Association Between Low-Dose Rivaroxaban With or Without Aspirin and Ischemic Stroke Subtypes A Secondary Analysis of the COMPASS Trial

Importance The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) randomized clinical trial was stopped early owing to the efficacy of low-dose rivaroxaban plus aspirin in preventing major cardiovascular events. The main reason for early trial termination was the effect of combination therapy on reducing ischemic strokes. Objective To analyze the association between low-dose rivaroxaban with or without aspirin and different ischemic stroke subtypes. Design, Setting, and Participants This is a secondary analysis of a multicenter, double-blind, randomized, placebo-controlled study that was performed in 33 countries from March 12, 2013, to May 10, 2016. Patients with stable atherosclerotic vascular disease were eligible, and a total of 27395 participants were randomized and followed up to February 6, 2017. All first ischemic strokes and uncertain strokes that occurred by this date were adjudicated using TOAST (Trial of Org 10172 in Acute Stroke Treatment) criteria. The analysis of ischemic stroke subtypes was evaluated using an intention-to-treat principle. Statistical analysis was performed from March 12, 2013, to February 6, 2017. Interventions Participants received rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban (5 mg twice a day), or aspirin (100 mg once a day). Main Outcomes and Measures Risk of ischemic stroke subtypes during follow-up. Results A total of 291 patients (66 women; mean [SD] age, 69.4 [8.5] years; 43 [14.8%] had a previous nonlacunar stroke) experienced an ischemic stroke. During the study, 49 patients (16.8%) received a diagnosis of atrial fibrillation. Applying TOAST criteria, 59 strokes (20.3%) were cardioembolic, 54 strokes (18.6%) were secondary to greater than 50% stenosis of the ipsilateral internal carotid artery, 42 strokes (14.4%) had a negative evaluation that met criteria for embolic stroke of undetermined source, and 21 strokes (7.2%) were secondary to small vessel disease. There were significantly fewer cardioembolic strokes (hazard ratio [HR], 0.40 [95% CI, 0.20-0.78]; P = .005) and embolic strokes of undetermined source (HR, 0.30 [95% CI, 0.12-0.74]; P = .006) in the combination therapy group compared with the aspirin-only group. A trend for reduction in strokes secondary to small vessel disease (HR, 0.36 [95% CI, 0.12-1.14]; P = .07) was not statistically significant. No significant difference was observed between the 2 groups in strokes secondary to greater than 50% carotid artery stenosis (HR, 0.85 [95% CI, 0.45-1.60]; P = .61). Rivaroxaban, 5 mg, twice daily showed a trend for reducing cardioembolic strokes compared with aspirin (HR, 0.57 [95% CI, 0.31-1.03]; P = .06) but was not associated with reducing other stroke subtypes. Conclusions and Relevance For patients with systemic atherosclerosis, low-dose rivaroxaban plus aspirin was associated with large, significant reductions in cardioembolic strokes and embolic strokes of undetermined source. However, these results of exploratory analysis need to be independently confirmed before influencing clinical practice. Question What is the association between low-dose rivaroxaban plus aspirin and ischemic stroke subtypes? Findings In this secondary analysis of a multinational randomized clinical trial of 27395 participants with systemic atherosclerotic disease who received low-dose rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone, 291 participants experienced an ischemic stroke. Treatment with low-dose rivaroxaban plus aspirin was associated with a significant reduction in cardioembolic stroke and embolic stroke of undetermined source compared with treatment with rivaroxaban alone or aspirin alone; this reduction was not seen in participants with other ischemic stroke subtypes. Meaning For patients with systemic atherosclerotic disease, treatment with low-dose rivaroxaban plus aspirin was associated with a significant reduction in cardioembolic stroke and embolic stroke of undetermined source. This secondary analysis of a multinational randomized clinical trial of 27395 participants with systemic atherosclerotic disease examines the association low-dose rivaroxaban plus aspirin, rivaroxaban alone, or aspirin alone and the risk of different ischemic stroke subtypes.