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

Heart failure (HF) is the inability of the heart to meetthe demands of the body. Although there are differentforms of HF, the majority of patients with HFhave impairment of left ventricular systolic function. The cardinalmanifestations of systolic HF are dyspnea and fatigue.

The American College of Cardiology and the AmericanHeart Association (ACC/AHA) have developed guidelinesfor classifying and treating patients with HF due to chronicleft ventricular systolic dysfunction. Stage A includespatients who are at high risk for developing HF due to thepresence of conditions that are strongly associated with itsdevelopment. Patients in Stage B have developed structuralheart damage but have never shown signs or symptoms ofHF. Stage C patients have structural heart damage and currentor prior symptoms of HF. Stage D includes patientswith advanced structural heart disease and marked symptomsat rest despite optimal therapy.¹

According to these guidelines, in the absence of contraindications,all patients in Stage A should receive anangiotensin-converting enzyme inhibitor (ACEI). Patients inStage B should receive an ACEI and a beta-blocker (BB). InStage C, a diuretic should be added if the patient has symptomsof fluid retention. Digoxin should be added if the patientis still symptomatic while receiving optimal doses of ACEIs,BBs, and diuretics. Angiotensin receptor blockers (ARBs) usuallyare reserved for patients who develop intolerance toACEIs due to cough or angioedema. In the setting of normalrenal function and normal serum potassium concentration,the addition of an aldosterone antagonist (AA) should be considered if a patient has experienced recent or current symptomsat rest despite optimal drug therapy^1-3 (Figure).

For many years, spironolactone has been the only AAavailable on the market. Because spironolactone is a steroid,it may have some effects at the glucocorticoid, progesterone,and androgen receptors that can lead to adverseeffects 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, inaddition to standard therapy, reduces the risk of morbidityand mortality in patients with severe HF. The trialincluded 1663 patients who had been classified in NewYork Heart Association (NYHA) class IV HF (symptoms atrest) within 6 months preceding enrollment, were inNYHA class III or IV at the time of enrollment, had beendiagnosed with HF at least 6 weeks prior to enrollment,had a left ventricular ejection fraction of ≤35% (mean25%), and were being treated mainly with an ACEI and adiuretic. Exclusion criteria included a serum creatinineconcentration of >2.5 mg/dL and a serum potassium levelof >5.0 mmol/L.

In this double-blind, placebo-controlled study, patientsreceived either 25 mg of spironolactone once daily or amatching placebo. The dose could be increased to 50 mgafter 8 weeks if the patient continued to show signs orsymptoms of HF and did not have hyperkalemia. If apatient developed hyperkalemia at any time during thestudy, 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 outcomeassociated with the use of spironolactone. The resultsshowed a significant decrease in total mortality and mortalityfrom cardiac causes and a significant decrease in risk ofhospitalization for cardiac causes. Spironolactone also wasassociated with an improvement in NYHA classification. Inthis study, however, gynecomastia, mastodynia, and hyperkalemiawere reported more with spironolactone treatmentthan with placebo.

Eplerenone, a new AA, works in a way similar to spironolactone,but it is more selective to the mineralocorticoidreceptors. The Eplerenone Post-Acute Myocardial InfarctionHeart Failure Efficacy and Survival Study (EPHESUS) waspublished recently. This study evaluated the effect of aldosteroneantagonism in moderate-to-severe HF. The investigatorsconcluded that the use of eplerenone in addition tooptimal, standard drug therapy reduced morbidity andmortality in patients with HF post acute myocardial infarction (MI).

The EPHESUS trial was a randomized, double-blind,placebo-controlled trial that included 6642 patients whomet the following inclusion criteria: acute MI in the previous3 to 14 days, ejection fraction of ≤40% (mean 33%), andHF as documented by pulmonary rales, pulmonary venouscongestion shown on radiography, or the presence of athird heart sound. Patients also received optimal medicaltherapy, which included ACEIs, ARBs, diuretics, BBs, andcoronary reperfusion therapy. Exclusion criteria includedthe use of potassium-sparing diuretics, a serum creatinineconcentration of >2.5 mg/dL, and a serum potassium levelof >5.0 mmol/L prior to randomization.

Patients were randomly assigned to receive eplerenone 25mg daily or a matching placebo for 4 weeks. After the first4 weeks, the dose of eplerenone was increased to a maximumof 50 mg/day. The primary end points were time todeath from any cause and time to death from cardiovascularcauses or first hospitalization for a cardiovascular eventincluding HF, recurrent acute MI, stroke, or ventriculararrhythmia.

Patients were followed for a mean of 16 months. Therewas a significant reduction in end points in patients receivingeplerenone, compared with those receiving placebo. Itshould be noted that 20% of the studied patients were overthe age of 75, and these patients did not appear to benefitfrom the use of eplerenone.

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

Discussion

It is clear that aldosterone antagonism is beneficial in themanagement 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 compareddirectly. Additionally, the study participants and thedesigns in the existing trials were different.

The current ACC/AHA guidelines, which were publishedbefore EPHESUS was completed, recommend consideringlow-dose spironolactone in patients with recent or currentsymptoms of HF at rest despite optimal use of an ACEI, aBB, and digoxin.

One should note that, although aldosterone antagonismcan result in hyperkalemia, it also has been shown to protectagainst hypokalemia, which may pose a particularly significantrisk in patients with HF. Before and during AA therapy, serumpotassium and creatinine should be monitored frequently.^5,9

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

The main difference between spironolactone, a nonselectiveAA, and eplerenone, a more selective AA, is the incidenceof sex hormone?related side effects such as gynecomastiaand mastodynia. Gynecomastia is the enlargementof the male breast resulting from proliferation in the glandulartissue of the breast determined by mammography orultrasonography.^10-12 It is important to note that, to the bestof our knowledge, this condition is benign and usually subsidespromptly, then eventually disappears after discontinuingthe medication.¹³

Women taking spironolactone have a slight chance ofexperiencing menstrual irregularity, postmenopausal bleeding,breast tenderness, hirsutism, and infertility, althoughthere was no report of incidence of these events in theRALES trial. These effects also are usually reversible after discontinuationof therapy.⁵

There is no evidence to suggest that either eplerenone orspironolactone is a more effective agent. Both have beenshown to be beneficial in HF, and both have produced a similaroccurrence of hyperkalemia. If the reversible, hormone relatedadverse effects such as gynecomastia, mastodynia, ormenstrual irregularities are of concern or have occurred in apatient previously, eplerenone may be considered the firstchoice.⁶ Because spironolactone has been on the market formany years and is available generically, it is a more cost-effectiveoption.¹⁴

As in any other clinical situation, each patient should beevaluated individually, and a decision should be made basedon specific needs. Table 1 describes some differences in thecharacteristics of spironolactone and eplerenone, and Table2 show the cost differences between the 2 agents.^5,9

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

For a list of references, send a stamped, self-addressed envelope to:References Department, Attn. A. Stahl, Pharmacy Times,241 Forsgate Drive, Jamesburg, NJ 08831;or send an e-mail request to: astahl@mwc.com.