Routine Use of High-Dose Spironolactone Not Beneficial in Acute HF

Persistent clinical and subclinical congestion at discharge after hospitalization for acute heart failure (HF) is associated with worse outcomes. Elevated aldosterone levels have also been associated with these outcomes as well as with diuretic resistance.

High-dose mineralocorticoid receptor antagonist therapy has been shown to overcome diuretic resistance in HF, and spironolactone has been associated with improved congestion and renal function in HF. However, data from a new study do not support the routine use of high-dose spironolactone in patients with acute HF.

On behalf of the National Heart, Lung, and Blood Institute's Heart Failure Clinical Research Network, Javed Butler, MD, of Stony Brook University in New York, presented the results of the Aldosterone Targeted Neurohormonal Combined With Natriuresis Therapy-Heart Failure trial at the Scientific Sessions of the American Heart Association held November 12 to 16, 2016, in New Orleans, LA. Investigators from Duke involved in the study were G. Michael Felker, MD, Kevin J. Anstrom, PhD, and Adrian F. Hernandez, MD.

The randomized, double-blind, placebo-controlled, multicenter trial was designed to test the hypothesis that high-dose spironolactone for patients with acute HF will lead to greater reductions in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels by 96 hours.

A total of 360 patients were enrolled in the study. Among the inclusion criteria were at least 1 symptom, 1 sign of congestion, and an estimated glomerular filtration rate of at least 30 mL/minute/1.73 m2. In addition, patients could not be currently taking a mineralocorticoid, but low-dose spironolactone (12.5 or 25 mg daily) was allowed.

Eligible patients were randomly assigned to treatment with high-dose spironolactone (100 mg; n = 182) or placebo (n = 178). Those assigned to the placebo group who had been taking a mineralocorticoid prior to admission continued to receive low-dose spironolactone.

Although the study was not powered for outcomes, Butler said that he and his colleagues evaluated all-cause mortality, hospitalization for HF, and visits to the emergency department as exploratory end points.

Secondary end points included congestion score, dyspnea relief, net urine output, net weight change, loop diuretic dose requirement, and worsening HF.

Butler reported that the study did not meet its primary end point, with no significant difference observed between the 2 groups with regard to either change in log NTproBNP or level of NTproBNP (Table).

Table. Change in End Points From Baseline to 96 Hours

End Point Placebo Spironolactone P Value
Log NTproBNP –0.49 –0.55 .57
NTproBNP, pg/mL –1072 –1796 .76
Dyspnea (visual analog scale) 15 15 .61
Clinical congestion score –6 –6 .416
Net urine output, mL 5584 6086 .57
Weight, pounds –6.1 –7.3 .33
Change in furosemide equivalent diuretic dose, mg –80 –80 .77
Worsening HF: inpatient, % 18 19 .76
Worsening HF: outpatient, % 10 11 .76

HF = heart failure, NTproBNP = N-terminal pro-brain natriuretic peptide.

The secondary end points were similar in both groups. 

Prespecified subgroup analysis showed no differences in the 2 groups when study patients were stratified by age, sex, and baseline use of low-dose vs no spironolactone. Outcomes, including mortality, hospitalization for HF, and emergency department visits, also did not differ.

Although the data did not support the routine use of spironolactone, Butler said that patients with a higher ejection fraction may gain some benefit from the drug.

For patients with an ejection fraction greater than 45%, the changes in log NTproBNP were –0.53 (–1.03, –0.14) in the spironolactone group and –0.42 in the placebo group (interaction P = .078). The changes in log NTproBNP did not differ between the 2 groups among patients with an ejection fraction of 45% or less (–0.55 and –0.54). Spironolactone was well tolerated, with no significant difference observed in worsening renal function or hyperkalemia between the 2 groups.

Source: Butler J, Konstam MA, Felker M, et al. Aldosterone targeted neurohormonal combined with natriuresis therapy in heart failure (ATHENA-HF) trial. Presented at: American Heart Association Scientific Sessions 2016; November 12-16, 2016; New Orleans, LA. Abstract LBCT.04.