Serelaxin: insights into its haemodynamic, biochemical, and clinical effects in acute heart failure

This editorial refers to ‘A randomized, double-blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure’, by P. Ponikowski et al. doi:10.1093/eurheartj/eht459 Treatment for acute heart failure (AHF) has not changed much in the last two decades.1 Intravenous (i.v.) drugs such as levosimendan, nesiritide, rolofylline, and tezosentan have been studied in phase III randomized controlled trials (RCTs) with disappointing results. None of these drugs improved dyspnoea, worsening heart failure, readmissions to hospital, cardiovascular mortality, or all-cause mortality in AHF patients, mostly during short-term follow-up.1 These drugs increased the probability of ventricular and atrial arrhythmias or symptomatic hypotension (levosimendan, nesiritide), or seizures and strokes (rolofylline). Ularitide, a novel natriuretic peptide, is undergoing a phase III RCT focused on symptoms and cardiovascular mortality. Several reasons for negative results are possible, including high heterogeneity of patients with AHF, several sources of bias in RCTs, scarcity of outcomes, and incomplete pre-clinical evaluation of drugs. Serelaxin, a recombinant human relaxin-2 peptide, regulates maternal adaptations to pregnancy, including arterial vasodilation, increased cardiac output, and increased renal blood flow.2 Given its potential for the treatment of AHF, this drug has been tested in phase II (Pre-RELAX-AHF)3 and phase III (RELAX-AHF)4 RCTs. These trials aimed to improve the design issues of other i.v. drugs for AHF. In the dose-finding Pre-RELAX-AHF trial,3 234 patients with AHF, dyspnoea, congestion on chest X-ray, increased brain natriuretic peptide (BNP) or N-terminal pro-hormone of BNP (NT-proBNP), mild to moderate renal insufficiency, and systolic blood pressure (SBP) >125 mmHg received a 48 h i.v. infusion of serelaxin vs. placebo. The authors felt that these patients had more chances to obtain benefit from serelaxin, with lower chances of harmful effects. Indeed, they found improvements in dyspnoea (as measured by a visual analogue scale …