Closure of a patent foramen ovale (PFO) with an atrial septal aneurysm, hypermobility, or size of 2 mm or greater reduces the risk of stroke recurrence in patients with cryptogenic stroke, according to research published online ahead of print March 12 in the Journal of the American College of Cardiology.

“Considering the high prevalence of PFO in the general population and cryptogenic stroke patients, the key to appropriate use of this medical device is determining how to select optimal candidates for the procedure,” said Jae-Kwan Song, MD, PhD, a Professor in the Department of Medicine at Asan Medical Center, University of Ulsan College of Medicine, in Seoul, South Korea. “With our study and other recent trials, the criteria for selecting patients for the procedure are becoming clearer; in particular, the results suggest that closure is beneficial for those with high-risk PFO.”

A Multisite Superiority Trial

Previous research has not offered a definitive answer to the question of whether physicians can determine the potential benefit of PFO closure according to the PFO’s morphologic characteristics. In an earlier study, Dr. Song and colleagues found that high-risk PFO, as defined by transesophageal echocardiography (TEE), helped to predict stroke recurrence. The investigators then initiated the DEFENSE-PFO trial to evaluate whether restricting treatment to patients with cryptogenic stroke and PFO morphology associated with a higher rate of recurrent stroke would enhance the benefits of PFO closure.

Dr. Song and colleagues conducted DEFENSE-PFO, an open-label superiority trial, at two sites in South Korea from June 2011 through October 2017. Eligible patients had an ischemic stroke within the previous six months with no identifiable cause other than a high-risk PFO with left-to-right shunting. The researchers performed a standardized evaluation to rule out other identifiable mechanisms of stroke. The exclusion criteria were at least 50% stenosis of a major vessel, occlusion of a major vessel, and stroke resulting from small-vessel occlusive disease. Dr. Song and colleagues performed Holter monitoring or prolonged monitoring of cardiac rhythm to rule out paroxysmal atrial fibrillation.

A high-risk PFO was defined as one with an atrial septal aneurysm (ie, protrusion of the dilated segment of the septum at least 15 mm beyond the level surface of the atrial septum), hypermobility (ie, phasic septal excursion of 10 mm or more into either atrium), or size (ie, maximum separation of the septum primum from the secundum during the Valsalva maneuver) of 2 mm or greater on TEE.

Patients were randomized in equal groups to transcatheter PFO closure with the Amplatzer PFO Occluder plus medical therapy or medical therapy alone. All participants received antiplatelet therapy or anticoagulation chosen by the local investigator. During follow-up visits at one, three, six, 12, and 24 months, investigators recorded clinical data.

The primary end point was a composite of stroke, vascular death, or Thrombolysis in Myocardial Infarction (TIMI)-defined major bleeding during two years of follow-up. The secondary end point was asymptomatic ischemic stroke on follow-up MRI.

No End-Point Events After PFO Closure

Dr. Song and colleagues identified 450 patients with cryptogenic stoke and PFO, of whom 175 had high-risk PFO. They randomized 60 patients to each study arm. Participants’ mean age was 51.8. The groups were well balanced in terms of age, sex, medical history, qualifying event, modified Rankin scale score at discharge, and the anatomic characteristics of the PFO and atrial septum.

Seven patients randomized to PFO closure declined the treatment. Dual antiplatelet therapy was the most common medication in both groups at 30 days after randomization. This trend continued for as long as 12 months in the medication-only group, but single antiplatelet therapy became the most common strategy after six months in the PFO-closure group. About 17% of patients in the PFO-closure group stopped medication after the intervention. The median duration of follow-up was 2.8 years.

In the intention-to-treat analysis, no patient in the PFO-closure group had a primary end point event, compared with six patients in the medication-only group. Events recorded in the latter group included five ischemic strokes, one cerebral hemorrhage, two TIMI-defined major bleeding events, and one transient ischemic attack. The Kaplan-Meier two-year cumulative estimate of the probability of stroke was 10.5% in the medication-only group. The number of patients needed to treat with PFO closure to avoid one stroke at two years thus was 10.

Implications for Selection Criteria

The DEFENSE-PFO study differs from two previous trials that found benefits of PFO closure, but did not consider the anatomic features of the atrial septum or PFO. “The only trial with stringent entry criteria similar to ours is the CLOSE trial, which required that patients have a large interatrial right-to-left shunt (more than 30 microbubbles in the left atrium within three cardiac cycles after opacification of the right atrium) or an atrial septal aneurysm (a septum primum excursion greater than 10 mm),” said Dr. Song and colleagues. “Both the CLOSE trial and our trial showed no occurrence of stroke in patients who underwent PFO closure, suggesting that the beneficial effect of percutaneous device closure of PFO can be maximized by adding the morphologic characteristics of PFO, as evaluated by TEE, to the selection criteria for the procedure.”

Because the DEFENSE-PFO study was terminated early for patient safety, it was underpowered to provide a hazard ratio for its primary end point. In addition, selection bias may have affected the study, since it was conducted at a small number of centers.

—Erik Greb

Suggested Reading

Lee PH, Song J-K, Kim JS, et al. Cryptogenic stroke and high-risk patent foramen ovale: The DEFENSE-PFO trial. J Am Coll Cardiol. 2018 Mar 12 [Epub ahead of print].

Mas JL, Derumeaux G, Guillon B, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377(11):1011-1021.

Closure of High-Risk PFOs Reduces Risk of Recurrent Stroke

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