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Am Fam Physician. 2003;68(11):2256-2258

The use of angiotensin-converting enzyme (ACE) inhibitors to treat patients with heart failure is standard practice. The addition of spironolactone for aldosterone blockade in patients already receiving ACE inhibitors has been shown to provide further benefits in risk reduction of death and rates of hospitalization. Pitt and other investigators from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) conducted a randomized, double-blinded, placebo-controlled study of eplerenone in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.

This international trial enrolled 6,642 patients three to 14 days after acute myocardial infarction if they had the following: left ventricular dysfunction and ejection fraction of 40 percent or lower on echocardiography, radionuclide angiography, or angiography of the left ventricle; and clinical evidence of heart failure, such as pulmonary rales, chest radiograph exhibiting pulmonary venous congestion, or presence of a third heart sound. All patients received standard medical therapy after infarction, including ACE inhibitors, angiotensin-receptor blockers, diuretics, beta blockers, and coronary revascularization, as indicated. Patients were excluded if they were already using potassium-sparing diuretics or if they had a serum creatinine concentration of more than 2.5 mg per dL (220 μmol per L) or a serum potassium concentration of more than 5 mEq per L (5 mmol per L). The number of excluded patients was not given.

Participants were randomized to receive eplerenone, 25 mg daily, or matching placebo. After four weeks, the dosage of eplerenone was increased to a maximum of 50 mg daily, if tolerated. Whenever a patient had a serum potassium concentration of more than 5.5 mEq per L (5.5 mmol per L), the study drug was reduced or discontinued until the serum potassium concentration fell below this cutoff value. Follow-up occurred at weeks 1 and 4, three months, and every three months until the end of the study. The mean follow-up time was 16 months.

The primary outcome for the study was death from all causes, which occurred in 478 patients (14.4 percent) receiving eplerenone and 554 patients (16.7 percent) receiving placebo; this was a statistically significant reduction. Other outcome measures also showed small benefits associated with the use of eplerenone, including death from cardiovascular causes, hospitalization rates, and sudden death.

Discontinuation of the study medication was fairly high; 528 patients (15.9 percent) receiving eplerenone and 493 patients (14.9 percent) receiving placebo discontinued their randomly assigned medication. Serious hyperkalemia (defined as a serum potassium concentration of at least 6 mEq per L [6 mmol per L]) occurred in 180 patients (5.5 percent) receiving eplerenone and 126 patients (3.9 percent) receiving placebo.

The authors conclude that adding the aldosterone blocker eplerenone to the standard treatment of patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure improves their survival and hospitalization rates.

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