MRAs in HF: Established and Emerging Roles

Abstract and Introduction

Abstract

The pathophysiology of heart failure (HF) is related to the overactivation of the mineralocorticoid receptor, leading to fluid retention and adverse myocardial remodeling. Although mineralocorticoid receptor antagonists (MRAs) are recommended for the treatment of heart failure with reduced ejection fraction (HFrEF), they remain underused due to adverse effects such as hyperkalemia; and their efficacy is controversial in heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF). Recent trials in people with diabetes and kidney disease have supported the use of nonsteroidal MRAs in reducing HF-related morbidity and mortality and have fewer side effects than their steroidal counterparts. The efficacy and safety of nonsteroidal MRAs have not been tested in HF and are currently being evaluated in additional clinical trials. This review comprehensively examines the current data regarding MRAs for HF and the future direction of nonsteroidal MRA research while exploring the causes of MRA underutilization.

Introduction

Heart failure (HF) affects more than 56.2 million people worldwide and poses a significant burden to the aging population.^[1] Chronic HF is characterized by the overactivation of the renin-angiotensin-aldosterone system. In particular, the mineralocorticoid aldosterone contributes substantively to the pathophysiology of HF. Current evidence-based therapy for HF includes the use of mineralocorticoid receptor antagonists (MRA), which have been shown to prevent many of the deleterious effects of aldosterone. Well-powered randomized clinical trials have demonstrated the efficacy of MRAs for treating heart failure with reduced ejection fraction (HFrEF), with an apparent reduction in mortality and readmissions among patients who receive MRAs.^[2]

Despite a strong level of evidence, MRAs remain underused for HFrEF for reasons including hyperkalemia and gynecomastia/ breast pain related to blockage of the androgen receptor.^[3,4] The Swedish Health Registry observed that only 40% of patients with HFrEF duration ≥6 months received MRA therapy. ^[5] EVOLUTION HF (Utilization of Dapagliflozin and Other Guideline Directed Medical Therapies in Heart Failure Patients: A Multinational Observational Study Based on Secondary Data) showed that only 5.1% of those with HF in Japan, Sweden, and the United States reached the target dose of MRAs, and 42.2% discontinued the drug within a 12-month period.⁶ Canadian data show that even after interventions meant to increase the use of guidelinedirected medical therapy in high-risk patients, uptake of MRAs remains low at <32%.^[7] Similarly, low and static rates of MRA use in HF are observed in the United States. The U.S. Get With The Guidelines-HF study from 2005-2007 reported 32% use of MRAs,^[8] and the more recent CHAMP-HF (Change the Management of Patients with Heart Failure) study reported 33% use of MRAs.^[9]

Although there are clinician concerns of hyperkalemia leading to underutilization of MRAs, research has shown that SGLT2 inhibitors or angiotensin receptor/neprilysin inhibitors may mitigate the risk of hyperkalemia in patients congruently taking MRAs.^[10,11,12] Potassium-binding agents have also been shown to reduce rates of hyperkalemia when taken with MRAs.^[13]

Table 1. Summary of Landmark for MRA Use in HFrEF
Trial Name, Year	Drug Studied	N	Mean Follow-Up, y	Inclusion Criteria: LVEF%, NYHA Functional Class	Primary Endpoint	Number of Events (Treatment vs Placebo)	RR or HR of Primary Outcome	Rate of Adverse Events
RALES, 1999	Spironolactone 25 mg vs placebo	1,663	2	LVEF <35%, NYHA functional class III or IV	Death from any cause	284 (35%) vs 386 (46%)	RR: 0.7 (95% CI: 0.60-0.82)	Serious hyperkalemia (serum potassium ≥6.0 mmol/L): 1% in placebo group vs 2% in spironolactone group; gynecomastia or breast pain: 1% of men in placebo group vs 10% of men in the spironolactone group
EMPHASIS-HF, 2011	Eplerenone 25 mg increased after 4 weeks to 50 mg once daily vs placebo	2,737	1.75	LVEF <35%, NYHA functional class II	Composite of death from cardiovascular causes or hospitalization for heart failure	249 (18.3%) vs 356 (25.9%)	HR: 0.63 (95% CI: 0.54-074)	Serious hyperkalemia (serum potassium ≥6.0 mmol/L): 1.9% in placebo group vs 2.5% in eplerenone group; gynecomastia or breast disorders: 1.0% of men in placebo group vs 0.7% of men in the eplerenone group

RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) are 2 landmark clinical trials that provided much of the evidence for the safety and efficacy of mineralocorticoid receptor antagonists (MRAs) for heart failure with reduced ejection fraction (HFrEF). Ultimately, these trials helped establish MRAs as an integral medication in the guideline-directed medical therapy for HFrEF.

LVEF = left ventricular ejection fraction; RR = relative risk.

Table 2. Future Steroidal MRA Clinical Trials
Trial Name	Drug Studied	Expected N	Inclusion Criteria	Primary Endpoints
SPIRIT-HF	Spironolactone vs placebo	1,300	NYHA functional class II or greater HF, LVEF ≥40%, NT-proBNP >300 pg/mL, controlled systolic blood pressure, and serum potassium <5.0 mmol/L	Cumulative number of primary composite events of cardiovascular death and total HF hospitalizations
SPIRRIT	Spironolactone þ usual care vs usual care only	3,500	Stable heart failure signs/symptoms, NYHA functional class II-IV HF, LVEF ≥40%, NT-proBNP ≥300 ng/L	Incidence rate of cardiovascular deaths or HF hospitalizations
Polydiuretic Therapy for Heart Failure With Preserved Ejection Fraction: A Pilot Trial	Bumetanide + eplerenone + empagliflozin vs empagliflozin monotherapy	30	NYHA functional class II-IV HF, LVEF ≥50%, NT-proBNP levels >300 pg/mL	Feasibility of recruitment and compliance with the study protocol (30 participants and 80% participant completion of study protocol)

SPIRIT-HF (Spironolactone in the Treatment of Heart Failure), SPIRRIT (Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction), and Polydiuretic Therapy for Heart Failure with Preserved Ejection Fraction are 3 ongoing/future clinical trials examining steroidal MRAs including spironolactone and eplerenone in heart failure with mildly reduced ejection fraction (HFmrEF) or heart failure with preserved ejection fraction (HFpEF). These trials will provide important data for the potential use of steroidal MRAs for this population following the mixed results seen in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist).

Abbreviations as in Table 1.

Authors and Disclosures

Joycie Chang, BA,^a,b Andrew P. Ambrosy, MD,^c,d Orly Vardeny, PHARMD, MS,^e,f Harriette G.C. Van Spall, MD, MPH,^g,h Robert J. Mentz, MD,ⁱ Andrew J. Sauer, MD^a,b

From the ^aSaint Luke’s Mid America Heart Institute, Kansas City, Missouri, USA; ^bUniversity of Missouri-Kansas City School of Medicine, Kansas City, Missouri, USA; ^cDepartment of Cardiology, Kaiser Permanente San Francisco Medical Center, San Francisco, California, USA; ^dDivision of Research, Kaiser Permanente Northern California, Pleasanton, California, USA; ^eMinneapolis VA Center for Care Delivery and Outcomes Research, Minneapolis, Minnesota, USA; ^fUniversity of Minnesota Department of Medicine, Minneapolis, Minnesota, USA; ^gFaculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada; ^hBaim Institute for Clinical Research, Boston, Massachusetts, USA; and the ⁱDivision of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

ADDRESS FOR CORRESPONDENCE: Dr Andrew Sauer, Saint Luke’s Mid America Heart Institute, 4401 Wornall Road, Kansas City, Missouri 64111, USA. E-mail: asauer@saint-lukes.org. X handle: @AndrewJSauer.

FUNDING SUPPORT AND AUTHOR DISCLOSURES: Dr Ambrosy has received institutional research grants from the National Heart, Lung, and Blood Institute (NHLBI) (K23HL150159), the American Heart Association (2nd Century Early Faculty Independence Award), The Permanente Medical Group, Northern California Community Benefits Programs, Garfield Memorial Fund, Abbott Laboratories, Amarin Pharma, Inc, Edwards Lifesciences LLC, Esperion Therapeutics, Inc, and Novartis. Dr Vardeny has received institutional research support from NHLBI, the Food and Drug Administration, AstraZeneca, Bayer, and Cardurion; and personal consulting fees from Bayer, Cardior, Cytokinetics, and Moderna. Dr Mentz has received research support and honoraria from Abbott, Alleviant Medical, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Lexicon, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Reprieve Cardiovascular, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor,Windtree Therapeutics, and Zoll. Dr Sauer has received research funding from the Heart Failure Society of America (HFSA), American Heart Association, AstraZeneca, Boehringer Ingelheim, Bayer, CSL Vifor, Pfizer, Rivus Pharmaceuticals, 35Pharma, Novo Nordisk, Edwards Lifesciences, and Story Health; has received consulting fees from Abbott, Boston Scientific, Edwards Lifesciences, Impulse Dynamics, Acorai, General Prognostics, Story Health, Amgen, and Bayer; and owns stock in ISHI and Pulsli (both privately held digital health companies). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Mineralocorticoid Antagonism in Heart Failure: Established and Emerging Therapeutic Role

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