Objectives

To assess whether high-dose spironolactone treatment for patients with acute heart failure lowers natriuretic peptide levels and improves outcomes better than usual care.

Background

Acute heart failure (AHF) accounts for more than a million hospitalizations in the United States annually. The role of low-dose mineralocorticoid receptors antagonists (MRAs) therapy as a neurohormonal antagonist is well established for the treatment of chronic heart failure and reduced ejection fraction. However, the role of high-dose MRA therapy in AHF remained uncertain. A previous clinical trial suggested that the benefits of high-dose MRA therapy in AHF included lower natriuretic peptide levels, less congestion, better renal function, and less need for an intravenous diuretic.

The use of intravenous loop diuretics can intensify secondary hyperaldosteronism among AHF patients and hyperaldosteronism directly contributes to diuretic resistance in AHF. Elevated aldosterone levels in AHF are associated with an increased risk of cardiovascular mortality and HF readmission. Hospitalizations for heart failure are associated with increased risk of mortality and/or readmission.

The HFN-ATHENA trial was conducted to determine if mineralocorticoid receptor antagonists administered at high doses relieved congestion, decreased diuretic resistance, and mitigated the effects of adverse neurohormonal activation in AHF.

Participants

Participants were deemed eligible if they had a clinical diagnosis of heart failure with at least 1 sign and 1 symptom of AHF and with an N-terminal pro-B-type natriuretic peptide (NT-proBNP) level ≥1000 pg/mL or ≥BNP level of 250 pg/mL measured within 24 hours of randomization. Eligible participants were either receiving no spironolactone or receiving low-dose spironolactone (12.5 or 25 mg per day) at home before hospital admission. Participants were also required to have a serum potassium concentration of ≤5.0 mEq/L, an estimated glomerular filtration rate of ≥30 mL/min/1.73m2, and a systolic blood pressure level of ≥90 mm Hg.

Patients receiving eplerenone or ≥25 mg of spironolactone were excluded. Additional exclusion criteria included: severe liver disease, active infection, active gastrointestinal bleeding, and active malignancy other than non-melanoma skin cancers.

The ATHENA trial enrolled 360 participants. Of these, 178 participants were randomized to usual care treatment (placebo or low-dose spironolactone) and 182 participants were randomized to high-dose spironolactone.

Design

The study intervention was initiated within 24 hours of patients receiving the first dose of intravenous diuretics. Participants not taking spironolactone at enrollment were randomized to 100 mg spironolactone or a placebo and participants taking low-dose spironolactone before their hospital admission were randomized to 100 mg or 25 mg per day in the usual care treatment arm. Prescription of all other medications, including diuretics, was left at the discretion of the treating physician. The study drug was discontinued after 96 hours and further MRA use was left to the treating physician’s discretion. The primary end point was the proportional change in the log NT-proBNP levels from randomization to 96 hours (or at the hospital discharge if the discharge occurred earlier than 96 hours). Secondary endpoints included: (1) a clinical congestion score, (2) dyspnea relief, (3) daily cumulative net urine output for up to 96 hours; (4) net weight change from baseline to 96 hours or discharge (whichever came first); (5) furosemide equivalents of the loop diuretic dosage at discharge; and (6) the development of in-hospital worsening HF, with signs and symptoms requiring additional therapy.

Conclusions

There was no significant difference in the primary or secondary endpoints between the high-dose treatment arm and the usual care treatment arm.

Butler J, Anstrom KJ, Felker GM, et al. Efficacy and Safety of Spironolactone in Acute Heart Failure: The ATHENA-HF Randomized Clinical Trial. JAMA Cardiol. 2017;2(9):950-958. doi:10.1001/jamacardio.2017.2198

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