Abstract

Some patients have poor outcomes despite small infarcts after endovascular therapy (EVT), while others with large infarcts do well. Understanding why these discrepancies occur may help to optimize EVT outcomes. To validate exploratory findings from the Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion with Emphasis on Minimizing CT to Recanalization Times (ESCAPE) trial regarding pretreatment, treatment-related, and posttreatment factors associated with discrepancies between follow-up infarct volume (FIV) and 90-day functional outcome. This cohort study is a post hoc analysis of the Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial, a double-blind, randomized, placebo-controlled, international, multicenter trial conducted from March 2017 to August 2019. Patients who participated in ESCAPE-NA1 and had available 90-day modified Rankin Scale (mRS) scores and 24-hour to 48-hour posttreatment follow-up parenchymal imaging were included. Small FIV (volume ≤25th percentile) and large FIV (volume ≥75th percentile) on 24-hour computed tomography/magnetic resonance imaging. Baseline factors, outcomes, treatments, and poststroke serious adverse events (SAEs) were compared between discrepant cases (ie, patients with 90-day mRS score ≥3 despite small FIV or those with mRS scores ≤2 despite large FIV) and nondiscrepant cases. Area under the curve (AUC) and goodness of fit of prespecified logistic models, including pretreatment (eg, age, cancer, vascular risk factors) and treatment-related and posttreatment (eg, SAEs) factors, were compared with stepwise regression-derived models for ability to identify small FIV with higher mRS score and large FIV with lower mRS score. Among 1091 patients (median [IQR] age, 70.8 [60.8-79.8] years; 549 [49.7%] women; median [IQR] FIV, 24.9 mL [6.6-92.2 mL]), 42 of 287 patients (14.6%) with FIV of 7 mL or less (ie, ≤25th percentile) had an mRS score of at least 3; 65 of 275 patients (23.6%) with FIV of 92 mL or greater (ie, ≥75th percentile) had an mRS score of 2 or less. Prespecified models of pretreatment factors (ie, age, cancer, vascular risk factors) associated with low FIV and higher mRS score performed similarly to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42). SAEs, specifically infarct in new territory, recurrent stroke, pneumonia, and congestive heart failure, were associated with low FIV and higher mRS scores; stepwise models also identified 24-hour hemoglobin as treatment-related/posttreatment factor (AUC, 0.92 [95% CI, 0.90-0.95] vs 0.94 [95% CI, 0.91-0.96]; P = .14). Younger age was associated with high FIV and lower mRS score; stepwise models identified absence of diabetes and higher baseline hemoglobin as additional pretreatment factors (AUC, 0.76 [95% CI, 0.70-0.82] vs 0.77 [95% CI, 0.71-0.83]; P = .82). Absence of SAEs, especially stroke progression, symptomatic intracerebral hemorrhage, and pneumonia, was associated with high FIV and lower mRS score2; stepwise models also identified 24-hour hemoglobin level, glucose, and diastolic blood pressure as posttreatment factors associated with discrepant cases (AUC, 0.80 [95% CI, 0.74-0.87] vs 0.79 [95% CI, 0.72-0.86]; P = .92). In this study, discrepancies between functional outcome and post-EVT infarct volume were associated with differences in pretreatment factors, such as age and comorbidities, and posttreatment complications related to index stroke evolution, secondary prevention, and quality of stroke unit care. Besides preventing such complications, optimization of blood pressure, glucose levels, and hemoglobin levels are potentially modifiable factors meriting further study.

Highlights

  • Endovascular thrombectomy (EVT) improves functional outcomes in patients with acute ischemic stroke caused by large-vessel occlusions (LVO),[1] partly by reducing infarct volumes.[2,3,4] Follow-up or final imaging infarct volume (FIV), measured 24 to 48 hours post stroke, is associated with functional outcomes at 90 days assessed using the modified Rankin Scale in patients with stroke due to LVO.[5,6,7] there is only a moderate correlation of FIV to clinical outcomes,[8,9] with FIV only explaining an estimated 12% of the variance in EVT treatment benefit using mediation analyses.[10]

  • Prespecified models of pretreatment factors associated with low FIV and higher modified Rankin Scale (mRS) score performed to models selected by stepwise regression (AUC, 0.92 [95% CI, 0.89-0.95] vs 0.93 [95% CI, 0.90-0.95]; P = .42)

  • In this study, discrepancies between functional outcome and post-EVT infarct volume were associated with differences in pretreatment factors, such as age and comorbidities, and posttreatment complications related to index stroke evolution, secondary prevention, and quality of stroke unit care

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Summary

Introduction

Endovascular thrombectomy (EVT) improves functional outcomes in patients with acute ischemic stroke caused by large-vessel occlusions (LVO),[1] partly by reducing infarct volumes.[2,3,4] Follow-up or final imaging infarct volume (FIV), measured 24 to 48 hours post stroke, is associated with functional outcomes at 90 days assessed using the modified Rankin Scale (mRS) in patients with stroke due to LVO.[5,6,7] there is only a moderate correlation of FIV to clinical outcomes,[8,9] with FIV only explaining an estimated 12% of the variance in EVT treatment benefit using mediation analyses.[10]. Factors associated with large FIV and mRS score of 2 or less included absence of vascular risk factors, lower 24-hour NIHSS, and absence of complications. This analysis was exploratory or hypothesis generating, and the models included a mix of patients with and without EVT. We sought to validate these exploratory findings by examining the performance of these models for FIV-mRS discrepancies in the larger Safety and Efficacy of Nerinetide in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, in which all patients underwent EVT. We aimed to examine the construct validity of the discordance between infarct volume and outcome in patients who received EVT as JAMA Network Open. 2021;4(11):e2132376. doi:10.1001/jamanetworkopen.2021.32376 (Reprinted)

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