GAITHERSBURG, Md. — An FDA advisory committee panel set aside their misgivings and voted overwhelmingly on Tuesday to recommend approval for cardiac contractility modulation (CCM) therapy with Impulse Dynamics’ Optimizer Smart Implantable Pulse Generator.
Meeting to evaluate a product that is the first to receive a “breakthrough device” designation from the FDA, the Circulatory Systems Device Panel voted 12-o (with one abstention) that the benefits of the device in certain heart failure patients outweigh the risks. Members also voted 12-1 that the device was adequately safe and 11-2 that it is effective for the proposed patient population.
CCM therapy uses non-excitatory electrical pulses to increase ventricular contractile strength. Optimizer Smart is proposed for class III heart failure patients not responding to optimal medical therapy who have QRS <120 ms on ECG and left ventricular ejection fraction in the 25%-45% range. Patients without prolonged QRS are not indicated for cardiac resynchronization therapy, which means the Optimizer would fill an unmet clinical need for this population.
The agency usually follows recommendations of its advisory committees but is under no obligation to do so.
Yet despite the overwhelmingly favorable votes, committee members spent most of the meeting picking at the device’s trial data.
“I came to the meeting prepared to vote no,” said John Hirshfeld Jr., MD, of Philadelphia’s University of Pennsylvania Hospital, who said he changed his mind after considering the Optimizer’s breakthrough device status. “Somewhere out there there is a population of people who benefit from this device. We just don’t know who they are.”
The main trial in question was the 160-patient FIX-HF-5C, which showed less decline in mean peak oxygen consumption (VO2) with the device at 24 weeks compared to medical therapy alone — mean peak VO2 was 0.836 mL/kg/min higher with CCM at that point — along with quality of life improvements.
That was with statistical imputation for missing data, however, and no sham to control for the placebo effect.
FIX-HF-5C also had 30% borrowing from FIX-HF-5, an older trial that had failed to meet its primary effectiveness endpoint of ventilatory anaerobic threshold improvement but had provided a signal of greater benefit in patients with ejection fraction 25% or higher.
It’s ultimately unclear what the data really say, the panelists said. Committee member Jeffrey Borer, MD, of State University of New York Downstate Medical Center in Brooklyn, admitted he was “left a little confused.”
“I would say that these data are reasonably convincing that there is an effect, a therapeutic effect, and that it probably means that there is an improvement in some of the clinical outcome variables that we measure,” he said before voting. But, he added quickly, “I have no idea how to relate these findings quantitatively to the clinical outcomes.”
“There are multiple concerns about the different endpoints and what they mean,” said John Somberg, MD, of Rush University Medical Center in Chicago. “I’m going to say that going back and forth all morning added to my confusion about the endpoint.”
There did appear to be consensus that there is likely a subgroup of heart failure patients who benefit from CCM therapy whereas most get nothing at all.
“We have a responsibility to determine who those patients are so we don’t subject 10 patients to the device to derive benefit for one patient,” said Hirshfeld.
Optimizer’s weakness in terms of safety appeared to be the sheer number of leads required: up to five leads in each patient.
Whereas the pulse generator did not increase the risk of all-cause mortality and hospitalizations, there were seven serious adverse events among 74 device recipients — including lead dislodgements and a lead extraction — yielding a point estimate of 9.5% for risk of complications.
“I have a hard time imagining managing these patients with so many leads,” said Kristen Patton, MD, of University of Washington, Seattle. She noted that the device-related complication rate approaching 10% is higher than what is seen with dual-chamber devices.
“Is this effect worth it? It may be a promising therapy, but, my lord, that’s a lot of leads,” Patton said.
The Optimizer Smart is not MRI-compatible, but development of the next iteration of the device will give it MRI-compatibility, according to Daniel Burkhoff, MD, PhD, medical consultant to Impulse Dynamics.
If the device is approved by the FDA, the advisory committee agreed, post-approval studies should be required to have more patients and longer follow-up. Minimums of 3 and 5 years were suggested.