Brain Frailty Rather than Age Alone Mediates the Lack of Benefit for Endovascular Thrombectomy in the Elderly Population of the <scp>RESILIENT</scp> Trial

OBJECTIVE: The objective of this study was to determine whether baseline computed tomography (CT) markers of cerebral small vessel disease (cSVD), as a surrogate of brain frailty, explain the association between age and functional outcome, potentially accounting for the reduced apparent benefit of mechanical thrombectomy (MT) in elderly patients in the RESILIENT trial. METHODS: RESILIENT was a multicenter, prospective, randomized, open-label trial with blinded outcome assessment conducted in Brazil. Patients with anterior circulation large-vessel occlusion stroke were randomized to MT plus guideline-based care or guideline-based care alone, including intravenous alteplase when eligible. A vascular neurologist blinded to clinical data evaluated baseline CT scans for cSVD markers (leukoaraiosis, lacunes, and atrophy) to derive a composite cSVD score. Multivariable logistic regression identified independent predictors of good functional outcome (modified Rankin Scale [mRS] = 0-2 at 90 days). Treatment effects were assessed across subgroups defined by age (<70 or ≥70 years) and cSVD score (0-1 vs 2-3). Mediation analysis quantified the indirect effect of age on outcome through cSVD. RESULTS: Patients with good outcomes were younger, had lower National Institutes of Health Stroke Scale (NIHSS) scores, better collaterals, lower glucose levels, lower cSVD burden, and were more frequently treated with MT. Independent predictors of good outcome included lower NIHSS, MT, lower cSVD score, and lower glucose levels. MT benefit was restricted to patients <70 years with low cSVD burden (odds ratio [OR] = 4.16, 95% confidence interval [CI] = 1.6-10.4, p < 0.01). No benefit was observed in older patients or in those with cSVD > 1. Mediation analysis showed that cSVD significantly mediated the association between age and outcome (average causal mediation effect [ACME] = -0.003, 95% CI = -0.005 to 0.00, p = 0.010). INTERPRETATION: Baseline CT markers of cSVD were independently associated with poorer outcomes and mediated the association between age and functional outcome in the RESILIENT trial, potentially explaining the lack of MT efficacy in older patients. ANN NEUROL 2026.