RESPECT and PC Trial Published: Results of PFO Closure Debated Again

March 20, 2013

SAN FRANCISCO — The Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) and PC Trial , presented at TCT 2012 after many years of anticipation, are published today in the New England Journal of Medicine[1,2]].

The studies, both of which were reported by heartwire , were randomized, controlled clinical trials, and both missed their primary end point, a finding that disappointed many hoping that closure of patent foramen ovale (PFO) with the Amplatzer occluder (St Jude Medical, St Paul, MN) would prevent stroke recurrence in patients who previously had a cryptogenic stroke.

However, as noted previously, the trials sparked debate and discussion about the merits of PFO closure in this patient population, given that the underpowered PC Trial was clearly negative and the RESPECT study showed a benefit only in the "per-protocol" and "as-treated" patients. In an editorial accompanying the studies[3], Dr Steven Messé (University of Pennsylvania, Philadelphia) and Dr David Kent (Tufts University, Boston, MA) said both trials have something for the believer and something for the skeptic.

"Advocates of closure will surely focus on the substantial relative effect size of the point estimates in both trials, the significance of the per-protocol and as-treated analyses in RESPECT, the arbitrariness of the conventional p value threshold of 0.05, and various other intriguing signals," they write.

However, the trials are unlikely to convince those skeptical of the procedure, given that the three trials to date, including the controversial CLOSURE I , "have failed to reject the null hypothesis in their primary intention-to-treat analyses," they add. In addition, there are concerns about potential sources of bias--namely, the uneven dropout rates and imbalanced referral for the adjudication of clinical end points. Acknowledging the uncertainty surrounding the studies, the editorialists do not advocate the routine closing of PFO in stroke patients.

"Given the prevalence of patent foramen ovale in the general population, the enormous potential for overuse of percutaneous closure of a patent foramen ovale, and the relatively low risk of stroke in patients who are treated medically, the routine use of this therapy seems unwise without a clearer view of who, if anyone, is likely to benefit," write Messé and Kent.

To heartwire , lead RESPECT investigator Dr John Carroll (University of Colorado, Denver) said the totality of clinical-trial evidence, including the positive prespecified per-protocol and as-treated results in RESPECT, moves the field forward. Although the trial missed the primary end point, he said that other significant findings, despite the inherent biases of per-protocol and as-treated analyses, help shed light on the benefits to the patients who received the device. In addition, the RESPECT and PC Trial showed there was a major improvement in the safety of PFO closure with the Amplatzer device compared with the STARFlex (NMT Medical) device tested in CLOSURE I.

"I would point out that these trials aren't like left-atrial-appendage trials looking at noninferiority of the device vs a medication strategy," he said. "PFO-closure trials for secondary prevention of ischemic stroke are superiority trials, and that is a higher level of evidence that we're after. RESPECT, with two of the three analyses showing superiority, is substantial." He added that three of the nine patients in the device arm of RESPECT who had a recurrent stroke did not have a device in place, and this raises some question as to the validity of the intention-to-treat results.

We can't look at clinical trials like sporting events, where there is a score with a winner and loser.

"We can't look at clinical trials like sporting events, where there is a score with a winner and loser," said Carroll. "The more fundamental question to ask when clinical trials are reported is whether or not the trial moves us forward in understanding the disease process, its treatments, and in whom the treatments might work with the greatest benefit. It's this kind of knowledge development that we're really after."

Dr Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA), who was not involved in the studies but who commented on the results at TCT 2012, said the publication of the data doesn't really change his opinion of PFO closure. He told heartwire that he holds the same position he did a few months ago when asked if the results from the PC Trial and RESPECT moved the needle in terms of his support for PFO closure to prevent stroke recurrence and he said it did, moving it from "not to maybe not."

"An important lesson to be learned from these trials is that it is the collective responsibility of all the stakeholders (patients, physicians, payers, sponsors, and regulators) to ensure completion of randomized trials in a timely and efficient manner," he said this week in an email. "It took over a decade to enroll about 2300 patients for these three trials. Over 80 000 PFOs were closed during this time without evidence of effectiveness. A classic example of putting the cart before the horse!"

The RESPECT and PC Trial, in a Nutshell

In the PC Trial, led by Dr Bernard Meier (University of Bern, Switzerland), which included 414 patients randomized to treatment with the transcatheter AmplatzerPFO occluder 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. There was an 80% reduction in the risk of stroke, but this reduction did not reach statistical significance

In the RESPECT trial, a multicenter, event-driven study that enrolled 980 patients over eight years, the 46.6% reduction in the risk of stroke was not statistically significant when assessed in the intention-to-treat analysis. 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.

At the time of the presentation, experts noted that the two PFO closure trials have been difficult to complete, given slow enrollment. Many of the TCT discussants had difficulty interpreting how the trials would shape clinical practice, especially given the mixed bag of results. Dr Gregg Stone (Columbia University, New York), the moderator of the late-breaking clinical-trials session, said the studies failed to provide definitive answers, as did others.

Totality of the Evidence

The editorialists, along with Carroll and the RESPECT investigators, highlight the need for further study of PFO closure in this patient population, something that is currently ongoing. More than 800 patients in RESPECT are still being followed, and data on these patients will eventually be reported. Second, there are plans to pool patient-level data from the RESPECT and PC Trial to address some of the issues of statistical power that have been raised with the PC Trial, as well as with the small number of events in RESPECT.

Over 80 000 PFOs were closed during this time without evidence of effectiveness. A classic example of putting the cart before the horse!

To heartwire , Carroll noted that recently presented neuroimaging data of the index stroke event showed that patients with transient ischemic attack and lacunar stroke were successfully excluded from the RESPECT trial, which helped produce an ideal group to study the superiority of the device compared with medical therapy alone. Second, for those with recurrent stroke, there was strong neuroimaging evidence supporting the biological effect of device closure, with patients in the medical-therapy arm who had a stroke more likely to have a stroke consistent with embolic etiology.

In the editorial, Messé and Kent praise the investigators for continuing to investigate the issue and to accrue data on the patients enrolled in these and other trials. They point out that misclassification of one or two events can have dramatic effects on clinical outcomes (and their significance) in studies with low outcome rates. While it is possible to combine RESPECT and the PC Trial, such a meta-analysis and its subsequent outcome will "depend on post hoc, data-driven design choices, such as whether to exclude CLOSURE I or which outcome measure to use in the primary analysis."

All eyes now will be on the Food and Drug Administration and Circulatory System Devices advisory panel that will hear the evidence presented again by the sponsor and investigators at a still-undecided date. Another trial, the REDUCE study, sponsored by Gore Medical, is currently ongoing, and the company received FDA approval to use its atrial septal defect (ASD) closure device in the study.

The PC Trial and RESPECT studies were sponsored by St Jude Medical. Carroll reports receiving support for travel to meetings for the study or other purposes from St Jude Medical and consulting for Gore and Philips Healthcare. His institution has received grants, consulting fees or honoraria, fees for participation in review activities such as data monitoring boards, statistical analysis, end point committees, etc, and payment for writing or reviewing the manuscript from St Jude Medical and grants from Phillips Healthcare. Disclosures for his coauthors are available at Meier reports receiving consulting fees from St Jude Medical and grant support through his institution from Abbott, Cordis, and Medtronic; disclosures for his coauthors are listed in the paper. Kent reports receiving grants from Gore; his institution has received grants from the National Institutes of Health. Messé reports consulting for GlaxoSmithKline, grants from Gore, and royalties from Up to Date; his institution has received grants from NMT Medical. Kaul reports no conflicts of interest related to PFO closure.