In a split vote, an advisory panel recommended that the US Food and Drug Administration (FDA) should accept St Jude Medical’s premarket approval application for its Amplatzer patent foramen ovale (PFO) occluder device, which percutaneously delivers a permanent cardiac implant for PFO closure.
The proposed indication is to prevent recurrent ischemic stroke in patients who have had a cryptogenic stroke due to a presumed paradoxical embolism.
The Circulatory System Devices Panel of the FDA Medical Devices Advisory Committee almost unanimously agreed that the device was safe, but the panel members did not all agree that the pivotal RESPECT trial convincingly demonstrated that the device was effective and had a superior risk/benefit profile for this indication.
The 16-member panel voted on three questions:
Is there reasonable assurance that the Amplatzer device is safe for use in patients who meet the criteria specified in the proposed indication?
Is there reasonable assurance that the Amplatzer device is effective for use in patients who meet the criteria specified in the proposed indication?
Do the benefits of the Amplatzer device outweigh the risks for use in patients who meet the criteria specified in the proposed indication?
Fifteen members voted “yes” and one voted “no” for the safety question. However, nine agreed and seven disagreed with the efficacy statement, and 11 agreed while five disagreed with the “greater-benefits-than-risks” statement.
“There is a real clinical need” for this device, noted Dr Jeffrey Brinker (Johns Hopkins Hospital, Baltimore, MD), who voted “yes” for all three questions. Dr Ralph Brindis (Oakland Kaiser Medical Center, CA) voted the same way and said the device should be a level 2b recommendation.
However, Dr Patrick Noonan Jr (Scott and White Memorial Hospital, Temple, TX) voted “no” on the two last questions, since “there was a hint, a signal” of effectiveness, and one “couldn’t say there was a definite benefit.”
Similarly, panel chair Dr Richard Page (University of Wisconsin School of Medicine & Public Health, Madison) who would have voted only if there had been a tie, said he would have voted this way also, for the same reason. Nevertheless, this split vote is “a good place” to be, he said.
The FDA generally follows its panels’ advice, but the strategy of PFO closure for stroke has been considered by the panel before and has proven to be a contentious topic between cardiologists and neurologists.
It has been a long process to get to this point. The RESPECT trial was approved by the FDA in September 2000 to evaluate the safety and efficacy of the device under the investigational device exemption (IDE); the trial was designed to show superiority of the device plus medical therapy vs medical therapy.
The primary trial end point was a composite of nonfatal stroke, postrandomization all-cause mortality, and fatal ischemic stroke. The trial was to be stopped if 25 primary events occurred.
In November 2012 the company submitted a premarket approval application (PMA) requesting marketing approval. After reviewing the application, the FDA convened the current panel.
Seeking Replies to Eight Questions
Clinical significance. In the intention-to-treat (ITT) population, there were nine primary-end-point events in the device group and 16 in the medical-management group; thus superiority was not achieved (relative risk reduction 0.53, 95% CI 0.23–1.22; P=0.157).
There was a big dropout rate. In the initial study until May 20, 2012, the dropout rate was 10.4% in the device group vs 19.1% in the medical-management group.
In the extended follow-up analysis until August 14, 2015, there were 18 primary events in the device group and 24 in the medical-management group, and the dropout rate was 18.2% vs 30.1% in these two groups, respectively.
“The wide confidence interval indicates a great deal of uncertainty, [and] the withdrawal rate was greater than the event rate, which can be concerning,” Dr Scott Evans (Harvard School of Public Health, Boston, MA) pointed out, adding that, nevertheless, it is also clear there was a treatment effect.
“What we are left with is essentially an underpowered trial,” said Dr Michael Lincoff (Cleveland Clinic, OH). The event rates were lower than expected, but what if it were a real effect? “Do we throw away these nine years or try to get understanding?” he asked.
“I would be wary of throwing out” these data, Dr Jeffrey Borer (State University of NY Downstate Medical Center, Brooklyn) said.
“This has taken 15 years; what we have are the data that we have,” Dr Page echoed.
In the extended follow-up, the event rate was 0.65 per 100 patient-years in the device group vs one in 100 patient-years in the medical-management group, which is important to that one patient, several panelists pointed out.
Additional analyses other than ITT. The FDA asked the panelists to comment on additional analyses, such as per-protocol, as-treated, and device-in-place populations.
Dr Ralph D’Agostino (Boston University, MA) said that these secondary analyses did not provide any great further insight. Dr Evans agreed saying, the ITT analysis is the only one that retains confounding factors.
Safety. “Overall, the adverse event rates are really low,” Dr Page summarized. A total of 4.5% of patients (21 of 467 patients) in the device group had a serious adverse event, including two patients who had ischemic stroke.
Brinker observed, “There should be a statement that more than 90% of patients in the device group were on antithrombotic therapy,” a sentiment also expressed by others.
The RESPECT trial showed that 4.2% of subjects in the device group vs 1.9% of those in the medical-management group had atrial fibrillation, which is misleading, according to a few panel members, since invasive procedures often trigger transient atrial fibrillation.
There were 18 patients in the device group and three patients in the medical-management group who had either deep vein thrombosis (DVT) or pulmonary embolism.
PFO closure. A total of 71.3% of the patients who received the device had complete PFO closure and 94% had effective PFO closure. “We assume the device is working. Blocking nearly all flow may be satisfactory, but we don’t know,” Dr Page summarized.
Proposed indications and labeling. These two questions were combined. “The panel generally feels that the proposed indication seems appropriate, although labeling would need to add information about anticoagulation, age perhaps, and presumption of etiology,” Dr Page summarized.
Risk/benefit analysis. The FDA wanted to know if the panel felt that the RESPECT trial supported an important role for PFO in cryptogenic stroke and offered compelling evidence that the device provides a meaningful reduction in risk of recurrent ischemic stroke vs medical therapy. The panel members generally felt that “modest,” “moderate,” or “uncertain” would be more accurate than “important” and “compelling.”
Postapproval study. The panel members stressed that postapproval studies should collect data bout AF, DVT, and—as patients in RESPECT who spoke at the meeting stressed—information about quality of life. There should be teams of neurologists and electrophysiologists.