High-Dose Spironolactone in Acute Heart Failure

Study Questions:

What is 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?


The ATHENA-HF study cohort was comprised of patients with acute heart failure (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 BNP levels of ≥250 pg/ml, regardless of ejection fraction. The patients were randomized to high-dose spironolactone (100 mg) versus placebo or 25 mg spironolactone (usual care) daily, in a randomized fashion. The study drug was discontinued after 96 hours and further mineralocorticoid receptor antagonist (MRA) use was left to the treating physician’s discretion. The primary endpoint was the change in NT-proBNP levels from baseline to 96 hours. Secondary endpoints included the clinical congestion score, dyspnea assessment, net urine output, and net weight change. Safety endpoints included hyperkalemia and changes in kidney function.


A total of 360 patients were randomized; median age was 65 years, 36% (n = 129) were women, 55.5% (n = 200) were white, 42% (n = 151) were black, 2% (n = 8) were Hispanic or Latino, 2.5% (n = 9) 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. The investigators found no significant difference in the log NT-proBNP reduction between the two groups (−0.55 [95% confidence interval, −0.92 to −0.18] with high-dose spironolactone and −0.49 [95% confidence interval, −0.98 to −0.14] with usual care, p = 0.57). None of the secondary endpoint or 30-day all-cause mortality or HF hospitalization rate differed between the two groups. The changes in serum potassium and estimated glomerular filtration rate at 24, 48, 72, and 96 hours were similar between the two groups. Only one patient in the group receiving usual care and 0 in the group taking high-dose spironolactone experienced serum potassium levels between 5.5 and 5.9 mEq/L, and no one had a potassium concentration of >6.0 mEq/L during the 96 hours of study treatment. Worsening kidney function, defined as an increase of 0.3 mg/dl in creatinine from baseline through 96 hours, occurred in 28% (51 of 182 patients) in those taking high-dose spironolactone and 32% (57 of 178 patients) receiving usual care (p = 0.42).


The authors concluded that 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 endpoints.


This is an important study because it demonstrates the safety of high-dose spironolactone in AHF. As the authors discuss, there may be several reasons that high-dose spironolactone did not improve endpoints in this study, including the fact that the dose of spironolactone may not be high enough, and the short of duration of therapy. Another reason for lack of efficacy may be due to variable intensity of secondary hyperaldosteronism in AHF. One could argue that future studies evaluating spironolactone in AHF should limit this therapy to patients who would potentially benefit the most from this treatment, that is, those who have hypokalemia.

Clinical Topics: Anticoagulation Management, Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Biological Markers, Creatinine, Dyspnea, Glomerular Filtration Rate, Heart Failure, Hyperaldosteronism, Hyperkalemia, Hypokalemia, Mineralocorticoid Receptor Antagonists, Natriuretic Peptide, Brain, Peptide Fragments, Spironolactone

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