Eplerenone in Patients with Systolic Heart Failure

and Mild SymptomsLaw San Fu Md

BACKGROUNDMineralocorticoid antagonists improve

survival among patients with chronic, severe systolic heart failure [NYHA] functional class III or IV symptoms and heart failure after myocardial infarction.

Inspra® (eplerenone) acts as a competitive and selective aldosterone blocker (SAB) at the mineralocorticoid receptor sites in various tissues throughout the body with a higher degree of selectivity than spironolactone.

Aim of StudyTo investigate the effects of eplerenone,

added to evidence-based therapy, on clinical outcomes in patients with systolic heart failure and mild symptoms (i.e., NYHA functional class II symptoms)

METHODSMultinational (270 centers in approximately

30 countries), randomized, double blind placebo controlled, parallel group trial.

2737 patients with New York Heart Association class II heart failure and an ejection fraction of no more than 35% to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. (treatment with (ACE) inhibitor, (ARB), or both and a beta-blocker).

Exclusion criteria wereAcute myocardial infarction .NYHA class III or IV heart failure. Serum potassium level exceeding 5.0 mmol

per liter.(GFR) of less than 30 ml per minute per 1.73

m2 of body-surface area, Using a potassium sparing diuretic, and any

other clinically significant, coexisting condition.

Study ProceduresEvaluated patients every 4 months Adjust the dose drug according to the serum

potassium level. (5.0 to 5.9 mmol per liter ).

Study Outcomes The primary outcome was a composite of

death from cardiovascular causes or hospitalization for heart failure.

The secondary outcomes were hospitalization for heart failure or death from any cause, death from any cause, death from cardiovascular causes, hospitalization for any reason, and hospitalization for heart failure, among others (listed in Table 2).

ResultsThe trial was stopped prematurely ,after a

median follow-up period of 21 months. The primary outcome occurred in 18.3% of

patients in the eplerenone group as compared with 25.9% in the placebo group (hazard ratio, 0.63; 95% confidence interval [CI], 0.54 to 0.74; P<0.001).

DiscussionActivation of the mineralocorticoid receptor by

both aldosterone and cortisol plays an important role in the pathophysiology of heart failure.

Mineralocorticoid receptors are overexpressed in the failing heart.

Despite therapy with ACE inhibitors, ARBs, and beta-blockers, patients with even mild heart failure may have persistently elevated plasma aldosterone and cortisol levels.

Mineralocorticoid receptors are not blocked by these treatments.

DiscussionThe use of mineralocorticoid-receptor

antagonists decreases extracellular-matrix turnover and provide cardiovascular protection in patients with heart failure.

The risk of hypokalemia was significantly reduced

Adverse events included hyperkalemia and renal impairment.

limitationsThe early stopping of the trial may have

resulted in overestimation of the magnitude of the treatment effect.

Results may not be applicable to all patients with mild symptoms.(age over 55 years, an ejection fraction of no more than 30%, and a recent hospitalization for a cardiovascular reason, use of an implantable cardioverter–defibrillator)

CONCLUSIONSEplerenone, as compared with placebo,

reduced both the risk of death and the risk of hospitalization among patients with systolic heart failure and mild symptoms.

Spironolactone Vs EplerenoneThere are differences in the tolerability profiles; a) Spironolactone is associated with dose-dependent sexual

side effects.( gynecomastia and sexual dysfunction in men and menstrual irregularities in women).

b) Compared with spironolactone, eplerenone has 1000-fold less binding to the androgen receptor and 100-fold less binding to the progesterone receptor, while having only a 20-fold reduction in binding to the mineralocorticoid-receptor that blocks the effects of aldosterone.

c) Both agents produce dose-dependent increases in potassium concentrations, although the effect with spironolactone appears to be greater when both agents are administered at recommended doses.

Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events.

Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head-to-head trials and differences between patient populations.