Final CLOSURE I Data Presented at AHA Meeting

November 15, 2010—At the American Heart Association's (AHA) Scientific Sessions 2010 in Chicago, Anthony J. Furlan, MD, presented late-breaking clinical trial results from CLOSURE I that found that a transcatheter procedure for patent foramen ovale (PFO) closure appears to be no more effective than drug therapy in preventing recurrent strokes.

The CLOSURE I trial sought to demonstrate the superiority of the StarFlex septal closure system (NMT Medical, Inc., Boston, MA) followed by clopidogrel over drug therapies alone (aspirin or warfarin or both) to prevent new strokes or transient ischemic attacks (TIAs) in patients with unexplained stroke or TIA and a PFO. However, the results showed no statistically significant differences between the two approaches to therapy.

“It is possible the procedure has a slight benefit, but you would need thousands of patients to find it in a randomized trial,” commented Dr. Furlan, who is the study's lead investigator.

According to the AHA, CLOSURE I is the first completed prospective, randomized, two-arm superiority trial comparing percutaneous PFO closure using the StarFlex system to medical therapy in cryptogenic stroke patients. The device applies a clamshell-type patch on both sides of the hole.

The trial's primary composite endpoint was the difference in stroke and TIA rates between the two patient groups at 2 years, death from all causes in the first 30 days, and death from neurological causes at 30 days or more.

The investigators enrolled 909 patients at 87 sites in the United States and Canada over 64 months, ending in October 2008. The patients were 60 years of age or younger, with an average age of 47 years. Researchers randomized patients to either medical therapy (325 mg of aspirin or the appropriate warfarin dose, or a combination of both) or PFO closure with subsequent medical therapy (75 mg of clopidogrel for 6 months and 325 mg of aspirin for 2 years).

The study found that percutaneous closure with StarFlex plus medical therapy did not offer any significant benefit over medical therapy alone. There was a slight, although not statistically significant, decrease in the primary endpoint for the PFO treatment group (5.5%) versus the medical therapy group (7.7%). The 2-year stroke recurrence rate was identical in both groups (3%), and researchers found no difference in outcomes between patients treated with aspirin versus warfarin; however, Dr. Furlan commented that the trial was not powered to determine the best medical therapy. He continued, saying that possible alternative explanations for the strokes and TIAs that occurred were found for 22 of 29 patients in the medication-only group and in 20 of 23 of the PFO-closure patients. The causes included a blood clot in the left atrium and new atrial fibrillation.

The AHA stated that no medical device has been approved by the US Food and Drug Administration for sealing PFOs, but physicians use devices approved for closing other types of heart defects to seal the opening between the right and left atria, usually with the aim of preventing a stroke.

“Based on the trial results, even though a patient has a PFO and a recurrent stroke, the hole may be totally coincidental to the second stroke,” noted Dr. Furlan. “The undeniable message here is that too many of these holes are being closed with an off-label procedure, but that's partly because we've never had a randomized trial to guide us.”

Dr. Furlan advised that the criteria for diagnosing paradoxical embolism and the potential efficacy of PFO closure in patient subgroups requires further study.

NMT Medical, which sponsored the study, announced that it is analyzing a number of CLOSURE I secondary and tertiary studies, including migraine. Additionally, NMT is working with the US Food and Drug Administration to evaluate possible next steps relating to stroke/TIA and expects to have a plan relating to a potential follow-up study within the next few weeks.