Risk of Intracranial Hemorrhage With Apixaban Versus Aspirin Therapy: A Meta-Analysis of Randomized Controlled Trials

BACKGROUND: Oral anticoagulants are superior to antiplatelet agents for preventing cardioembolic stroke but concerns about increased risk of intracranial hemorrhage limit their use. Although rivaroxaban demonstrably increases intracranial bleeding risk compared with aspirin, the comparative risk of intracranial hemorrhage with apixaban versus aspirin remains uncertain. We aimed to clarify this risk through a meta-analysis of randomized controlled trials. METHODS: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized controlled trials comparing apixaban with aspirin for ischemic stroke prevention. Studies were excluded if no intracranial hemorrhage events were reported in either arm. In the primary analysis, we used the Mantel-Haenszel method to meta-analyze the relative risk of intracranial hemorrhage with apixaban versus aspirin therapy. We conducted sensitivity analyses to examine the strength of these findings and to examine the secondary outcome of hemorrhagic stroke (which excludes epidural and subdural hematomas). RESULTS: Three randomized controlled trials met our inclusion criteria, comprising a total of 10 626 patients and 74 incident intracranial hemorrhage events. In the pooled analysis, the relative risk of intracranial hemorrhage with apixaban versus aspirin therapy was 0.67 ([95% CI, 0.43–1.08]; P =0.10). These findings were consistent in sensitivity analyses utilizing alternative statistical estimators, in analyses limited to primary prevention trials, and in analyses utilizing the outcome of hemorrhagic stroke (relative risk, 0.72 [95% CI, 0.39–1.31]; P =0.28). CONCLUSIONS: In randomized controlled trials evaluating ischemic stroke prevention, apixaban demonstrated a safety profile comparable—and potentially superior—to aspirin with respect to intracranial hemorrhage risk. These findings warrant a reconsideration of clinical practices that favor aspirin over apixaban, because of the concerns about intracranial hemorrhage risk.