P3522Vagus nerve stimulation for chronic heart failure: differences in therapy delivery and clinical efficacy in ANTHEM-HF, INOVATE-HF, and NECTAR-HF
Authors: Anand I , Konstam M , Udelson J , Butler J , Klein H , Parker J , Teerlink J , Libbus I , Amurthur B , Kenknight B , Ardell J , Gregory D , Massaro J , Dicarlo L 
Published: October 2019

Abstract

Background
Vagus Nerve Stimulation (VNS) is meant to deliver Autonomic Regulation Therapy (ART) to neurological targets with sufficient neuromodulation (NM) to ameliorate chronic heart failure (CHF). VNS delivery consists of its intensity (a combination of pulse amplitude, pulse frequency, and pulse duration), polarity, duty cycle (DC; stimulation “on” time and “off” time), and mode (continuous, or intermittent and periodic). In the ANTHEM-HF Pilot Study patients with CHF and reduced ejection fraction (HFrEF), VNS intensity was up-titrated until a change in heart rate (HR) dynamics was objectively confirmed. This did not require any change in GDMT and was associated with significant improvements in LVEF, 6-minute walk distance (6MWD), Minnesota Living with HF (MLWHF) score, and HR variability.

Methods
Qualitative and quantitative analyses used data from peer-reviewed publications and other sources in the public domain to compare VNS delivery in ANTHEM-HF, INOVATE-HF, and NECTAR-HF.
Results (Table): Up-titration of VNS intensity was attempted in all 3 studies. In contrast to ANTHEM-HF, INOVATE-HF aimed only at peripheral neural targets. VNS intensity was delivered at a lower pulse frequency, and had a variable DC as a consequence of R-wave synchronization and only intermittent, periodic stimulation. In NECTAR-HF VNS intensity was delivered at a higher pulse frequency, and this was associated with intolerable adverse off-target effects which restricted VNS up-titration. Significant improvements in EF, 6MWD, MLWHF, and SDNN occurred in ANTHEM-HF relative to the other studies.
ANTHEM-HF (n=60) INOVATE-HF (n=436) NECTAR-HF (n=63) Neural Target Central/Peripheral Peripheral Central/Peripheral Delivery Site Left or right CVN Right CVN Right CVN Delivery Intensity:   Amplitude (milliamperes) 2.0±0.6 3.9±1.0 1.4±0.8   Frequency (Hertz) 10 1–2 20   Duration (microseconds) 250 500 300 Electrode Polarity (Cathode) Caudal Cephalad Caudal Duty Cycle 23% 25% 17% On Time/Off Time (seconds) 18/62 Variable 10/50 Mode of Delivery Cyclic/Continuous Intermittent/Periodic Cyclic/Continuous Clinical Efficacy at 6 Months:   EF 32.4±7.2 to 37.2±10.4 Not available 30.5±6.0 to 32.7±6.4   6MWD 287±66 to 346±78 317±109 to 347±123 Not available   MLWHFS 40±14 to 21±10 Not available 44.2±22.2 to 35.8±20.8   SDNN 94±26 to 111±50 Not available 146±48 to 130±52 Values reported as mean ± standard deviation; CVN = Cervical vagus nerve. *p<0.05 versus NECTAR-HF; **p<0.05 versus INOVATE-HF; ***p<0.025 versus NECTAR-HF; ****p<0.001 versus NECTAR-HF (Analysis using two-sample t-test of the means).

Conclusion
VNS differed in ANTHEM-HF when compared to INOVATE-HF and NECTAR-HF. The neural targets, pulse frequencies for titration, and the DC for NM were different. VNS in ANTHEM-HF was clinically efficacious. The ongoing ANTHEM-HFrEF Pivotal Study uses a similar paradigm.

Acknowledgement/Funding
LivaNova PLC