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<sup>-</sup><sup>2</sup>, 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<sup>-1</sup> 1.73 m<sup>-</sup><sup>2</sup>, 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 .

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Journal
Nature Medicine
Published
2025-08-31
DOI
https://doi.org/10.1038/s41591-025-03939-6
Citations
4
Primary Topic
Pregnancy-related medical research
Type
article
Field-Weighted Citation Impact
7.51

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article

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

Mark C. Petrie, Jeffrey Moore Testani, Miguel Hominal, Barry A. Borlaug et al.
4 citations
Nature Medicine
Pregnancy-related medical research
7.51
article

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

Mark C. Petrie, Jeffrey Moore Testani, Miguel Hominal, Barry A. Borlaug, Chris Miller, Julio E. Núñez, Toshiaki Kadokami, Jan Bělohlávek, Aguinaldo Figueiredo Freitas, Edimar Alcides Bocchi, Flora Sam, Subodh Verma, Jonathan W. Cunningham, Béla Péter Merkely, Mehmet Birhan Yılmaz, Zhenzhong Wang, Kirkwood F. Adams, Offer Amir, Ena Oru
article en
4 citations

Abstract

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<sup>-</sup><sup>2</sup>, 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<sup>-1</sup> 1.73 m<sup>-</sup><sup>2</sup>, 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 .

Nature MedicineVol. 31(11)
Semmelweis University (HU), University of North Carolina at Chapel Hill (US), Brigham and Women's Hospital (US), St. Michael's Hospital (CA), Mayo Clinic (US), Harvard University (US), Eli Lilly (United States) (US), Universidade de São Paulo (BR), University of Toronto (CA), Dokuz Eylül University (TR), Charles University (CZ), Manchester Academic Health Science Centre (GB), Hadassah Medical Center (IL), University of Manchester (GB), Universidad Nacional del Litoral (AR), British Heart Foundation (GB), Yale University (US), Wroclaw Medical University (PL), St Michael’s Hospital (IE), Manchester University NHS Foundation Trust (GB), Hospital Clínico Universitario de Valencia (ES), Social Welfare Organization Saiseikai Imperial Gift Foundation (JP), Mayo Clinic in Arizona (US), Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR), Mayo Clinic in Florida (US), INCLIVA Health Research Institute (ES), Instituto de Física del Litoral (AR), General University Hospital in Prague (CZ), University of Glasgow (GB)
U.S. Department of Defense, Amgen, Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Alnylam Pharmaceuticals, Edwards Lifesciences, Boston Scientific Corporation, Regeneron Pharmaceuticals, LivaNova, Cytokinetics, Amicus Therapeutics, Moderna, Horizon Therapeutics, Abiomed, British Heart Foundation, University of Toronto, Novo Nordisk, Dokuz Eylül Üniversitesi, Servier, Sun Pharma, INCLIVA Instituto de Investigación Sanitaria, HLS Therapeutics, Relypsa, National Heart, Lung, and Blood Institute, Congressionally Directed Medical Research Programs
Openalex Percentile: Top 3%
Pregnancy-related medical research
7.51
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