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Randomized Controlled Trial
. 2024 Jan 2;7(1):e2349628.
doi: 10.1001/jamanetworkopen.2023.49628.

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

Faysal Benali  1   2   3   4   5 , Nishita Singh  1   2   3   6 , Joachim Fladt  1   2   3   4   7 , Tanaporn Jaroenngarmsamer  1 , Fouzi Bala  1   2   3   4   8 , Johanna M Ospel  1   2   3   4   9 , Brian H Buck  10 , Dar Dowlatshahi  11 , Thalia S Field  12 , Ricardo A Hanel  13 , Lissa Peeling  14 , Michael Tymianski  15 , Michael D Hill  1   2   3   4   16   17 , Mayank Goyal  1   2   3 , Aravind Ganesh  1   2   3   16   17 ; ESCAPE-NA1 Investigators
Collaborators, Affiliations
Randomized Controlled Trial

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

Faysal Benali et al. JAMA Netw Open. .

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Fladt reported receiving grants from the Swiss National Science Foundation outside the submitted work. Dr Ospel reported receiving personal fees for consulting from Nicolab outside the submitted work. Dr Field reported receiving grants from Bayer Canada and personal fees from Roche, HLS Therapeutics, and AstraZeneca outside the submitted work and serving as a board member of DESTINE Health. Dr Hanel reported receiving personal fees from Medtronic, Stryker, Cerenovous, Balt, and phenox outside the submitted work. Dr Tymianski reported being an employee of NoNO Inc during the conduct of the study and a shareholder of NoNO Inc outside the submitted work; having a patent for nerinetide related to the drug in the Safety and Efficacy of Nerinetide (NA-1) in Subjects Undergoing Endovascular Thrombectomy for Stroke (ESCAPE-NA1) trial; and being founder and chief executive officer of NoNO Inc (the sponsor of the ESCAPE-NA1 trial). Dr Hill reported receiving grants from NoNO Inc and the Canadian Institutes of Health Research to the University of Calgary during the conduct of the study and receiving grants from Medtronic, Boehringer-Ingelheim, and Microvention to the University of Calgary outside the submitted work. Dr Goyal reported receiving a research grant from NoNO Inc to the University of Calgary during the conduct of the study. Dr Ganesh reported receiving grants from the Canadian Institutes of Health Research, the Canadian Cardiovascular Society, Alberta Innovates, Campus Alberta Neuroscience, the government of Canada for the INOVAIT program and for the New Frontiers in Research Fund, Microvention, the Alzheimer Society of Canada, the Alzheimer Society of Alberta and Northwest Territories, the Heart and Stroke Foundation of Canada, Panmure House, Brain Canada, and the M.S.I. Foundation; receiving personal fees for consulting from MD Analytics, My Medical Panel, Figure 1, CTC Communications Corp, Atheneum, DeepBench, Research on Mind, Creative Research Designs, AlphaSights, 42 Market Research, Alexion, Biogen, and Servier Canada; for expert testimony from Grosso Harper Law; and for editorial contributions from the American Academy of Neurology; having stock options in SnapDx Inc and Let’s Get Proof (Collavidence Inc); and receiving funding from Let’s Get Proof (Collavidence Inc) outside the submitted work; and reported having patents pending for a patient monitoring system and delivery of remote ischemic conditioning or other cuff-based therapies to SnapDx Inc and for systems and methods for enhancing the efficiency of initiating, conducting, and funding research projects to Collavidence Inc. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Study Flowchart
CC/IT indicates ratio of intercaudate distance to inner table width; FU, focused ultrasound; GCA, global cortical atrophy; MRI, magnetic resonance imaging; NCCT, noncontrast computed tomography. aAt least axial fluid-attenuated inversion recovery sequences available.
Figure 2.
Figure 2.. Causal Hypothesis Diagram
The direct effect is defined as pathway C, and the indirect effect is defined as pathways A × B. Rectangles represent observed variables; ovals represent latent variables. Linear equations are built by using arrows between the variables; 90-day functional outcome was included as an ordinal variable following the full categorical scale (ie, modified Rankin Scale, which ranges from 0 to 6, with 0 indicating perfect health without symptoms and 6 indicating death). aThis model is repeated 2 times; a different model is created for each latent variable as a different mediator (ie, neuroimaging frailty and composite frailty).
Figure 3.
Figure 3.. Structural Equation Models Including Different Latent Variables as Possible Mediator
Each causal hypothesis diagram includes a latent variable (brain frailty) as a possible mediator for the association of chronological age and 90-day functional outcome. Each model includes a different latent variable: imaging measures of brain frailty (A) and a total construct of brain frailty (B). Adjustments for all models were made for the administration of nerinetide and/or alteplase, onset-to-puncture time, National Institutes of Health Stroke Scale at baseline, and Alberta Stroke Program Early Computed Tomography Score at baseline. Rectangles represent observed variables; ovals represent latent variables. Linear equations are built by using arrows between the variables; 90-day functional outcome was included as an ordinal variable following the full categorical scale (ie, modified Rankin Scale [mRS] scale, which ranges from 0 to 6, with 0 indicating perfect health without symptoms and 6 indicating death).
See this image and copyright information in PMC

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