Intravenous Thrombolysis in Patients With Ischemic Stroke and Recent Ingestion of Direct Oral Anticoagulants

Abstract

Importance: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC).

Objective: To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion.

Design, setting, and participants: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32 375 controls without recent DOAC use. Data were collected from January 2008 to December 2021.

Exposures: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation.

Main outcomes and measures: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses.

Results: Of 33 207 included patients, 14 458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion.

Conclusions and relevance: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Meinel reported grants from Bangerter-Rhyner Foundation during the conduct of the study. Dr Gensicke reported personal fees from Daiichi Sankyo, Bristol Myers Squibb/Pfizer, and AbbVie and grants from Swiss National Science Foundation outside the submitted work. Dr Scheitz reported personal fees from AstraZeneca outside the submitted work. Dr Nolte reported grants from the German Ministry of Research and Education, German Center for Neurodegenerative Diseases, and German Center for Cardiovascular Research as well as personal fees from Abbott, Boehringer Ingelheim, Alexion, Bayer Pharma, Bristol Myers Squibb, Daiichi Sankyo, and Pfizer Pharma outside the submitted work. Dr Ringleb reported personal fees from Boehringer Ingelheim, Bayer, Pfizer, and Daiichi Sankyo outside the submitted work. Dr Kaesmacher reported grants from Swiss National Science Foundation, Inselspital, Swiss Academy of Medical Sciences, and Swiss Stroke Society outside the submitted work. Dr Bae reported grants from AstraZeneca, AstraZeneca Korea, Bayer Korea, Boehringer Ingelheim Korea, Bristol Myers Squibb, Chong Gun Dang Pharmaceutical, Daiichi Sankyo, Dong-A ST, GNT Pharma, Jeil Pharmaceutical, Korean Drug Co, Samjin Pharm, Shinpoong Pharm Co, Takeda Pharmaceuticals Korea, and Yuhan Corporation as well as personal fees from Amgen Korea, Hanmi Pharmaceutical, Otsuka Korea, SK Chemicals, and Viatris Korea outside the submitted work. Dr Kermer reported personal fees from Boehringer Ingelheim, Bayer, Daiichi Sankyo, and Bristol Myers Squibb outside the submitted work. Dr Kimura reported personal fees from Bristol Myers Squibb, Bayer Healthcare, and Daiichi Sankyo, grants from Nippon Boehringer Ingelheim, Daiichi Sankyo, and Pfizer Japan during the conduct of the study, and grants from Medtronic and Teijin Pharma outside the submitted work. Dr Kallmuenzer reported personal fees from Daiichi Sankyo, Pfizer, Bayer, Boehringer Ingelheim, and Medtronic outside the submitted work. Dr Koga reported personal fees from Daiichi Sankyo as well as grants from Daiichi Sankyo, Nippon Boehringer Ingelheim, and Shionogi outside the submitted work. Dr Michel reported grants from Swiss Heart Foundation and Swiss National Science Foundation outside the submitted work. Dr Kleinig reported nonfinancial support from Boehringer Ingelheim outside the submitted work. Dr Zini reported personal fees from Boehringer Ingelheim, Alexion, and CLS Behring as well as grants from Italian Health Ministry. Dr Kellert reported grants from Boehringer Ingelheim as well as personal fees from Alexion, Bayer Vital, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Pfizer, and AstraZeneca outside the submitted work. Dr Barber reported personal fees from Boehringer Ingelheim outside the submitted work. Dr Thomalla reported personal fees from Acandis, Alexion, Amarin, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Stryker, and Portola outside the submitted work. Dr S. Poli reported grants from Bristol Myers Squibb/Pfizer, Daiichi Sankyo, European Union, German Federal Joint Committee Innovation Fund, and German Federal Ministry of Education and Research; nonfinancial support from Boehringer Ingelheim, Helena Laboratories, and Werfen; and personal fees from Alexion, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Portola, and Werfen outside the submitted work. Dr Béjot reported personal fees from Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Amgen, Servier, Medtronic, and Novo Nordisk outside the submitted work. Dr Garcia-Esperon reported personal fees from Boehringer Ingelheim and Bayer. Dr Cordonnier reported grants from French Ministry of Health and personal fees from Bristol Myers Squibb outside the submitted work. Dr Uphaus reported personal fees from Merck Serono, Pfizer, and Bristol Myers Squibb as well as grants from Else Kröner-Fresenius Stiftung and the German Research Foundation outside the submitted work. Dr Steiner has received personal fees from Bayer, Boehringer Ingelheim, AstraZeneca/Alexion, Daiichi Sankyo, and Pfizer. Dr Werring reported personal fees from Bayer, Novo Nordisk, and Alexion outside the submitted work. Dr Wegener reported grants from Swiss National Science Foundation, UZH Clinical Research Priority Program Stroke, and Baugarten Foundation during the conduct of the study; grants from Zurich Neuroscience Center; and personal fees from Amgen, Springer, Teva Pharma, Bayer, and Novartis outside the submitted work. Dr Martí-Fàbregas reported personal fees from Pfizer and Daichii Sankyo outside the submitted work. Dr Veltkamp reported grants from the NIHR Imperial Biomedical Research Centre, European Union Horizon 2020, Boehringer Ingelheim, Bayer, Daiichi Sankyo, Bristol Myers Squibb, Pfizer, Medtronic, and Biogen as well as personal fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Daichi Sankyo, Portola, Biogen, Medtronic, Morphosys, and Amgen outside the submitted work. Dr Strbian reported grants from Boehringer Ingelheim. Dr Ranta reported grants from Health Research Council of New Zealand and Whatu Ora Health NZ outside the submitted work. Dr Arnold reported AstraZeneca, Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Medtronic, Pfizer, Sanofi, and Novartis as well as grants from Swiss Heart Foundation and Swiss National Science Foundation outside the submitted work. Dr Fischer reported grants from the Swiss National Science Foundation, Swiss Heart Foundation, and Medtronic as well as personal fees from CSL Behring, Boehringer Ingelheim, Medtronic, Styker, and Portola/Alexion outside the submitted work. Dr Padjen reported grants from Pfizer, Stago, Daiichi Sankyo, University Hospital Basel, University Hospital for Geratric Medicine Felix Platter, Swiss Heart Foundation, and Swiss National Science Foundation; personal fees from Boehringer Ingelheim, Pfizer, Medtronic, Bayer, Daiichi Sankyo, Bristol Myers Squibb, and MindMaze outside the submitted work; and serves on the editorial board of Stroke. Dr Engelter reported grants from Daiichi Sankyo outside the submitted work. Dr Purrucker reported personal fees from Pfizer, Boehringer Ingelheim, Akcea, Abbott, Daiichi Sankyo, and Bayer outside the submitted work. Dr Seiffge reported grants from Bangerter Rhyner Foundation during the conduct of the study; personal fees from Bayer, Alexion, and VarmX outside the submitted work. No other disclosures were reported.