Prior Reperfusion Strategy Does Not Modify Outcome in Early Versus Late Start of Anticoagulants in Patients With Ischemic Stroke: Prespecified Subanalysis of the Randomized Controlled ELAN Trial

Anke Wouters¹, Jelle Demeestere^{1

2}, Jean-Benoît Rossel³, Annemie Devroye², Philippe Desfontaines⁴, Peter Vanacker⁵, Dimitri Hemelsoet⁶, Laetitia Yperzeele^{7

8}, Matthieu Pierre Rutgers⁹, André Peeters¹⁰, Jan Vynckier¹¹, Takeshi Yoshimoto¹², Kanta Tanaka¹³, Jochen Vehoff¹⁴, Kosuke Matsuzono¹⁵, Caterina Kulyk¹⁶, Gerli Sibolt¹⁷, Peter Slade¹⁸, Alexander Salerno¹⁹, Takenobu Kunieda²⁰, Arsany Hakim²¹, Roman Rohner^{21

22}, Stefanie Abend²³, Martina Goeldlin²³, Jesse Dawson²⁴, Urs Fischer^#^{23

25}, Robin Lemmens^#^{1

2}; ELAN Investigators

Affiliations

¹ Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven Brain Institute, Belgium (A.W., J. Demeestere, R.L.).
² Department of Neurology, University Hospitals Leuven, Belgium (J. Demeestere, A.D., R.L.).
³ Department of Clinical Research (J.-B.R.), University of Bern, Switzerland.
⁴ Department of Neurology, Stroke Unit, CHC Montlégia Hospital, Liège, Belgium (P.D.).
⁵ Department of Neurology, Algemeen Ziekenhuis Groeninge Kortrijk, Belgium (P.V.).
⁶ Department of Neurology, Ghent University Hospital, Belgium (D.H.).
⁷ Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium (L.Y.).
⁸ Stroke Unit and Neurovascular Center, Department of Neurology, Antwerp University Hospital, Edegem, Belgium (L.Y.).
⁹ Neurology Department, Europe Hospitals (M.P.R.), H.uni - UCLouvain, Brussels, Belgium.
¹⁰ Neurology Department, Cliniques Universitaires Saint Luc (A.P.), H.uni - UCLouvain, Brussels, Belgium.
¹¹ Department of Neurology, Onze-Lieve-Vrouwziekenhuis Aalst, Belgium (J. Vynckier).
¹² Departments of Neurology (T.Y.), National Cerebral and Cardiovascular Center, Osaka, Japan.
¹³ Cerebrovascular Medicine (K.T.), National Cerebral and Cardiovascular Center, Osaka, Japan.
¹⁴ Department of Neurology University Teaching and Research Hospital St. Gallen, Switzerland (J. Vehoff).
¹⁵ Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan (K.M.).
¹⁶ Department of Neurology, Kepler University Hospital GmbH, Johannes Kepler University, Linz, Austria (C.K.).
¹⁷ Neurology and Clinical Neurosciences, University of Helsinki and Helsinki University Hospital, Finland (G.S.).
¹⁸ Morriston Hospital, Swansea Hospital, Wales, United Kingdom (P.S.).
¹⁹ Stroke Center, Neurology Service, Lausanne University Hospital and University of Lausanne, Switzerland (A.S.).
²⁰ Department of Neurology, Kansai Medical University, Hirakata (T.K.).
²¹ Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital (A.H., R.R.), University of Bern, Switzerland.
²² Graduate School for Health Sciences (R.R.), University of Bern, Switzerland.
²³ Department of Neurology, University Hospital Bern, Inselspital (S.A., M.G., U.F.), University of Bern, Switzerland.
²⁴ School of Cardiovascular and Metabolic Health, Queen Elizabeth University Hospital, University of Glasgow, United Kingdom (J. Dawson).
²⁵ Department of Neurology, University and University Hospital Basel, Switzerland (U.F.).

^# Contributed equally.

PMID: 40402090
DOI: 10.1161/STROKEAHA.125.050646

Randomized Controlled Trial

Prior Reperfusion Strategy Does Not Modify Outcome in Early Versus Late Start of Anticoagulants in Patients With Ischemic Stroke: Prespecified Subanalysis of the Randomized Controlled ELAN Trial

Anke Wouters et al. Stroke. 2025 Aug.

. 2025 Aug;56(8):2000-2008.

doi: 10.1161/STROKEAHA.125.050646. Epub 2025 May 22.

Authors

Affiliations

¹ Department of Neurosciences, Experimental Neurology, KU Leuven, Leuven Brain Institute, Belgium (A.W., J. Demeestere, R.L.).
² Department of Neurology, University Hospitals Leuven, Belgium (J. Demeestere, A.D., R.L.).
³ Department of Clinical Research (J.-B.R.), University of Bern, Switzerland.
⁴ Department of Neurology, Stroke Unit, CHC Montlégia Hospital, Liège, Belgium (P.D.).
⁵ Department of Neurology, Algemeen Ziekenhuis Groeninge Kortrijk, Belgium (P.V.).
⁶ Department of Neurology, Ghent University Hospital, Belgium (D.H.).
⁷ Translational Neurosciences Research Group, Faculty of Medicine and Health Sciences, University of Antwerp, Belgium (L.Y.).
⁸ Stroke Unit and Neurovascular Center, Department of Neurology, Antwerp University Hospital, Edegem, Belgium (L.Y.).
⁹ Neurology Department, Europe Hospitals (M.P.R.), H.uni - UCLouvain, Brussels, Belgium.
¹⁰ Neurology Department, Cliniques Universitaires Saint Luc (A.P.), H.uni - UCLouvain, Brussels, Belgium.
¹¹ Department of Neurology, Onze-Lieve-Vrouwziekenhuis Aalst, Belgium (J. Vynckier).
¹² Departments of Neurology (T.Y.), National Cerebral and Cardiovascular Center, Osaka, Japan.
¹³ Cerebrovascular Medicine (K.T.), National Cerebral and Cardiovascular Center, Osaka, Japan.
¹⁴ Department of Neurology University Teaching and Research Hospital St. Gallen, Switzerland (J. Vehoff).
¹⁵ Division of Neurology, Department of Medicine, Jichi Medical University, Tochigi, Japan (K.M.).
¹⁶ Department of Neurology, Kepler University Hospital GmbH, Johannes Kepler University, Linz, Austria (C.K.).
¹⁷ Neurology and Clinical Neurosciences, University of Helsinki and Helsinki University Hospital, Finland (G.S.).
¹⁸ Morriston Hospital, Swansea Hospital, Wales, United Kingdom (P.S.).
¹⁹ Stroke Center, Neurology Service, Lausanne University Hospital and University of Lausanne, Switzerland (A.S.).
²⁰ Department of Neurology, Kansai Medical University, Hirakata (T.K.).
²¹ Institute for Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital (A.H., R.R.), University of Bern, Switzerland.
²² Graduate School for Health Sciences (R.R.), University of Bern, Switzerland.
²³ Department of Neurology, University Hospital Bern, Inselspital (S.A., M.G., U.F.), University of Bern, Switzerland.
²⁴ School of Cardiovascular and Metabolic Health, Queen Elizabeth University Hospital, University of Glasgow, United Kingdom (J. Dawson).
²⁵ Department of Neurology, University and University Hospital Basel, Switzerland (U.F.).

^# Contributed equally.

PMID: 40402090
DOI: 10.1161/STROKEAHA.125.050646

Abstract

Background: Early initiation of direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation and acute ischemic stroke is beneficial and safe. Whether prior acute reperfusion therapy modifies the treatment effect of early versus late DOAC initiation is unknown.

Methods: For this post hoc analysis of the multicenter, randomized controlled ELAN trial (Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischaemic Stroke Patients With Atrial Fibrillation), all participants with data concerning reperfusion treatment were included. The primary outcome was the composite outcome of recurrent ischemic stroke, symptomatic intracranial hemorrhage, major extracranial bleeding, systemic embolism, or vascular death within 30 days. Patients were divided into 4 groups based on prior reperfusion therapy: no treatment, intravenous thrombolysis (IVT), endovascular treatment (EVT), or IVT combined with EVT. We performed logistic regression adjusted for age, hypertension, infarct location/size, pre-modified Rankin Scale, NIHSS, and hemorrhagic transformation, including the interaction term between treatment groups (early versus late DOAC) and reperfusion strategy.

Results: We included 1973 of 2013 (98%) patients of the ELAN trial population, with a median age of 77 (71-84) years and of whom 899 (46%) were female. Of them, 1015 (51%) underwent no prior reperfusion treatment, 519 (26%) IVT, 190 (10%) EVT, and 249 (13%) IVT+EVT. We did not identify an interaction for any of the outcome events between prior reperfusion therapy and timing of DOAC initiation. Rates were numerically lower in the early DOAC-initiated group for the following: no reperfusion therapy, 17 (3.3%) versus 24 (4.8%; adjusted odds ratio, 0.69 [95% CI, 0.36-1.28]); EVT, 1 (1.2%) versus 7 (6.4%; adjusted odds ratio, 0.25 [95% CI, 0.03-1.21]); and EVT+IVT, 3 (2.4%) versus 4 (3.3%; adjusted odds ratio, 0.76 [95% CI, 0.17-3.23]). In patients who had received IVT, the rates were 3% (n=8) in the early group versus 2% (n=5) in the late group (adjusted odds ratio, 1.52 [95% CI, 0.52-4.84]).

Conclusions: Prior reperfusion therapy does not modify the effect of early versus late DOAC initiation on clinical outcomes in patients with atrial fibrillation and acute ischemic stroke.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03148457.

Keywords: atrial fibrillation; embolism; hypertension; infarction; ischemic stroke.

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Conflict of interest statement

Dr Rossel is affiliated with CTU Bern, Department of Clinical Research, University of Bern, which has a staff policy of not accepting honoraria or consultancy fees. However, CTU Bern is involved in the design, conduct, or analysis of clinical studies funded by not-for-profit and for-profit organizations. In particular, pharmaceutical and medical device companies provide direct funding to some of these studies. For an up-to-date list of CTU Bern’s conflicts of interest, see https://dcr.unibe.ch/services/terms__conditions/index_eng.html. Dr Yperzeele has received speaker and consultancy fees from Bayer, Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi Sankyo, PPD Global, and Janssen Research & Development (payment to organization, not to personal account). Dr Rutgers has received fees as a consultant from Daiichi Sankyo, Teva Pharmaceuticals, and Novartis and as Data Monitoring Committee Member for Medpace, Inc. Dr Yoshimoto reports compensation from Daiichi Sankyo for other services and compensation from Stryker for other services. Dr Hakim received a grant from Schweizerische Herzstiftung. Dr Rohner received grants from Schweizerische Herzstiftung and the Department of Teaching and Research, Insel Group AG, and Gottfried und Julia Bangerter-Rhyner-Stiftung (outside the submitted work). Dr Goeldlin received a travel grant of the European Academy of Neurology, grant from the European Stroke Organisation, the Gottfried und Julia Bangerter-Rhyner-Stiftung, Inselspital Bern University Hospital, Mittelbauvereinigung Universitaet Bern, Swiss Heart Foundation, Swiss Neurological Society, and the Swiss Stroke Society. Dr Dawson reports speaker fees from AstraZeneca, Pfizer, Bristol Myers Squibb, Bayer, and Daiichi Sankyo and a grant from the Stroke Association. Dr Fischer reports research support from the Swiss National Science Foundation and the Swiss Heart Foundation. He is a principal investigator of the ELAN trial (Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischaemic Stroke Patients With Atrial Fibrillation) and a co-principal investigator of the DISTAL (Endovascular Therapy Plus Best Medical Treatment [BMT] Versus BMT Alone for Medium Vessel Occlusion Stroke), TECNO (Safety and Efficacy of Intra-Arterial Tenecteplase for Non-Complete Reperfusion of Intracranial Occlusions), SWIFT DIRECT (Bridging Thrombolysis Versus Direct Mechanical Thrombectomy in Acute Ischemic Stroke), SWITCH (Decompressive Hemicraniectomy in Intracerebral Hemorrhage), ELAPSE (Early Closure of Left Atrial Appendage for Patients With Atrial Fibrillation and Ischemic Stroke Despite Anticoagulation Therapy), and ICARUS (Colorectal Cohort Analysis From the Intraperitoneal Chemotherapy After Cytoreductive Surgery for Peritoneal Metastasis) trials. He also reports research grants from Medtronic (BEYOND SWIFT [Bernese-European Registry for Ischemic Stroke Patients Treated Outside Current Guidelines With Neurothrombectomy Devices Using the SOLITAIRE FR With the Intention for Thrombectomy] and SWIFT DIRECT) and from Stryker, Rapid Medical, Penumbra, Medtronic and Phenox (DISTAL), and Boehringer Ingelheim (TECNO); support from the Horton Foundation for the DO IT trial (The DOAC International Thrombolysis); consultancies for Medtronic (fees paid to institution); and participation in an advisory board for AstraZeneca (former Alexion/Portola), Bayer, Boehringer Ingelheim, Biogen, AbbVie, and Siemens (fees paid to institution). He is the member of a clinical event committee of the COATING study (Coating to Optimize Aneurysm Treatment in the New Flow Diverter Generation; Phenox); member of the data and safety monitoring committee of the TITAN (A Study of Apalutamide [JNJ-56021927, ARN-509] Plus Androgen Deprivation Therapy [ADT] Versus ADT in Participants With mHSPC), LATE_MT, IN EXTREMIS (Large Stroke Therapy Evaluation), and RapidPulse trials; and president of the Swiss Neurological Society and president-elect of the European Stroke Organisation. Dr Lemmens has no personal disclosures but reports institutional fees for consultancy from Boehringer Ingelheim and Pfizer. The other authors report no conflicts.

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Prior Reperfusion Strategy Does Not Modify Outcome in Early Versus Late Start of Anticoagulants in Patients With Ischemic Stroke: Prespecified Subanalysis of the Randomized Controlled ELAN Trial

Affiliations

Prior Reperfusion Strategy Does Not Modify Outcome in Early Versus Late Start of Anticoagulants in Patients With Ischemic Stroke: Prespecified Subanalysis of the Randomized Controlled ELAN Trial

Authors

Affiliations

Abstract

Conflict of interest statement

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Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical