Endovascular Therapy for Late-Window M2-Segment Middle Cerebral Artery Occlusion: Analysis of the CLEAR Study

Simon Winzer^#^{1

2}, Daniel P O Kaiser^#^{3

2}, Muhammad M Qureshi^{4

5}, Alicia C Castonguay⁶, Daniel Strbian⁷, Raul G Nogueira⁸, Simon Nagel^{9

10}, Jean Raymond¹¹, Mohamad Abdalkader⁴, Jelle Demeestere^{12

13}, João Pedro Marto¹⁴, Hiroshi Yamagami¹⁵, Kanta Tanaka¹⁶, Sunil A Sheth¹⁷, Anne Dusart¹⁸, Patrik Michel¹⁹, Marta Olive Gadea²⁰, Marc Ribo²⁰, Osama O Zaidat²¹, Diogo C Haussen²², Hilde Henon²³, Mahmoud H Mohammaden²², Markus A Möhlenbruch²⁴, James E Siegler²⁵, Ajit S Puri²⁶, Johannes Kaesmacher²⁷, Piers Klein⁴, Liisa Tomppo^{7

28}, Francois Caparros²³, João Nuno Ramos²⁸, Mouhammad Jumaa⁶, Syed Zaidi⁶, Nicolas Martinez-Majander⁷, Stefania Nannoni²⁹, Lieselotte Vandewalle^{12

13}, Flavio Bellante¹⁸, Milagros Galecio-Castillo³⁰, Sergio Salazar-Marioni¹⁷, Pekka Virtanen³¹, Anke Wouters^{12

13}, Rita Ventura¹⁴, Jessica Jesser²⁴, Adnan Mujanovic²⁷, Liqi Shu³², Abiya Qureshi⁴, Zhongming Qiu³³, Hesham E Masoud³⁴, Manuel Requena²⁰, Mikko Sillanpää³¹, Wei Hu³⁵, Eugene Lin²¹, Charlotte Cordonnier²³, Daniel Roy¹¹, Shadi Yaghi³³, Davide Strambo¹⁹, Urs Fischer³⁶, Santiago Ortega-Gutierrez³¹, Robin Lemmens^{12

13}, Peter A Ringleb¹⁰, Thanh N Nguyen^#^{4

37}, Volker Puetz^#^{1

2}

Affiliations

¹ Neurology (S.W., V.P.), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
² Dresden Neurovascular Center (S.W., D.P.O.K., V.P.), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
³ Institute of Neuroradiology (D.P.O.K.), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
⁴ Radiology (M.M.Q., M.A., P.K., A.Q., T.N.N.), Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, MA.
⁵ Radiation Oncology (M.M.Q.), Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, MA.
⁶ Neurology, University of Toledo, OH (A.C.C., M.J., S.Z.).
⁷ Neurology (D. Strbian, L.T., N.M.-M.), Helsinki University Hospital, University of Helsinki, Finland.
⁸ Neurology, Neurosurgery, University of Pittsburgh Medical Center, PA (R.G.N.).
⁹ Neurology, Klinikum Ludwigshafen, Germany (S. Nagel).
¹⁰ Neurology (S. Nagel, P.A.R.), Heidelberg University Hospital, Germany.
¹¹ Interventional Neuroradiology, Centre Hospitalier de l'Universite de Montreal, Radiology, Canada (J.R., D.R.).
¹² Neurology, UZ Leuven, Belgium (J.D., L.V., A.W., R.L.).
¹³ Laboratory for Neurobiology, KU Leuven, Belgium (J.D., L.V., A.W., R.L.).
¹⁴ Neurology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Portugal (J.P.M., R.V.).
¹⁵ Division of Stroke Prevention and Treatment, University of Tsukuba, Japan (H.Y.).
¹⁶ Stroke Center, Kindai University Hospital, Osakasayama, Japan (K.T.).
¹⁷ Neurology, UTHealth McGovern Medical School, Neurology, Houston, TX (S.A.S., S.S.-M.).
¹⁸ Neurology, Hôpital Civil Marie Curie, Charleroi, Belgium (A.D., F.B.).
¹⁹ Neurology, Lausanne University Hospital and University of Lausanne, Switzerland (P.M., D. Strambo).
²⁰ Neurology, Hospital Vall d'Hebron, Barcelona, Spain (M.O.G., M. Ribo, M. Requena).
²¹ Neuroscience and Stroke Program, Bon Secours Mercy Health St. Vincent Hospital, Toledo, OH (O.O.Z., E.L.).
²² Neurology, Grady Memorial Hospital, Atlanta, GA (D.C.H., M.H.M.).
²³ Neurology, Centre Hospitalier Universitaire de Lille, France (H.H., F.C., C.C.).
²⁴ Radiology (M.A.M., J.J.), Heidelberg University Hospital, Germany.
²⁵ Neurology, University of Chicago, IL (J.E.S.).
²⁶ Division of Interventional Neuroradiology, University of Massachusetts Memorial Medical Center, Worcester (A.S.P.).
²⁷ Diagnostic and Interventional Neuroradiology (J.K., A.M.), University Hospital Bern, Switzerland.
²⁸ Neuroradiology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Portugal (L.T., J.N.R.).
²⁹ Clinical Neurosciences, University of Cambridge, United Kingdom (S. Nannoni).
³⁰ Neurology, University of Iowa (M.G.-C.).
³¹ Radiology (P.V., M.S., S.O.-G.), Helsinki University Hospital, University of Helsinki, Finland.
³² Neurology, Rhode Island Hospital, Providence (L.S.).
³³ Neurology, 903rd Hospital of The Chinese People's Liberation Army, Hangzhou (Z.Q., S.Y.).
³⁴ Neurology, State University of New York, Upstate Medical University, Syracuse (H.E.M.).
³⁵ Neurology, The First Affiliated Hospital of University of Science and Technology of China (USTC), China (W.H.).
³⁶ Neurology (U.F.), University Hospital Bern, Switzerland.
³⁷ Neurology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, MA (T.N.N.).

^# Contributed equally.

PMID: 40405459
DOI: 10.1161/STROKEAHA.124.048840

Free article

Multicenter Study

Endovascular Therapy for Late-Window M2-Segment Middle Cerebral Artery Occlusion: Analysis of the CLEAR Study

Simon Winzer et al. Stroke. 2025 Jul.

Free article

. 2025 Jul;56(7):1671-1680.

doi: 10.1161/STROKEAHA.124.048840. Epub 2025 May 22.

Authors

Affiliations

¹ Neurology (S.W., V.P.), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
² Dresden Neurovascular Center (S.W., D.P.O.K., V.P.), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
³ Institute of Neuroradiology (D.P.O.K.), Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
⁴ Radiology (M.M.Q., M.A., P.K., A.Q., T.N.N.), Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, MA.
⁵ Radiation Oncology (M.M.Q.), Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, MA.
⁶ Neurology, University of Toledo, OH (A.C.C., M.J., S.Z.).
⁷ Neurology (D. Strbian, L.T., N.M.-M.), Helsinki University Hospital, University of Helsinki, Finland.
⁸ Neurology, Neurosurgery, University of Pittsburgh Medical Center, PA (R.G.N.).
⁹ Neurology, Klinikum Ludwigshafen, Germany (S. Nagel).
¹⁰ Neurology (S. Nagel, P.A.R.), Heidelberg University Hospital, Germany.
¹¹ Interventional Neuroradiology, Centre Hospitalier de l'Universite de Montreal, Radiology, Canada (J.R., D.R.).
¹² Neurology, UZ Leuven, Belgium (J.D., L.V., A.W., R.L.).
¹³ Laboratory for Neurobiology, KU Leuven, Belgium (J.D., L.V., A.W., R.L.).
¹⁴ Neurology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Portugal (J.P.M., R.V.).
¹⁵ Division of Stroke Prevention and Treatment, University of Tsukuba, Japan (H.Y.).
¹⁶ Stroke Center, Kindai University Hospital, Osakasayama, Japan (K.T.).
¹⁷ Neurology, UTHealth McGovern Medical School, Neurology, Houston, TX (S.A.S., S.S.-M.).
¹⁸ Neurology, Hôpital Civil Marie Curie, Charleroi, Belgium (A.D., F.B.).
¹⁹ Neurology, Lausanne University Hospital and University of Lausanne, Switzerland (P.M., D. Strambo).
²⁰ Neurology, Hospital Vall d'Hebron, Barcelona, Spain (M.O.G., M. Ribo, M. Requena).
²¹ Neuroscience and Stroke Program, Bon Secours Mercy Health St. Vincent Hospital, Toledo, OH (O.O.Z., E.L.).
²² Neurology, Grady Memorial Hospital, Atlanta, GA (D.C.H., M.H.M.).
²³ Neurology, Centre Hospitalier Universitaire de Lille, France (H.H., F.C., C.C.).
²⁴ Radiology (M.A.M., J.J.), Heidelberg University Hospital, Germany.
²⁵ Neurology, University of Chicago, IL (J.E.S.).
²⁶ Division of Interventional Neuroradiology, University of Massachusetts Memorial Medical Center, Worcester (A.S.P.).
²⁷ Diagnostic and Interventional Neuroradiology (J.K., A.M.), University Hospital Bern, Switzerland.
²⁸ Neuroradiology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Portugal (L.T., J.N.R.).
²⁹ Clinical Neurosciences, University of Cambridge, United Kingdom (S. Nannoni).
³⁰ Neurology, University of Iowa (M.G.-C.).
³¹ Radiology (P.V., M.S., S.O.-G.), Helsinki University Hospital, University of Helsinki, Finland.
³² Neurology, Rhode Island Hospital, Providence (L.S.).
³³ Neurology, 903rd Hospital of The Chinese People's Liberation Army, Hangzhou (Z.Q., S.Y.).
³⁴ Neurology, State University of New York, Upstate Medical University, Syracuse (H.E.M.).
³⁵ Neurology, The First Affiliated Hospital of University of Science and Technology of China (USTC), China (W.H.).
³⁶ Neurology (U.F.), University Hospital Bern, Switzerland.
³⁷ Neurology, Boston Medical Center, Boston University Chobanian and Avedisian School of Medicine, MA (T.N.N.).

^# Contributed equally.

PMID: 40405459
DOI: 10.1161/STROKEAHA.124.048840

Abstract

Background: There is uncertainty about whether patients with M2 occlusion benefit from endovascular therapy (EVT) in the late (6-24-hour) time window. We evaluated the clinical outcomes of patients with M2 occlusion selected for EVT compared with those who received medical management (MM) in the late window.

Methods: This multinational cohort study was conducted at 66 sites across 10 countries (January 2014 to May 2022). We included consecutive patients with late-window stroke due to M2 occlusion, baseline National Institutes of Health Stroke Scale score of ≥5, and premorbid modified Rankin Scale score of ≤2 who received EVT or MM alone. The primary end point was 90-day ordinal shift in the modified Rankin Scale score. Safety end points were symptomatic intracranial hemorrhage and 90-day mortality. Differences in outcomes were determined using inverse probability of treatment weighting-adjusted logistic regression models.

Results: Among 5098 patients, 496 met inclusion criteria (median [interquartile range] age, 74 years [62-81 years]; baseline National Institutes of Health Stroke Scale score, 12 [8-17]), of whom 394 (79.4%) received EVT and 102 (20.6%) MM. In inverse probability of treatment weighting adjusted analyses, there was no favorable 90-day ordinal modified Rankin Scale shift (odds ratio, 1.39 [95% CI, 0.92-2.12]) and no difference of functional independence rates (modified Rankin Scale score of 0-2; odds ratio, 1.72 [95% CI, 0.93-3.15]) with EVT compared with MM. Moreover, symptomatic intracranial hemorrhage risk (odds ratio, 3.46 [95% CI, 0.50-23.92]) and 90-day mortality (odds ratio, 1.11 [95% CI, 0.66-1.87]) were not statistically different between treatment groups.

Conclusions: In patients with M2 occlusion in the 6- to 24-hour time window, there was no difference in disability outcomes or symptomatic intracranial hemorrhage risk between patients treated with EVT compared with MM. Results of ongoing randomized trials will provide further insight.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04096248.

Keywords: cohort studies; endovascular procedures; intracranial hemorrhage; ischemic stroke; middle cerebral artery.

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Conflict of interest statement

Dr Cordonnier reported compensation from American Stroke Association for other services and compensation from Boehringer Ingelheim for other services. Dr Castonguay reports employment by Medtronic. Dr Dobrocky reports consulting for MicroVention. Dr Dusart reports compensation from MIVI for data and safety monitoring services. Dr Fischer reports research support from the Swiss National Science Foundation, Medtronic, Stryker, Rapid Medical, Penumbra, and Phenox consulting for Stryker and CSL Behring; and being part of the advisory board of Alexion/Portola, Boehringer Ingelheim, Biogen, and Acthera. Dr Haussen reports consulting for Vesalio, Cerenovus, Stryker, Brainomix, Poseydon Medical, Chiesi USA; data safety and monitoring board: Jacobs Institute; and stock options at VizAI. Dr Kaesmacher reports grants from the Swiss Academy of Medical Sciences/Bangerter Foundation, Swiss Stroke Society, and Clinical Trials Unit Bern. Dr Henon reports grants from Sanofi-Aventis US LLC and compensation from Novartis Pharma for other services. Dr Kaiser reports grants from the Joachim-Herz-Foundation. Dr Lin reports compensation from Imperative Care Inc for consultant services. Dr Martinez-Majander reports grants from the Finnish Medical Foundation. Dr Marto reports consulting for Amicus Therapeutics and Boehringer Ingelheim and speaker with Boehringer Ingelheim. Dr Michel reports grants from the University of Lausanne and the Swiss National Science Foundation. Dr Möhlenbruch reports grants from Medtronic, Stryker, and MicroVention. Dr Nagel reports consulting for Brainomix and speaker with Boehringer Ingelheim, Pfizer. Dr Nguyen reports research support from Medtronic; part of the advisory board at Brainomix; speaker with Genentech and Kaneka; and Associate Editor for Stroke. Dr Nogueira reports consulting for Biogen, Brainomix, Corindus, Cerenovus, Stryker, Medtronic, Ceretrieve, Anaconda, Biomed, Vesalio, Imperative Care, NeuroVasc Technologies, VizAI, Genentech, Prolong Pharmaceuticals, Perfuze, Phenox, and RapidPulse; stock options at VizAI, Vesalio, Perfuze, Corindus, Brainomix, Ceretrieve; and grants from Cerenovus and Stryker. Dr Ortega-Gutierrez reports grants from National Institutes of Health (NIH), Siemens, Stryker, methinks, MicroVention Inc, and NIH; compensation from Medtronic, MicroVention Inc, and Stryker for consultant services; and employment by Carver College of Medicine, University of Iowa. Dr Puetz reports lecturer’s fees from Boehringer Ingelheim, Daichii Sankyo, AstraZeneca, and Bristol Myers Squibb and travel support from NoNo Inc. Dr Puri reports compensation from Merit Medical Systems Inc, Stryker, Route 92 Medical Inc, Johnson & Johnson Health Care Systems Inc, MicroVention Inc, Balt USA, LLC, Merit Medical Systems Inc, and Medtronic for consultant services. Dr Ribo reports consulting for Medtronic, MiniMed, Cerenovus, AptaTargets, Stryker, and Philips and stock holdings at Methinks, Nora, and Anaconda Biomed. Dr Ringleb reports travel support from Bayer and Bristol Myers Squibb and consulting for Daiichi Sankyo Company and Boehringer Ingelheim. Dr Roy reports compensation from Johnson and Johnson International for other services. Dr Sheth reports consulting for Imperative Care, VizAI, Penumbra, and Motif Neurosciences; and grant from NIH. Dr Siegler reports grants from VizAI and Philips; compensation from AstraZeneca for other services; and employment by the University of Chicago. Dr Strbian reports employment by Helsingin ja Uudenmaan Sairaanhoitopiiri; compensation from AstraZeneca AB for consultant services; and grants from Boehringer Ingelheim. Dr Yaghi reports employment by Brown University and compensation from Medtronic USA Inc for other services. Dr Yamagami reports grants from Bristol Myers Squibb and lecturer’s fees from Stryker, Medtronic, J&J, Bayer, Daiichi Sankyo, Bristol Myers Squibb, and Otuska Pharmaceutical. The other authors report no conflicts.

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Endovascular Therapy for Late-Window M2-Segment Middle Cerebral Artery Occlusion: Analysis of the CLEAR Study

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Endovascular Therapy for Late-Window M2-Segment Middle Cerebral Artery Occlusion: Analysis of the CLEAR Study

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