MIAMI — Everyone agrees: the Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) and PC Trial both missed their primary end point, and that's probably where the consensus ends. The two trials had assessed whether a patent foramen ovale (PFO) closure device could reduce the risk of recurrent stroke in patients who had experienced cryptogenic stroke. Results were presented today at TCT 2012.

As both studies were negative, one clearly so and the other with a benefit when evaluating the "as-treated" patients only, researchers and clinicians were left to interpret the results in light of positive secondary end points and past observational reports suggesting a possible benefit of closing PFOs in these patients. One believes the PC and RESPECT results shouldn't change clinical practice, while another was more generous and said that while the study results weren't a "home run," clinicians should look toward the totality of the PFO-closure data, as no one trial provides good direction on whether or not the treatment is effective for the prevention of future stroke.

In the PC Trial, presented by Dr Stephen Windecker (University of Bern, Switzerland), which included 414 patients randomized to treatment with the transcatheter Amplatzer PFO occluder (St Jude Medical, St Paul, MN) or medical therapy, closing the PFO failed to reduce the primary end point of death from any cause, nonfatal stroke, transient ischemic attack, and peripheral embolism [1]. There was an 80% reduction in the risk of stroke, but this reduction did not reach statistical significance.

In the RESPECT trial, the 46.6% reduction in the risk of stroke was not statistically significant when assessed in the intention-to-treat analysis [2]. However, when the investigators analyzed the data among patients treated per protocol, the 63.4% reduction in stroke was statistically significant, as was the 72.7% reduction in stroke when analyzed by patients who actually received the device.

Dr John Carroll (University of Colorado, Denver), the lead investigator of the RESPECT study, was pleased with the results, telling the media that the totality of the evidence now supports the use of PFO closure in this group of patients at risk for a second stroke following a cryptogenic stroke. He said the study will have a substantial impact on the treatment of at-risk patients, as it "provides an amazing amount of evidence-based medicine to the field.

"We conclude from these data and other data that in carefully selected patients with a history of cryptogenic stroke and PFO that this provides evidence of a benefit in stroke risk reduction from closure with this particular device over medical management alone," said Carroll. "The primary analysis, which was the intention to treat, was borderline and formally not statistically significant, but trended toward superiority, while the secondary analysis suggested that this is a superior treatment."

Dr Alice Jacobs (Boston University, MA), who commented on the study, was lukewarm on the results and wants to get a full look at the published data. She told heartwire that her hospital stopped performing PFO closures after the publication of the CLOSURE I study, and it's too early to determine whether these new studies tip the scales in favor of starting the procedure again. "I guess it's up to us to put the totality of evidence together. When you look at the intention-to-treat analysis, it's not a positive study," she said, but added that when these data are combined with other observational reports the data are "heartening."

In a discussion of the results following the late-breaking clinical-trials session, Dr Gregg Stone (Columbia University, New York), the session moderator, acknowledged the complexity of understanding the PC Trial and RESPECT results when both missed their primary end points but yet seemed to suggest a benefit when the secondary end points were analyzed. While many praised the study investigators for carrying out the studies, they also acknowledged that the trials don't provide any definitive answers.

"I think you have to be cautious with such a small number of events," Dr David Faxon (Brigham and Women's Hospital, Boston, MA) said in reference to the RESPECT trial. "I also think the trial was designed as an intention-to-treat trial, so that's the way you have to analyze it. I view this more as hypothesis generating as a trial that shows us the possibility. These are tantalizing results. They aren't definitive, and they're probably not going to change clinical practice at this point in time, but they do lead us to the next step."

The RESPECT and PC Trial Studies

RESPECT was a multicenter, event-driven study that enrolled 980 patients over eight years. All patients were diagnosed with a cryptogenic stroke and PFO, with 49% of patients having large strokes as their qualifying stroke event. Patients in the study were relative young at an average age of 46 years.

In the intention-to-treat analysis, there was a nonsignificant 46.6% reduction in the risk of stroke. In the Kaplan-Meier intention-to-treat analysis, there was a 50.8% relative reduction in stroke risk--nine strokes in the PFO closure arm vs 16 events in the medical-therapy arm--but this reduction was not statistically significant. In the per-protocol and as-treated analyses, the 63.4% and 72.7% relative reduction in risk was statistically significant. In the as-treated analysis, there were five strokes in the PFO closure arm and 16 strokes in the medical-therapy arm.

RESPECT Analysis: Efficacy

Analysis Relative risk reduction (%) p
Intention-to-treat analysis (raw count)* 46.6 0.157
Intention-to-treat (Kaplan-Meier) 50.8 0.083
Per-protocol analysis 63.4 0.032
As-treated analysis 72.7 0.007

*Primary end point: Raw count intention-to-treat analysis includes patients counted in the study arm they are randomized to regardless of the treatment they receive. Assumes a similar study population is maintained in each arm.

The PC Trial included 414 patients also randomized to PFO closure or medical therapy. Patients were included in the study if they were younger than 60 years of age and had a clinically or neuroradiologically verified ischemic stroke or transient ischemic attack with a documented intracranial ischemic lesion. As noted, there was a nonsignificant 37% relative reduction in the primary end point of death from any cause, nonfatal stroke, transient ischemic attack, and peripheral embolism.

PC Trial: Efficacy Analysis

Endpoint Relative risk reduction (%) p
Death from any cause, nonfatal stroke, transient ischemic attack, and peripheral embolism* 37 0.34
Stroke 80 0.14
Transient ischemic attack 29 0.58

*Primary end point

To heartwire , Dr Ted Feldman (NorthShore University HealthSystem, Evanston, IL) said that putting aside the negative results, the aggregate of data arms physicians so that they are able to have conversations with patients about preventing their future risk of stroke. "Yesterday, I would have this discussion with an individual patient based on registry data, and today I can have that conversation based on randomized controlled trials. It's not like turning on a light switch. If the trial were positive statistically, it would be just as difficult to say to the patient that we're going to prevent your next stroke, because it isn't all or none. It's nice to talk about trials as an all-or-none winner, but that's not what trials are for--trials are there to inform our decision making."

Feldman said that he had hoped the PC Trial and RESPECT would provide a degree of certainty.

Speaking with the media, Dr Ajay Kirtane (Columbia University, New York) pointed out that these cryptogenic-stroke patients are not typical stroke patients, as they are often young and healthy. With the stroke, they are now faced with a lifetime of medical therapy, with all its question marks, or undergoing an interventional procedure that allows them to stop treatment. Feldman agreed.

"The probability that the stroke is related to the PFO is one of the fundamental problems in selecting patients," said Feldman. "If you treat a 70-year-old with a PFO and a stroke, the potential that the stroke etiology is hypertension, vascular disease, or an intermittent arrhythmia becomes very cloudy. In this younger population, the likelihood that it is due to the PFO increases. But this is an issue when you counsel a patient. It's a probability discussion. You can't tell anyone that you're going to prevent their next stroke. You can tell them the likelihood that you're going to reduce their risk over a period of years."

Next steps will likely include pooling the CLOSURE I, PC Trial, and RESPECT studies to understand what high-risk patients might benefit from PFO closure. Another trial, the REDUCE study, sponsored by Gore Medical, is currently ongoing, and the company just received FDA approval to use its atrial septal defect (ASD) closure device in the study. As an aside, Jacobs pointed out that both the PC Trial and RESPECT--and quite likely future trials--had a hard time enrolling patients because many physicians were already convinced that PFO closure was effective for reducing the risk of stroke.

Carroll reports research support and consulting fees from AGA Medical/St Jude Medical. Windecker reports grant/research support from Abbott, Biosensors, Biotronik, Boston Scientific, Cordis, Medtronic, and St Jude Medical.