Heart Failure

ANTHEM-HFrEF — Vagal Nerve Stimulation in HFrEF (Pivotal Trial)

• Authors: ANTHEM-HFrEF investigators
• Journal / date: JACC, May 2026
• DOI / URL: 10.1016/j.jacc.2026.03.040 | PMID 42159539
• Source basis: Full text (JACC login)
• Study type: Pivotal RCT (2:1 VNS vs control), terminated early by sponsor
• Population: N=532 (target was ≤1,000 adaptive). NYHA II-III, LVEF ≤35%, NT-proBNP ≥800 pg/mL on background GDMT
• Intervention / comparator: VNS device vs control (no VNS)
• Primary endpoint & result: Time to CV death or HF hospitalization — HR 0.84 (95% CI 0.62-1.12; 1-sided p=0.115). NOT met (underpowered after early termination).
• Secondary endpoints:
• LVEF: unchanged
• 6MWD, KCCQ, NYHA class: favorable trends, hypothesis-generating
• Autonomic engagement: persisted long-term
• Safety: 96.7% freedom from procedure- or device-related serious AEs
• Why it matters (clinical takeaway):
• No new evidence-based indication for VNS in HFrEF — the trial was terminated early by the sponsor and the primary endpoint was neutral.
• Safety was good; autonomic engagement was real; but efficacy remains unproven.
• Practical: when patients ask about VNS for HFrEF, the answer remains "not supported by RCT evidence at this time."
• The paper also documents how investigators handled premature sponsor termination — useful for trialists.
• Caveats / limitations: Underpowered after early termination, neutral primary endpoint, exploratory wins should not be over-interpreted.
• Trial registry: NCT03425422
• Referenced trials pulled forward: None.