Sex differences in brain frailty measures and outcomes after endovascular thrombectomy: ESCAPE-NA1 analysis

Background: Brain frailty, characterized by atrophy and/or chronic vascular lesions, is associated with worse outcomes after endovascular thrombectomy (EVT), but whether its impact differs by sex remains unclear. Therefore, we investigated sex differences in the association between imaging brain frailty markers and 90-day outcome after EVT. Methods: We conducted a post-hoc analysis of the ESCAPE-NA1 randomized trial, which evaluated intravenous nerinetide in patients undergoing EVT for acute ischemic stroke due to large vessel occlusion. Brain frailty markers—including global cortical atrophy (GCA) scale, subcortical atrophy, Fazekas score, lacunes, and old infarctions—were assessed on baseline non-contrast CT (NCCT), and among those with follow-up MRI, perivascular spaces and microbleeds were also evaluated. The primary outcome was a modified Rankin Scale (mRS) score of 0–2 at 90 days. Multivariable logistic regression was performed, stratified by sex. Results: Among 1102 patients with NCCT (568 with MRI), no significant sex interactions were identified between brain frailty markers and 90-day outcomes. However, exploratory sex-stratified analyses showed that several brain frailty markers were associated with a lower likelihood of achieving functional independence (mRS 0–2) at 90 days in women, whereas no clear associations were observed in men. For example, cortical atrophy was associated with a lower likelihood of achieving an mRS score of 0–2 in women but not in men (adjusted OR for GCA 1 vs. 0: 0.54, 95% CI 0.32–0.91 in women; 0.76, 95% CI 0.45–1.28 in men). Similar patterns were observed for subcortical atrophy. Conclusions: Although sex-stratified analyses suggested nominal differences, no statistically significant sex-by-brain frailty interactions were observed. Brain frailty should be considered a prognostic marker irrespective of sex, and these exploratory findings warrant further investigation in adequately powered studies.