Antithrombotic Treatment in Cryptogenic Stroke Patients With PFO

Study Questions:

In patients with patent foramen ovale (PFO) and a history of stroke or transient ischemic attack (TIA) of undetermined cause, is anticoagulation or antiplatelet therapy better for preventing stroke recurrence?


The authors conducted a systematic review for relevant studies published before July 16, 2019. The outcomes of interest included stroke recurrence, major bleeding, and the composite of stroke recurrence or major bleeding. Intention-to-treat data were used. Given the small number of included studies and anticipated heterogeneity among studies, the results of three different random-effects models were reported.


Five relevant randomized controlled trials were identified (PICSS 2002 [98 subjects]; Shariat et al., 2013 [44 subjects]; CLOSE 2017 [361 subjects]; NAVIGATE ESUS 2018 [534 subjects]; and RESPECT ESUS 2019 [680 subjects]). Across these studies, 1,720 patients were included, of whom 830 patients were assigned to anticoagulation and 890 were assigned to antiplatelet therapy. The estimated mean follow-up was 2.3 ± 0.5 years.

Stroke recurrence occurred in 82/1,720 subjects (2.1 per 100 patient-years). In the anticoagulation group, stroke occurred at a rate of 1.73 per 100 patient-years, whereas in the antiplatelet group, stroke occurred at a rate of 2.39 per 100 patient-years (hazard ratio [HR], 0.68-0.70 in the three models; p > 0.05 in the three models). Major bleeding occurred in 34/1,622 patients (0.91 per 100 patient-years) with no difference observed between the antiplatelet and anticoagulation groups (HR, 1.61 for anticoagulation in the three models; p > 0.05 in the three models). Combined stroke recurrence or major bleeding occurred in 52/786 (6.6%) anticoagulant-assigned patients and 54/833 (6.5%) antiplatelet-assigned patients (odds ratio, 1.05 for the three models; p > 0.05 for the three models).


While the point estimate for stroke recurrence was higher in the antiplatelet arm than the anticoagulation arm, these results did not meet statistical significance. For the combined endpoint of recurrent stroke or major bleeding, there was no difference in point estimates between the two groups. The authors propose an anticoagulation versus antiplatelet randomized clinical trial for patients with PFO who are above the age threshold (60 years) for PFO closure or are ineligible for PFO closure due to comorbidities.


Regardless of treatment, the risk of recurrent stroke was low (<3 events per 100 patient-years in both arms). When recurrent stroke and major bleeding were evaluated as a combined (and arguably more clinically meaningful) endpoint, the two groups were strikingly similar. Interpretation of the results of this meta-analysis is complicated by evidence from the 2017 REDUCE and CLOSE trials suggesting a role for PFO closure in select patients ≤60 years of age. The authors’ proposed anticoagulation versus antiplatelet randomized clinical trial for PFO patients who are above this age threshold or are ineligible for closure due to comorbidities is unlikely to show a benefit of anticoagulation on the combined endpoint of recurrent stroke or major bleeding given the higher risk of bleeding complications anticipated in these populations.

Clinical Topics: Anticoagulation Management, Congenital Heart Disease and Pediatric Cardiology, Prevention, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Quality Improvement

Keywords: Anticoagulants, Comorbidity, Foramen Ovale, Patent, Heart Defects, Congenital, Hemorrhage, Ischemic Attack, Transient, Platelet Aggregation Inhibitors, Risk, Secondary Prevention, Stroke, Vascular Diseases

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