1

Introduction

Stroke is the third leading cause of death in the United States and accounts for 1 in every 18 deaths nationwide . With more than 4.4 million stroke survivors today, stroke is the most common cause of long-term disability. In younger adults despite undergoing an extensive work-up, the etiology of an ischemic stroke remains unknown (or “cryptogenic”) in as many as 35% . Patent foramen ovale (PFO), an embryonic remnant of the fetal cardiac circulation, exists in approximately 25–30% of the general population . Autopsy studies have shown that its prevalence decreases progressively with age from 34.3% in the first three decades of life to 20.2% during the 9th and 10th . Data from large studies evaluating the independent relationship of PFO with cryptogenic stroke have been conflicting. The mechanism of stroke due to PFO is believed to be paradoxical embolism.

Closure of a PFO can be achieved surgically or percutaneously. The effectiveness of a percutaneous PFO closure in the prevention of recurrent cryptogenic strokes has not been established. Potential reasons of recurrent stroke despite successful PFO closure include (1) thrombus formation on the left side of the closure device, (2) new arrhythmia after device placement, (3) residual shunt allowing recurrent paradoxical embolism, (4) the possibility that the PFO was not related to the initial stroke or even (5) the possibility that the initial stroke was PFO related and not the recurrent one . While over a million of percutaneous PFO closures have been performed worldwide, none of the existing percutaneous PFO closure devices is FDA-approved and PFO closure is still performed in the US under specific exemptions.

In a recent meta-analysis of 10 observational studies with 1886 patients comparing percutaneous PFO closure and medical therapy for prevention of recurrent neurological events (RNE), the authors demonstrated a statistically significant risk reduction in the closure group [RR: 0.25, 95% CI: 0.11–0.58] . In another recent elegant propensity matched study of 308 patients, PFO closure was associated with an impressive 10% absolute risk reduction in the composite endpoint of stroke, TIA or peripheral embolism over a median follow up of 9 years . This study also showed a mortality benefit when patients were analyzed as per time period passed with or without a PFO device in place. While observational studies are important in reflecting “real-world” experience, selection bias for treatment selection limits their value in testing comparative effectiveness treatment modalities. Randomized controlled trials (RCT) are the benchmark for establishing the efficacy of a treatment modality vs. standard therapy. Until recently, the final results of only one randomized trial (CLOSURE-1) have been available. This trial failed to demonstrate a significant decreased in RNE with percutaneous PFO closure . Since the published statement from the American Heart Association/American Stroke Association/American College of Cardiology Foundation requesting the completion of randomized clinical trials regarding the effectiveness of percutaneous PFO closure for the preventions of cryptogenic stroke , data from two randomized trials have been recently reported .

We present a comprehensive meta-analysis of existing data from randomized clinical studies comparing percutaneous PFO closure with medical therapy in patients with cryptogenic stroke/TIA.