Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Abstract

Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.

The year in cardiology 2017: heart failure

“…72 Similarly, early administration of serelaxin did not improve the composite endpoint of worsening HF at 5 days or CV death at 6 months in RELAX-AHF2. 73 Interestingly, an observational study suggested that treatment with intravenous loop diuretic within 1-h of presentation to the emergency department was associated with lower in-hospital mortality, 74 but the observational nature of this study precludes any conclusions regarding optimal type or timing of AHF interventions.…”

Peripartum cardiomyopathy

“…Serelaxin is a recombinant form of relaxin-2 that showed some evidence of benefit in alleviating dyspnea in acute heart failure in the RELAX-AHF trial,141 although it had no effect on mortality from cardiovascular disease (RELAX-AHF-2) 142. In a mouse model of PPCM, relaxin increased angiogenesis and cardiomyocyte hypertrophy but did not improve systolic function 143.…”

Highlights in heart failure

“…47,57,90,150,[219][220][221] This is consistent with the relatively high proportion of patients who have an early rehospitalization for non-cardiac causes. 228,229 The role of sudden cardiac death (SCD) in postdischarge outcomes was investigated in an analysis from Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. Such acute injury, shown by laboratory markers, has independent prognostic value and may be a cause of poor post-discharge outcomes.…”