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CLOSURE I: Superiority not substantiated for PFO closure vs. anticoagulation therapies
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Coverage from the Transcatheter Cardiovascular Therapeutics (TCT) 2010 meeting
Overestimated success rates and a short follow-up period were cited as potential explanations for CLOSURE I not achieving its primary endpoint in terms of failing to demonstrate a significant benefit of patent foramen ovale closure in patients with cryptogenic stroke or transient ischemic attack.
The CLOSURE I study included 800 patients with cryptogenic stroke or transient ischemic attack who were treated for patent foramen ovale (PFO) closure with either a closure device (Starflex, NMT Medical) plus 325 mg aspirin, or anticoagulation and/or aspirin 325 mg (medical arm). The expected 2-year event rates were 6% in the medical arm and 2% in the device arm.
According to results presented by trial researcher Michael J. Mullen, MD, of The Heart Hospital, University College Hospital, London, United Kingdom, patients in the device arm showed a small but statistically nonsignificant benefit vs. optimal medical therapy for preventing recurrent stroke or TIA, with a closure rate of 86.5%. Full results from CLOSURE I are expected to be reported at the American Heart Association meeting in November.
Among the possible explanations for the trial’s failure to achieve the primary endpoint, Mullen cited the unrealistic 67% expected reduction in the 2-year event rate between the two study arms, as well as inadequate follow-up
“It was also likely to have failed because it failed to adequately identify patients at risk and was probably underpowered because of the insufficient follow-up for hard events,” he said.
John D. Carroll, MD, of the University of Colorado, Denver, provided perspective on additional studies examining PFO closure.
Carroll focused specifically on the ongoing RESPECT trial, currently testing for superiority of percutaneous PFO closure using the Amplatzer PFO Occluder (AGA Medical Corp.) against current medical treatment for the prevention of recurrent embolic stroke. Carroll said that trial success will be declared if the device is shown to be significantly better than the standard of care.
Carroll also highlighted a number of challenges that he said may be impeding PFO trial outcomes, even characterizing the slow and low enrollment of the studies as the “big elephant in the room.”
“We have tried to look at this because we do have concern that many others have, which is that high-risk patients get off-labeled and low-risk patients get referred for trials,” he said in his presentation. “Guess what that does to trials?”
“The way the PFO studies are currently designed is not to give a choice in terms of two effective therapies, but really to demonstrate superiority,” he added. “So, while CLOSURE I may fail in its primary endpoint to show superiority, showing equivalency and perhaps enhanced safety, unfortunately, does not necessarily lead to device improvement.”
Disclosures:
- Dr. Mullen reports receiving research grants from NMT Medical Inc.
- Dr. Carroll reports being a member of the steering committee for RESPECT and consulting for AGA Medical.