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Original Investigation
September 2017

Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial

Author Affiliations
  • 1Department of Medicine, Stony Brook University, Stony Brook, New York
  • 2Duke Clinical Research Institute, Duke University, Durham, North Caroline
  • 3Department of Medicine, Duke University, Durham, North Carolina
  • 4Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 5Department of Medicine, Emory University, Atlanta, Georgia
  • 6The CardioVascular Center, Tufts Medical Center, Boston, Massachusetts
  • 7Department of Medicine, Washington University, St Louis, Missouri
  • 8Department of Medicine, University of Pennsylvania, Philadelphia
  • 9Department of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
  • 10Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
  • 11Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
  • 12National Center for Advancing Translational Sciences, National Institutes of Health, Baltimore, Maryland
  • 13Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, Baltimore, Maryland
  • 14Associate Editor, JAMA Cardiology
JAMA Cardiol. 2017;2(9):950-958. doi:10.1001/jamacardio.2017.2198
Key Points

Question  Does adding high-dose spironolactone treatment for patients with acute heart failure lower natriuretic peptide levels and improve outcomes better than usual care?

Findings  In this randomized clinical trial, high-dose spironolactone use in acute heart failure was not associated with greater improvement in natriuretic peptide levels, symptoms, congestion, urine output, weight loss, or clinical outcomes than treatment with usual care.

Meaning  Routinely using high-dose spironolactone in acute heart failure is not recommended; further studies targeting specifically patients who are resistant to diuretics with high-dose spironolactone are needed.


Importance  Persistent congestion is associated with worse outcomes in acute heart failure (AHF). Mineralocorticoid receptor antagonists administered at high doses may relieve congestion, overcome diuretic resistance, and mitigate the effects of adverse neurohormonal activation in AHF.

Objective  To assess the effect of high-dose spironolactone and usual care on N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels compared with usual care alone.

Design, Setting, and Participants  This double-blind and placebo (or low-dose)-controlled randomized clinical trial was conducted in 22 US acute care hospitals among patients with AHF who were previously receiving no or low-dose (12.5 mg or 25 mg daily) spironolactone and had NT-proBNP levels of 1000 pg/mL or more or B-type natriuretic peptide levels of 250 pg/mL or more, regardless of ejection fraction.

Interventions  High-dose spironolactone (100 mg) vs placebo or 25 mg spironolactone (usual care) daily for 96 hours

Main Outcomes and Measures  The primary end point was the change in NT-proBNP levels from baseline to 96 hours. Secondary end points included the clinical congestion score, dyspnea assessment, net urine output, and net weight change. Safety end points included hyperkalemia and changes in renal function.

Results  A total of 360 patients were randomized, of whom the median age was 65 years, 129 (36%) were women, 200 (55.5%) were white, 151 (42%) were black, 8 (2%) were Hispanic or Latino, 9 (2.5%) were of other race/ethnicity, and the median left ventricular ejection fraction was 34%. Baseline median (interquartile range) NT-proBNP levels were 4601 (2697-9596) pg/mL among the group treated with high-dose spironolactone and 3753 (1968-7633) pg/mL among the group who received usual care. There was no significant difference in the log NT-proBNP reduction between the 2 groups (−0.55 [95% CI, −0.92 to −0.18] with high-dose spironolactone and −0.49 [95% CI, −0.98 to −0.14] with usual care, P = .57). None of the secondary end point or day-30 all-cause mortality or heart failure hospitalization rate differed between the 2 groups. The changes in serum potassium and estimated glomerular filtration rate at 24, 48, 72, and 96 hours. were similar between the 2 groups.

Conclusions and Relevance  Adding treatment with high-dose spironolactone to usual care for patients with AHF for 96 hours was well tolerated but did not improve the primary or secondary efficacy end points.

Trial Registration  clinicaltrials.gov Identifier: NCT02235077