BeAT-HF: Baroreflex Activation Therapy Improves Outcomes in Subset of HF Patients

SAN FRANCISCO, CA—In patients with heart failure with reduced ejection fraction (HFrEF) who are not candidates for cardiac resynchronization therapy, baroreflex activation therapy (BAT) provides at least short-term benefits, results from the BeAT-HF trial show.

Modulating the autonomic nervous system in this way—on top of optimal medical therapy—improved quality of life and exercise capacity and allowed most patients to remain free from major adverse neurological and cardiovascular events (MANCE) through 6 months of follow-up when compared with medical therapy alone. Michael Zile, MD (Medical University of South Carolina, Charleston), reported the results here last week at the Heart Rhythm Society (HRS) 2019 Scientific Sessions.

Those differences were seen despite an increase in medication use in the control arm, he noted.

“To our knowledge, this is the first successful pivotal trial of a device-based neuromodulation therapy for patients with heart failure and reduced ejection fraction,” Zile said during his presentation.

He added later at a news conference that BAT fills an unmet need for patients who have NYHA class III symptoms and are not candidates for cardiac resynchronization therapy, which he estimated would encompass 40% to 50% of the HFrEF population.

Commenting for TCTMD, Clyde Yancy, MD (Northwestern Medicine, Chicago, IL), said the results are encouraging and raise the prospect of being able to intervene on patients with less-severe heart failure to prevent them from progressing.

“If there is a way that we can now truly target the autonomic nervous system and if the benefit of targeting is not for advanced disease but to prevent people from progressing, then I think that really defines a clinical niche that we haven’t staked out in the past,” Yancy said. “So I’ll be curious to see how this unfolds.”

If there is a way that we can now truly target the autonomic nervous system and if the benefit of targeting is not for advanced disease but to prevent people from progressing, then I think that really defines a clinical niche that we haven’t staked out in the past. Clyde Yancy

Noting that prior attempts at manipulating the autonomic nervous system to improve heart failure outcomes have failed in the past, however, he remained circumspect when discussing the potential impact of the findings right now. He cited lingering questions about the durability of the treatment effects, complications, potential off-target effects, the impact on morbidity and mortality over the longer term, cost-effectiveness, and how patients would feel about this type of intervention.

Nevertheless, Yancy said, “the data look promising.”

Defining an ‘Intended Use Population’

BeAT-HF is a phase III, multicenter, randomized trial that was designed and performed in collaboration with the US Food and Drug Administration through its “Breakthrough Therapy” program. The trial initially randomized 271 patients with NYHA class III symptoms; an LVEF of ≤ 35%; and either an N-terminal pro-B-type natriuretic peptide (NT-proBNP) of ≥ 1,600 pg/mL or a prior heart failure hospitalization to BAT plus optimal medical therapy or optimal medical therapy alone. All patients were ineligible for cardiac resynchronization therapy.

BAT was delivered using the Barostim Neo device (CVRx), which consists of a subcutaneously implanted pulse generator connected to a 2-mm electrode placed on the carotid sinus. Pulses stimulate the baroreceptors, generating a signal that results in reduced sympathetic activity and enhanced parasympathetic activity.

Patients were followed for 6 months to assess three primary effectiveness endpoints—6-minute walk distance, quality of life on the Minnesota Living With Heart Failure questionnaire, and NT-proBNP level–along with MANCE-free rate, the primary safety endpoint.

In the initial analysis, BAT improved all outcomes except for NT-proBNP level, which declined to a similar extent in both arms (P = 0.66). The MANCE-free rate of 94% exceeded the performance goal of 85%, the improvement in quality of life was 12.6 points greater in the BAT arm, and walk distance—which improved with BAT but declined in the control group—was 60.9 m better with the device-based intervention (P < 0.001 for all).

The lack of a difference in NT-proBNP levels was unexpected, Zile said, because a previous phase II study showed a large reduction in levels with BAT, a discrepancy the FDA encouraged the investigators to explore.

Discussing those efforts at HRS, Zile said a key difference between the trials was that BeAT-HF required patients to have either a prior heart failure hospitalization or an elevated NT-proBNP to be included, whereas the phase II trial had no such requirement. He also noted that in BeAT-HF, patients with an NT-proBNP of 1,600 pg/mL or higher had more advanced disease and, on average, were older and had a lower LVEF, a shorter walk distance, more diuretic use, and a greater number of previous heart failure hospitalizations.

Evidence from other studies suggests, however, that heart failure therapies work better in patients with lower—not higher—NT-proBNP levels, Zile said. So, in collaboration with the FDA, the researchers defined an “intended use population” of patients with an NT-proBNP level below 1,600 pg/mL and enrolled a second group of 102 patients who came in under that bar. They then performed additional analyses on a combined cohort of 264 patients—the 102 new ones and 162 from the original cohort with lower NT-proBNP levels.

In both the new cohort and the combined cohort, adding BAT to optimal medical therapy resulted in a significant reduction in NT-proBNP levels as well as the other benefits seen in the initial analyses. In the combined cohort, the reduction was an absolute 24.6% greater in the BAT arm (P = 0.004). “If you look in other populations of heart failure with a reduced ejection fraction, [this] predicts a marked decrease in morbidity and mortality,” Zile said at the news conference, noting that follow-up will continue see if that is borne out in this trial.

Clinically Valuable, but Not a Game Changer

Zile said that even as follow-up and enrollment continue, CVRx has already submitted the premarket approval application for the Barostim Neo device for this purpose to the FDA.

And the device will have clinical value if it is approved, according to Shaline Rao, MD (NYU Langone Health, New York, NY), who was not involved with the study. She said it was important that BeAT-HF showed that BAT provided benefits on top of optimal medical therapy for patients with NYHA class III heart failure—who are symptomatic but recoverable and stand to gain from this type of approach.

“You don’t want to have this in all-comers because medical therapy is very effective. You would overimplant and it would be hard to tease out the true benefit of this device. In that regard, I think they narrowed it down to the right group,” Rao commented to TCTMD, estimating that about two-thirds of patients who would eligible to receive the device would be willing to undergo to undergo implantation.

Rao said that if the device is eventually approved, it would not necessarily be a game changer for the treatment of heart failure because of the existence of effective medical therapies.

I think what we’re looking at is: how do you move the margin on those people who don’t get better despite medical therapy? And are there ways for us to be targeting neurohormonal cascades in ways that we aren’t already? Shaline Rao

“But we do still see persistent heart failure above and beyond medical therapy. We’re still transplanting patients. We’re still putting left ventricular assist devices in patients,” she said. “So I think what we’re looking at is: how do you move the margin on those people who don’t get better despite medical therapy? And are there ways for us to be targeting neurohormonal cascades in ways that we aren’t already?”

If BAT can keep patients at home and out of the hospital, she said, it would be clinically valuable.

“I do think there’s a role. It’s a smaller subset of heart failure where this is going to be appropriate, but given those are also high healthcare utilizers [with a] high cost to the system, this would be a potentially cost-effective way of managing these patients,” Rao said.

Yancy put the findings into the context of a larger trend occurring in the field of heart failure in recent years, with a reemergence of interest that has given rise to some successes following years of disappointing trial results.

“I’m pretty enthused that the field has been reinvigorated, and this is another example of that reinvigoration . . . . So it’s a good day to be involved in heart failure. A lot of things are being discussed, contemplated, pursued. If the end result from this wave of excitement is another set of effective therapies, then that will be for the good,” he said.