Marvin A Konstam1, James E Udelson1, Javed Butler2, Helmut U Klein3, John D Parker4, John R Teerlink5, Patricia M Wedge6, Benjamin R Saville7, Jeffrey L Ardell8, Imad Libbus9, Lorenzo A DiCarlo9. 1. The CardioVascular Center at Tufts Medical Center, Boston, MA (M.A.K., J.E.U.). 2. Department of Medicine, University of Mississippi Medical Center, Jackson, MS (J.B.). 3. Department of Medicine, University of Rochester Medical Center, NY (H.U.K.). 4. University of Toronto, Mount Sinai Hospital, Division of Cardiology, Sinai Health Systems and University Health Network, Toronto, Canada (J.D.P.). 5. Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California (J.R.T.). 6. Cardiovascular Clinical Science Foundation, Boston, MA (P.M.W.). 7. Berry Consultants LLC, Austin TX and Department of Biostatistics, Vanderbilt University, Nashville TN (B.R.S.). 8. Neurocardiology Center, University of California, Los Angeles (J.L.A.). 9. LivaNova USA Incorporated, Houston, TX (I.L., L.A.D.).
Abstract
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: http://www.clinicaltrials.gov. Unique identifier: NCT03425422.
RCT Entities:
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: http://www.clinicaltrials.gov. Unique identifier: NCT03425422.
Authors: Imad Libbus; Scott R Stubbs; Scott T Mazar; Scott Mindrebo; Bruce H KenKnight; Lorenzo A DiCarlo Journal: J Interv Card Electrophysiol Date: 2021-08-31 Impact factor: 1.759
Authors: James H Park; Jonathan Gorky; Babatunde Ogunnaike; Rajanikanth Vadigepalli; James S Schwaber Journal: Front Neurosci Date: 2020-05-20 Impact factor: 4.677
Authors: Inder S Anand; Marvin A Konstam; Helmut U Klein; Douglas L Mann; Jeffrey L Ardell; Douglas D Gregory; Joseph M Massaro; Imad Libbus; Lorenzo A DiCarlo; John James E Udelson; Javed Butler; John D Parker; John R Teerlink Journal: ESC Heart Fail Date: 2020-01-27
Authors: Asif Machhada; Patrick S Hosford; Alex Dyson; Gareth L Ackland; Svetlana Mastitskaya; Alexander V Gourine Journal: JACC Basic Transl Sci Date: 2020-07-15