Long-term vagal stimulation for heart failure: Eighteen month results from the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) trial
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
References (25)
- et al.
Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial
J. Card. Fail.
(2014) - et al.
Vagus nerve stimulation for the treatment of heart failure: the INOVATE-HF trial
J. Am. Coll. Cardiol.
(2016) - et al.
Complications of vagal nerve stimulation for drug-resistant epilepsy: a single center longitudinal study of 143 patients
Seizure
(2013) - et al.
Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension
J. Am. Coll. Cardiol.
(1996) - et al.
Vagus nerve stimulation improves left ventricular function in a canine model of chronic heart failure
Eur. J. Heart Fail.
(2013) - et al.
Vagal nerve stimulation markedly improves long-term survival after chronic heart failure in rats
Circulation
(2004) Vagal stimulation in heart failure
J. Cardiovasc. Transl. Res.
(2014)- et al.
Long term vagal stimulation in patients with advanced heart failure: first experience in man
Eur. J. Heart Fail.
(2008) - et al.
Chronic vagus nerve stimulation: a new and promising therapeutic approach for chronic heart failure
Eur. Heart J.
(2011) - et al.
Rationale and study design of the NEuroCardiac TherApy foR Heart Failure Study: NECTAR-HF
Eur. J. Heart Fail.
(2014)
Chronic vagal stimulation for the treatment of low ejection fraction heart failure: results of the NEural Cardiac TherApy foR Heart Failure (NECTAR-HF) randomized controlled trial
Eur. Heart J.
Vagal nerve stimulation evoked heart rate changes and protection from cardiac remodeling
J. Cardiovasc. Transl. Res.
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