FDA Panel Supports AV Block Indication for BiV Pacing

October 09, 2013

GAITHERSBURG, MD — Indications for biventricular (BiV) pacing should be extended to include patients with systolic heart failure and first-, second-, or third-degree atrioventricular (AV) block, the FDA's Circulatory System Devices advisory panel decided here yesterday by a thin majority vote.

Their important caveat: BiV pacing in first-degree AV block should be only for patients for whom there is "a verifiable confidence that ventricular pacing is going to be necessary most of the time," said panel chair Dr Richard L Page (University of Wisconsin, Madison) during the proceedings. With the panel having overwhelmingly decided that BiV pacing would be both safe (by a six to one vote) and effective (unanimously), a lone abstention on the third issue of whether benefits would outweigh attendant risks led Page to cast a tie-breaking vote in support of the expanded indication.

Panelist Dr David Kandzari (Piedmont Heart Institute, Atlanta, GA), explaining his abstention to heartwire , said that the pivotal Medtronic-sponsored BLOCK-HF [1,2] trial supporting the extended indication didn't follow patients long enough to capture BiV pacing's inevitable long-term risks. "We just didn't have that kind of information. I think if we saw more compelling reductions in clinical outcomes with the therapy other than just avoidance of heart-failure hospitalization, it would have been a much easier decision," he said. "Even quality of life was not compellingly different."

Page observed for heartwire that "everybody wrestled with risk vs benefit, but at the end of the day, the majority felt that the benefit outweighed the risk."

Why BiV Pacing, and Why Not in All First-Degree AV Block?

BLOCK-HF randomized 691 patients with any degree of AV block, NYHA class 1–3 heart failure, and an LVEF <50% implanted with three-lead devices programmed to either BiV pacing or to standard RV pacing. As previously reported by heartwire , a primary end point composite of all-cause mortality, HF-related urgent care, or a >15% increase in LV end-systolic volume index (LVESVI) fell by a significant one-fourth over three years in the BiV group.

BiV pacemakers have been heretofore reserved for cardiac resynchronization therapy (CRT) in heart-failure patients with prolonged QRS intervals and an LVEF <35%. BiV pacing is now only sometimes used off-label in patients like those in BLOCK-HF, but it's likely to become much more common if the FDA takes the panel's advice on the Medtronic application. If the new BiV niche is approved, clinicians would likely more routinely use BiV pacemakers for AV block whether on-label with Medtronic units or off-label with those of other companies. That goes for BiV pacemakers with or without defibrillating capability, so-called CRT-D and CRT-P devices, respectively, both of which were allowed in BLOCK-HF.

The panel included only patients with first-degree AV block expected to need a lot of RV pacing in the proposed indication because they have the greatest need to avoid it. RV pacing necessarily induces ventricular dyssynchrony and so can exacerbate heart failure, whereas BiV imposes synchrony. But a lower-risk, lower-cost dual-chamber pacemaker could well be enough for patients with first-degree AV block that doesn't require much RV pacing.

Hazard Ratio (95% CI) for BLOCK-HF Primary End Point*, BiV Pacing vs RV Pacing

Group Hazard ratio (95% CI)
CRT-P (n=484) 0.72 (0.57–0.90)
CRT-D (n=207) 0.74 (0.56–1.00)
Total cohort 0.73 (0.59–0.89)
*Composite of all-cause mortality, HF-related urgent care, or a >15% increase in LVESVI
CRT-P=pacing-only cardiac resynchronization therapy device
CRT-D=defibrillating cardiac resynchronization therapy device
Source: FDA document

The FDA questioned whether the third lead's risks, given an estimated attendant complication risk of 6.3%, were worth any benefits when compared with, for example, BLOCK-HF's only slight improvement in HF events; it was a major issue with panelists, too.

Electrophysiologist Dr Patricia A Kelly (Community Medical Center, Missoula, MT) described how BiV pacemakers entail late risks that wouldn't have been evident in the pivotal trial, persuading a number of other panelists. "The risks of the LV lead extend past the peri-implant period. Generator life is shorter, there are more generator changes, there's the attendant increase in risk of infection with every generator change. The risks are more significant than they [seem] if we just look at the risks we've been presented today." Kelly voted "no" to whether the expanded indication's benefits outweigh risks.

Panelist Dr David D Yuh (Yale University, New Haven, CT) agreed and voted the same way. "As a surgeon, having had to put in a lot of epicardial LV leads for coronary sinus leads that have failed, I appreciate the persistent added risk associated with BiV systems in terms of generator changes and lead changes," he said. "The majority of benefit in terms of heart-failure admissions or treatments was realized in the first year, and these more downstream risks I think do accumulate and eventually overwhelm that."

Divisive Primary End Point

The FDA also had reservations about the trial's primary outcome, a benefit driven by improvements by LVESVI, with far less coming from the two clinical components, especially mortality.

Component % Contribution to Composite Primary End Point by BiV vs RV pacing groups in BLOCK-HF

Primary end point components BiV-pacing arm RV-pacing arm
Death 11.9 7.9
HF urgent care 35.0 32.5
LVESVI up >15% 53.1 59.7
Source: FDA document

The panelists were split on whether the LVESVI results were adequately informative. According to Page, the echo parameter can reflect clinical deterioration, and data from BLOCK-HF and other studies "influenced [much of] the panel that it might be of value as a surrogate." And he noted the trial's LVESVI results and two clinical end points went in the same favorable direction. "The concordance of the outcomes among different [patient] groups was striking, and I think for those of us who were persuaded that the benefits outweighed the risks, that was a major factor."

Others on the panel were less convinced. Dr Richard Lange (University of Texas Health Science Center, San Antonio) said the focus should be on the primary end point's clinical components. "The changes in LVESVI are not really clinically relevant." Lange ultimately voted that BiV pacing's risks outweighed its benefits in the expanded indication.

Panelists also questioned the proposed indication's inclusion of patients with NYHA class 1 heart failure, which characterizes HF patients who have become asymptomatic on medications.

The trial included patients in NYHA class 1 and so supports their use of BiV pacing, "but I still have real problems with offering a BiV system, with all the attendant baggage associated with that device compared with single chamber systems, to class 1 patients," Yuh said.

"I'm skeptical that we'd get much bang for the buck," Lange agreed. "The potential complications are high, including the initial implant complications, and subsequent follow-up and reimplantation. And when we look at the outcome of people with NYHA class 1 symptoms, their outcomes are terrific."

Responding to a query from Page, Lange said he would support the exclusion of NYHA class 1 patients from any expanded indications, something the panel ultimately did not do.

Additional meeting materials are available here.

Medtronic sponsored the BLOCK-HF trial and led the expanded-indication case before the FDA and its advisory panel.

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

processing....

Recommendations