EPHESUS: Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study -- Patients With a Baseline History of Hypertension

Linda Brookes, MSc


December 30, 2003

Editorial Collaboration

Medscape &

Presenter: Bertram Pitt, MD, University of Michigan Medical Center (Ann Arbor)

For patients who present with essential hypertension and further symptoms of possible heart failure, it is important for physicians to consider and treat the patient's underlying disease. A retrospective analysis of the landmark Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) indicates that the selective aldosterone blocker eplerenone is especially beneficial in reducing mortality and morbidity in patients with a history of hypertension as well as acute myocardial infarction (AMI) complicated by systolic left ventricular (LV) dysfunction.[1]

In the EPHESUS trial overall, eplerenone significantly improved survival and reduced cardiovascular mortality/cardiovascular hospitalization in patients with heart failure post AMI.[2] In the 4E study, which compared the effects of eplerenone, enalapril, and eplerenone plus enalapril, eplerenone reduced blood pressure, LV mass, and the incidence of microalbuminuria in patients with essential hypertension and LV hypertrophy.[3]

In view of these effects of eplerenone, the subset of EPHESUS patients with a history of hypertension was analyzed retrospectively to investigate the potential of eplerenone to treat patients with essential hypertension.

Patients With History of Hypertension

In EPHESUS, patients with AMI, LV ejection fraction ≤40 %, and rales who were on standard therapy were randomized 3-14 days post AMI to treatment with eplerenone 25 mg daily titrated to 50 mg daily or to placebo. About two thirds of the total EPHESUS population had a history of hypertension at baseline, 1983 of whom were randomized to eplerenone and 2024 to placebo. Baseline characteristics were relatively similar for patients with and without a history of hypertension, except for some slight but significant differences. The patients with a history of hypertension were older, there were more males, and they had higher blood pressure (although still within the normotensive range), higher serum creatinine, a higher incidence of diabetes, and a greater incidence of MI and heart failure compared with those without a history of hypertension. In addition, patients with a history of hypertension were taking more antihypertensive medications at baseline, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, and potassium supplements.

Primary and Secondary Endpoints

In these hypertensive patients, eplerenone significantly reduced the coprimary endpoints: total mortality by 23% (P = .001) and cardiovascular mortality/cardiovascular hospitalization, including hospitalization for nonfatal MI, nonfatal stroke, ventricular arrhythmias, and heart failure, by 16% (P = .002) (Table). Sudden cardiac death, the most frequent cause of cardiac death in the patients with a history of hypertension, was reduced by 26% (P = .021).

Table. Primary and Secondary Endpoints
Cumulative Incidence RR 95% CI P
Total mortality 0.77 0.66-0.90 .001
CV mortality/CV hospitalization 0.84 0.57-0.96 .002
Sudden cardiac death 0.74 0.57-0.96 .021

Heart failure was the most frequent cause of cardiovascular hospitalization in these patients. A borderline, nonsignificant reduction of 14% in heart failure mortality and hospitalizations due to heart failure was seen in patients randomized to eplerenone (P = .06). Patients with pulse pressure above the median (≥ 50 mm Hg) had a significantly greater effect on total mortality with eplerenone. Eplerenone also tended to show a greater effect on the other endpoints in these patients with hypertension. As in the main trial, no effect was seen on stroke.

Side Effects

Use of eplerenone was associated with decreased rates of hypokalemia and increased rates of hyperkalemia, which were similar to those seen in the overall EPHESUS trial.

Mechanism of Action

Dr. Pitt suggested that the reason why eplerenone appeared to have a better effect in patients with a history of hypertension was that they probably already had vascular and ventricular remodeling and thus gene processes and mechanisms that would be favorably affected by eplerenone. A small magnetic resonance imaging substudy of ventricular remodeling in the EPHESUS trial that is currently being analyzed may provide more information.


The potential of eplerenone alone or in combination with other antihypertensive medications to reduce mortality and morbidity in patients with essential hypertension and preserved systolic function appears promising but will require further exploration in prospective randomized studies.


Eplerenone has been approved, but not yet marketed, in the United States for the treatment of hypertension and to improve survival of stable patients with LV systolic dysfunction (ejection fraction ≤ 40%) and clinical evidence of congestive heart failure after an AMI. It is anticipated that the drug will become available through an early-access program in November 2003, and will be commercially available as of December 2003.

  1. Pitt B, Krum H, Nicolau JC, et al. The EPHESUS Trial: effect of eplerenone in patients with a baseline history of hypertension. Abstracts from Scientific Sessions 2003, November 9-12, Orlando, Florida. Circulation. 2003;106(17 suppl):IV-599. Abstract 2727.

  2. Pitt B, Remme W, Zannad F, et al, for the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348:1309-1321.

  3. Pitt B, Reichek N, Willenbrock R, et al. Effects of eplerenone, enalapril, and eplerenone/enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation. 2003;108:1831-1838.