Ziltivekimab in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the ATHENA and HERMES trials

Abstract Background For decades inflammation has been postulated to play a key pathophysiological role in heart failure (HF), particularly in HF with preserved ejection fraction (HFpEF). Previous attempts to target inflammation in HF have been unsuccessful, possibly due to the choice of therapeutic target or the characteristics of the patient population studied. We hypothesized that targeting interleukin-6 (IL-6)—a cytokine central to NLRP3 inflammasome activation that is associated with both the onset and progression of 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 IL-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, multicenter, double-blind, placebo-controlled trials randomising adults with HFpEF/HFmrEF and cardiovascular inflammation (hsCRP ≥2mg/L) to ziltivekimab 15 mg or placebo, administered subcutaneously once-monthly on top of standard of care. Eligible participants have a left ventricular ejection fraction 40%, elevated NTproBNP 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, hospitalisation for HF or urgent HF visit. ATHENA has a fixed duration of 12 months whereas the HERMES trial is event-driven (approximately 845 adjudicated primary events) with a minimum exposure of 6 months from randomisation to last treatment visit. Conclusions 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.