Early vs Late Anticoagulation in Minor, Moderate, and Major Ischemic Stroke With Atrial Fibrillation
Authors: Goeldlin Martina B. , Hakim Arsany , Branca Mattia , Abend Stefanie , Kneihsl Markus , Valenzuela Pinilla Waldo , Fenzl Sabine , Rezny-Kasprzak Beata , Rohner Roman , Strbian Daniel , Paciaroni Maurizio , Thomalla Goetz , Michel Patrik , Nedeltchev Krassen , Gattringer Thomas , Sandset Else Charlotte , Bonati Leo , Aguiar de Sousa Diana , Sylaja P. N. , Ntaios George , Koga Masatoshi , Gdovinova Zuzana , Lemmens Robin , Bornstein Natan M. , Kelly Peter , Katan Mira , Horvath Thomas , Dawson Jesse , Fischer Urs ,   ELAN Investigators, Adeyemi Adedolapo Kamaldee , Vedamurthy Adhiyaman , Scutelnic Adrian , Hisanao Akiyama , Wilson Alastair , Tarnutzer Alexander  Andrea , Pichler Alexander , Salerno Alexander , Vanhoorne Alexander , Polymeris Alexandros , 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 , Liesz Arthur , Annamalai Arunkumar , Sharma Arvind Vijaysharan , Paliantonis Asterios , Nallasivan Aumugam , Abdul-Rahim Azmil , 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 , 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 , 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 , Katan Mira , Mako Miroslav , Polavarapu Naren , Martinez-Majander Nicolas , Del Gaudio Nicole , Caracciolo Nicoletta G. , Peters Nils , Mahajan Niranjan , Silimon Norbert , Onur Oezguer A. , Olbert Elisabeth , Morten Rønning Ole , Kelly Peter , 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 , 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: May 2024

ImportanceWhether infarct size modifies the treatment effect of early vs late direct oral anticoagulant (DOAC) initiation in people with ischemic stroke and atrial fibrillation is unknown.ObjectiveTo assess whether infarct size modifies the safety and efficacy of early vs late DOAC initiation.Design, Setting, and ParticipantsPost hoc analysis of participants from the multinational (&amp;gt;100 sites in 15 countries) randomized clinical Early Versus Later Anticoagulation for Stroke With Atrial Fibrillation (ELAN) trial who had (1) acute ischemic stroke, (2) atrial fibrillation, and (3) brain imaging available before randomization. The ELAN trial was conducted between October 2017 and December 2022. Data were analyzed from October to December 2023 for this post hoc analysis.InterventionEarly vs late DOAC initiation after ischemic stroke. Early DOAC initiation was within 48 hours for minor or moderate stroke or on days 6 to 7 for major stroke; late DOAC initiation was on days 3 to 4 for minor stroke, days 6 to 7 for moderate stroke, and days 12 to 14 for major stroke.Main Outcomes and MeasuresThe primary outcome was a composite of recurrent ischemic stroke, symptomatic intracranial hemorrhage, extracranial bleeding, systemic embolism, or vascular death within 30 days. The outcome was assessed according to infarct size (minor, moderate, or major) using odds ratios and risk differences between treatment arms. Interrater reliability for infarct size between the core laboratory and local raters was assessed, and whether this modified the estimated treatment effects was also examined.ResultsA total of 1962 of the original 2013 participants (909 [46.3%] female; median [IQR] age, 77 [70-84] years) were included. The primary outcome occurred in 10 of 371 participants (2.7%) with early DOAC initiation vs 11 of 364 (3.0%) with late DOAC initiation among those with minor stroke (odds ratio [OR], 0.89; 95% CI, 0.38-2.10); in 11 of 388 (2.8%) with early DOAC initiation vs 14 of 392 (3.6%) with late DOAC initiation among those with moderate stroke (OR, 0.80; 95% CI, 0.35-1.74); and in 8 of 219 (3.7%) with early DOAC initiation vs 16 of 228 (7.0%) with late DOAC initiation among those with major stroke (OR, 0.52; 95% CI, 0.21-1.18). The 95% CI for the estimated risk difference of the primary outcome in early anticoagulation was −2.78% to 2.12% for minor stroke, −3.23% to 1.76% for moderate stroke, and −7.49% to 0.81% for major stroke. There was no significant treatment interaction for the primary outcome. For infarct size, interrater reliability was moderate (κ = 0.675; 95% CI, 0.647-0.702) for local vs core laboratory raters and strong (κ = 0.875; 95% CI, 0.855-0.894) between core laboratory raters.Conclusions and RelevanceThe treatment effect of early DOAC initiation did not differ in people with minor, moderate, or major stroke assessed by brain imaging. Early treatment was not associated with a higher rate of adverse events, especially symptomatic intracranial hemorrhage, for any infarct size, including major stroke.Trial RegistrationClinicalTrials.gov Identifier: NCT03148457