Final RESPECT Data Support PFO Closure for Cryptogenic Stroke Prevention

WASHINGTON, DC—Final results of the RESPECT trial suggest that perseverance has paid off for patent foramen ovale (PFO) closure for secondary stroke prevention after more than a decade of study.

“In the RESPECT trial, PFO closure with the Amplatzer PFO Occluder was more beneficial than medical management alone,” said David Thaler, MD, PhD (Tufts Medical Center, Boston, MA), who presented the 10-year RESPECT data today at TCT 2016. “For patients with cryptogenic stroke and PFO, closure with the AMPLATZER PFO Occluder is an appropriate treatment option that reduces the risk of recurrent stroke.

The FDA granted marketing approval to this device, manufactured by St. Jude Medical, for recurrent stroke prevention in the setting of cryptogenic stroke last week.

Focusing on Preventable Strokes

In the original RESPECT findings, presented at TCT 2013 and published in the New England Journal of Medicine, the rate of the primary endpoint—recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization in the intention-to-treat population of 980 patients—was similar among patients diagnosed with cryptogenic stroke who were randomized to PFO closure with the Amplatzer device compared with guideline-directed medical therapy over 270 days. Last year, the researchers presented data showing a 54% relative risk reduction in the specific recurrence of cryptogenic stroke for patients treated with closure over about 5 years.

In an effort to focus only on cryptogenic stroke prevention, Thaler explained that this intention-to-treat analysis excluded those with strokes of known mechanism—strokes that PFO closure could “never prevent”—over the study period. For this population, PFO closure resulted in a 62% relative risk reduction in secondary stroke (95% CI 0.18-0.79) compared with medical management. This effect was magnified further when the population was narrowed to only include patients under than 60 years (HR 0.42; 95% CI 0.21-0.83).

There were no instances of intraprocedural stroke, device embolization, device thrombosis, or device erosion among patients who received closure. Major vascular complications occurred in 0.9% and device explants in 0.4%. Also, there were no differences between the study arms in A-fib, major bleeding, or all-cause death, but patients who underwent closure had a higher rate of DVT/PE compared with those who did not (P = 0.006).

Outdated Guidelines?

In July, the American Academy of Neurology (AAN) released an updated recommendations statement discouraging the use of PFO closure for cryptogenic stroke, citing the rarity of these events in comparison with how common PFOs are in the general population. This statement was published only months after the FDA’s Circulatory System Devices Panel gave a mixed thumbs up for the agency to approve the device.

Because the AAN published their document “without the benefit of the data that were presented at the May panel meeting, . . . the moment those guidelines hit the press, they were out of date,” Thaler said. “I have a problem with that.”

But contending that everyone who has worked on PFO closure for years feels “really strongly that this needs to be a collaborative effort going forward,” Thaler said “the book that goes out to all the cardiologists should be titled 'not every dizzy spell is a TIA,' because you need to have a neurologist on your side to help identify the appropriate patients that would have been respectable. ‘RESPECT’ in all caps, because those are the ones [for whom] we now know based on these data that there is a benefit to PFO closure for secondary stroke prevention. But if it gets disseminated crazily and people are not careful with patient selection, I think that would be a real problem for the cardiology field. I think we need to continue to work together on this.”

Following up, press conference panelist David R. Holmes Jr, MD (Mayo Clinic, Rochester, MN), said he holds a position at his institution in what is known as the Heart Brain Clinic. “Rather than a Heart Team, it’s a Stroke Team,” he explained. “So all these patients are seen by neurology and cardiology. . . . That’s part of the culture now, and it’s a terribly important part.”

A Long Path

The long path to positive results—and an approval—was also a key topic of discussion with the media.

Because mean follow-up among the 499 patients treated with the Amplatzer PFO Occluder in the study was 6.3 years, Jeffrey Popma, MD (Beth Israel Deaconess Medical Center, Boston, MA), also participating in the morning press conference, questioned the optimal point in the product’s lifecycle when neurologists would be “comfortable recommending this for [their] patients.”

“Do we have to wait 10 years until after the trial has been completed in order to now have a definitive statement that this is really beneficial? If a device doesn’t do harm [and] has a mechanistic potential benefit, should we have earlier access to these devices as we’re following these patients out to get to a 10-year endpoint?” he asked.

Thaler answered that they observed a “steady decline” in secondary strokes by “about a percent per year—which over the lifetime of a 30-year-old is [not insignificant]. We don't know that over 60 years it will be 60% in that population, but we have no indication that it stops at least for the longest-term data there are for this.”

These data, he continued, are likely the best that the medical community will have for this procedure. “There isn’t going to be a bigger trial. There isn't going to be longer follow-up,” Thaler said, adding that there will be a postapproval study and that the results of REDUCE, using the Helex and Cardioform septal occluders (WL Gore & Associates), will likely be released within a year.

An earlier version of this story incorrectly referred to the device in REDUCE as the Helix septal occluder. In fact, the trial started with the Helex device, but in 2012 the FDA granted WL Gore permission to use its newer-generation device in the trial.