Vagal Nerve Stimulation in Patients With Heart Failure and Reduced Ejection Fraction

BACKGROUND: Vagal nerve stimulation (VNS) may reverse autonomic dysfunction in heart failure (HF). This paper describes results from a pivotal trial, while addressing challenges investigators face following premature trial termination. OBJECTIVES: We report VNS actions in patients with HF with reduced ejection fraction and investigators response to early discontinuation. METHODS: Randomization was 2:1 to VNS or control. Entry required NYHA functional class II or III, left ventricular ejection fraction (LVEF) ≤35%, and N-terminal pro-B-type natriuretic peptide ≥800 pg/mL. Primary efficacy endpoint was time to cardiovascular death or HF hospitalization. Secondary endpoints included LVEF, 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire. Adaptive sample sizing targeted ≤1,000 patients. P values are 1-sided. RESULTS: After randomizing 532 patients, the sponsor terminated enrollment, unrelated to futility or efficacy. The primary efficacy endpoint was not met (HR: 0.84; 95% CI: 0.62-1.12; P = 0.115). The primary safety endpoint achieved 96.7% freedom from procedure- or device-related serious adverse events. Autonomic engagement persisted long-term. Findings were favorable, although inconclusive, for the primary endpoint, HF hospitalization, Kansas City Cardiomyopathy Questionnaire, NYHA functional class, and 6-minute walk distance. LVEF was unchanged. The still-blinded investigators, seeking to extend data reporting while maintaining scientific integrity, had prespecified a single exploratory outcomes-symptoms win ratio. Results were favorable although merely hypothesis-generating, given primary endpoint neutrality, multiplicity, subjective bias, and marginal statistical significance. CONCLUSIONS: Early termination outside Data Monitoring Committee processes challenged investigators to maintain scientific and ethical integrity and transparency, while optimizing data reporting. The underpowered primary endpoint was neutral. Data documented feasibility, safety, and autonomic engagement. Trends favoring outcomes, symptoms, and function were inconclusive although hypothesis-generating, Importantly, we provide guidance for investigators facing trial discontinuation. (ANTHEM-HFrEF Pivotal Study Autonomic Regulation Therapy to Enhance Myocardial Function and Reduce Progression of Heart Failure with Reduced Ejection Fraction; NCT03425422).