Comparison of symptomatic and functional responses to vagus nerve stimulation in ANTHEM‐HF, INOVATE‐HF, and NECTAR‐HF

Abstract

Aims Clinical studies of vagal nerve stimulation (VNS) for heart failure with reduced ejection fraction have had mixed results to date. We sought to compare VNS delivery and associated changes in symptoms and function in autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure (ANTHEM‐HF), increase of vagal tone in heart failure (INOVATE‐HF), and neural cardiac therapy for heart failure (NECTAR‐HF) for hypothesis generation. Methods and results Descriptive statistics were used to analyse data from the public domain for differences in proportions using Pearson's chi‐square test, differences in mean values using Student's unpaired t‐test, and differences in changes of mean values using two‐sample t‐tests. Guideline‐directed medical therapy recommendations were similar across studies. Fewer patients were in New York Heart Association 3, and baseline heart rate (HR) was higher in ANTHEM‐HF. In INOVATE‐HF, VNS was aimed at peripheral neural targets, using closed‐loop delivery that required synchronization of VNS to R‐wave sensing by an intracardiac lead. Pulse frequency was low (1–2 Hz) because of a timing schedule allowing ≤3 pulses of VNS following at most 25% of detected R waves. NECTAR‐HF and ANTHEM‐HF used open‐loop VNS delivery (i.e. independent of any external signal) aimed at both central and peripheral targets. In NECTAR‐HF, VNS delivery at 20 Hz caused off‐target effects that limited VNS up‐titration in a majority of patients. In ANTHEM‐HF, VNS delivery at 10 Hz allowed up‐titration until changes in HR dynamics were confirmed. Six months after VNS titration, significant improvements in both HR and HR variability occurred only in ANTHEM‐HF. When ANTHEM‐HF and NECTAR‐HF were compared, greater improvements from baseline were observed in ANTHEM‐HF in standard deviation in normal‐to‐normal R‐R intervals (94 ± 26 to 111 ± 50 vs. 146 ± 48 to 130 ± 52 ms; P < 0.001), left ventricular ejection fraction (32 ± 7 to 37 ± 0.4 vs. 31 ± 6 to 33 ± 6; P < 0.05), and Minnesota Living with Heart Failure mean score (40 ± 14 to 21 ± 10 vs. 44 ± 22 to 36 ± 21; P < 0.002). When compared with INOVATE‐HF, greater improvement in 6‐min walk distance was observed in ANTHEM‐HF (287 ± 66 to 346 ± 78 vs. 304 ± 111 to 334 ± 111 m; P < 0.04). Conclusions In this post‐hoc analysis, differences in patient demographics were seen and may have caused the differential responses in symptoms and function observed in association with VNS. Major differences in technology platforms, neural targets, VNS delivery, and HR and HR variability responses could have also potentially played a very important role. Further study is underway in a randomized controlled trial with these considerations in mind.

Autonomic Modulation for Cardiovascular Disease

“…At these stimulation parameters, it is hypothesized that afferent fibers were preferentially activated, rather than efferent motor fibers, which may, in part, explain the lack of efficacy observed (De Ferrari et al, 2017;Anand et al, 2020).…”

“…Given the relevance of autonomic dysregulation in the development and progression of heart failure and arrhythmias, trials exploring the efficacy and safety of VNS for cardiovascular disease have received significant national attention since the initial report of its use for heart failure in 2008 ( Schwartz et al, 2008 ; De Ferrari et al, 2011 ; Premchand et al, 2014 ; Gold et al, 2016 ; De Ferrari et al, 2017 ). Initial clinical trials of VNS, in combination with medical therapy, for CHF demonstrated mixed results, attributed to variation in study design, sidedness of stimulation, and vagal nerve stimulation protocols ( Anand et al, 2020 ). Importantly, VNS protocols represent the total dose of “therapy” delivered to the patient as a function of current intensity, frequency, pulse width, and duty cycle (time on vs. off), and thus are hypothesized to have a substantial impact on efficacy of therapy, as well as side effects ( Anand et al, 2020 ).…”

“…Initial clinical trials of VNS, in combination with medical therapy, for CHF demonstrated mixed results, attributed to variation in study design, sidedness of stimulation, and vagal nerve stimulation protocols ( Anand et al, 2020 ). Importantly, VNS protocols represent the total dose of “therapy” delivered to the patient as a function of current intensity, frequency, pulse width, and duty cycle (time on vs. off), and thus are hypothesized to have a substantial impact on efficacy of therapy, as well as side effects ( Anand et al, 2020 ).…”

Neuromodulation Therapy in Heart Failure: Combined Use of Drugs and Devices

“…The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in HF (ANTHEM-HF) trial was able to show a beneficial effect of VNS, while the Increase of Vagal Tone in Chronic HF (INOVATE-HF) and Neural Cardiac Therapy for HF (NECTAR-HF) trials revealed no significant improvement in HF. [68][69][70][71] It is worth noting that each of these trials used a different stimulation protocol and titration of output. In the ANTHEM-HF trial, the titration of output was based upon the confirmation of autonomic engagement using changes in HR, 68 while, in the other two studies, no significant reduction was observed in HR.…”

Auricular Vagus Neuromodulation – A Systematic Review on Quality of Evidence and Clinical Effects

“…Implantable VNS is believed to recruit A and B fibers (Krahl, 2012) for its anti-epileptic effects and parasympathetic efferent B fibers innervating the heart for its cardiac effects (Sabbah et al, 2011). Despite the similar epineurial cuff electrode designs used in implantable VNS for epilepsy and heart failure, different stimulation parameters (Anand et al, 2020) are used to recruit different fiber pathways. Meanwhile, aVNS is hypothesized to achieve therapeutic potency by activating myelinated Abeta fibers on the auricular branch of the vagus nerve (Kaniusas, 2019), which in the auricle exits as a web of axons.…”