sirimarco, Gek Shim, Gemma Marie Smith, Georg  Royl, George Pope, Georgia Salanti, Gerli Sibolt, German Guzman-Gutierrez, Gian Marco De Marchis, Giovanni Bianco, Harvey Dymond, Hege Ihle-Hansen, Helen Thomas, Henning R. Stetefeld, Himanshu Koundal, Honig Asaf, Ijaz Anwar, Ilaria Leone De Magistris, Imelda Noone, Ingrid Olave Bersas, Ioan-Paul Muresan, Isabelle Vanpanteghem, Jan Gralla, Jan Vynckier, Jelle Demeestere, Jens Offermann, Jeyaraj Durai Pandian, João André Sousa, João Pedro Marto, João Sargento-Freitas, Jochen Vehoff, Johann Pelz, John J. McCabe, Joseph Harbison, Joshua Mbroh, Judith Wagner, Julien Niederhauser, Jussi Sipilä, Kanta Tanaka, Karthika Rani, Katarina Klimcikova, Kerry Smith, Klaudia Soltesova, Kosmas Macha, Kosuke Matzusono, Kristina Szabo, Laetitia Yperzeele, Lars Alteheld, Lars Kellert, Liam Healy, Liqun Zhang, Loraine Fisch, Luana Gentile, Ludwig Schelosky, Lukas Kellermair, Lukuman  Gbadamosh, Lynn Dixon, Makoto Nakajima, Manabu Inoue, Manju Krishnan, Manuel Bolognese, Marcel Arnold, Maria Giulia Mosconi, Marianne Altmann, Marie Lang, Marios Psychogios, Marjaana Tiainen, Mark Barber, Markus Arnold, Markus Kneihsl, Marta Magriço, Martin Müller, Mary Joan MacLeod, Matthias Greulich, Matthieu Pierre Rutgers, Maximilian Schell, Melissa  Garcia-Pons, Mette Pøhner Skahjem, Michael Haley, Michael Marnane, Milan Vosko, Miroslav Mako, Naren Polavarapu, Nicolas Martinez-Majander, Nicole Del Gaudio, Nicoletta G. Caracciolo, Nils Peters, Niranjan Mahajan, Norbert Silimon, Oezguer A. Onur, Ole Morten Rønning, Peter Ringleb, Peter Slade, Peter Vanacker, Philippe Desfontaines, Priya Nair, Rados Marian, Rajsrinivas Parthasarathy            , Rea Hidalgo, Riona Mulcahy, Risa Kato, Rohit Bhatia, Ronan Collins, Ronen R. Leker, Roni Eichel, Sabine Fenzl, Ryota Tanaka, Samer Al Hussayni Husseini, Sandra Clarke, Sapna Erat Sreedharan, Sarah Ostanek, Sellimi Amina, Seraina Beyeler, Sharon Storton, Shigeru Fujimoto, Silja Räty, Simon Fandler-Höfler, Sofia Galego, Sohei Yoshimura, Soichiro Matsubara, Stefan Greisenegger, Stefan Oberndorfer, Sucharita Ray, Susanne Renaud, Susanne Riebau, Sven Poli, Svetlana Politz, Sylvan J. Albert, Takenobu Kunieda, Takeo Sato, Takeshi Yoshimoto, Tal Anjum, Tatjana Pap, Telma Costa, Teresa Pinho e Melo, Thomas Iype, Tim Cassidy, Tim J. Von Oertzen, Timo Kahles, Toni Danilo, Torstein Spetalen, Turgut Tatlisumak, Veerle De Herdt, Victoria Borisova, Vijaya Pamidimukkala, Vikram Huded, Vipul Gupta , Vishav Kumar, Vivek Nambiar, Waltraud Pfeilschifter, Wendy Stoop, Yasuyuki Iguchi, Yngve Müller Seljeseth, Youssif Abousleiman, Yusuke Yakushiji, Zoltan Pencz
Journal: JAMA Network Open (2025)

Importance The net clinical effect of early vs later direct oral anticoagulant (DOAC) initiation after atrial fibrillation–associated ischemic stroke is unclear. Objective To investigate whether early DOAC treatment is associated with a net clinical benefit (NCB). Design, Setting, and Participants This was a post hoc analysis of the Early Versus Late Initiation of Direct Oral Anticoagulants in Post–Ischaemic Stroke Patients With Atrial Fibrillation (ELAN) open-label randomized clinical trial conducted across 103 sites in 15 countries in Europe, the Middle East, and Asia between November 6, 2017, and September 12, 2022, with a 90-day follow-up. Participants included patients with atrial fibrillation–associated acute ischemic stroke, excluding those with therapeutic anticoagulation at stroke onset or with severe hemorrhagic transformation of the ischemic infarct. Intervention Early DOAC initiation (&amp;amp;lt;48 hours after minor and moderate stroke, 6-7 days after major stroke) vs later initiation (3-4 days after minor stroke, 6-7 days after moderate stroke, and 12-14 days after major stroke). Main Outcomes and Measures The main measure was the NCB of early treatment over later treatment, calculated by subtracting the weighted rate of excess bleeding events (major extracranial or intracranial hemorrhage) attributable to early treatment from the rate of excess ischemic events (recurrent stroke or systemic embolism) possibly prevented by early treatment within 30 days (main analysis) or 90 days (ancillary analysis). An established weighting scheme was used to account for the different clinical impact of bleeding relative to ischemic outcomes. Event rates were derived from adjusted logistic models. The analysis included all evaluable randomized ELAN participants. Results Of the original 2013 ELAN participants, 1966 were eligible for analysis (977 [49.7%] assigned to early DOAC initiation, 989 [50.3%] assigned to later DOAC initiation; median [IQR] age 77 [70-84] years; 1075 [54.7%] male). The 30-day NCB of early treatment over later treatment ranged from 1.73 (95% CI, 0.06-3.40) to 1.72 (95% CI, −0.63 to 3.98) weighted events possibly prevented per 100 participants for intracranial hemorrhage weights 1.5 to 3.3. The 90-day NCB ranged from 2.16 (95% CI, 0.30-3.87) to 2.14 (95% CI, −0.26 to 4.41) weighted events per 100 participants. Conclusions and Relevance This post hoc analysis of a randomized clinical trial estimated a sizeable NCB of early anticoagulation for patients after atrial fibrillation–associated ischemic stroke. Although estimates cannot exclude the possibility of no benefit or small net harm, the findings suggest that early treatment may be more favorable. Trial Registration ClinicalTrials.gov Identifier: NCT03148457