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 Oppenheim, Richard 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

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. To study whether FIV mediates the relationship between EVT and functional outcome in patients with acute ischemic stroke. 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. The 90-day functional outcome via the modified Rankin Scale (mRS). 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. 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.