Functional Outcome of Intravenous Thrombolysis in Patients With Lacunar Infarcts in the WAKE-UP Trial | Cerebrovascular Disease | JAMA Neurology | JAMA Network
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Original Investigation
March 25, 2019

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

Author Affiliations
  • 1Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 2Hospices Civils de Lyon, Service de Biostatistique, Lyon, France
  • 3Université Lyon 1, Villeurbanne, France
  • 4Centre National de la Recherche Scientifique, Unité de Mixte de Recherche 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France
  • 5Department of Stroke Medicine, Université Claude Bernard Lyon 1, CREATIS Centre National de la Recherche Scientifique Unité de Mixte de Recherche 5220, Institut National de la Santé et de la Recherche Médicale U1206, Institut National des Sciences Appliquées–Lyon, Lyon, France
  • 6Hospices Civils de Lyon, Lyon, France
  • 7Centrum für Schlaganfallforschung Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • 8Neurologie der Rehaklinik Medical Park Humboldtmühle, Berlin, Germany
  • 9Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
  • 10Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
  • 11Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom
  • 12Department of Radiology, Institut de Diagnostic per la Image, Hospital Dr Josep Trueta, Institut d’Investigació Biomèdica de Girona, Salt, Girona, Spain
  • 13Department of Neurology, University Hospitals Leuven, Leuven, Belgium
  • 14Department of Neurosciences, Experimental Neurology, Katholieke Universiteit Leuven, Leuven, Belgium
  • 15Vlaams Instituut voor Biotechnologie, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium
  • 16Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
  • 17Department of Neurology, Austin Health, Heidelberg, Victoria, Australia
  • 18Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, United Kingdom
  • 19Department of Neurology, Aarhus University Hospital, Aarhus, Denmark
JAMA Neurol. 2019;76(6):641-649. doi:10.1001/jamaneurol.2019.0351
Key Points

Questions  Is intravenous thrombolysis with alteplase efficacious in patients with lacunar stroke?

Findings  In this secondary post hoc analysis of the randomized clinical WAKE-UP trial of magnetic resonance imaging–guided intravenous alteplase administration to patients with stroke of unknown onset, 108 of 503 patients had magnetic resonance imaging–defined lacunar infarcts. Treatment outcomes of alteplase in patients with lacunar infarcts were similar to those in patients with nonlacunar infarcts and resulted in a numerically higher rate of favorable outcome at 90 days (59% vs 46%) and a numerical shift toward better outcomes across all categories of the modified Rankin Scale.

Meaning  Per this analysis, intravenous alteplase appears to be as effective in patients with lacunar stroke as in those with nonlacunar stroke.


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.