Hypertension With High-Risk Features in Cryptogenic Stroke: An Exploratory Analysis of the ARCADIA Randomized Clinical Trial.

Importance: Multiple trials have found no difference in secondary stroke prevention between anticoagulation and antiplatelet therapy after cryptogenic stroke. Due to limitations of current stroke mechanism classification, one possible explanation is the failure to exclude patients with hypertension-related cerebrovascular disease. Objective: To determine whether hypertension with high-risk features is associated with treatment effect modification of anticoagulation vs antiplatelet therapy. Design, Setting, and Participants: This exploratory analysis of the Apixaban to Prevent Recurrence After Cryptogenic Stroke in Patients With Atrial Cardiopathy (ARCADIA) randomized clinical trial was conducted between April and August 2025. The original trial was conducted from February 2018 to February 2023 at 185 sites in North America. From 1015 randomized patients with a recent cryptogenic stroke and atrial cardiopathy, 945 with available hypertension data were included in this analysis after exclusions for missing blood pressure and echocardiography data. Interventions: Apixaban, 5 mg or 2.5 mg, twice daily vs aspirin, 81 mg, once daily. Main Outcomes and Measures: The primary outcome was recurrent ischemic stroke or systemic embolism. Hypertension with high-risk features was defined as systolic blood pressure ≥160 mm Hg at enrollment, left ventricular hypertrophy on echocardiography, or both. Cox proportional hazards models evaluated treatment interaction with hypertension with high-risk features and estimated hazard ratios within hypertension with high-risk features subgroups. Results: Among 945 patients (mean [SD] age, 68.0 [10.8] years; 513 [54.3%] female), 351 (37.1%) met criteria for hypertension with high-risk features. Over a median (IQR) follow-up of 1.6 (0.7-3.0) years within the analytic cohort, 67 patients experienced a recurrent ischemic stroke or systemic embolism. A significant interaction between hypertension with high-risk features and antithrombotic treatment was observed. In 594 patients without hypertension with high-risk features, apixaban was associated with lower risk compared to aspirin (hazard ratio [HR], 0.43; 95% CI, 0.22-0.85; annualized rate difference: -3.4%), whereas no significant association was observed in patients with hypertension with high-risk features (HR, 1.68; 95% CI, 0.78-3.62; annualized rate difference: 2.4%). Conclusions and Relevance: The findings in this study indicate that hypertension with high-risk features may be associated with modifications in the effect of antithrombotic treatment in patients with cryptogenic stroke. An unappreciated inclusion of strokes due to hypertensive arteriopathy may account for the lack of benefit with anticoagulation in prior trials of embolic stroke of undetermined source. Trial Registration: ClinicalTrials.gov Identifier: NCT03192215.