Patent Foramen Ovale: To Close or Not to Close?

In the past, cardiologists and neurologists tended to vote along party lines in the debate over closure devices vs. medical management of patients with a patent foramen ovale (PFO). Have results from recent trials created a middle ground?

Three recent trials of two devices, the Amplatzer PFO Occluder by St. Jude Medical and the STARFlex device by NMT Medical, failed to show that PFO closure significantly reduced the risk of recurrent ischemic stroke, transient ischemic attacks and/or death compared to using only anticoagulant or antiplatelet medications.

Results from the CLOSURE I trial (Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale) involving more than 900 patients with a PFO and a history of cryptogenic stroke  found no significant differences in risk for recurrent stroke between patients who underwent device closure with antiplatelet therapy and patients treated with medical therapy alone (5.5 percent vs. 6.8 percent) (N Engl J Med 2012; 366[11]:991-999).

Major procedural vascular complications occurred in only the device group, and these patients experienced atrial fibrillation significantly more often. NMT Medical funded this study, but has since gone out of business and the device is no longer available.

One year later, the New England Journal of Medicine published two other trials. Both used the Amplatzer PFO Occluder with antithrombotic drugs and compared it to medical therapy alone. St. Jude Medical paid for both studies.

In the PC trial (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale Using the Amplatzer PFO Occluder with Medical Treatment in Patients with Cryptogenic Embolism), researchers enrolled more than 400 patients from 29 centers in Europe, Canada, Brazil and Australia who suffered a cryptogenic stroke (N Engl J Med 2013; 368[12]:1083-1091). After about four years of follow-up, investigators found a nonsignificant 37 percent decrease in recurrent stroke risk in the device group. The primary endpoint was a composite of death, nonfatal stroke or transient ischemic attack and peripheral embolism.

The findings were similar in the RESPECT trial (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment) (N Engl J Med 2013; 368[12]:1092-1100). RESPECT enrolled 980 patients and randomized them to either PFO closure or medical therapy alone. After following up for an average of 2.5 years, the device group had a 51 percent reduced risk of recurrent stroke in the intention-to-treat analysis, but the result was nonsignificant.

Closure’s advocates

The results from the three trials have divided medical experts. Some say despite the failure of the studies to meet the primary endpoints, the data still favor PFO closure while others say the evidence to support PFO closure is insufficient at this point.

Despite not meeting its primary endpoint of nonfatal ischemic strokes, RESPECT’s lead investigator, John D. Carroll, MD, of the University of Colorado Denver, says that the data “are on the side of PFO closure being a benefit as part of a comprehensive stroke prevention.”

In the intention-to-treat group, there were nine instances of nonfatal ischemic strokes among patients assigned to the device group and 16 in the medical therapy only group. Although the data were not statistically significant, Carroll believes those numbers are a “strong signal” of the benefits, “especially when considering the results of the actual treatment received.”

Jonathan Tobis, MD, a cardiologist at the University of California, Los Angeles, calls himself a proponent of PFO closure and sees the data from the RESPECT and PC trials in a positive light. “The individual trials were not powered enough. There were not enough participants,” he says. “Patients with the highest risk of having recurrent strokes did not participate in these trials. They had their PFOs closed off-label with devices approved for the closure of atrial septal defects.” The StarFlex device used in CLOSURE 1 led to serious problems, he says, such as thrombi and atrial fibrillation.

There were also few stroke events.  In the three trials, there were only 56 stroke events among 2,303 patients over more than 10 years.

Sanjay Kaul, MD, MPH, a cardiologist in Los Angeles who was not involved in any of the trials, says the events in each of the individual trials were not frequent enough to yield more definite results. “One way to overcome this is to pool the results from three completed trials (CLOSURE, RESPECT and PC) and one ongoing trial (REDUCE) to increase the power to detect treatment difference,” he explains in an email. 

The REDUCE trial compares PFO closure with an atrial septal occluder to antiplatelet therapy, and Kaul says until that trial is complete, “it is difficult to say if the pooled results will favor PFO closure overall.”

Neurologists more leery

Neurologists are inclined to favor a more cautious approach. In fact, the American Academy of Neurology guidelines state that “[t]here is insufficient evidence regarding the effectiveness of either surgical or percutaneous closure of PFO.”

In an editorial that accompanied the RESPECT trial, neurologists Steven R. Messe, MD, of the Hospital of the University of Pennsylvania in Philadelphia, and David M. Kent, MD, of Tufts University in Boston argue PFO closure may be overused, given the prevalence of PFO and the low risk of stroke in patients treated with medical therapy (N Engl J Med 2013; 368[12]:1152-1153). They called for a better understanding of who benefits before routine use of devices. 

Messe says that the evidence is not yet there to support PFO closure as a way to reduce the risk of recurrent strokes. “PFOs are frequently seen in the general population and many have been closed inappropriately in the past,” he says. “If the PFO isn’t related to the stroke or TIA [transient ischemic attack], then patients should not have their PFO closed. Unfortunately, it is very challenging to make that determination and we have not yet confirmed that there is a group of patients who will benefit.”

Who benefits?

Some physicians argue that there are subsets of patients who are more likely to benefit from closure.

Kaul recommends PFO closure in high-risk patients—such as those with a large shunt or an atrial septal aneurysm—who have recurrent strokes but don’t have the common risk factors for stroke and who cannot or will not take antithrombotic therapy, such as women who may become pregnant.

Clay Johnston, MD, PhD, a neurologist at the University of California, San Francisco, agrees that patients who cannot use anticoagulants or antithrombotics or whose stroke was caused by deep vein thrombosis or PFO are likely to benefit from closure. Johnston, however, does not support device closure in other patients with PFOs.

Tobis says other potential reasons to close PFOs include migraines, sleep apnea, orthodeoxia and decompression illness.

Procedure tolerated but costly

Despite his reservations, Messe says the procedure itself is well-tolerated, although long-term safety issues have yet to be established. Carroll also considers the procedure safe, based on data from the study. “There were adverse events, but they occurred in both the device closure and the medical therapy groups. The ones related to the procedure or the device only occurred in 21 of the 499 patients in the device group,” he says.
The high cost of an unproven procedure also raises concerns.

In an editorial that accompanied the CLOSURE I study,  Johnston argued that each procedure costs about $10,000 and that 80,000 PFO device closures were used between study start and publication (N Engl J Med 2012:366[11]:1048-1050). Treating only half of the patients would mean “$400 million was spent on a procedure that had no apparent benefit,” he wrote.

He favors restricting device closure to the remaining clinical trials as well as prohibiting reimbursement of an unproven therapy unless the device is part of a clinical trial. “All that money spent on this procedure that could have been spent on something more effective is a waste,” Johnston says.

But Tobis counters the cost of preventing another stroke is worth every penny. “If you’ve had a stroke, what is the cost financially of a stroke and what’s the cost that’s worth it to prevent another stroke? My feeling after talking to people who have had strokes is that they wouldn’t bat an eye spending that money to prevent another one.”