PFO clinical trial results: more questions than answers

By Larry Haimovitch

Medical Device Daily Contributing Writer

October 30, 2012

MIAMI BEACH — The release of data from two key patent foramen ovale (PFO) clinical trials was one of the most widely anticipated events here last week.

A PFO is defined as a congenital, flap-like opening between the atrial septum. The prevalence of a PFO is up to three times greater in the population of patients that suffers from a cryptogenic (no identified cause) stroke. It has been estimated that approximately 40% of ischemic strokes are cryptogenic.

One of the key points that was emphasized on several occasions here this past week is that cryptogenic stroke victims are almost always quite young (less than 55 years old) and that a stroke at this age is especially devastating because they are in the prime of their life. Determining what is the appropriate course of intervention, medical management to thin the blood or a device to close the flap, is thus even more important in these patients than in an elderly stroke population.

The excitement for the data was illustrated by the fact that there were several sessions devoted to this controversial and highly debated topic before the final release of the data last Thursday. Then, there was a lengthy session that focused on the detailed analysis and discussion after the data was released, with numerous physicians weighing in with their expertise and opinions.

The Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) tiral and the European PC trial were presented at the Late Breaking Clinical Trial session on Thursday. Supported by St. Jude Medical (St. Paul, Minnesota), they were designed to answer the hotly debated question of whether a device implant is safer and more effective than medical management for patients who have had a cryptogenic stroke and want to prevent a recurrent stroke.

And, when it was all said and done by the end of last week, this long simmering debate will likely continue to rage as both trials failed to meet their primary endpoints. Conversely, there was more than enough positive aspects to the trials and therefore glimmers of hope that maybe there is indeed a role for a device-based approach in the management of patients who have had a cryptogenic stroke, have a documented PFO and are trying to avoid recurrent strokes.

The more widely recognized and rigorous North America-based RESPECT trial randomized 980 patients over the course of eight years to either PFO closure with the Amplatzer PFO Occluder or best medical management. Although showing a 46.6% reduction of stroke in favor of the device, this was not statistically significant vs. medical management alone and therefore the trial missed its primary endpoint.

The smaller mostly European PC trial also failed to meet its primary endpoint, the reduction in ischemic and bleeding events. There was unanimity that with only 414 patients in the trial, it was significantly underpowered and almost certainly doomed to fail. However, several comments also echoed the attitude toward RESPECT, i.e., the trial did fail but showed that PFO closure in certain patients appears to have merit.

The failure of these two trials mirrors the results of another large (909 patients) randomized multi-center trial called CLOSURE-1, which was sponsored by now defunct NMT Medical. That trial, with preliminary data released in June 2010, did not achieve its primary endpoint as device closure with NMT's STARFlex technology was not superior to best medical therapy. However, the trial did show that closure provided a small, but not statistically significant, benefit over current best medical therapy.

So, whereas there was tremendous anticipation that these two trials would finally resolve a controversy that has been going on for about a decade or even more, this did not happen. Indeed, the cardiology community is now even more uncertain about how to best manage these patients.

At a TCT sponsored press conference, several physicians expressed their frustration with the equivocal results. For example, Ted Feldman, MD, a interventional cardiologist at NorthShore University HealthSystem (Evanston, Illinois) said that the management of cryptogenic stroke patients was "a tangled web of yarn before these data were available and now it is even more so." Further, he said "we cannot just look at the statistics provided by these two trials but we need to look at each patient and then decide what is right for them."

In an interview with MDD, Feldman cited a real life example he recently faced – a young woman who had had a cryptogenic, PFO-related stroke and now wanted to have a child. Medical management would be contraindicated because of a bleeding risk during delivery so Feldman recommended PFO closure.

Feldman further commented that perhaps REDUCE, another large randomized trial which is currently in the enrollment phase, might shed further light on this topic. This trial, sponsored by W. L. Gore (Flagstaff, Arizona), uses the HELEX Septal Occluder and some physicians believe that the superiority of this device, coupled with a different study design, may yet support the superiority of PFO closure. Unfortunately, data from REDUCE is not unlikely to be available for about three years.

In another interview, Alice Jacobs, MD, director of the cardiac catheterization laboratory at the Boston University School of Medicine (Boston), said that after CLOSURE 1 data was released her hospital stopped performing PFO closure. However, she was very encouraged by the excellent safety data of the Amplatzer PFO occluder and said that she could now see a subset of patients that she would recommend closure over medical management. However, Jacobs cautioned, that "the data was clearly not positive enough to warrant inclusion in any guidelines for the management of cryptogenic stroke."

Another opinion came from David Faxon, MD, an interventional cardiologist at Brigham and Women's Hospital (Boston) who said the results from RESPECT were "tantalizing though clearly not definitive." Further he added that "they're probably not going to change clinical practice at this point in time."

Whereas some physicians expressed disappointment at the outcome, John Carroll, MD, University of Colorado Medical School (Denver), the lead cardiology investigator of the RESPECT study, was pleased with the results. He said that "the totality of the evidence now supports the use of PFO closure in this group of patients at risk for a second stroke following a cryptogenic stroke. Moreover, RESPECT "provides an amazing amount of evidence-based medicine to the field."

There was considerable discussion about whether the data are strong enough to support an FDA approval and while no consensus was attained, it seems unlikely, with three failed trials, that FDA will approve it. It is worth noting that the PROTECT-AF trial for the Boston Scientific (Natick, Massachusetts) Watchman left atrial appendage closure device met its primary endpoint but an FDA advisory committee voted against approval. Boston Sci is now in the midst of enrolling for a second confirmatory study.

Another important issue is how these results will affect the off-label use of PFO closure devices. The best "guesstimates" is that there are roughly 5,000 to 10,000 off-label PFO procedures per year in the U.S. That number has been declining in the past couple of years, due to the failure of the CLOSURE 1 trial and greater scrutiny by private insurance carriers. It is now anyone's guess how these latest trial results will affect its off label usage.

TCT 2012

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