White matter lesions modifying endovascular therapy outcomes in large ischemic core stroke: A secondary analysis of the ANGEL–ASPECT trial

Background: Severe white matter lesions (WMLs) have been linked to poorer functional outcomes following endovascular therapy (EVT) in patients with acute ischemic stroke (AIS) due to large-vessel occlusion (LVO). However, the absence of a control group in previous studies has limited the ability to determine the benefit of EVT to patients with severe WMLs. Methods: This work is a secondary analysis of the Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients with a Large Infarct Core trial, a multicenter, randomized controlled trial conducted at 46 comprehensive stroke centers across China, which enrolled 456 patients with AIS with anterior–circulation LVO and large ischemic cores between October 2020 and May 2022. WML severity was graded using the van Swieten Scale on pretreatment noncontrast computed tomography (CT). For supplementary analyses, WML severity was further assessed using T2 fluid-attenuated inversion recovery (T2-FLAIR) magnetic resonance imaging (MRI) and graded according to the Fazekas scale, with WMLs categorized into periventricular and deep subtypes. Treatment effect on the primary outcome (90-day modified Rankin Scale [mRS] score) was assessed using multivariable ordinal logistic regression, and a treatment-by-WML interaction term was tested to evaluate effect modification. Results: In patients with absent-to-moderate WMLs, EVT was associated with a favorable shift in the distribution of 90-day mRS scores (adjusted common odds ratio [cOR] 2.15, 95% confidence interval [CI, 1.48–3.13], P <0.001). However, this benefit was less pronounced in those with severe WMLs (adjusted cOR 2.25, 95% CI [0.95–5.30], P = 0.065). No significant interaction between WML severity and treatment effect was detected ( P interaction = 0.888). Similarly, only among patients with absent-to-moderate WMLs, EVT significantly increased rates of mRS scores of 0–2 (adjusted OR 4.86, 95% CI [2.66–8.86], P <0.001), the rates of mRS scores of 0–3 (adjusted OR 2.23, 95% CI [1.39–3.57], P = 0.001), and the rates of early neurological improvement (adjusted OR 5.22, 95% CI [1.31–20.79], P = 0.019) compared to medical management alone. Supplementary analyses using T2-FLAIR MRI to stratify patients by WML burden yielded results consistent with those of the primary analyses. Conclusions: EVT significantly improved functional outcomes in patients with LVO–AIS with absent-to-moderate WMLs, while the benefit in those with severe WMLs appeared less pronounced. However, estimates within subgroups were underpowered. Future pooled analyses of randomized clinical trials with adequate statistical power are needed to clarify the impact of WML severity on EVT outcomes and to refine patient selection criteria. Registration: ClinicalTrials.gov, No. NCT04551664.