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 .

2nd Department of Internal Medicine Cardiovascular Medicine General University Hospital and 1st Faculty of Medicine Charles University Prague Prague Czechia

BHF Manchester Centre for Heart and Lung Magnetic Resonance Research Manchester University NHS Foundation Trust Manchester UK

Brigham and Women's Hospital Harvard Medical School Boston MA USA

Centro de Investigaciones Clínicas del Litoral Santa Fe Argentina

Department of Cardiology Faculty of Medicine Dokuz Eylul University Izmir Turkey

Department of Cardiology Hospital Clínico Universitario de Valencia Valencia Spain

Department of Cardiovascular Diseases Mayo Clinic Rochester MN USA

Department of Internal Medicine Section of Cardiovascular Medicine Yale University School of Medicine New Haven CT USA

Department of Surgery University of Toronto Toronto Ontario Canada

Departments of Medicine and Radiology University of North Carolina Chapel Hill NC USA

Division of Cardiac Surgery St Michael's Hospital Unity Health Toronto Toronto Ontario Canada

Division of Cardiovascular Sciences University of Manchester Manchester Academic Health Science Centre Manchester UK

Eli Lilly and Company Indianapolis IN USA

Futsukaichi Hospital of Saiseikai Imperial Gift Foundation Fukuoka Japan

Heart and Vascular Center Semmelweis University Budapest Hungary

Heart Failure Clinics Instituto do Coração do Hospitasl das Clínicas da Faculdade de Medicina da USP São Paulo Brazil

Heart Institute Hadassah Medical Center Jerusalem Israel

INCLIVA and Department of Medicine Universidad de Valencia Valencia Spain

Institute for Heart Diseases Wroclaw Medical University Wrocław Poland

School of Cardiovascular and Medical Sciences British Heart Foundation Glasgow Cardiovascular Research Centre University of Glasgow Glasgow UK

Universidade de São Paulo São Paulo Brazil

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ClinicalTrials.gov
NCT05592275