Chicago, IL - Doctors and regulators concerned about the spike in off-label patent foramen ovale (PFO) closure procedures now have some numbers to fall back on. A research letter appearing in the February 7, 2008 issue of the Journal of the American Medical Association reports that the number of adults undergoing PFO/atrial septal defect (ASD) closure between 1998 and 2004 increased more than 50-fold, despite a lack of randomized clinical-trial evidence proving that PFO closure prevents stroke or transient ischemic attack (TIA) [1].

During this time period, the number of surgical closure procedures has remained relatively stable, while percutaneous procedures increased by at least 50% each year, from 14 in 1998, to 82 in 2001, to 815 in 2004. Percutaneous procedures as of 2004 represented 92.5% of all closure procedures, up from 18.5%.

In an interview with heartwire, lead author on the analysis, cardiology fellow Dr Alexander Opotowsky (University of Pennsylvania, Philadelphia), said that he and his coauthors were primarily interested in PFO-closure procedures, which are "more controversial," but that these could not be differentiated from ASD closures, which share the same ICD-9 code [ICD-9 35.52, "Repair of ASD with prosthesis, closed technique"].

It's a tough situation: these are patients who are having real issues now and are living with the constant anxiety of a possible devastating neurological event at any time.

"While the population represented a combination of PFOs and ASDs, the increase in volume is probably due mostly to PFO closure," he said. "These are adults, making PFOs more likely; the lack of change in surgical volume is also suggestive. There's no way to differentiate, but the reason to think that the majority are PFOs is that there has been no major change in indications for ASD closure. The main change is that we now have a percutaneous option."

The big question, he continued, is whether there is any benefit to closing PFOs at all. "No one really knows. There are good reasons to close ASDs, and the two options are surgical or percutaneous. There's no reason to think that the number of patients requiring closure of an ASD would have increased 50-fold over seven years. Either people are closing ASDs they wouldn't have closed before, or they are closing PFOs percutaneously in people who wouldn't have been referred for surgical closure."

In 2006, the FDA opted to withdraw humanitarian device exemption (HDE) approval for the only two dedicated PFO-closure devices that held it. HDE approval is intended to encourage the development of therapies for rare conditions affecting less than 4000 patients. The FDA maintained that the number of patients receiving PFO-closure devices under the HDE had far outstripped this cutoff and was likely stymieing attempts to reach enrollment targets in the PFO-closure/stroke clinical trials.

Until now, says Opotowsky, "There are not a lot of data out there looking at how often these procedures are being done, which is somewhat surprising. The only hint, other than anecdotal experience, that the numbers might be increasing was that the FDA's actions suggested that there were greater than 4000 PFO closures being performed per year, but beyond that I don't think this has been looked at before."

Opotowsky et al's study does not encompass the time period after HDE was withdrawn for PFO-closure devices, so it sheds no light on whether the FDA's strategy will help boost the number of patients in clinical trials. Opotowsky, however, has his doubts, especially since physicians were using ASD-closure devices to close PFOs before dedicated PFO devices were developed. "There were certain institutions that were very good at encouraging patients to go into trials, and others that would tend to do more off-label procedures, and I don't know how much that has changed. The ASD devices are still available, and so there are still ways around it. So I don't know if the decision to revoke HDE has increased PFO-trial enrollment, and these data can't give evidence to that."

He points out that even if there were separate ICD-9 codes to help track PFO- and ASD-closure procedures separately, it still would be difficult to get an accurate idea of what devices are being used and for what procedures. Some physicians using ASD-closure devices off label have, for regulatory reasons or billing purposes, charted the procedure as an ASD closure. Opotowsky downplayed the potential financial motives for doing the off-label procedures and instead insists that many physicians either are already persuaded that PFO closure prevents strokes or at least believe that the minimal risks of the procedure are worth taking if there is a potential for benefit. And in some cases, he adds, it is patients who come in asking for the procedure.

"It's difficult for clinicians to withhold a relatively safe procedure when the other therapeutic options, namely antiplatelet agents or anticoagulants, have a known, significant failure rate," he explained. "These patients are often young healthy people who have had a stroke and who are petrified of a recurrent event and its potentially devastating consequences. It's difficult to withhold this option, and it's difficult to convince a patient to enter a study that may randomize him to medical therapy when this procedure is available elsewhere. I think this is the main driver. It's not only personal conviction regarding efficacy but also the relatively low perceived downside of the intervention."

He continued: "It's a tough situation: these are patients who are having real issues now and are living with the constant anxiety of a possible devastating neurological event at any time. And then there's a relatively safe device whose benefit is entirely unproven. It's a very difficult decision for patients and doctors to make."

Asked to comment on the study for heartwire, Dr Ziyad Hijazi (Rush University, Chicago, IL) agreed that the increasing number of procedures likely reflects increased use of ASD-closure devices off label. "ASD cases would not have increased in this time period," he explained. "In fact, there has been a decrease in the number of ASD closures, because prior to device approval we had thousands of patients waiting for these devices. When they were approved in 2001, we were doing two or three cases every day. Over the past three years, the number of ASD cases started to go down, because there are only a certain number of people born each year in the US with ASDs, about 5000 cases a year. Essentially we've finished our stock of patients, and we're waiting for new patients to be born with ASDs, then get to about three or four years of age when they can be treated."

If anything, he expects the number of ASD-closure procedures to decline. "But since there are no approved indications for percutaneously PFO closure outside the trials, everyone is using these devices off label."