GAITHERSBURG, Md. -- An FDA advisory panel was less than definitive in its advice on expanding approved use of cardiac resynchronization therapy (CRT) devices for patients with less severe heart failure.
The Circulatory System Device Panel of the FDA's Medical Devices Advisory Committee voted 4-3 Tuesday, with one abstention, to recommend expanding the label of Medtronic's CRT pacemaker and defibrillator devices.
Medtronic is seeking FDA go-ahead to treat patients with New York Heart Association (NYHA) Class I or II heart failure and more mild left ventricular function, defined as 50% or less with second- or third-degree atrioventricular (AV) block.
"The data were so consistent, and I thought compelling in terms of marginally the benefit outweighing the risk in this population," panel chair Richard Page, MD, of the University of Wisconsin School of Medicine in Madison, said after casting the tie-breaking vote.
The pacemaker in question is already approved for patients with severe categories of heart disease (NYHA III and IV) with impaired left ventricle function (ejection fraction of 35% or less). The defibrillator in question is indicated for patients with more mild heart failure (NYHA II) and impaired left ventricle function.
Before voting on recommending the devices' approval, Page stripped language in the proposed label allowing the device to be used to treat first-degree AV block and documented Wenckebach periodicity (a type of second-degree AV block). The chair said there were many questions around the efficacy in these patients raised during the panel's afternoon discussion and, after consulting with FDA staff, he felt it was best to strip it out of language to vote on.
A randomized controlled trial of nearly 700 patients showed that fewer of those with mild heart failure receiving biventricular pacing met the trial's primary endpoints -- including death and urgent care -- compared with those who received only right ventricular pacing (45.8% versus 55.8%, respectively), according to FDA data. Endpoints were death, time to first urgent care event for heart failure, or a 15% or greater increase in Left Ventricular End Systolic Volume Index (LVESVI) from post-implant baseline.
However, the trial's success was largely due to changes in LVESVI, FDA reviewers said, and the clinical meaning of changes in that index is unclear. Urgent care visits dropped for biventricular pacing patients compared with the right-ventricular-pacing group (16.0% versus 18.1%) but deaths didn't (5.4% versus 4.4%), the reviewers said.
The panelists in comments Tuesday were conflicted -- just as the FDA was -- in LVESVI's clinical meaning. However, it has been a fair indicator of efficacy in the past, the agency said.
Roughly half of the panelists questioned whether or not class I patients should be removed from the proposed indications. While the trial data support use in least severe patients, panelist David Yuh, MD, of the Yale University School of Medicine, said he would have trouble treating class I patients with a CRT device with biventricular pacing.
Said panelist Patricia Kelly, MD, of the Community Medical Center in Missoula, Mont., "I'm not convinced that the benefit is large enough to outweigh the commutative, long-term risks."
Panelist Richard Lange, MD, of the University of Texas at San Antonio, noted that class I patients are generally healthy and don't immediately die from heart failure. Furthermore, data show the devices only delay hospitalization by 6 months. "We have a lower-risk population, and I'm not sure the benefit outweighs the risks," he said.
Lange, Kelly, and Yuh were the three 'no' votes Tuesday.
Medtronic has proposed a post-approval study should its devices receive the indications it is asking for. The observational study would follow 300 patients for 3 years with 6 month check-ups along the way. It would track all-cause death and first heart failure-related hospitalization as primary endpoints, and all heart failure-related events as a secondary endpoint.
Some panelists wanted more data on certain subpopulations like women, whom the FDA said were under-represented in the study.
The FDA isn't bound to follow to decisions of its advisory committees but usually does.