Renal Hemodynamic Effects of Serelaxin in Patients With Chronic Heart Failure: A Randomized, Placebo-Controlled Study Adriaan A. Voors, Marion Dahlke, Sven Meyer, Janina Stepinska, Stephen S. Gottlieb, Andrew Jones, Yiming Zhang, Didier Laurent, Riemer H.J.A. Slart and Gerjan J. Navis Circ Heart Fail. published online October 6, 2014; Circulation: Heart Failure is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Copyright © 2014 American Heart Association, Inc. All rights reserved. Print ISSN: 1941-3289. Online ISSN: 1941-3297

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Renal Hemodynamic Effects of Serelaxin in Patients With Chronic Heart Failure: A Randomized, Placebo-Controlled Study Voors et al: Renal Hemodynamic Effects of Serelaxin in CHF

Adriaan A. Voors, MD, PhD;1 Marion Dahlke, MD, PhD;2 Sven Meyer, MD;1 Janina Stepinska, MD, PhD;3 Stephen S. Gottlieb, MD;4 Andrew Jones, MD, BSc, MSc;2 Yiming Zhang, PhD;5 Didier Laurent, PhD;2 Riemer H.J.A. Slart, MD, PhD;1 Gerjan J. Navis, MD, PhD1

1

University of Groningen, University Medical Center Groningen, n, th thee Ne Neth Netherlands ther th erla er land la nd

2

Novartis Pharma ma A AG, AG G Basel, G, Bas a el el, Switzerland

3

Institute of Cardiology, dio ology, Wa W Warsaw, arrsaw aw, Po Poland

4

University of Maryland, M Baltimore Baltimore, r , MD re

5

Novartis Pharmaceuticals, maceuticcal alss, East Eas astt Hanover, H no Ha ove ver, r N NJJ

Correspondence to Adriaan Voors, MD, PhD Department of Cardiology University Medical Center Groningen Hanzeplein 1, PO Box 30.001, 9700 RB Groningen, the Netherlands Tel. +31 50 3612355 Fax. +31 50 361 4391 Email: [email protected] DOI: 10.1161/CIRCHEARTFAILURE.114.001536 Journal Subject Codes: [10] Cardio-renal physiology/ pathophysiology, [11] Other heart failure

1 

Abstract Background—Serelaxin is a promising therapy for acute heart failure. The renal hemodynamic effects of serelaxin in patients with chronic heart failure (CHF) are unknown. Methods and Results—In this double-blind, randomized, placebo-controlled multicenter study, patients with NYHA Class II–III CHF, left ventricular ejection fraction ”45% and estimated glomerular filtration rate (eGFR) 30–89 mL/min/1.73m2 received intravenous serelaxin 30 ȝg/kg/day or placebo for 24 hours. Primarily, we assessed the difference between serelaxin and placebo on renal plasma flow (RPF; para-aminohippuric acid clearance) and GFR (iothalamate clearance) over 8–24 hours. All 22 patients from one clinical site were au ausi usi s bl blee me meas asur as urem ur em excluded from primary analyses prior to unblinding due to implausible measurements. The yearrs 89% 89% were weerre male, mean primary analysis comprised 65 patients, mean age was 68 (±10) years, 1 ) mL/min/1.73m 19) mL/min in n/1 / .773m2, 34 eGFR was 64 (±19) 34% % ha hhad ad d NYHA NY YHA AC Class lass IIII la lass III ssymptoms. ym mpt ptom omss. R om RPF PF increased i by 29% with serelaxin with placebo relative x aand xin nd 14% 14% %w i h pl it lac a eb e o (1 (13% 3% rre ela lati tive ti vee iincrease ncre nc reeas asee with wiith sserelaxin; errel e ax axin in;; p=0.0386), in gess did ge did no nott differ diff di ffer ff er ssignificantly ig gni nifi fica fi cant ca ntly nt ly oover verr 88–24 ve –24 24 hhours. ours ou rs. Fi rs Filt ltra lt rati ra tion ti on fraction ffract ract ra ctio ct io o (FF) while GFR changes Filtration increased by 36% with serelaxin and 62% with placebo (16% relative decrease with serelaxin; p=0.0019) during 8–24 hours. Changes in systolic blood pressure were largely similar and creatinine clearance did not differ between groups. Adverse event rates were similar with serelaxin (20.5%) and placebo (25.0%). Conclusions—In patients with CHF, serelaxin increased RPF and reduced the increase in FF compared with placebo, but did not affect GFR. These results suggest beneficial renal hemodynamic effects in patients with CHF. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT01546532. Key Words: heart failure, kidney, trials, hemodynamics

2 

Renal dysfunction is often present in patients with heart failure, and is related to a poorer prognosis.1,2 Patients with chronic heart failure are often treated with ACE-inhibitors and mineralocorticoid receptor antagonists (MRAs), although they often cause a further deterioration of renal function. Patients with acute heart failure are often treated with loop diuretics, which might also further deteriorate renal function. So far, no drugs that are used for treating chronic or acute heart failure have proved to improve renal function. Serelaxin, a recombinant human relaxin-2, is a promising and novel investigational therapy for the treatment of acute heart failure (AHF). In the RELAX-AHF study, early infusion of serelaxin was associated with a decrease in dyspnea and lower 180-day all-cause mortality in patients admitted for AHF.3Additionally, the study showed that treatment nt wi with th sserelaxin erel er elax el ax xin iis associated with lower serum creatinine and pplasma cystatin C concentrations with y ns compared com ompa om pare pa p red re dw wi ith placebo.4 Other studies also o iindicate ndicate po ppossible ssib ss ible ib le bbeneficial en nef efic i iall eeffects ic ffeectss of sserelaxin errellax xin i oon n re renal ena n l fu func function. ncti nc A study renal naal ef ffeect ctss of of sserelaxin erel elax el axin iin ax n 11 hhuman um uman man a vvolunteers o un ol unte teerss sh teer howed ow w dam arr investigating the rena effects showed marked increase of renal plasma flow compared significant change flow (RPF) (RP PF)) by by 47% 47% co comp mp par ared ed with wit ith h baseline baase b s li line ne levels, lev evel els, s,, bbut ut nno o si sign gnif gn ifi fii was observed in glomerular filtration rate (GFR).5 In models of chronic kidney disease, relaxin showed protective effects on kidney structure and function.6 However, prospective controlled studies on the renal hemodynamic effects of serelaxin in patients with heart failure, using the gold-standard methods for measuring GFR and RPF, are lacking. Therefore, we assessed the renal hemodynamic effects of serelaxin in patients with symptomatic chronic heart failure (CHF), impaired renal function, and a baseline systolic blood pressure (SBP) •110 mmHg.

3 

Methods Study Design, Population and Treatment This study was a double-blind, randomized, parallel-group, placebo-controlled, multicenter study. Inclusion criteria were: CHF with standard oral therapy including stable oral furosemide 40–240 mg/day or equivalent, reduced left ventricular ejection fraction (”45% within the past 6 months), brain natriuretic peptide (BNP) •100 pg/mL or N-terminal prohormone of brain natriuretic peptide (NT-proBNP) •400 pg/mL, NYHA Class II–III, worsening symptoms within the previous 3 months, and mild-to-moderate renal impairment (estimated GFR [eGFR] 30–89 mL/min/1.73m2). Key exclusion criteria comprised SBP 500 ȝmol/L or hepatic impairment, >50 spontaneous international normalized ratio >2.0, were not considered for the study. Interventional treatment consisted of serelaxin (30 ȝg/kg/day) or matching placebo, each provided as a 24-hour IV infusion. A central randomization scheme was used, and subjects were randomized using consecutive randomization numbers in blocks of four for each of the two stratification factors: subjects with prescribed daily dose of furosemide

Renal hemodynamic effects of serelaxin in patients with chronic heart failure: a randomized, placebo-controlled study.

Serelaxin is a promising therapy for acute heart failure. The renal hemodynamic effects of serelaxin in patients with chronic heart failure are unknow...
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