Anticoagulation versus antiplatelet therapy in patients with embolic stroke of unknown source: A systematic review and meta-analysis

Embolic stroke of undetermined source (ESUS) carries a substantial clinical burden due to high stroke recurrence rate.(1) Recent randomised trials have tested whether anticoagulation is more effective than antiplatelet therapy in ESUS patients. Although anticoagulation is not superior to antiplatelet therapy in this setting, the full safety profile of anti-coagulation compared to anti-platelet therapy has not been reported, limiting assessment of the risk:benefit ratio and therapeutic decision making.

This meta-analysis reports the comparative safety and efficacy of anticoagulation versus antiplatelet therapy in ESUS patients.

A systematic search of MEDLINE, EMBASE, and CENTRAL databases was conducted from inception to August 19, 2024. Eligible randomised trials reported recurrent stroke, cerebral emboli, and safety outcomes, including bleeding events. The meta-analysis used a random-effects model to estimate pooled risk ratios (RR) with heterogeneity assessed via I² values. The efficacy outcome was recurrent stroke, systemic thromboembolism or myocardial infarction, whilst the safety outcome was haemorrhagic stroke, major bleeding or clinically relevant non-major bleeding. Direct communication with study teams was used to clarify outcome events where these were not reported in primary publications.

Of 365 records screened, four trials (RE-SPECT ESUS, NAVIGATE ESUS, ATTICUS, and ARCADIA) with a total of 13,970 patients were included.(2-5) Recurrent stroke occurred in 841 patients (6%), with similar rates in the anticoagulation (5.7%) and antiplatelet (6.2%) groups (RR 0.96, CI 0.81–1.11, p=0.581, I2=21.6%). No significant reduction was observed in the composite efficacy outcome (RR 0.94, CI 0.82-1.07, p=0.335, I2=4.95%)(Figure 1). However, the composite safety outcome was significantly greater amongst patients receiving anticoagulation (RR 1.58, CI 1.20–2.07, p=0.009, I2=48.81%)(Figure 2). Clinically relevant non-major bleeding was higher in the anticoagulation group (3.0% vs. 1.9%, RR 1.56, CI 1.25–1.95, p<0.001).

This meta-analysis found no significant benefit of anticoagulation over antiplatelet therapy in reducing recurrent stroke or the composite outcome of ischemic stroke, systemic thromboembolism, and myocardial infarction in ESUS patients. Anticoagulation was associated with an increased risk of bleeding, particularly clinically relevant non-major bleeding, and a significantly greater relative risk of the composite safety outcome of major bleeding, haemorrhagic stroke, and non-major bleeding. These findings highlight the need for improved patient selection to identify those ESUS patients who might benefit from anticoagulation, allowing for safer and more tailored secondary prevention strategies.