Mineralocorticoid Receptor Antagonist Eplerenone in Cardiovascular Disease

    Authors

    Abstract

    Aldosterone and eplerenone are mineralocorticoid receptor antagonists with one of the main roles in the treatment of heart failure, as demonstrated by large randomized controlled trials. Effects on patient outcomes are the result of blocking the renin-angiotensin-aldosterone system, which improves cardiac remodeling. Besides heart failure, mineralocorticoid receptor antagonists are used in treatment of patients with resistant arterial hypertension. This review focuses on the pharmacokinetics, pharmacodynamics, clinical effects, and safety profile of eplerenone.

    Keywords

    mineralocorticoid receptor antagonists, eplerenone, heart failure, arterial hypertension, hyperkalemia

    DOI

    https://doi.org/10.15836/ccar2019.263

    Full Text

    ## Introduction Aldosterone was isolated in the 1950s, but further research of its physiology was relatively slow over the next decades. In spite of that, it was already in the early days that Hungarian-Canadian endocrinologist Hans Selye observed an increase in nephrosclerosis and myocardial hypertrophy in animal models exposed to high aldosterone levels. The first aldosterone antagonists were synthesized soon after aldosterone isolation (spironolactone precursors and spironolactone itself). Although their mechanisms of action were unknown, beneficial effects on cardiac remodeling were observed. ( 1 , 2 ) One of the key events in steroid hormone research was synthesis of mineralocorticoid receptors and discovery of its microstructure in the 1980s, allowing design and discovery of new mineralocorticoid receptor antagonists (MRA) such as eplerenone. ( 1 , 2 ) ## Aldosterone physiology and pathophysiology The renin-angiotensin-aldosterone system (RAAS) has a central role in cardiovascular physiology and pathophysiology. RAAS activation is associated with adverse outcomes, whereas its blockade has been shown to be beneficial in several randomized controlled trials (RCTs). Aldosterone is mainly produced by zona glomerulosa cells of the adrenal gland cortex. To a lesser extent it is also produced locally, by vascular endothelium and smooth-muscle cells of different organs. ( 3 , 4 ) In normal conditions, aldosterone regulates renal sodium and potassium transport by genomic pathways. Aldosterone binds to intracytosolic receptors that are in fact transcription factors regulating gene expression for sodium absorption and potassium secretion channels. The net result is plasma volume expansion and blood pressure elevation. It also regulates expression of profibrotic (collagen and transforming growth factor-beta (TGF-beta)) and proinflammatory genes. Mineralocorticoid receptors can be found in the endothelium, myocardium, macrophages, gastrointestinal epithelium, and the eye. ( 5 - 8 ) Aldosterone, predominantly when produced locally, also acts through fast non-genomic pathways directly in smooth-muscle vascular cells. Coronary artery vasoconstriction and increase in systemic vascular resistance are examples of non-genomic aldosterone actions. ( 8 ) Adverse myocardial effects of aldosterone have been shown in animal models independently of blood pressure increase. Aldosterone causes myocardial fibrosis and myocardial hypertrophy. Although hypertrophy can be alleviated by angiotensin-converting enzyme (ACE) inhibitors, they have no effect on fibrosis, indicating mechanisms of fibrosis other than through angiotensin II. Aldosterone increases tissue ACE and receptors for angiotensin 1 (AT1), resulting in a vicious circle of adverse effects. Tissue ACE activation and AT 1 receptor production are responsible for “aldosterone escape”, a phenomenon that occurs several months into treatment with ACE inhibitors and that may be associated with new worsening of heart failure symptoms despite ACE inhibitors therapy. ( 9 ) ## Eplerenone Eplerenone is a competitive MRA. Although it is highly selective for mineralocorticoid receptors, its affinity is 10-20 times lower than spironolactone. However, clinical research has shown that eplerenone has at least 50-75% of the potency of spironolactone due to compensating low affinity with better bioavailability. Peak eplerenone plasma concentrations are reached 1.5 h after oral intake, and concomitant food ingestion has no effect on absorption. Its half-life in plasma is 4-6 hours. ( 2 , 8 ) Eplerenone is metabolized primarily via hepatic cytochrome P450 (CYP3A4), indicating that ketokonazole, ribonavir, and clarithromycin increase its plasma concentrations while phenobarbital lowers them by inducing CYP3A4. ( 4 ) In comparison with spironolactone, eplerenone has a much lower affinity for androgen and progesterone receptors, translating into no adverse androgen effects – no painful gynecomastia or erectile dysfunction in men or menstrual problems in young women. ( 8 ) ## Eplerenone in heart failure The RALES study (the Randomized Aldactone Evaluation Study) was the first to give evidence of improved outcomes of patients treated with spironolactone in comparison with placebo. The trial included 1663 patients with chronic heart failure with reduced ejection fraction (average ejection fraction (EF) in the trial was 25%), NYHA class III or IV, that were already treated with standard heart failure therapy at the time (ACE inhibitors, digoxin, diuretics). The trial was terminated early due to significantly lower overall mortality in the group receiving spironolactone. ( 10 ) Major objections to the study included exclusion of patients with significant chronic renal failure and the small percentage of patients treated with beta-blockers. The RALES results were not applied so well in clinical practice due to higher incidence of hyperkalemia and renal insufficiency in real-life post-marketing studies. ( 11 ) In this context, a better safety profile and wider clinical use was expected from eplerenone, a more selective MRA. The EPHESUS randomized controlled trial (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) significantly contributed to wider clinical use of eplerenone. 6642 patients were randomized to eplerenone or placebo 3-14 days after myocardial infarction with systolic dysfunction of the left ventricle (EF <40%) and signs of heart failure (or just systolic dysfunction of the LV in patients with diabetes mellitus). In comparison with the RALES study, most of the patients were now treated with standard therapy for myocardial infarction with heart failure (ACE inhibitors or angiotensin-receptor blockers (ARB), beta-blockers, acetyl-salicylic acid, and diuretics). Significantly lower cardiovascular mortality, rates of sudden cardiac death, and less hospitalizations were demonstrated in patients treated with eplerenone. It is important to emphasize that the overall lower rates of cardiovascular mortality were primarily due to lower rates of sudden cardiac death, and this effect was already observed at 30 days post randomization. ( 12 ) One of the EPHESUS trial sub-analyses showed that a positive effect of eplerenone on major outcomes was observed only if eplerenone was started early in the course of treatment, i.e. in the first 7 days following myocardial infarction. ( 13 ) Given that fact, eplerenone became one of the standard therapies for patients with myocardial infarction and heart failure. Treatment with eplerenone is also supported by findings of the EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure). In this trial, 2737 patients with heart failure with reduced EF (<30-35%) and NYHA II class were randomized to eplerenone or placebo. Additional criteria that patients had to meet for eligibility was either a cardiovascular hospitalization 6 months prior to randomization or elevated biomarkers (BNP or NT-proBNP). Patients treated with eplerenone had 37% lower cardiovascular mortality and a lower number of heart failure hospitalizations. ( 14 ) Patients with heart failure with preserved EF often have the same signs and symptoms as those with heart failure with reduced ejection fraction. Their mortality is also similar, with significant burden of sudden cardiac death. ( 15 ) Therefore, one of the leading problems of modern-day cardiology is the lack of evidence-based treatments for patients in this heart failure category. Heart failure with preserved EF shares similar pathophysiological pathways, including adverse activation of RAAS and subsequent negative cardiac remodeling in terms of interstitial fibrosis and left ventricular hypertrophy. Furthermore, some authors consider endothelial dysfunction to be one of the key mechanisms underlying this syndrome. All of these mechanisms indicate a potential role of MRA in patients with heart failure with preserved EF. ( 16 , 17 ) Small studies have shown positive effects of MRA on left ventricular hypertrophy and echocardiographic diastolic function indices, while positive effects on major outcomes have not yet been shown. ( 18 ) The clear beneficial signal of spironolactone in this patient population comes from the overall negative RCT TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). Although the trial did not prove lower mortality overall in patients with heart failure with preserved EF treated with spironolactone, it did show lower incidence of heart failure hospitalizations. ( 19 ) Several sub-analysis of the trial focusing only on patients from North and South America showed geographical differences in outcomes and positive effect of spironolactone on cardiovascular mortality in those patients. ( 20 ) These data indicate the existence of specific patient profiles that clearly benefit from treatment with mineralocorticoid receptor antagonists. ( 5 , 21 ) ## Effect on myocardial excitability The EPHESUS trial results showed positive effects of eplerenone on sudden cardiac death in patients soon after myocardial infarction with heart failure. ( 12 ) Furthermore, the EMPHASIS-HF study showed significant reduction of its secondary endpoint of atrial fibrillation incidence in the group of patients treated with eplerenone (42% reduction in comparison with the control group). ( 14 , 22 ) ## Eplerenone in specific patient populations In the EMPHASIS-HF trial, outcome benefits of eplerenone were present even in subgroups with greater risk of worse outcomes, such as patients with chronic renal disease, diabetes mellitus, and in those older than 75 years. ( 23 ) The results of a few small studies indicate greater benefit of eplerenone treatment in comparison with spironolactone for patients with heart failure and diabetes mellitus. Patients treated with spironolactone had higher HbA1c and cortisol and worse endothelial dysfunction in comparison with those treated with eplerenone. The selectivity of eplerenone may partially explain this observation. Nevertheless, the results of this studies require confirmation in large RCTs. ( 24 , 25 ) ## Eplerenone in treatment of patients with myocardial infarction Given the anti-inflammatory and anti-fibrotic properties of eplerenone, its early administration following myocardial infarction in patients without heart failure was also studied. The REMINDER clinical trial randomized 1012 patients with myocardial infarction without heart failure to early administration of eplerenone or placebo. Although it did not have the statistical power to assess major outcomes, it did show excellent eplerenone tolerability if administered within 24 hours of myocardial infarction and patients receiving eplerenone had significantly lower NT-proBNP concentrations at 30 days as well as 18 months after myocardial infarction. ( 26 ) ## Eplerenone in resistant arterial hypertension The latest European Society of Cardiology guidelines for treating arterial hypertension define resistant arterial hypertension as not achieving target blood pressure values (systolic <140 mmHg and/or diastolic <90 mmHg) by standard treatment (optimal or maximally tolerated doses of ACE inhibitors/ARBs, calcium blockers, or thiazide diuretics), confirmed by ambulatory blood pressure monitoring in patients who are fully compliant to prescribed therapies. Adding spironolactone 50 mg daily, and, if not tolerated, eplerenone in a dose of 50-100 mg daily has the I B recommendation level for management of resistant arterial hypertension ( Table 1 ). ( 27 ) ## Eplerenone safety In all of the large RCTs patients receiving eplerenone had significantly higher creatinine and potassium, but without difference in renal failure incidence. Furthermore, there was no death attributable to hyperkalemia in any of the trials. Viewed from a different perspective, there is significantly less hypokalemia and less deaths induced by ventricular arrhythmias as a consequence of hypokalemia. Generally, there is a low risk of hyperkalemia in patients with no preexistent renal disease. It is recommended to check potassium levels approximately one month after initiation of therapy. In patients with chronic renal disease, acute exacerbation of chronic renal disease, or who concomitantly take nephrotoxic drugs, potassium and renal function should be monitored more closely. ( 5 , 28 - 30 ) ## Conclusion Large RCTs have demonstrated the beneficial effects of eplerenone on survival of patients with heart failure with reduced EF. This is the reason why large cardiological societies included eplerenone as one of the essential treatments in their guidelines, in addition to ACE inhibitors/ARBs, and beta-blockers. Further RCTs are needed to confirm the effects of eplerenone on outcomes in patients with heart failure with preserved EF as well as in patients with myocardial infarction and no systolic dysfunction. Eplerenone safety profile is of great importance for everyday clinical practice, as well as its high tolerability that contributes to patient compliance.

    Cardiologia Croatica
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    Mineralocorticoid Receptor Antagonist Eplerenone in Cardiovascular Disease

    Review Article
    Issue9-10
    Published
    Pages263-269
    PDF via DOIhttps://doi.org/10.15836/ccar2019.263
    mineralocorticoid receptor antagonists
    eplerenone
    heart failure
    arterial hypertension
    hyperkalemia

    Authors

    Ivo Planinc*ORCIDUniversity Hospital Centre Zagreb, Zagreb, Croatia

    Abstract

    Aldosterone and eplerenone are mineralocorticoid receptor antagonists with one of the main roles in the treatment of heart failure, as demonstrated by large randomized controlled trials. Effects on patient outcomes are the result of blocking the renin-angiotensin-aldosterone system, which improves cardiac remodeling. Besides heart failure, mineralocorticoid receptor antagonists are used in treatment of patients with resistant arterial hypertension. This review focuses on the pharmacokinetics, pharmacodynamics, clinical effects, and safety profile of eplerenone.

    Full Text

    ## Introduction Aldosterone was isolated in the 1950s, but further research of its physiology was relatively slow over the next decades. In spite of that, it was already in the early days that Hungarian-Canadian endocrinologist Hans Selye observed an increase in nephrosclerosis and myocardial hypertrophy in animal models exposed to high aldosterone levels. The first aldosterone antagonists were synthesized soon after aldosterone isolation (spironolactone precursors and spironolactone itself). Although their mechanisms of action were unknown, beneficial effects on cardiac remodeling were observed. ( 1 , 2 ) One of the key events in steroid hormone research was synthesis of mineralocorticoid receptors and discovery of its microstructure in the 1980s, allowing design and discovery of new mineralocorticoid receptor antagonists (MRA) such as eplerenone. ( 1 , 2 ) ## Aldosterone physiology and pathophysiology The renin-angiotensin-aldosterone system (RAAS) has a central role in cardiovascular physiology and pathophysiology. RAAS activation is associated with adverse outcomes, whereas its blockade has been shown to be beneficial in several randomized controlled trials (RCTs). Aldosterone is mainly produced by zona glomerulosa cells of the adrenal gland cortex. To a lesser extent it is also produced locally, by vascular endothelium and smooth-muscle cells of different organs. ( 3 , 4 ) In normal conditions, aldosterone regulates renal sodium and potassium transport by genomic pathways. Aldosterone binds to intracytosolic receptors that are in fact transcription factors regulating gene expression for sodium absorption and potassium secretion channels. The net result is plasma volume expansion and blood pressure elevation. It also regulates expression of profibrotic (collagen and transforming growth factor-beta (TGF-beta)) and proinflammatory genes. Mineralocorticoid receptors can be found in the endothelium, myocardium, macrophages, gastrointestinal epithelium, and the eye. ( 5 - 8 ) Aldosterone, predominantly when produced locally, also acts through fast non-genomic pathways directly in smooth-muscle vascular cells. Coronary artery vasoconstriction and increase in systemic vascular resistance are examples of non-genomic aldosterone actions. ( 8 ) Adverse myocardial effects of aldosterone have been shown in animal models independently of blood pressure increase. Aldosterone causes myocardial fibrosis and myocardial hypertrophy. Although hypertrophy can be alleviated by angiotensin-converting enzyme (ACE) inhibitors, they have no effect on fibrosis, indicating mechanisms of fibrosis other than through angiotensin II. Aldosterone increases tissue ACE and receptors for angiotensin 1 (AT1), resulting in a vicious circle of adverse effects. Tissue ACE activation and AT 1 receptor production are responsible for “aldosterone escape”, a phenomenon that occurs several months into treatment with ACE inhibitors and that may be associated with new worsening of heart failure symptoms despite ACE inhibitors therapy. ( 9 ) ## Eplerenone Eplerenone is a competitive MRA. Although it is highly selective for mineralocorticoid receptors, its affinity is 10-20 times lower than spironolactone. However, clinical research has shown that eplerenone has at least 50-75% of the potency of spironolactone due to compensating low affinity with better bioavailability. Peak eplerenone plasma concentrations are reached 1.5 h after oral intake, and concomitant food ingestion has no effect on absorption. Its half-life in plasma is 4-6 hours. ( 2 , 8 ) Eplerenone is metabolized primarily via hepatic cytochrome P450 (CYP3A4), indicating that ketokonazole, ribonavir, and clarithromycin increase its plasma concentrations while phenobarbital lowers them by inducing CYP3A4. ( 4 ) In comparison with spironolactone, eplerenone has a much lower affinity for androgen and progesterone receptors, translating into no adverse androgen effects – no painful gynecomastia or erectile dysfunction in men or menstrual problems in young women. ( 8 ) ## Eplerenone in heart failure The RALES study (the Randomized Aldactone Evaluation Study) was the first to give evidence of improved outcomes of patients treated with spironolactone in comparison with placebo. The trial included 1663 patients with chronic heart failure with reduced ejection fraction (average ejection fraction (EF) in the trial was 25%), NYHA class III or IV, that were already treated with standard heart failure therapy at the time (ACE inhibitors, digoxin, diuretics). The trial was terminated early due to significantly lower overall mortality in the group receiving spironolactone. ( 10 ) Major objections to the study included exclusion of patients with significant chronic renal failure and the small percentage of patients treated with beta-blockers. The RALES results were not applied so well in clinical practice due to higher incidence of hyperkalemia and renal insufficiency in real-life post-marketing studies. ( 11 ) In this context, a better safety profile and wider clinical use was expected from eplerenone, a more selective MRA. The EPHESUS randomized controlled trial (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) significantly contributed to wider clinical use of eplerenone. 6642 patients were randomized to eplerenone or placebo 3-14 days after myocardial infarction with systolic dysfunction of the left ventricle (EF <40%) and signs of heart failure (or just systolic dysfunction of the LV in patients with diabetes mellitus). In comparison with the RALES study, most of the patients were now treated with standard therapy for myocardial infarction with heart failure (ACE inhibitors or angiotensin-receptor blockers (ARB), beta-blockers, acetyl-salicylic acid, and diuretics). Significantly lower cardiovascular mortality, rates of sudden cardiac death, and less hospitalizations were demonstrated in patients treated with eplerenone. It is important to emphasize that the overall lower rates of cardiovascular mortality were primarily due to lower rates of sudden cardiac death, and this effect was already observed at 30 days post randomization. ( 12 ) One of the EPHESUS trial sub-analyses showed that a positive effect of eplerenone on major outcomes was observed only if eplerenone was started early in the course of treatment, i.e. in the first 7 days following myocardial infarction. ( 13 ) Given that fact, eplerenone became one of the standard therapies for patients with myocardial infarction and heart failure. Treatment with eplerenone is also supported by findings of the EMPHASIS-HF trial (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure). In this trial, 2737 patients with heart failure with reduced EF (<30-35%) and NYHA II class were randomized to eplerenone or placebo. Additional criteria that patients had to meet for eligibility was either a cardiovascular hospitalization 6 months prior to randomization or elevated biomarkers (BNP or NT-proBNP). Patients treated with eplerenone had 37% lower cardiovascular mortality and a lower number of heart failure hospitalizations. ( 14 ) Patients with heart failure with preserved EF often have the same signs and symptoms as those with heart failure with reduced ejection fraction. Their mortality is also similar, with significant burden of sudden cardiac death. ( 15 ) Therefore, one of the leading problems of modern-day cardiology is the lack of evidence-based treatments for patients in this heart failure category. Heart failure with preserved EF shares similar pathophysiological pathways, including adverse activation of RAAS and subsequent negative cardiac remodeling in terms of interstitial fibrosis and left ventricular hypertrophy. Furthermore, some authors consider endothelial dysfunction to be one of the key mechanisms underlying this syndrome. All of these mechanisms indicate a potential role of MRA in patients with heart failure with preserved EF. ( 16 , 17 ) Small studies have shown positive effects of MRA on left ventricular hypertrophy and echocardiographic diastolic function indices, while positive effects on major outcomes have not yet been shown. ( 18 ) The clear beneficial signal of spironolactone in this patient population comes from the overall negative RCT TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist). Although the trial did not prove lower mortality overall in patients with heart failure with preserved EF treated with spironolactone, it did show lower incidence of heart failure hospitalizations. ( 19 ) Several sub-analysis of the trial focusing only on patients from North and South America showed geographical differences in outcomes and positive effect of spironolactone on cardiovascular mortality in those patients. ( 20 ) These data indicate the existence of specific patient profiles that clearly benefit from treatment with mineralocorticoid receptor antagonists. ( 5 , 21 ) ## Effect on myocardial excitability The EPHESUS trial results showed positive effects of eplerenone on sudden cardiac death in patients soon after myocardial infarction with heart failure. ( 12 ) Furthermore, the EMPHASIS-HF study showed significant reduction of its secondary endpoint of atrial fibrillation incidence in the group of patients treated with eplerenone (42% reduction in comparison with the control group). ( 14 , 22 ) ## Eplerenone in specific patient populations In the EMPHASIS-HF trial, outcome benefits of eplerenone were present even in subgroups with greater risk of worse outcomes, such as patients with chronic renal disease, diabetes mellitus, and in those older than 75 years. ( 23 ) The results of a few small studies indicate greater benefit of eplerenone treatment in comparison with spironolactone for patients with heart failure and diabetes mellitus. Patients treated with spironolactone had higher HbA1c and cortisol and worse endothelial dysfunction in comparison with those treated with eplerenone. The selectivity of eplerenone may partially explain this observation. Nevertheless, the results of this studies require confirmation in large RCTs. ( 24 , 25 ) ## Eplerenone in treatment of patients with myocardial infarction Given the anti-inflammatory and anti-fibrotic properties of eplerenone, its early administration following myocardial infarction in patients without heart failure was also studied. The REMINDER clinical trial randomized 1012 patients with myocardial infarction without heart failure to early administration of eplerenone or placebo. Although it did not have the statistical power to assess major outcomes, it did show excellent eplerenone tolerability if administered within 24 hours of myocardial infarction and patients receiving eplerenone had significantly lower NT-proBNP concentrations at 30 days as well as 18 months after myocardial infarction. ( 26 ) ## Eplerenone in resistant arterial hypertension The latest European Society of Cardiology guidelines for treating arterial hypertension define resistant arterial hypertension as not achieving target blood pressure values (systolic <140 mmHg and/or diastolic <90 mmHg) by standard treatment (optimal or maximally tolerated doses of ACE inhibitors/ARBs, calcium blockers, or thiazide diuretics), confirmed by ambulatory blood pressure monitoring in patients who are fully compliant to prescribed therapies. Adding spironolactone 50 mg daily, and, if not tolerated, eplerenone in a dose of 50-100 mg daily has the I B recommendation level for management of resistant arterial hypertension ( Table 1 ). ( 27 ) ## Eplerenone safety In all of the large RCTs patients receiving eplerenone had significantly higher creatinine and potassium, but without difference in renal failure incidence. Furthermore, there was no death attributable to hyperkalemia in any of the trials. Viewed from a different perspective, there is significantly less hypokalemia and less deaths induced by ventricular arrhythmias as a consequence of hypokalemia. Generally, there is a low risk of hyperkalemia in patients with no preexistent renal disease. It is recommended to check potassium levels approximately one month after initiation of therapy. In patients with chronic renal disease, acute exacerbation of chronic renal disease, or who concomitantly take nephrotoxic drugs, potassium and renal function should be monitored more closely. ( 5 , 28 - 30 ) ## Conclusion Large RCTs have demonstrated the beneficial effects of eplerenone on survival of patients with heart failure with reduced EF. This is the reason why large cardiological societies included eplerenone as one of the essential treatments in their guidelines, in addition to ACE inhibitors/ARBs, and beta-blockers. Further RCTs are needed to confirm the effects of eplerenone on outcomes in patients with heart failure with preserved EF as well as in patients with myocardial infarction and no systolic dysfunction. Eplerenone safety profile is of great importance for everyday clinical practice, as well as its high tolerability that contributes to patient compliance.