The role of aldosterone receptor antagonists in the management of heart failure: An update
ABSTRACTThe aldosterone receptor antagonists (ARAs) spironolactone (Aldactone) and eplerenone (Inspra) have become part of standard medical therapy for heart failure, having shown clinical efficacy in randomized trials in patients with advanced symptomatic systolic heart failure, postinfarction heart failure with cardiac dysfunction, and systolic heart failure with mild symptoms. The benefits include a lower rate of death. Yet to be answered is whether the two drugs are clinically equivalent; another question is whether they may benefit everyone with symptomatic heart failure, including diastolic heart failure.
KEY POINTS
- Although caution is advised in starting ARAs, these drugs are commonly underused in heart failure.
- Aldosterone “escape” can blunt the effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. This is the rationale for also using ARAs.
- The major trials of ARAs in heart failure to date have been the Randomized Aldactone Evaluation Study (RALES), the Eplerenone Post-acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS), and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF).
- Close monitoring is essential when starting an ARA, as severe hyperkalemia and renal insufficiency can occur.
ADVERSE EFFECTS OF ARAs
Hyperkalemia, hyperkalemia, hyperkalemia
Potassium excretion is physiologically regulated by the serum aldosterone concentration and by the delivery of sodium to the distal nephron. Aldosterone increases potassium excretion. As a result of decreased renal perfusion that occurs with heart failure, sodium is intensely reabsorbed in the proximal tubule, and very little sodium reaches the distal nephron. When aldosterone receptors are blocked by ARAs, the risk of hyperkalemia increases.23
Other electrolyte abnormalities associated with ARAs are hyponatremia and hyperchloremic metabolic acidosis (Table 1). There could be a reversible decline in the glomerular filtration rate as well.24 Of note, most patients with chronic systolic heart failure in the RALES and EMPHASIS-HF trials were already receiving a diuretic; thus, the adverse effect profile of ARAs in otherwise euvolemic (or even hypovolemic) patients is not well appreciated.
Failure to closely monitor electrolyte levels increases the risk of hyperkalemia and renal failure, so there is a need for regular follow-up visits for patients taking an ARA.25 This was made clear when a population-based analysis from Canada compared the rates of hyperkalemia-related hospitalization and death before and after the RALES trial was published. The prescription rate for spironolactone increased threefold, but the rate of hyperkalemia-related hospitalization increased fourfold and the rate of death increased sixfold.26
Although caution is recommended when starting a patient on an ARA, a recent trial conducted in 167 cardiology practices noted that ARAs were the most underused drugs for heart failure. In this study, an ARA was prescribed to only 35% of eligible patients. The prescription rate was not significantly higher even in dedicated heart failure clinics.27 Possible reasons suggested by the authors were drug side effects, the need for closer monitoring of laboratory values, and a lack of knowledge.
A population-based analysis from the United Kingdom found a significant increase over time in spironolactone prescriptions after the release of the RALES trial results, but there was no increase in the rate of serious hyperkalemia (serum potassium > 6 mmol/L) or hyperkalemia-related hospitalization.28 The authors suggested that careful monitoring could prevent hyperkalemia-related complications. They also observed that 75% of patients who had spironolactone-associated hyperkalemia were over 65 years old. Hence, we recommend closer monitoring when starting an elderly patient on an ARA.
Breast, gastrointestinal symptoms
The nonselective ARA spironolactone is associated with antiandrogenic side effects. In a smaller study in patients with resistant hypertension, Nishizaka et al noted that low-dose spironolactone (up to 50 mg/day) was associated with breast tenderness in about 10%.29 Breast symptoms with spironolactone are dose-related, and the incidence can be as high as 50% when the drug is used in dosages of 150 mg/day or higher.30
In one population-based case-control study, spironolactone was associated with a 2.7 times higher risk of gastrointestinal side effects (bleeding or ulcer).31
ARAs IN HEART FAILURE WITH PRESERVED EJECTION FRACTION
The concept of diastolic heart failure or “heart failure with preserved ejection fraction” has been growing. A significant proportion of patients with a diagnosis of heart failure have preserved left ventricular ejection fraction (≥ 50%) and diastolic dysfunction.
Despite multiple trials, no treatment has been shown to lower the mortality rate in heart failure with preserved ejection fraction.32,33 A recently published randomized controlled trial in 44 patients with this condition showed reduction in serum biochemical markers of collagen turnover and improvement in diastolic function with ARAs, but there was no difference in exercise capacity.34 A larger double-blind randomized control trial, Aldosterone Receptor Blockade in Diastolic Heart Failure (Aldo-DHF), is under way to evaluate the effects of ARAs on exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction.35
In January 2012, the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT) completed enrollment of 3,445 patients to study the effect of ARAs in reducing the composite end point of cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization. Long-term follow-up of this event-driven study is currently under way.
ARAs IN DIABETES MELLITUS AND CHRONIC KIDNEY DISEASE
Under physiologic conditions, the serum aldosterone level is regulated by volume status through the renin-angiotensin system. But in patients with chronic kidney disease, the serum aldosterone level could be elevated without renin-angiotensin system stimulation.36
High aldosterone levels were associated with proteinuria and glomerulosclerosis in rats.37 In a study in 83 patients, aldosterone receptor blockade was shown to decrease proteinuria and possibly to retard the progression of chronic kidney disease. In this trial, baseline serum aldosterone levels correlated with proteinuria.38 Animal studies suggest that adipocyte-derived factors may stimulate aldosterone, which may be relevant in patients who have both chronic kidney disease and metabolic syndrome.39
The impact of ARAs in patients with diabetes mellitus is often overlooked. In EPHESUS, diabetes mellitus was an inclusion criterion even in the absence of heart failure signs and symptoms in the postinfarction setting of impaired left ventricular ejection fraction.15
In patients with diabetic nephropathy, there is growing evidence that ARAs can decrease proteinuria, even if the serum aldosterone level is normal. For example, in a study in 20 patients with diabetic nephropathy, spironolactone reduced proteinuria by 32%. This reduction was independent of serum aldosterone levels.40
In diabetic rats, hyperglycemia was noted to cause podocyte injury through mineralocorticoid receptor-mediated production of reactive oxygen species, independently of serum aldosterone levels. Spironolactone decreased the production of reactive oxygen species, thereby potentially reducing proteinuria.41
RECOMMENDATIONS ARE BEING REVISED
The most recent joint guidelines of the American Heart Association and the American College of Cardiology for the management of heart failure42 were published in 2009, which was before the EMPHASIS-HF results. An update is expected soon. In the 2009 version, ARAs received a class I recommendation for patients with moderately severe to severe symptoms, decreased ejection fraction, normal renal function, and normal potassium levels. The guidelines also said that the risks of ARAs may outweigh their benefits if regular monitoring is not possible.
The recommended starting dosage is 12.5 mg/day of spironolactone or 25 mg/day of eplerenone; the dose can be doubled, if tolerated.
Close monitoring is recommended, ie, measuring serum potassium and renal function 3 and 7 days after starting therapy and then monthly for the first 3 months. Closer monitoring is needed if an ACE inhibitor or an ARB is added later. In elderly patients, the glomerular filtration rate is preferred over the serum creatinine level, and ARA therapy is not advisable if the glomerular filtration rate is less than 30 mL/min/1.73 m2.
Avoid concomitant use of the following:
- Potassium supplements (unless persistent hypokalemia is present)
- Nonsteroidal anti-inflammatory drugs
- An ACE inhibitor and an ARB in combination
- A high dose of an ACE inhibitor or ARB.
Conditions that can lead to dehydration (eg, diarrhea, excessive use of diuretics) or acute illness should warrant reduction (or even withholding) of ARAs. When to discontinue ARA therapy is not well described, nor is the safety of starting ARAs in the hospital. However, it is clear that many patients who are potentially eligible for ARAs are not prescribed them.43
The guidelines are currently being revised, and will likely incorporate the new data from EMPHASIS-HF to extend to a broader population. The benefits of ARAs can be met only if the risks are minimized.
WHICH ARA IS BETTER?
The pharmacologic differences between the two ARAs have been described earlier, and guidelines have advocated evidence-based use of ARAs for their respective indications. There have been no large-scale, head-to-head comparisons of spironolactone and eplerenone in the heart failure population, and in clinical practice the drugs are prescribed interchangeably in most patients.
A double-blind randomized controlled trial in 141 patients with hypertension and primary hyperaldosteronism found that spironolactone lowered diastolic blood pressure more, but it also caused antiandrogenic effects more often.44
There is some evidence to suggest that eplerenone has a better metabolic profile than spironolactone. The data came from a small randomized controlled trial in 107 stable outpatients with mild heart failure.45 Patients who were prescribed spironolactone had a higher cortisol level and hemoglobin A1c level 4 months after starting treatment. This effect was not seen in patients who were on eplerenone. However, these findings need to be confirmed in larger trials.
While the differences between the two drugs remain to be determined, the most important differences in clinical practice are selectivity for receptors (and hence their antiandrogenic side effects) and price. Even though it is available as a generic drug, eplerenone still costs at least three times more than spironolactone for the same dosage and indication.
