Mediation of Successful Reperfusion Effect through Infarct Growth and Cerebral Edema: A Pooled, Patient-level Analysis of EXTEND-IA Trials and SELECT Prospective Cohort. Annals of neurology Sarraj, A., Pujara, D. K., Churilov, L., Sitton, C., Ng, F., Hassan, A. E., Abraham, M. G., Blackburn, S. L., Sharma, G., Yassi, N., Kleinig, T., Shah, D., Wu, T. Y., Tekle, W. G., Budzik, R. F., Hicks, W. J., Vora, N., Edgell, R. C., Haussen, D., Ortega-Gutierrez, S., Toth, G., Maali, L., Ammar Abdulrazzak, M., Al-Shaibi, F., AlMaghrabi, T., Yogendrakumar, V., Shaker, F., Mir, O., Arora, A., Duncan, K., Sundararajan, S., Opaskar, A., Hu, Y., Ray, A., Sunshine, J., Bambakidis, N., Martin-Schild, S., Hussain, M. S., Nogueira, R., Furlan, A., Sila, C. A., Grotta, J. C., Parsons, M., Mitchell, P. J., Donnan, G. A., Davis, S. M., Albers, G. W., Campbell, B. C., SELECT, E. 2022


INTRODUCTION: Reperfusion therapy is highly beneficial for ischemic stroke. Reduction in both infarct growth and edema are plausible mediators of clinical benefit with reperfusion. We aimed to quantify these mediators and their interrelationship.METHODS: In a pooled, patient-level analysis of EXTEND-IA trials and SELECT study, we employed a mediation analysis framework to quantify infarct growth and cerebral edema(midline shift) mediation effect on successful reperfusion(mTICI=2b) association with functional outcome(mRS distribution). Further, we evaluated an additional pathway to the original hypothesis, where infarct growth mediated successful reperfusion effect on midline shift.RESULTS: 542/665(81.5%) eligible patients achieved successful reperfusion. Baseline clinical and imaging characteristics were largely similar between those achieving successful vs unsuccessful reperfusion. Median(IQR) infarct growth was 12.3(1.8-48.4)ml and median(IQR) midline shift was 0(0,2.2)mm. Of 249(37%) demonstrating a midline shift of =1mm, median(IQR) shift was 2.75(1.89, 4.21)mm). Successful reperfusion was associated with reductions in both predefined mediators; infarct growth (beta, -1.19; 95%CI, -1.51to-0.88;p<0.001) and midline shift (aOR:0.36,95%CI:0.23-0.57,p<0.001). Successful reperfusion association with improved functional outcome (acOR:2.68; 95%CI:1.86-3.88,p<0.001), became insignificant (acOR:1.39, 95%CI:0.95-2.04,p=0.094) when infarct growth and midline shift were added to the regression model. Infarct growth and midline shift explained 45% and 34% of successful reperfusion effect. Analysis considering alternative hypothesis demonstrated consistent results.CONCLUSIONS: In this mediation analysis from a pooled, patient-level cohort, a significant proportion(~80%) of successful reperfusion effect on functional outcome was mediated through reduction in infarct growth and cerebral edema. Further studies are required to confirm our findings, detect additional mediators to explain successful reperfusion residual effect and identify novel therapeutic targets to further enhance reperfusion benefits. This article is protected by copyright. All rights reserved.

View details for DOI 10.1002/ana.26587

View details for PubMedID 36571388