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NewsletterDrug and Innovation Review Eplerenone, SARA of EPHESUS KW Tim Park, MD
Eplerenone is a novel selective aldosterone receptor antagonist (SARA). It has similar efficacy to spironolactone in blocking aldosterone receptors, lowering blood pressure, and moderating hormonal and neurohumoral markers of heart failure (1). However, eplerenone is at least 100 times more specific for aldosterone receptors than spironolactone and has significantly less affinity for androgen and progesterone receptors. As a result, eplerenone is not expected to be associated with a significant incidence of gynecomastia, breast pain, impotence, and changes in menstrual patterns or libido. The second "A" in the Renin-Angiotensin-Aldosterone system has drawn increasing attention in the recent years. Benefits of inhibiting the first "A" with angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been well established in heart failure (HF), myocardial infarction (MI), vascular disease, and prevention of renal failure (2). However, despite use of ACEIs and ARBs, aldosterone escape may occur, leading to perivascular inflammatory changes. Addition of aldosterone blockade may therefore lead to a further reduction in morbidity and mortality in patients with heart failure. In the RALES (Randomized Aldactone Evaluation Study) trial, 1,663 patients with severe HF and a left ventricular ejection fraction < 35 % who were already being treated with an ACEI, a loop diuretic, and digoxin were randomized to receive either spironolactone or a placebo. Spironolactone was shown to reduce the 2-year mortality by 30 % (primarily by decreased deaths from HF and sudden cardiac death) and the frequency of hospitalizations due to HF by 35 % (3). The benefits of aldosterone blockade were not explained just by the mineralocorticoid properties of the hormone in retaining sodium and excreting potassium and magnesium. Aldosterone has also been shown (a) to have tropic properties and contribute to left ventricular hypertrophy in hypertensive patients, (b) to increase plasminogen activator inhibitor levels, (c) to cause perivascular inflammation and fibrosis and decrease vascular compliance, (d) to cause endothelial dysfunction, and (e) to block the myocardial uptake of norepinephrine. Thus aldosterone blockade can prevent myocardial and perivascular fibrosis, decrease plasma catecholamine levels and ventricular ectopy, and improve endothelial function and fibrinolytic balance (1). In the EPHESUS (Eplerenone Post-AMI Heart Failure Efficacy and Survival Study) trial, the efficacy of eplerenone in reducing mortality in patients with HF due to systolic dysfunction after an acute MI was examined. The EPHESUS trial was different from the RALES trial in that the former studied a SARA in a model of acute HF, whereas the latter studied a nonselective aldosterone blocker in a model of chronic HF. The proposed mechanisms of benefit included maintenance of plasma potassium and magnesium levels, prevention of sudden cardiac death by reducing plasma catecholamine levels and limiting myocardial and perivascular fibrosis, and prevention of reocclusion and reinfarction by favorably affecting the fibrinolytic balance. The study was event-driven and was concluded on August 30, 2002 with the 1,023rd death among about 6,200 enrolled patients. Results of the EPHESUS trial were recently published in the New England Journal of Medicine (4). In the 3313 patients randomized to eplerenone, there were fewer overall deaths at 16 months (relative risk 0.85, p=0.008), fewer deaths or hospitalizations due to cardiovascular causes (relative risk 0.87, p=0.002), and fewer sudden deaths from cardiac causes (relative risk 0.79 p=0.03) compared to the placebo group (n=3319). The rate of serious hyperkalemia was 5.5% in the eplerenone group compared to 3.9% in the placebo group (p=0.002). These benefits attributed to eplerenone therapy in patients with left ventricular dysfunction after myocardial infarction have far reaching implications for reducing mortality after MI as well as in other cardiovascular diseases. References 1. Pitt B, Williams G, Remme W, et al. The EPHESUS trial: Eplerenone in patients with heart failure due to systolic dysfunction in complicating acute myocardial infarction. Cardiovasc Drug Ther 2001; 15:79-87. 2. Pfeffer MA. New treasures from old? EHESUS. Cardiovasc Drug Ther 2001; 15:11-13. 3. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341:709-17. 4. Pitt B, Remme W, Zannad F, et al. Eplereonone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocarial infarction. N Engl J Med 2003;348:1309-21.
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