ConsensusUpdate on Aldosterone Antagonists Use in Heart Failure With Reduced Left Ventricular Ejection Fraction Heart Failure Society of America Guidelines Committee
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
Name Consulting Fees/Honoraria Speaker’s Bureau Research Grants Equity Interests/Stock/Stock Options Equity Interests Royalty Income Non-Royalty Payments Other Financial Benefit Salary Intellectual Property Rights Fellowship Support Randall C. Starling, MD, MPH Biocontrol, Medtronic, Novartis, Novella, Thoratec None Biotronik (paid to Cleveland Clinic) CardioMEMS None None None UNOS Board Member None None None William G. Stevenson, MD None None None None None None None None None None None Adrian F. Hernandez, MD None None None None
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Current Management of Heart Failure. When to Refer to Heart Failure Specialist and When Hospice is the Best Option.
2015, Medical Clinics of North AmericaCitation Excerpt :Utility of aldosterone antagonists such as spironolactone or eplerenone are limited in an acute HF setting, and are further discussed in the section on chronic HF. Aldosterone antagonists facilitate the diuretic effect of loop diuretics in a congested HF patient.21,22 In HF patients with significant renal dysfunction or uncontrolled hypertension despite a maximum dose of ACE and BBs, afterload reducers such as a combination of hydralazine and nitrates can be used.
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2015, American Heart JournalCitation Excerpt :Furthermore, in the EMPHASIS-HF, eplerenone, another MRA agent, reduced both the risk of death and hospitalization in systolic HF patients with mild symptoms.3 Following these lines of evidence, current guidelines recommend use of MRA in HFREF.9-11 However, patients enrolled in the RALES and EMPHASIS-HF trials were clearly different from those seen in real-world clinical practice,5,6,23 and the relationship between MRA and clinical outcomes may vary depending on the background characteristics of the patients.
Aldosterone signaling and soluble adenylyl cyclase-A nexus for the kidney and vascular endothelium
2014, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :Spironolactone was followed by eplerenone, which is less potent but MR-selective [69] with shorter half-life and inactive metabolites. Today, MRAs are guideline-recommended drugs for patients with moderate to severe heart failure (HF) [70]. Large clinical trials including the Randomized Aldactone Evaluation Study (RALES) [71] and the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) [72], demonstrated that MRAs can significantly reduce morbidity and mortality in HF patients.
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.