Ziltivekimab in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the ATHENA and HERMES trials
Year: 2026
Type: article
Study design: Study Protocol
Abstract: AIMS: We hypothesized that targeting interleukin-6-a cytokine central to NOD-like receptor protein 3 (NLRP3) inflammasome activation that is associated with both the onset and progression of heart failure (HF)-may be beneficial in patients with HF and circulating evidence of cardiovascular inflammation but without overtly reduced ejection fraction (EF). We describe the rationale and design of two clinical trials (ATHENA and HERMES) investigating ziltivekimab, a human monoclonal antibody directed against the interleukin-6 ligand, in patients with HF and mildly reduced or preserved EF (HFmrEF/HFpEF) and cardiovascular inflammation. METHODS: ATHENA (n = 673) and HERMES (n = 4900) are international, multi-centre, double-blind, placebo-controlled trials randomizing adults with HFpEF/HFmrEF and cardiovascular inflammation (high-sensitivity C-reactive protein ≥2 mg/l) to ziltivekimab 15 mg or placebo, administered subcutaneously once monthly on top of standard of care. Eligible participants have a left ventricular EF >40%, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP), and serum high-sensitivity C-reactive protein ≥2 mg/l. The primary endpoint in ATHENA is the change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at 12 months. The primary endpoint in HERMES is time to first composite of cardiovascular death, hospitalization for HF, or urgent HF visit. ATHENA has a fixed duration of 12 months, whereas the HERMES trial is event driven (∼845 adjudicated primary events) with a minimum exposure of 6 months from randomization to the last treatment visit. CONCLUSION: ATHENA and HERMES will investigate the effect of ziltivekimab in HFpEF/HFmrEF and cardiovascular inflammation. ATHENA will determine the effect of ziltivekimab on health status. HERMES will determine the efficacy and safety of ziltivekimab on morbidity and mortality.
DOI: 10.1093/ejhf/xuag153
Institutions: Universitat Autònoma de Barcelona, Hospital de Sant Pau, Spanish National Centre for Cardiovascular Research, Centro de Investigación en Red en Enfermedades Cardiovasculares, Institut de Recerca Sant Pau, Brigham and Women's Hospital, Mayo Clinic, Montreal Heart Institute, Université de Montréal, National University of Singapore, National University Heart Centre Singapore, Baim Institute for Clinical Research, National Heart Centre Singapore, University Medical Center Groningen, University of Groningen, Novo Nordisk (Denmark), University Hospital Centre Zagreb, University of Zagreb, Duke Medical Center, British Heart Foundation, University of Glasgow
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,300
OpenAlex ID: W7160779177