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, Ivo G.H. Jansen, Scott Brown, Hester F. Lingsma, Ludo F.M. Beenen, Thomas G. Devlin, Luis San Román, Ji Hoe Heo, Marc Ribó, Mohammed A. Almekhlafi, David S. Liebeskind, Jeanne Teitelbaum, Patricia Cuadras, Richard Du Mesnil De Rochemont, Marine Beaumont, Martin M. Brown, Albert J. Yoo, Geoffrey A. Donnan, Jean Louis Mas, Catherine OppenheimRichard J. Dowling, Thierry Moulin, Nelly Agrinier, Demetrius K. Lopes, Lucía Aja Rodríguez, Kars C.J. Compagne, Fahad S. Al-Ajlan, Jeremy Madigan, Gregory W. Albers, Sebastien Soize, Jordi Blasco, Stephen M. Davis, Raul G. Nogueira, Antoni Dávalos, Bijoy K. Menon, Aad Van Der Lugt, Keith W. Muir, Yvo B.W.E.M. Roos, Phil White, Peter J. Mitchell, Andrew M. Demchuk, Wim H. Van Zwam, Tudor G. Jovin, Robert J. Van Oostenbrugge, Diederik W.J. Dippel, Bruce C.V. Campbell, Francis Guillemin, Serge Bracard, Michael D. Hill, Mayank Goyal, Henk A. Marquering, Charles B.L.M. Majoie

Research output: Contribution to journalArticle

11 Citations (Scopus)

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..

Original languageEnglish
Pages (from-to)194-202
Number of pages9
JournalJAMA Neurology
Volume76
Issue number2
DOIs
Publication statusPublished - 2019 Feb

Bibliographical note

Funding Information:
Jansen, Marquering, and Majoie are shareholders of Nico.lab, a company that focuses on the use of artificial intelligence for medical image analysis. Dr Scott Brown acts as a consultant for Medtronic. Dr Donnan has received grants from the Australian National Health and Medical Research Council, nonfinancial support from Boehringer Ingelheim, and has served on the advisory boards of Boehringer Ingelheim, AstraZeneca, Bristol-Myers Squibb, and Merck Sharp and Dohme. Dr Albers holds equity and has consulted for iSchemaView and Medtronic. Dr Davis has received lecture fees from Covidien (Medtronic). Dr Dávalos serves on the advisory board of Medtronic Neurovascular (Steering Committee Solitaire FR Thrombectomy for Acute Revascularization [STAR] trial). Dr Menon is a member of the steering and executive committee of the Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke (ESCAPE) trial, which received support from Covidien; a site principal investigator of the Acute Stroke or Transient Ischaemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial, sponsored by AstraZeneca; a board member of QuikFlo Health; has received honoraria from Penumbra; has provisional patent 62/086077 for triaging systems in ischemic stroke; and has received research funding from the Canadian Institutes of Health Research, Heart and Stroke Foundation of Canada, Alberta Innovates – Health Solution, Hotchkiss Brain Institute, and the Faculty of Medicine, University of Calgary. Dr van der Lugt has received honoraria from Stryker as well as unrestricted research grants from Stryker and Penumbra, which were paid to the Erasmus University Medical Center. Dr Mitchell has received unrestricted grant funding for the Extending the Time for Thrombolysis in Emergency Neurological Deficits–Intra-Arterial (EXTEND-IA) trial to the Florey Institute of Neuroscience and Mental Health from Covidien (Medtronic); has served as an unpaid consultant to Codman Johnson and Johnson; and has received unrestricted research funding and grants from Codman Johnson and Johnson, Medtronic, and Stryker, which were paid to the University of Melbourne. Dr Demchuk has received grant support and personal fees from Covidien (Medtronic). Dr van Zwam has received honoraria from Stryker, which were paid to the Erasmus University Medical Center. Dr Jovin has consulted for Codman Neurovascular and Neuravi, holds stock in Silk Road and Blockade, has acted as an unpaid consultant to Stryker as principal investigator of the Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention With Trevo (DAWN) trial, and served as an unpaid member of the advisory board for Medtronic. Dr Dippel has received honoraria from Stryker, which were paid to the Erasmus University Medical Center, and unrestricted research grants the from Dutch Heart Foundation, AngioCare, Medtronic/ Covidien/Ev3, medac/Lamepro, Penumbra, Stryker, Stryker European, and Top Medical/Concentric for the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) and from the Dutch Heart Foundation, Dutch Brain Foundation, Stryker European, Medtronic, and Penumbra for other research, all paid to the Erasmus University Medical Center. Dr Campbell has received research support from the National Health and Medical Research Council of Australia (grants GNT1043242 and GNT1035688), Royal Australasian College of Physicians, Royal Melbourne Hospital Foundation, National Heart Foundation, National Stroke Foundation of Australia, and unrestricted grant funding for the EXTEND-IA trial to the Florey Institute of Neuroscience and Mental Health from Covidien (Medtronic). Dr Hill has received unrestricted grant funding for the ESCAPE trial to the University of Calgary from Covidien (Medtronic) as well as in-kind support consortium of the Heart and Stroke Foundation, Alberta Innovates Health Solutions, Alberta Health Services, and the University of Calgary (Hotchkiss Brain Institute, Departments of Clinical Neurosciences and Radiology, and Calgary Stroke Program); has received personal fees from Merck; and has received nonfinancial support from Hoffmann-La Roche. Dr Hill has a patent for systems and methods for assisting in decision making and triaging for patients with acute stroke (62/086077) pending to the US Patent and Trademark Office and owns stock in Calgary Scientific Incorporated, a company that focuses on medical imaging software. Dr Goyal has received grants and personal fees from Covidien. In addition, Dr Goyal has a patent for systems and methods for diagnosing strokes (PCT/CA2013/000761) licensed to GE Healthcare. Dr Majoie has received speakers’ fees from Stryker, which were paid to the University of Amsterdam. No other disclosures were reported.

Funding Information:
Reperfusion Evaluated in Multiple Endovascular Stroke Trials collaboration was funded by Medtronic through an unrestricted grant to the University of Calgary.

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

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