Ewgenia Barow1, Florent Boutitie2,3,4, Bastian Cheng1, Tae-Hee Cho5,6, Martin Ebinger7,8, Matthias Endres7,9, Jochen B Fiebach7, Jens Fiehler10, Ian Ford11, Ivana Galinovic7, Alina Nickel1, Josep Puig12, Pascal Roy2, Anke Wouters13,14,15, Tim Magnus1, Vincent Thijs16,17, Robin Lemmens13,14,15, Keith W Muir18, Norbert Nighoghossian5,6, Salvador Pedraza12, Claus Z Simonsen19, Christian Gerloff1, Götz Thomalla1. 1. Klinik und Poliklinik für Neurologie, Kopf- und Neurozentrum, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 2. Hospices Civils de Lyon, Service de Biostatistique, Lyon, France. 3. Université Lyon 1, Villeurbanne, France. 4. Centre National de la Recherche Scientifique, Unité de Mixte de Recherche 5558, Laboratoire de Biométrie et Biologie Evolutive, Equipe Biostatistique-Santé, Villeurbanne, France. 5. Department 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. 6. Hospices Civils de Lyon, Lyon, France. 7. Centrum für Schlaganfallforschung Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany. 8. Neurologie der Rehaklinik Medical Park Humboldtmühle, Berlin, Germany. 9. Klinik und Hochschulambulanz für Neurologie, Charité-Universitätsmedizin Berlin, Berlin, Germany. 10. Department of Diagnostic and Interventional Neuroradiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 11. Robertson Centre for Biostatistics, University of Glasgow, Glasgow, United Kingdom. 12. Department of Radiology, Institut de Diagnostic per la Image, Hospital Dr Josep Trueta, Institut d'Investigació Biomèdica de Girona, Salt, Girona, Spain. 13. Department of Neurology, University Hospitals Leuven, Leuven, Belgium. 14. Department of Neurosciences, Experimental Neurology, Katholieke Universiteit Leuven, Leuven, Belgium. 15. Vlaams Instituut voor Biotechnologie, Center for Brain & Disease Research, Laboratory of Neurobiology, Leuven, Belgium. 16. Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia. 17. Department of Neurology, Austin Health, Heidelberg, Victoria, Australia. 18. Institute of Neuroscience & Psychology, University of Glasgow, Glasgow, United Kingdom. 19. Department of Neurology, Aarhus University Hospital, Aarhus, Denmark.
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.
RCT Entities:
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.
Authors: Götz Thomalla; Florent Boutitie; Henry Ma; Masatoshi Koga; Peter Ringleb; Lee H Schwamm; Ona Wu; Martin Bendszus; Christopher F Bladin; Bruce C V Campbell; Bastian Cheng; Leonid Churilov; Martin Ebinger; Matthias Endres; Jochen B Fiebach; Mayumi Fukuda-Doi; Manabu Inoue; Timothy J Kleinig; Lawrence L Latour; Robin Lemmens; Christopher R Levi; Didier Leys; Kaori Miwa; Carlos A Molina; Keith W Muir; Norbert Nighoghossian; Mark W Parsons; Salvador Pedraza; Peter D Schellinger; Stefan Schwab; Claus Z Simonsen; Shlee S Song; Vincent Thijs; Danilo Toni; Chung Y Hsu; Nils Wahlgren; Haruko Yamamoto; Nawaf Yassi; Sohei Yoshimura; Steven Warach; Werner Hacke; Kazunori Toyoda; Geoffrey A Donnan; Stephen M Davis; Christian Gerloff Journal: Lancet Date: 2020-11-08 Impact factor: 79.321
Authors: Eivind Berge; William Whiteley; Heinrich Audebert; Gian Marco De Marchis; Ana Catarina Fonseca; Chiara Padiglioni; Natalia Pérez de la Ossa; Daniel Strbian; Georgios Tsivgoulis; Guillaume Turc Journal: Eur Stroke J Date: 2021-02-19
Authors: Ewgenia Barow; Hans Pinnschmidt; Florent Boutitie; Alina Königsberg; Martin Ebinger; Matthias Endres; Jochen B Fiebach; Jens Fiehler; Vincent Thijs; Robin Lemmens; Keith W Muir; Norbert Nighoghossian; Salvador Pedraza; Claus Z Simonsen; Christian Gerloff; Götz Thomalla; Bastian Cheng Journal: Neurol Res Pract Date: 2020-08-03
Authors: Zien Zhou; Candice Delcourt; Chao Xia; Sohei Yoshimura; Cheryl Carcel; Takako Torii-Yoshimura; Shoujiang You; Alejandra Malavera; Xiaoying Chen; Maree L Hackett; Mark Woodward; John Chalmers; Jianrong Xu; Thompson G Robinson; Mark W Parsons; Andrew M Demchuk; Richard I Lindley; Grant Mair; Joanna M Wardlaw; Craig S Anderson Journal: Neurology Date: 2021-02-03 Impact factor: 9.910
Authors: Bruce C V Campbell; Maarten G Lansberg; Gregory W Albers; Joseph P Broderick; Colin P Derdeyn; Pooja Khatri; Amrou Sarraj; Jeffrey L Saver; Achala Vagal Journal: Stroke Date: 2021-07-08 Impact factor: 10.170