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The role of aldosterone receptor antagonists in the management of heart failure: An update

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ABSTRACTThe aldosterone receptor antagonists (ARAs) spironolactone (Aldactone) and eplerenone (Inspra) have become part of standard medical therapy for heart failure, having shown clinical efficacy in randomized trials in patients with advanced symptomatic systolic heart failure, postinfarction heart failure with cardiac dysfunction, and systolic heart failure with mild symptoms. The benefits include a lower rate of death. Yet to be answered is whether the two drugs are clinically equivalent; another question is whether they may benefit everyone with symptomatic heart failure, including diastolic heart failure.

KEY POINTS

  • Although caution is advised in starting ARAs, these drugs are commonly underused in heart failure.
  • Aldosterone “escape” can blunt the effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. This is the rationale for also using ARAs.
  • The major trials of ARAs in heart failure to date have been the Randomized Aldactone Evaluation Study (RALES), the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).
  • Close monitoring is essential when starting an ARA, as severe hyperkalemia and renal insufficiency can occur.


 

References

Figure 1.

Over the past 30 years, the focus of treating heart failure has shifted from managing symptoms to prolonging lives. When the neurohormonal hypothesis (ie, the concept that neurohormonal dysregulation and not merely hemodynamic changes are responsible for the onset and progression of heart failure) was introduced, it brought a dramatic change that included new classes of drugs that interfere with the renin-angiotensin-aldosterone system, ie, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and, most recently, aldosterone receptor antagonists (ARAs) (Figure 1).

Evidence supporting the use of the ARAs spironolactone (Aldactone) and eplerenone (Inspra) in heart failure has been growing, as has evidence of their usefulness in treating diabetes and chronic renal disease. Still, these drugs must be used cautiously, as they can cause hyperkalemia.

This paper will review the clinical use of ARAs in symptomatic systolic heart failure, their side effects, the findings and implications of recent trials, and controversies in this area, notably whether there is any evidence favoring the use of one drug over another.

ALDOSTERONE IN HEART FAILURE

Aldosterone, a hormone secreted by the zona glomerulosa of the adrenal gland, was first isolated by Simpson and Tait more than half a century ago.1 Later, it was found to promote reabsorption of sodium and excretion of potassium in the kidneys and hence was categorized as a mineralocorticoid hormone.

Release of aldosterone is stimulated by decreased renal perfusion via angiotensin II, hyperkalemia, and possibly adrenocorticotropic hormone.2 Aldosterone exerts its effects by binding to mineralocorticoid receptors in renal epithelial cells.

Aldosterone has several deleterious effects on the failing heart, primarily sodium and fluid retention, but also endothelial dysfunction, left ventricular hypertrophy, and myocardial fibrosis.2,3 Plasma aldosterone levels can be markedly elevated in patients with heart failure, likely due to activation of the renin-angiotensin-aldosterone system. Elevated aldosterone and angiotensin II levels have been associated with higher mortality rates.4

ALDOSTERONE ‘ESCAPE’ BLUNTS THE EFFECT OF ACE INHIBITORS AND ARBs

ACE inhibitors and ARBs have become standards of care for patients with systolic heart failure, and for many years, it was believed that these drugs suppressed aldosterone levels sufficiently. But elevated aldosterone levels have been noted in up to 38% of patients on chronic ACE inhibitor therapy.5 In one study, patients on dual blockade, ie, on both an ACE inhibitor and an ARB, had significantly lower aldosterone levels at 17 weeks of therapy, but not at 43 weeks.6 This phenomenon is known as “aldosterone escape.”

Several mechanisms might explain this phenomenon. Angiotensin II, a potent inducer of aldosterone, is “reactivated” during long-term ACE inhibitor therapy. Interestingly, patients progress toward aldosterone escape regardless of whether the ACE inhibitor dose is low or high.7 There is evidence that some aldosterone is produced by endothelial cells and vascular smooth muscle in the heart and blood vessels,8 but ACE inhibitors and ARBs suppress only the aldosterone secreted by the adrenal glands.

Regardless of the mechanism, aldosterone escape can blunt the effects of ACE inhibitors and ARBs, reducing their favorable effects on the risk of death in heart failure patients. This is the rationale for also using ARAs.

ARAs IN HEART FAILURE

Aldosterone acts by regulating gene expression after binding to mineralocorticoid receptors. These receptors are found not only in epithelial tissue in the kidneys and glands, but also in nonepithelial tissues such as cardiomyocytes, vessel walls, and the hippocampus of the brain.9 The nonepithelial effects were first demonstrated 2 decades ago by Brilla et al,10 who noted that chronically elevated aldosterone levels in rats promoted cardiac fibroblast growth, collagen accumulation, and, hence, ventricular remodeling.

The hypertensive effect of aldosterone may also be mediated through mineralocorticoid receptors in the brain. Gomez-Sanchez et al11 found that infusing aldosterone into the cerebral ventricles caused significant hypertension. A selective mineralocorticoid antagonist inhibited this effect when infused into the cerebral ventricles but not when given systemically.

In 1959, Cella and Kagawa created spironolactone, a nonselective ARA, by combining elements of progesterone for its antimineralocorticoid effect and elements of digitoxin for its cardiotonic effect.12 Although spironolactone is very effective in treating hypertension and heart failure, its use is limited by progestational and antiandrogenic side effects. This led, in 1987, to the invention by de Gasparo et al of a newer molecule, a selective ARA now called eplerenone.13 Although eplerenone may be somewhat less potent than spironolactone in blocking mineralocorticoid receptors, no significant difference in efficacy has been noted in randomized clinical trials, and its antiandrogenic action is negligible.12

Although these drugs target aldosterone receptors, newer drugs may target different aspects of mineralocorticoid activities, and thus the term “mineralocorticoid receptor antagonist” has been proposed.

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