Advisory Panel Splits Over Expanded Indications for Medtronic’s CRT Line

A divided Circulatory System Devices Panel grappled with fine distinctions in risk-benefit tradeoffs before voting to expand use of two Medtronic heart failure products to treat patients with atrial ventricular block and reduced heart function.

The question on the table Tuesday was whether Medtronic’s Cardiac Resynchronization Therapy-Pacemaker (CRT-P) and Cardiac Resynchronization Therapy-Defibrillator (CRT-D) should be indicated for use in patients meeting all of the following criteria:

• Class I or IIa pacing indication;
• New York Heart Association Class I, II or III; and
• Left Ventricular Ejection Fraction of at least 50 percent.

Patients who meet those criteria would also need to meet one of the following:

• Second or third degree atrioventricular (AV) block;
• First degree AV block with pacemaker syndrome; or
• Documented Wenckebach or PR interval of more than 300 ms when paced at 100 ppm.

The panel voted 6-1 that CRT-D and CRT-P are safe, and unanimously that they are effective for the proposed indications. However, members split 3-3, with one abstention, that the benefits outweigh risks. Panel chairman Richard Page, University of Wisconsin School of Medicine, stepped in to provid a tie-breaking vote on the third question.

The new indications are supported by the BLOCK HF study, which examined whether biventricular pacing via the CRT product line was superior to conventional right ventricular pacing. The 10-year, 918-patient study found a 27 percent reduction in deaths and hospitalizations in patients treated with CRT-D or CRT-P.

All of the panelists agreed that the randomized, blinded study represented an ideal clinical trial.

However, the FDA and panelists expressed some concerns about the data. For example, the study found patients treated with CRT experienced an increase in left ventricular end systolic volume, or LVESV, which is seen as a marker for improved heart function. But LVESV improvements did not correlate to reduced heart failure or death rates in the trial, said Brian Lewis, a reviewer in the cardiac division of CDRH’s Office of Device Evaluation. Moreover, rates of adverse events and deaths in the CRT group after the first year were about the same as those in patients treated with right ventricular pacing.

Add in the risk of complications from the CRT surgery itself and “I’m skeptical we’ll get much bang for the buck,” said panelist Richard Lange, University of Texas. Lange reasoned the complication rate would be too high and the improvement to patient prognosis too modest to support the expanded indication into Class I patients.

Patients Have Few Options

Still, most panelists felt even a modest improvement could be helpful to heart failure patients.

“We’re at a stage where we don’t have many cures; we’re talking more about palliative and about incremental changes,” said panelist David Naftel of the University of Alabama at Birmingham. While he voted to recommend the new indications, he also expressed concern that the benefits were limited and occurred mainly during the first year.

The BLOCK HF trial also came under criticism for its heavy representation of men versus women. All four subgroups were at least 70 percent male, with the CRT-D patient cohort comprising 82 percent men.

Patient representative Kristine Mattivi of the Colorado Foundation for Medical Care acknowledged the “gold standard”-level quality of the study, but said she was miffed by the lack of female subjects. “I find it interesting that, over the course of 10 years, there’s a significant population not often seen in clinical settings and yet there are others that are overrepresented,” she told the panel. She said she’d particularly like to see more older women with pacemakers in any postmarket study.

Medtronic expressed optimism about the broader indication following the meeting. “As the regulatory process continues, we look forward to working with the FDA to expand the use of our CRT devices to treat this specific patient population,” said David Steinhaus, vice president and general manager for heart failure and medical director of Medtronic’s cardiac rhythm management business. — Elizabeth Orr