Should We Be EMPHASIzing Eplerenone In Systolic Heart Failure?

Are all of your patients with symptomatic heart failure and a low ejection fraction receiving an aldosterone antagonist?  Why not?  Randomized, double-blind, multi-center clinical trials using aldosterone-receptor antagonists have demonstrated mortality benefits in patients with symptomatic heart failure when added to evidence-based therapy, including ACE-inhibitors.^1,2,3  The recent Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms (EMPHASIS-HF) trial further demonstrated these benefits in patients with mild heart failure symptoms and low ejection fractions.² Aldosterone plays a critical role in the progression of heart failure.  Aldosterone augments sodium retention, promotes loss of potassium and magnesium, and causes sympathetic activation, parasympathetic inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, and vascular damage, in addition to impairing arterial compliance.¹ Mineralocorticoid receptors are over-expressed in the failing heart.² ACE-inhibitors suppress aldosterone through inhibition of angiotensin II formation, however they do not prevent aldosterone release from non-ACE-dependent angiotensin II production or activation of aldosterone receptors.^2,4

The Randomized Aldactone Evaluation Study (RALES) published in 1999 provided evidence to support increased use of aldosterone-receptor blockers in patients with NYHA Class III or IV heart failure with systolic left ventricular dysfunction. Spironolactone 25-50 mg daily demonstrated mortality benefits and a favorable safety profile compared to placebo in patients receiving ACE-inhibitors, diuretics, and digoxin.¹ The Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) published in 2003 established the benefits of aldosterone blockade in post-myocardial infarction patients with systolic left ventricular dysfunction.  Eplerenone 25-50 mg daily also demonstrated mortality benefits and a favorable safety profile compared with placebo in patients receiving standard heart failure therapy, including ACE-inhibitors, beta-blockers, aspirin, and statins.³  The patient populations who enrolled in these studies are described in the table below.^1,3

EMPHASIS-HF is the latest study to examine the benefits of aldosterone antagonists.  This study evaluated eplerenone in patients with mild heart failure symptoms and a low ejection fraction (EF).  This was a randomized, double-blind, placebo-controlled, multi-center trial in which 2737 patients received eplerenone in doses up to 50 mg daily or placebo, in addition to recommended heart failure therapy.  Inclusion criteria were age ≥55 years, NYHA class II symptoms, an EF of ≤35%, and treatment with an ACE-inhibitor, ARB, or both, and a beta-blocker (unless contraindicated).  Major exclusion criteria were acute myocardial infarction, NYHA class III or IV heart failure, potassium level >5.0 mmol/L, GFR <30 mL/min/1.73m², potassium-sparing diuretic use, or any other coexisting, clinically significant condition.  The primary outcome was a composite of death from cardiovascular causes or a first hospitalization for heart failure.  Secondary outcomes included hospitalization for heart failure or all-cause mortality, cardiovascular death, hospitalization, and hospitalization for heart failure in addition to others.  Baseline characteristics were similar between the two groups.  The “average” participant in EMPHASIS-HF study was a 68 year old, obese, Caucasian male with ischemic heart disease, an EF=26%, a serum creatinine (SCr) =1.1 mg/dL, and a potassium=4.3 mmol/L.  The mean duration of heart failure was 5 years.  Mean dose of eplerenone was 39 mg daily.  EMPHASIS-HF was stopped early due to the statistically significant reduction in primary mortality outcome demonstrated after 21-months of follow-up.  Primary and major secondary outcomes are compared to the results of the RALES and EPHESUS trials in the table below.

Eplerenone was well-tolerated. The only statistically significant differences between eplerenone and placebo with respect to adverse effects were hyperkalemia (more in eplerenone group) and hypokalemia (more in placebo group).  Most patients experienced a small elevation in SCr or reduction in blood pressure.  Potential limitations of this study include early trial termination, enrolling relatively few patients with an implantable cardioverter-defibrillator, and narrowing the patient population by requiring them to have mild symptoms and additional cardiovascular risk factors.  EMPHASIS-HF proved that adding eplerenone to evidence-based heart failure therapy in patients with NYHA class II symptoms reduced the risk of death from cardiovascular causes or hospitalization for heart failure.²

Prior to EMPHASIS-HF, no clinical trial had evaluated the efficacy of adding aldosterone receptor blockers to recommended treatment in heart failure patients with mild symptoms.²  RALES and EPHESUS demonstrated the benefits of aldosterone receptor blockade in heart failure patients with low EF and moderate to severe symptoms.^1,3  Some pharmacists and other providers questioned the utility of aldosterone receptor blockade in patients with mild symptoms – the patients most commonly seen in primary care settings.  Others argued that because aldosterone promotes cardiac fibrosis and other processes that cause progression of heart failure, aldosterone receptor blockers would likely be of benefit because they would slow the cardiac remodeling associated with heart failure.  Combined with the evidence from earlier studies, EMPHASIS-HF clearly demonstrates that aldosterone receptor blockers are beneficial in most patients with heart failure and a low EF.²

Adverse effects with aldosterone receptor blockers have often limited their use in heart failure patients.  Hyperkalemia and increasing renal dysfunction are two potential adverse effects that must be monitored in patients taking aldosterone receptor blockers.^1,2,3    In RALES, EPHESUS, and EMPHASIS-HF, hyperkalemia was more common in the active treatment groups.  However, severe hyperkalemia (potassium ≥6 mmol/L) was uncommon.^1,2,3  By initiating therapy at an appropriate dose and with careful monitoring, the  risk of hyperkalemia can be minimized.  Patients were excluded in the eplerenone clinical trials if their baseline potassium was >5.0 mmol/L or serum creatinine was >2.5 mg/dL.^2,3  Hypokalemia, serum potassium concentrations below 4.0 mmol/L, is associated with increased mortality in patients with systolic heart failure.²  In EPHESUS AND EMPHASIS-HF, eplerenone-treated patients were significantly less likely to develop hypokalemia than placebo-treated patients.^2,3   This may explain, in part, some of the mortality benefits observed in these studies.  Moreover, use of aldosterone receptor blockers may negate the need for potassium supplements.  Serum potassium monitoring is recommended at baseline, within the first week of initiating therapy, at one month, and periodically thereafter.  Potassium should also be monitored one month after starting a moderate CYP3A4 inhibitor in patients on eplerenone.  The dose should be reduced when the serum potassium is >5.5 mmol/L or when renal function worsens to a GFR between 30-49 mL/min/1.73 m².  More frequent monitoring is recommended in patients with declining renal function.⁵  In clinical trials with spironolactone and eplerenone, the SCr increased by 0.05-0.15 mg/dL from baseline.^1,2,3

Gynecomastia associated with spironolactone has limited the use of aldosterone receptor blockers in many patients with heart failure.^1,2,3,6  Significantly more men in the spironolactone group in RALES experienced gynecomastia or breast pain when compared to men in the placebo group.¹  However, gynecomastia, breast pain, and impotence were no more common among eplerenone users in EPHESUS or EMPHASIS-HF trials than in the placebo groups.^2,3  Eplerenone more selectively blocks mineralocorticoid receptors than spironolactone and does not cause these adverse effects.^2,3,6 

Spironolactone is a low-cost generic product covered on most prescription discount plans.⁷  Eplerenone has higher acquisition cost.  However, some Medicare plans cover this as a preferred (tier 1 or 2) agent, so the out-of-pocket costs to the patient may be minimal.⁸

Should we EMPHASIze eplerenone based on this new evidence?  Eplerenone has demonstrated all-cause mortality benefit in multiple clinical trials.^2,3,5 Currently, ACC/AHA guidelines only recommend aldosterone antagonists in moderate to severe heart failure.  EMPHASIS challenges these guidelines and revisions should encourage the earlier and widespread use of aldosterone antagonists in the treatment of heart failure.^2,9  The improved tolerability of eplerenone, specifically the lack of gynecomastia, is clinically important.  If most patients with systolic heart failure should be taking an aldosterone antagonist, shouldn’t our first-line recommendation be eplerenone?   EMPHASIS-HF is too compelling to ignore and makes eplerenone the drug of choice for patients with an EF < 40%.  What do you think?