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

• Type of Material: Article
• Authors: Javed Butler, Emory University; Kevin J. Anstrom, Duke University; G. Michael Felker, Duke University; Michael M. Givertz, Harvard Medical School; Andreas Kalogeropoulos, Emory University; Marvin A. Konstam, Tufts Medical Center; Douglas L. Mann, Washington University; Kenneth B. Margulies, University of Pennsylvania; Steven E. McNulty, Duke University; Robert J. Mentz, Duke University; Margaret M. Redfield, Mayo Clinic; W. H. Wilson Tang, Cleveland Clinic; David J. Whellan, Thomas Jefferson University; Monica Shah, National Institutes of Health; Patrice Desvigne-Nickens, National Heart, Lung, and Blood Institute; Adrian F. Hernandez, Duke University; Eugene Braunwald, Harvard Medical School
• Language: English
• Date: 2017-09-01
• Publisher: American Medical Association (AMA)
• Publication Version: Final Published Version
• Copyright Statement: © 2017 American Medical Association. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1001/jamacardio.2017.2198
• Title of Journal or Parent Work: JAMA Cardiology
• ISSN: 2380-6583
• Volume: 2
• Issue: 9
• Start Page: 950
• End Page: 958
• Grant/Funding Information: Research reported in this article was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award U10 HL084904 (for the Coordinating Center) and awards U10 HL110297, U10 HL110342, U10 HL110309, U10 HL110262, U10 HL110338, U10 HL110312, U10 HL110302, U10 HL110336, and U10 HL110337 (for Regional Clinical Centers).
• Keywords: Life Sciences & Biomedicine; RATIONALE; Science & Technology; DISEASE; MORTALITY; EVEREST TRIAL; Cardiac & Cardiovascular Systems; ANTAGONIST; Cardiovascular System & Cardiology; HOSPITALIZATION; ALDOSTERONE; DESIGN
• Research Categories: Health Sciences, Rehabilitation and Therapy; Health Sciences, General

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.