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; 366:991-999).
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; 368:1083-1091). 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; 368:1092-1100). 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.
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