Brain Frailty Rather than Age Alone Mediates the Lack of Benefit for Endovascular Thrombectomy in the Elderly Population of the RESILIENT 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 ( 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.