Cerebral microbleeds and treatment effect of intravenous thrombolysis in acute stroke: an analysis of the WAKE-UP randomized clinical trial

Schlemm, L. et al. (2022) Cerebral microbleeds and treatment effect of intravenous thrombolysis in acute stroke: an analysis of the WAKE-UP randomized clinical trial. Neurology, 98(3), e302-e314. (doi: 10.1212/WNL.0000000000013055) (PMID:34782419) (PMCID:PMC8792812)

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Background and Objectives: 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. Methods: 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. Results: 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. Discussion: 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. Trial registration: 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). Classification of Evidence: 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.

Item Type:Articles
Additional Information:The WAKE-UP trial was funded by the European Union Seventh Framework Program (278276).
Glasgow Author(s) Enlighten ID:Muir, Professor Keith
Creator Roles:
Muir, K.Writing – original draft, Writing – review and editing, Data curation, Formal analysis
Authors: Schlemm, L., Braemswig, T. B., Boutitie, F., Vynckier, J., Jensen, M., Galinovic, I., Simonsen, C. Z., Cheng, B., Cho, T.-H., Fiehler, J., Puig, J., Thijs, V., Fiebach, J., Muir, K., Nighoghossian, N., Ebinger, M., Pedraza, S., Thomalla, G., Gerloff, C., Endres, M., Lemmens, R., and Nolte, C. H.
College/School:College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience
Journal Name:Neurology
Publisher:American Academy of Neurology
ISSN (Online):1526-632X
Published Online:15 November 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Neurology 98(3): e302-314
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
166040WAKE-UPKeith MuirEuropean Commission (EC)Muir, Prof KeithNP - Stroke & Brain Imaging