Elsevier

The Lancet

Volume 381, Issue 9860, 5–11 January 2013, Pages 29-39
The Lancet

Articles
Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial

https://doi.org/10.1016/S0140-6736(12)61855-8Get rights and content

Summary

Background

Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.

Methods

RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806.

Findings

1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120–775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74–1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42–0·93; p=0·019).

Interpretation

Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality.

Funding

Corthera, a Novartis affiliate company.

Introduction

Heart failure is a major worldwide health problem and the most frequent cause of admission to hospital in patients older than 65 years.1, 2, 3, 4 Although existing treatments substantially improve the clinical course and prognosis of ambulatory patients with chronic heart failure, treatment of patients admitted to hospital for acute heart failure has not changed in recent decades3, 5 with no treatments showing safe improvement in outcomes. Despite a favourable response to initial treatment, most patients remain symptomatic at 24 h and up to 25% develop worsening symptoms during the hospital stay.6, 7, 8 Sustained relief of these signs and symptoms remains an important goal of treatment.9, 10, 11

Admission to hospital for heart failure portends an increased risk of poor outcomes, with a 5–15-times increase in the risk of death compared with ambulatory patients and a mortality rate of 10–20% in the 6 months after hospital discharge.12, 13 Although hospital admission could simply herald disease progression, this event and the related interventions might also directly contribute to poor outcomes through increased neurohormonal and inflammatory activation, haemodynamic compromise, and consequent end-organ damage.12, 14 Drugs that prevent or treat these factors might favourably affect the clinical course and prognosis of these patients, even if given for a short time during the acute episode.

Serelaxin is recombinant human relaxin-2, a naturally occurring peptide that regulates maternal adaptations to pregnancy15 with several effects potentially relevant to the treatment of acute heart failure, including increased arterial compliance, cardiac output, and renal blood flow.16, 17 Pre-RELAX-AHF,18 a phase 2, dose-finding study with 234 patients, suggested beneficial effects of serelaxin on both dyspnoea and post-discharge clinical outcomes in patients admitted for acute heart failure, with evidence of congestion, normal-to-raised blood pressure, and mild-to-moderate renal dysfunction. The RELAXin in Acute Heart Failure (RELAX-AHF) trial was done in the same targeted patient population to evaluate the effects of serelaxin on dyspnoea relief and post-discharge clinical efficacy outcomes, as well as its safety and tolerability.19

Section snippets

Study design

RELAX-AHF was a prospective, randomised, double-blind, placebo-controlled, parallel-group trial comparing serelaxin with placebo in patients admitted to hospital for acute heart failure. Patients were enrolled at 96 sites in 11 countries. Centres included cardiology units and emergency medicine departments. The study background and design have been published19 and the protocol and statistical analysis plan are available in the appendix. The ethics committee at each centre approved the study,

Results

From Oct 11, 2009 to Feb 14, 2012, 1161 patients were enrolled (placebo, 580; serelaxin, 581), of whom 1138 (98%) received randomised study treatment (figure 1). Vital status at 180 days was ascertained for all but 14 patients (two lost to follow-up; 12 withdrew consent); baseline variables are shown in table 1.

Serelaxin significantly improved the primary dyspnoea efficacy endpoint compared with placebo, as evaluated by the VAS AUC (448 mm × h, 95% CI 120–775; p=0·007), fulfilling the

Discussion

In RELAX-AHF, a 48-h infusion of serelaxin resulted in mild improvements in measures of dyspnoea, associated with significant reductions in early worsening heart failure events, signs and symptoms of congestion, initial length of hospital stay, and duration of intensive care (panel). However, there was no improvement in readmission to hospital for heart failure or renal failure. A 37% reduction in cardiovascular and all-cause mortality was also noted in the serelaxin-treated patients. Serelaxin

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