Medical Device Daily

Recent results from the CLOSURE I PFO clinical study, released last month at the American Heart Association (AHA; Dallas) annual meeting by NMT Medical (Chicago) (Medical Device Daily, Nov. 17, 2010) aren't stopping W. L. Gore & Associates (Flagstaff, Arizona) in its efforts to press forward with its REDUCE clinical study, the company said.

NMT's study was a prospective, multi-center randomized controlled trial of PFO closure evaluating the Starflex device vs. best medical therapy for the prevention of recurrent stroke and/or transient ischemic attack (TIA) in patients with cryptogenic stroke / TIA and PFO. The study included 910 patients under 60-years-old from 87 sites who had either a cryptogenic stroke or transient ischemic attack and a PFO.

Half of the patients received best medical therapy (aspirin, warfarin, or combination) while the other half had their PFO closed and took six months of aspirin and clopidogrel followed by 18 months of aspirin. Although there was no statistically significant difference between the two groups in terms of adverse events; there was slightly, but not significant, fewer strokes and TIAs in the device group.

The results of the study, as presented, showed no statistically significant difference between device closure and best medical therapy. In a discussant presentation, investigators for CLOSURE I concluded that PFO closure is not needed for the majority of patients with stroke and PFO and should not be performed in routine practice.

The conclusion could take some momentum from Gore in its bid to complete the REDUCE study which has been ongoing for two years now.

“Clearly there have been a lot of questions from physicians on what to do with the results of CLOSURE I,“ John Rhodes, MD, a principal investigator for REDUCE, told Medical Device Daily. “I think the study that we'll be doing is a bit different.“

Rhodes and the Gore REDUCE Clinical Study Steering Committee pointed out that there are several key issues that they believe could limit the impact of the CLOSURE I results on the study.

These issues, according to the committee, are mostly related to device and patient selection and include:

CLOSURE I included patients with clinically-defined (not imaging-confirmed) TIAs. Recent studies have shown that MRI-negative TIAs are associated with an extremely low risk of subsequent stroke. Inclusion of such patients likely resulted in an underestimation of stroke event rates in both arms of the trial as compared to a population with strokes confirmed by imaging.

The majority of the stroke endpoint events during follow-up appeared to have a determinable origin, suggesting that these patients likely had alternative explanations for their index stroke. Stroke due to atherosclerosis or small vessel disease would not be affected by PFO closure, and therefore would bias the results toward underestimating a potential treatment effect for PFO closure.

• Nearly half of the stroke endpoint events in the PFO closure arm of CLOSURE I appeared to be directly related to the device itself, and about a quarter of these occurred in the first 30 days after implantation.

The committee said that alternative devices (like the GORE Helex Septal Occluder) may offer substantial advantages and fewer complications, thereby increasing the differences between device and medical therapy.

Although device-related complications were considered insignificant, the incidence of new atrial fibrillation (5.7%) and device thrombus (four cases and two cases lead to a subsequent stroke) appear to be associated with recurrent events and more frequent when compared to the Gore Helex Septal Occluder reports.

Medical therapy differed between PFO closure and control arm, thereby introducing a confounding effect on the study endpoints in CLOSURE I.

“We conclude that improved patient selection focused on truly cryptogenic strokes (rather than other causes of stroke or TIA) and use of a device with a low complication rate is needed to determine whether PFO closure is superior to best medical therapy,“ the REDUCE Clinical Study Steering Committee said in a statement.

The group added that “at this point in time there is no compelling reason to alter the current clinical study. It remains imperative, as it has since the beginning of the trial, that we recruit patients with truly cryptogenic stroke (and PFO) to get a definitive answer to these essential questions.“

Gore said that additionally, in June, the FDA also recommended that the REDUCE clinical study continue as originally planned.

The REDUCE clinica study is a prospective, randomized, multi-center, multi-national trial designed to demonstrate safety and effectiveness of the GORE Helex Septal Occluder for PFO closure in patients with history of cryptogenic stroke or imaging-confirmed TIA. The study includes up to 50 investigational sites in the U.S. and Europe.

“These particular trials take quite a bit of time,“ Rhodes said. “So we're looking at possibly finishing in 8 or nine years. We're already two years in. No results from [REDUCE] have been released yet. We're probably going to need a little bit more time before we get any results.“

Omar Ford, 404-262-5546;