Autonomic regulation therapy in chronic heart failure with preserved/mildly reduced ejection fraction: ANTHEM-HFpEF study results.

Background: Autonomic regulation therapy (ART) utilizing cervical vagus nerve stimulation (VNS) appeared to be safe and to improve autonomic tone, symptoms, and cardiac mechanical function in patients with symptomatic heart failure and reduced ejection fraction in the ANTHEM-HF Study. The ANTHEM-HFpEF Study is the first investigation to evaluate the safety and feasibility of ART in patients with symptomatic heart failure and preserved or mildly reduced ejection fraction (HFpEF, HFmrEF).

Methods: This open-label interventional study enrolled 52 patients with HFpEF or HFmrEF, NYHA Class II-III, and LVEF ≥40%, who received stable guideline-directed medical therapy.

Advances in Our Clinical Understanding of Autonomic Regulation Therapy Using Vagal Nerve Stimulation in Patients Living With Heart Failure.

The ANTHEM-HF, INOVATE-HF, and NECTAR-HF clinical studies of autonomic regulation therapy (ART) using vagus nerve stimulation (VNS) systems have collectively provided dose-ranging information enabling the development of several working hypotheses on how stimulation frequency can be utilized during VNS for tolerability and improving cardiovascular outcomes in patients living with heart failure (HF) and reduced ejection fraction (HFrEF). Changes in heart rate dynamics, comprising reduced heart rate (HR) and increased HR variability, are a biomarker of autonomic nerve system engagement and cardiac control, and appear to be sensitive to VNS that is delivered using a stimulation frequency that is similar to the natural operating frequency of the vagus nerve. Among prior studies, the ANTHEM-HF Pilot Study has provided the clearest evidence of autonomic engagement with VNS that was delivered using a stimulation frequency that was within the operating range of the vagus nerve.

Persistent Autonomic Engagement and Cardiac Control After Four or More Years of Autonomic Regulation Therapy Using Vagus Nerve Stimulation.

Introduction: Although heart failure (HF) outcomes have improved dramatically with the use of guideline directed medical therapy and implantable devices, the overall prognosis of patients with HF and reduced ejection fraction (HFrEF) remains poor. Autonomic Regulation Therapy (ART) using chronic vagus nerve stimulation (VNS) has been evaluated in the ANTHEM-HF study, using changes in heart rate (HR) dynamics as a biomarker of autonomic nervous system engagement and cardiac control to guide VNS titration. ART was associated with sustained improvement in cardiac function and HF symptoms in patients with HFrEF and persistent HF symptoms despite guideline-directed medical therapy (GDMT).

Therapeutic responsiveness to vagus nerve stimulation in patients receiving beta-blockade for heart failure with reduced ejection fraction.

Background: The effect of beta-blockade (BB) on response to vagus nerve stimulation (VNS) has not been reported in patients with heart failure and reduced ejection fraction (HFrEF). In the ANTHEM-HF Study, 60 patients received chronic cervical VNS. Background pharmacological therapy remained unchanged during the study, and VNS intensity was stable once up-titrated.

Implantable vagus nerve stimulation system performance is not affected by internal or external defibrillation shocks.

Purpose: Autonomic regulation therapy (ART) for heart failure (HF) is delivered using vagus nerve stimulation (VNS), and has been associated with improvement in cardiac function and HF symptoms. VNS is delivered using an implantable pulse generator (IPG) and a lead placed around the cervical vagus nerve. Because HF patients may receive concomitant cardiac defibrillation therapy, testing was conducted to determine the effect of defibrillation (DF) on VNS system performance.

Effect of defibrillation on the performance of an implantable vagus nerve stimulation system.

Background: Vagus Nerve Stimulation (VNS) delivers Autonomic Regulation Therapy (ART) for heart failure (HF), and has been associated with improvement in cardiac function and heart failure symptoms. VNS is delivered using an implantable pulse generator (IPG) and lead with electrodes placed around the cervical vagus nerve. Because HF patients may receive concomitant cardiac defibrillation therapy, testing was conducted to determine the effect of defibrillation (DF) on the VNS system.

Vagus Nerve Stimulation Provides Multiyear Improvements in Autonomic Function and Cardiac Electrical Stability in the ANTHEM-HF Study.

Background: Patients with heart failure with reduced left ventricular ejection fraction (LVEF) (HFrEF) experience long-term deterioration of autonomic function and cardiac electrical stability linked to increased mortality risk. The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) trial reported improved heart rate variability (HRV) and heart rate turbulence (HRT) and reduced T-wave alternans (TWA) after 12 months of vagus nerve stimulation (VNS). We investigated whether the benefits of chronic VNS persist in the long term.

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

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.

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

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.

Impact of Autonomic Regulation Therapy in Patients with Heart Failure: ANTHEM-HFrEF Pivotal Study Design.

Background: The ANTHEM-HFrEF (Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction) pivotal study is an adaptive, open-label, randomized, controlled study evaluating whether autonomic regulation therapy will benefit patients with advanced HFrEF. While early-phase studies have supported potential use of vagus nerve stimulation to deliver autonomic regulation therapy for HFrEF, results of larger clinical trials have been inconsistent. The ANTHEM-HFrEF study uses a novel design, with adaptive sample size selection, evaluating effects on morbidity and mortality as well as symptoms and function.

Background pharmacological therapy in the ANTHEM-HF: comparison to contemporary trials of novel heart failure therapies.

Aims: Clinical trials of new heart failure (HF) therapies administer guideline-directed medical therapy (GDMT) as background pharmacologic treatment (BPT). In the ANTHEM-HF Pilot Study, addition of autonomic regulation therapy to GDMT significantly improved left ventricular function, New York Heart Association (NYHA) class, 6 min walk distance, and quality of life in patients with HF with reduced ejection fraction (HFrEF). A post hoc analysis was performed to compare BPT in ANTHEM-HF with two other trials of novel HF therapies: the PARADIGM-HF study of sacubitril-valsartan and the SHIFT study of ivadrabine.

Autonomic regulation therapy to enhance myocardial function in heart failure patients: the ANTHEM-HFpEF study.

Background: Approximately half of the patients presenting with new-onset heart failure (HF) have HF with preserved left ventricular ejection fraction (HFpEF) and HF with mid-range left ventricular ejection fraction (HFmrEF). These patients have neurohormonal activation like that of HF with reduced ejection fraction; however, beta-blockers and angiotensin-converting enzyme inhibitors have not been shown to improve their outcomes, and current treatment for these patients is symptom based and empiric. Sympathoinhibition using parasympathetic stimulation has been shown to improve central and peripheral aspects of the cardiac nervous system, reflex control, induce myocyte cardioprotection, and can lead to regression of left ventricular hypertrophy.

Patient-Centered Home Care Using Digital Medicine and Telemetric Data for Hypertension: Feasibility and Acceptability of Objective Ambulatory Assessment.

Objective information that can be passively obtained in an ambulatory setting could be potentially useful for determining appropriate care in blood pressure (BP) management. This study utilized digital medicine (DM) prototypes and telemetric data acquisition to directly confirm medication use and to assess habits of daily living in a hypertensive population. Thirty-seven patients (23 men age 62±9 years) used the system for 6 weeks.

Extended Follow-Up of Patients With Heart Failure Receiving Autonomic Regulation Therapy in the ANTHEM-HF Study.

Objective: Evaluate the effects of a novel autonomic regulation therapy (ART) via vagus nerve stimulation (VNS) in patients with chronic heart failure (HF) and reduced left ventricular ejection fraction during a 12-month follow-up period.

Methods: The Autonomic Regulation Therapy for the Improvement of Left Ventricular Function and Heart Failure Symptoms (ANTHEM-HF) study enrolled 60 subjects with New York Heart Association class II-III HF and low left ventricular ejection fraction (≤40%), who received open-loop ART using VNS randomized to left or right cervical vagus nerve placement and followed for 6 months after titration to a therapeutic output current (2.0 ± 0.

Autonomic regulation therapy via left or right cervical vagus nerve stimulation in patients with chronic heart failure: results of the ANTHEM-HF trial.

Objective: ANTHEM-HF evaluated a novel autonomic regulation therapy (ART) via either left or right vagus nerve stimulation (VNS) in patients with heart failure (HF) and reduced ejection fraction (HFrEF).

Methods And Results: Sixty subjects (New York Heart Association [NYHA] functional class II-III, left ventricular ejection fraction (LVEF) ≤ 40%, left ventricular end-diastolic diameter ≥ 50 mm to < 80 mm) receiving optimal pharmacologic therapy were randomized at 10 sites. VNS systems were randomly implanted on the left (n = 31) or right (n = 29) side.

First experience with a wireless system incorporating physiologic assessments and direct confirmation of digital tablet ingestions in ambulatory patients with schizophrenia or bipolar disorder.

Objective: To characterize the feasibility and safety of a wireless networked system incorporating physiologic assessments and direct confirmation of digital tablet ingestions in ambulatory patients with schizophrenia or bipolar disorder.

Method: In this 4-week observational study conducted between May 2010 and May 2011 at 2 US academic clinical study sites, 12 adults with bipolar disorder and 16 adults with schizophrenia (all diagnosed according to DSM-IV criteria) utilized a digital health feedback system (DHFS). All subjects were on a stable regimen of oral medication.

Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial.

Objectives: The aim of this study was to assess the lipid-altering efficacy and safety of ETC-1002 in subjects with hypercholesterolemia.

Background: ETC-1002 is a small molecule that modulates pathways of cholesterol, fatty acid, and carbohydrate metabolism and may have therapeutic benefits in treating hypercholesterolemia and other cardiometabolic risk factors.

Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients (n = 177) with elevated low-density lipoprotein cholesterol (LDL-C) (130 to 220 mg/dl), who were stratified by baseline triglycerides (not elevated [<150 mg/dl] or elevated [150-<400 mg/dl]) and randomized to receive 40, 80, or 120 mg of ETC-1002 or placebo once daily for 12 weeks.

Role for direct electronic verification of pharmaceutical ingestion in pharmaceutical development.

Identifying a dosing regimen for recommended use is one of the more difficult tasks in pharmaceutical development and has major therapeutic and economic consequences. In the clinical phase of pharmaceutical development, pharmacokinetic-pharmacodynamic (PK/PD) models are used to characterize the relationship between drug exposure and clinical outcome. When adherence to the prescribed drug dosage is known, true dose-response can be validly estimated, while non-compliance with the nominal prescribed dosage causes unintended variability in actual drug exposure and ensuing difficulty in determining dose-response.

Early clinical experience with networked system for promoting patient self-management.

Objective: To gain early experience with a networked system designed to assess a patient's adherence to oral medication and physiologic metrics in an ambulatory, at-home setting.

Study Design: Prospective, observational studies.

Materials And Methods: This networked system for patient self-management consists of ingestible markers and a wearable, personal monitor.