SAN FRANCISCO—Closure of the patent foramen ovale (PFO) by way of a small, investigational medical device inserted through the leg vein is more effective than is medical management for reducing recurrent cryptogenic ischemic stroke, according to long-term outcomes in the prospective, randomized, multicenter RESPECT trial.

Closure Benefited Various Subpopulations

At a mean follow-up of more than five years, significantly fewer recurrent cryptogenic strokes occurred among 499 patients randomized to undergo PFO closure with the AMPLATZER PFO Occluder device (manufactured by St. Jude Medical) than among 481 patients randomized to receive guideline-directed medical treatment (10 vs 19; hazard ratio [HR], 0.460), said John D. Carroll, MD, Professor of Medicine at the University of Colorado at Denver in Aurora, and Director of Interventional Cardiology at the University of Colorado Hospital in Denver. He presented the findings at the Transcatheter Cardiovascular Therapeutics (TCT) Annual Meeting.

When only participants under age 60 were examined, the PFO-closure group also experienced significantly fewer recurrent strokes of any mechanism. The number of strokes among 475 patients younger than age 60 in that group was 12, compared with 22 in 463 patients under age 60 in the medical-management group (HR, 0.476), said Dr. Carroll.

Among patients with substantial shunt or atrial septal aneurysm, the benefits were even more pronounced, with a 75% relative risk reduction for recurrent cryptogenic strokes. Four strokes occurred in 319 such patients in the PFO-closure group, compared with 13 strokes in 301 patients in the medical-management group (HR, 0.245).

There were no cases of intraprocedure stroke, device embolization, device thrombosis, or device erosion, said Dr. Carroll.

“The treatment effect is fully manifest in the types of strokes for which PFO closure is intended,” he said, adding that the superiority of the AMPLATZER device over guideline-directed medical therapy was “substantial and sustained.”

“The procedure and the device now have long-term data showing their safety,” he said, noting that the number of patients with recurrent strokes that were not PFO-mediated underscores another important principle. “There has to be attention to other modification of stroke risk factors.”

Long-Term Follow-Up in RESPECT

Investigators began enrolling patients into the event-driven RESPECT trial in 2003, and primary results of the trial were analyzed when 25 primary end point events had been observed and adjudicated. A total of 980 patients aged 18 to 60 (mean age, 45.9) were enrolled at 69 sites within 270 days of a prior cryptogenic stroke. No significant benefit was seen with PFO closure in the intention-to-treat population, but closure was superior to medical therapy alone in the prespecified per-protocol and as-treated analysis.

The current analysis incorporated extended follow-up of as long as 10 years and more than 5,000 patient-years of follow-up, thus making RESPECT the largest trial of its type with the longest follow-up. The data confirm the benefit of PFO closure for reducing the risk of recurrent PFO-related strokes, said Dr. Carroll.

Interpreting the Data

In response to concerns that the primary end point in the original trial was not met, Dr. Carroll noted that with long-term follow-up, especially in a trial with so many younger patients, recurrent strokes from other mechanisms that can’t be prevented by PFO closure are inevitable. One in five study subjects is now over age 60, and the risk of such strokes is thus increased.

“The confounding impact of other etiologies of stroke was seen,” he said, explaining that A Severity Characterization of Trauma (ASCOT) analysis was used to stratify patients based on risk etiologies. Since that analysis was not prespecified, an additional analysis was performed to examine recurrent strokes in patients under age 60—the target age group in the study.

“And here, once again, we see by this separate sensitivity analysis the superiority of PFO closure,” he said, adding that this finding is “an important lesson in terms of the age group.”

Performing an ASCOT analysis and age censoring was key to revealing the significant and clinically important risk reduction for the kinds of strokes PFO closure prevents, he explained.

That 600 patients remained in the trial at five years is remarkable, he added. “This adds knowledge.”

“If you have a stroke and you have a PFO, does this randomized trial show that you will reduce recurrent stroke risk by closing it? The answer is no. But, if you happen to be a young patient where it’s likely to be cryptogenic, or if you happen to have features that would predispose you to that, there are clear data, at least in my mind, that it would make sense, based on these results, to close the PFO,” said Ajay J. Kirtane, MD, TCT Codirector and Director of Interventional Cardiology Fellowship Training at NewYork-Presbyterian Hospital and Columbia University Medical Center in New York City.

—Sharon Worcester

PFO Closure Reduces Recurrent Cryptogenic Stroke