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Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial
BACKGROUND AND OBJECTIVES: Cerebral microbleeds (CMBs) are common in patients with acute ischemic stroke 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...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792812/ https://www.ncbi.nlm.nih.gov/pubmed/34782419 http://dx.doi.org/10.1212/WNL.0000000000013055 |
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author | 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 Fiebach, Jochen Muir, Keith Nighoghossian, Norbert Ebinger, Martin Pedraza, Salvador Thomalla, Götz Gerloff, Christian Endres, Matthias Lemmens, Robin Nolte, Christian H. |
author_facet | 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 Fiebach, Jochen Muir, Keith Nighoghossian, Norbert Ebinger, Martin Pedraza, Salvador Thomalla, Götz Gerloff, Christian Endres, Matthias Lemmens, Robin Nolte, Christian H. |
author_sort | Schlemm, Ludwig |
collection | PubMed |
description | BACKGROUND AND OBJECTIVES: Cerebral microbleeds (CMBs) are common in patients with acute ischemic stroke 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 prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging–fluid-attenuated inversion recovery 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 IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke 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. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99–5.43, p = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59–1.64, p = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07–2.43, p = 0.022) without evidence of heterogeneity in relation to CMB presence (p of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution. DISCUSSION: In the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 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 INFORMATION: ClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days. |
format | Online Article Text |
id | pubmed-8792812 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-87928122022-01-27 Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial 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 Fiebach, Jochen Muir, Keith Nighoghossian, Norbert Ebinger, Martin Pedraza, Salvador Thomalla, Götz Gerloff, Christian Endres, Matthias Lemmens, Robin Nolte, Christian H. Neurology Research Article BACKGROUND AND OBJECTIVES: Cerebral microbleeds (CMBs) are common in patients with acute ischemic stroke 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 prespecified analysis of the prospective randomized controlled multicenter Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke (WAKE-UP) trial including patients with acute ischemic stroke with unknown time of symptom onset and diffusion-weighted imaging–fluid-attenuated inversion recovery 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 IV thrombolysis with alteplase at 0.9 mg/kg body weight or placebo. CMB status (presence, number, and distribution) was assessed after study completion by 3 raters blinded to clinical information following a standardized protocol. Outcome measures were excellent functional outcome at 90 days, defined by modified Rankin Scale (mRS) score ≤1, and symptomatic ICH according to National Institutes of Neurological Disease and Stroke 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. Ninety-eight (21.4%) had at least 1 CMB on baseline imaging; 45 (9.8%) had exactly 1 CMB; 37 (8.1%) had 2 to 4 CMBs; and 16 (3.5%) had ≥5 CMBs. Presence of CMBs was associated with a nonsignificant increased risk of symptomatic ICH (11.2% vs 4.2%; adjusted odds ratio [OR] 2.32, 95% confidence interval [CI] 0.99–5.43, p = 0.052) but had no effect on functional outcome at 90 days (mRS score ≤1: 45.8% vs 50.7%; adjusted OR 0.99, 95% CI 0.59–1.64, p = 0.955). Patients receiving alteplase had better functional outcome (mRS score ≤1: 54.6% vs 44.6%, adjusted OR 1.61, 95% CI 1.07–2.43, p = 0.022) without evidence of heterogeneity in relation to CMB presence (p of the interactive term = 0.546). Results were similar for subpopulations with strictly lobar (presumed cerebral amyloid angiopathy related) or not strictly lobar CMB distribution. DISCUSSION: In the randomized-controlled WAKE-UP trial, we saw no evidence of reduced treatment effect of alteplase in patients with acute ischemic stroke with ≥1 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 INFORMATION: ClinicalTrials.gov identifier NCT01525290; ClinicalTrialsRegister.EU identifier 2011-005906-32. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with acute ischemic stroke with unknown time of onset and diffusion-weighted imaging–fluid-attenuated inversion recovery mismatch who received IV alteplase, CMBs are not significantly associated with functional outcome at 90 days. Lippincott Williams & Wilkins 2022-01-18 /pmc/articles/PMC8792812/ /pubmed/34782419 http://dx.doi.org/10.1212/WNL.0000000000013055 Text en Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. |
spellingShingle | Research Article 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 Fiebach, Jochen Muir, Keith Nighoghossian, Norbert Ebinger, Martin Pedraza, Salvador Thomalla, Götz Gerloff, Christian Endres, Matthias Lemmens, Robin Nolte, Christian H. Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial |
title | Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial |
title_full | Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial |
title_fullStr | Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial |
title_full_unstemmed | Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial |
title_short | Cerebral Microbleeds and Treatment Effect of Intravenous Thrombolysis in Acute Stroke: An Analysis of the WAKE-UP Randomized Clinical Trial |
title_sort | cerebral microbleeds and treatment effect of intravenous thrombolysis in acute stroke: an analysis of the wake-up randomized clinical trial |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8792812/ https://www.ncbi.nlm.nih.gov/pubmed/34782419 http://dx.doi.org/10.1212/WNL.0000000000013055 |
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