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

      1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 9 , 10 , 11 , 11 , 12 , 13 , 14 , 14 , 15 , 16 , 16 , 4 , 17 , 18 , 19 , 19 , 20 , 20 , 21 , 22 , 23 , 24 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 9 , 38 , 39 , 40 , 41 , 1 , 1 , 4 , 42 , 2 , 3 , 9 , 1 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 43 , 1 , 44 , 4 , 5 , 6 , 8 , 45 , 46 , 47 , 15 , 17 , 18 , 48 , 21 , 23 , 49 , 26 , 27 , 28 , 29 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 72 , 73 , International DOAC-IVT, TRISP, and CRCS-K-NIH Collaboration, DOAC-IVT Writing Group
      JAMA Neurology
      American Medical Association (AMA)

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          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.

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          Most cited references49

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          2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation

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            Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association

            Background and Purpose- The purpose of these guidelines is to provide an up-to-date comprehensive set of recommendations in a single document for clinicians caring for adult patients with acute arterial ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators. These guidelines supersede the 2013 Acute Ischemic Stroke (AIS) Guidelines and are an update of the 2018 AIS Guidelines. Methods- Members of the writing group were appointed by the American Heart Association (AHA) Stroke Council's Scientific Statements Oversight Committee, representing various areas of medical expertise. Members were not allowed to participate in discussions or to vote on topics relevant to their relations with industry. An update of the 2013 AIS Guidelines was originally published in January 2018. This guideline was approved by the AHA Science Advisory and Coordinating Committee and the AHA Executive Committee. In April 2018, a revision to these guidelines, deleting some recommendations, was published online by the AHA. The writing group was asked review the original document and revise if appropriate. In June 2018, the writing group submitted a document with minor changes and with inclusion of important newly published randomized controlled trials with >100 participants and clinical outcomes at least 90 days after AIS. The document was sent to 14 peer reviewers. The writing group evaluated the peer reviewers' comments and revised when appropriate. The current final document was approved by all members of the writing group except when relationships with industry precluded members from voting and by the governing bodies of the AHA. These guidelines use the American College of Cardiology/AHA 2015 Class of Recommendations and Level of Evidence and the new AHA guidelines format. Results- These guidelines detail prehospital care, urgent and emergency evaluation and treatment with intravenous and intra-arterial therapies, and in-hospital management, including secondary prevention measures that are appropriately instituted within the first 2 weeks. The guidelines support the overarching concept of stroke systems of care in both the prehospital and hospital settings. Conclusions- These guidelines provide general recommendations based on the currently available evidence to guide clinicians caring for adult patients with acute arterial ischemic stroke. In many instances, however, only limited data exist demonstrating the urgent need for continued research on treatment of acute ischemic stroke.
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              2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS)

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                Author and article information

                Journal
                JAMA Neurology
                JAMA Neurol
                American Medical Association (AMA)
                2168-6149
                January 03 2023
                Affiliations
                [1 ]Stroke Research Center Bern, Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Switzerland
                [2 ]Department of Neurology, Christchurch Hospital, Christchurch, New Zealand
                [3 ]New Zealand Brain Research Institute, Christchurch, New Zealand
                [4 ]Stroke Center, Department of Neurology, University Hospital Basel, Basel, Switzerland
                [5 ]Neurology and Neurorehabilitation, University Department of Geriatric Medicine Felix Platter, University of Basel, Basel, Switzerland
                [6 ]Department of Neurology, Berlin Institute of Health, Charité–Universitätsmedizin Berlin, Berlin, Germany
                [7 ]German Center for Cardiovascular Research Partner Site Berlin, Germany
                [8 ]Center for Stroke Research Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany
                [9 ]Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany
                [10 ]Institute of Diagnostic and Interventional Neuroradiology, Stroke Research Center Bern, Inselspital, Bern University Hospital, University of Bern, Switzerland
                [11 ]Department of Neurology, Cerebrovascular Disease Center, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam-si, South Korea
                [12 ]Department of Neurology, Friesland Kliniken, Sande, Germany
                [13 ]Department of Neurology, University Medicine Göttingen, Göttingen, Germany
                [14 ]Department of Neurology, Nippon Medical School, Tokyo, Japan
                [15 ]Department of Neurology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
                [16 ]Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
                [17 ]Service of Clinical Neurosciences, Department of Neurology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
                [18 ]Department of Neurology, Royal Adelaide Hospital, Adelaide, Australia
                [19 ]IRCCS Istituto Delle Scienze Neurologiche Di Bologna, Department of Neurology and Stroke Center, Maggiore Hospital, Bologna, Italy
                [20 ]Department of Neurology, University Hospital, LMU Munich, Munich, Germany
                [21 ]Department of Neurology, Akershus University Hospital, Lørenskog, Norway
                [22 ]Department of General Practice, Institute of Health and Society (HELSAM), University of Oslo, Oslo, Norway
                [23 ]Department of Medicine and Neurology, Melbourne Brain Centre at The Royal Melbourne Hospital, University of Melbourne, Parkville, Australia
                [24 ]Department of Medicine, Auckland University, Auckland, New Zealand
                [25 ]Stroke Center and Department of Neurology, Neurocenter of Southern Switzerland, Lugano, Switzerland
                [26 ]Klinik und Poliklinik Für Neurologie, Kopf, und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
                [27 ]Department of Neurology Kansai Medical University, Hirakata, Japan
                [28 ]Department of Neurology and Stroke, University of Tübingen, Tübingen, Germany
                [29 ]Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany
                [30 ]Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
                [31 ]Neurology and Stroke Unit, Department of Neuroscience, Bufalini Hospital, Cesena, Italy
                [32 ]Neurology Unit, Stroke Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy
                [33 ]Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
                [34 ]Department of Neurology, School of Medicine, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
                [35 ]Department of Neurology, University Medical Center of the Johannes Gutenberg University Mainz, Germany
                [36 ]Division of Neurology and Stroke Unit, Department of Neurology, Gubbio and Città di Castello Hospital, Perugia, Italy
                [37 ]Department of Neurology, Stroke Unit, Hospital Universitari Bellvitge, Barcelona, Spain
                [38 ]Klinik für Neurologie, Alfried Krupp Krankenhaus, Essen, Germany
                [39 ]Department of Brain Sciences, Imperial College London, London, United Kingdom
                [40 ]Department of Medicine, University of Otago, Wellington, New Zealand
                [41 ]Department of Neurology, Capital and Coast District Health Board, Wellington, New Zealand
                [42 ]Department of Neurology, Dong-A University Hospital, Busan, South Korea
                [43 ]and the DOAC-IVT Writing Group
                [44 ]Department of Neurology, Cantonal Hospital, St Gallen, Switzerland
                [45 ]Berlin Institute of Health at Charité–Universitätsmedizin Berlin, Berlin, Germany
                [46 ]German Center for Cardiovascular Research Partner Site Berlin, Berlin, Germany
                [47 ]German Center for Neurodegenerative Diseases Partner Site Berlin, Berlin, Germany
                [48 ]Department of Neurology, Canterbury District Health Board, Christchurch, New Zealand
                [49 ]Department of Neurology, Amsterdam UMC, Location AMC, University of Amsterdam, Amsterdam, the Netherlands
                [50 ]Department of Neurology, University Hospital Dijon, Dijon, France
                [51 ]Division of Neurology, Department of Medicine and Therapeutics Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
                [52 ]John Hunter Hospital, Newcastle, Australia
                [53 ]Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia
                [54 ]Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece
                [55 ]Lille Neuroscience and Cognition Research Center, INSERM, CHU Lille, Lille, France
                [56 ]Department of Neurology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal
                [57 ]Department of Neurology, University Hospital Modena, Modena, Italy
                [58 ]Department of Neurology, GHU Paris Psychiatrie et Neurosciences, Université de Paris, Paris, France
                [59 ]Department of Neuroscience, Eastern Health, Eastern Health Clinical School, Monash University, Melbourne, Australia
                [60 ]Department of Neurology, Klinikum Frankfurt Höchst, Frankfurt am Main, Germany
                [61 ]Department of Neurology, Universität Heidelberg, Heidelberg, Germany
                [62 ]Stroke Unit, Neurology Department, Hospital Universitari Joan XXIII, Tarragona, Spain
                [63 ]Stroke Research Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
                [64 ]Department of Neurology, University Hospital Zurich, University of Zurich, Zurich, Switzerland
                [65 ]Department of Clinical and Experimental Sciences, Neurology Clinic, University of Brescia, Neurology Unit, ASST Spedali Civili, Brescia, Italy
                [66 ]Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, China
                [67 ]Institute of Clinical Neurology, Fujian Medical University, Fuzhou, China
                [68 ]Stroke Unit, Department of Neurology, Institute of Biomedical Research Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
                [69 ]Neurology Department, Hospital Parc Tauli, Sabadell, Spain
                [70 ]Department of Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
                [71 ]Neurology Clinic, Clinical Centre of Serbia, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
                [72 ]Department of Neurology, The Warren Alpert Medical School of Brown University, Providence, Rhode Island
                [73 ]Department of Neurology, Chonnam National University Hospital, Gwangju, South Korea
                Article
                10.1001/jamaneurol.2022.4782
                17398290-62f8-4f0e-ac9e-bf11f5794811
                © 2023
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