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Randomized Controlled Trial
. 2019 Jun 1;76(6):641-649.
doi: 10.1001/jamaneurol.2019.0351.

Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial

Ewgenia Barow  1 , Florent Boutitie  2   3   4 , Bastian Cheng  1 , Tae-Hee Cho  5   6 , Martin Ebinger  7   8 , Matthias Endres  7   9 , Jochen B Fiebach  7 , Jens Fiehler  10 , Ian Ford  11 , Ivana Galinovic  7 , Alina Nickel  1 , Josep Puig  12 , Pascal Roy  2 , Anke Wouters  13   14   15 , Tim Magnus  1 , Vincent Thijs  16   17 , Robin Lemmens  13   14   15 , Keith W Muir  18 , Norbert Nighoghossian  5   6 , Salvador Pedraza  12 , Claus Z Simonsen  19 , Christian Gerloff  1 , Götz Thomalla  1 ; WAKE-UP Investigators
Affiliations
Randomized Controlled Trial

Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial

Ewgenia Barow et al. JAMA Neurol. .

Abstract

Importance: The rationale for intravenous thrombolysis in patients with lacunar infarcts is debated, since it is hypothesized that the microvascular occlusion underlying lacunar infarcts might not be susceptible to pharmacological reperfusion treatment.

Objective: To study the efficacy and safety of intravenous thrombolysis among patients with lacunar infarcts.

Design, setting, and participants: This exploratory secondary post hoc analysis of the WAKE-UP trial included patients who were screened and enrolled between September 2012 and June 2017 (with final follow-up in September 2017). The WAKE-UP trial was a multicenter, double-blind, placebo-controlled randomized clinical trial to study the efficacy and safety of intravenous thrombolysis with alteplase in patients with an acute stroke of unknown onset time, guided by magnetic resonance imaging. All 503 patients randomized in the WAKE-UP trial were reviewed for lacunar infarcts. Diagnosis of lacunar infarcts was based on magnetic resonance imaging and made by consensus of 2 independent investigators blinded to clinical information.

Main outcomes and measures: The primary efficacy variable was favorable outcome defined by a score of 0 to 1 on the modified Rankin Scale at 90 days after stroke, adjusted for age and severity of symptoms.

Results: Of the 503 patients randomized in the WAKE-UP trial, 108 patients (including 74 men [68.5%]) had imaging-defined lacunar infarcts, whereas 395 patients (including 251 men [63.5%]) had nonlacunar infarcts. Patients with lacunar infarcts were younger than patients with nonlacunar infarcts (mean age [SD], 63 [12] years vs 66 [12] years; P = .003). Of patients with lacunar infarcts, 55 (50.9%) were assigned to treatment with alteplase and 53 (49.1%) to receive placebo. Treatment with alteplase was associated with higher odds of favorable outcome, with no heterogeneity of treatment outcome between lacunar and nonlacunar stroke subtypes. In patients with lacunar strokes, a favorable outcome was observed in 31 of 53 patients (59%) in the alteplase group compared with 24 of 52 patients (46%) in the placebo group (adjusted odds ratio [aOR], 1.67 [95% CI, 0.77-3.64]). There was 1 death and 1 symptomatic intracranial hemorrhage according to Safe Implementation of Thrombolysis in Stroke-Monitoring Study criteria in the alteplase group, while no death and no symptomatic intracranial hemorrhage occurred in the placebo group. The distribution of the modified Rankin Scale scores 90 days after stroke also showed a nonsignificant shift toward better outcomes in patients with lacunar infarcts treated with alteplase, with an adjusted common odds ratio of 1.94 (95% CI, 0.95-3.93).

Conclusions and relevance: While the WAKE-UP trial was not powered to demonstrate the efficacy of treatment in subgroups of patients, the results indicate that the association of intravenous alteplase with functional outcome does not differ in patients with imaging-defined lacunar infarcts compared with those experiencing other stroke subtypes.

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Conflict of interest statement

Conflict of Interest 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 Endres reports grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, Amgen, GlaxoSmithKline, Sanofi Aventis, Covidien, Ever, and Novartis outside the submitted work. Dr Fiebach reports personal fees from Bioclinica, Artemida, Cerevast, and Nicolab outside the submitted work. Dr Magnus reports grants from Deutsche Forschungsgemeinschaft and Bundesministerium für Bildung und Forschung, the Schilling Foundation, Merck-Serono, and Grifols outside the submitted work. Dr Thijs reports personal fees and nonfinancial support from Boehringer Ingelheim, Pfizer/Bristol-Myers Squibb, 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 reports grants from Novo Nordisk Foundation and personal fees from Bayer outside the submitted work. Dr Gerloff reports personal fees from Amgen, Bayer Vital, Bristol-Myers Squibb, Boehringer Ingelheim, Sanofi Aventis, Abbott, and Prediction Biosciences outside the submitted work. Dr Thomalla reports personal fees from Acandis, Boehringer Ingelheim, BMS/Pfizer, Stryker, Daiichi Sankyo; grants and personal fees from Bayer; and grants from Corona Foundation, German Innovation Fonds, and Else Kroener Fresenius Foundation outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Magnetic Resonance Imaging in Patients With Lacunar Infarcts
Example magnetic resonance images of 2 randomized patients with a lacunar infarct in the left internal capsule (A) and brain stem (C). Before randomization for treatment (A and C), both infarcts presented with a hyperintense signal on diffusion-weighted imaging (DWI) without signal alterations in the corresponding area on fluid-attenuated inversion recovery (FLAIR). According to the mandatory DWI-FLAIR mismatch, patients were randomized and treated either with alteplase or placebo. Follow-up magnetic resonance images 22 to 36 hours after treatment (B and D) also show a hyperintense signal on FLAIR corresponding to the lesion area detected on DWI.
Figure 2.
Figure 2.. Association of Alteplase With Favorable Outcome
Forest plots demonstrate a treatment outcome favoring alteplase in both lacunar and nonlacunar infarcts, with no evidence of a significant interaction between stroke subtype and treatment outcome.
Figure 3.
Figure 3.. Distribution of Modified Rankin Scale Scores at 90 Days After Stroke
Distributions of scores on the modified Rankin Scale show a favoring of the alteplase group compared with the placebo group. Modified Rankin Scale scores range from 0 to 6 (0, no symptoms; 1, no clinically significant disability; 2, slight disability; 3, moderate disability; 4, moderately severe disability; 5, severe disability; and 6, death).
See this image and copyright information in PMC

Comment in

References

    1. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333(24):1581-1587. doi: 10.1056/NEJM199512143332401 - DOI - PubMed
    1. Sandercock P, Wardlaw JM, Lindley RI, et al. ; IST-3 collaborative group . The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial. Lancet. 2012;379(9834):2352-2363. doi: 10.1016/S0140-6736(12)60768-5 - DOI - PMC - PubMed
    1. Caplan LR, Mohr JP, Kistler JP, Koroshetz W. Should thrombolytic therapy be the first-line treatment for acute ischemic stroke? Thrombolysis—not a panacea for ischemic stroke. N Engl J Med. 1997;337(18):1309-1310. doi: 10.1056/NEJM199710303371812 - DOI - PubMed
    1. Fisher CM. Lacunes: small, deep cerebral infarcts. Neurology. 1965;15:774-784. doi: 10.1212/WNL.15.8.774 - DOI - PubMed
    1. Álvarez-Sabín J, Maisterra O, Santamarina E, Kase CS. Factors influencing haemorrhagic transformation in ischaemic stroke. Lancet Neurol. 2013;12(7):689-705. doi: 10.1016/S1474-4422(13)70055-3 - DOI - PubMed

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