Collateral-based selection for endovascular treatment of acute ischaemic stroke in the late window (MR CLEAN-LATE): 2-year follow-up of a phase 3, multicentre, open-label, randomised controlled trial in the Netherlands - 21/06/24

Doi : 10.1016/S1474-4422(24)00228-X

Ilse Huijberts, BSc ^a,^d,⁎ , Florentina M E Pinckaers, MD ^a,^e,^f, Susanne G H Olthuis, MD ^b,^e, Sander M J van Kuijk, PhD ^c, Alida A Postma, PhD ^a,^g, Hieronymus D Boogaarts, ProfPhD ^h, Yvo B W E M Roos, ProfPhD ^j, Charles B L M Majoie, ProfPhD ⁱ, Aad van der Lugt, ProfPhD ^k, Diederik W J Dippel, ProfPhD ^l, Wim H van Zwam, ProfPhD ^a,^e, Robert J van Oostenbrugge, ProfPhD ^b,^e
on behalf of the
MR CLEAN-LATE investigators^{^†}
Members are listed in the Supplementary Material)
Robert van Oostenbrugge, Wim van Zwam, Susanne Olthuis, Anne Pirson, Wouter Hinsenveld, Robert-Jan Goldhoorn, Julie Staals, Diederik Dippel, Aad van der Lugt, Adriaan van Es, Bob Roozenbeek, Pieter-Jan van Doormaal, Yvo Roos, Charles Majoie, Jonathan Coutinho, Bart Emmer, Bart van der Worp, Rob Lo, Marianne van Walderveen, Marieke Wermer, Ewoud van Dijk, Sjoerd Jenniskens, Hieronymus Boogaarts, Maarten Uyttenboogaart, Reinoud Bokkers, Koos Keizer, Rob Gons, Lonneke Yo, Heleen den Hertog, Boudewijn van Hasselt, Wouter Schonewille, Jan-Albert Vos, Julia van Tuijl, Issam Boukrab, Hans Kortman, Jeannette Hofmeijer, Jasper Martens, Ido van den Wijngaard, Jelis Boiten, Geert Lycklama à Nijeholt, Paul Brouwers, Emiel Sturm, Tomas Bulut, Karlijn de Laat, Lukas van Dijk, Michel Remmers, Thijs de Jong, Anouk Rozeman, Otto Elgersma, Bas Van der Veen, Davy Sudiono, Heinrich Mattle, Jens Fiehler, Sander van Kuijk, Daan Nieboer, Hester Lingsma, Rick van Nuland, Stefan Roosendaal, Menno Krietemeijer, Alida Postma, René Van den Berg, Ludo Beenen, Sebastiaan Hammer, Anton Meijer, Anouk van der Hoorn, Albert Yoo, Dick Gerrits, Ben Jansen, Martine Truijman, Sanne Manschot, Henk Kerkhoff, Peter Koudstaal, Vicky Chalos, Olvert Berkhemer, Adriaan Versteeg, Lennard Wolff, Jiahang Su, Matthijs van der Sluijs, Henk van Voorst, Manon Tolhuisen, Hugo ten Cate, Moniek de Maat, Samantha Donse-Donkel, Heleen van Beusekom, Aladdin Taha, Aarazo Barakzie, Kilian Treurniet, Sophie van den Berg, Natalie LeCouffe, Rob van de Graaf, Inger de Ridder, Florentina Pinckaers, Angelique Ceulemans, Robrecht Knapen, Quirien Robbe, Lotte Sondag, Manon Kappelhof, Rik Reinink, Suzanne Silvis, Floris Schreuder, Simone Uniken Venema, Laura van Meenen, Sabine Collette, Wilma van Wijngaarden, Wouter van der Steen, Jan Hoving, Sabrina Verheesen, Martin Sterrenberg, Naziha El Ghannouti, Rita Sprengers, Ayla van Ahee, Berber Zweedijk, Wilma Pellikaan, Irati Schonewille, Kitty Blauwendraat, Yvonne Drabbe, Anke Kleine-Kathöfer, Joke de Meris, Michelle Sandiman, Tamara Dofferhoff-Vermeulen, Michelle Simons, Hester Bongenaar, Maylee Smallegange, Anja van Loon, Karin Kraus, Erna Bos-Verheij, Ester Santegoets, Suze Kooij, Annemarie Slotboom, Eva Ponjee, Rieke Eilander, Hanneke Droste, Esther van Veen, Rosalie Visser, Jasmijn Lodico, Marieke de Jong, Friedus van der Minne, Eefje Cleophas, Ernst Muskens, Amy Nijst, Leontien Heiligers, Yvonne Martens, Miranda Slotboom, Rogier Hintzen, Bart Jacobs

^a Department of Radiology and Nuclear Medicine, Maastricht University Medical Center+, Maastricht, Netherlands
^b Department of Neurology, Maastricht University Medical Center+, Maastricht, Netherlands
^c Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Center+, Maastricht, Netherlands
^d Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, Netherlands
^e School for Cardiovascular Diseases, Maastricht University, Maastricht, Netherlands
^f Care and Public Health Research Institute, Maastricht University, Maastricht, Netherlands
^g School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
^h Department of Neurosurgery, Radboud University Medical Center, Nijmegen, Netherlands
ⁱ Department of Radiology and Nuclear Medicine, Amsterdam Neurosciences, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
^j Department of Neurology, Amsterdam UMC location University of Amsterdam, Amsterdam, Netherlands
^k Department of Radiology and Nuclear Medicine, Erasmus, University Medical Center Rotterdam, Rotterdam, Netherlands
^l Department of Neurology, Erasmus, University Medical Center Rotterdam, Rotterdam, Netherlands

^*Correspondence to: Ilse Huijberts, Department of Radiology and Nuclear Medicine, Maastricht University Medical Center+, Maastricht 6229HX, NetherlandsDepartment of Radiology and Nuclear MedicineMaastricht University Medical Center+Maastricht6229HXNetherlands

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Summary

Background

The MR CLEAN-LATE trial provided evidence for the safety and efficacy of endovascular treatment for acute ischaemic stroke within the late window (after 6–24 h) in patients who were preselected based on the presence of collateral flow on CT angiography. We aimed to evaluate clinical outcomes 2 years after randomisation.

Methods

MR CLEAN-LATE was a phase 3, multicentre, open-label, blinded-endpoint, randomised controlled trial conducted at 18 stroke intervention centres in the Netherlands. If endovascular treatment could be initiated within 6–24 h of symptom onset or last seen well, patients (aged 18 years or older) with an acute ischaemic stroke due to a large vessel occlusion in the anterior circulation and at least some collateral flow in the affected middle cerebral artery territory on CT angiography were randomly assigned (1:1) to either endovascular treatment with best medical treatment (endovascular treatment group) or best medical treatment alone (control group). Web-based randomisation, stratified by centre, was performed with the use of permuted blocks (block size eight to 20). The researchers who collected clinical outcomes and analysed the results were masked to treatment allocation; treating physicians, local investigators, and patients were aware of the received treatment. The primary outcome of MR CLEAN-LATE was the modified Rankin Scale (mRS) score at 90 days after randomisation. For this 2-year prespecified analysis, the primary outcome was mRS score at 2 years (minus 3 months to plus 6 months). Primary and safety analyses were performed based on the modified intention-to-treat principle, and included patients who provided (deferred) consent or died before consent could be obtained. Missing data were handled with multiple imputation by chained equations. The trial is completed and is registered at ISRCTN, ISRCTN19922220.

Findings

Between Feb 2, 2018, and Jan 27, 2022, 535 patients were randomly assigned in the MR CLEAN-LATE trial, of whom 502 (94%) gave deferred consent and comprised the modified intention-to-treat population (255 in the endovascular treatment group and 247 in the control group). 261 (52%) patients were female and 241 (48%) were male. Data for mRS score at 2 years were available for 226 (89%) patients in the endovascular treatment group and for 202 (82%) patients in the control group. The median mRS score at 2 years was 4 (IQR 2–6) in the endovascular treatment group and 6 (2–6) in the control group. The endovascular treatment group demonstrated a shift towards better functional outcomes on the mRS (adjusted common odds ratio 1·41 [95% CI 1·00–1·99]; p=0·049). All-cause mortality at 2 years was 34% (87 of 255) in the endovascular treatment group and 41% (101 of 247) in the control group (adjusted hazard ratio 0·81 [95% CI 0·60–1·08]; p=0·15). Major vascular events (ie, transient ischaemic attack, ischaemic stroke, haemorrhagic stroke, and cardiac events) were reported between 90 days and 2 years in 23 patients in the endovascular treatment group and 13 patients in the control group.

Interpretation

Our results show that the effectiveness of late-window (after 6–24 h) endovascular treatment in improving clinical outcomes is sustained for up to 2 years in a population preselected based on the presence of collateral flow on CT angiography. This finding might be important for prompting further evaluations of cost-effectiveness, health-care policy development, and clinical decision making.

Funding

The Dutch Organization for Health Research and Health Innovation (ZonMW), Collaboration for New Treatments of Acute Stroke Consortium, Dutch Heart Foundation, Stryker, Medtronic, Cerenovus, Health Holland Top Sector Life Sciences & Health, and the Netherlands Brain Foundation.

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