CHICAGO – Closure-device problems did not explain why endovascular closure of patent foramen ovale in patients with a history of cryptogenic stroke failed to produce better outcomes than those of medically-treated patients. The device performed well, Dr. Anthony J. Furlan said at the annual scientific sessions of the American Heart Association.
The problem was patient selection.
"For the vast majority of patients who have had a cryptogenic stroke and a patent foramen ovale [PFO] medical therapy is a good first-choice," said Dr. Furlan, professor and chairman of neurology at Case Western Reserve University in Cleveland. "The challenge now to the endovascular community is to refine the patient selection criteria and not close these holes so liberally."
Based on the results from A Prospective, Multicenter, Randomized Controlled Trial to Evaluate the Safety and Efficacy of the STARFlex Septal Closure System Versus Best Medical Therapy in Patients With a Stroke and/or Transient Ischemic Attack Due to Presumed Paradoxical Embolism Through a Patent Foramen Ovale (CLOSURE I), the first randomized study to compare anticoagulant therapy and endovascular PFO closure, "we should see a significant drop in the number of PFOs that get closed," Dr. Furlan said.
The CLOSURE I investigators selected patients "who are being closed worldwide," he said. "Many patients who have a cryptogenic stroke also have a hole and nothing else, but people don’t look that hard. Assessments tend to stop when they find a PFO, he said.
The CLOSURE I results "clearly showed that in patients with stroke of unknown cause and PFO there is no need for systematic PFO closure because it is not effective and may be associated with major vascular complications, atrial fibrillation, or bleeding," said Dr. Pierre Amarenco, professor and chairman of the department of neurology and stroke center at Bichat Hospital in Paris. "Cryptogenic stroke likely includes a broad range of underlying etiologies that may have diluted the true, causal effect of PFO. These results should now be translated into practice for the million patients with stroke of unknown cause and PFO. On a case-by-case basis, after careful evaluation by a vascular neurologist, there may be some patients for whom closing the PFO can be deemed useful, but these cases are likely very rare."
CLOSURE I enrolled 18- to 60-year-olds who had a cryptogenic stroke or transient ischemic attack (TIA) within the past 6 months, and a PFO documented by transesophageal echocardiography. Investigators at 87 centers in the United States and Canada randomized 909 patients during June 2003–October 2008 to endovascular closure with the STARFlex device or to medical therapy. Patients in the closure group also received aspirin and clopidogrel for 6 months following their procedure, followed by aspirin alone for an additional 18 months. Patients in the medical-treatment arm received warfarin alone, dosed to a target international normalized ratio of 2.0-3.0 (139 patients), warfarin plus aspirin (80 patients), or aspirin alone (243 patients) throughout their follow-up. The average age of the patients was 46; 52% were men. Nearly three-quarters had an index cryptogenic stroke.
"We believe the study population was representative of patients aged 60 or younger with cryptogenic stroke or TIA and a PFO," Dr. Furlan said.
The study’s primary end points were the individual rates of stroke and TIA and the composite rate after 2 years of follow-up on an intent-to-treat basis. The composite rates were 5.9% among the 447 patients in the closure group and 7.7% among 462 patients in the medical-therapy group, a difference that was not statistically significant. The numeric difference was driven primarily by a difference in the TIA rate, 3.3% in the closure group and 4.6% in the medical therapy group, not significantly different. The stroke rates were nearly identical in the two groups, 3.1% and 3.4%. The composite end point showed no significant difference between the two treatment arms regardless of the shunt severity or whether or not the patients had an atrial septal aneurysm.
Roughly 80% of the strokes that occurred during follow-up in both arms of the study had no relationship to paradoxical embolism, suggesting that in many of these patients the PFO may be coincidental, Dr. Furlan said.
In the control arm, the outcomes did not significantly differ regardless of whether patients received warfarin plus aspirin, warfarin alone, or aspirin alone. Dr. Furlan noted that the study was not powered to find significant differences among these three subgroups.
The overall rate of major adverse events was similar, 17%, in both treatment arms (see table). Patients who underwent PFO closure had significantly more major vascular complications and atrial fibrillations. Vascular complications occurred completely secondary to the closures, with none in the medically-managed patients, Dr. Furlan said. The closure procedure achieved technical success in 90% of patients in that arm of the study, with 86% of the PFOs closed at 6 months after treatment based on follow-up echocardiography examinations.