The following are key points to remember from this review of cryptogenic stroke and patent foramen ovale (PFO):

1. PFO is associated with cryptogenic stroke (stroke of unclear etiology). PFO is present in 20-25% of the adult population, but in 40% of adults with cryptogenic stroke. The current article serves to summarize the history and present state of PFO closure for secondary stroke prevention.
2. Despite the association between PFO and cryptogenic stroke, three early randomized clinical trials (CLOSURE I, PC trial, and RESPECT short-term) did not show a clear benefit of PFO closure for secondary stroke prevention. These results led to a generally decreased interest in PFO closure for stroke prevention.
3. In March 2016, a meta-analysis of patient-level data from CLOSURE I, PC, and RESPECT was published. This meta-analysis found that PFO closure was superior to medical therapy for the prevention of recurrent ischemic stroke (adjusted hazard ratio [aHR], 0.58; 95% confidence interval [CI], 0.34-0.99). When the analysis was restricted to the trials in which only the Amplatzer PFO occluder device was used (PC and RESPECT), the benefit appeared even greater (aHR, 0.41; 95% CI, 0.20-0.88).
4. In October 2016, the Food and Drug Administration (FDA) approved the Amplatzer PFO occluder device for patients 18-60 years old with PFO and cryptogenic stroke.
5. In the last year, two new randomized controlled trials of PFO closure versus medical therapy were published: CLOSE and REDUCE. These trials used stricter enrollment criteria than the three previous trials.
6. In CLOSE, eligible patients were 16-60 years old, had had a cryptogenic stroke with corroborating imaging findings within the prior 6 months, had a PFO, and had a large interatrial shunt or atrial septal aneurysm. Patients could not have small vessel disease or ≥30% stenosis of an artery supplying the brain. After a mean follow-up of 5.3 years, subjects who underwent PFO closure had a lower risk of recurrent stroke than those maintained on antiplatelet therapy (0% vs. 6%; HR, 0.03; 95% CI, 0-0.26).
7. The data from CLOSE suggest that, for every 20 closed patients, one stroke is avoided at 5 years. However, the avoided stroke may not be a disabling stroke. No patients (of 238) in the closure group had a disabling stroke; 1 patient (of 235) in the antiplatelet group had a disabling stroke.
8. In REDUCE, eligible patients were 18-59 years, had had a recent cryptogenic stroke within the prior 6 months, had symptoms lasting ≥24 hours or positive imaging, and had a PFO. Patients could not have a stenosis of ≥50% of a major vessel, a lacunar stroke, or uncontrolled stroke risk factors. After a median follow-up of 3.2 years, subjects who underwent PFO closure had a lower risk of recurrent stroke than those maintained on antiplatelet therapy (1.4% vs. 5.4%; HR, 0.23; 95% CI, 0.09-0.62).
9. The data from REDUCE suggest that, for every 28 closed patients, one stroke is avoided at 2 years.
10. In both REDUCE and CLOSE, PFO closure was associated with a higher risk of atrial fibrillation, which was believed to be primarily due to the closure procedure itself (i.e., self-limited).
11. CLOSE and REDUCE were likely positive because of stricter enrollment criteria, leading to the inclusion of subjects whose presenting stroke was secondary to PFO rather than another etiology (such as large artery atherosclerosis, small vessel disease, or atrial fibrillation).
12. In summary, PFO closure is of moderate benefit compared to antiplatelet therapy alone in the prevention of recurrent ischemic stroke in adults up to 60 years of age. It remains unknown how PFO closure compares to systemic anticoagulation (e.g., with novel oral anticoagulants) for the prevention of recurrent ischemic stroke.

Keywords: Aneurysm, Anticoagulants, Atrial Fibrillation, Brain Ischemia, Constriction, Pathologic, Foramen Ovale, Patent, Heart Defects, Congenital, Platelet Aggregation Inhibitors, Risk Factors, Secondary Prevention, Septal Occluder Device, Stroke, Stroke, Lacunar, Thrombolytic Therapy, Vascular Diseases

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