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The tide may be turning on patent foramen ovale (PFO) closure to prevent recurrent cryptogenic strokes, with three new trials reporting that the procedure can be effective with careful patient selection.

In October 2016, the Amplatzer PFO Occluder won FDA approval despite the large RESPECT trial showing it was not significantly better than medical management at preventing recurrent ischemic strokes.

How do the latest trial data -- all published in the Sept. 14 issue of the New England Journal of Medicine -- push PFO closure into positive territory? Following are highlights from the three new analyses.

CLOSE

There were whereas they occurred in 6.0% of those receiving antiplatelet therapy alone (HR 0.03, 95% CI 0-0.26) among patients eligible for either therapy (including those contraindicated to anticoagulants).

Atrial fibrillation (Afib) rates were elevated after PFO closure, however (4.6% versus 0.9% for antiplatelets-alone, P=0.02), in the randomized, multicenter CLOSE study conducted in France and Germany by Jean-Louie Mas, MD, PhD, of the Hôpital Sainte-Anne in Paris, and colleagues.

CLOSE enrolled 663 patients ages 16-60 with cryptogenic stroke attributed to PFO within the previous 6 months, and with an associated atrial septal aneurysm or large interatrial shunt. All were randomized to transcatheter PFO closure plus long-term antiplatelet therapy, antiplatelets alone, or oral anticoagulation.

Eleven different occluder devices were available for PFO occlusion.

Patients contraindicated to PFO closure exhibited stroke rates of 1.6% and 4.0% on anticoagulants and antiplatelet therapy, respectively.

While 5.9% of patients in the PFO closure arm had procedural complications, this group was at no greater risk for serious adverse events.

RESPECT Extension

With follow-up extended to a median 5.9 years, participants in RESPECT randomized to Amplatzer PFO closure had than the medical therapy group: 0.58 versus 1.07 events per 100 patient-years, HR 0.55, 95% CI 0.31-0.999).

ASCOD-adjudicated recurrent strokes of undetermined cause were reduced in this group (0.32 versus 0.86 per 100 patient-years, HR 0.38, 95% CI 0.18-0.79), as were TOAST-adjudicated cryptogenic strokes (0.03 versus 0.41 per 100 patient-years, HR 0.08, 95% CI 0.01-0.58), according to the team led by Jeffrey L. Saver, MD, of UCLA.

These investigators did not find significantly more periprocedural Afib after PFO occlusion (0.48 versus 0.34 per 100 patient-years with medical therapy, HR 1.47, 95% CI 0.64-3.37).

RESPECT randomized 980 patients to PFO closure or medical therapy alone. Notably, the extended follow-up period saw a particularly high dropout rate in the medical-therapy group (33.3% versus 20.8% with the occluder).

Gore REDUCE

PFO closure scored another win with the Gore Helex and Cardioform Septal Occluders, which brought recurrent strokes over a median 3.2 years' follow-up (versus 5.4% for antiplatelets only, HR 0.23, 95% CI 0.09-0.62), according to the Gore REDUCE data.

The 24-month incidence of new brain infarcts -- combined clinical ischemic strokes and silent brain infarctions -- was halved (5.7% versus 11.3%, RR 0.51, 95% CI 0.29-0.91), reported Scott E. Kasner, MD, of Philadelphia's University of Pennsylvania, and colleagues. This finding was driven by the advantage in reduced clinical strokes (1.3% versus 6.8%, RR 0.19, 95% CI 0.07-0.54) -- with no difference detected for silent infarcts.

Device-related events occurred 1.4% of the time. After PFO closure, 6.6% still experienced Afib (versus 0.4% of controls, P<0.001).

Gore REDUCE was a multicenter trial conducted across North America and Europe. Its 664 participants received baseline and 24-month brain imaging and were randomized 2:1 to PFO closure or antiplatelet therapy alone.

Rates of serious adverse events were no different between groups (23.1% versus 27.8%, P=0.22).

Making Sense of the Data

"How can we now have three trials showing that closure prevents recurrent stroke, given that in the past 5 years, the Journal published articles from three other trials that showed the opposite?" asked Allan Ropper, MD, of Brigham and Women's Hospital in Boston, in an .

Ropper declared it "futile" to try to find the answer in antithrombotic therapy or follow-up duration differences among the trials (although he called the extended RESPECT trial "the most provocative" of the three because of the longer follow-up, he maintained that it doesn't answer the question).

Instead, he zeroed in on the "stringent" entry criteria in the CLOSE trial, which showed no strokes at all after PFO closure and had required that patients present at enrollment with a large interatrial shunt at rest (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).

"The Gore REDUCE trial, a trial with positive results that are also reported in this issue of the Journal, represented a middle ground by including patients with a moderate-to-large interatrial shunt but not requiring that patients have an atrial septal aneurysm (approximately 20% of the patients in the PFO closure group were found to have one at the time of the procedure)," he noted. Accordingly, Gore REDUCE still exhibited a low stroke rate over 3-year follow-up.

It appears that the effectiveness of PFO closure depends on choosing the right patients, the editorialist concluded. "[I]n 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 to occur, the effect of closure becomes persuasive."

The FDA's Take

In an , three FDA officials practically gloated at the new results.

"The published results of these trials appear to support the general conclusions reached by the FDA in the evaluation of the Amplatzer PFO Occluder," wrote Andrew Farb, MD, and two colleagues from the agency's Center for Devices and Radiological Health.

Last year, the FDA decided that despite the uncertainty regarding the reduction in stroke risk attributable to the device, the potential benefit of PFO closure was viewed favorably in light of a low rate of serious adverse events. "[T]he balance was found to be acceptable for appropriate patients," Farb's group recalled.

"When determining whether to use this device, it's important that clinicians perform the recommended testing to target appropriate patients, understand the strengths and limitations of available clinical trial data, and discuss potential risks and benefits with their patients."