End-organ protective effect of serelaxin in patients hospitalized for heart failure: Results of the biomarker substudy of Relaxin in Acute Heart Failure-2 (RELAX-AHF-2)

Adriaan A Voors; Marco Metra; Douwe Postmus; Barry H Greenberg; Gadi Cotter; Beth A Davison; Iris E Beldhuis; G Michael Felker; Gerasimos Filippatos; Peter S Pang; Piotr Ponikowski; Claudio Gimpelewicz; John R Teerlink

doi:10.1002/ejhf.3551

End-organ protective effect of serelaxin in patients hospitalized for heart failure: Results of the biomarker substudy of Relaxin in Acute Heart Failure-2 (RELAX-AHF-2)

Eur J Heart Fail. 2024 Dec 12. doi: 10.1002/ejhf.3551. Online ahead of print.

Authors

Affiliations

¹ University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
² Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University of Brescia, Brescia, Italy.
³ Division of Cardiology, University of California, San Francisco, San Diego, CA, USA.
⁴ Momentum Research, Durham, NC, USA.
⁵ Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
⁶ Department of Cardiology, Atttikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
⁷ Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
⁸ Department of Heart Diseases, Medical University, Military Hospital, Wrocław, Poland.
⁹ Novartis Pharma, Basel, Switzerland.
¹⁰ Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California, San Francisco, San Francisco, CA, USA.

PMID: 39663924
DOI: 10.1002/ejhf.3551

Abstract

Aims: Serelaxin is recombinant human relaxin-2, a hormone responsible for haemodynamic adaptations and organ protection in pregnancy. In the RELAX-AHF trial, serelaxin demonstrated reductions in cardiac, renal and hepatic damage. In RELAX-AHF-2, organ damage-related biomarkers were assessed in a biomarker substudy.

Methods and results: Patients enrolled within 16 h of presentation for heart failure hospitalization were randomized to 48-h infusions of either serelaxin (30 μg/kg/day) or placebo, and plasma samples were obtained at baseline, 2, 5, and 14 days in patients participating in the biomarker substudy. Of the 6545 patients analysed in RELAX-AHF-2, 1020 (15.6%) patients (mean age 72 ± 12 years; 61% male) were enrolled in the biomarker substudy. Compared to placebo, serelaxin decreased percentage change from baseline in troponin T through day 14 (serelaxin +0.2% vs. placebo +40.3%; p = 0.042), as well as creatinine (-0.8% vs. +5.8%; p = 0.002), cystatin C (+3.8% vs. +8.3%; p = 0.016), and uric acid (+0.8% vs. +7.2%; p = 0.0014) at day 2. The decrease of N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to day 2 was greater in serelaxin-treated patients (-39.8% vs. -27.6%; p = 0.002). Early changes in NT-proBNP and troponin, but not creatinine, cystatin C and uric acid, were associated with 180-day mortality. In this substudy population, serelaxin did not reduce 180-day cardiovascular death (hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.49-1.25; p = 0.30), but significantly reduced worsening heart failure through day 5 (HR 0.55; 95% CI 0.33-0.93; p = 0.027).

Conclusion: In this substudy, serelaxin decreased plasma concentrations of cardiac, renal and hepatic injury markers. Changes of most of these markers were associated with cardiovascular mortality. In this pre-specified biomarker subgroup, serelaxin did not reduce 180-day cardiovascular mortality but significantly reduced worsening heart failure through day 5.

Keywords: Acute heart failure; Biomarkers; Organ protection; Pharmacotherapy.