Striking Benefit From Baroreflex-Activation Device in CRT-Ineligible Class 3 Heart Failure: Early Results

May 19, 2015

BOSTON, MA — As likely new neurohormonal-modulation drug options for heart failure seem to diminish, ablative or device-based neuromodulation techniques are an active research area. Different approaches have shown mixed, often-disappointing results, but a small pilot trial of carotid baroreflex activation therapy (BAT) that uses a tiny electrode surgically placed on the carotid sinus has tentatively showed striking benefits in patients with NYHA class 3 reduced-ejection-fraction (EF) heart failure who couldn't be treated with biventricular pacing[1].

The tantalizing but preliminary benefits in exercise capacity, LVEF, HF hospitalization days, and quality of life were significant overall, even more pronounced in patients who were not eligible for cardiac resynchronization therapy (CRT) and possibly absent in patients with CRT. Those "remarkable" gains, Dr Michael R Zile (Medical University of South Carolina, Charleston), who presented the study here at the Heart Rhythm Society 2015 Scientific Sessions, included a 30% improvement in NYHA class and 12-point improvement in Minnesota Living With Heart Failure Questionnaire (MLWHF) quality-of-life score.

"A decrease [improvement] by 12 points is enormous. For most pharmacologic therapies that are used in heart failure with reduced ejection fraction, you have a decrease of 5 points. In the original CRT studies, it was a decrease of 10 points," Zile told heartwire from Medscape. "This is clearly even larger than that, and that's on top of preexisting [optimal medical] therapies."

Following the primary results reported at the American College of Cardiology 2015 Scientific Sessions, the current 140-patient prespecified analysis by whether patients did or did not get CRT showed that the measured outcomes improved numerically regardless of CRT therapy, "but the significantly different results were all in the no-CRT group. None of the differences in the CRT group made statistical significance," Zile said.

But he and his colleagues aren't concluding that their patients with CRT were BAT nonresponders, because they and their event numbers were too few for conclusive results. "We are just are noting the fact that the no-CRT group seemed to have a more pronounced response."

Patients made the study's no-CRT group, for the most part, because they lacked the recommended QRS and left-bundle-branch block (LBBB) criteria, according to Zile. But at baseline, there were no significant differences between CRT and no-CRT patients in demographics, HF medications, LVEF, functional capacity, or quality-of-life scores.

BAT as performed in this study, he said, "represents a therapy that can be applied to those patients in whom you've exhausted all other therapies, and it can be applied to patients who are not candidates for CRT. So it will fit into a unique position of therapy for this group of symptomatic patients."

Speaking with heartwire , Dr Fred M Kusumoto (Mayo Clinic, Jacksonville, FL) observed that "Those patients who don't qualify for CRT, where we don't have additional treatment options, would be sort of the sweet spot for this device initially." Kusumoto was not involved in the study.

Why didn't CRT patients seem to respond to BAT? Heart failure is associated with increased sympathetic and decreased parasympathetic activity. Stimulation of the carotid baroreceptor spurs reduction of the former and an increase in the latter, Zile explained. One of CRT's effects also seems to be restoration of the two systems, perhaps making it more of a challenge for carotid sinus stimulation to make a difference, he speculated.

Of 140 patients randomized to BAT or no BAT, 45 were on CRT at baseline (including 24 BAT patients) and 95 were no-CRT patients (including 47 assigned to BAT). All were in NYHA class 3 heart failure at baseline despite optimal medications and had an LVEF fraction <35%.

Six-Month Outcomes of Baroreflex Activation Therapy vs Control (Change from Baseline) in HF Patients Without CRT (n=95)

End points Baroreflex activation Control group P
Quality-of-life score* -21.6 +3.5 <0.001
6-min-hall-walk distance (m) +85.5 +3.6 0.003
NT-proBNP (pg/mL) -97 +116 0.03
HF hospitalization (d) -8.9 +0.18 0.05
*Minnesota Living with Heart Failure Questionnaire (reduced score means improvement)

Zile said the device is available in Europe for treatment of heart failure and hypertension, and the Food and Drug Administration has signed off on a US trial with a projected 480 patients at 90 centers that will evaluate BAT in heart failure for CV death and hospitalization for worsening HF. Only no-CRT patients will be included; otherwise, the trial will enter patients like those in the overall pilot trial.

"There's something there," Kusumoto said of the controversy over whether researchers are on the right track with a variety of possible neuromodulation treatments for HF and hypertension—whether it's BAT, spinal-cord stimulation, vagal stimulation, or other techniques. There is "some nugget of truth" in mixed but sometimes-encouraging results so far. But is BAT going to emerge as the best neuromodulating therapy and show improvement in meaningful clinical outcomes? "We don't know."

Zile discloses receiving consulting fees or honoraria and research grants from CVRx. Disclosures for the coauthors are listed in the abstract. Kusumoto had no disclosures.

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