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Jan.30.2012

Aldosterone Receptor Antagonists

Summary

  • Eplerenone and spironolactone are both approved for heart failure and hypertension; however, spironolactone is also indicated for the treatment of hypokalemia, hyperaldosteronism, and edematous conditions for patients with cirrhosis of the liver.
  • Spironolactone is a nonspecific aldosterone receptor antagonist and is associated with with progestogenic and androgenic effects (e.g., gynecomastia, erectile dysfunction, menstrual irregularities, hirsutism, mastalgia); eplerenone has lower affinity for androgen, progesterone, and glucocorticoid receptors and thus a lower incidence of these adverse effects.
  • Both eplerenone and spironolactone are associated with hyperkalemia, which can be severe; risk factors include renal impairment, heart failure, diabetes mellitus, and age >= 65 years.
  • Eplerenone is a CYP3A4 substrate, which affects drug interaction potential and increases the risk of of hyperkalemia; use of eplerenone is contraindicated with strong CYP3A4 inhibitors.

Pharmacology/Mechanism of Action

Aldosterone receptor antagonists (ARA)s, also called mineralocorticoid receptor antagonists, competitively inhibit aldosterone at the mineralocorticoid receptor, thus reducing the adverse effects of elevated plasma aldosterone concentrations, including the cardiovascular effects of elevated blood pressure, left ventricular hypertrophy, and myocardial fibrosis in heart failure.[50352] The mechanism of action of ARAs in heart failure and other indications is complex and appears to be independent of diuretic and potassium-sparing effects. [50353][50354]

Spironolactone, a nonselective ARA with similar structure to progesterone, is associated with dose-dependent progestogenic and antiandrogenic adverse effects, including gynecomastia, impotence, and menstrual irregularities. Eplerenone was developed to avoid these adverse effects, possessing a 100- to 1000-fold lower affinity for androgen, progesterone, and glucocorticoid receptors than spironolactone. While in vitro studies show that spironolactone has greater affinity than eplerenone at the aldosterone receptor, eplerenone inhibits aldosterone binding in vivo at a lower dosage than spironolactone.[50355]

Spironolactone has a shorter half-life than eplerenone and has active metabolites (including canrenone) that prolong its activity. Eplerenone undergoes rapid metabolism by the liver to inactive metabolites. Elimination of both agents occurs predominately via the kidneys; however, a higher percentage of spironolactone than eplerenone is eliminated through the feces. Elimination properties of spironolactone and eplerenone have an important role in determining appropriate doses in patients with renal and/or hepatic dysfunction.

Therapeutic Use

Hypertension

  • Spironolactone is indicated for patients who cannot be treated adequately with other antihypertensive drugs or for whom other agents are considered inappropriate; spironolactone is usually used in combination with other drugs.
  • Eplerenone is FDA approved as monotherapy or combination therapy with efficacy reported as equivalent to that of an ACE inhibitor.[50362][50363]

Heart failure

  • Three large randomized, controlled trials of ARAs in patients with heart failure and reduced LVEF – ie, RALES, EPHESUS, EMPHASIS-HF – have demonstrated significant reductions in mortality and morbidity.
  • A comparison of the efficacy of spironolactone and eplerenone in heart failure based on RALES, EPHESUS, and EMPHASIS-HF is limited by differences in patient populations, baseline medications, and achieved dose.
  • Based on these landmark trials, the American College of Cardiology Foundation/American Heart Association guidelines and the Heart Failure of Society guidelines recommend the use of ARAs in the following 3 situations:[46155][50360]
    • low-dose spironolactone or eplerenone in patients with LVEF <= 35% and New York Heart Association (NYHA) Class III-IV symptoms in absence of significant renal dysfunction or hyperkalemia
    • eplerenone in patients after acute myocardial infarction (AMI) with clinical heart failure signs and symptoms and LVEF < 40%.
    • eplerenone in patients with LVEF <= 30% (or if LVEF > 30 to 35, QRS > 130 ms), NYHA Class II symptoms and another high risk feature [eg, age > 55 years, heart failure hospitalization within the previous 6 months, or brain natriuretic peptide > 250 pg/mL, N-terminal prohormone of brain natriuretic peptide > 500 pg/mL (men) or >750 pg/mL (women)].

Dosing information

  • Indications, renal function, and drug interactions are the main determinants of which agent will be selected for a particular patient.

Comparative Dosage of Aldosterone Receptor Antagonists

 

Hypertension

Daily Dose (mg)

Heart Failure

Daily dose (mg)

  Initial Range Initial Range
Eplerenone 50 mg 25-100 25 25-100
Spironolactone 50-100 50-200 25 12.5-50

Comparative Efficacy

Aldosterone Receptor Antagonist Comparative Efficacy Trials

Heart Failure
Citation/StudyDesign/RegimenResults

Conclusion

 

Pitt B, et al. N Engl J Med. 1999;341:709-717. (RALES) [17186]

Randomized, double-blind, placebo-controlled. Mean follow-up 24 months

 

1663 patients with NYHA Class III/IV (ischemic 54-55%)

 

Spironolactone 25 mg daily versus placebo

 

Baseline ACE inhibitor or angiotensin receptor blocker: 94-95%, beta-blocker: 10-11%

All-cause mortality:

35% spironolactone vs

46% placebo 

RR 0.70 (95% CI 0.60-0.82), p<0.001

 

CV death or CV hospitalization:

RR 0.68 (95% CI, 0.59-0.78), p<0.001

 

Serious hyperkalemia (=6 mmol/L):

2% spironolactone vs

1% placebo (p=0 .42)

Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe HF

 

Pitt B, et al. N Engl J Med. 2003;348:1309-1321. (EPHESUS) [17219]

Randomized, double-blind, placebo-controlled. Mean follow-up 16 months

 

6632 patients with recent (3-14 days) AMI, LVEF = 40, and HF symptoms

 

Eplerenone 25 mg daily initially, titrated to maximum of 50 mg per day, versus placebo

 

Baseline ACE inhibitor or angiotensin receptor blocker: 86-87%, beta-blocker: 75

All-cause mortality:

14.4% eplerenone vs

16.7% placebo 

RR 0.85 (95% CI, 0.75-0.96), p=0.008

 

CV death or CV hospitalization:

26.7% eplerenone vs

30.0% placebo 

RR 0.87 (95% CI 0.79-0.95), p=0.002

 

Serious hyperkalemia (=6 mmol/L):

5.5% eplerenone vs

3.9% placebo (p=0 .02)

Addition of eplerenone to optimal medical therapy reduces morbidity and mortality among patients with AMI complicated by left ventricular dysfunction and HF
Zannad F, et al. N Engl J Med. 2011;364:11-21. (EMPHASIS-HF)[50148]

Randomized, double-blind, placebo-controlled. Median follow-up 21 months

 

2737 patients with NYHA Class II (ischemic 68-70%)

 

Eplerenone 25 mg daily initially, titrated to maximum of 50 mg per day, versus placebo

 

Baseline ACE inhibitor or angiotensin receptor blocker: 93-94%, beta-blocker: 87%

 

 

All-cause mortality:

12.5% eplerenone vs

15.5% placebo 

RR 0.76 (95% CI 0.62-0.93), p=0.008

 

CV death or HF hospitalization:

18.3% eplerenone vs

25.9% placebo 

HR 0.63 (95% CI, 0.54-0.74), p<0.001

 

Serious hyperkalemia (>6 mmol/L):

2.5% eplerenone vs

1.9% placebo (p=0 .29)

Eplerenone, compared with placebo, reduced risk of death and risk of hospitalization among patients with systolic HF and mild symptoms
Hypertension
 Multicenter, double-blind, placebo controlled trial comparing eplerenone 50, 100, or 400 mg once daily, eplerenone 25, 50, or 200 mg twice daily, and spironolactone 50 mg twice daily for 8 weeks

Adjusted mean change in baseline to final visit for seated
and standing diastolic blood pressure (DBP) measured at trough 

-4.1 mmHg eplerenone 50 mg daily vs -1.5 mmHg placebo

-5.9 mmHg eplerenone 100 mg daily vs -1.5 mmHg placebo

-8.4 mmHg eplerenone 400 mg daily vs -1.5 mmHg placebo (p< 0.05)

-4.8 mmHg eplerenone 25 mg twice daily vs -1.5 mmHg placebo

-7 mmHg eplerenone 50 mg twice daily vs -1.5 mmHg placebo (p< 0.05)

-12.1 mmHg eplerenone 200 mg twice daily vs -1.5 mmHg placebo (p< 0.05)

-9.6 mmHg spironolactone 50 mg twice daily vs -1.5 mmHg placebo (p< 0.05)

Eplerenone 50 to 400 mg given once daily or in 2 divided doses
lowered DBP in a dose-related manner over a 24-hour period

Adverse Reactions/Toxicities

Hyperkalemia

Spironolactone and eplerenone are associated with dose-related increases in serum potassium concentrations by blocking potassium excretion in the renal distal tubule and collecting ducts.[50357][50358] Serious hyperkalemia (> 5.5 or 6 mmol/L) has been reported and can cause life-threatening cardiac arrhythmias.[46156] If hyperkalemia occurs, ARAs should be discontinued immediately and specific measures taken to reduce serum potassium concentrations. Subsequently, a reduction in the dose of the ARA may be warranted.

Gynecomastia / Endocrine adverse reactions

Spironolactone may cause gynecomastia, libido decrease, and impotence (erectile dysfunction) in men.[46156] Women taking spironolactone may experience menstrual irregularity, postmenopausal bleeding, breast tenderness or mastalgia, hirsutism, deepened voice, and amenorrhea. These effects are usually reversible following discontinuation of therapy. Endocrine-related effects may also be seen with eplerenone, but they occur at a much lower incidence.

Hepatotoxicity

Hepatic enzymes (i.e. ALT, GGT) increased in a dose-related manner with eplerenone. In clinical trials at 50 mg/day, on average the serum alanine aminotransferase (ALT) increased 0.8 Units/L and gamma glutamyl transpeptidase (GGT) increased 3.1 Units/L.

Hyponatremia

Eplerenone appears to decrease the serum sodium concentration in a dose-dependent manner. Spironolactone alone does not usually cause hyponatremia, but it can develop in patients taking spironolactone with other diuretic therapy.

Drug Interactions

Drugs that increase serum potassium concentrations

Use of ARAs with other drugs that block potassium excretion or raise serum potassium concentrations should be avoided with the exception of ACE inhibitors or angiotensin receptor blockers, which should be used with caution. Any substance containing potassium salts should also be avoided because of increased risk of hyperkalemia, especially in the presence of renal impairment. In patients with hypertension, administration of eplerenone with potassium supplements or potassium-sparing diuretics (e.g., amiloride, spironolactone, or triamterene) is contraindicated due to the risk of hyperkalemia.

Drugs that inhibit CYP 3A4

Eplerenone is a substrate of the cytochrome P450 3A4 isoenzyme and is contraindicated for use by patients taking strong 3A4 inhibitors.[50365] In patients taking eplerenone for hypertension who are taking a moderate to weak inhibitor of CYP3A4, reduce the starting dose to 25 mg once daily. For all patients, check serum potassium and serum creatinine in 3-7 days after starting a moderate 3A4 inhibitor.

Digoxin

Spironolactone increases the half-life of digoxin. A reduction in the dose of digoxin may be needed.

Antihypertensive drugs

Spironolactone and eplerenone can have additive hypotensive effects when administered with other antihypertensive agents.

Safety Issues

Hyperkalemia

Both spironolactone and eplerenone can cause hyperkalemia and are contraindicated for use in patients with hyperkalemia. Caution is advised in those patients at risk for hyperkalemia, including those with underlying renal dysfunction, heart failure or diabetes. Additionally, elderly patients are also at increased risk.[50359]

Renal impairment

ARAs are contraindicated for use by patients with various degrees of renal impairment as renal impairment increases the risk of hyperkalemia. Specifically, spironolactone is contraindicated in patients with anuria, acute renal insufficiency, or significant impairment of renal excretory function. Eplerenone is contraindicated in patients with a CrCl <= 30 ml/min, except when used for hypertension. In hypertension, it is contraindicated in patients with a CrCl < 50 ml/min, a serum creatinine > 2 mg/dl (males) or > 1.8 mg/dl (females), and type 2 diabetes with microalbuminuria.

Secondary malignancy

Spironolactone has been shown to be a tumorigen in chronic toxicity studies in rats, and breast cancer has been reported in patients taking spironolactone, although a cause and effect relationship has not been established. Avoid unnecessary spironolactone use, and only use it for FDA-approved indications.

[17186]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;341:709-17

[17219]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;348:1309-21

[46155]Hunt SA, Abraham WT, Chin MH, et al.; American College of Cardiology Foundation, American Heart Association. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90

[46156]Ezekowitz JA, McAlister FA. Aldosterone blockade and left ventricular dysfunction: a systematic review of randomized clinical trials. Eur Heart J. 2009;30:469-77

[50148]Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11-21

[50352]Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001;345:1689-1697.

[50353]Tang WH, Parameswaran AC, Maroo AP, Francis GS. Aldosterone receptor antagonists in the medical management of chronic heart failure. Mayo Clin Proc. 2005;80:1623-1630.

[50354]Rossignol P, Menard J, Fay R, et al. Eplerenone survival benefits in heart failure patients post-myocardial infarction are independent from its diuretic and potassium-sparing effects. Insights from an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) substudy. J Am Coll Cardiol. 2011;58:1958-1966.

[50355]Struthers A, Krum H, Williams GH. A comparison of the aldosterone-blocking agents eplerenone and spironolactone. Clin Cardiol. 2008;31:153-158

[50357]Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, DeVries C, et al. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol. 1987;60:820-825.

[50358]Weinberger MH, Roniker B, Krause SL,Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens. 2002;15:709-716

[50359]Sica DA. Pharmacokinetics and pharmacodynamics of mineralocorticoid blocking agents and their effects on potassium homeostasis. Heart Fail Rev. 2005;10:23-29.

[50360]Butler J, Ezekowitz JA, Collins SA, et al. Update on aldosterone antagonists use in heart failure with reduced left ventricular ejection fraction. Heart Failure Society of America Guidelines Committee. J Cardiac Fail. 2012;18:265-281.

[50362]Croom KF, Perry CM. Eplerenone: a review of its use in essential hypertension. Am J Cardiovasc Drugs. 2005;5:51-69.

[50363]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.

[50365]Cook CS, Berry LM, Burton E. Prediction of in vivo drug interactions with eplerenone in man from in vitro metabolic inhibition data. Xenobiotica. 2004;34:215-228.

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