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