Aldosterone receptor antagonists spironolactone and eplerenone for congestive heart failure

Evidence Summaries

Level of Evidence = A
Aldosterone receptor antagonists decrease mortality and hospitalization in patients with congestive heart failure with an increased risk of hyperkalemia.

In a randomized trial 1 patients (n=1,663) with severe congestive heart failure, an ejection fraction 35% or less and receiving ACE inhibitors and loop diuretics received either spironolactone 25mg/day or placebo. Potassium-sparing diuretics were not permitted. Patients were excluded from the study if they had primary operable valvular heart disease (other than mitral or tricuspid regurgitation with clinical symptoms due to left ventricular systolic heart failure), congenital heart disease, unstable angina, primary hepatic failure, active cancer, or any life-threatening disease (other than heart failure). Patients who had undergone heart transplantation or were awaiting the procedure were also ineligible. Other criteria for exclusion were a serum creatinine concentration of more than 2.5 mg per deciliter (221 µmol per liter) and a serum potassium concentration of more than 5.0 mmol per liter. The relative risk for total mortality at two years was 0.70 (95% CI 0.60 to 0.82) and the relative risk for hospitalisation was 0.65 (95% CI 0.54 to 0.77) in favour of spironolactone. Also symptoms of heart failure decreased with spironolactone therapy. Severe hyperkalemia was rare.

According to a Canadian population-based time-series analysis 2 the publication of RALES was associated with increases in the rate of prescriptions for spironolactone (from 34 per 1000 patients in 1994 to 149 per 1000 patients by late 2001; P<0.001), in the rate of hospitalization for hyperkalemia (from 2.4 per 1000 patients in 1994 to 11.0 per 1000 patients in 2001; P<0.001), and the associated mortality (from 0.3 per 1000 to 2 per 1000 patients; P<0.001).

In a randomized trial 3 patients (n=6,632) with acute myocardial infarction complicated by left ventricular dysfunction (LVEF ≤ 40%) and heart failure or diabetes received either eplerenone (25 mg - 50 mg per day) or placebo in addition to optimal medical therapy. Criteria for exclusion were the use of potassium-sparing diuretics, a serum creatinine concentration of more than 2.5 mg per deciliter (220 µmol per liter), and a serum potassium concentration of more than 5.0 mmol per liter before randomization. The relative risk for total mortality (mean follow-up of 16 months) was 0.85 (95% CI 0.75 to 0.96) and for cardiovascular disease mortality 0.83 (95% CI 0.72 to 0.94). Also the rate of death from cardiovascular causes or hospitalization for cardiovascular events was reduced by eplerenone (RR 0.87, 95% CI 0.79 to 0.95). The rate of serious hyperkalemia was 5.5 percent in the eplerenone group and 3.9 percent in the placebo group (P=0.002), whereas the rate of hypokalemia was 8.4 percent in the eplerenone group and 13.1 percent in the placebo group (P<0.001).

In a randomized trial 4 (EMPHASIS-HF) 2737 patients with NYHA class II heart failure, an ejection fraction of no more than 35% (mean 26%), and already using diuretics, ACE inhibitors/angiotensin receptor blockers and beta-blockers, received either eplerenone (up to 50 mg/d) or placebo. The trial was stopped early after a median follow-up of 21 months. The primary composite outcome (cardiovascular death or hospitalization for heart failure) occurred in 18.3% of patients in the eplerenone group and 25.9% in the placebo group (HR 0.63, 95% CI 0.54 to 0.74). A total of 12.5% of patients receiving eplerenone and 15.5% of those receiving placebo died (HR 0.76, 95% CI 0.62 to 0.93). A serum potassium level exceeding 5.5 mmol/ll occurred in 11.8% of patients in the eplerenone group and 7.2% of those in the placebo group.

A systematic review and meta-analysis 5 included 8 studies with a total of 3,929 subjects with congestive heart failure with NYHA classes I to II. Aldosterone antagonists reduced all cause mortality (RR 0.79, 95% CI 0.66, 0.95) and re-hospitalization for cardiac causes (RR 0.62, 95% CI 0.52, 0.74) compared to control. A stratified analysis showed a statistical superiority in the benefits of spironolactone over eplerenone in reducing left ventricular end-diastolic volume and left ventricular end-systolic volume. Aldosterone antagonists reduced B-type natriuretic peptide concentrations, P < 0.00001), increased serum creatinine, and occurrence of hyperkalaemia (RR 1.78, 95% CI 1.43, 2.23).

The following decision support rules contain links to this evidence summary:


1. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999 Sep 2;341(10):709-17.  [PMID:10471456]
2. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004 Aug 5;351(6):543-51.  [PMID:15295047]
3. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M, Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003 Apr 3;348(14):1309-21.  [PMID:12668699]
4. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B, EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011 Jan 6;364(1):11-21.  [PMID:21073363]
5. Hu LJ, Chen YQ, Deng SB et al. Additional use of an aldosterone antagonist in patients with mild to moderate chronic heart failure: a systematic review and meta-analysis. Br J Clin Pharmacol 2013;75(5):1202-12.  [PMID:23088367]

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