May 26, 2012 (Silver Spring, Maryland) — More studies of atrial septal defect (ASD) occluders are needed to better understand the incidence and causes of rare life-threatening adverse events related to the devices, an FDAadvisory panel concluded at its May 24 meeting [1].
At the meeting, the agency's Circulatory System Devices Advisory Committee had a wide-ranging and complex discussion on how the agency, manufacturers, researchers, and clinicians can better understand why a small number of ASD occluders are malfunctioning and which patients are most at risk for these rare events. "There's a lot we don't know, and this is an opportunity to better define the space. If today has been anything, it's been instructive in how many unanswered questions there are in the field," panel chair Dr Clyde Yancy (Northwestern University, Chicago, IL) said.
St Jude's Amplatzer septal occluder was first introduced to the US market in 2001, followed by the Gore Helex in 2006. As reported by heartwire , erosions of the device through cardiac tissue, embolizations requiring percutaneous or surgical retrieval, device fractures, and thrombus formation on the device are among the adverse events reported in the scientific literature and the FDA's Manufacturer and User Facility Device Experience Database (MAUDE). While the risk of some of these problems was revealed in the premarket studies, other issues, most notably erosion, are relatively new phenomena that the manufacturers and specialists who implant the devices are still trying to understand.
The panel agreed that St Jude and the FDA should develop a new study of the Amplatzer, with particular attention paid to understanding why the device, two nitinol mesh disks that cover either side of the septal defect, sometimes begins to erode through the cardiac tissue. So far, 705 medical device reports about the Amplatzer have been logged in MAUDE, including 26 fatal events. Embolization is the most common problem, constituting about 47% of all the Amplatzer-related events, but there have been 109 reports of erosions, including 13 linked to patient deaths. Signs and symptoms of erosion include cardiac tamponade, pericardial effusion, hemodynamic compromise, chest pain, shortness of breath, syncope, and sudden cardiac death.
Statistician Dr Kevin Kip (University of South Florida, Tampa) insisted that the best way to understand the cause of these erosions would be a case-control study that retrospectively compares the patients who suffer these erosions with Amplatzer recipients who do not. He said he did not expect much useful information to come from a prospective registry study, even though this was the study type most favored by the professional societies whose representatives presented at the meeting, including the American Heart Association, American College of Cardiology, Society of Cardiovascular Angiography and Intervention, and Society of Thoracic Surgeons.
"The incidence rates [of adverse events], while being academically important, are of less importance. Let's be real; it's a rare event no matter what the incidence is, so having that precise estimate is clearly of less value than the etiological question and the mechanism, which by all accounts, is [unknown]," Kip said.
"I'm surprised that all of the major societies have all essentially proposed a prospective registry, which will be very time-[consuming] and highly inefficient and will not get those answers quickly. It has to be a case-type study," he said. "All the action is in the cases, so you need a design that has cases, meaning the vast majority has to be retrospective, as in what's happened over the past 10 years. There's not going to be that many cases that accumulate over the coming years. So in order to get at etiology, which is the best chance at reducing the incidents in the future from what's learned from that, you've got to use a case approach, and I'm leaning toward a case-control design."
Most of the panel agreed that a similar case-control study of Gore's Helex device is not yet necessary because, so far, there have not been any reported cases of erosion with that device, and only one death, most likely caused by a perforation, linked to the Helex appears in the MAUDE reports. There are 150 adverse-event reports for the Helex in MAUDE and, as with the Amplatzer, the most frequently reported problem is device embolization (38% of reports). However, there have been six reports of Helex devices fracturing, whereas there has only been one such report with the Amplatzer.
While most of the panelists said they did not see a need for a case-control study of the Helex, some of the panelists disagreed, noting that the Helex may have yielded fewer adverse-event reports than the Amplatzer simply because it has not been on the market nearly as long. Yancy said, "Just from a position of equity, and understanding that we still have an incomplete database on both devices--but especially on Helex, because the use hasn't been the same--the concerns we have about the fractures shouldn't be any less simply because the manifestations haven't been as dramatic. It's still a concern. So if there's enough imperative based on our concerns over erosion for an [FDA-mandated, manufacturer-sponsored] study for the Amplatzer device, I see very little [reason], based on the concerns about fracture, not to do the same things with Helex."
Despite Kip's contention that registry data will not yield much new useful information about ASD occluder adverse events, the panel generally favored the creation of a registry that captures event incidence rates. They did not come to a consensus on exactly how that registry would be funded and administered, but the professional societies offered several options for this registry, such as the American College of Cardiology Foundation's National Cardiovascular Data Registry, which now includes the Improving Pediatric and Adult Congenital Treatment(IMPACT) registry, that could be adapted to track events with ASD occluders.
Statistician Dr Greg Wellenius (Brown University, Providence, RI) explained that "if you want to estimate the incidence of a rare event, then I think you have to use a registry study. Any type of case-control study . . . is not going to give you a measure of the incidence of rare events." He suggested that it wouldn't necessarily have to be an enormous registry. "What you need is very careful monitoring of the outcomes and adjudication of outcomes. That's going to answer the question of the incidence rates of the events."
The panel also agreed that both St Jude and Gore should continue the postmarket studies of their respective devices that they have already begun. St Jude is conducting a prospective, nonrandomized, multisite, single-arm clinical study in about 100 patients to evaluate the incidence of hemodynamic compromise and to obtain survival data on patients implanted with the Amplatzer for at least two years postimplantation. Gore is following the 50 subjects enrolled in its continued-access study of the Helex, plus another 200 subjects, for at least five years.
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