Differential Effect of Ticagrelor Versus Clopidogrel by Causative Classification of Stroke Classification and Vascular Cellular Adhesion Molecule‐1 Level on the Risk of Recurrent Stroke: A Post Hoc Analysis of the CHANCE‐2 Trial

Background VCAM‐1 (vascular cellular adhesion molecule‐1) is an inflammatory biomarker linked to the occurrence and recurrence of stroke. However, it is uncertain if dual antiplatelet treatments may have distinct benefit for patients with varied stroke causes and VCAM‐1 levels. Methods This post hoc study of the CHANCE‐2 (Ticagrelor or Clopidogrel in High‐Risk Patients With Acute Nondisabling Cerebrovascular Events II) trial included 5651 patients in total. All patients were classified using the Causative Classification of Stroke system categorization as well as the mean of baseline VCAM‐1 level. The primary outcome was any stroke within 90 days. During the 90‐day follow‐up period, the cumulative incidence of outcomes between 2 dual antiplatelet treatments was compared using the Kaplan–Meier analysis and log‐rank test. The Cox proportional hazards model was used to further assess the hazard ratios (HRs) and 95% CIs for the associations of small artery occlusion cause and VCAM‐1 level with efficiency and safety outcomes. Results The median age of 5651 patients was 64.8 years, 1908 of whom were women. Among all the subtypes, patients with nonelevated VCAM‐1 (<1715.9 ng/mL) and small artery occlusion subtype (N=1252) got more benefit from aspirin‐ticagrelor therapy to reduce recurrent stroke within 90 days (7.5% versus 2.9%, hazard ratio [HR], 0.37 [95% CI, 0.22–0.64], P <0.001). Regarding safety outcomes, the risk of mild bleeding was increased in the ticagrelor‐aspirin group (1.4% versus 6.7%, HR, 4.85 [95% CI, 2.36–9.96]), but no significant difference was found between the 2 groups in moderate or severe bleeding (0.6% versus 0.5%, HR, 0.75 [95% CI, 0.17–3.35]). Conclusions VCAM‐1 level combined with ischemic stroke cause classification subtypes might predict the effect of ticagrelor‐aspirin or clopidogrel‐aspirin dual antiplatelet therapy in preventing recurrent stroke within 90 days in patients with minor ischemic stroke or transient ischemic attack carrying CYP2C19 loss‐of‐function alleles. Patients with small artery occlusion subtype and nonelevated VCAM‐1 received more clinical benefit from ticagrelor‐aspirin versus clopidogrel‐aspirin. Registration URL: http://www.clinicaltrials.gov ; Unique Identifier: NCT04078737.