Long-term Follow-Up of Patients with Heart Failure and Reduced Ejection Fraction Receiving Autonomic Regulation Therapy in the ANTHEM-HF Pilot Study

Abstract

Background:The ANTHEM-HF pilot study was an open-label study that evaluated the safety and feasibility of autonomic regulation therapy (ART) utilizing cervical vagus nerve stimulation (VNS) for patients with chronic HF with reduced EF (HFrEF). Patients in NYHA class II-III with EF ≤40% (n = 60) received ART for 6 months post-titration. ART was associated with sustained improvement in left ventricular (LV) function and HF symptoms at 6 and 12 months. Methods: Continuously cyclic VNS was maintained to determine longer-term safety and chronic effects of ART. Echocardiographic parameters and HF symptoms were assessed throughout a follow-up period of at least 42 months. Results: Between 12 and 42 months after initial titration, there were no device-related SAEs or malfunctions. There were 10 SAEs adjudicated to be unrelated to VNS, including 5 deaths. There were 6 non-serious adverse events that were adjudicated to be device-related (2 oropharyngeal pain, 1 implant site pain, 2 voice alteration, and 1 hoarseness). At 42 months, there was significant improvement from baseline in LVEF, NYHA class, 6-min walk distance, and MLHFQ score. However, these improvements at 42 months were not significantly different from mean values at 6 and 12 months. Conclusions: In a 42-month follow-up, ART was durable, safe, and was associated with beneficial effects on LVEF and 6-min walk distance. Long term, chronic, open-loop ART continued to be well-tolerated in patients with HFrEF. The open label, randomized, controlled, ANTHEM-HFrEF Pivotal Study is currently underway to further evaluate ART in patients with advanced HF.

The evolving obesity challenge: targeting the vagus nerve and the inflammatory reflex in the response

“…These preclinical and clinical advances considerably contributed to and streamlined the rapidly developing field of Bioelectronic Medicine ( Pavlov & Tracey, 2019a ). Bioelectronic VNS has now been explored in the treatment of numerous disorders and conditions including inflammatory and autoimmune diseases, pain, bleeding, heart failure, and the current opioid epidemic in the United States ( Czura et al, 2010 ; DiCarlo et al, 2018 ; Koopman et al, 2016 ; Pavlov & Tracey, 2019a ; Qureshi, Datta-Chaudhuri, Tracey, Pavlov, & Chen, 2020 ; Sharma et al, 2020 ). Implanted device-generated VNS, similar to VNS that is clinically-approved for the treatment of pharmacoresistant epilepsy and depression has been increasingly utilized and the underlying bioelectronic technology improved ( Levine, Faltys, & Chernoff, 2019 ).…”

Autonomic Modulation for Cardiovascular Disease

“…The Autonomic Neural Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) evaluated the adjunct use of the Demipulse (LivaNova, Houston, TX) VNS system for left or right cervical vagal nerve stimulation in a cohort of patients with heart failure with reduced ejection fraction and New York Heart Association functional class II-III symptoms (Premchand et al, 2016;Dicarlo et al, 2018;Konstam et al, 2019;Sharma et al, 2020). Improvement in primary endpoints including left ventricular ejection fraction, heart rate variability, and 6-min walk tests, were noted, with follow-up at 1 year demonstrating persistent improvement (Figure 10; Premchand et al, 2016;Dicarlo et al, 2018;Konstam et al, 2019;Sharma et al, 2020). In the setting of heart failure with preserved ejection fraction (HFpEF), a more clinically challenging entity to treat, a similar VNS protocol by the same investigators is presently enrolling (Dicarlo et al, 2018).…”

“…While pharmacologic therapy targets cardiac disease through neurohormonal blockade, results have not been as promising as hoped (Florea and Cohn, 2014;McMurray et al, 2014;. This has led to increasing interest in neuromodulation as a new therapeutic approach, with therapies such as vagal nerve stimulation (VNS) and video-assisted thoracoscopic sympathectomy showing efficacy for the treatment of heart failure and refractory ventricular arrhythmias (Schwartz et al, 2004(Schwartz et al, , 2008Wilde et al, 2008;Bourke et al, 2010;Vaseghi et al, 2014;Sharma et al, 2020). Though these early studies are promising, a better understanding of the anatomy and function of the cardiac nervous system is imperative to developing and implementing precise neuromodulatory therapies.…”

Vagus Nerve Stimulation in Early Stage of Acute Myocardial Infarction Prevent Ventricular Arrhythmias and Cardiac Remodeling

“…However, two large clinical trials failed to demonstrate that VNS could improve cardiac function or reduce mortality (10,11). Another study showed VNS was a promising therapy in heart failure (HF) (12)(13)(14)(15)(16). The interfaces and stimulation protocols used among the abovementioned studies were various, probably contributing to different results (17)(18)(19).…”