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April 9, 2014

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PFO closure with percutaneous device plus antiplatelet therapy may not be superior to medical therapy alone for secondary prevention of stroke/TIA in patients with cryptogenic stroke or TIA who have a PFO

Reference: N Engl J Med. 2012 Mar 15:366(11):991-9, (level 2 [mid-level] evidence)


A patent foramen ovale (PFO) is an interatrial communication with the potential to allow paradoxical emboli to cross from the venous system to the arterial side. Prevalence rates of PFO are as high as 25% (Conn Med. 2011 Feb;75(2):97-105). Most PFOs are asymptomatic. However, PFO is more common in patients who have a cryptogenic stroke or transient ischemic attack (TIA) than in the general population. Cryptogenic strokes account for 40% of all acute ischemic strokes with a PFO being one potential etiology. Options for secondary prevention of cryptogenic stroke/TIA in the presence of a PFO include antiplatelet and/or anticoagulation therapy or percutaneous or surgical closure with antiplatelet therapy.

CLOSURE I was a randomized trial that had 909 patients (between the ages of 18 and 60 years) with a recent history of cryptogenic stroke or TIA and a PFO. Patients were randomly assigned to 2 groups. In the closure group, 447 patients underwent percutaneous closure of PFO with the STARFlex device followed by antiplatelet therapy (clopidogrel 75 mg daily for 6 months and aspirin 81 or 325 mg daily for 2 years). In the medical therapy group, 462 patients were treated with warfarin (INR goal 2-3), aspirin 325 mg daily, or both. 87 sites in USA and Canada participated in this study. The trial was sponsored by NMT Medical and was not blinded given the nature of the treatment arms. The primary end point was a composite of stroke, TIA, death from any cause during the first 30 days and death from neurological causes between 31 days and 2 years. Secondary end points included major bleeding, death from any cause, stroke and TIA.

Transesophageal echocardiography obtained at the 6 month visit in the closure group revealed an effective closure rate of 86.1%. In the closure group, the composite primary end point occurred in 5.5% compared to 6.8% in medical therapy group (not statistically significant). With regards to recurrent stroke at 2 years, the rate was 2.9% in closure group compared to 3.1% in medical therapy group (not statistically significant). The rate for TIA was 3.1% in closure group compared to 4.1% in medical therapy group (not statistically significant). Notably, atrial fibrillation was more frequent in the closure group than in medical therapy group. It was noted in 23 patients (5.7%) in closure group compared to 3 patients (0.7%) in medical therapy group; (P<0.001). Atrial fibrillation occurred during periprocedural period in 14 out of 23 patients in the closure group (61%), which suggests that the closure procedure itself may increase the risk of developing atrial fibrillation.

This study had some limitations. First, the study was powered to detect a two-thirds reduction in risk, and therefore was not sufficiently powered to inform us if the 20% relative risk reduction was significant. Second, the authors pointed out that most of the recurrent strokes and TIAs were caused by factors other than paradoxical emboli and likely not related to the PFO at all.

In addition to the CLOSURE I trial, two other recent trials have been done on similar populations with the same outcomes. The RESPECT trial (N Engl J Med. 2013 Mar 21;368(12):1092-100) was a randomized and multicenter trial done for the same purpose. 980 patients with a PFO and a recent history of stroke or TIA were randomly assigned to antiplatelet medication or warfarin therapy vs. PFO closure by Amplatzer PFO occluder device and antiplatelet therapy. Again, there was no statistically significant difference between these two groups regarding rates of stroke during the median 2.1 year follow up period. In the PC trial (N Engl J Med. 2013 Mar 21;368(12):1083-91), 414 patients with a PFO and history of stroke, TIA, or peripheral thromboembolic event were randomly assigned to PFO closure by Amplatzer PFO occluder device plus antiplatelet medications vs. antithrombotic medication alone. The trial showed no statistically significant difference between the two groups in rates of mortality, stroke or TIA.

In brief, PFO closure with a percutaneous device plus antiplatelet therapy was not superior to aspirin and/or warfarin therapy for secondary prevention of stroke/TIA in patients with cryptogenic stroke or TIA who have PFO. Moreover, PFO closure with a percutaneous device appears to increase a patient�s risk of developing atrial fibrillation. This patient population should be encouraged to enroll in a clinical trial to identify the most effective and safe treatment for secondary prevention of stroke/TIA.

For more information, see Patent foramen ovale and other atrial septal defects in DynaMed.

About the Author

Mohamed Elshayeb, MD, is a second year resident of Saint Joseph Mercy Hospital Residency Program in Ann Arbor, Michigan. Faculty contribution by Amanda Rabquer, MD.

For more information about the residency program, visit the Saint Joseph Mercy Hospital webpage.

Dr. Elshayeb has declared no financial or other competing interests.

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