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Table 1.  

Major Inclusion and Exclusion Criteria of RALES and EPHESUS

Box 1.  

  • Impaired renal function is a risk factor for hyperkalemia during treatment with aldosterone-receptor antagonists. The risk of hyperkalemia increases progressively when serum creatinine exceeds 141.0 µmol/l (1.6 mg/dl).a In elderly patients or others with low muscle mass in whom serum creatinine does not accurately reflect glomerular filtration rate, it is recommended that glomerular filtration rate or creatinine clearance exceeds 0.5 ml/s (30.0 ml/min)
  • Aldosterone-receptor antagonists should not be administered to patients with baseline serum potassium in excess of 5.0 mmoI/l (5.0 mEq/l)
  • An initial dose of 12.5 mg spironolactone or 25.0 mg eplerenone is recommended, after which the dose can be increased to 25.0 mg spironolactone or 50.0 mg eplerenone if appropriate
  • The risk of hyperkalemia is increased with concomitant use of higher doses of angiotensin-converting-enzyme inhibitors (?75 mg captopril daily; ?10 mg enalapril or lisinopril daily)
  • NSAIDs and cyclo-oxygenase 2 inhibitors should be avoided
  • Potassium supplements should be discontinued or reduced
  • Close monitoring of serum potassium is required; potassium levels and renal function should be checked within 3 days and at 1 week after initiation of therapy and at least monthly for the first 3 months
  • Diarrhea or other causes of dehydration should be addressed immediately

ACC/AHA guidelines for Minimizing the Risk of Hyperkalemia in Patients Treated With Aldosterone-receptor Antagonists

aAlthough the entry criteria for the trials of aldosterone-receptor antagonists included creatinine greater than 221.0 µmol/l (>2.5 mg/dl), the majority of patients had much lower creatinine levels; in 1 trial, 95% of patients had creatinine ?150.0 µmol/l (?1.7 mg/dl). From Hunt SA et al. (2005) ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult. Circulation 112: e154-e235 Epub 2005 Sep 13, with permission.

Drug Insight: Aldosterone-Receptor Antagonists in Heart Failure -- The Journey Continues

Authors: Srinivasa R. Kalidindi ; W.H. Wilson Tang ; Gary S. Francis, MDFaculty and Disclosures


Summary and Introduction


Aldosterone is an important mediator in the pathogenesis of heart failure, and increased plasma aldosterone levels are associated with a poor prognosis. Aldosterone-receptor blocking drugs can slow the progression of left ventricular remodeling and reduce the occurrence of sudden cardiac death. Two widely publicized clinical trials provide data demonstrating survival benefits with spironolactone and eplerenone in chronic and postinfarction heart failure. The publication of these trials has generated widespread enthusiasm for spironolactone and eplerenone, leading to the more frequent and sometimes unbridled use of these drugs in the medical community. We herein describe the likely mechanisms of action of aldosterone-receptor antagonists, discuss the existing clinical evidence supporting their use, and provide practical advice on their use in the management of patients with heart failure.


Heart failure (HF) is a chronic, progressive disease associated with high morbidity and mortality. The prevalence of the disease is fast reaching epidemic proportions, especially in Western countries. The associated economic burden is enormous; in the US alone, the estimated direct and indirect cost of HF for 2007 is US$33.2 billion.[1] Although the use of angiotensin-converting-enzyme (ACE) inhibitors and β-blockers has prolonged survival of patients with HF,[2-4] the incidence of this disease has not receded, which has in turn led to increased prevalence. Moreover, although ACE inhibitors and β-blockers significantly reduce mortality in patients with HF, clinical events continue to occur. The introduction of aldosterone-receptor antagonists has provided the clinician with an additional tool in the fight against HF. The use of these drugs, however, has not been without controversy. In this Review, we discuss the likely mechanisms of action of aldosterone-receptor antagonists, the existing clinical evidence supporting their use, and provide practical advice on how to use these drugs in the management of patients with HF.

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