RESPECT 10-Year Data Strengthens Case for PFO Closure After Cryptogenic Stroke

Deborah Brauser

October 16, 2015

SAN FRANCISCO, CA — Using a device designed to close the patent foramen ovale (PFO) in patients who have had a cryptogenic ischemic stroke may reduce their risk of having another stroke, suggests newly released 10-year data from the RESPECT trial.

In the extended follow-up's intention-to-treat (ITT) population, those who underwent PFO closure with an Amplatzer PFO occluder (St Jude Medical) poststroke had a 54% relative risk reduction for recurrent cryptogenic stroke vs those assigned to medical management (anticoagulants).

Although the original 980-person trial showed superiority of PFO closure over medical management in as-treated and prespecified per-protocol analyses, it missed its primary end point of significant risk reduction of recurrent stroke in the ITT analysis.

Dr John D Carroll

However, in the extended analysis, "the treatment effect was fully manifested in the types of strokes for which closure is intended," Dr John D Carroll (University of Colorado School of Medicine, Aurora) told attendees at a press briefing here at TCT 2015. "The procedure and the device are safe, and treatment with the occluder was superior to medical management."

Carroll later told heartwire from Medscape that this has been a difficult area to study and has taken several years "to refine what we're doing and the questions that we're asking. Key questions can't be answered over just a few years."

Difficult Population

Press briefing discussant Dr Roxana Mehran (Mount Sinai School of Medicine, New York) agreed but emphasized that because the original trial didn't meet its end points, "we should take all of this with a little grain of salt," especially because the study had high dropout rates.

Still, Mehran noted that "long-term follow-up does show that the curves continued to separate," and the new results were especially strong for several subgroups.

"If I had PFO and a stroke, I'd want my PFO closed," added moderator Dr Ajay J Kirtane (New York-Presbyterian Hospital/Columbia University Medical Center). "A dropout rate from 900 to 600 patients at the 5-year mark doesn't really pass muster in most clinical-trial follow-ups. But this is a challenging group, and I believe in the results."

Carroll noted that PFO is a known major cause of cryptogenic stroke, especially in individuals who are younger than 60 years. "One-third of ischemic strokes are classified as cryptogenic," he said, adding that this stroke type is defined as a "brain infarction not clearly attributable to a cause despite extensive investigation."

For PFO patients with a prior cryptogenic stroke, current guidelines call for treatment with anticoagulants to prevent stroke recurrence.

As reported by heartwire , results from the main RESPECT trial were first presented at TCT 2012 and subsequently published in the New England Journal of Medicine. The researchers assessed outcomes in PFO patients who were under the age of 60 years and had a cryptogenic stroke in the previous 270 days. A total of 499 were randomly assigned to PFO closure with the small Amplatzer occluder device, which is inserted via leg vein, and 481 were assigned to medical management. Initial analysis included 3.0 and 2.7 years of follow-up, respectively.

ITT analysis showed a 46.6% risk reduction of stroke for the PFO-closure group, which was not statistically significant. However, the reduction went up to 63.4% when patients treated per protocol were assessed.

"Longest Follow-Up"

In the new, extended analysis, the PFO-closure group had a mean follow-up of 5.5 years vs 4.9 years for those receiving medical management—for 2769 and 2376 total patient-years, respectively. "This was the longest follow-up ever conducted in the largest randomized trial [of this type]," said Carroll, with trial duration lasting more than 10 years.

There were no significant between-group differences for all-cause strokes in the overall ITT analysis, which included both cryptogenic strokes and those classified as "other." However, there was a significant reduction for PFO closure vs medical management when researchers looked specifically at incidence of cryptogenic stroke (10 strokes vs 19, respectively; hazard ratio 0.46, P=0.04).

Carroll noted that a study complication was that 20% of the patient population aged past the original cutoff point of 60 years, making the older patients more susceptible to noncryptogenic strokes—which cannot be prevented by PFO closure.

When limiting ITT to those under the age of 60, the relative risk reduction for all-cause stroke was 52% for the PFO-closure vs control group (P =0.035). In addition, there was a 75% relative risk reduction for cryptogenic stroke for the PFO-closure patients who had atrial septal aneurysm or "substantial shunts"(P=0.007).

There were no device- or procedure-related incidents of intraprocedure stroke or device erosion, thrombosis, or embolization during follow-up. The rate of vascular complications was 0.9%, and the rate of device explantation was 0.4%. The only significant between-group difference in adjudicated serious adverse events was in deep vein thrombosis/pulmonary embolism (17 events vs three events, respectively).

Carroll reported that the dropout rate was not inconsequential. Although there were about 600 total patients still enrolled at the 4- to 5-year follow-up, that number dropped to about 150 at the 8-year point and just 30 at the 10-year point. Interestingly the medical-management arm had significantly higher discontinuation rates vs the PFO-closure arm. "This probably wasn't random. The people who dropped out to seek off-label closure elsewhere [11%] had a previous stroke before their index stroke. So going down the street to get off-label closure was probably a major draw," he explained.

Still, "I think the data are now very compelling," said Carroll. "There was a substantial reduction of stroke risk that was sustained, which means a lot for these people," he said. "There's a real need for randomized, long-term data, and that's what we've provided as best we can."

He added that the intent is now to move toward presentation to the FDA for possible eventual approval.

"Profound Reduction"

"To summarize: if you have a stroke and you have a PFO, does this randomized trial show that you'll reduce recurrent stroke by closing? The answer is no," said moderator Kirtane during the press briefing.

"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, then, at least to my mind, it would make sense based upon these results to close the PFO." However, he added that the approval process for the device and procedure "will be challenging."

When the nine-person expert panel was asked if they had PFO and were in their 40s, which of them would have this procedure done, all but one member raised their hands. Dr Jeffrey Popma (Beth Israel Deaconess Medical Center) said that he would want to thoroughly look at all the data in that scenario. "But based on these long-term results, I'd probably do it."

Mehran later told heartwire that the study was "very important" because of the huge amount of work done and the long follow-up. "It makes you feel very compelled to say that we now have much more evidence on top of what we had before that patients with a stroke and a PFO and no other cause should have their PFO closed for prevention of cryptogenic stroke."

Regarding the hand-raising by the panel, Mehran said that that illustrates the importance of these issues. "Although the trial data don't look great, because you have dropouts, etc, and as a purist you might say 'this is never going to pass muster' or 'this is slicing and dicing data,' it still showed such a profound reduction in stroke in young patients," she said.

"The comorbidity is so huge with a stroke in a young person and the cost is so huge, that if you can just close it in a safe way, as they did, why not do this?"

"Core of Meaningful Therapy"

After the study's presentation at the TCT's last late-breaking clinical-trial session, several of the discussants called the study data "quite strong."

"We've been watching and waiting for this for a long time," said Dr Stephen JD Brecker (St George's Hospital, London, UK).He reported that the current status in his country is that PFO closure can be performed if it adheres to a very specific guideline. "This [study] has taught us what we thought we knew: that we have to select patients very carefully, not only on their clinical presentation but on their PFO anatomy as well."

Moderator Dr Martin B Leon (New York-Presbyterian Hospital/Columbia University Medical Center)added that "most of us believe that there is a core of meaningful therapy here that needs to find its way to regulatory expression."

The study was funded by St Jude Medical. Carroll reported being part of the steering committee for RESPECT and receiving consulting fees from St Jude.

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