American Heart Association
American Heart Association
November 30, 2016
3 min read

ATHENA-HF: High-dose spironolactone does not benefit patients with acute HF

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NEW ORLEANS — The ATHENA-HF trial, designed to assess the safety and efficacy of high dose mineralocorticoid receptor antagonist therapy in patients with acute HF, did not meet its primary or secondary endpoints, according to results presented at the American Heart Association Scientific Sessions.

Patients with acute HF who receive high doses of mineralocorticoid receptor antagonists (MRA) may experience congestion relief and mitigated effects of adverse neurohormonal activation, often associated with acute HF, Javed Butler, MD, MPH, MBA, FACC, FAHA, FESC, professor of medicine, physiology and biophysics, co-director of the Heart Institute and chief of the division of cardiology at Stony Brook University, Stony Brook, New York, said during a presentation.

For ATHENA-HF, a randomized, double blind, placebo-controlled, multicenter trial, Butler and colleagues hypothesized that patients who received high-dose spironolactone therapy in addition to standard care would show greater reductions in N-terminal pro-B-type natriuretic peptide levels compared with patients receiving standard care.

Javed Butler
Javed Butler

Secondary endpoints of the study included dyspnea relief, urine output, weight changes and in-hospital worsening of HF.

The 360 patients (mean age, 65 years; 36% women) from 22 sites included in the study were aged 21 years or older, had at least one sign and one symptom of congestion, estimated glomerular filtration rate ≥ 30 mL/min/1.73m², serum potassium ≤ 5 mmol/L, NT-proBNP ≥ 1,000 pg/mL or BNP ≥ 250 pg/mL within 24 hours of randomization, could not be on an MRA or only on low-dose spironolactone at baseline and had to be randomized within 24 hours of the IV diuretic dose.

Patients were randomly assigned high-dose spironolactone (n = 182) or the usual care (n = 178); of the usual care group, 46 received low-dose spironolactone and 132 received placebo.

At 96 hours or discharge, change in log NT-pro BNP was –0.49 (95% CI, –0.98 to –0.14) in the usual care group and –0.55 (95% CI, –0.92 to –0.18) in the high-dose spironolactone group (P = .57), Butler said. 

Absolute changes in NT-proBNP at 96 hours or discharge were –1,072 pg/mL (95% CI, –3,182 to –231) in the usual care group and –1796 (95% CI, –3883 to –571) in the high-dose spironolactone group (P = .76), he said.

The primary endpoint results were consistent regardless of age, sex or baseline use of low-dose vs. no spironolactone, according to the researchers.

Butler said there was also no difference between the groups at 96 hours in change in dyspnea by Likert Score (P = .3) or Visual Analog Scale (P = .61), change in clinical congestion score (P = .416), urine output change (P = .57), weight change (P = .33), furosemide-equivalent diuretic dose (P = .77) or worsening HF (P = .76).

“These data do no support the routine use of high dose spironolactone in [acute] HF,” Butler, a Cardiology Today Editorial Board member, said. “The role of high-dose MRA targeted to patients resistant to loop diuretics needs to be further studied.”

He told Cardiology Today that “unlike patients with chronic HF, in this study there was no higher risk for hyperkalemia with high-dose spironolactone in patients with acute HF, which may be related to the active diuresis in this setting. This open the possibility for future research in these patients with diuretic resistance and worse renal function.”

In a discussant presentation, Lars H. Lund, MD, PhD, said there were several possible reasons for the negative outcomes. He said the pathophysiology and treatment are correct, but cited wrong dosage, wrong inclusion criteria and wrong endpoints as some of the possible problems with the study.

“High-dose MRA should be further explored in acute HF, given earlier and particularly with confirmed diuretic resistance, should be a higher dose, larger sample size and with hard endpoints; noting that numerically, there have been fewer deaths,” Lund said. “In fact, this may open a potential pragmatic trial proposal, because acute HF and in-hospital treatment with approved and generic medications, such as spironolactone, are very well suited for a phase 3 pragmatic registry-based trial with morbidity and mortality as the primary endpoint.”– by Dave Quaile


Butler, J, et al. LBCT.04 – Guiding the Momentum to Effect HF Outcomes – Ironing Out the Wrinkles. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.

Disclosure: Butler reports consulting for Amgen, Bayer, Boehringer Ingelheim, Cardiocell, CVRx, Merck, Novartis, Medtronic, Relypsa and ZS Pharma. Lund reports receiving research grants from AstraZeneca and Boston Scientific and speaker’s honoraria from AstraZeneca, Bayer, Medtronic, Novartis, St. Jude Medical and Vifor Pharma.