Mediation of Age and Thrombectomy Outcome by Neuroimaging Markers of Frailty in Patients With Stroke

What the fuck good did this research do to get survivors recovered?  I'd fire everyone involved! If you're not even trying to solve stroke: GET THE HELL OUT!

Mediation of Age and Thrombectomy Outcome by Neuroimaging Markers of Frailty in Patients With Stroke

Faysal Benali, MD^1,2,3,4,5; Nishita Singh, MD^1,2,3,6; Joachim Fladt, MD^1,2,3,4,7; et al Tanaporn Jaroenngarmsamer, MD¹; Fouzi Bala, MD^1,2,3,4,8; Johanna M. Ospel, MD, PhD^1,2,3,4,9; Brian H. Buck, MD¹⁰; Dar Dowlatshahi, MD¹¹; Thalia S. Field, MD¹²; Ricardo A. Hanel, MD, PhD¹³; Lissa Peeling, MD¹⁴; Michael Tymianski, MD¹⁵; Michael D. Hill, MD^{1,2,3,4,16,17}; Mayank Goyal, MD, PhD^1,2,3; Aravind Ganesh, MD, PhD^1,2,3,16,17; for the ESCAPE-NA1 Investigators

Author Affiliations Article Information

JAMA Netw Open. 2024;7(1):e2349628. doi:10.1001/jamanetworkopen.2023.49628

Key Points

Question  To what extent do neuroimaging markers of brain frailty mediate associations between age and postthrombectomy outcomes in ischemic stroke?

Findings  In this cohort study, a post hoc analysis of the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, markers of brain frailty on routine computed tomography images (brain atrophy, chronic infarcts, and small vessel disease) mediated 85.1% of the total association of age with 90-day functional outcome after thrombectomy.

Meaning  The findings of this study suggest that neuroimaging markers of frailty are important to consider when performing outcome predictions in clinical practice and when adjusting for primary outcome analyses in future trials, since imbalances in brain frailty features could confound treatment effects.

Abstract

Importance  Age is a leading predictor of poor outcomes after brain injuries like stroke. The extent to which age is associated with preexisting burdens of brain changes, visible on neuroimaging but rarely considered in acute decision-making or trials, is unknown.

Objectives  To explore the mediation of age on functional outcome by neuroimaging markers of frailty (hereinafter neuroimaging frailty) in patients with acute ischemic stroke receiving endovascular thrombectomy (EVT).

Design, Setting, and Participants  This cohort study was a post hoc analysis of the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) randomized clinical trial, which investigated intravenous (IV) nerinetide in patients who underwent EVT within a 12-hour treatment window. Patients from 48 acute care hospitals in 8 countries (Canada, US, Germany, Korea, Australia, Ireland, UK, and Sweden) were enrolled between March 1, 2017, and August 12, 2019. Markers of brain frailty (brain atrophy [subcortical or cortical], white matter disease [periventricular or deep], and the number of lacunes and chronic infarctions) were retrospectively assessed while reviewers were blinded to other imaging (eg, computed tomography angiography, computed tomography perfusion) or outcome variables. All analyses were done between December 1, 2022, and January 31, 2023.

Exposures  All patients received EVT and were randomized to IV nerinetide (2.6 mg/kg of body weight) and alteplase (if indicated) treatment vs best medical management.

Main Outcome and Measures  The primary outcome was the proportion of the total effect of age on 90-day outcome, mediated by neuroimaging frailty. A combined mediation was also examined by clinical features associated with frailty and neuroimaging markers (total frailty). Structural equation modeling was used to create latent variables as potential mediators, adjusting for baseline, early ischemic changes; stroke severity; onset-to-puncture time; nerinetide treatment; and alteplase treatment.

Results  Among a total of 1105 patients enrolled in the study, 1102 (median age, 71 years [IQR, 61-80 years]; 554 [50.3%] male) had interpretable imaging at baseline. Of these participants, 549 (49.8%) were treated with IV nerinetide. The indirect effect of age on 90-day outcome, mediated by neuroimaging frailty, was associated with 85.1% of the total effect (β coefficient, 0.04 per year [95% CI, 0.02-0.06 per year]; P < .001). When including both frailty constructs, the indirect pathway was associated with essentially 100% of the total effect (β coefficient, 0.07 per year [95% CI, 0.03-0.10 per year]; P = .001).

Conclusions and Relevance  In this cohort study, a secondary analysis of the ESCAPE-NA1 trial, most of the association between age and 90-day outcome was mediated by neuroimaging frailty, underscoring the importance of features like brain atrophy and small vessel disease, as opposed to chronological age alone, in predicting poststroke outcomes. Future trials could include such frailty features to stratify randomization or improve adjustment in outcome analyses.