Early vs Late Anticoagulation in Minor, Moderate, and Major Ischemic Stroke With Atrial Fibrillation (2024)

• ¹Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

• ²University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

  See Also

  Minor in NeuroscienceNeuroscience Minor < University of North Carolina at Chapel HillComputational Neuroscience Minor | NeuroscienceMinor in Neuroscience: Neuroscience : Loyola University Chicago

• ³Clinical Trials Unit, University of Bern, Bern, Switzerland

• ⁴Department of Neurology, University of Basel and University Hospital Basel, Basel, Switzerland

• ⁵Department of Neurology, Medical University of Graz, Graz, Austria

• ⁶Division of Neuroradiology, Vascular and Interventional Radiology, Department of Radiology, Medical University of Graz, Graz, Austria

• ⁷Support Center for Advanced Neuroimaging, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland

• ⁸Department of Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland

• ⁹Internal, Vascular, and Emergency Medicine, Stroke Unit, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy

• ¹⁰Department of Neurology, University Medical Center Hamburg–Eppendorf, Hamburg, Germany

• ¹¹Department of Neurology, University Hospital Lausanne, University of Lausanne, Lausanne, Switzerland

• ¹²Department of Neurology, Cantonal Hospital Aarau, Aarau, Switzerland

• ¹³Department of Neurology, Oslo University Hospital, Oslo, Norway

• ¹⁴Research Department, Reha Rheinfelden, Rheinfelden, Switzerland

• ¹⁵Stroke Center, Lisbon Central University Hospital, Lisbon, Portugal

• ¹⁶Faculty of Medicine, Institute of Anatomy, University of Lisbon, Lisbon, Portugal

• ¹⁷Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India

• ¹⁸Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece

• ¹⁹Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan

• ²⁰Department of Neurology, Pavol Jozef Šafárik University, Košice, Slovakia

• ²¹Faculty of Medicine, Louis Pasteur University Hospital, Košice, Slovakia

• ²²Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven, Belgium

• ²³Department of Neurology, University Hospitals Leuven, Leuven, Belgium

• ²⁴Department of Neurology, Shaare-Zedek Medical Center, Jerusalem, Israel

• ²⁵Stroke Clinical Trials Network Ireland, School of Medicine, University College Dublin and Department of Neurology, Mater University Hospital, Dublin, Ireland

• ²⁶School of Cardiovascular and Metabolic Health, Queen Elizabeth University Hospital, University of Glasgow, Glasgow, United Kingdom

Key Points

Question Does infarct size modify the safety and efficacy of early vs late initiation of direct oral anticoagulation (DOAC) after ischemic stroke in people with atrial fibrillation?

Findings In this post hoc analysis of 1962 participants from the Early Versus Later Anticoagulation for Stroke With Atrial Fibrillation (ELAN) randomized clinical trial, the odds of the primary outcome (recurrent ischemic stroke, symptomatic intracranial hemorrhage, extracranial bleeding, systemic embolism, or vascular death within 30 days) were similar for early vs late DOAC initiation among participants with minor, moderate, and major stroke.

Meaning Early DOAC treatment was not associated with a higher rate of bleeding complications, especially symptomatic intracranial hemorrhage, or any adverse events regardless of infarct size, including major stroke.

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

Anticoagulation Neurology Cerebrovascular Disease Stroke Cerebrovascular Infarction Clinical Pharmacy and Pharmacology Atrial Fibrillation Cardiology Rhythm Disorders Bleeding and Transfusion Cerebrovascular Hemorrhage

Citation

Goeldlin MB, Hakim A, Branca M, et al. Early vs Late Anticoagulation in Minor, Moderate, and Major Ischemic Stroke With Atrial Fibrillation: Post Hoc Analysis of the ELAN Randomized Clinical Trial. JAMA Neurol. Published online May 28, 2024. doi:10.1001/jamaneurol.2024.1450

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