Baroreflex Activation Device in CRT-Ineligible Heart Failure Scores Again, FDA Watching

May 17, 2019

SAN FRANCISCO — Neuromodulation management of heart disease continues to advance, as patients with reduced-ejection-fraction heart failure (HFrEF) showed significant quality-of-life and functional gains after 6 months of carotid baroreflex activation therapy (BAT) in a randomized, controlled study.

The patients, not candidates for cardiac resynchronization therapy (CRT), had been implanted with a pacemaker-like pulse generator (Barostim Neo, CVRx), its single-lead extravascular electrode positioned over the carotid sinus.

The treatment is thought to counter the neurohormonal and cardiac remodeling effects of heart failure by inhibiting sympathetic activity and boosting parasympathetic activity, said Michael R. Zile, MD, Medical University of South Carolina, Charleston, when presenting the results here at the Heart Rhythm Society 2019 Scientific Sessions.

"BAT significantly improves patient-centered symptomatic end points — quality of life and exercise capacity," he said.

"These results were supported by objective evidence of a significant reduction in NT-proBNP," the biomarker N-terminal probrain-type natriuretic peptide, which when decreased is thought to predict a good clinical response to HF therapy.

The current 6-month results from the ongoing Baroreflex Activation for Heart Failure (BeAT-HF) trial are consistent with earlier research in HFrEF with the device, which is on the market in Europe but not the United States. American regulators have agreed to consider the Barostim Neo for approval based on BeAT-HF.

The device fills an unmet clinical need for patients with NYHA class 3 HF who "cannot or should not receive" a CRT device, which may amount to half of the population of patients with HFrEF, Zile told | Medscape Cardiology.

"There is a large cohort of patients whom this fits," he said, "and we've shown a successfully positive trial."

Zile said results for the study's primary safety outcome — device- or procedure-related major adverse cardiac and neurologic events — will be reported later, after more patients are accrued, but he hopes that will be a postapproval process.

Although there have been huge advances in pharmacologic therapy of HFrEF aimed at the autonomic nervous system, "we've run into limits as to what we can do with drugs," observed Andrew D. Krahn, MD, University of British Columbia, Vancouver, Canada.

"This I think is the first compelling evidence of a positive electromechanical intervention that makes a difference. The technology, the platform, the ease of implantation, the interaction with other devices — these are all issues that would need to play out as it gets implemented in practice," said Krahn, who isn't associated with BeAT-HF but commented on the study at a briefing for journalists.

"I'm quite enthusiastic hearing about this technology, because in the pediatric world, we really like the idea of nonpharmacologic therapy. And the reason is, it's hard to get kids to actually take medicine consistently," said another observer of the trial, George F. Van Hare, MD, Washington University Medical School, Saint Louis, at the press conference.

Both the BAT and control groups were on optimal medical therapy, taking an average of four heart failure meds each, including beta blockers in 95% of patients.

About 79% of patients in both groups had an implantable cardioverter defibrillator (ICD). Zile said Europe's longer experience with the device has shown no hazard from interaction between the BAT device and ICDs.

The trial included some patients who had failed to respond to CRT, in addition to patients who didn't qualify for the pacing therapy based on electrocardiography. The mean QRS interval across all randomized patients was about 110 ms, far shorter than guideline-specified wide-QRS recommendation for eligibility.

BAT, therefore, "is likely to have some effect" in patients treated with CRT but who don't respond to it, Zile said when interviewed.

But it may also help qualifying patients who decline CRT or whose physicians don't refer them for it. "It's a single electrode, easily placed, with a complication rate that's almost zero," he said. "In those patients who don't choose to receive CRT, this is certainly an alternative therapy which I think will provide substantial symptom relief."

With CRT, "we have run into a bit of a brick wall with our inability to get past about 70% in meaningful response rates, and so that is a huge opportunity and need," Krahn told | Medscape Cardiology. And a patient with an ICD who is offered CRT as an upgrade may see an obstacle in the added risk associated with a left-ventricular lead.

It could turn out that with new implantable neuromodulation devices, "the added risk might be so trivial that the risk decision favors it as a next step in that population," Krahn said, cautioning that such considerations about BAT and CRT are speculation for now.

But Zile doubts that BAT would be appropriate to recommend as an alternative to CRT in patients with a class I indication for the pacing therapy. "I honestly don't think we should go in that direction," he said when interviewed.

"CRT is such a well-established therapy that I'd be hard pressed to suggest that this either delays or removes the need for CRT. We don't have any data to support that."

However, it's an "open question" whether BAT could be effective on top of CRT to enhance its effect, Zile said. "My own sense for this is that it may very well be additive," particularly in patients with less than end-stage disease, like those targeted in BeAT-HF.

Although the study indeed suggests that BAT could emerge as a new option for CRT-ineligible patients with NYHA class 3 heart failure, "we must have a note of caution," observed Sanjeev Saksena, MBBS, MD, RWJ Barnabas Health, Warren, New Jersey, as invited discussant after Zile's formal presentation of BeAT-HF.

"There is no echocardiographic data of remodeling, and we are still awaiting long-term data on device performance and the durability of symptomatic benefit."

Also, "the acceptance in clinical practice is really going to be dependent on what is the true autonomic contribution to heart failure in the stages of heart failure," Saksena said.

"Does it permit correction of the autonomic dysfunction, or modulation? Will it halt the development of the disease at this point, will it delay it, or will it not affect it? Those questions remain to be answered."

Entry to BeAT-HF required that patients be in NYHA class 3 with an LVEF of 35% or less, achieve a 6-minute hall walk (6MHW) distance of 150 to 400 m, and be on stable optimal meds for at least a month.

It entered 162 patients who were a subgroup, those with NT-proBNP levels initially below 1600 pg/mL, of a preceding cohort of 271 patients previously randomized to BAT or a control group. Followed for 6 months, they had shown some significant responses to the treatment.

That subgroup was combined with 102 prospectively entered new patients meeting the same criteria, including the natriuretic-peptide cut off.

The two-stage randomization was part of a methodology the US Food and Drug Administration (FDA) approved for letting the trial proceed in patients selected for being perhaps most likely to respond to the new treatment, Zile explained.

The second randomization of the combined 264-patient cohort assigned 130 to receive and 134 not to receive BAT, with both groups maintaining guideline-based meds. They were followed another 6 months.

BAT With Optimal Meds vs Meds Alone, Between-Group Difference in Change from Baseline to 6 Months
Parameters1 Initial Cohort2 Second Cohort Combined Cohort
NT-proBNP (% change) –17.9 (P = .08) –36.5 (P = .01) –24.6 (P = .004)
MLWHF-QoL3 (point change) –12.1 (P < .001) –17.8 (P < .001) –14.1 (P < .001)
6MHW distance (m change) +60.9 (P < .001) +48.0 (P < .001) +56.5 (P < .001)
1. Values represent differences between BAT and control group in changes from baseline in adjusted analysis
2. Subgroup with baseline NT-proBNP <1600 pg/mL
3. Minnesota Living With Heart Failure–Quality of Life instrument, reduced scores represent improvement

After his formal presentation of BeAT-HF at the meeting, Zile was asked by panelists whether the control group should have received a sham BAT device and procedure, to help avoid influences of a placebo effect.

The use of a sham control group was considered but ruled out, Zile replied, because of the time they would have had to be implanted with the device. "We did not feel that was strictly ethical, because we expected a 2- to 3-year follow-up period."

Zile agreed that the MLWHF questionnaire can provide only subjective information. But, "when you see a quality-of-life change of 14 points, which is double or triple what most consider to be significant in the heart-failure world, I think you overwhelm any chance that this is a placebo effect," he replied.

"When you combine that with the other measures, I think these data are convincing."

BeAT-HF was sponsored by CVRx, from which Zile discloses receiving research grants and honoraria or speaking or consulting fees. Krahn, Van Hare, and Saksena report no relevant disclosures.

Heart Rhythm Society (HRS) 2019 Scientific Sessions: Abstract S-LBCT01-04. Presented May 9, 2019.

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