RELAXin in Acute Heart Failure-2 - RELAX-AHF-2

Contribution To Literature:

The RELAX-AHF-2 trial showed that short-term intravenous infusion of serelaxin does not improve outcomes compared with placebo in patients with ADHF.


The goal of this trial was to assess safety and efficacy of serelaxin compared with placebo in reducing cardiovascular (CV) mortality in patients presenting with acute decompensated heart failure (ADHF).

Study Design

Patients were randomly assigned in a 1:1 ratio to receive either serelaxin 30 μg/kg per day (n = 3,274) or placebo (n = 3,271).

  • Total number of enrollees: 6,545
  • Duration of follow-up: 6 months
  • Mean patient age: 73 years
  • Percentage female: 40%
  • Percentage with diabetes: 46%
  • Ejection fraction: 40%
  • New York Heart Association class: 1 month prior to admission: III (46%), IV (11%)

Inclusion criteria:

Hospitalized for AHF:

  • Dyspnea at rest or with minimal exertion
  • Pulmonary congestion on chest radiograph
  • B-type natriuretic peptide (BNP) ≥500 pg/ml or N-terminal pro-BNP ≥2000 pg/ml
  • Received ≥40 mg intravenous (IV) furosemide (or equivalent) at any time between admission to emergency services (either ambulance or hospital, including the emergency department) and the start of screening for the study
  • Systolic blood pressure >125 mm Hg
  • Impaired renal function on admission (estimated glomerular filtration rate [eGFR] 30-75 ml/min/1.73 m2)
  • Randomized within 16 hours from presentation
  • Age ≥18 years of age
  • Body weight <160 kg

Exclusion criteria:

  • Current or planned treatment with any IV therapies or mechanical support (except IV diuretics or IV nitrates if systolic blood pressure >150 mm Hg at screening)
  • Clinical evidence of acute coronary syndrome within 30 days prior to enrollment
  • AHF due to significant arrhythmias
  • Dyspnea due to noncardiac causes
  • Chronic obstructive pulmonary disease requiring daily steroids
  • Systolic BP >180 mm Hg or persistent heart rate >130 bpm
  • eGFR of <25 ml/min/1.73 m2 and/or those receiving current or planned dialysis or ultrafiltration

Principal Findings:

  • Primary efficacy endpoint, CV mortality at 6 months for serelaxin vs. placebo: 8.7% vs. 8.9%, p = 0.39
  • Worsening CHF: 6.9% vs. 7.7%, p = 0.10

Secondary endpoints for serelaxin vs. placebo:

  • All-cause mortality: 11.2% vs. 11.9%, p = 0.39
  • Length of stay: 6.8 vs. 6.9 days, p = 0.56
  • Safety: Hypotension: 2.4% vs. 2.0%, hypokalemia: 8.1% vs. 7.5%, p > 0.05


The results of the phase III RELAX-AHF trial indicate that a 48-hour infusion of serelaxin, a recombinant version of human relaxin (a peptide hormone secreted during pregnancy), does not improve outcomes compared with placebo in patients presenting with ADHF. These results are contrary to the phase II RELAX-AHF trial, where an improvement in hemodynamics and biomarkers was accompanied by reduction in CV and all-cause mortality with serelaxin noted at 6 months compared with placebo.

 This is an important trial that comes close on the heels of another vasodilator trial for ADHF – ULTRA-AHF, which was also negative. For ADHF, IV natriuretic vasodilators such as nesiritide, ularitide, and now serelaxin appear to decongest the system rapidly, but this does not seem to improve CV outcomes. Further exploration of this conundrum, as well as outlining patient populations that may benefit from these therapies, will be important.


Teerlink JR, Voors AA, Ponikowski P, et al. Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX-AHF-2 study. Eur J Heart Fail 2017;Apr 28:[Epub ahead of print].

Presented by Dr. John R. Teerlink at the ESC World Congress on Acute Heart Failure, April 29, 2017, Paris, France.

Clinical Topics: Heart Failure and Cardiomyopathies, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Atrial Natriuretic Factor, Biological Markers, Dyspnea, Furosemide, Glomerular Filtration Rate, Heart Failure, Hypokalemia, Hypotension, Length of Stay, Natriuretic Peptide, Brain, Physical Exertion, Relaxin, Vasodilator Agents

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