UPDATE: FDA panel hands Medtronic a narrow win

A panel of experts yesterday narrowly recommended that the FDA expand indications for all Medtronic (NYSE:MDT) pulse generators already on the market, adding labeling to treat patients at risk of developing new or worsened heart failure due to their need for right ventricular pacing.

The FDA’s Circulatory System Devices Panel voted 4-3, with 1 abstention, that the benefits of programming patients for bi-ventricular pacing using Medtronic pulse generators outweigh the risks.

Dr. David Steinhaus, Medtronic’s general manager for heart failure and medical director for its cardiac rhythm disease management business, told MassDevice.com that he was pleased with the outcome of the advisory panel meeting.

"As the longest-running trial of its kind, Block HF has shown superior long-term outcomes of bi-ventricular pacing for these patients," Steinhaus told us. "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."

Panelists were split on the benefits of programming patients for bi-ventricular pacing because the study to support the expanded indication did not take certain risks into account, including shorter generator life, which involves more generator changes, and an increased risk of infection with every generator change.

"With this study, I don’t think we can really quantify the risks of the [left ventricular dysfunction] all that much … so I think the risks are more significant than they are if we just look at the risks we’ve been presented today," Dr. Patricia Kelly of Community Medical Center in Missoula, Mont., said.

"If you take all people with heart failure and do bi-ventricular pacing, it’s not helpful. If you take all people with left bundle branch block, it’s not helpful. But if you take those with left bundle branch block and heart failure, it’s helpful. We found that many of the these patients are New York Heart Assn. Class I and their annual mortality is only about 6%, so I think that what we have here is a lower-risk population and in that, I’m not sure that the benefit of the procedure outweighs the risk," Dr. Richard Lange of University of Texas in San Antonio added.

Panelists were unanimous that these devices were effective when programmed for bi-ventricular pacing, and voted 6-1 that they are safe.

The expanded indication, which Medtronic announced earlier this year that it would pursue, applies to all of the company’s market-cleared cardiac resynchronization therapy pacemaker and cardiac resynchronization therapy defibrillator devices. Expanded indication was supported by the medtech giant’s Block HF trial.

More than 1 million Americans have AV block, which reduces the heart’s ability to properly function by blocking the electrical signals between its top and bottom chambers, Medtronic said in a press release. While RV pacing helps restore heart function in patients with AV block, studies suggest that in patients with both AV block and LV dysfunction, this type of pacing may escalate the progression of heart failure. Heart failure will cost the U.S. for an estimated $32 billion in 2013, with projections showing a 120% increase in cost by 2030 for a total of $70 billion.

Panelists mull meaning of Block HF trial data

The Block HF study aimed to demonstrate that heart failure patients programmed for bi-ventricular pacing lived longer, notched fewer urgent care visits and experienced significant increase in left ventricular end systolic volume index, as compared with patients programmed for right ventricular pacing.

Medtronic’s CRT-P devices are currently approved for use in patients with marked-to-severe heart failure. The company’s CRT-D devices are currently approved for patients at risk of developing life-threatening ventricular arrhythmias and who have either mild or severe heart failure.

The Medtronic pulse generators in question include both those with defibrillation capabilities and those without, and both types require implantation of at least a right ventricular and a left ventricular lead in order for sensing and pacing to work. The RV lead used with a CRT-D device can also deliver high voltage energy. Clinicians have discretion in whether to implant a right atrial lead for both devices.

"The results of Block HF offer us a potential new treatment paradigm for heart failure patients with AV block," lead investigator Dr. Anne Curtis of the Medicine Dept. at the University at Buffalo School of Medicine and Biomedical Sciences in New York said in the release. "This new approach could fill an unmet need for these patients."

Although the prospective, multi-site, randomized, double-blinded, parallel-controlled Block HF met its primary objective, the FDA had questions about the clinical meaning of increase in left ventricular end systolic volume index demonstrated by the study. LVESVI events accounted for more than half of the primary endpoint events in the Block HF analysis, the agency noted in its executive summary posted ahead of the meeting.

The FDA questioned the significance of a change in LVESVI, because an increased LVESVI does not seem to strongly predict future heart failure urgent care events or death, the panelists said. And, when LVESVI is excluded from an exploratory analysis of Block HF’s primary objective, the magnitude of benefit observed is reduced.

The panel had mixed perspectives on the clinical meaning of an increase of greater than or equal to 15% LVESVI and the impact of LVESVI events on the success of the study. Some panelists said the change in LVESVI was not meaningful, while others said it had limited meaning, but the degree and importance were unclear.

"In terms of the importance of the finding, at least we’re reassured that it goes the way we would expect it to go in terms of evident benefit for bi-ventricular pacing. In terms of, if this were not included, likewise there’s comment from the panel that there is consistency in the signals that we’re seeing that we believe that at least the heart failure finding appears not universally, but the majority take that as a clinically relevant finding," Dr. Richard Page of the University Wisconsin School of Medicine & Public Health in Madison said. "The data set are satisfactory from a statistical standpoint."

Piedmont Heart Institute’s Dr. David Kandzari pointed out that LVESVI has been demonstrated to have clinical meaning in other studies, just not in Block HF.

"I don’t think we can readily discount the role of LV end systolic volume index, as previous trials have shown it to be predictive. It just wasn’t in this trial," Kandzari said. "We would expect a beneficial therapy that could reduce mortality and heart failure to also improve indices that have traditionally been related to heart failure and this is 1 of them. I think if the LV and systolic volume actually worsened, we perhaps wouldn’t be sitting here today."

Medtronic proposed expanding treatment indications for its pace generators to include New York Heart Assn. Class I, II and III heart failure, patients with pacemaker-indicated 1st-, 2nd- or 3rd-degree AV block.

But the panel suggested the FDA remove some of the proposed indications and exclude patients with 1st-degree AV block and documented Wenckebach or PR interval of more than 300 ms when paced at 100 ppm, to ensure that benefits of bi-ventricular programmed pace generators outweigh the risks.

In addition, panelists recommended the FDA ask Medtronic to gather data in a post-approval study of bi-ventricular pacing in its pulse generators that is larger than 300 patients. The post-approval study should include Class I indications, women and minorities, and examine whether patients are optimized in real-world clinical care. It should also address whether epicardial LD leads are being placed and what the results are from that surgical intervention, panelists noted.