Changes in Infarct Volume and Cerebral Edema After Mechanical Thrombectomy in Patients With Stroke Randomized to ApTOLL or Placebo: A Secondary Analysis of April Trial

BACKGROUND: APRIL, a randomized placebo-controlled phase Ib/IIa trial, showed safety and reduced mortality and disability at 90 days of ApTOLL 0.2 mg/kg in combination with endovascular treatment in patients with acute large vessel occlusion within a 6-hour window. We studied the effect of ApTOLL against placebo on final infarct volume, infarct growth, and cerebral edema. METHODS: Post hoc analysis of a trial was conducted between 2020 and 2022 in Spain and France. Patients allocated to ApTOLL doses of 0.05 and 0.2 mg/kg and placebo were selected. The early infarct growth rate was defined as admission relative cerebral blood flow <30% volume/time elapsed from last-known well to imaging, considering fast progressors when >10 mL/h. An imaging core laboratory evaluated final infarct volume and cerebral edema on fluid-attenuated inversion recovery or noncontrast computed tomography at 72 hours if fluid-attenuated inversion recovery was not available. Cerebral edema was evaluated according to the SITS-MOST (Safe Implementation of Thrombolysis in Stroke-Monitoring Study) edema scale (cerebral edema degree [CED]; less severe: CED1; more severe: CED2; and with midline shift: CED3). Infarct growth was calculated as the final infarct volume: relative cerebral blood flow <30% volume at admission. Associations were studied through linear or ordinal models adjusted by prespecified variables. Admission relative cerebral blood flow <30% volume, fast recruitment, and final expanded Thrombolysis in Cerebral Infarction, among others, were examined for interaction with ApTOLL on final infarct volume and CED. RESULTS: A total of 136 of 139 patients had sufficient radiological data. Median admission relative cerebral blood flow <30% was 18 mL, and median final infarct volume was 36.53 mL. Edema grade was CED1 in 45%, CED2 in 34%, and CED3 in 21% patients. Compared with placebo, ApTOLL 0.2 mg/kg was independently associated with a lower final infarct volume (relative reduction, –45.2% [95% CI, −65% to −15%]), a lower infarct growth (61.51% [95% CI, −79% to −29%]), and a lower edema grade (cOR, 0.38 [95% CI, 0.15–0.96]). No associations were found for ApTOLL 0.05 mg/kg. The study of interactions showed a greater benefit of ApTOLL 0.2 mg/kg among patients with larger core volume at admission, fast progressors, and patients achieving incomplete reperfusion (expanded Thrombolysis in Cerebral Infarction <2b). CONCLUSIONS: ApTOLL 0.2 mg/kg in combination with mechanical thrombectomy significantly reduced final infarct volume, infarct growth, and cerebral edema at 72 hours. ApTOLL seemed to be more effective under conditions prone to infarct growth.