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Title: | Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial. |
Austin Authors: | Schlemm, Ludwig;Braemswig, Tim Bastian;Boutitie, Florent;Vynckier, Jan;Jensen, Märit;Galinovic, Ivana;Simonsen, Claus Z;Cheng, Bastian;Cho, Tae-Hee;Fiehler, Jens;Puig, Josep;Thijs, Vincent N ;Fiebach, Jochen;Muir, Keith;Nighoghossian, Norbert;Ebinger, Martin;Pedraza, Salvador;Thomalla, Götz;Gerloff, Christian;Endres, Matthias;Lemmens, Robin;Nolte, Christian H |
Affiliation: | German Center for Neurodegenerative Diseases (DZNE), Partner Site Berlin, Berlin, Germany The Florey Institute of Neuroscience and Mental Health Klinik und Hochschulambulanz für Neurologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin, Berlin, Germany Berlin Institute of Health (BIH), Berlin, Germany Hospices Civils de Lyon, Service de Biostatistique, Lyon, France Université Lyon 1 and Centre National de la Recherche Scientifique, UMR 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France Department of Neurology, Medical Park Berlin Humboldtmühle, Berlin, Germany Department of Neurology, University Hospitals Leuven, Leuven, Belgium Department of Neurosciences, Experimental Neurology, KU Leuven-University of Leuven, Leuven, Belgium VIB-KU Leuven Center for Brain and Disease Research, Laboratory of Neurobiology, Leuven, Belgium Klinik und Hochschulambulanz für Neurologie, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health (BIH), Berlin, Germany. Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin, Berlin, Germany Berlin Institute of Health (BIH), Berlin, Germany German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany Department of Neurology, University Hospital Bern, Bern, Switzerland Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin, Berlin, Germany Department of Neurology, Aarhus University Hospital, Aarhus, Denmark Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon, Lyon, France Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany Department of Radiology, Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona, Spain Center for Stroke Research Berlin (CSB), Charité - Universitätsmedizin, Berlin, Germany Institute of Neuroscience and, University of Glasgow, Glasgow, United Kingdom Department of Stroke Medicine, Université Claude Bernard Lyon 1, and Hospices Civils de Lyon, Lyon, France Department of Radiology, Hospital Universitari Doctor Josep Trueta, Institut d'Investigació Biomèdica de Girona, Girona, Spain Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany |
Issue Date: | 18-Jan-2022 |
Date: | 2021 |
Publication information: | Neurology 2022; 98(3): e302-e314 |
Abstract: | Cerebral microbleeds (CMBs) are common in acute ischemic stroke patients and are associated with increased risk of intracerebral hemorrhage (ICH) after intravenous thrombolysis. Whether CMBs modify the treatment effect of thrombolysis is unknown. We performed a pre-specified analysis of the prospective randomized controlled multicenter WAKE-UP trial including patients with acute ischemic stroke with unknown time of symptom onset and DWI-FLAIR mismatch on MRI receiving alteplase or placebo. Patients were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). Patients were randomized to treatment with intravenous thrombolysis with alteplase at 0.9 mg / kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by three raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale score (mRS)≤1, and symptomatic intracerebral hemorrhage (ICH) according to NINDS trial criteria 22 to 36 hours after treatment. Of 503 patients enrolled in the WAKE-UP trial, 459 (91.3%; 288 [63%] men) were available for analysis; 98 (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB, 37 (8.1%) had 2-4 CMBs, and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a non-significant increased risk of symptomatic ICH (11.2% versus 4.2%; adjusted odds ratio 2.32 [95% CI 0.99-5.43]; P=.052), but had no effect on functional outcome at 90 days (mRS≤1: 45.8% versus 50.7%; adj. OR 0.99 [0.59-1.64]; P=.955). Patients receiving alteplase had better functional outcome (mRS≤1: 54.6% versus 44.6%, adj. OR 1.61 [1.07-2.43], P=.022) without evidence of heterogeneity in relation to CMB presence (P value of the interactive term .546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy-related) or non-strictly-lobar CMB distribution. In the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in acute ischemic stroke patients with one or more CMBs. Additional studies are needed to determine the treatment effect of alteplase and its benefit-harm-ratio in patients with a larger number of CMBs. ClinicalTrials.gov number, NCT01525290 (https://clinicaltrials.gov/ct2/show/NCT01525290); EudraCT number, 2011-005906-32 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2011-005906-32/GB). This study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and DWI-FLAIR mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days. |
URI: | https://ahro.austin.org.au/austinjspui/handle/1/28063 |
DOI: | 10.1212/WNL.0000000000013055 |
ORCID: | 0000-0003-4165-2366 0000-0001-6112-2800 0000-0001-5338-961X 0000-0001-7793-0941 0000-0001-8533-7478 0000-0002-6614-8417 0000-0002-7936-6958 0000-0001-9535-022X 0000-0002-4948-5956 0000-0001-5577-1775 |
Journal: | Neurology |
PubMed URL: | 34782419 |
Type: | Journal Article |
Appears in Collections: | Journal articles |
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