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

Circ Heart Fail. 2019 Nov;12(11):e005879. doi: 10.1161/CIRCHEARTFAILURE.119.005879. Epub 2019 Nov 14.


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.

Methods: The ANTHEM-HFrEF study will randomize patients (2:1) to autonomic regulation therapy plus guideline-directed medical therapy, or guideline-directed medical therapy alone. The morbidity and mortality trial utilizes a conventional frequentist approach for analysis of the primary outcome end point-reduction in the composite of cardiovascular death or first HF hospitalization-and a Bayesian adaptive approach toward sample size selection. Embedded within the ANTHEM-HFrEF study is a second trial evaluating improvement in symptoms and function. Symptom/function success will require meeting 2 risk-related conditions (trend for reduced cardiovascular death/HF hospitalization and sufficient freedom from device-related serious adverse events) and 3 efficacy end point components (changes in left ventricular EF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire overall score).

Conclusions: Vagus nerve stimulation remains a promising, yet unproven treatment in HFrEF. A successful ANTHEM-HFrEF pivotal study would provide an important advance in HFrEF treatment and offer a model for expediting evaluation of new therapies.

Clinical trial registration: URL: Unique identifier: NCT03425422.

Keywords: cardiomyopathies; heart failure; risk; sample size; vagus nerve stimulation.

Publication types

  • Clinical Trial Protocol
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autonomic Nervous System / physiopathology*
  • Cardiovascular Agents / adverse effects
  • Cardiovascular Agents / therapeutic use*
  • Combined Modality Therapy
  • Disease Progression
  • Europe
  • Heart / innervation*
  • Heart Failure / diagnosis
  • Heart Failure / mortality
  • Heart Failure / physiopathology
  • Heart Failure / therapy*
  • Humans
  • Multicenter Studies as Topic
  • North America
  • Randomized Controlled Trials as Topic
  • Recovery of Function
  • Time Factors
  • Treatment Outcome
  • Vagus Nerve Stimulation* / adverse effects


  • Cardiovascular Agents

Associated data