Two New Trials Buoy Outlook for PFO Closure in Patients With Cryptogenic Stroke

The REDUCE and CLOSE trials have provided fresh support for endovascular patent foramen ovale (PFO) closure in patients with cryptogenic stroke by showing that use of an occluder in conjunction with antiplatelet therapy reduces recurrent events compared with antiplatelet therapy alone.

Both trials met their primary endpoints, a feat that was not achieved in three prior trials of PFO closure—CLOSURE I, PC, and RESPECT. Subsequent meta-analyses and longer-term data, however, have shown benefits for PFO closure, at least in terms of reducing recurrent stroke. Those studies led the US Food and Drug Administration last October to approve the Amplatzer PFO Occluder device (St. Jude Medical), which was evaluated in PC and RESPECT, for the prevention of recurrent strokes in patients with cryptogenic stroke.

Nevertheless, the American Academy of Neurology (AAN) maintains a strong recommendation against routine use of PFO closure for these patients outside of a research setting and advises offering it “in rare circumstances.”

It would be premature to consider changes to those recommendations based on the findings of REDUCE and CLOSE, which were presented last week at the European Stroke Organisation Conference (ESOC) in Prague, Czech Republic, according to Shunichi Homma, MD (NewYork-Presbyterian/Columbia University Medical Center, New York, NY), a cardiologist involved in crafting the AAN guidance.

The full details of the trials would first need to be examined in order to answer questions about complications, dropouts, and other issues, “but these are certainly encouraging studies,” Homma told TCTMD.

REDUCE

Scott Kasner, MD (University of Pennsylvania, Philadelphia), presented results from the REDUCE trial, which was conducted at 63 sites in seven countries in North America and Europe and randomized 664 patients 2:1 to PFO closure with the Gore Helex Septal Occluder or the Gore Cardioform Septal Occluder (both WL Gore & Associates) plus antiplatelet therapy or antiplatelet therapy alone. Patients were between 18 and 59 years of age, had a confirmed PFO on transesophageal echocardiography, and had experienced a cryptogenic ischemic stroke within the past 180 days.

Antiplatelet therapy regimens allowed in the study were aspirin alone, aspirin plus dipyridamole, or clopidogrel alone. Anticoagulation could not be used.

There were two primary endpoints, both of which were met.

Recurrent clinical ischemic stroke through at least 2 years (average follow-up was 3.4 years) occurred in six patients (1.4%) in the closure group and 12 (5.4%) in the control group, a relative risk reduction of 77% (HR 0.23; 95% CI 0.09-0.62). The number needed to treat was 28.

The other primary endpoint, a composite of new clinical ischemic stroke or silent brain infarct on MRI through 2 years, occurred in 5.7% of patients who underwent PFO closure and 11.3% of the controls, a relative reduction of 49% (RR 0.51; 95% CI 0.29-0.91).

Those findings were consistent across various subgroups.

“All in all, results suggest a really highly significant and consistent and practice-changing effect of PFO closure with the Gore devices compared to antiplatelet therapy alone,” Kasner told TCTMD.

He reported a low risk of device- or procedure-related complications, although there was a higher risk of A-fib in the closure group, which has been seen in prior trials. Kasner said most cases were not considered serious by local teams and resolved quickly. He noted that the A-fib rate has increased slightly across successive trials of PFO closure, speculating that it could be that researchers are simply looking harder for the arrhythmia over time. But, he said, the importance of the issue needs to be explored further.

CLOSE

Positive results also came out of the CLOSE trial, which was presented by Jean-Louis Mas, MD, PhD (Hôpital Sainte-Anne, Paris, France). Conducted at 32 sites in France and two in Germany, the investigator-driven trial included 663 patients randomized to three trial arms:

• PFO closure with any approved device plus antiplatelet therapy
• Antiplatelet therapy alone
• Oral anticoagulation alone

Patients were between 16 and 60 years of age, had a PFO with an atrial septal aneurysm or large shunt, and had had a cryptogenic stroke within the past 6 months.

The primary outcome (fatal or nonfatal stroke through a mean follow-up of 5.3 years) was reduced with PFO closure by a relative 97% compared with antiplatelet therapy alone (HR 0.03; 95% CI 0-0.12). There were no strokes in the closure group and 14 in the controls.

A separate analysis suggested that oral anticoagulation alone might be superior to antiplatelet therapy alone, but the difference did not reach statistical significance (HR 0.43; 95% CI 0.10-1.50). Mas did not report a comparison between closure and oral anticoagulation.

As in REDUCE, there was a higher risk of new-onset A-fib following PFO closure—11 new-onset cases compared two in the control group.

Succeeding Where Others Failed

When asked why REDUCE and CLOSE were able to show a benefit of PFO closure on the primary endpoints of the trials, Kasner pointed to patient selection as the biggest factor. He said thorough evaluations were performed to identify patients with truly cryptogenic strokes, noting that none of the recurrent strokes seemed to be due to underlying causes other than the PFO.

“That’s speculation at this point,” he added. “All we know is how many strokes we had. We know what our population was. We still need to go and explore exactly what these recurrent strokes were like in terms of their location, shape, size, those kinds of things.”

It’s possible, too, that device-specific factors may have made a difference, Kasner said.

Regardless of the reasons, the positive results from REDUCE and CLOSE and the “strongly suggestive nature” of the prior trials “together, I think, should change practice and guidelines,” Kasner said.

REDUCE, in particular, provides solid support for a practice change, Kasner said, because it included MRI-based assessments of silent infarcts as part of one of the primary endpoints. That represents “strong, objective evidence that closure is reducing events, and that’s not really subject to bias,” he said.

Homma agreed that evaluating silent infarcts increases the validity of the clinical stroke findings, but maintained there are numerous unanswered questions that would need to be addressed before modifying guidance.

Prior trials have had high dropout rates, and it’s unclear what they were in REDUCE and CLOSE, he said. There is also little information available so far regarding complication rates and whether shunt size affects the impact of PFO closure. Also missing, Homma said, was a comparison of PFO closure with oral anticoagulation in CLOSE.

“These are some of the questions that we need to answer before we widely recommend closing PFO for the population,” he said.