The cardiovascular effects of eplerenone, a selective aldosterone-receptor antagonist

BACKGROUND: The role of the renin-angiotensin-aldosterone system in the pathophysiology and treatment of hypertension and heart failure has been extensively studied. Angiotensin-converting enzyme inhibitors and angiotensin II-receptor blockers have been shown to effectively reduce blood pressure, protect the kidney, and reduce morbidity and mortality in patients with heart failure. Therefore, there is increased interest in the effects of aldosterone and the use of aldosterone-receptor antagonists in the treatment of cardiovascular disease. Eplerenone is the first selective aldosterone-receptor antagonist approved for the treatment of hypertension and left ventricular (LV) dysfunction after acute myocardial infarction (AMI). OBJECTIVE: The goal of this article was to review the pharmacologic properties, clinical efficacy, and tolerability of eplerenone in the treatment of hypertension, LV dysfunction, and proteinuria. METHODS: Relevant English-language articles were identified through searches of MEDLINE (1966-May 2003), Current Contents, and International Pharmaceutical Abstracts (1970-May 2003) using the terms hypertension, heart failure, eplerenone, aldosterone, and aldosterone antagonist. Other pertinent publications were identified from the reference lists of the identified articles. Information was also obtained from abstracts presented at national meetings and data on file with the manufacturer. RESULTS: In clinical trials, eplerenone alone and in combination with renin-angiotensin blockade significantly reduced both systolic and diastolic blood pressure compared with placebo (P < 0.05 to P < 0.001). In EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study), the addition eplerenone to optimal medical therapy reduced morbidity and mortality in patients with AMI and LV dysfunction, although the incidence of serious hyperkalemia was also significantly greater. In comparisons with spironolactone, eplerenone was associated with a lower incidence of gynecomastia and other sex hormone-related adverse effects. CONCLUSIONS: Either alone or in combination with other antihypertensive agents, eplerenone appears to be effective for the treatment of hypertension. Morbidity and mortality were reduced when eplerenone was added to standard therapy for LV dysfunction complicating AMI. The use of eplerenone for hypertension or heart failure may be limited in patients at risk for hyperkalemia.     

Eplerenone: a selective aldosterone receptor antagonist for patients with heart failure

OBJECTIVE: To evaluate the pharmacology, pharmacokinetics, safety, and clinical use of eplerenone in heart failure (HF). DATA SOURCES: English-language MEDLINE searches were performed from 1966 to May 2004. Key words included eplerenone, aldosterone receptor antagonist, heart failure, myocardial infarction, left-ventricular dysfunction, and cost-effectiveness. Additional references were identified from bibliographies of selected articles. STUDY SELECTION AND DATA EXTRACTION: Human trials evaluating the efficacy, safety, and cost-effectiveness of aldosterone receptor antagonists in HF were evaluated. DATA SYNTHESIS: Eplerenone is the first selective aldosterone receptor antagonist. The drug is indicated to improve the survival of stable patients with left-ventricular systolic dysfunction (ejection fraction <40%) and clinical evidence of HF following acute myocardial infarction. Efficacy and safety in this population have been demonstrated in a large, randomized clinical trial. Eplerenone is associated with severe and sometimes life-threatening hyperkalemia. Patients with reduced renal function and diabetes, as well as those on other drugs that increase potassium levels, are at highest risk. Eplerenone is metabolized by the cytochrome P450 system and may interact with drugs that interfere with this system. A major advantage of eplerenone over the nonselective aldosterone receptor antagonist spironolactone is lack of binding to progesterone and androgen receptors, which is associated with drug-induced gynecomastia, breast pain, and impotence. CONCLUSIONS: The addition of eplerenone to traditional HF therapy has been shown to reduce morbidity and mortality in patients who develop left-ventricular dysfunction after acute myocardial infarction. Eplerenone's selectivity reduces sex hormone-related adverse effects. Despite these benefits, the overall cost-effectiveness has yet to be determined.     

New treatment option for heart failure patients: eplerenone

Aldosterone plays an important role in the harmful cardiac remodeling process and pathophysiology of heart failure after a myocardial infarction. Until recently, spironolactone (Aldactone) was the only pharmacologic agent available to directly block the deleterious effects of aldosterone. The use of spironolactone is complicated by its antiprogesterone and antiandrogen side effects, such as gynecomastia and menstrual irregularities. Eplerenone (Inspra), a member of a new class of drugs called selective aldosterone receptor antagonists, was recently approved for the treatment of both hypertension and post-myocardial infarction heart failure and appears to be devoid of the antiprogesterone and antiandrogen effects. In a trial in patients with heart failure following a myocardial infarction, eplerenone treatment significantly reduced mortality and morbidity compared to placebo. Eplerenone may be considered as part of the therapeutic plan in patients who have suffered a myocardial infarction and demonstrate evidence of heart failure.     

Eplerenone in the treatment of chronic heart failure

There has been a recent revival of interest in aldosterone receptor antagonists for the treatment of chronic heart failure. This was largely triggered by fresh insights into the role of aldosterone in a number of key pathophysiological processes, including fibrosis and remodeling, inflammation, and the potentiation of catecholamine effects. The therapeutic efficacy of spironolactone (Aldactone), Pfizer) in severe chronic heart failure was established by the Randomized Aldactone Evaluation Study, but hormonal side effects (gynecomastia) associated with the drug posed a problem. More recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study has provided firm support for the use of eplerenone (Inspra, Pfizer) in heart failure following acute myocardial infarction in addition to neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and beta-blockers. This strategy can be expected to benefit both mortality and morbidity. Due to the fact that eplerenone is a selective aldosterone receptor antagonist, it does not cause troublesome hormonal side effects. This is an important feature of the drug that is likely to help maintain compliance.     

Nebivolol: a third-generation beta-adrenergic blocker

OBJECTIVE: To describe the pharmacologic and pharmacokinetic properties of a new beta-adrenergic blocker, nebivolol, and review the literature evaluating its efficacy in the treatment of hypertension and heart failure. DATA SOURCES: Articles were identified through searches of MEDLINE (1996-May 2006) and International Pharmaceutical Abstracts (1970-May 2006), using the key word nebivolol. Additional references were selected from the bibliographies of the articles cited. Searches were not limited by language, time, or human subject. STUDY SELECTION AND DATA EXTRACTION: Preclinical studies evaluating the pharmacologic and pharmacokinetic properties of nebivolol in humans were selected for review. Randomized, controlled, blinded clinical trials assessing the efficacy of nebivolol for the treatment of hypertension and heart failure were also included. DATA SYNTHESIS: Preclinical data have established nebivolol as a third-generation beta-adrenergic blocker, as it possesses vasodilatory properties that contribute to its hemodynamic effects beyond those achieved at beta-adrenergic receptors. Short-term, randomized, controlled clinical trials have shown nebivolol to be as effective as other antihypertensive therapies at lowering blood pressure. One long-term trial showed a significant reduction in death and hospital admissions for cardiovascular causes when nebivolol was compared with placebo in patients with heart failure (31.1% vs 65.3%; HR 0.86; 95% CI 0.74 to 0.99). CONCLUSIONS: Nebivolol is a novel beta-adrenergic blocker that possesses unique pharmacologic properties, compared with other agents in its class. Nebivolol appears to be as effective as other antihypertensive agents at lowering blood pressure and possesses benefits for patients with heart failure. Additional studies are needed to address the long-term benefits of nebivolol for hypertension, to compare nebivolol with other beta-adrenergic blockers for heart failure, and to investigate the clinical relevance of nitric oxide-mediated vasodilation.     

Long-term safety and efficacy of the selective aldosterone blocker eplerenone in patients with essential hypertension

BACKGROUND: Even within the normal range, aldosterone levels are linked to end-organ toxicity and mortality in patients with hypertension. Treatment with angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers does not sufficiently reduce plasma aldosterone levels. OBJECTIVE: This study was conducted to assess the long-term safety profile and efficacy of the selective aldosterone blocker eplerenone. METHODS: This was a multicenter, open-label, uncontrolled trial in patients with mild to moderate essential hypertension. After a 1-week washout of previous antihypertensive medications, eplerenone was initiated at 50 mg once daily; the dose was titrated to a maximum of 200 mg/d to achieve a diastolic blood pressure <90 mm Hg and a systolic blood pressure <140 mm Hg. Thereafter, another antihypertensive agent could be added and titrated once, or another agent could be substituted for eplerenone. Eplerenone treatment was continued for up to 14 months in a subset of patients. RESULTS: Five hundred eighty-six patients were enrolled in the study. Their adjusted mean blood pressure (BP) at baseline was 150/96 mm Hg. The majority (80.4%) were white; 51.5% were male and 48.5% were female; 62.3% were between the ages of 45 and 64 years and 21.7% were aged >64 years. Three hundred eighty-five patients (65.7%) completed the study; 98 (16.7%) were withdrawn due to treatment failure (only 4.8% of them after month 4), and 40 (6.8%) were withdrawn due to treatment-emergent adverse events. Four hundred thirty-three of 582 (74.4%) patients in the intent-to-treat population achieved BP control during eplerenone treatment: 261 (44.8%) received eplerenone monotherapy and 172 (30.0%) received eplerenone plus another antihypertensive agent. CONCLUSIONS: Eplerenone therapy was effective in the treatment of mild to moderate hypertension over a 14-month period, either as monotherapy or in combination with another antihypertensive agent. Use of eplerenone was well tolerated in the population studied.     

Eplerenone in the treatment of chronic heart failure

There has been a recent revival of interest in aldosterone receptor antagonists for the treatment of chronic heart failure. This was largely triggered by fresh insights into the role of aldosterone in a number of key pathophysiological processes, including fibrosis and remodeling, inflammation, and the potentiation of catecholamine effects. The therapeutic efficacy of spironolactone (Aldactone^®, Pfizer) in severe chronic heart failure was established by the Randomized Aldactone Evaluation Study, but hormonal side effects (gynecomastia) associated with the drug posed a problem. More recently, the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study has provided firm support for the use of eplerenone (Inspra?, Pfizer) in heart failure following acute myocardial infarction in addition to neurohormonal blockade with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers and β-blockers. This strategy can be expected to benefit both mortality and morbidity. Due to the fact that eplerenone is a selective aldosterone receptor antagonist, it does not cause troublesome hormonal side effects. This is an important feature of the drug that is likely to help maintain compliance.     

Aldosteron und Aldosteronrezeptorantagonisten in der Herzinsuffizienztherapie

In addition to the classical effects exerted by aldosterone on water and electrolyte haemostasis, recent data suggest additional roles in the pathophysiology of cardiovascular diseases. Examples are the regulation of blood pressure (by direct aldosterone effects on vessels and the CNS), myocardial hypertrophy and remodelling. Two aldosterone receptor antagonists, spironolactone and eplerenone, are currently available for the long-term therapy of chronic heart failure. Both compounds have clearly demonstrated their efficacy in heart failure treatment in end-point based clinical trials. Spironolactone, in addition to its antagonistic effects on the mineralocorticoid receptor, has anti-androgenic and gestagenic actions which can lead to endocrine side effects. Eplerenone selectively blocks aldosterone receptors and thus lacks adverse effects caused by non-specific steroid receptor blockade. The elimination half-life of eplerenone is shorter than the half-life of the active metabolites of spironolactone. Eplerenone is metabolised by CYP3A4, and pharmacokinetic interactions with inhibitors and inducers of this enzyme have to be considered. Essential for the clinical use of aldosterone antagonists in heart failure is the careful monitoring of potassium levels and renal function. The recommended doses should be followed precisely. Higher doses increase the risk of developing life-threatening hyperkalemia. Particular attention has to be paid to patients with impaired renal function. Aldosterone receptor antagonists should not be used when the glomerular filtration rate is below 50 ml/min.     

Aldosterone receptor antagonists for heart failure: current status, future indications

Many patients with heart failure should receive an aldosterone receptor antagonist, ie, either spironolactone (Aldactone) or the newer agent eplerenone (Inspra)--in addition to an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) or both, and a beta-blocker. We review the evidence and indications.     

Spironolactone in the treatment of congestive heart failure

OBJECTIVE: To evaluate evidence supporting the use of spironolactone in managing congestive heart failure. DATA SOURCES: Literature accessed through MEDLINE (January 1966-December 1999) and cross-referencing of selected articles. Search terms included spironolactone and heart failure. DATA SYNTHESIS: Heart failure is a leading cause of morbidity and mortality. Through aldosterone antagonism, spironolactone may be an effective pharmacotherapeutic addition to patients not responding to standard drug therapy for heart failure. RESULTS: Clinical trials have demonstrated that, in patients with heart failure, spironolactone improves laboratory indices, quality of life, and morbidity. Recently, spironolactone has been demonstrated to improve the survival of patients with New York Heart Association (NYHA) III or IV heart failure. CONCLUSIONS: Spironolactone use should be considered in patients with NYHA Class III or IV heart failure.     

Rimonabant--a selective CB1 antagonist

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of rimonabant, a new selective cannabinoid receptor antagonist. DATA SOURCES: Primary literature and review articles were obtained via a MEDLINE search (1966-November 2004) using the key terms obesity, smoking cessation, cannabinoid, rimonabant, SR 141716, and SR 141716a. Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles related to rimonabant and the endocannabinoid system were reviewed. Data pertinent to this article were included. DATA SYNTHESIS: Rimonabant is a selective cannabinoid receptor antagonist. Recent data have demonstrated beneficial effects of rimonabant in obesity, smoking cessation, and metabolic syndrome. Animal studies using rimonabant have shown a positive role for reducing hunger, caloric intake, and body weight and in increasing satiety. In humans, rimonabant appears to be effective for treatment of obesity and smoking cessation. Ongoing studies will examine the effect of rimonabant on obesity, metabolic syndrome, smoking cessation, and alcohol abuse. To date, the incidence of adverse effects with rimonabant has been slightly greater than placebo, with the most common being nausea. CONCLUSIONS: Rimonabant appears to be a promising drug in an entirely new class called selective cannabinoid CB1 receptor antagonists. The drug may be approved for treatment of obesity and smoking cessation in 2005. Additional studies are ongoing that may provide information on other clinical uses for this medication.     

Mineralocorticoid receptor blocker eplerenone improves endothelial function and inhibits Rho-associated kinase activity in patients with hypertension

Hypertension is associated with endothelial dysfunction and activated Rho-associated kinases (ROCKs). The purpose of this study was to evaluate the effects of the selective mineralocorticoid receptor blocker, eplerenone, on endothelial function and ROCK activity in patients with hypertension. The study was carried out over 48 weeks in 60 untreated patients with hypertension who were randomly assigned to eplerenone, nifedipine, and losartan groups. We evaluated the effects of each treatment on flow-mediated vasodilation (FMD) and ROCK activity in peripheral leukocytes. Eplerenone increased FMD and decreased leukocyte ROCK activity. Nifedipine decreased ROCK activity but did not alter FMD. Losartan increased FMD but did not alter ROCK activity. Hypotensive effects were similar in the three groups, as was nitroglycerin-induced vasodilation during the follow-up period. There were no significant differences between the groups with respect to other parameters. The study results show that eplerenone improves endothelial function and inhibits ROCK activity in patients with essential hypertension.     

The role of aldosterone receptor antagonists in the management of heart failure: An update

The 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.     

Candesartan cilexetil: an angiotensin II receptor blocker

OBJECTIVE: To summarize and critique the medical literature on candesartan cilexetil, an angiotensin II receptor blocker (ARB). DATA SOURCES: MEDLINE searches (January 1966-January 1999) and manufacturer prescribing literature were used to identify articles on candesartan cilexetil. Bibliographies were also reviewed for germane articles. STUDY SELECTION: Study and review articles describing the chemistry, human pharmacology, pharmacodynamics, pharmacokinetics, placebo-controlled trials, comparative trials, and clinical application of candesartan cilexetil based on the published literature and premarketing clinical trials were reviewed. DATA EXTRACTION: All literature on the use of candesartan cilexetil for treating hypertension and congestive heart failure were included. DATA SYNTHESIS: ARBs are a new class of drugs with increasing use in treating hypertension. Studies are ongoing to determine the role of these agents in preventing remodeling after myocardial infarction and in patients with congestive heart failure. Candesartan cilexetil is among the newest drugs in the class that includes losartan, irbesartan, and valsartan. Candesartan cilexetil has more than 1000 times more affinity for the angiotensin II, type AT1 receptor ARBs, and the binding affinity and competitive angiotensin II receptor antagonism is stronger than that of losartan. Clinical studies in patients with hypertension have demonstrated that candesartan cilexetil, in doses of 4-16 mg, is more effective in reducing sitting diastolic blood pressure than are placebo and losartan 50 mg. Candesartan cilexetil has demonstrated reductions in blood pressure comparable to those of enalapril, with the rate of adverse events greater in the enalapril group. Dosage adjustments are not necessary in elderly patients or in patients with mild hepatic or renal dysfunction. In diabetic patients, blood glucose, hemoglobinA1c, and serum lipids are not affected. The clinical studies demonstrated that the adverse effect profile of candesartan cilexetil was similar to that of placebo and there were no dose-dependent adverse effects. CONCLUSIONS: Candesartan cilexetil provides an alternative antihypertensive therapy that is well tolerated and effective in reducing blood pressure in a wide range of patients. Due to its greater binding affinity to the angiotensin II receptor, candesartan cilexetil appears to have a longer antihypertensive effect than losartan. This may be advantageous in decreasing morbidity and mortality associated with hypertension, although further studies are required to validate this potential advantage.     

High-versus low-dose ACE inhibitor therapy in chronic heart failure

OBJECTIVE: To discuss the controversy associated with the optimal dosing of angiotensin-converting enzyme (ACE) inhibitors in the management of patients with systolic heart failure; specifically, to review data related to the use of high-dose ACE inhibitors related to both neurohormonal and clinical outcomes associated with doses similar to, lower than, and higher than those used in the large, randomized clinical trials. DATA SOURCES: Primary, review, and meta-analysis articles were identified by MEDLINE search (1987-September 2002) and through secondary sources. STUDY SELECTION AND DATA EXTRACTION: All of the articles identified from the data sources were evaluated, and all information deemed relevant was included in this discussion. All available comparative dose trials, both prospective and retrospective, were evaluated for clinical and neurohormonal outcomes. DATA SYNTHESIS: The majority of data comparing the effect of high- with low-dose ACE inhibitors on neurohormonal outcomes demonstrate dose-related reduction in various neurohormonal measurements including plasma ACE, aldosterone, atrial natriuretic peptide, B-type natriuretic peptide, and interleukin-6 levels. Clinical endpoints including New York Heart Association class and heart failure-related hospitalizations were reduced by higher doses, but a dose-related survival benefit has not been demonstrated. Differences in duration of therapy and study design may account for variability in neurohormonal and morbidity results among various studies. CONCLUSIONS: Despite documented underutilization in clinical practice of doses of ACE inhibitors demonstrated in large controlled trials to improve morbidity and mortality, clinicians should attempt to reach these target doses if possible in patients with heart failure. Higher doses may improve surrogate markers for heart failure without impacting survival.     

Aldosterone antagonists in heart failure

Aldosterone antagonists represented by nonselective spironolactone and mineralocorticoid-selective eplerenone are approved for treatment of symptomatic heart failure with reduced systolic function. Their cardioprotective, antifibrotic, and antiarrhythmic effects have been proven in animal experiments, and their effects on morbidity and mortality have been demonstrated in randomized clinical trials. Yet, they remain the most underutilized of all classes of medications for heart failure, primarily because of fear of hyperkalemia. Thorough patient screening and selection is the key for minimizing risks and optimizing benefits from these drugs. Ongoing trials will demonstrate whether the indication for aldosterone antagonists can be expanded to less severe heart failure or patients with preserved systolic function.     

The resurrection of spironolactone on its golden anniversary.

The edematous states, specifically those in CHF and cirrhosis of the liver, are associated with excessive aldosterone secretion and represent states of secondary hyperaldosteremia. Aldosterone promotes sodium retention by the renal tubules. Spironolactone, first introduced 50 years ago (1953), blocks the action of aldosterone on renal transport of electrolytes, thus acting as an effective diuretic, and in addition, has potentiating effects on other diuretics, including the thiazides. Spironolactone has undesirable side effects that have limited its clinical use; the most significant are impotence, gynecomastia, and hirsutism. Eplerenone, a recently introduced selective ARA, decreases morbidity and mortality in patients with CHF following MI and has none of the androgenic or estrogenic side effects of spironolactone. Eplerenone is an effective alternative for spironolactone.     

Nesiritide: a novel approach for acute heart failure

OBJECTIVE: To review preclinical and clinical information related to nesiritide, a recombinant form of B-type natriuretic peptide approved for treatment of acutely decompensated heart failure. DATA SOURCES: Primary and review articles were identified by MEDLINE search (1966-May 2002) using the key words natriuretic peptide and heart failure, and through secondary sources. Natrecor's document submitted for the Food and Drug Administration (FDA) New Drug Application were obtained from the FDA Web site. STUDY SELECTION/DATA EXTRACTION: Peer-reviewed articles and abstracts of randomized clinical trials in humans were included in this review. DATA SYNTHESIS: Nesiritide has beneficial actions for treatment of heart failure, including arterial and venous dilatation, enhanced sodium and urinary excretion, and suppression of the renin-angiotensin-aldosterone and sympathetic nervous systems. It has been shown to improve hemodynamic parameters, primarily pulmonary capillary wedge pressure, as well as clinical symptoms in patients with acutely decompensated heart failure. Nesiritide produced more rapid hemodynamic improvement and caused significantly fewer adverse effects than intravenous nitroglycerin. The incidence of hypotension, the most common adverse effect, was comparable between nesiritide and nitroglycerin. Additionally, nesiritide is associated with a lower incidence of arrhythmias than dobutamine and has a neutral effect on mortality. CONCLUSIONS: Nesiritide offers an alternative for management of acutely decompensated heart failure. It is considered an option for patients who do not respond to other vasodilators, inotropes, or diuretics and for those at high risk of arrhythmias. Further pharmacoeconomic investigations for nesiritide are warranted.     

Comparing therapies for postmenopausal osteoporosis prevention and treatment

OBJECTIVE: To review the literature concerning the efficacy of calcium, hormone replacement therapy (HRT), bisphosphonates, selective estrogen receptor modulators, and calcitonin in the prevention and treatment of postmenopausal osteoporosis. DATA SOURCES: Articles were identified through searches of the MEDLINE (1966-July 2002), EMBASE (1980-July 2002), and International Pharmaceutical Abstracts (1970-July 2002) databases using the key words osteoporosis, postmenopausal, fracture, calcium, vitamin D, hormone replacement therapy, bisphosphonates, alendronate, risedronate, raloxifene, and calcitonin. Additional references were located through review of the bibliographies of the articles cited. Searches were not limited by time restriction, language, or human subject. STUDY SELECTION AND DATA EXTRACTION: Experimental and observational studies of the use of calcium and antiresorptive therapies for the prevention and treatment of postmenopausal osteoporosis were selected. Articles evaluating bone mineral density (BMD) or fracture efficacy were included in this review. DATA SYNTHESIS: HRT, bisphosphonates, raloxifene, and calcitonin have demonstrated stabilization of and improvement in BMD. Randomized clinical trials have shown fracture risk reduction with bisphosphonates, raloxifene, HRT, calcium, and calcitonin. The largest risk reductions have been reported with use of bisphosphonates in several trials. CONCLUSIONS: Several therapeutic options with well-documented improvements in BMD and reductions in fracture risk are available to women for the prevention and treatment of postmenopausal osteoporosis.