Rationale and Design of the ATHENA-HF Trial: Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy in Heart Failure

JACC Heart Fail. 2016 Sep;4(9):726-35. doi: 10.1016/j.jchf.2016.06.003. Epub 2016 Aug 10.


Although therapy with mineralocorticoid receptor antagonists (MRAs) is recommended for patients with chronic heart failure (HF) with reduced ejection fraction and in post-infarction HF, it has not been studied well in acute HF (AHF) despite being commonly used in this setting. At high doses, MRA therapy in AHF may relieve congestion through its natriuretic properties and mitigate the effects of adverse neurohormonal activation associated with intravenous loop diuretics. The ATHENA-HF (Aldosterone Targeted Neurohormonal Combined with Natriuresis Therapy in Heart Failure) trial is a randomized, double-blind, placebo-controlled study of the safety and efficacy of 100 mg/day spironolactone versus placebo (or continued low-dose spironolactone use in participants who are already receiving spironolactone at baseline) in 360 patients hospitalized for AHF. Patients are randomized within 24 h of receiving the first dose of intravenous diuretics. The primary objective is to determine if high-dose spironolactone, compared with standard care, will lead to greater reductions in N-terminal pro-B-type natriuretic peptide levels from randomization to 96 h. The secondary endpoints include changes in the clinical congestion score, dyspnea relief, urine output, weight change, loop diuretic dose, and in-hospital worsening HF. Index hospital length of stay and 30-day clinical outcomes will be assessed. Safety endpoints include risk of hyperkalemia and renal function. Differences among patients with reduced versus preserved ejection fraction will be determined. (Study of High-dose Spironolactone vs. Placebo Therapy in Acute Heart Failure [ATHENA-HF]; NCT02235077).

Keywords: acute heart failure; aldosterone; heart failure; hospitalization; mineralocorticoid receptor antagonist; natriuretic peptides.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Cause of Death
  • Disease Progression
  • Double-Blind Method
  • Dyspnea / etiology
  • Dyspnea / physiopathology
  • Heart Failure / blood
  • Heart Failure / complications
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Humans
  • Hyperkalemia / chemically induced
  • Mineralocorticoid Receptor Antagonists / therapeutic use*
  • Mortality
  • Natriuretic Peptide, Brain / blood*
  • Patient Readmission
  • Peptide Fragments / blood*
  • Sodium Potassium Chloride Symporter Inhibitors / administration & dosage
  • Spironolactone / therapeutic use*
  • Treatment Outcome


  • Mineralocorticoid Receptor Antagonists
  • Peptide Fragments
  • Sodium Potassium Chloride Symporter Inhibitors
  • pro-brain natriuretic peptide (1-76)
  • Natriuretic Peptide, Brain
  • Spironolactone

Associated data

  • ClinicalTrials.gov/NCT02235077