BACKGROUND:

Embolic stroke of undetermined source (ESUS) is a nonlacunar ischemic stroke with no clear cause, having a 4%-5% annual recurrence rate. The potential benefits of direct oral anticoagulants (DOACs) relative to aspirin in patients with ESUS remain unclear.

OBJECTIVE:

We aimed to perform a systematic review and meta-analysis to determine the efficacy of the DOACs in secondary prevention for patients with ESUS compared with aspirin.

METHODS:

MEDLINE, Embase, Cochrane, and ClinicalTrias.gov were searched for RCTs comparing DOACs versus aspirin for secondary stroke prevention after ESUS. We performed a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Review (PRISMA) and Cochrane guidelines. Statistical analysis was performed using R software 4.3.2. A random-effects model was employed to measure mean differences and hazard ratios (HR) with 95% confidence intervals (CI).

RESULTS:

We included 4 RCTs comprising 13,970 patients. The median age was 67 years (IQR 65.5-68.2), 61% were male, 76% had hypertension, and 51% had diabetes. DOACs were administered to 50% of the participants. No significant difference was found between groups for stroke recurrence [RR 0.95 (95% CI 0.8-1.11) p=0.52; I2=0%]. Death from any cause [HR 1.11 (95% CI 0.87-1.42) p=0.38; I2=0%], cardiovascular death [HR 1.08 (95% CI 0.61-1.94) p=0.77; I2=18%] and myocardial infarction [HR 0.92 (95% CI 0.54-1.54) p=0.76; I2=16%] were also similar between groups. However, there was a significant increase in clinically relevant non-major bleeding for patients treated with DOACs [HR 1.53 (95% CI 1.22-1.92) p<0.001; I2=9%].

CONCLUSION:

In patients with ESUS, DOACs were not superior to aspirin for the secondary prevention of stroke. However, there was a significant increase in clinically relevant non-major bleeding among patients treated with DOACs. These findings suggest that aspirin remains a viable option for secondary prevention in ESUS patients.