In post-myocardial infarction patients who also have left ventricular dysfunction and heart failure, ACE inhibitors and beta blockade are the therapies of choice. While treatment is effective, these patients still experience considerable morbidity and mortality.

Some recent efforts have failed to achieve additional improvements in these patients. However, one approach with promise is the use of aldosterone blocking agents. Recent research shows that aldosterone blockade can decrease mortality and morbidity in patients who have severe chronic heart failure from left ventricular dysfunction. One aldosterone blocker under study is spironolactone. In the Randomized Aldactone Evaluation Study (RALES), spironolactone reduced mortality by 30% in heart failure patients who were taking ACE inhibitors.

Another potentially useful agent is eplerenone, a selective aldosterone blocker that is approved in the United States for treating hypertension. Dr. Pitt and colleagues hypothesized that eplerenone would reduce both mortality and morbidity in post-myocardial infarction patients with left ventricular dysfunction and heart failure.

To test this, they enrolled more than 6,600 patients with acute myocardial infarction, left ventricular ejection fraction less than or equal to 40%, and documented heart failure. Patients underwent randomization to eplerenone or placebo in addition to optimal medical therapy. The eplerenone dose was 25 mg per day, titrated upward to a maximum of 50 mg per day. In addition, all patients received optimal medical therapy; this could include ACE inhibitors, beta blockers, diuretics, angiotensin-receptor blockers and coronary reperfusion therapy.

One primary endpoints of the study was all cause mortality. Dr. Pitt reported that there were significantly fewer deaths in the eplerenone group. Over a mean 16 months of follow-up, investigators recorded 478 deaths in that group, compared with 554 deaths in the placebo group, with a relative risk of 0.85 (95% CI 0.75 - 0.96; p=0.008).

Another primary endpoint was the composite of cardiovascular death and hospitalization for acute myocardial infarction, heart failure, stroke or arrhythmia. Again, there were fewer cardiovascular deaths or hospitalizations in the eplerenone group, with a relative risk of 0.87 (95% CI 0.79 - 0.95; p=0.002).

Eplerenone was also superior to placebo in a variety of secondary endpoints, including death from any cause or any hospitalization (8% reduction, p=0.02), sudden cardiac death (21% reduction, p=0.03) and episodes of hospitalization from heart failure (23%, p=0.02).

Investigators reported that hyperkalemia was a side effect of eplerenone treatment. They saw a 5.5% rate of serious hyperkalemia, versus 3.9% for placebo (p=0.002). The rate of hypokalemia was 8.4% percent for the eplerenone group, compared with 13.1% percent for placebo (p<0.001).

These findings suggest adding eplerenone to optimal medical treatment can decrease morbidity and mortality in acute myocardial infarction patients who have left ventricular dysfunction and heart failure. They strongly support the suggestion that many post-myocardial infarction patients should be taking an aldosterone receptor blocker in addition to beta blockers and ACE inhibitors.

While this was not a comparative trial, Dr. Pitt said he believed eplerenone and spironolactone would provide a similar degree of aldosterone blockade. However, there would likely be a difference in side effect profile. Spironolactone treatment can result in impotence, gynecomastia and breast pain, among other side effects. In the EPHESUS study, investigators reported no excess of gynecomastia or impotence. Because of this difference, eplerenone may have the potential to extend the benefits of aldosterone blockade to a much wider group of patients, Dr. Pitt said.