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Original Investigation
January 7, 2019

Mediation of the Relationship Between Endovascular Therapy and Functional Outcome by Follow-up Infarct Volume in Patients With Acute Ischemic Stroke

Anna M. M. Boers, PhD1,2,3; Ivo G. H. Jansen, MD, PhD1,2; Scott Brown, PhD4; et al Hester F. Lingsma, PhD5; Ludo F. M. Beenen, MD2; Thomas G. Devlin, MD, PhD6; Luis San Román, MD, PhD7; Ji-Hoe Heo, MD, PhD8; Marc Ribó, MD9; Mohammed A. Almekhlafi, MD, FRCPC10; David S. Liebeskind, MD11; Jeanne Teitelbaum, MD12; Patricia Cuadras, MD13; Richard du Mesnil de Rochemont, MD, PhD14; Marine Beaumont, PhD15; Martin M. Brown, MD, FRCP16; Albert J. Yoo, MD, PhD17; Geoffrey A. Donnan, MD18; Jean Louis Mas, MD19; Catherine Oppenheim, PhD20; Richard J. Dowling, MBBS21; Thierry Moulin, MD, PhD22; Nelly Agrinier, MD, PhD23; Demetrius K. Lopes, MD24; Lucía Aja Rodríguez, MD25; Kars C. J. Compagne, MSc26,27; Fahad S. Al-Ajlan, MD28; Jeremy Madigan, MB ChB29; Gregory W. Albers, MD30; Sebastien Soize, MD31; Jordi Blasco, MD, PhD7; Stephen M. Davis, MD32; Raul G. Nogueira, MD33; Antoni Dávalos, MD, PhD34; Bijoy K. Menon, MD35; Aad van der Lugt, MD, PhD26; Keith W. Muir, MD36; Yvo B. W. E. M. Roos, MD, PhD37; Phil White, MD, PhD38; Peter J. Mitchell, MD21; Andrew M. Demchuk, MD, FRCPC35; Wim H. van Zwam, MD39; Tudor G. Jovin, MD40; Robert J. van Oostenbrugge, MD, PhD41; Diederik W. J. Dippel, MD, PhD27; Bruce C. V. Campbell, PhD, FRACP32; Francis Guillemin, MD, PhD23; Serge Bracard, PhD42; Michael D. Hill, MD35; Mayank Goyal, MD, FRCPC35; Henk A. Marquering, PhD1,2; Charles B. L. M. Majoie, MD, PhD2
Author Affiliations
  • 1Department of Biomedical Engineering and Physics, Amsterdam University Medical Center, location AMC, Amsterdam, the Netherlands
  • 2Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, location AMC, Amsterdam, the Netherlands
  • 3Department of Robotics and Mechatronics, University of Twente, Enschede, the Netherlands
  • 4Altair Biostatistics, Mooresville, North Carolina
  • 5Department of Public Health, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 6Department of Neurology, Erlanger Hospital, University of Tennessee at Chattanooga
  • 7Department of Interventional Neuroradiology, Hospital Clinic of Barcelona, Barcelona, Catalonia, Spain
  • 8Department of Neurology, Yonsei University, Seoul, South Korea
  • 9Department of Neurology, Vall d’Hebron University Hospital, Barcelona, Catalonia, Spain
  • 10Department of Neurology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
  • 11Department of Neurology, University of California, Los Angeles
  • 12Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, McGill University, Montreal, Quebec, Canada
  • 13Department of Radiology, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
  • 14Department of Radiology, Goethe University Hospital, University of Frankfurt, Frankfurt, Germany
  • 15Inserm CIC-IT 1433, University of Lorraine and University Hospital of Nancy, Nancy, France
  • 16Institute of Neurology, University College London, London, United Kingdom
  • 17Division of Neurointervention, Texas Stroke Institute, Dallas
  • 18The Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
  • 19Department of Neurology, Sainte-Anne Hospital and Paris-Descartes University, INSERM U894, Paris, France
  • 20Department of Neuroradiology, Sainte-Anne Hospital and Paris-Descartes University, INSERM U894, Paris, France
  • 21Department of Radiology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
  • 22Department of Neurology, University Hospital of Besançon, University of Franche-Comté, Besançon, France
  • 23Inserm, Centre Hospitalier Régional et Universitaire de Nancy, Université de Lorraine, CIC1433-Epidémiologie Clinique, Nancy, France
  • 24Department of Neurological Surgery, Rush University Medical Center, Chicago, Illinois
  • 25Neuroradiology Department, Hospital Universitari de Bellvitge, Barcelona, Catalonia, Spain
  • 26Department of Radiology and Nuclear Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 27Department of Neurology, Erasmus University Medical Center, Rotterdam, the Netherlands
  • 28Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  • 29St George’s University Hospital, London, United Kingdom
  • 30Department of Neurology, Stanford Stroke Center, Palo Alto, California
  • 31Department of Neuroradiology, University Hospital of Reims, Reims, France
  • 32Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia
  • 33Department of Neurology, Neurosurgery and Radiology, Grady Memorial Hospital, Emory University School of Medicine, Atlanta, Georgia
  • 34Department of Neuroscience, Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain
  • 35Department of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Foothills Hospital, Calgary, Alberta, Canada
  • 36Institute of Neuroscience and Psychology, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, United Kingdom
  • 37Department of Neurology, Amsterdam University Medical Center, location AMC, Amsterdam, the Netherlands
  • 38Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, United Kingdom
  • 39Department of Radiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center+, Maastricht, the Netherlands
  • 40Stroke Institute, Department of Neurology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
  • 41Department of Neurology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Center+, Maastricht, the Netherlands
  • 42Department of Diagnostic and Interventional Neuroradiology, INSERM U947, University of Lorraine and University Hospital of Nancy, Nancy, France
JAMA Neurol. Published online January 7, 2019. doi:10.1001/jamaneurol.2018.3661
Key Points

Question  To what extent can the beneficial effect of endovascular therapy for acute ischemic stroke on functional outcome be explained by treatment-related reduced follow-up infarct volume?

Findings  In this pooled data mediation analysis of randomized clinical trials including 1665 patients with acute ischemic stroke, follow-up infarct volume reduction was a predictor of functional outcome but only explained 12% of the benefit of endovascular therapy.

Meaning  Infarct volume assessed on posttreatment imaging is currently not a valid proxy for estimating treatment effect in phase II and III trials.

Abstract

Importance  The positive treatment effect of endovascular therapy (EVT) is assumed to be caused by the preservation of brain tissue. It remains unclear to what extent the treatment-related reduction in follow-up infarct volume (FIV) explains the improved functional outcome after EVT in patients with acute ischemic stroke.

Objective  To study whether FIV mediates the relationship between EVT and functional outcome in patients with acute ischemic stroke.

Design, Setting, and Participants  Patient data from 7 randomized multicenter trials were pooled. These trials were conducted between December 2010 and April 2015 and included 1764 patients randomly assigned to receive either EVT or standard care (control). Follow-up infarct volume was assessed on computed tomography or magnetic resonance imaging after stroke onset. Mediation analysis was performed to examine the potential causal chain in which FIV may mediate the relationship between EVT and functional outcome. A total of 1690 patients met the inclusion criteria. Twenty-five additional patients were excluded, resulting in a total of 1665 patients, including 821 (49.3%) in the EVT group and 844 (50.7%) in the control group. Data were analyzed from January to June 2017.

Main Outcome and Measure  The 90-day functional outcome via the modified Rankin Scale (mRS).

Results  Among 1665 patients, the median (interquartile range [IQR]) age was 68 (57-76) years, and 781 (46.9%) were female. The median (IQR) time to FIV measurement was 30 (24-237) hours. The median (IQR) FIV was 41 (14-120) mL. Patients in the EVT group had significantly smaller FIVs compared with patients in the control group (median [IQR] FIV, 33 [11-99] vs 51 [18-134] mL; P = .007) and lower mRS scores at 90 days (median [IQR] score, 3 [1-4] vs 4 [2-5]). Follow-up infarct volume was a predictor of functional outcome (adjusted common odds ratio, 0.46; 95% CI, 0.39-0.54; P < .001). Follow-up infarct volume partially mediated the relationship between treatment type with mRS score, as EVT was still significantly associated with functional outcome after adjustment for FIV (adjusted common odds ratio, 2.22; 95% CI, 1.52-3.21; P < .001). Treatment-reduced FIV explained 12% (95% CI, 1-19) of the relationship between EVT and functional outcome.

Conclusions and Relevance  In this analysis, follow-up infarct volume predicted functional outcome; however, a reduced infarct volume after treatment with EVT only explained 12% of the treatment benefit. Follow-up infarct volume as measured on computed tomography and magnetic resonance imaging is not a valid proxy for estimating treatment effect in phase II and III trials of acute ischemic stroke.

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