Introduction

Neurohormonal mechanisms play a central role in mediating the end-organ dysfunction that occurs in heart failure (HF) syndromes. Systemic activation of the mineralocorticoid receptor triggers cellular and genomic changes that underlie the functional and structural cardiorenal deterioration.⁽¹⁾ Mineralocorticoid receptor antagonists (MRA) have emerged as a class of therapeutic agents that act to prevent receptor activation and modulate its deleterious downstream effects. Over the last two decades, MRAs have joined the current drug armamentarium of lifesaving therapies available in HF (β-blockers, ACE-inhibitors). The recent American College of Cardiology Foundation (ACCF) / American Heart Association (AHA) management guideline update has reinforced the utility of MRAs (class I indication, “is recommended”) for patients with chronic HF.⁽²⁾ Despite these recommendations, a large quality improvement program found that less than one-third of eligible patients admitted with HF received aldosterone antagonist therapy at discharge.⁽³⁾ In an analysis of U.S. pharmacy/medical claims of almost 400,000 patients with presumable diagnosis of HF, less than 1% received eplerenone and only 15.5% received any aldosterone blocker.⁽⁴⁾ Similar disappointing rates of MRA discharge prescription were noted in various regions of the world and were substantially lower than other lifesaving therapies, particularly in North America.⁽⁵⁾

Relatively low doses of MRAs are known to improve clinical outcomes in a broad spectrum of patients with HF. However, they may be associated with an increased risk for hyperkalemia, particularly in patients with renal insufficiency, diabetes and/or in those concurrently taking other RAAS inhibitors. The potential risk of hyperkalemia does not explain the reduced uptake of this therapy in North America.^(3,4)

Matching this therapeutic intervention with the right patient is of paramount importance. We attempt to characterize the patient profiles that are best suited for a therapeutic trial with MRAs in the outpatient setting or in the hospital, hoping that higher and more appropriate utilization of this life-saving therapy can be achieved.

Chronic Heart Failure

Three large trials, RALES (Randomized Aldactone Evaluation Study)⁽⁶⁾, EPHESUS (Eplerenone Heart Failure Efficacy and Survival Study)⁽⁷⁾, and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure)⁽⁸⁾ have helped us define the therapeutic boundaries of aldosterone blockade in patients with chronic HF.

The RALES trial⁽⁶⁾ enrolled patients with moderate-to-severe symptomatic HF including patients with New York Heart Association (NYHA) class III or IV and reduced EF (mean of 25.6%). After a mean follow-up of 24 months, there was a 30% risk reduction in all-cause mortality, a 35% reduction in rates of rehospitalization and a 36% reduction in progressive HF in the spironolactone arm compared to placebo. Concomitant treatment with β-blockers was low in this trial (11%). The EPHESUS trial⁽⁷⁾ included patients 3-14 days post-AMI with either HF with reduced EF or diabetes. Notably, mean EF in this study sample was higher (33%) and included patients with less severe symptoms (NYHA classes II-IV). Eplerenone, a selective MRA, achieved similar reductions in mortality and rehospitalization compared to placebo after a mean follow-up of 16 months. It is known that heightened neurohormonal activation may contribute to fatal ventricular arrhythmias in the background of a failing myocardium.⁽⁹⁾ Moreover, eplerenone reduced the risk of early post-MI sudden cardiac death (SCD) just thirty days after randomization by 37%⁽¹⁰⁾, an effect that was more pronounced in patients with EFs less than 30%.⁽¹¹⁾ Since implantable cardioverter-defibrillators in patients hospitalized with worsening HF are associated with poor post-discharge outcomes⁽¹²⁾, MRAs may be a critical intervention in the post-MI patient. Most recently, the EMPHASIS-HF study evaluated the effects of eplerenone in 2,737 patients with chronic HF with mild symptoms (NYHA class II). The “typical” patient represented in this trial was an older, obese Caucasian male with a mean EF of 26%. After a median follow-up of 21 months, composite cardiac death and hospitalization occurred in 18.3% of patients receiving eplerenone and 25.9% of patients in the placebo arm.⁽⁸⁾ Interestingly, these favorable endpoints were primarily driven by reductions in early hospitalization, rather than cardiac mortality. This is surprising given that rehospitalization is integrally related to congestion, remodeling and adverse outcomes.⁽¹³⁾ Event rates were especially high in this trial, primarily because patients were randomized after hospitalization for HF.

The primary concern related to the use of these agents is the rates of life-threatening hyperkalemia and renal dysfunction, especially when co-administered with ACE-inhibitors. In RALES, serious hyperkalemia occurred infrequently with rates of only 2% (14/822) in the spironolactone arm. Overall, the rates of any adverse effect requiring discontinuation during the trial period were also minimal (8% in the spironolactone group vs. 5% in placebo).⁽⁶⁾ Despite these low reported trial rates, a population-based study from Canada has demonstrated that increased rates of prescription of spironolactone after publication of the RALES trial correlated with the higher rates of hyperkalemia-related hospitalizations.⁽¹⁴⁾ More recently, in EMPHASIS-HF, the incidence of hyperkalemia (>5.5 mmol/L) was higher in the eplerenone-treated group compared to the placebo group (11.8% vs. 7.2%).⁽⁸⁾ We must keep in mind that in all three trials, there was no mortality directly related to hyperkalemia. Other less-serious side effects experienced by patients taking spironolactone included gynecomastia, menstrual irregularities and impotence. These sexual side effects are minimized by the use of the more selective MRA, eplerenone.

Based on our existing knowledge in chronic HF, MRAs have clinical utility in several important subsets. All patients with mild, moderate or severe chronic HF with evidence of LV systolic dysfunction and patients after AMI with clinical HF symptomatology should be considered for MRA therapy. Theoretically, use of these agents with non-potassium-sparing diuretics may be beneficial to help correct renal electrolyte imbalances. Notably, the risk of hypokalemia (<4.0 mmol/L) in EMPHASIS-HF was significantly reduced in the eplerenone group. Certainly, we must limit use of MRAs in the patients who were excluded from these trials including those with serum creatinine >2.5 mg/dL and serum potassium >5.0 mmol/L. Furthermore, it is essential that judicious use of these agents be exercised in patients with established comorbid conditions that increase risk for developing hyperkalemia including diabetes and renal dysfunction. In all three trials, MRAs reduced the rates of the primary outcome in all pre-specified groups including patients with baseline renal dysfunction. Additionally, with ever-growing drug cocktails in HF, it is important for clinicians to be mindful of drug interactions that can result in metabolic abnormalities. Interestingly, despite the increased risk of hyperkalemia with concomitant use of ACE-inhibitors, the mortality benefits of MRAs were uniformly superior in patients already on ACE-inhibitors and B-blockers at the time of trial enrollment.^(7,8) The incremental benefits of MRAs were also particularly evident in patients receiving digoxin. This is important since digoxin use has decreased substantially in the last decade, despite being approved by the FDA.⁽¹⁵⁾

Acute Heart Failure Syndromes

Excess sympathetic drive and compensatory activation may have similar detrimental consequences in patients with acute heart failure syndromes (AHFS) as they do in chronic HF.⁽¹⁶⁾ In addition, patients presenting with right-sided HF and hepatic congestion may have impaired clearance of aldosterone and elevated circulating neurohormonal factors.⁽¹⁷⁾ Although we lack definitive clinical evidence, MRAs may have a dual effect in AHFS: preventing progression of HF and as a safe and effective diuretic, possibly preventing the potential negative effects of non-potassium diuretics on end outcomes. Indeed, insight from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial revealed that elevated serum levels of aldosterone and lack of provision of MRAs at discharge were independently associated with adverse outcomes in this population.⁽¹⁸⁾ Moreover, the mortality benefit observed in our chronic HF trials utilized non-natriuretic doses of MRAs. Carefully up-titrating to maximally tolerated dosage may help relieve congestion and improve HF symptomatology in acutely decompensating patients.⁽¹⁹⁾ Furthermore, patients with acutely decompensated HF treated with long-term loop diuretics may be predisposed to developing diuretic resistance and its attendant adverse events. MRAs have been shown to ameliorate receptor-level responsiveness and augment natriuresis in AHFS.^(20-22) In these small studies, the rates of hyperkalemia and renal dysfunction were minimal and normalized shortly after MRA discontinuation.

Clinicians are hesitant to initiate MRA therapy during hospitalization, as evidenced by the poor rates of discharge prescription. We speculate that this may be primary related to concerns of hyperkalemia and adverse side effect profiles of these agents in the acute setting since a significant number of patients have a hospital course complicated by worsening renal function, many have diabetes (~40%) and the majority are concomitantly taking an ACE-inhibitor or ARB. However, patients may be particularly amenable to change during hospitalization and adding underutilized, but efficacious, agents to their existing regimen may be beneficial. The hospitalization provides a unique opportunity for clinicians to optimize medical therapy and provide assistance extending beyond mere symptomatic relief.^(23,24) If MRAs are administered as indicated with close monitoring and surveillance, especially immediately after initiation and at higher therapeutic doses, metabolic derangements can be identified early and successfully managed. There is an enormous unmet need in AHFS with alarmingly high mortality and rehospitalization rates seen within the first 90 days of discharge.⁽²⁵⁾ The minor risk of metabolic fluctuations may be a small price to pay for these dismal event rates.

Table: Study design, clinical characteristics, major outcomes and rates of hyperkalemia in RALES, EPHESUS and EMPHASIS-HF
	RALES6	EPHESUS7	EMPHASIS-HF8
No. of patients	1663	6632	2737
NYHA Class	III, IV	II-IV, post-MI	II
MRA	Spironolactone	Eplerenone	Eplerenone
Mean Dose (mg daily)	26	43	39
Follow-up (months)	24	16	21
Mean Age (years)	65	64	69
Male (%)	73	72	77
Mean EF (%)	26	33	26
All-cause mortality (ARR %)	11.3	2.3	3.0
Cardiac mortality (ARR %)	9.8	2.3	2.7
All-cause hospitalization (ARR%)	8.3	1.1	5.9
Hyperkalemia Definition	≥6 mmol/L	≥6 mmol/L	≥5.5 mmol/L
Hyperkalemia (Risk excess %)	0.5	1.6	4.6
NYHA = New York Heart Association; MRA = mineralocorticoid receptor antagonists; EF = ejection fraction; ARR = absolute risk reduction

Matching the Right Drug with the Right Patient

MRAs have successfully linked our basic science understanding of HF pathophysiology to its direct clinical management. Although MRAs are well-established and provide a consistent mortality benefit (albeit through an unknown mechanism), they remain an underutilized class of agents in the setting of HF. Currently, we are only offering this potentially life-saving therapy to a minority of eligible patients. Treatment should not be provided based solely on structured algorithms, clinical care teams involving physicians, nurses, pharmacists, patients and their families must work together to determine appropriateness of MRA initiation.

It is also important to appropriately adjust and up-titrate dosage to achieve maximal natriuretic and mortality benefit. Initial studies suggest that MRAs may have two distinct beneficial effects in HF. At lower doses (25-50 mg/day), the drug has minimal cardiac penetration, but has a documented mortality benefit. Mean doses utilized in RALES, EPHESUS and EMPHASIS-HF were 26 mg, 43 mg and 39 mg daily, respectively. At higher drug levels (50-75 mg/day), similar to dosing employed by our hepatology colleagues, natriuretic effects are achieved and help to modulate intravascular volume and congestion. At these dosing ranges in the RALES trial, spironolactone significantly decreased sodium retention within days of drug initiation.⁽⁶⁾ Starting at trial doses and up-titrating if necessary (and tolerated) to attain diuretic effect may be a plausible treatment strategy.

As our clinical experience and familiarity with this class of agents continue to grow, we will hopefully be able to close this apparent gap between evidence-based guidelines and clinical practice in the setting of HF. As with most agents available for use in the setting of HF, one size certainly does not fit all. Careful selection of patients and vigilant follow-up after initiation of MRAs are imperative for therapeutic success. Despite initial concerns that a treatment-patient mismatch existed for MRAs, contemporary appropriateness guidelines have shown that use of these agents in patients with documented contraindications was only 0.5%.⁽³⁾

Further research will be necessary to shed light on whether we can extend the clinical usefulness of MRAs to other important patient populations with HF. Unfortunately, we currently lack substantial clinical evidence regarding the efficacy of aldosterone blockade in the setting of HF with preserved EF and in AHFS. In the near future, hopefully we will be able to better ascertain drug appropriateness in these special populations. We also eagerly await the development of novel MRAs that confer higher receptor specificity that may lessen the metabolic fluctuations and adverse risk profiles associated with current therapies. In this era of heart failure management, clinical trials tend to define the limits of our therapeutic boundaries. However, we must also be mindful of our lack of understanding of MRA effectiveness in “real world”, unselected patients. Tailoring and individualizing therapy to fully balance the benefits and risks of aldosterone antagonism will be necessary for the treatment of each and every patient.

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References

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17. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53:557-73.
18. O'Connor CM, Miller AB, Blair JE, et al. Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program. Am Heart J 2010;159:841-9 e1.
19. Schrier RW, Gheorghiade M. Challenge of rehospitalizations for heart failure: potential of natriuretic doses of mineralocorticoid receptor antagonists. Am Heart J 2011;161:221-3.
20. Ceremuzynski L, Budaj A, Michorowski B. Single-dose i.v. Aldactone for congestive heart failure: a preliminary observation. Int J Clin Pharmacol Ther Toxicol 1983;21:417-21.
21. Hensen J, Abraham WT, Durr JA, Schrier RW. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention. Am J Nephrol 1991;11:441-6.
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23. Gheorghiade M, Peterson ED. Improving postdischarge outcomes in patients hospitalized for acute heart failure syndromes. JAMA 2011;305:2456-7.
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25. Gheorghiade M, Abraham WT, Albert NM, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 2006;296:2217-26.

Keywords: Adrenergic beta-Antagonists, Aldosterone, American Heart Association, Angiotensin-Converting Enzyme Inhibitors, Mineralocorticoid Receptor Antagonists, Receptors, Mineralocorticoid, Spironolactone

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