ALDOSTERONE ANTAGONISTS (POTASSIUM-SPARING DIURETICS)
Although short-term therapy with both ACEIs and ARBs can lower circulating levels of aldosterone, such suppression may not be sustained during long-term treatment. The lack of long-term suppression may be important, because experimental data suggest that aldosterone exerts adverse effects on the structure and function of the heart, independently of and in addition to the deleterious effects produced by angiotensin II.
In a large-scale, long-term trial68, low doses of spironolactone (starting at 12.5 mg daily) were added to ACEI therapy for patients with class IV HF symptoms or class III symptoms and recent hospitalization. The risk of death was reduced from 46% to 35% (30% relative risk reduction) over 2 years, with 35% reduction in HF hospitalization and an improvement in functional class.
A recent trial investigated the newer aldosterone antagonist eplerenone in patients with LVEF less than or equal to 40% and clinical evidence of HF or diabetes mellitus within 14 days of MI. Mortality was decreased from 13.6% to 11.8% at 1 year. Hyperkalemia occurred in 5.5% of patients treated with eplerenone compared with 3.9% of those given placebo overall and in up to 10.1% versus 4.6% of patients with estimated creatinine clearance less than 50 ml per min69.
Recommendations concerning aldosterone antagonists
The addition of low-dose aldosterone antagonists should be considered in carefully selected patients with moderately severe or severe HF symptoms and recent decompensation or with LV dysfunction early after MI. These recommendations are based on the strong data demonstrating reduced death and re-hospitalization in 2 clinical trial populations described above.
To minimize the risk of life-threatening hyperkalemia in patients with low LVEF and symptoms of HF, patients should have initial serum creatinine less than 2.0 mg per dl to 2.5 mg per dl, without recent worsening, and serum potassium less than 5.0 mEq per dl, without a history of severe hyperkalemia. The safety of the combination of ACEIs, ARBs, and aldosterone antagonists has not been explored adequately, and this combination cannot be recommended.
Practical use of Aldosterone Antagonists
68 Pitt B, Zannad F, Remme WJ, et al, for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709 –17.
69 Pitt B, Williams G, Remme W, et al. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction: Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 2001;15:79–87.