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Randomized Controlled Trial
. 2024 Jul 1;81(7):693-702.
doi: 10.1001/jamaneurol.2024.1450.

Early vs Late Anticoagulation in Minor, Moderate, and Major Ischemic Stroke With Atrial Fibrillation: Post Hoc Analysis of the ELAN Randomized Clinical Trial

Martina B Goeldlin  1 , Arsany Hakim  2 , Mattia Branca  3 , Stefanie Abend  1 , Markus Kneihsl  1   4   5   6 , Waldo Valenzuela Pinilla  7 , Sabine Fenzl  2 , Beata Rezny-Kasprzak  2 , Roman Rohner  2 , Daniel Strbian  8 , Maurizio Paciaroni  9 , Goetz Thomalla  10 , Patrik Michel  11 , Krassen Nedeltchev  1   12 , Thomas Gattringer  5   6 , Else Charlotte Sandset  13 , Leo Bonati  4   14 , Diana Aguiar de Sousa  15   16 , P N Sylaja  17 , George Ntaios  18 , Masatoshi Koga  19 , Zuzana Gdovinova  20   21 , Robin Lemmens  22   23 , Natan M Bornstein  24 , Peter Kelly  25 , Mira Katan  4 , Thomas Horvath  1 , Jesse Dawson  26 , Urs Fischer  1   4 ; ELAN Investigators
Collaborators, Affiliations
Randomized Controlled Trial

Early vs Late Anticoagulation in Minor, Moderate, and Major Ischemic Stroke With Atrial Fibrillation: Post Hoc Analysis of the ELAN Randomized Clinical Trial

Martina B Goeldlin et al. JAMA Neurol. .

Abstract

Importance: Whether 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.

Objective: To assess whether infarct size modifies the safety and efficacy of early vs late DOAC initiation.

Design, setting, and participants: Post hoc analysis of participants from the multinational (>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.

Intervention: Early 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 measures: The 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.

Results: A 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 relevance: The 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 registration: ClinicalTrials.gov Identifier: NCT03148457.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Goeldlin reported receiving grants from the Bangerter-Rhyner-Foundation/Swiss Academy of Medical Sciences during the conduct of the study; and receiving grants from the Bangerter-Rhyner-Foundation/Swiss Academy of Medical Sciences, Insel Gruppe AG, European Stroke Organisation, Swiss Stroke Society, Mittelbauvereinigung der Universität Bern, European Academy of Neurology, and Pfizer outside the submitted work. Dr Hakim reported receiving grants from the Swiss Heart Foundation during the conduct of the study; and receiving personal fees from Bayer outside the submitted work. Dr Fenzl reported receiving grants from the Swiss Heart Foundation during the conduct of the study. Dr Rohner reported receiving grants from the Swiss Heart Foundation during the conduct of the study. Dr Strbian reported advisory board participation for AstraZeneca and receiving a grant from Boehringer Ingelheim outside the submitted work. Dr Paciaroni reported receiving personal fees from Bristol Myers Squibb, iRhythm, Daiichi Sankyo, Pfizer, and Sanofi outside the submitted work. Dr Thomalla reported receiving grants from the European Union, German Research Foundation, German Federal Ministry of Education and Research, and the German Innovation Fund and receiving personal fees from Acandis, Alexion, Amarin, Amazon, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, AstraZeneca, Portola, and Stryker outside the submitted work. Dr Michel reported receiving grants from the Swiss National Science Foundation, Swiss Heart Foundation, and Faculty of Biology and Medicine, University of Lausanne during the conduct of the study. Dr Nedeltchev reported receiving grants from Bayer, Daiichi Sankyo, Bristol Myers Squibb/Pfizer, and Alexion and serving on advisory boards for Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Bristol Myers Squibb/Pfizer outside the submitted work. Dr Gattringer reported receiving grants from the Austrian Science Fund and Austrian Neurological Society and personal fees from Bristol Myers Squibb/Pfizer, Bayer, Boehringer Ingelheim, Novartis, Amgen, and AstraZeneca outside the submitted work. Dr Sandset reported receiving personal fees from Daiichi Sankyo and Boston Scientific and serving as a steering committee member and national coordinator of the ANNEXA-I trial supported by AstraZeneca, the OCEANIC trial supported by Bayer, and the AXIOMATIC trial supported by Bristol Myers Squibb outside the submitted work. Dr Bonati reported receiving grants from AstraZeneca and the Swiss National Science Foundation and personal fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Claret Medical, InnovHeart, and Bayer outside the submitted work. Dr Aguiar de Sousa reported receiving personal fees from Daiichi Sankyo, AstraZeneca, Bayer, Boehringer Ingelheim, Bial, Organon, and Johnson & Johnson and serving on the data and safety monitoring board of the SECRET trial outside the submitted work. Dr Ntaios reported receiving personal fees from Abbott, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, Elpen, Ferrer, Javelin, Novartis, and Sanofi outside the submitted work. Dr Koga reported receiving grants from the National Cerebral and Cardiovascular Center during the conduct of the study; and receiving grants from Daiichi Sankyo and Nippon Boehringer Ingelheim and personal fees from Bayer Yakuhin, Daiichi Sankyo, Mitsubishi Tanabe Pharma Corp, Bristol Myers Squibb/Pfizer, Otsuka Pharmaceutical, and Bristol Myers Squibb/Janssen Pharmaceuticals outside the submitted work. Dr Gdovinova reported receiving personal fees from Biogen, Boehringer Ingelheim, MSD, Novartis, Pfizer, Sandoz, Schwabe, and TEVA outside the submitted work. Dr Lemmens reported receiving consultant institutional fees from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, and Medtronic during the conduct of the study. Dr Bornstein reported receiving personal fees from Ever Neuro Pharma outside the submitted work. Dr Kelly reported receiving grants from Health Research Board Ireland, Bayer, Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, and Daiichi Sankyo and serving on advisory boards for Alexion and Novo Nordisk outside the submitted work. Dr Katan reported receiving grants from the Swiss National Science Foundation, Swiss Heart Foundation, and USZ Foundation during the conduct of the study; and receiving nonfinancial support from BRAHMS, Thermo Fisher Scientific, and Roche Diagnostics and personal fees from Pfizer/Bristol Myers Squibb/Janssen, AstraZeneca, and Medtronic outside the submitted work. Dr Dawson reported receiving grants from the Stroke Association during the conduct of the study; and receiving grants from Pfizer and Bristol Myers Squibb and personal fees from Boehringer Ingelheim, Bayer, Medtronic, Daiichi Sankyo, and Pfizer outside the submitted work. Dr Fischer reported receiving grants from the Swiss National Science Foundation Fees and Swiss Heart Foundation during the conduct of the study; and receiving grants from Medtronic, Stryker, Rapid Medical, Penumbra, Phenox, and Boehringer Ingelheim, receiving personal fees from Medtronic, Stryker, and CSL Behring, participating on advisory boards for Alexion/Portola, Boehringer Ingelheim, Biogen, and Acthera, serving as a member of a clinical event committee of the COATING study (Phenox), serving as a member of the data and safety monitoring committee of the TITAN, LATE_MT, and IN EXTREMIS trials, and serving as president of the Swiss Neurological Society outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Trial Flowchart
Minor, moderate, and major refer to infarct size. CT indicates computed tomography; MRI, magnetic resonance imaging.
Figure 2.
Figure 2.. Unadjusted Odds Ratios (ORs) of the Primary Composite Outcome and Secondary Outcomes at 30 Days
The incidences of the primary and secondary outcomes at 30 days were comparable for all infarct size groups, including minor (A), moderate (B), and major (C) stroke. DOAC indicates direct oral anticoagulant.
Figure 3.
Figure 3.. Distribution of Modified Rankin Scale (mRS) Score Categories at 90 Days
In all infarct size groups, including minor (A), moderate (B), and major (C) stroke, the mRS score distribution at 90 days was similar between early and late direct oral anticoagulant (DOAC) initiation. For mRS score shifts between early and late DOAC initiation, the odds ratio was 0.86 (95% CI, 0.65-1.13) for minor stroke, 0.92 (95% CI, 0.69-1.22) for moderate stroke, and 1.04 (95% CI, 0.69-1.56) for major stroke.
See this image and copyright information in PMC

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