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Randomized Controlled Trial
. 2017 Sep 1;2(9):950-958.
doi: 10.1001/jamacardio.2017.2198.

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

Javed Butler  1 , Kevin J Anstrom  2 , G Michael Felker  3 , Michael M Givertz  4 , Andreas P Kalogeropoulos  5 , Marvin A Konstam  6 , Douglas L Mann  7 , Kenneth B Margulies  8 , Steven E McNulty  2 , Robert J Mentz  3 , Margaret M Redfield  9 , W H Wilson Tang  10 , David J Whellan  11 , Monica Shah  12 , Patrice Desvigne-Nickens  13 , Adrian F Hernandez  3   14 , Eugene Braunwald  4 ; National Heart Lung and Blood Institute Heart Failure Clinical Research Network
Affiliations
Randomized Controlled Trial

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

Javed Butler et al. JAMA Cardiol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosure: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Butler receives research support from the National Institutes of Health, European Union, and the Patient Centered Outcomes Research Institute and consulting fees from Amgen, Astra Zeneca, Bayer, Boehringer Ingelheim, BMS, CVRx, Janssen, Medtronic, Novartis, Relypsa, and ZS Pharma. Dr Felker receives grant support from the National Institutes of Health, American Heart Association, Novartis, Amgen, and Merck and consulting fees from Novartis, Amgen, Glaxo Smith Kline, BMS, Myokardia, and Medtronic. Dr Konstam is the data monitoring committee chair for Novartis, Amgen, and BMS; receives research support and an honorarium from Otsuka; and receives consulting fees from Johnson & Johnson. Dr Mentz receives research support from Amgen and Novartis. Dr Hernandez receives research support from AstraZeneca, Bayer, Luitpold, Merck, Novartis, and Portola Pharmaceuticals and honoraria from Bayer, Boston Scientific, Myokardia, and Novartis. Dr Braunwald receives grant support from Duke University as Chair of the Heart Failure Network of the National Heart, Lung, and Blood Institute Heart Failure Network and from Merck and Company, Astra Zeneca, Novartis, Daiichi Sankyo, and Glaxo Smith Kline; and consulting fees from The Medicines Company and Theravance; personal fees for lectures from Medscape and Menarini International. He was also uncompensated for consultancies and lectures from Merck and Novartis. No other disclosures are reported.

Figures

Figure 1.
Figure 1.. CONSORT Flow Diagram
NT-proBNP indicates N-terminal pro-B-type natriuretic peptide.
Figure 2.
Figure 2.. Time to First Heart Failure Rehospitalization, Emergency Department Visit, or Death
There were no significant differences noted in the postdischarge outcomes among patients randomized to receive the usual care alone vs the group who received high-dose spironolactone. Receiving high-dose spironolactone vs usual care had a hazard ratio of 1.22 (95% CI, 0.68-2.19; P = .50).
See this image and copyright information in PMC

Comment in

References

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