title: Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial.
abstract: BACKGROUND
  Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo.
  
  
  METHODS
  RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806.
  
  
  RESULTS
  1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120-775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74-1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42-0·93; p=0·019).
  
  
  CONCLUSIONS
  Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality.
  
  
  BACKGROUND
  Corthera, a Novartis affiliate company.
authors.affiliation: University of California at San Francisco and San Francisco Veterans Affairs Medical Center, San Francisco, CA 94121-1545, USA. john.teerlink@ucsf.edu
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
authors.forename: Gad
authors.initials: G
authors.lastname: Cotter
authors.forename: Beth A
authors.initials: BA
authors.lastname: Davison
authors.forename: G Michael
authors.initials: GM
authors.lastname: Felker
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Filippatos
authors.forename: Barry H
authors.initials: BH
authors.lastname: Greenberg
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.forename: Elaine
authors.initials: E
authors.lastname: Unemori
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.forename: Kirkwood F
authors.initials: KF
authors.lastname: Adams
authors.forename: Maria I
authors.initials: MI
authors.lastname: Dorobantu
authors.forename: Liliana R
authors.initials: LR
authors.lastname: Grinfeld
authors.forename: Guillaume
authors.initials: G
authors.lastname: Jondeau
authors.forename: Alon
authors.initials: A
authors.lastname: Marmor
authors.forename: Josep
authors.initials: J
authors.lastname: Masip
authors.forename: Peter S
authors.initials: PS
authors.lastname: Pang
authors.forename: Karl
authors.initials: K
authors.lastname: Werdan
authors.forename: Sam L
authors.initials: SL
authors.lastname: Teichman
authors.forename: Angelo
authors.initials: A
authors.lastname: Trapani
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Bush
authors.forename: Rajnish
authors.initials: R
authors.lastname: Saini
authors.forename: Christoph
authors.initials: C
authors.lastname: Schumacher
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Severin
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
mesh_terms: D000208:Acute Disease; D000368:Aged; D004311:Double-Blind Method; D004417:Dyspnea / Q000188:drug therapy / Q000209:etiology; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D007902:Length of Stay; D008297:Male; D011994:Recombinant Proteins / Q000627:therapeutic use; D012065:Relaxin / Q000627:therapeutic use*; D015996:Survival Rate
chemical_list: C095068:RLN2 protein, human; D011994:Recombinant Proteins; C577649:serelaxin protein, human; D012065:Relaxin