NEJM Publishes Two More Trials Weakening the Case for PFO Closure

 

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Percutaneous closure of patent foramen ovale (PFO) in patients with cryptogenic thromboembolism failed to prevent subsequent stroke and other adverse events in 2 randomized trials published in the March 21, 2013, issue of the New England Journal of Medicine. However, the findings contain some gray areas that will likely keep hope alive among proponents of the transcatheter treatment.

Results from the PC Trial and RESPECT were first presented in October 2012 at the annual Transcatheter Cardiovascular Therapeutics scientific symposium in Miami, FL.

RESPECT: Secondary Analyses Find Benefit

For the RESPECT trial, John D. Carroll, MD, of the University of Colorado, Denver (Aurora, CO), and colleagues randomly assigned 980 patients with cryptogenic stroke at 69 international sites to medical therapy—consisting of at least 1 antiplatelet (74.8%) or warfarin (25.2%)—or to PFO closure using the Amplatzer PFO Occluder (St. Jude Medical, Secaucus, NJ). Due to a higher dropout rate among medical therapy patients, the treatment exposure between the 2 groups was unequal at 1,375 patient-years for closure and 1,184 patient-years for medical therapy (P = 0.009).

In the main intention-to-treat analysis, stroke recurrence trended lower with PFO closure than with medical therapy. Two prespecified analyses—per protocol (which included only patients who received their allocated treatment) and as treated (which calculated results according to what patients actually received, irrespective of randomization)—significantly favored closure (table 1).

Table 1. RESPECT: Recurrent Stroke Rate per 100 Patient-Years

 

 

Closure

Medical Therapy

HR (95% CI)

P Value

Intention to Treat

0.66

1.38

0.49 (0.22-1.11)

0.08

Per Protocol

0.46

1.30

0.37 (0.14-0.96)

0.03

As Treated

0.39

1.45

0.27 (0.10-0.75)

0.007


Six months after treatment, 72.7% of patients in the device group had complete closure and 93.5% had effective closure. Moreover, the rate of serious adverse events was similar between the closure and medical therapy groups (23.0% vs. 21.6%; P = 0.65).

Further analyses suggested that closure provided greater protection than medical therapy in patients with substantial (grade 3) right-to-left shunt (HR 0.18; 95% CI 0.04-0.81) and atrial septal aneurysm (HR 0.19; 95% CI 0.04-0.87). According to the paper, epidemiologic studies have linked these characteristics to PFO-related stroke, and “therefore provide supportive evidence of a true biologic effect and rationale for closure.” Patients whose index infarct was superficial also appeared to derive benefit, though the difference was not significant (HR 0.37; 95% CI 0.13-1.04).

PC Trial: Closure Not Effective

The PC Trial, led by Bernhard Meier, MD, of Bern University Hospital (Bern, Switzerland), enrolled 414 patients with PFO and prior ischemic stroke, transient ischemic attack (TIA), or peripheral thrombotic event at 29 centers worldwide. Patients were randomized to receive medical therapy (n = 210) or PFO closure (n = 214) with the Amplatzer device.

Over a mean follow-up duration of approximately 4 years, results for the primary endpoint (composite of death, nonfatal stroke, TIA, or peripheral embolism) as well as the individual component endpoints of nonfatal stroke and TIA all favored closure but did not reach statistical significance (table 2).

Table 2. PC Trial: Intention-to-Treat Analysis

 

 

Closure
(n = 214)

Medical Therapy
(n = 210)

HR (95% CI)

P Value

Primary Composite

3.4%

5.2%

0.63 (0.24-1.62)

0.34

Nonfatal Stroke

0.5%

2.4%

0.20 (0.02-1.72)

0.14

TIA

2.5%

3.3%

0.71 (0.23-2.24)

0.56


However, with lower than expected event rates, the trial is underpowered, the researchers caution. “Thus, there is a risk of a type II error in our trial,” they write, “that is, a clinically relevant benefit of the closure of patent foramen ovale might exist but we were unable to detect it.”

Trials Offer Something for Everyone

Steven R. Messé, MD, of the Hospital of the University of Pennsylvania (Philadelphia, PA), and David M. Kent, MD, of Tufts University (Boston, MA), write in an accompanying editorial that unlike the negative CLOSURE I trial, published last year in NEJM, the results of RESPECT and the PC Trial may “encourage” supporters of PFO closure.

“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 intriguing signals,” they say. “Yet these trials will probably not convince skeptics, who will focus on the fact that 3 consecutive trials have failed to reject the null hypothesis in their primary intention-to-treat analyses, on the imprecision in the effect estimates, and on potential sources of bias, which included uneven dropout rates and unblinded (and imbalanced) referral for adjudication of endpoints.”

In addition, enrollment in each trial spanned more than 8 years, a situation that the editorial attributes to “widespread off-label use of atrial septal closure devices.”

Even though the controversy over the efficacy of PFO closure remains unsettled, the evident safety of the Amplatzer device compared with the StarFlex device (NMT Medical, Boston, MA) tested in CLOSURE I represents good news, Drs. Messé and Kent add.

Evidence ‘Compelling’ Despite Caveats

Robert J. Sommer, MD, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview that RESPECT and the PC Trial should not be lumped together. The PC Trial is “just a very different, much less specific population, and as a result, [its findings] are sort of scattered. It’s not conclusive of anything,” he cautioned.

RESPECT, meanwhile, offers a “strong indication that this is an effective therapy for the [stroke] population as a whole,” Dr. Sommer said, but even more importantly identifies the subgroups most likely to benefit.

However, even with the newly published findings, “You know that this controversy is never going to end,” he stressed.

In an e-mail communication, Brian K. Whisenant, MD, of Intermountain Medical Group (Salt Lake City, UT), agreed that “physicians will likely find evidence supporting their prior opinions on PFO closure in these papers.”

Both Drs. Sommer and Whisenant highlighted the safety of the Amplatzer device. In addition, Dr. Whisenant said, the “per-protocol and as-treated results [of RESPECT] are uniquely relevant given the tremendous challenges of enrolling and following patients who could choose off-label closure either before enrollment or after randomization. [These analyses] are the only valid option to evaluate the treatment effect.”

Dr. Whisenant expressed optimism that the US Food and Drug Administration (FDA) will approve the Amplatzer device based on its safety and efficacy. However, “the FDA, [Centers for Medicare and Medicaid Services], and conscientious physicians will want to see PFO closure limited to patients with large shunts and a neurologist opinion of likely PFO-mediated stroke,” he commented.

Dr. Sommer was similarly positive. “The FDA is so tired of this issue,” he said. While the RESPECT data are not definitive, he added, the agency “would be justified in a limited approval for patients who meet the criteria as outlined in the trial.”

He reported that with NMT Medical now out of business, WL Gore (Flagstaff, AZ) is discussing plans to study late follow-up from CLOSURE I. In addition, RESPECT is slated for 5-year follow-up. The REDUCE trial of Gore’s Helex septal occluder is ongoing, but the study is likely underpowered, Dr. Sommer concluded. In short, he said, “I don’t think we’re going to get any better information from that then we got from RESPECT.”

 

 


 

Sources:1. Meier B, Kalesan B, Mattle HP, et al. Percutaneous closure of patent foramen ovale in cryptogenic embolism. N Engl J Med. 2013;368:1083-1091.

 

2. Carroll JD, Saver JL, Thaler DE, Closure of patent foramen ovale versus medical therapy after cryptogenic stroke. N Engl J Med. 2013;368:1092-1100.

3. Messé SR, Kent DM. Still no closure on the question of PFO closure. N Engl J Med. 2013;368:1152-1153.

 

 

 

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Disclosures
  • The PC Trial and RESPECT were supported by St. Jude Medical.
  • Dr. Meier reports receiving consulting fees from St. Jude Medical and grant support through his institution from Abbott, Cordis, and Medtronic.
  • Disclosures for Drs. Carroll, Kent, and Messé are available at NEJM.org.
  • Dr. Sommer reports serving as a physician trainer for WL Gore as well as on the medical advisory board for Coherex.
  • Dr. Whisenant reports having financial interest in and serving as a director of Coherex Medical. He has received research support and consulted for WL Gore.

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