NEJM: Will study results provide CLOSURE for PFO patients?

STARFlex septal closure system Source: J Am Coll Cardiol, 2006; 48:538-544

After nine years of waiting, the results are out on a trial evaluating whether device closure offered benefit over medical therapy alone for the prevention of stroke or transient ischemic attack (TIA) in patent foramen ovale (PFO) patients. However, the CLOSURE I trial may have missed its mark, as it was found that undergoing an expensive device closure procedure may be no more effective than medical therapy.

The results were published March 15 in the New England Journal of Medicine, and first presented at the 2010 American Heart Association (AHA) scientific sessions. PFOs are incidental findings in many stroke patients, and currently, devices to close the PFO are used off-label, as they are not approved by the FDA to prevent recurrent stroke in these patients.

In the multicenter, randomized, open-label CLOSURE I trial, Anthony J. Furlan, MD, of the University Hospitals Case Medical Center in Cleveland, and colleagues enrolled 909 patients; 447 patients who presented with cryptogenic stroke of TIA who received either closure plus antiplatelet medical therapy and 462 who received medical therapy between June 23, 2003, and Oct. 24, 2008.

During the study, the researchers evaluated a composite of stroke or TIA during the two-year follow-up period, death from any cause during the first 30 days or death from neurologic causes between 31 days and two years.

Composite results were similar for the patients in the closure group (STARFlex Septal Closure System) and the medical therapy group (aspirin or warfarin), 5.5 percent vs. 6.8 percent, respectively. The rates for stroke and TIA were 2.9 percent vs. 3.1 percent and 3.1 percent vs. 4.1 percent, respectively. No deaths were reported in either group at 30 days and there were no deaths from neurologic causes during the two-year follow-up.

CLOSURE I set out with a bold objective: to find a two-thirds reduction in risk of recurrent events in the closure group. However, the goal was not met, as the trial was not sufficiently powered.

“The insignificant trend toward a higher rate of the primary outcome in the medical-therapy group was driven by the lower rate of TIAs in the closure group,” the authors wrote. “The two-year rate of stroke (approximately 3 percent) was low and virtually identical in the closure and medical-therapy groups, suggesting that a much larger sample would be required if stroke were the only end point and that a follow-up interval longer than two years would be unlikely to show a significant difference in stroke outcomes.”

The authors did note an increase of atrial fibrillation (AF) in patients who underwent closure. AF has been reported in 5 percent to 20 percent of the PFO population in previous studies.

“Our findings do not preclude a possible role for closure of a patent foramen ovale in highly selected patient populations,” Furlan et al wrote.

In a previous interview, Furlan said, “It would be incorrect to say that CLOSURE I proved that there is no indication for closure, but the indications may be very limited.”

S. Claiborne Johnston, MD, PhD, of the University of California, San Francisco, wrote in an accompanying editorial, "The results of the trial do not support closure of a patent foramen ovale to prevent stroke in patients who have had a stroke or a TIA of unclear etiology. The closure procedure can have complications, is costly, and offers no proven benefits.”

Johnston added that nearly 80,000 patients have had a PFO closed with a device, and the average cost per procedure is $10,000. “Even if only half these patients were treated by this method for the purpose of preventing stroke, it would suggest that during that period of time $400 million was spent on a procedure that had no apparent benefit, to say nothing of the potential clinical risks involved.”

Johnston suggested that closing PFOs with devices should be limited to clinical trials, which she noted could help curb the high costs associated with the procedure. Additionally, she said that withholding reimbursements seems justified in this specific scenario.

“Denial of insurance coverage outside of clinical trials spurred the completion of earlier studies to evaluate carotid and intracranial stenting for stroke prevention, ultimately reducing the waste and complications related to both indications,” Johnston summed. “The costs of developing new devices have been increasing rapidly, yet the costs to society of unproven interventions are also extremely high.”