CLOSURE I: PFO Closure Fails to Beat Medical Therapy for Stroke, TIA

Shelley Wood

June 18, 2010

June 18, 2010 (Updated June 21, 2010) (Montreal, Quebec and Boston, Massachusetts) — Preliminary results of the CLOSURE I trial, released mid-afternoon yesterday by the company, show that patent foramen ovale (PFO) closure using the Starflex device is not superior to best medical therapy for preventing recurrent stroke or transient ischemic attack (TIA) [1]. The surprising news--not expected for several months--will likely have implications for other ongoing trials.

According to the statement released by NMT Medical, the trial failed to meet its primary end point, although preliminary results suggest a small, but not statistically significant, benefit of device closure over current best medical therapy. The device also demonstrated a low rate of adverse events, including thrombus formation, and actual closure rates were consistent with other studies of the Starflex, at 86.5%--and "in line with other transcatheter closure devices."

News of the disappointing results will come as a blow to cardiologists, many of whom, based on retrospective and nonrandomized studies, have been convinced that closing a PFO can cure or vastly reduce rates of cryptogenic stroke and TIA. Indeed, closure devices including the Starflex are approved for stroke prevention via PFO closure in Europe and Canada but have never been approved for this indication by the FDA, which was awaiting the CLOSURE I results. The news may also prove devastating to NMT, whose share price plunged by more than 75% after the news was released.

"Although we are disappointed that we did not meet the primary end point, we are currently in discussions with the US FDA to evaluate our possible next steps relating to the stroke/TIA indication," NMT president and CEO Frank Martin said in the statement. "In addition, we are working with our clinical investigators, contract research organization, and the CLOSURE I executive committee to analyze the full trial data set to help us better understand and evaluate our clinical and regulatory options."

The full results will likely be presented at the American Heart Association meeting in November 2010, he added.

By twist of fate, a talk entitled "PFO closure: The evidence and the controversy" was on the program for the 2010 Montreal Interventional Cardiology meeting, delivered by PFO expert Dr Michael Mullen less than an hour after the NMT announcement was posted online. Mullen, who has been a principal investigator and investigator for other NMT trials, spoke for some time about CLOSURE I without mentioning the NMT announcement one hour previously.

"I don't know what the results will be," he told the Montreal audience. "I think if it is a completely negative trial, then PFO closure is going to die a sudden death. If it is a positive trial, I would guess the controversy will go on and there will be lots of debate about the end points, because I suspect it will primarily be positive for TIA and not for stroke, and then there will be a lot of debate over what is a TIA if you can't see it on the MRI scan."

Calling the trial "very, very important," Mullen pointed to the other major trials currently ongoing: AGA Medical's randomized RESPECTtrial using its Amplatzer closure device and its randomized PC Trial in Europe. Gore Medical is also randomizing patients in the multinational REDUCE study, using its Helex septal occluder. "The outcome of these trials and the other smaller trials going on around the world will be predicated on this, because I think it may be very hard for them to continue depending on the results of CLOSURE I."

Contacted by emailafter his presentation, Mullen said he hadn't known about NMT's press release before his talk. "I am sure this result will be a disappointment to all involved in trying to understand the role of PFO closure in patients with stroke. As I said in my talk, if CLOSURE I is negative, it would have an impact on the whole PFO market. I think we need to wait and see what the full results show us before we conclude what that impact might be. There may yet be some positive messages in the trial data."

Not everyone agrees with his predictions with regard to the impact on other studies, however. Dr Jonathan Tobis (University of California, Los Angeles), an implanting physician for the RESPECT trial and principal investigator for AGA's PFO/migraine trial, PREMIUM, who has also consulted for both AGA and Gore, told heartwire "the other trials will continue."

Co–principal investigator for CLOSURE I, Dr Anthony Furlan (Case Western Reserve University, Cleveland, OH), told heart wire he could not comment on the announcement at this time. Dr Mark Reisman (Swedish Medical Center, Seattle, WA) is CLOSURE I co–principal investigator.

Editor's note: An earlier version of this story erroneously identified Furlan as CLOSURE I co–principal investigator and as being from the Cleveland Clinic.