Consensus
Update on Aldosterone Antagonists Use in Heart Failure With Reduced Left Ventricular Ejection Fraction Heart Failure Society of America Guidelines Committee

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Abstract

Aldosterone antagonists (or mineralocorticoid receptor antagonists [MRAs]) are guideline-recommended therapy for patients with moderate to severe heart failure (HF) symptoms and reduced left ventricular ejection fraction (LVEF), and in postmyocardial infarction patients with HF. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial evaluated the MRA eplerenone in patients with mild HF symptoms. Eplerenone reduced the risk of the primary endpoint of cardiovascular death or HF hospitalization (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54–0.74, P < .001) and all-cause mortality (adjusted HR 0.76, 95% CI 0.62–0.93, P < .008) after a median of 21 months. Based on EMPHASIS-HF, an MRA is recommended for patients with New York Heart Association (NYHA) Class II–IV symptoms and reduced LVEF (<35%) on standard therapy (Strength of Evidence A). Patients with NYHA Class II symptoms should have another high-risk feature to be consistent with the EMPHASIS-HF population (age >55 years, QRS duration >130 msec [if LVEF between 31% and 35%], HF hospitalization within 6 months or elevated B-type natriuretic peptide level). Renal function and serum potassium should be closely monitored. Dose selection should consider renal function, baseline potassium, and concomitant drug interactions. The efficacy of eplerenone in patients with mild HF symptoms translates into a unique opportunity to reduce morbidity and mortality earlier in the course of the disease.

Section snippets

Pathophysiology of Aldosterone in HF

More than 50 years ago, Luetscher and Johnson12 first observed that adults and children with HF secrete a steroid hormone in the urine with sodium-retaining properties. Using selective venous sampling and liquid chromatography, Davis et al13 then identified this hormone as aldosterone and found that it was produced in excess in the adrenal gland in edematous states. Subsequent studies have shown that plasma aldosterone levels are elevated in patients with HF despite maximal renin-angiotensin

Overview of Pharmacology

Aldosterone exerts its effects by binding to the mineralocorticoid receptor. In the United States, 2 pharmacologic agents competitively inhibit aldosterone at the mineralocorticoid receptor sites, spironolactone and eplerenone. Spironolactone is a nonselective MRA that is structurally similar to progesterone. In addition to its aldosterone-blocking effects, spironolactone inhibits the effects of dihydrotestosterone at the receptor site and increases the peripheral conversion of testosterone

Review of the Evidence

Several randomized controlled trials of aldosterone antagonists in patients with HF and reduced LVEF have been conducted to date (Table 2). A systematic review of these and other studies with aldosterone receptor antagonists included 10 trials that have specifically enrolled New York Heart Association (NYHA) Class II patients with reduced LVEF.34

Recommended Clinical Approach

After ACE inhibitor and β-blocker therapy, the 2010 HFSA guideline recommendation supports the consideration of an ARB (Level of Evidence A) or an aldosterone antagonist (moderate HF Level of Evidence C; severe HF Level of Evidence A) as add-on therapy.1 Based on the totality of evidence, an aldosterone receptor antagonist should now be considered as first-line add-on therapy for patients who are eligible based on serum potassium and creatinine levels. An ARB should be considered as first-line

Safety: Monitoring and Follow-up

As with all medical therapy, there are risks to be considered with aldosterone receptor antagonists, especially in conjunction with other medications that block the renin-angiotensin system, alter volume status, or influence potassium levels. The principal risks of aldosterone receptor antagonists are hyperkalemia, renal dysfunction, and gynecomastia.40, 50, 51, 52

Pharmacokinetic

Eplerenone is a substrate of the cytochrome P-450 3A4 isoenzyme.54, 55 Thus, the serum concentration of eplerenone is affected by concomitant use of CYP 3A4 inhibitors or inducers (Table 6). Concomitant use of a CYP 3A4 inhibitor inhibits eplerenone metabolism, thereby increasing eplerenone serum concentrations, enhancing the risk for hyperkalemia. Drugs that are potent inhibitors of CYP 3A4 (ketoconazole) increase the eplerenone area under the curve (AUC) by 5-fold and should be avoided in

HF With Preserved Ejection Fraction

HF with preserved ejection fraction (HFPEF) accounts for approximately half of the overall HF burden in the community.61 Over the past 2 decades, the prevalence growth rate for HFPEF has exceeded that of HF with reduced EF.62 This trend may be related to the aging of the population and the age-related changes in cardiac structure and function.63 No interventions tested to date have been shown to reduce all-cause mortality in this patient population. Patients with HFPEF have a mortality and

Conclusion

In earlier trials, aldosterone receptor antagonists, or MRAs, demonstrated clinically meaningful improvements in rehospitalizations and survival and are now an established, though underused, part of the standard therapy of selected patients with HF or post-MI LV dysfunction. The results of the EMPHASIS-HF trial have filled a prominent knowledge gap and support the addition of an MRA to standard therapy in selected patients with mild HF with reduced EF. Although formal revisions to established

Acknowledgments

The HFSA Guideline Committee acknowledges the administrative support of Cheryl Yano, Executive Director, HFSA and Bart Galle, PhD. We also acknowledge the HFSA Executive Council for their careful review of this manuscript, and their contributions to the document: Barry M. Massie, MD; Thomas Force, MD; Hani N. Sabbah, PhD; Mandeep R. Mehra, MD; Douglas L. Mann, MD; Inder S. Anand, MD, PhD; John C. Burnett, Jr., MD; John Chin, MD; Steven R. Houser, PhD; Sharon A. Hunt, MD; JoAnn Lindenfeld, MD;

Disclosures

NameConsulting Fees/HonorariaSpeaker’s BureauResearch GrantsEquity Interests/Stock/Stock OptionsEquity InterestsRoyalty IncomeNon-Royalty PaymentsOther Financial BenefitSalaryIntellectual Property RightsFellowship Support
Randall C. Starling, MD, MPHBiocontrol, Medtronic, Novartis, Novella, ThoratecNoneBiotronik (paid to Cleveland Clinic)CardioMEMSNoneNoneNoneUNOS Board MemberNoneNoneNone
William G. Stevenson, MDNoneNoneNoneNoneNoneNoneNoneNoneNoneNoneNone
Adrian F. Hernandez, MDNoneNoneNoneNone

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    This article was reviewed and approved by the HFSA Executive Council on February 20, 2012. The HFSA Executive Council members are listed in the Acknowledgment.

    See page 278 for disclosure information.

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