SAN FRANCISCO – Closure of the patent foramen ovale (PFO) by way of a small investigational medical device inserted via 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.

At a mean follow-up of more than 5 years, significantly fewer recurrent cryptogenic strokes occurred among 499 patients randomized to undergo PFO closure by way of the AMPLATZER PFO Occluder device (St. Jude Medical) than among 481 patients randomized to receive guideline-directed medical treatment (10 vs. 19; hazard ratio, 0.460), reported Dr. John D. Carroll, professor of medicine at the University of Colorado at Denver, Aurora, and director of interventional cardiology at the University of Colorado Hospital, Denver. He presented the findings at the Transcatheter Cardiovascular Therapeutics annual meeting.

When only those under age 60 years were looked at, the PFO closure group also experienced significantly fewer recurrent strokes of any mechanism; the number of strokes among 475 patients younger than age 60 years in that group was 12, compared with 22 in 463 patients under age 60 years in the medical management group (HR, 0476), Dr. Carroll reported at the meeting, which was sponsored by the Cardiovascular Research Foundation.

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; 4 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, Dr. Carroll said.

“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 take-home lesson: “There has to be attention to other modification of stroke risk factors.”

The event-driven RESPECT trial began enrolling patients in 2003, and primary results of the trial were analyzed when 25 primary endpoint events had been observed and adjudicated. A total of 980 patients aged 18-60 years (mean of 45.9 years) 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 with extended follow-up of up to 10 years with more than 5,000 patient-years of follow-up, making RESPECT the largest trial of its type with the longest follow-up, confirms the benefit of PFO closure for reducing the risk of recurrent PFO-related strokes, Dr. Carroll said.

In response to concerns that the primary endpoint 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 the age of 60 years, and the risk of such strokes is thus increased.

“The confounding impact of other etiologies of stroke was seen,” he said, explaining that an ASCOT (A Severity Characterization of Trauma) analysis was used to stratify patients based on risk etiologies, and since that analysis was not prespecified, an additional analysis was performed to look at recurrent strokes in those under age 60 years – 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 is “an important lesson in terms of the age group.”

Doing an ASCOT analysis and an 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 5 years is remarkable, he added. “This adds knowledge.”

Session moderator Dr. Ajay J. Kirtane, TCT codirector and director of interventional cardiology fellowship training at NewYork-Presbyterian Hospital/Columbia University Medical Center, summarized the findings: “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.”

The RESPECT trial was funded by St. Jude Medical. Dr. Carroll reported serving on the steering committee for the RESPECT trial, with compensation paid to the University of Colorado.

sworcester@frontlinemedcom.com

TCT: Extended follow-up supports PFO closure in cryptogenic stroke