Intravenous Thrombolysis in Patients With Recent Intake of Direct Oral Anticoagulants: A Target Trial Analysis and Comparison With Reversal Agent Use

Thomas R Meinel¹, Philipp Bücke¹, Lucio D'Anna², Giovanni Merlino³, Diana Aguiar de Sousa^{4

5

6}, Sven Poli^{7

8}, Jan C Purrucker⁹, Davide Strambo¹⁰, Michele Romoli¹¹, Gian Marco De Marchis^{12

13}, Waltraud Pfeilschifter¹⁴, Marialuisa Zedde¹⁵, João Pedro Marto¹⁶, Paolo Candelaresi¹⁷, Robin Lemmens^{18

19}, Pasquale Scoppettuolo²⁰, Malin Woock²¹, Pawel Kermer²², Espen Saxhaug Kristoffersen²³, Malik Ghannam²⁴, Senta Frol²⁵, Christian H Nolte²⁶, Yusuke Yakushiji²⁷, Emmanuel Touzé²⁸, Timo Uphaus²⁹, Marina Mannino³⁰, George Ntaios³¹, Visnja Padjen³², Nils Henninger³³, Freschta Zipser-Mohammadzada¹, Marisa E Mariano^{4

5

6}, Carolina Guerreiro^{4

5

6}, Alessandra Burini³, Laura Ceccarelli³, Mariarosaria Valente³, Alexandra Gomez-Exposito^{7

8}, Antonia Kleeberg⁹, Guillaume Thevoz¹⁰, Patrik Michel¹⁰, Gianluca Stufano¹¹, Dimitrios Vlachos^{12

13}, Matthias Herrmann¹⁴, Bárbara Rodrigues¹⁶, Emanuele Spina¹⁷, Vincenzo Andreone¹⁷, Arne Allardt²¹, Qasem N Alshaer²⁴, Christoph Riegler²⁶, Takenobu Kunieda²⁷, Marion Boulanger²⁸, Marianne Hahn²⁹, Dimitra Papadimitriou³¹, Jayachandra Muppa³³, Louise Maes^{18

19}, Anna Ranta³⁴, Alicia Tyson³⁴, P Alan Barber³⁵, Alan J Davis³⁶, Teddy Y Wu³⁷, Johannes Kaesmacher^{38

39

40}, Urs Fischer¹, David J Seiffge¹; International DO-IT Collaboration

Collaborators, Affiliations

Collaborators

Affiliations

¹ Department of Neurology, Stroke Research Center Bern (T.R.M., P.B., F.Z.-M., U.F., D.J.S.), Inselspital, Bern University Hospital, University of Bern, Switzerland.
² Division of Brain Sciences, Imperial College London, United Kingdom (L.D.).
³ Clinical Neurology and Stroke Unit, Department of Head, Neck and Neurosciences, Udine University Hospital, Italy (G.M., A.B., L.C., M.V.).
⁴ Stroke Centre, Lisbon Central University Hospital Center-ULS São José, Portugal (D.A.d.S., M.E.M., C.G.).
⁵ CEEM e Instituto de Anatomia, Faculdade de Medicina, Universidade de Lisboa, Portugal (D.A.d.S., M.E.M., C.G.).
⁶ Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal (D.A.d.S., M.E.M., C.G.).
⁷ Department of Neurology and Stroke (S.P., A.G.-E.), University of Tübingen, Germany.
⁸ Hertie Institute for Clinical Brain Research (S.P., A.G.-E.), University of Tübingen, Germany.
⁹ Department of Neurology, Heidelberg University Hospital, Germany (J.C.P., A.K.).
¹⁰ Stroke Center, Neurology Service, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Switzerland (D.S., G.T., P.M.).
¹¹ Neurology and Stroke Unit, Department of Neurosciences, Bufalini Hospital, AUSL Romagna, Cesena, Italy (M.R., G.S.).
¹² Department of Neurology and Stroke Center, University Research and Teaching Hospital, Cantonal Hospital St. Gallen, Switzerland (G.M.D.M., D.V.).
¹³ Medical Faculty, University of Basel, Switzerland (G.M.D.M., D.V.).
¹⁴ Department of Neurology and Clinical Neurophysiology, Klinikum Lueneburg, Germany (W.P., M. Herrmann).
¹⁵ Neurology Unit, Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Italy (M.Z.).
¹⁶ Department of Neurology, Centro Hospitalar Lisboa Ocidental, Hospital de Egas Moniz, Lisbon, Portugal (J.P.M., B.R.).
¹⁷ Neurology and Stroke Unit, A.O.R.N. Antonio Cardarelli, Napoli, Italy (P.C., E.S., V.A.).
¹⁸ Department of Neurosciences, Experimental Neurology, KU Leuven, Belgium (R.L., L.M.).
¹⁹ Department of Neurology, University Hospitals Leuven, Belgium (R.L., L.M.).
²⁰ Neurology Department, Cliniques Universitaires Saint Luc-UCL, Bruxelles, Belgique (P.S.).
²¹ Department of Neurology, Sahlgrenska University Hospital, Göteborg, Sweden (M.W., A.A.).
²² Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Friesland Kliniken GmbH, Sande and University Medicine Göttingen, Germany (P.K.).
²³ Department of Neurology, Akershus University Hospital, Lørenskog, Norway (E.S.K.).
²⁴ Department of Neurology, University of Iowa Hospitals and Clinics (M.G., Q.N.A.).
²⁵ Department of Vascular Neurology, University Medical Center Ljubljana, Faculty of Medicine, University of Ljubljana, Slovenia (S.F.).
²⁶ Department of Neurology with Experimental Neurology and Center for Stroke Research, Charité-Universitätsmedizin Berlin, Germany (C.H.N., C.R.).
²⁷ Department of Neurology, Kansai Medical University, Osaka, Japan (Y.Y., T.K.).
²⁸ Department of Neurology, CHU de Caen Normandie, France (E.T., M.B.).
²⁹ Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany (T.U., M. Hahn).
³⁰ Department of Neurology and Stroke Unit, AOOR Villa Sofia-V. Cervello, Palermo, Italy (M.M.).
³¹ 1 Propaedeutic Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece (G.N., D.P.).
³² Neurology Clinic, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Serbia (V.P.).
³³ Department of Neurology, University of Massachusetts Chan Medical School, Worcester (N.H., J.M.).
³⁴ Department of Neurology, Wellington Hospital, New Zealand (A.R., A.T.).
³⁵ Department of Medicine, University of Auckland, New Zealand (P.A.B.).
³⁶ Department of Medicine, Whangarei Hospital, New Zealand (A.J.D.).
³⁷ Department of Neurology, Christchurch Hospital, New Zealand (T.Y.W.).
³⁸ University Institute of Diagnostic and Interventional Neuroradiology (J.K.), Inselspital, Bern University Hospital, University of Bern, Switzerland.
³⁹ Diagnostic and Interventional Neuroradiology, Tours, France (J.K.).
⁴⁰ Le Studium Loire Valley Institute for Advanced Studies, Orléans, France (J.K.).

PMID: 40693390
DOI: 10.1161/STROKEAHA.125.051384

Comparative Study

Intravenous Thrombolysis in Patients With Recent Intake of Direct Oral Anticoagulants: A Target Trial Analysis and Comparison With Reversal Agent Use

Thomas R Meinel et al. Stroke. 2025 Oct.

. 2025 Oct;56(10):2836-2845.

doi: 10.1161/STROKEAHA.125.051384. Epub 2025 Jul 22.

Authors

Collaborators

Affiliations

¹ Department of Neurology, Stroke Research Center Bern (T.R.M., P.B., F.Z.-M., U.F., D.J.S.), Inselspital, Bern University Hospital, University of Bern, Switzerland.
² Division of Brain Sciences, Imperial College London, United Kingdom (L.D.).
³ Clinical Neurology and Stroke Unit, Department of Head, Neck and Neurosciences, Udine University Hospital, Italy (G.M., A.B., L.C., M.V.).
⁴ Stroke Centre, Lisbon Central University Hospital Center-ULS São José, Portugal (D.A.d.S., M.E.M., C.G.).
⁵ CEEM e Instituto de Anatomia, Faculdade de Medicina, Universidade de Lisboa, Portugal (D.A.d.S., M.E.M., C.G.).
⁶ Gulbenkian Institute for Molecular Medicine, Lisbon, Portugal (D.A.d.S., M.E.M., C.G.).
⁷ Department of Neurology and Stroke (S.P., A.G.-E.), University of Tübingen, Germany.
⁸ Hertie Institute for Clinical Brain Research (S.P., A.G.-E.), University of Tübingen, Germany.
⁹ Department of Neurology, Heidelberg University Hospital, Germany (J.C.P., A.K.).
¹⁰ Stroke Center, Neurology Service, Department of Clinical Neurosciences, Lausanne University Hospital and University of Lausanne, Switzerland (D.S., G.T., P.M.).
¹¹ Neurology and Stroke Unit, Department of Neurosciences, Bufalini Hospital, AUSL Romagna, Cesena, Italy (M.R., G.S.).
¹² Department of Neurology and Stroke Center, University Research and Teaching Hospital, Cantonal Hospital St. Gallen, Switzerland (G.M.D.M., D.V.).
¹³ Medical Faculty, University of Basel, Switzerland (G.M.D.M., D.V.).
¹⁴ Department of Neurology and Clinical Neurophysiology, Klinikum Lueneburg, Germany (W.P., M. Herrmann).
¹⁵ Neurology Unit, Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Italy (M.Z.).
¹⁶ Department of Neurology, Centro Hospitalar Lisboa Ocidental, Hospital de Egas Moniz, Lisbon, Portugal (J.P.M., B.R.).
¹⁷ Neurology and Stroke Unit, A.O.R.N. Antonio Cardarelli, Napoli, Italy (P.C., E.S., V.A.).
¹⁸ Department of Neurosciences, Experimental Neurology, KU Leuven, Belgium (R.L., L.M.).
¹⁹ Department of Neurology, University Hospitals Leuven, Belgium (R.L., L.M.).
²⁰ Neurology Department, Cliniques Universitaires Saint Luc-UCL, Bruxelles, Belgique (P.S.).
²¹ Department of Neurology, Sahlgrenska University Hospital, Göteborg, Sweden (M.W., A.A.).
²² Department of Neurology, Nordwest-Krankenhaus Sanderbusch, Friesland Kliniken GmbH, Sande and University Medicine Göttingen, Germany (P.K.).
²³ Department of Neurology, Akershus University Hospital, Lørenskog, Norway (E.S.K.).
²⁴ Department of Neurology, University of Iowa Hospitals and Clinics (M.G., Q.N.A.).
²⁵ Department of Vascular Neurology, University Medical Center Ljubljana, Faculty of Medicine, University of Ljubljana, Slovenia (S.F.).
²⁶ Department of Neurology with Experimental Neurology and Center for Stroke Research, Charité-Universitätsmedizin Berlin, Germany (C.H.N., C.R.).
²⁷ Department of Neurology, Kansai Medical University, Osaka, Japan (Y.Y., T.K.).
²⁸ Department of Neurology, CHU de Caen Normandie, France (E.T., M.B.).
²⁹ Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg-University, Mainz, Germany (T.U., M. Hahn).
³⁰ Department of Neurology and Stroke Unit, AOOR Villa Sofia-V. Cervello, Palermo, Italy (M.M.).
³¹ 1 Propaedeutic Department of Internal Medicine, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece (G.N., D.P.).
³² Neurology Clinic, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Serbia (V.P.).
³³ Department of Neurology, University of Massachusetts Chan Medical School, Worcester (N.H., J.M.).
³⁴ Department of Neurology, Wellington Hospital, New Zealand (A.R., A.T.).
³⁵ Department of Medicine, University of Auckland, New Zealand (P.A.B.).
³⁶ Department of Medicine, Whangarei Hospital, New Zealand (A.J.D.).
³⁷ Department of Neurology, Christchurch Hospital, New Zealand (T.Y.W.).
³⁸ University Institute of Diagnostic and Interventional Neuroradiology (J.K.), Inselspital, Bern University Hospital, University of Bern, Switzerland.
³⁹ Diagnostic and Interventional Neuroradiology, Tours, France (J.K.).
⁴⁰ Le Studium Loire Valley Institute for Advanced Studies, Orléans, France (J.K.).

PMID: 40693390
DOI: 10.1161/STROKEAHA.125.051384

Abstract

Background: Intravenous thrombolysis (IVT) in patients with recent ingestion of direct oral anticoagulants (DOACs) is a frequent challenge and remains controversial. The benefit of DOAC reversal before IVT is uncertain.

Methods: Using target trial methodology, we analyzed data from 28 comprehensive stroke centers. Patients on DOACs were included if they met IVT criteria, had a National Institutes of Health Stroke Scale score of ≥2, and last DOAC intake within 48 hours or was undeterminable. Safety and efficacy outcomes (symptomatic intracerebral hemorrhage, any intracerebral hemorrhage, major bleeding, 90-day mortality, and good functional outcome [modified Rankin Scale score of 0-2 or return to baseline]) were compared between those receiving IVT versus no IVT and IVT with versus without reversal. In addition, a comparison was made with patients from the New Zealand stroke registry, all of whom underwent reversal with idarucizumab. We adjusted for covariates known to be associated with safety and efficacy outcomes, including age, stroke severity, intended thrombectomy, blood glucose, blood pressure, DOAC reversal, and time from last intake.

Results: Overall, 1342 patients fulfilled the target trial criteria. The median age was 80 (interquartile range, 73-86) years, median National Institutes of Health Stroke Scale score was 11, 50% were female, and 52% of patients received endovascular therapy. IVT was given in 342 of 1342 (25%) patients. Of these, 141 (41.2%) had verified DOAC intake <12 hours before admission, and 92 (26.9%) within 12 to 24 hours. Symptomatic intracerebral hemorrhage occurred in 10 of 328 (3.0%) of patients receiving IVT and 54 of 921 (5.9%) patients not receiving IVT (adjusted difference, -2.1% [95% CI, -5.3% to +1.2]). Patients receiving IVT were more likely to have good functional outcomes (adjusted difference, +14.4% [95% CI, +7.1% to +21.8%]). Comparing 289 patients with reversal (from the additional New Zealand registry) and 283 patients without reversal before IVT (from the target trial population), there was no significant difference in symptomatic intracerebral hemorrhage, major bleeding, or efficacy outcomes.

Conclusions: This target trial confirms previous observational data regarding the safety of off-label IVT in patients with recent DOAC intake. More data and dedicated trials are needed for patients with confirmed high DOAC plasma levels and regarding the efficacy and safety of DOAC reversal before IVT.

Keywords: anticoagulants; atrial fibrillation; stroke; therapeutic thrombolysis.

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Conflict of interest statement

Dr Meinel reports grants from Bangerter-Rhyner Foundation, Swiss Heart Foundation, Swiss National Science Foundation, Inselspital Bern, University Bern, and Baasch-Medicus Foundation. D. Aguiar de Sousa reports compensation from Johnson and Johnson, Daiichi Sankyo, AstraZeneca, and Bayer for other services; compensation from Organon & Co. for consultant services; and compensation from University of British Columbia for data and safety monitoring services. S. Poli reports grants from Boehringer Ingelheim, Daiichi Sankyo Company, Bundesministerium für Bildung und Forschung, Helena Laboratories Corporation, Innovationsausschuss beim Gemeinsamen Bundesausschuss, European Commission, Bristol-Myers Squibb; compensation from Portola Pharmaceuticals, LLC, AstraZeneca, Alexion Pharmaceuticals Inc, and Werfen USA LLC for consultant services; travel support from Hybernia Medical; compensation from Bayer Healthcare, Daiichi Sankyo Company, Bristol-Myers Squibb, and Boehringer Ingelheim for other services. D. Strambo reports grants from Université de Lausanne. G.M. De Marchis reports travel support from Pfizer and Medtronic and compensation from Bayer for consultant services. W. Pfeilschifter reports grants from AstraZeneca, Daiichi Sankyo, German Research Foundation, Laerdal Foundation for Acute Medicine, Pfizer, Stryker, Boehringer Ingelheim, and Bayer Healthcare. Dr Marto reports grants from Fundação para a Ciência e a Tecnologia. R. Lemmens reports compensation from Boehringer Ingelheim and Pfizer for other services. P. Kermer reports compensation from Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, AstraZeneca for other services, and Alexion Pharmaceuticals for other services. C.H. Nolte reports compensation from Pfizer, Bristol-Myers Squibb, and Alexion Pharmaceuticals for consultant services; grants from the German Center for Cardiovascular Research and German Center for Neurodegenerative Disease; compensation from Novartis and AstraZeneca for other services. Dr Yakushiji reports grants from Bayer, Daiichi Sankyo, and Bristol-Myers Squibb. E. Touzé reports employment by Caen and compensation from Elsevier for other services. V. Padjen reports grants from Medtronic and Pfizer Canada Inc and travel support from Boehringer Ingelheim. P. Michel reports grants from Porphyrogenis Foundation Lausanne. A. Ranta reports employment by the University of Otago and Capital & Coast District Health Board and grants from the Health Research Council of New Zealand. Dr Tyson reports employment by Wellington Regional Hospital. P.A. Barber reports travel support from Medtronic Vascular Inc, Boehringer Ingelheim, Biogen, and Roche; grants from Neurological Foundation of New Zealand and Neurological Foundation of New Zealand; and gifts from Boehringer Ingelheim. J. Kaesmacher reports grants from Siemens Healthcare, Gottfried und Julia Bangerter-Rhyner-Stiftung, Swiss National Science Foundation, Boehringer Ingelheim, and Swiss Heart Foundation to other and grants from Le Studium. U. Fischer reports compensation from the Swiss Neurological Society for other services. D.J. Seiffge reports compensation from AstraZeneca for consultant services and grants from AstraZeneca. The other authors report no conflicts.

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Intravenous Thrombolysis in Patients With Recent Intake of Direct Oral Anticoagulants: A Target Trial Analysis and Comparison With Reversal Agent Use

Collaborators

Affiliations

Intravenous Thrombolysis in Patients With Recent Intake of Direct Oral Anticoagulants: A Target Trial Analysis and Comparison With Reversal Agent Use

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

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