PFO Closure Faces Renewed Scrutiny in Patient-Level Meta-Analysis

PFO Closure Faces Renewed Scrutiny in Patient-Level Meta-AnalysisA pooled analysis of 3 studies comparing PFO closure with optimal medical therapy in patients with cryptogenic stroke offers evidence that closure generally produces better outcomes.

That being said, the advantage is hardly clear cut, researchers report. Specifically, the intervention’s main benefit seems to hinge on protection from stroke, rather than death or TIA, and treated patients are at higher risk of developing A-fib.

Writing the next chapter of the unending saga over whether or not closure is the best strategy for this population, David M. Kent, MD, of Tufts University School of Medicine (Boston, MA), and colleagues, combined patient-level data from the following studies:

  • CLOSURE I: 909 patients randomized to medical therapy with or without STARFlex umbrella occluder (NMT Medical) implantation
  • RESPECT: 980 patients to medical therapy with or without Amplatzer PFO occluder (AGA Medical/St. Jude) implantation
  • PC: 414 patients randomized to medical therapy with or without Amplazter implantation

The study was published online this week ahead of print in the March 1, 2016, issue of the Journal of the American College of Cardiology.

While PFO closure devices have never been approved by the US FDA for general use, many patients have been lured away from trial participation through the years by operators offering off-label procedures with devices approved for ASD closure. Of the devices used in this meta-analysis, STARFlex is no longer manufactured and the Amplatzer PFO occluder is awaiting FDA approval.

Overall, 1.5% of those who received PFO closure in the studies had a primary composite outcome event—stroke, TIA, or death—compared with 2.3% in the medical therapy arm. Yet the difference only became significant when accounting for possible confounders (adjusted HR 0.68; 95% CI 0.46-1.00). But for stoke alone, closure led to better outcomes in both unadjusted (HR 0.58; 95% CI 0.34-0.98) and adjusted analyses (adjusted HR 0.58; 95% CI 0.34-0.99).

Bleeding rates were similar between the study arms, but A-fib was seen 3 times more often among patients who had their PFOs closed than in those receiving medical therapy (HR 3.22; 95% CI 1.76-5.90).

“People who favor PFO [closure] will look at this as a very positive study, whereas the community of people who really are skeptical about PFO closure will still remain unconvinced,” Kent told TCTMD, adding that the “ultimate question” will be which evidentiary standards the FDA decides to use to potentially approve the Amplatzer device.

Between Optimism and Evidence

In an interview with TCTMD, vascular neurologist Bartlomiej Piechowski-Jozwiak, MD, of King’s College Hospital (London, England), said previous PFO closure trials have been backed by a “big cardiology lobby,” and that the debate about its appropriateness has been powered by an “overly optimistic approach from cardiology and a sort of neutral evidence-based approach from neurology.”

The truth of the matter, he said, “is somewhere in the middle, which this meta-analysis demonstrates very nicely with some statistical significance in favor of PFO closure. But the patient populations were very divergent, and the studies were done at different times with different access to different medications and different devices.”

Piechowski-Jozwiak likened the current climate around PFO closure to that of asymptomatic carotid surgery. “Neurologists are less keen to send people with asymptomatic stenosis to surgery and the surgeons are slightly in favor of the procedure,” he explained. “So we all have our biases in a way, but the best way to deal with this is thorough discussion.”

Advocating multidisciplinary team meetings, Piechowski-Jozwiak said vascular surgeons or cardiologists should take the time to meet with neurology and hematology specialists and “have a discussion about every [PFO] patient” to ensure best management practices.

Taking STARFlex Out of the Picture

Kent’s team performed a subsequent analysis of only the 1,394 patients enrolled in one of the 2 Amplatzer vs medical therapy trials and again found better outcomes with closure, but still the unadjusted analysis was not statistically significant. Even so, the effect of closure over medical therapy on stroke alone was greater than in the overall analysis (HR 0.39; 95% CI 0.19-0.82).

“Basically, what we showed is somewhat but not completely different from what was previously shown, and that was that it appears that the effect estimate favors closure,” Kent said. “But there’s a lot of uncertainty around the effect estimates and the P value is right on the cusp of statistical significance.”

Additionally, the difference in A-fib occurrence after closure or medical therapy was narrower when the STARFlex patients were taken out of the equation, he said, indicating that Amplatzer is the safer device.

Kent argued that “A-fib itself is not as bad an outcome as stroke” since it is merely a stroke risk factor. “For [the] small amount of people who might get A-fib from closure of a PFO, they’re replacing 1 risk factor for stroke with another,” he explained.

“From a risk standpoint, PFO closure appears to be a very safe procedure in experienced hands,” write Barry A. Love, MD, of Mount Sinai Medical Center (New York, NY), and Hans-Christoph Diener, MD, PhD, of University Hospital Essen (Essen, Germany), in an accompanying editorial.

They note a growing impatience with the medical community to “figure out” the PFO closure situation. The meta-analysis “takes us a step closer to ‘figuring it out,’” Love and Diener write. But the only way the issue will be solved will be by unearthing definitive evidence—unlikely to happen given the expense and difficulty in planning and executing a larger, longer trial—or letting patients have the autonomy to make their own choice amid the “current (albeit imperfect) state of knowledge.”

1. Kent DM, Dahabreh IJ, Ruthazer R, et al. Device closure of patent foramen ovale after stroke: pooled analysis of completed randomized trials. J Am Coll Cardiol. 2016;67:907-917.
2. Love BA, Diener H-C. PFO: “please figure out,” or now “potentially figured out?” [editorial]. J Am Coll Cardiol. 2016;67:918-920.

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  • The study was supported by the National Institutes of Health, Patient-Centered Outcomes Research Institute, and PACE Center Funds, Tufts Medical Center.
  • Dr. Kent reports no relevant conflicts of interest.
  • Dr. Love reports receiving honoraria for participating in clinical trials, proctoring, contribution to advisory boards, and oral presentations from St. Jude Medical and W.L. Gore and Associates.
  • Dr. Diener reports receiving honoraria for participation in clinical trials, contribution to advisory boards, and oral presentations from multiple pharmaceutical and device companies and financial support for research projects from AstraZeneca and GlaxoSmithKline.