Serelaxin A Novel Therapy for Acute Heart Failure

Authors: Javier Díez

Publish Date: 2014/03/04

Volume: 14, Issue: 4, Pages: 275-285

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Abstract

Acute heart failure AHF is characterized by high morbidity and mortality and high costs Although the treatment of AHF has not changed substantially in recent decades it is becoming clear that treatment strategies for AHF need to address both the immediate hemodynamic abnormalities giving rise to congestion as well as prevent organ damage that can influence longterm prognosis Serelaxin the recombinant form of human relaxin2 a naturally occurring peptide hormone has been found to significantly improve symptoms and signs of AHF prevent inhospital worsening heart failure as well as significantly improve 180day cardiovascular and allcause mortality after a 48h infusion commenced within 16 h of presentation RELAXAHF study Available data suggest that the clinical benefits may be attributable to a potential combination of multiple actions of serelaxin including improving systemic cardiac and renal hemodynamics and protecting cells and organs from damage via antiinflammatory anticell death antifibrotic antihypertrophic and proangiogenic effects This manuscript describes the short and longterm effects of serelaxin in AHF patients analyzing how these effects can be explained by taking into account the range of hemodynamic and nonhemodynamic actions of serelaxin In addition this paper also addresses several aspects related to the role of serelaxin in the therapy of AHF that remain to be clarified and warrant further investigationHeart failure HF is thought to affect approximately 15 million patients in Europe and 5 million in the USA 1 2 HF places a large burden on patients and healthcare systems 1 3 4 and hospitalization for acute HF AHF contributes to much of the economic burden 1 There are more than 1 million hospitalizations for AHF each year in the USA 2 and each hospitalization for AHF costs in the region of US19000 5 AHF is associated with high rates of subsequent mortality and hospital readmission and is an increasing problem due to an aging population and the increasing prevalence of risk factors 1 6 7 8 9 Treatment of AHF has not changed substantially in recent decades and major trials with new therapies have failed likely due to a poor understanding of the pathophysiology of AHF as well as an insufficient knowledge of the mechanisms of action of the new agents used to treat patients with AHF 10AHF is a syndrome the pathophysiology of which is complex and not fully understood probably due to the lack of adequate experimental models of AHF It is now known that it involves not only impaired hemodynamic function but also neurohormonal activation inflammation and oxidative stress which can promote myocardial renal and hepatic injury and remodeling 11 12 13 This multiorgan damage may accelerate disease progression and impact longterm prognosis Indeed many existing and emerging markers of cardiac and extracardiac injury confirm that such damage is associated with worse longterm outcomes in AHF 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Therefore it appears that treatment strategies for AHF need to address both the immediate hemodynamic abnormalities giving rise to dyspnea and congestion as well as prevent organ damage by addressing the myocardial and extracardiac cell injury and remodeling that influence longterm prognosisSerelaxin is the recombinant form of human relaxin2 a naturally occurring peptide hormone that mediates systemic hemodynamic and renal adaptive changes during pregnancy 31 Serelaxin mediates its actions by binding to a member of the Gproteincoupled receptors known as relaxin family peptide RXFP receptors that are located in heart tissue blood vessels and the kidneys 31 32 Binding of serelaxin to its RXFP1 receptor activates multiple signaling pathways promoting systemic and renal hemodynamic effects 32 33 However serelaxin also appears to have multiple additional effects in the cardiovascular CV system and other organs including antiinflammatory anticell injury/death antifibrotic antihypertrophic and proangiogenic effects 33 34 35 The combination of the hemodynamic and organprotective effects of serelaxin may contribute to the short and longterm benefits of this agent in AHF as shown in a recent phase III study of serelaxin in AHF the RELAXAHF RELAXin in Acute Heart Failure studyThis review aims to outline the clinical data with serelaxin in patients with AHF integrating and extrapolating the available mechanistic data that could help to explain both the short and longterm clinical effects observed with this novel agent Some of these mechanistic studies have investigated the effects of nonhuman forms of relaxin2 instead of serelaxin recombinant human relaxin2 and where possible this review tries to highlight the form used eg porcine relaxin2 vs serelaxin This review also provides a critical analysis of the issues still pending clarification regarding the role of serelaxin in the therapy of AHFRELAXAHF was a phase III multicenter randomized doubleblind placebocontrolled study designed to investigate the efficacy and safety of serelaxin in the treatment of AHF 36 37 Patients hospitalized for AHF with systolic blood pressure SBP 125 mmHg mildtomoderate renal impairment and increased levels of Nterminal proBtype natriuretic peptide NTproBNP were randomized within 16 h to serelaxin 30 μg/kg/day as a 48h intravenous infusion or placebo both on top of standard of care Serelaxin significantly reduced the shortterm effects of AHF including symptoms and signs of congestion during hospitalization and inhospital outcomes compared with placebo Serelaxin significantly improved the primary efficacy endpoint of dyspnea relief through day 5 assessed by the visual analog scale compared with placebo p = 0007 It also provided a numerical but not statistically significant improvement in dyspnea relief assessed by the Likert scale at 6 12 and 24 h 36 Serelaxintreated patients experienced significant improvements in other symptoms and signs of AHF dyspnea on exertion orthopnea edema rales at day 2 compared with placebotreated patients Consistent with prompt decongestion serelaxin treatment was associated with significantly lower NTproBNP levels at day 2 compared with placebo p  0001 36 In terms of inhospital measures significantly fewer serelaxintreated patients experienced inhospital worsening HF through day 5 compared with placebo p  0001 and serelaxin treatment was associated with a significantly shorter length of hospital stay p = 00039 36In the RELAXAHF study serelaxin was associated with a reduced risk of allcause mortality compared with placebo This effect was consistent with that observed in the phase II PreRELAXAHF study 14 Reprinted from Metra 14 copyright 2013 with permission from ElsevierInsights into the possible mechanisms involved in these shortterm effects of serelaxin are given by the interpretation of results of earlier clinical studies In a study of stable patients with compensated HF serelaxin provided hemodynamic improvements including reduced pulmonary capillary wedge pressure PCWP and systemic vascular resistance SVR and increased cardiac index suggesting it may reduce cardiac overload and improve cardiac performance 41 42 Similarly reductions in SVR and PCWP and increases in cardiac index have been observed with serelaxin in patients with AHF 43 Serelaxin has also been shown to increase renal plasma flow and reduce renal vascular resistance in rats 44 and in healthy volunteers 45 suggesting it may increase renal perfusion Such improvements in myocardial and renal function will decrease preload and afterload leading to relief of the symptoms and signs of congestion and renal impairment

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