Aldosterone

Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348:1309-1321.

* PRACTICE RECOMMENDATIONS

Eplerenone, a selective mineralocorticoid receptor antagonist currently approved by the Food and Drag Administration for treatment of hypertension, reduces mortality following myocardial infarction (MI) in patients with left ventricular dysfunction and clinical signs of congestive heart failure. Previous research by the same group established that spironolactone does the same at lower cost thou eplenerone. (1)

* BACKGROUND

Family physicians commonly manage patients with congestive heart failure following acute MI. This trial examined the effects of selective aldosterone blockade on morbidity and mortality in patients who suffered an acute MI complicated by left ventricular dysfunction and clinical signs of congestive heart failure.

* POPULATION STUDIED

This industry-sponsored study enrolled 6642 patients at medical centers in 37 different countries. Inclusion criteria included acute MI (diagnosed according to "standard criteria") within the previous 2 weeks; left ventricular dysfunction (ejection fraction <40%), and heart failure as documented by clinical findings of pulmonary rales, radiographic changes, or a third heart sound.

Exclusion criteria included the use of potassium-sparing diuretics, a baseline serum creatinine over 2.5 mg/dL, or baseline serum potassium over 5.0 mmol/L. The average patient age was 64 years; 70% were male and 90% were white. The average left ventricular ejection fraction at the time of enrollment was 33%.

More than 80% of study patients were taking angiotensin-converting enzyme (ACE) inhibitors, 75% were taking beta-blockers, 60% were taking diuretics, and nearly 50% were on statin therapy. This degree of medical therapy is higher than generally cited(2,3) and thus might impact generalizability.

* STUDY DESIGN AND VALIDITY

Subjects were randomized to receive either eplerenone 25 mg/d titrated to a maximum of 50 mg/d (n=3391), or placebo (n=3313). All patients concurrently received "optimal medical management" that included ACE inhibitors, beta-blockers, diuretics, aspirin, statins, and coronary reperfusion therapy. Endpoints were analyzed using the Cox proportional-hazards regression and the time to event was summarized using standard Kaplan-Meier curves. All final data analysis was performed by the study sponsor.

The study design was good: it was well-powered to detect an 18% difference in death from any cause between groups. Randomization was stratified according to clinical site and statistical analysis was performed using the appropriate models. Weaknesses include no mention of concealed subject allocation, which could lead to an overestimation of the magnitude of treatment effect.

* OUTCOMES MEASURED

Primary endpoints were time to death from any cause and time to death or hospitalization for cardiovascular events (stroke, MI, heart failure, or arrhythmia). Secondary endpoints were the absolute presence of death or hospitalization. Endpoints were adjudicated by blinded assessors.

* RESULTS

Groups were similar at baseline. Patients were followed every 3 months for an average of 16 months. Mortality from all causes was lower in the eplerenone group (14.4% vs 16.7%; P<.01; number needed to treat [NNT]=44). Cardiovascular death and hospitalization were also reduced in the eplerenone group (26.7% vs 30%; P<.01; NNT=33).

Patients in the eplerenone group were more likely to discontinue medication use (528 vs 493) and more likely to have serious hyperkalemia (5.5% vs 3.9%; P<.01; number need to harm=63).

REFERENCES

(1.) Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341:709-717.

(2.) Dargie HJ. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001; 357:1385-1390.

(3.) Dickstein K, Kjekshus J; OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomized trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet 2002; 360:752-760.

Mark B. Stephens, MD, MS, Flight Line Clinic Naval Hospital, Sigonella, Italy; Uniformed Services University of the Health Sciences, Bethesda, Md. E-mail: mbstephens@sig.med.navy.mil.

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