Effects of volenrelaxin in worsening heart failure with preserved ejection fraction: a phase 2 randomized trial

Relaxin is a peptide hormone that may decrease circulatory congestion and improve kidney function. In this study, we conducted a double-blind, international, multicenter trial to test whether volenrelaxin, a long-acting form of human relaxin, can improve left atrial (LA) function, reduce congestion and improve kidney function in patients with heart failure and preserved ejection fraction (HFpEF). We randomly assigned patients with New York Heart Association (NYHA) class II–IV HFpEF and recent heart failure (HF) decompensation to 25-mg, 50-mg or 100-mg volenrelaxin or placebo administered subcutaneously once weekly. The primary outcome was the change in LA reservoir strain at 26 weeks, with key secondary endpoints including changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP), estimated glomerular filtration rate (eGFR) and safety. The trial was stopped early by the sponsor because of evidence for worsening congestion after 332 participants had been enrolled (mean age 74 years, 49% women, mean body mass index 30.6 kg m⁻², 31.9% NYHA class III–IV). Compared to placebo, 25-mg volenrelaxin improved LA reservoir strain (+3.9%, 95% confidence interval (CI): 1.1–6.6, P = 0.006) but did not have effects on this outcome at 50-mg (+1.3%, 95% CI: −1.3 to 3.9, P = 0.332) or 100-mg (+0.9%, 95% CI: −1.8 to 3.6, P = 0.521) doses. At 26 weeks, volenrelaxin (pooling all dosages) increased NT-proBNP levels (+24.5%, 95% CI: 2.0–51.8) and had no significant effect on eGFR (+2.2 ml min⁻¹ 1.73 m⁻², 95% CI: −1.8 to 6.3). Volenrelaxin was also associated with a non-significant increase in risk for HF hospitalization compared to placebo (hazard ratio = 2.64, 95% CI: 0.93–7.56, P = 0.070), along with signals for an increased number of cardiovascular and renal serious adverse events (odds ratio = 2.52, 95% CI: 0.95–6.68, P = 0.056). In conclusion, despite some evidence for improvement in LA function at a low dose, treatment with this long-acting form of human relaxin was associated with worsening congestion in patients with recently decompensated HFpEF. ClinicalTrials.gov identifier: NCT05592275.