Elsevier

International Journal of Cardiology

Volume 244, 1 October 2017, Pages 229-234
International Journal of Cardiology

Long-term vagal stimulation for heart failure: Eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial

https://doi.org/10.1016/j.ijcard.2017.06.036Get rights and content

Abstract

Background

The NECTAR-HF study evaluated safety and feasibility of vagal nerve stimulation (VNS) for the treatment of heart failure patients. The first six-month randomized phase of the study did not show improvement in left ventricular remodelling in response to VNS. This study reports the 18-month results and provides novel findings aiming to understand the lack of efficacy of VNS, including a new technique assessing the effects of VNS.

Methods

Ninety-six patients were randomized 2:1 to active or inactive VNS for 6 months, thereafter VNS was activated for all patients. The primary safety endpoint was 18-month all-cause mortality.

Results

Ninety-one patients continued in the long-term evaluation with active VNS. The on-therapy survival estimate at 18 months was 95% with a 95% one-sided lower confidence limit of 91%, (better than the predefined criterion).

Left ventricular systolic volume decreased in the crossover group (VNS OFF  ON; 144 ± 37 to 139 ± 40, p < 0.05) after VNS activation; LVESD (5.02 ± 0.77 to 4.96 ± 0.82, p > 0.05) and LVEF (33.2 ± 4.9 to 33.3 ± 6.5, p > 0.05) did not change.

A new technique to detect subtle heart rate changes during Holter recordings, i.e. “heat maps”, revealed that VNS evoked heart rate response in only 13/106 studies (12%) at 6 and 12 months with active VNS.

Conclusions

Although a favourable long-term safety profile was found, improvements in the efficacy endpoints were not seen with VNS. A new technique for detecting acute heart rate responses to VNS suggests that the recruitment of nerve fibres responsible for heart rate changes were substantially lower in NECTAR-HF than in pre-clinical models.

Introduction

Heart failure is associated with signs of increased sympathetic and reduced parasympathetic activation and this autonomic imbalance may contribute to disease progression. Vagal nerve stimulation (VNS) has been found to reduce pathologic remodelling and mortality in animal models of ischemic heart failure [1], [2], [3]. Non-controlled clinical studies showed promising results [4], [5], [6]. The NECTAR-HF trial was designed to test the hypotheses that delivery of right sided VNS is feasible, safe, capable of modulation autonomic tone, and will result in improvement of cardiac function [7]. Patients were randomized to either active VNS or inactive VNS during the first six months of the trial. Active VNS failed to demonstrate a greater improvement in cardiac remodelling and function over that of inactive control therapy, although quality of life measures improved more in patients receiving active VNS [8].

The present study had two goals: first to report on the second phase of the NECTAR-HF trial, designed to test the safety and feasibility of VNS up to 18 months, second to describe novel findings including a novel methodology to assess the effects of VNS aiming to better understand the causes of a non-beneficial outcome of the primary endpoint.

Section snippets

Study design

The NECTAR-HF study design has been published previously (www.clinicaltrials.gov, NCT01385176) [7]. Briefly, 96 patients in NYHA functional class II or III and a documented LV ejection fraction (LVEF) of ≤ 35%, with a LV end diastolic dimension (LVEDD) of ≥ 55 mm were enrolled in the study. The study consisted of two phases. The first phase was a 6 month randomized controlled evaluation of patients receiving active VNS versus an implanted but inactive VNS system. The second phase of the trial,

Follow-up and disposition of patients

Ninety-six patients were enrolled in the six-month primary phase of the study. The baseline characteristics are summarized in Table 1. Baseline characteristic by randomization were previously published [8]. Ischemic cardiomyopathy was present in 67% of all enrolled patients, and 10% had implanted CRT devices. One patient died after implant, but death occurred prior to randomization. Sixty-three patients were randomized to VNS-ON and 32 to VNS-OFF. Three patients died and one was lost to follow

Discussion

Although neuromodulation for heart failure has a very strong rationale and promising preliminary data were available [13], the two controlled clinical studies with vagal stimulation failed to show significant effectiveness [8], [14]. Specifically, NECTAR-HF found no improvement in the primary efficacy endpoint, LVESD, when comparing active to inactive VNS groups at 6 months [8]. Consistent with this, LVESD did not decrease when VNS was activated in the crossover group (VNS OFF  ON; 6–18 months).

Conclusions

A favourable adverse event profile and an acceptable survival rate at 18 months were seen during long-term evaluation of VNS in patients with heart failure, enrolled in NECTAR-HF. Improvement in the primary efficacy endpoint, LVESD, was not found when comparing active to inactive VNS groups at 6 months or when VNS was activated in the control group (6–18 months within group change). Reasons for a lack of VNS benefit may include absence of active inflammation in the enrolled patients and

Funding

This study was funded fully by Boston Scientific Corporation, 300 Boston Scientific Way, Marlborough, MA 01752-1234.

Conflict of interest

Faiez Zannad receives honoraria from Air Liquide, Bayer, Biomérieux, Biotronik, Boston Scientific, CVCRx, Janssen, Novartis, Pfizer, Resmed, Roche Diagnostics, Sanofi, Servier, St Jude, Takeda, speaker fees from Mitsubishi and owns stocks at CVCT and CardioRenal diagnosticS; Gaetano M De Ferrari receives honoraria from Amgen, Boston Scientific, Menarini and Merck; Anton E Tuinenburg receives honoraria from Boston Scientific; D Jay Wright receives honoraria from Boston Scientific, Medtronic, St

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