Management of Patients with Chronic Heart Failure: A Focus on Aldosterone Antagonists

AUGUST 01, 2004
Mohammad J. Tafreshi, PharmD, BCPS, and Melinda L. Adkins, PharmD

Heart failure (HF) is the inability of the heart to meet the demands of the body. Although there are different forms of HF, the majority of patients with HF have impairment of left ventricular systolic function. The cardinal manifestations of systolic HF are dyspnea and fatigue.

The American College of Cardiology and the American Heart Association (ACC/AHA) have developed guidelines for classifying and treating patients with HF due to chronic left ventricular systolic dysfunction. Stage A includes patients who are at high risk for developing HF due to the presence of conditions that are strongly associated with its development. Patients in Stage B have developed structural heart damage but have never shown signs or symptoms of HF. Stage C patients have structural heart damage and current or prior symptoms of HF. Stage D includes patients with advanced structural heart disease and marked symptoms at rest despite optimal therapy.1

According to these guidelines, in the absence of contraindications, all patients in Stage A should receive an angiotensin-converting enzyme inhibitor (ACEI). Patients in Stage B should receive an ACEI and a beta-blocker (BB). In Stage C, a diuretic should be added if the patient has symptoms of fluid retention. Digoxin should be added if the patient is still symptomatic while receiving optimal doses of ACEIs, BBs, and diuretics. Angiotensin receptor blockers (ARBs) usually are reserved for patients who develop intolerance to ACEIs due to cough or angioedema. In the setting of normal renal function and normal serum potassium concentration, the addition of an aldosterone antagonist (AA) should be considered if a patient has experienced recent or current symptoms at rest despite optimal drug therapy1-3 (Figure).

For many years, spironolactone has been the only AA available on the market. Because spironolactone is a steroid, it may have some effects at the glucocorticoid, progesterone, and androgen receptors that can lead to adverse effects such as gynecomastia, impotency, mastodynia (breast pain), and irregular menses.4-6

Clinical Trials

The Randomized Aldactone Evaluation Study (RALES) found that aldosterone antagonism by spironolactone, in addition to standard therapy, reduces the risk of morbidity and mortality in patients with severe HF. The trial included 1663 patients who had been classified in New York Heart Association (NYHA) class IV HF (symptoms at rest) within 6 months preceding enrollment, were in NYHA class III or IV at the time of enrollment, had been diagnosed with HF at least 6 weeks prior to enrollment, had a left ventricular ejection fraction of ≤35% (mean 25%), and were being treated mainly with an ACEI and a diuretic. Exclusion criteria included a serum creatinine concentration of >2.5 mg/dL and a serum potassium level of >5.0 mmol/L.

In this double-blind, placebo-controlled study, patients received either 25 mg of spironolactone once daily or a matching placebo. The dose could be increased to 50 mg after 8 weeks if the patient continued to show signs or symptoms of HF and did not have hyperkalemia. If a patient developed hyperkalemia at any time during the study, the dose could be decreased to 25 mg every other day. The primary end point was mortality from all causes.

This trial was terminated early due to the positive outcome associated with the use of spironolactone. The results showed a significant decrease in total mortality and mortality from cardiac causes and a significant decrease in risk of hospitalization for cardiac causes. Spironolactone also was associated with an improvement in NYHA classification. In this study, however, gynecomastia, mastodynia, and hyperkalemia were reported more with spironolactone treatment than with placebo.

Eplerenone, a new AA, works in a way similar to spironolactone, but it is more selective to the mineralocorticoid receptors. The Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) was published recently. This study evaluated the effect of aldosterone antagonism in moderate-to-severe HF. The investigators concluded that the use of eplerenone in addition to optimal, standard drug therapy reduced morbidity and mortality in patients with HF post acute myocardial infarction (MI).

The EPHESUS trial was a randomized, double-blind, placebo-controlled trial that included 6642 patients who met the following inclusion criteria: acute MI in the previous 3 to 14 days, ejection fraction of ≤40% (mean 33%), and HF as documented by pulmonary rales, pulmonary venous congestion shown on radiography, or the presence of a third heart sound. Patients also received optimal medical therapy, which included ACEIs, ARBs, diuretics, BBs, and coronary reperfusion therapy. Exclusion criteria included the use of potassium-sparing diuretics, a serum creatinine concentration of >2.5 mg/dL, and a serum potassium level of >5.0 mmol/L prior to randomization.

Patients were randomly assigned to receive eplerenone 25 mg daily or a matching placebo for 4 weeks. After the first 4 weeks, the dose of eplerenone was increased to a maximum of 50 mg/day. The primary end points were time to death from any cause and time to death from cardiovascular causes or first hospitalization for a cardiovascular event including HF, recurrent acute MI, stroke, or ventricular arrhythmia.

Patients were followed for a mean of 16 months. There was a significant reduction in end points in patients receiving eplerenone, compared with those receiving placebo. It should be noted that 20% of the studied patients were over the age of 75, and these patients did not appear to benefit from the use of eplerenone.

As with spironolactone, hyperkalemia occurred more often in the eplerenone group than in the placebo group. In both groups, the incidence of hyperkalemia was higher in those with a lower baseline creatinine clearance (<50 mL/min).7-9


It is clear that aldosterone antagonism is beneficial in the management of some patients with HF. Controversy exists, however, over which agent, spironolactone or eplerenone, is a better choice for these patients.

Spironolactone and eplerenone have not been compared directly. Additionally, the study participants and the designs in the existing trials were different.

The current ACC/AHA guidelines, which were published before EPHESUS was completed, recommend considering low-dose spironolactone in patients with recent or current symptoms of HF at rest despite optimal use of an ACEI, a BB, and digoxin.

One should note that, although aldosterone antagonism can result in hyperkalemia, it also has been shown to protect against hypokalemia, which may pose a particularly significant risk in patients with HF. Before and during AA therapy, serum potassium and creatinine should be monitored frequently.5,9

Both eplerenone and spironolactone have potential for causing drug?drug interactions. Eplerenone is metabolized through the CYP3A4 pathway. The use of eplerenone with highly potent inhibitors of CYP3A4 is contraindicated. Spironolactone is metabolized extensively in the liver, although not by CYP3A4. It has been shown to increase the serum half-life of digoxin, which may result in digitalis toxicity. Spironolactone also has been associated with a decreased anticoagulation response to warfarin. In addition, the use of salicylates, such as aspirin, with spironolactone may increase the risk of hyperkalemia and renal toxicity.5

The main difference between spironolactone, a nonselective AA, and eplerenone, a more selective AA, is the incidence of sex hormone?related side effects such as gynecomastia and mastodynia. Gynecomastia is the enlargement of the male breast resulting from proliferation in the glandular tissue of the breast determined by mammography or ultrasonography.10-12 It is important to note that, to the best of our knowledge, this condition is benign and usually subsides promptly, then eventually disappears after discontinuing the medication.13

Women taking spironolactone have a slight chance of experiencing menstrual irregularity, postmenopausal bleeding, breast tenderness, hirsutism, and infertility, although there was no report of incidence of these events in the RALES trial. These effects also are usually reversible after discontinuation of therapy.5

There is no evidence to suggest that either eplerenone or spironolactone is a more effective agent. Both have been shown to be beneficial in HF, and both have produced a similar occurrence of hyperkalemia. If the reversible, hormone related adverse effects such as gynecomastia, mastodynia, or menstrual irregularities are of concern or have occurred in a patient previously, eplerenone may be considered the first choice.6 Because spironolactone has been on the market for many years and is available generically, it is a more cost-effective option.14

As in any other clinical situation, each patient should be evaluated individually, and a decision should be made based on specific needs. Table 1 describes some differences in the characteristics of spironolactone and eplerenone, and Table 2 show the cost differences between the 2 agents.5,9

Dr. Tafreshi is an associate professor of pharmacy and medicine and director of the cardiology pharmacy practice residency at Midwestern University, College of Pharmacy—Glendale, Glendale, Ariz. Dr. Adkins is a pharmacist at Banner Thunderbird Medical Center in Glendale.

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