Clinical Trial

. 2024 Dec;9(4):907-917.

doi: 10.1177/23969873241249406. Epub 2024 May 17.

Safety and clinical outcomes of endovascular therapy versus medical management in late presentation of large ischemic stroke

Adnan Mujanovic¹, Daniel Strbian², Jelle Demeestere^{3

4}, João Pedro Marto⁵, Volker Puetz^{6

7}, Raul G Nogueira^{8

9}, Mohamad Abdalkader^{10

11}, Simon Nagel^{12

13}, Jean Raymond¹⁴, Marc Ribo¹⁵, Patrik Michel¹⁶, Shinichi Yoshimura¹⁷, Osama O Zaidat¹⁸, Simon Winzer^{6

7}, Santiago Ortega-Gutierrez¹⁹, Sunil A Sheth²⁰, James E Siegler²¹, Anne Dusart²², Diogo C Haussen²³, Hilde Henon²⁴, Bettina L Serrallach¹, Mahmoud H Mohammaden²³, Markus A Möhlenbruch²⁵, Marta Olive-Gadea¹⁵, Ajit S Puri²⁶, Nobuyuki Sakai²⁷, Piers Klein^{10

11}, Liisa Tomppo², Francois Caparros²⁴, João Nuno Ramos²⁸, Mouhammad Jumaa²⁹, Syed Zaidi²⁹, Tomas Dobrocky¹, Nicolas Martinez-Majander², Stefania Nannoni³⁰, Flavio Bellante²², Aaron Rodriguez-Calienes¹⁹, Sergio Salazar-Marioni²⁰, Pekka Virtanen³¹, Daniel Po Kaiser^{7

32}, Rita Ventura⁵, Jessica Jesser²⁵, Alicia C Castonguay²⁹, Muhammad M Qureshi^{9

33}, Hesham E Masoud³⁴, Milagros Galecio-Castillo¹⁹, Manuel Requena¹⁵, Riikka Lauha³¹, Wei Hu³⁵, Eugene Lin¹⁸, Zhongrong Miao³⁶, Daniel Roy¹⁴, Hiroshi Yamagami³⁷, David J Seiffge³⁸, Davide Strambo¹⁶, Peter A Ringleb¹³, Robin Lemmens^{3

4}, Urs Fischer^{38

39}, Thanh N Nguyen^{11

40}, Johannes Kaesmacher¹

Affiliations

¹ Diagnostic and Interventional Neuroradiology, University Hospital Bern, University of Bern, Bern, Switzerland.
² Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
³ Neurology, UZ Leuven, Leuven, Belgium.
⁴ Laboratory for Neurobiology, KU Leuven, Leuven, Belgium.
⁵ Neurology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.
⁶ Neurology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁷ Dresden Neurovascular Center, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁸ Neurology, University of Pittsburgh Medical Center, Pittsburgh, USA.
⁹ Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, USA.
¹⁰ Neurology, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, USA.
¹¹ Radiology, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, USA.
¹² Neurology, Klinikum Ludwigshafen, Ludwigshafen, Germany.
¹³ Neurology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁴ Interventional Neuroradiology, Centre Hospitalier de l'Universite de Montreal, Radiology, Montreal, Canada.
¹⁵ Neurology, Hospital Vall d'Hebron, Barcelona, Spain.
¹⁶ Neurology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁷ Neurosurgery, Hyogo Medical University, Japan.
¹⁸ Neuroscience and Stroke Program, Bon Secours Mercy Health St. Vincent Hospital, Toledo, USA.
¹⁹ Neurology, University of Iowa, Iowa City, USA.
²⁰ Neurology, UTHealth McGovern Medical School, Neurology, Houston, USA.
²¹ Neurology, University of Chicago, Chicago, USA.
²² Neurology, Hôpital Civil Marie Curie, Charleroi, Belgium.
²³ Neurology, Grady Memorial Hospital, Atlanta, USA.
²⁴ Neurology, Centre Hospitalier Universitaire de Lille, Lille, France.
²⁵ Radiology, Heidelberg University Hospital, Heidelberg, Germany.
²⁶ Division of Interventional Neuroradiology, University of Massachusetts Memorial Medical Center, Worcester, USA.
²⁷ Neurosurgery, Seijinkai Shimizu Hospital, Kyoto, Japan.
²⁸ Neuroradiology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Occidental, Lisbon, Portugal.
²⁹ Neurology, University of Toledo, Toledo, USA.
³⁰ Clinical Neurosciences, University of Cambridge, Cambridge, UK.
³¹ Radiology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
³² Institute of Neuroradiology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
³³ Radiation Oncology, Boston Medical Center, USA.
³⁴ Neurology, State University of New York, Syracuse, USA.
³⁵ Neurology, The First Affiliated Hospital of USTC, China.
³⁶ Interventional Neuroradiology, Beijing Tiantan Hospital, Beijing, China.
³⁷ Division of Stroke Prevention and Treatment, University of Tsukuba, Tsukuba, Japan.
³⁸ Neurology, University Hospital Bern, University of Bern, Bern, Switzerland.
³⁹ Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.
⁴⁰ Neurology, Boston Medical Center, Boston, USA.

PMID: 38757713
PMCID: PMC11569454
DOI: 10.1177/23969873241249406

Clinical Trial

Safety and clinical outcomes of endovascular therapy versus medical management in late presentation of large ischemic stroke

Adnan Mujanovic et al. Eur Stroke J. 2024 Dec.

. 2024 Dec;9(4):907-917.

doi: 10.1177/23969873241249406. Epub 2024 May 17.

Authors

Affiliations

¹ Diagnostic and Interventional Neuroradiology, University Hospital Bern, University of Bern, Bern, Switzerland.
² Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
³ Neurology, UZ Leuven, Leuven, Belgium.
⁴ Laboratory for Neurobiology, KU Leuven, Leuven, Belgium.
⁵ Neurology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Ocidental, Lisbon, Portugal.
⁶ Neurology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁷ Dresden Neurovascular Center, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
⁸ Neurology, University of Pittsburgh Medical Center, Pittsburgh, USA.
⁹ Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, USA.
¹⁰ Neurology, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, USA.
¹¹ Radiology, Boston Medical Center, Boston University Chobanian & Avedisian School of Medicine, USA.
¹² Neurology, Klinikum Ludwigshafen, Ludwigshafen, Germany.
¹³ Neurology, Heidelberg University Hospital, Heidelberg, Germany.
¹⁴ Interventional Neuroradiology, Centre Hospitalier de l'Universite de Montreal, Radiology, Montreal, Canada.
¹⁵ Neurology, Hospital Vall d'Hebron, Barcelona, Spain.
¹⁶ Neurology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁷ Neurosurgery, Hyogo Medical University, Japan.
¹⁸ Neuroscience and Stroke Program, Bon Secours Mercy Health St. Vincent Hospital, Toledo, USA.
¹⁹ Neurology, University of Iowa, Iowa City, USA.
²⁰ Neurology, UTHealth McGovern Medical School, Neurology, Houston, USA.
²¹ Neurology, University of Chicago, Chicago, USA.
²² Neurology, Hôpital Civil Marie Curie, Charleroi, Belgium.
²³ Neurology, Grady Memorial Hospital, Atlanta, USA.
²⁴ Neurology, Centre Hospitalier Universitaire de Lille, Lille, France.
²⁵ Radiology, Heidelberg University Hospital, Heidelberg, Germany.
²⁶ Division of Interventional Neuroradiology, University of Massachusetts Memorial Medical Center, Worcester, USA.
²⁷ Neurosurgery, Seijinkai Shimizu Hospital, Kyoto, Japan.
²⁸ Neuroradiology, Hospital de Egas Moniz, Centro Hospitalar Lisboa Occidental, Lisbon, Portugal.
²⁹ Neurology, University of Toledo, Toledo, USA.
³⁰ Clinical Neurosciences, University of Cambridge, Cambridge, UK.
³¹ Radiology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
³² Institute of Neuroradiology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
³³ Radiation Oncology, Boston Medical Center, USA.
³⁴ Neurology, State University of New York, Syracuse, USA.
³⁵ Neurology, The First Affiliated Hospital of USTC, China.
³⁶ Interventional Neuroradiology, Beijing Tiantan Hospital, Beijing, China.
³⁷ Division of Stroke Prevention and Treatment, University of Tsukuba, Tsukuba, Japan.
³⁸ Neurology, University Hospital Bern, University of Bern, Bern, Switzerland.
³⁹ Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.
⁴⁰ Neurology, Boston Medical Center, Boston, USA.

PMID: 38757713
PMCID: PMC11569454
DOI: 10.1177/23969873241249406

Abstract

Introduction: The benefit of endovascular therapy (EVT) among stroke patients with large ischemic core (ASPECTS 0-5) in the extended time window outside of trial settings remains unclear. We analyzed the effect of EVT among these stroke patients in real-world settings.

Patients and methods: The CT for Late Endovascular Reperfusion (CLEAR) study recruited patients from 66 centers in 10 countries between 01/2014 and 05/2022. The extended time-window was defined as 6-24 h from last-seen-well to treatment. The primary outcome was shift of the 3-month modified Rankin scale (mRS) score. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and mortality. Outcomes were analyzed with ordinal and logistic regressions.

Results: Among 5098 screened patients, 2451 were included in the analysis (median age 73, 55% women). Of patients with ASPECTS 0-5 (n = 310), receiving EVT (n = 209/310) was associated with lower 3-month mRS when compared to medical management (median 4 IQR 3-6 vs 6 IQR 4-6; aOR 0.4, 95% CI 0.2-0.7). Patients undergoing EVT had higher sICH (11.2% vs 4.0%; aOR 4.1, 95% CI 1.2-18.8) and lower mortality (31.6% vs 58.4%, aOR 0.4; 95% CI 0.2-0.9) compared to medically managed patients. The relative benefit of EVT was comparable between patients with ASPECTS 0 and 5 and 6-10 in the extended time window (interaction aOR 0.9; 95% CI 0.5-1.7).

Conclusion: In the extended time window, patients with ASPECTS 0-5 may have preserved relative treatment benefit of EVT compared to patients with ASPECTS 6-10. These findings are in line with recent trials showing benefit of EVT among real-world patients with large ischemic core in the extended time window.

Trial registration number: clinicaltrials.gov; Unique identifier: NCT04096248.

Keywords: Endovascular therapy; best medical treatment; extended time-window; large ischemic core; mechanical thrombectomy.

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Conflict of interest statement

Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: U.Fischer reported research support of the Swiss National Science Foundation and the Swiss Heart Foundation; research grants from Medtronic (BEYOND SWIFT, SWIFT DIRECT) and from Stryker, Rapid medical, Penumbra and Phenox (DISTAL); consultancies for Medtronic, Stryker, and CSL Behring; participation in an advisory board for Alexion/Portola, Boehringer Ingelheim, Biogen and Acthera; member of a clinical event committee (CEC) of the COATING study (Phenox) and member of the data and safety monitoring committee (DSMB) of the TITAN, LATE_MT and IN EXTREMIS trials; presidency of the Swiss Neurological Society. All fees are paid to institutions. T.Dobrocky reported MicroVention consultancy. H.Henon reported grants from SANOFI-AVENTIS U.S. LLC. D.Haussen reported consultancy for Vesalio, Cerenovus, Stryker, Brainomix, Poseydon Medical, and Chiesi USA; DSMB from Jacobs Institute; stock options in Viz AI. J.Kaesmacher reported grants from Swiss Academy of Medical Sciences/Bangerter Foundation, Swiss Stroke Society, Clinical Trials Unit Bern. J. Siegler reported grants from Medtronic and Philips. D.Kaiser reported grants from Joachim Herz Foundation. N.Martinez-Majander reported grants from Finnish Medical Foundation. J.P.Marto reported consulting and speaker fees from Amicus Therapeutics and Boehringer Ingelheim. P.Michel reported grants from University of Lausanne, Swiss National Science Foundation. M.Möhlenbruch reported grants from Medtronic, Stryker, MicroVention. S.Nagel reported consultancy for Brainomix; speaker Boehringer Ingelheim, Pfizer. T.Nguyen discloses research support from Medtronic to her institution; advisory board Idorsia, Brainomix, ArunaBio; Associate Editor of Stroke. R.Nogueira reported consultancy for Biogen, Brainomix, Corindus, Cerenovus, Stryker, Medtronic, Ceretrieve, Anaconda, Biomed, Vesalio, Imperative Care, NeuroVasc Technologies, Viz AI, Genentech, Prolong Pharmaceuticals, Perfuze, Phenox, RapidPulse; stock options Viz AI, Vesalio, Perfuze, Corindus, Brainomix, Ceretrieve; grants from Cerenovus, Stryker. V.Puetz reported lecturer fee for Daiichi Sankyo. M.Ribo reported consultancy for Medtronic, MiniMed, Cerenovus, AptaTargets, Stryker, Philips; stock holdings in Methinks, Nora, Anaconda Biomed. P.Ringleb reported travel support from Bayer, Bristol Myers Squibb; consultancy for Daiichi Sankyo Company, Boehringer Ingelheim. S.Sheth reported consultancy for Imperative Care, Viz AI, Penumbra, Motif Neurosciences; NIH grant. S. Yoshimura reported research grants from Medico’s Hirata, Medtronic, and Terumo; and lecturer fees from Medtronic, Kaneka, Stryker, Daiichi Sankyo, Bristol-Meyers Squibb, and Johnson & Johnson. Sakai reported a research grant from Japan Lifeline, Kaneka, Medtronic, Terumo and TG Medical; lecturer’s fees from Asahi-Intec, Kaneka, Medtronic, Stryker and Terumo; advisory boards for Johnson&Johnson, Medtronic and Terumo. H.Yamagami reported research grants from Bristol-Myers Squibb; lecturer’s fees from Stryker, Medtronic, J&J, Bayer, Daiichi Sankyo, Bristol-Myers Squibb, Otuska Pharmaceutical; advisory board for Daiichi Sankyo. D. Strbian reported research grant from the governmental educational funding (Finland), hospital research funds (HUS), unrestricted educational grant (Boehringer Ingelheim), whereas all funds were handled by hospital-based institution; partner of the consortium funding for the PROOF trial (EU), LVO check (EU), and electric impedance tomography project (Jane ja Aatos Erkon Säätiö); consultancies and advisory scientific board for Orion, Herantis Pharma, Boehringer Ingelheim, Portola, Alexion, AstraZeneca, Bristol-Meyers-Squibb, Janssen; member of the DSMB on the ENDOLOW trial. All other authors declare no conflict of interest.

Figures

**Figure 1.**
Adjusted ordinal regression among patients with low ASPECTS. mRS: modified Rankin Scale; aOR: adjusted odds ratios; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale; pre-mRS: pre-stroke modified Rankin Scale score; EVT: endovascular therapy. Odds ratios in ordinal regression > 1 indicate an unfavorable shift on the mRS, while odds ratios < 1 indicate a favorable shift on the mRS.

**Figure 2.**
Modified Rankin Scale score shift at 3-month follow-up. ASPECTS: Alberta Stroke Program Early Computed Tomography Score. Ordinal shift on the mRS (dashed black line for independent ambulation) was observed among patients with both high and low ASPECTS. After adjustment, the association between endovascular therapy and independent ambulation remained (ordinal regression aOR 0.4, 95% CI 0.2–0.7).

**Figure 3.**
Adjusted ordinal regression among all patients. mRS: modified Rankin Scale; aOR: adjusted odds ratios; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale; pre-mRS: pre-stroke modified Rankin Scale score; ASPECTS: Alberta Stroke Program Early Computed Tomography Score; EVT: endovascular therapy. Odds ratios in ordinal regression > 1 indicate an unfavorable shift on the mRS, while odds ratios < 1 indicate a favorable shift on the mRS.

**Figure 4.**
Adjusted logistic regression among all patients. mRS: modified Rankin Scale; aOR: adjusted odds ratios; CI: confidence interval; NIHSS: National Institutes of Health Stroke Scale; pre-mRS: pre-stroke modified Rankin Scale score; EVT: endovascular therapy. After adjustment for the prespecified confounders, the interaction term ASPECTS × Treatment was not associated with independent ambulation at 3 months (aOR 1.9, 95% CI 0.9–4.4).

See this image and copyright information in PMC

References

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Safety and clinical outcomes of endovascular therapy versus medical management in late presentation of large ischemic stroke

Affiliations

Safety and clinical outcomes of endovascular therapy versus medical management in late presentation of large ischemic stroke

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Associated data

LinkOut - more resources

Full Text Sources

Medical