Perspective:

This is a contemporary review of evidence from basic science and clinical studies of mineralocorticoid antagonists in patients with heart failure. Ten points to remember about this review are:

1. Evidence supports the addition of mineralocorticoid receptor antagonists (MRAs) to angiotensin inhibitor and beta-blocker therapies in patients with systolic heart failure (HF) (left ventricular ejection fraction [LVEF] ≤35%) and mild to severe symptomatology, and in patients with HF (LVEF <40%) after acute myocardial infarction. Significant improvements in all-cause mortality and cardiovascular hospitalizations have been demonstrated with MRA.

2. Studies suggest that only 33-36% of patients who are eligible for treatment with an MRA receive therapy.

3. Animal studies suggest that improved clinical outcomes in HF from MRA therapy include a reduction in signals (e.g., reactive oxygen species, sympathetic nervous system) triggering adverse remodeling (cardiac fibrosis, myocyte hypertrophy) and an increase in signals triggering favorable ‘reverse remodeling.’

4. MRA may lead to a reduction in atrial and ventricular dysrhythmias through antagonism of the sympathetic nervous system, a reduction in myocardial fibrosis, and/or by improving potassium homeostasis.

5. There are three MRA agents (spironolactone, eplerenone, canrenoate) with different pharmacokinetic and pharmacodynamic properties. Some studies suggest spironolactone (but not eplerenone) may lead to an increase in glycated hemoglobin levels by increasing cortisol. However, the RALES trial showed benefit in both diabetics and nondiabetics.

6. Spironolactone is a nonselective MRA and binds androgen and progesterone receptors. Eplerenone is a selective MRA. The incidence of antiandrogenic side effects is 10% with spironolactone compared with 0.5% with eplerenone.

7. Metabolites of spironolactone have a much longer half-life (up to 35 hours) compared with eplerenone (4-6 hours), which may account for slow reversal of hyperkalemia in patients on spironolactone. Drugs (e.g., verapamil, erythromycin, ketoconazole) that inhibit cytochrome P450 3A4 can lead to elevations of potassium in patients taking eplerenone.

8. The rate of hyperkalemia in major clinical trials ranges (based on definition) from 2-12%. Predictors of hyperkalemia following MRA administration include a history of diabetes, antiarrhythmic use, an estimated glomerular filtration rate <60 ml/min/1.73 m², and a baseline serum potassium of >4.3 mEq/L.

9. Labs are recommended at 72 hours after MRA initiation, at 4 weeks, and then every 3-4 months thereafter. It is recommended that the drug be held for a potassium >6.0 mmol/L and dose reduced if >5.5 mmol/L.

10. While data are inconsistent, MRA may lead to an increase in serum creatinine. Given the concomitant reduction in microalbuminuria noted in diabetics, it is hypothesized that MRA reduces intraglomerular pressure, which may overall be renal protective.