Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): A randomised placebo-controlled trial

John R. Teerlink, Gad Cotter, Beth A. Davison, G. Michael Felker, Gerasimos Filippatos, Barry H. Greenberg, Piotr Ponikowski, Elaine Unemori, Adriaan A. Voors, Kirkwood F. Adams, Maria I. Dorobantu, Liliana R. Grinfeld, Guillaume Jondeau, Alon Marmor, Josep Masip, Peter Pang, Karl Werdan, Sam L. Teichman, Angelo Trapani, Christopher A. BushRajnish Saini, Christoph Schumacher, Thomas M. Severin, Marco Metra

Research output: Contribution to journalArticle

623 Citations (Scopus)

Abstract

Background Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic eff ects. 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 insuffi ciency, 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 fi rst 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806. Findings 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 signifi cant eff ect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No signifi cant eff ects 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 signifi cant reductions of other prespecifi ed 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). Interpretation Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no eff ect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality. Funding Corthera, a Novartis affi liate company.

Original languageEnglish (US)
Pages (from-to)29-39
Number of pages11
JournalThe Lancet
Volume381
Issue number9860
DOIs
StatePublished - Jan 2013
Externally publishedYes

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Relaxin
Randomized Controlled Trials
Heart Failure
Placebos
Dyspnea
Patient Readmission
Therapeutics
Brain Natriuretic Peptide
Visual Analog Scale
Area Under Curve
Blood Pressure
Peptide Hormones
Kaplan-Meier Estimate
Random Allocation
Intravenous Infusions
Renal Insufficiency
Thorax
Hemodynamics
Kidney

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Teerlink, J. R., Cotter, G., Davison, B. A., Felker, G. M., Filippatos, G., Greenberg, B. H., ... Metra, M. (2013). Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): A randomised placebo-controlled trial. The Lancet, 381(9860), 29-39. https://doi.org/10.1016/S0140-6736(12)61855-8

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF) : A randomised placebo-controlled trial. / Teerlink, John R.; Cotter, Gad; Davison, Beth A.; Felker, G. Michael; Filippatos, Gerasimos; Greenberg, Barry H.; Ponikowski, Piotr; Unemori, Elaine; Voors, Adriaan A.; Adams, Kirkwood F.; Dorobantu, Maria I.; Grinfeld, Liliana R.; Jondeau, Guillaume; Marmor, Alon; Masip, Josep; Pang, Peter; Werdan, Karl; Teichman, Sam L.; Trapani, Angelo; Bush, Christopher A.; Saini, Rajnish; Schumacher, Christoph; Severin, Thomas M.; Metra, Marco.

In: The Lancet, Vol. 381, No. 9860, 01.2013, p. 29-39.

Research output: Contribution to journalArticle

Teerlink, JR, Cotter, G, Davison, BA, Felker, GM, Filippatos, G, Greenberg, BH, Ponikowski, P, Unemori, E, Voors, AA, Adams, KF, Dorobantu, MI, Grinfeld, LR, Jondeau, G, Marmor, A, Masip, J, Pang, P, Werdan, K, Teichman, SL, Trapani, A, Bush, CA, Saini, R, Schumacher, C, Severin, TM & Metra, M 2013, 'Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): A randomised placebo-controlled trial', The Lancet, vol. 381, no. 9860, pp. 29-39. https://doi.org/10.1016/S0140-6736(12)61855-8
Teerlink, John R. ; Cotter, Gad ; Davison, Beth A. ; Felker, G. Michael ; Filippatos, Gerasimos ; Greenberg, Barry H. ; Ponikowski, Piotr ; Unemori, Elaine ; Voors, Adriaan A. ; Adams, Kirkwood F. ; Dorobantu, Maria I. ; Grinfeld, Liliana R. ; Jondeau, Guillaume ; Marmor, Alon ; Masip, Josep ; Pang, Peter ; Werdan, Karl ; Teichman, Sam L. ; Trapani, Angelo ; Bush, Christopher A. ; Saini, Rajnish ; Schumacher, Christoph ; Severin, Thomas M. ; Metra, Marco. / Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF) : A randomised placebo-controlled trial. In: The Lancet. 2013 ; Vol. 381, No. 9860. pp. 29-39.
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abstract = "Background Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic eff ects. 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 insuffi ciency, 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 fi rst 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806. Findings 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 signifi cant eff ect on the other primary endpoint (Likert scale; placebo, 150 patients [26{\%}]; serelaxin, 156 [27{\%}]; p=0·70). No signifi cant eff ects 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 signifi cant reductions of other prespecifi ed 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). Interpretation Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no eff ect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality. Funding Corthera, a Novartis affi liate company.",
author = "Teerlink, {John R.} and Gad Cotter and Davison, {Beth A.} and Felker, {G. Michael} and Gerasimos Filippatos and Greenberg, {Barry H.} and Piotr Ponikowski and Elaine Unemori and Voors, {Adriaan A.} and Adams, {Kirkwood F.} and Dorobantu, {Maria I.} and Grinfeld, {Liliana R.} and Guillaume Jondeau and Alon Marmor and Josep Masip and Peter Pang and Karl Werdan and Teichman, {Sam L.} and Angelo Trapani and Bush, {Christopher A.} and Rajnish Saini and Christoph Schumacher and Severin, {Thomas M.} and Marco Metra",
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doi = "10.1016/S0140-6736(12)61855-8",
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TY - JOUR

T1 - Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF)

T2 - A randomised placebo-controlled trial

AU - Teerlink, John R.

AU - Cotter, Gad

AU - Davison, Beth A.

AU - Felker, G. Michael

AU - Filippatos, Gerasimos

AU - Greenberg, Barry H.

AU - Ponikowski, Piotr

AU - Unemori, Elaine

AU - Voors, Adriaan A.

AU - Adams, Kirkwood F.

AU - Dorobantu, Maria I.

AU - Grinfeld, Liliana R.

AU - Jondeau, Guillaume

AU - Marmor, Alon

AU - Masip, Josep

AU - Pang, Peter

AU - Werdan, Karl

AU - Teichman, Sam L.

AU - Trapani, Angelo

AU - Bush, Christopher A.

AU - Saini, Rajnish

AU - Schumacher, Christoph

AU - Severin, Thomas M.

AU - Metra, Marco

PY - 2013/1

Y1 - 2013/1

N2 - Background Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic eff ects. 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 insuffi ciency, 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 fi rst 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806. Findings 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 signifi cant eff ect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No signifi cant eff ects 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 signifi cant reductions of other prespecifi ed 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). Interpretation Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no eff ect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality. Funding Corthera, a Novartis affi liate company.

AB - Background Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic eff ects. 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 insuffi ciency, 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 fi rst 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806. Findings 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 signifi cant eff ect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No signifi cant eff ects 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 signifi cant reductions of other prespecifi ed 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). Interpretation Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no eff ect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality. Funding Corthera, a Novartis affi liate company.

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