CLOSE to the Heart: Patent Foramen Ovale Closure in Cryptogenic Stroke

Tim, a 47-year-old man, presents to your neurology clinic 3 months after suffering a nonlacunar ischemic stroke. A recent transthoracic echocardiogram demonstrated a patent foramen ovale (PFO) with a large interatrial shunt. He has no other risk factors for cryptogenic stroke (including paroxysmal atrial fibrillation, carotid stenosis, or hypercoagulable state) but expresses concern that this PFO may put him at higher risk for stroke recurrence. He asks if something should be done about his newly discovered PFO. How should you advise him?

The literature to date is mixed on the efficacy of PFO closure for the prevention of a second stroke. In the Closure of Patent Foramen Ovale, Oral Anticoagulant or Antiplatelet Therapy to Prevent Stroke Recurrence (CLOSE) trial, published this week in NEJM, Mas and colleagues examined the efficacy of PFO closure in preventing stroke recurrence in patients aged 16 to 60 years for whom PFO was the likely sole contributor to their initial stroke.

In this multicenter, open-label trial, 663 patients were randomized to receive PFO closure plus long-term antiplatelet therapy, antiplatelet therapy alone, or oral anticoagulation. After a mean of 5.3 +/- 2 years, PFO closure greatly reduced the primary outcome of stroke recurrence, compared to antiplatelet treatment alone (0% vs. 6.0%; P<0.001). The risk of complications associated with PFO closure was 5.9%, and the procedure was associated with a higher risk of transient atrial fibrillation than antiplatelet treatment alone (4.6% vs. 0.9% P=0.02). In a separate comparison of oral anticoagulation and antiplatelet therapy alone, stroke occurred in 1.6% and 4.0% of patients, respectively, but the study was not powered to analyze statistical significance for this comparison.

In an accompanying editorial, NEJM Deputy Editor, Allan H. Ropper, critically appraised the CLOSE trial, noting the discrepancy in results among three prior negative trials and two other positive trials on PFO closure published this week in NEJM. He points to the entry criteria in the CLOSE trial — that selected for patients with large interatrial shunt at rest (≥30 microbubbles within 3 cardiac cycles) or with an atrial septal aneurysm larger than 10 mm³ — as a driver of the positive findings in this trial. He adds, “…in patients who have had a stroke, are younger than 60 years of age, and have a PFO with characteristics that are highly likely to allow paradoxical embolism, the effect of closure becomes persuasive.”

The CLOSE trial presents useful new evidence on the role for PFO closure in the management of stroke. The results demonstrate the benefits of PFO closure in a selected patient population with high-risk characteristics of the PFO. It would be reasonable to review the controversy and these new results with Tim and have a candid discussion about the benefit of reduced stroke risk as well as the risks (including an increased risk of atrial fibrillation) of this procedure. Because Tim’s PFO is associated with a large interatrial shunt, he could be advised to have the PFO closed.

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Lisa is a 2017-2018 NEJM Editorial Fellow. An otolaryngologist-head and neck surgeon by training, she graduated from the University of Toronto Medical School and completed her residency training at the University of Ottawa. She has a Master's in Public Health from the Harvard T. H. Chan School of Public Health.