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Randomized Controlled Trial
. 2023 Jul;54(7):1718-1725.
doi: 10.1161/STROKEAHA.122.040247. Epub 2023 May 25.

Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial

Benedikt M Frey  1 , Farhad Shenas  1 , Florent Boutitie  2 , Bastian Cheng  1 , Tae-Hee Cho  3 , Martin Ebinger  4   5 , Matthias Endres  4   6 , Jochen B Fiebach  4 , Jens Fiehler  7 , Ivana Galinovic  4 , Ewgenia Barow  1 , Alina Königsberg  1 , Eckhard Schlemm  1 , Salvador Pedraza  8 , Robin Lemmens  9   10   11 , Vincent Thijs  12   13 , Keith W Muir  14 , Norbert Nighoghossian  3 , Claus Z Simonsen  15 , Christian Gerloff  1 , Götz Thomalla  1 ; WAKE-UP Investigators
Affiliations
Randomized Controlled Trial

Intravenous Thrombolysis in Patients With White Matter Hyperintensities in the WAKE-UP Trial

Benedikt M Frey et al. Stroke. 2023 Jul.

Abstract

Background: White matter hyperintensities of presumed vascular origin (WMH) are the most prominent imaging feature of cerebral small vessel disease (cSVD). Previous studies suggest a link between cSVD burden and intracerebral hemorrhage and worse functional outcome after thrombolysis in acute ischemic stroke. We aimed to determine the impact of WMH burden on efficacy and safety of thrombolysis in the MRI-based randomized controlled WAKE-UP trial of intravenous alteplase in unknown onset stroke.

Methods: The design of this post hoc study was an observational cohort design of a secondary analysis of a randomized trial. WMH volume was quantified on baseline fluid-attenuated inversion recovery images of patients randomized to either alteplase or placebo in the WAKE-UP trial. Excellent outcome was defined as score of 0-1 on the modified Rankin Scale after 90 days. Hemorrhagic transformation was assessed on follow-up imaging 24-36 hours after randomization. Treatment effect and safety were analyzed by fitting multivariable logistic regression models.

Results: Quality of scans was sufficient in 441 of 503 randomized patients to delineate WMH. Median age was 68 years, 151 patients were female, and 222 patients were assigned to receive alteplase. Median WMH volume was 11.4 mL. Independent from treatment, WMH burden was statistically significantly associated with worse functional outcome (odds ratio, 0.72 [95% CI, 0.57-0.92]), but not with higher chances of any hemorrhagic transformation (odds ratio, 0.78 [95% CI, 0.60-1.01]). There was no interaction of WMH burden and treatment group for the likelihood of excellent outcome (P=0.443) or any hemorrhagic transformation (P=0.151). In a subgroup of 166 patients with severe WMH, intravenous thrombolysis was associated with higher odds of excellent outcome (odds ratio, 2.40 [95% CI, 1.19-4.84]) with no significant increase in the rate of hemorrhagic transformation (odds ratio, 1.96 [95% CI, 0.80-4.81]).

Conclusions: Although WMH burden is associated with worse functional outcome, there is no association with treatment effect or safety of intravenous thrombolysis in patients with ischemic stroke of unknown onset.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT01525290.

Keywords: alteplase; cerebral small vessel disease; ischemic stroke; thrombolytic therapy.

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Conflict of interest statement

Disclosures Dr Barow reports grants from the German Parkinson Society and ACTELION Pharmaceuticals Deutschland GmbH, outside the submitted work. Dr Boutitie reports grants from University Medical Center Hamburg-Eppendorf during the conduct of the study. Dr Ebinger reports grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, Amgen, GlaxoSmithKlineGSK, Sanofi, Covidien, Ever, Novartis, all outside the submitted work. Dr Fiebach reports personal fees from Bioclinica, Artemida, Cerevast, and Nicolab outside the submitted work. R.L. has no personal disclosures, but reports consultancy fees paid to the institution from Ischemaview and Boehringer-Ingelheim. Dr Thijs reports personal fees and nonfinancial support from Boehringer Ingelheim, Pfizer/BMS, Bayer, Sygnis, Amgen and Allergan outside the submitted work. Dr Muir reports personal fees and nonfinancial support from Boehringer Ingelheim outside the submitted work. Dr Simonsen is supported by research grants from Novo Nordisk Foundation and Health Research Foundation of Central Denmark Region. CG reports personal fees from AMGEN, Bayer Vital, BMS, Boehringer Ingelheim, Sanofi Aventis, Abbott, and Prediction Biosciences outside the submitted work. GT reports personal fees from Acandis, Boehringer Ingelheim, BMS/Pfizer, Stryker, Portola, Daiichi Sankyo, grants and personal fees from Bayer, grants from Corona Foundation, German Innovation Fonds and Else Kroener Fresenius Foundation outside the submitted work. Dr Königsberg reports grants from European Union 7th Framework Program during the conduct of the study. All remaining authors declare no competing interests.

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