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

ImportanceThe net clinical effect of early vs later direct oral anticoagulant (DOAC) initiation after atrial fibrillation–associated ischemic stroke is unclear.ObjectiveTo investigate whether early DOAC treatment is associated with a net clinical benefit (NCB).Design, Setting, and ParticipantsThis 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.InterventionEarly DOAC initiation (&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 MeasuresThe 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.ResultsOf 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 RelevanceThis 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 RegistrationClinicalTrials.gov Identifier: NCT03148457