Closure, Anticoagulation, or Antiplatelet Therapy for Cryptogenic Stroke With Patent Foramen Ovale: Systematic Review of Randomized Trials, Sequential Meta‐Analysis, and New Insights From the CLOSE Study

BACKGROUND: We conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) comparing patent foramen ovale (PFO) closure, anticoagulation, and antiplatelet therapy to prevent stroke recurrence in patients with PFO‐associated cryptogenic stroke. METHODS AND RESULTS: We searched Medline, Cochrane Library, and EMBASE through March 2018. The primary outcome was stroke recurrence. Pooled incidences, hazard ratios, and risk ratios (RRs) were calculated in random‐effects meta‐analyses. PFO closure was associated with a lower risk of recurrent stroke compared with antithrombotic therapy (antiplatelet therapy or anticoagulation: 3560 patients from 6 RCTs; RR=0.36, 95% CI: 0.17–0.79; I(2)=59%). The effect of PFO closure on stroke recurrence was larger in patients with atrial septal aneurysm or large shunt (RR=0.27, 95% CI, 0.11–0.70; I(2)=42%) compared with patients without these anatomical features (RR=0.80, 95% CI, 0.43–1.47; I(2)=12%). Major complications occurred in 2.40% (95% CI, 1.03–4.25; I(2)=77%) of procedures. New‐onset atrial fibrillation was more frequent in patients randomized to PFO closure versus antithrombotic therapy (RR=4.33, 95% CI, 2.37–7.89; I(2)=14%). One RCT compared PFO closure versus anticoagulation (353 patients; hazard ratio=0.14, 95% CI, 0.00–1.45) and 2 RCTs compared PFO closure versus antiplatelet therapy (1137 patients; hazard ratio=0.18, 95% CI, 0.05–0.63; I(2)=12%). Three RCTs compared anticoagulation versus antiplatelet therapy, with none showing a significant difference. CONCLUSIONS: PFO closure is superior to antithrombotic therapy to prevent stroke recurrence after cryptogenic stroke. The annual absolute risk reduction of stroke was low, but it has to be tempered by a substantial time at risk (at least 5 years) in young and middle‐aged patients. PFO closure was associated with an increased risk of atrial fibrillation.