Autonomic dysfunction is increasingly recognized as a contributor to progression of heart failure with reduced ejection fraction (HFrEF), and vagal nerve stimulation (VNS) has emerged as a potential therapeutic strategy. A pivotal randomized trial published in the Journal of the American College of Cardiology evaluated the efficacy and safety of VNS in patients with symptomatic HFrEF and also examined challenges related to premature trial termination.

Patients with New York Heart Association (NYHA) class II or III heart failure, left ventricular ejection fraction (LVEF) ≤35%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥800 pg/mL were randomized in a 2:1 ratio to VNS or control therapy. The primary efficacy endpoint was time to cardiovascular death or HF hospitalization.

The trial planned adaptive sample sizing with enrollment targeting up to 1,000 patients. However, enrollment was terminated early by the sponsor after randomization of 532 patients for reasons unrelated to efficacy or futility.

Findings

• The primary efficacy endpoint was not significantly reduced with VNS compared with control therapy (hazard ratio [HR] 0.84; 95% CI 0.62-1.12; P = 0.115).
• The primary safety endpoint showed 96.7% freedom from procedure- or device-related serious adverse events.
• Autonomic engagement with VNS persisted during long-term follow-up.
• Favorable trends were observed for HF hospitalization, Kansas City Cardiomyopathy
• Questionnaire scores, NYHA functional class, and 6-minute walk distance, although findings remained inconclusive.
• Left ventricular ejection fraction remained unchanged during follow-up.

The prematurely terminated VNS trial in HFrEF demonstrated feasibility, sustained autonomic engagement, and favorable safety outcomes but did not significantly reduce cardiovascular death or HF hospitalization. Improvements in symptoms and functional measures remained hypothesis-generating because of the neutral primary endpoint and limited statistical power.