This study investigated the effects of adding eplerenone to evidence-based heart failure therapies in patients with mild systolic heart failure symptoms. The study randomized 2,737 patients to receive either eplerenone or placebo. The primary outcome of death from cardiovascular causes or hospitalization for heart failure occurred in 18.3% of the eplerenone group compared to 25.9% of the placebo group, demonstrating that eplerenone reduced risks. The trial was stopped early due to these benefits after a median follow up of 21 months. Eplerenone was found to provide cardiovascular protection in patients with heart failure compared to placebo.

1. Law San Fu Md

2. BACKGROUND
 Mineralocorticoid 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.

3. Aim of Study
 To 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)

4. METHODS
 Multinational (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).

5. Exclusion criteria were
 Acute 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.

6. Study Procedures
 Evaluated patients every 4 months
 Adjust the dose drug according to the serum
potassium level. (5.0 to 5.9 mmol per liter ).

7. 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).

9. Results
 The 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).

11. Discussion
 Activation 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.

12. Discussion
 The 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.

13. limitations
 The 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)

14. CONCLUSIONS
 Eplerenone, as compared with placebo, reduced both
the risk of death and the risk of hospitalization among
patients with systolic heart failure and mild symptoms.

15. Spironolactone Vs Eplerenone
 There 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.

16.  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.