血管舒张素对射血分数保留的心力衰竭恶化的影响：一项2期随机试验。

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

作者信息

Borlaug Barry A, Testani Jeffrey M, Petrie Mark C, Wang Zhenzhong, Cunningham Jonathan, Adams Kirkwood F, Amir Offer, Bělohlávek Jan, Bocchi Edimar, Freitas Aguinaldo, Hominal Miguel, Kadokami Toshiaki, Merkely Bela, Miller Christopher A, Nuñez Julio, Verma Subodh, Yilmaz Mehmet Birhan, Oru Ena, Sam Flora

机构信息

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.

出版信息

Nat Med. 2025 Aug 31. doi: 10.1038/s41591-025-03939-6.

DOI:10.1038/s41591-025-03939-6

PMID:40887551

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, 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 1.73 m, 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 .

摘要

松弛素是一种肽类激素，可能会减轻循环系统充血并改善肾功能。在本研究中，我们进行了一项双盲、国际、多中心试验，以测试长效人松弛素沃伦松弛素是否能改善射血分数保留的心力衰竭（HFpEF）患者的左心房（LA）功能、减轻充血并改善肾功能。我们将纽约心脏协会（NYHA）II-IV级HFpEF且近期发生心力衰竭（HF）失代偿的患者随机分为三组，分别皮下注射每周一次的25毫克、50毫克或100毫克沃伦松弛素或安慰剂。主要结局是26周时LA储备应变的变化，关键次要终点包括N末端B型利钠肽原（NT-proBNP）、估算肾小球滤过率（eGFR）的变化以及安全性。在招募了332名参与者（平均年龄74岁，49%为女性，平均体重指数30.6 kg/m²，31.9%为NYHA III-IV级）后，由于有证据表明充血情况恶化，主办方提前终止了该试验。与安慰剂相比，25毫克沃伦松弛素改善了LA储备应变（增加3.9%，95%置信区间（CI）：1.1-6.6，P = 0.006），但50毫克（增加1.3%，95% CI：-1.3至3.9，P = 0.332）或100毫克（增加0.9%，95% CI：-1.8至3.6，P = 0.521）剂量对该结局无影响。在26周时，沃伦松弛素（汇总所有剂量）使NT-proBNP水平升高（增加24.5%，95% CI：2.0-51.8），对eGFR无显著影响（增加2.2 ml/min/1.73 m²，95% CI：-1.8至6.3）。与安慰剂相比，沃伦松弛素还与HF住院风险非显著增加相关（风险比 = 2.64，95% CI：0.93-7.56，P = 0.070），同时有心血管和肾脏严重不良事件数量增加的信号（优势比 = 2.52，95% CI：0.95-6.68，P = 0.056）。总之，尽管有证据表明低剂量时LA功能有所改善，但这种长效人松弛素治疗与近期失代偿的HFpEF患者充血情况恶化相关。ClinicalTrials.gov标识符：NCT05592275 。