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Serelaxin: a novel therapy for acute heart failure with a range of hemodynamic and non-hemodynamic actions

Significance Statement

Acute heart failure (AHF) is a heterogeneous and complex syndrome that associates central and/or peripheral fluid accumulation to a variable degree of end organ hypoperfusion and damage. The syndrome of AHF comprises activation of multiple systems/pathways (neuro-hormonal, immune, inflammatory) in multiple organs (heart, kidney, liver, gastrointestinal tract and endothelium) that make management complex, and result in an unfavourable long-term outcome. Furthermore, the heterogeneous population of AHF patients affected with potentially multiple operative pathophysiologic mechanisms makes a single targeted therapy a challenge. This may explain that in the last 2 decades more than 20 phase III trials with novel agents have not improved intermediate to long-term clinical outcomes and/or have yielded to concerns about safety. Serelaxin, a recombinant form of human relaxin-2 (a naturally occurring vasoactive peptide hormone with diverse vascular [e.g., it induces time-dependent vasodilatation and reduces arterial vascular resistance or large artery stiffness] and biological [e.g., it inhibits inflammation, oxidative stress, cell death and fibeosis, and stimulates angiogenesis] effects), yielded promising hemodynamic and neurohormonal effects in phase II trials and in predefined subpopulations. In the larger placebo controlled serelaxin, recombinant human relaxin-2, for treatment of Acute Heart Failure (RELAX-AHF) trial, a 48 h infusion of serelaxin (30 µg/kg/d) improved dyspnea, reduced end organ damage, and resulted in lower 180-day mortality in AHF patients with a systolic blood pressure greater than 125 mm Hg, an estimated glomerular filtration rate of 30-75 mL/min·1.73 m2, and BNP levels ≥350 ng/L or NT-proBNP levels ≥ 1400 ng/L who were not receiving nitrates or nitroprusside therapy. Inspired by these findings and based on currently existing preclinical data, a working hypothesis for mechanisms by which a short-term serelaxin therapy yields long-term benefits in patients with AHF proposes that it might remedy key histopathology of the failing heart and/or protect against AHF-associated end organ damage. The adequately powered RELAX-AHF2 randomised trial is now assessing the mortality benefit of serelaxin against placebo. Cardiovascular mortality during at 180 days is the primary endpoint of RELAX-AHF2.

Serelaxin A Novel Therapy for Acute Heart Failure with Range of Hemodynamic Non-Hemodynamic Actions. Global Medical Discovery

 

 

 

 

 

 

 

 

Journal Reference

Díez J. Am J Cardiovasc Drugs. 2014 Aug;14(4):275-85.

School of Medicine, University of Navarra, Pamplona, Spain, [email protected]

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 long-term prognosis. Serelaxin, the recombinant form of human relaxin-2, a naturally occurring peptide hormone, has been found to significantly improve symptoms and signs of AHF, prevent in-hospital worsening heart failure, as well as significantly improve 180-day cardiovascular and all-cause mortality after a 48-h infusion commenced within 16 h of presentation (RELAX-AHF 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 anti-inflammatory, anti-cell death, anti-fibrotic, anti-hypertrophic, and pro-angiogenic effects. This manuscript describes the short- and long-term effects of serelaxin in AHF patients, analyzing how these effects can be explained by taking into account the range of hemodynamic and non-hemodynamic 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 investigation.

Go To American Journal of Cardiovascular Drugs

 

 

 

 

 

 

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