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.     

Eplerenone--a novel selective aldosterone blocker

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and safety of eplerenone, a new selective aldosterone blocker. DATA SOURCES: Primary literature and review articles were obtained via MEDLINE search (1966-April 2002). Additional studies and abstracts were identified from the bibliographies of reviewed literature. STUDY SELECTION AND DATA EXTRACTION: Studies and review articles related to eplerenone, aldosterone, aldosterone antagonist, and spironolactone were reviewed. Data pertinent to this article were included. DATA SYNTHESIS: Eplerenone is a selective aldosterone blocker. Recent data have demonstrated the deleterious effects of aldosterone in several chronic disease states including hypertension and heart failure. Animal studies using eplerenone have shown a positive role for aldosterone antagonism in the treatment of hypertension, heart failure, myocardial infarction, renal disease, and atherosclerosis. In humans, eplerenone appears to be effective for the treatment of hypertension. An ongoing study will examine the effect of eplerenone for heart failure. To date, the incidence of adverse effects with eplerenone has been slightly lower than with spironolactone. CONCLUSIONS: Eplerenone appears to be a promising drug in a new class of agents called selective aldosterone blockers. The drug may be approved for treatment of hypertension in 2002. Additional studies are ongoing that may provide information on other clinical uses for this medication.     

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.     

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.     

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 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.     

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.     

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.     

Trandolapril: a newer angiotensin-converting enzyme inhibitor

BACKGROUND: Trandolapril is a newer angiotensin-converting enzyme (ACE) inhibitor that is approved by the US Food and Drug Administration for the treatment of hypertension and for use in stable patients who have evidence of left ventricular (LV) systolic dysfunction or symptoms of chronic heart failure within the first 2 days after an acute myocardial infarction (AMI). The fixed-dose combination of trandolapril and verapamil extended release (ER) is approved for the treatment of hypertension only. OBJECTIVE: The purpose of this article was to review the pharmacology, pharmacokinetics, clinical efficacy, and safety profile of trandolapril as monotherapy and in fixed-dose combination with verapamil ER. METHODS: Relevant studies were identified through a MEDLINE/PubMed search of the English-language literature published between January 1983 and August 2002 and a review of the bibliographies of identified articles. RESULTS: Trandolapril has a sufficient duration of inhibition of plasma ACE activity to allow once-daily dosing. It is converted by esterases to the active trandolaprilat metabolite, with mean terminal disposition half-lives of < 1 and approximately 75 hours for the prodrug and metabolite, respectively. In comparative trials in the management of hypertension, trandolapril 1 to 4 mg/d was statistically indistinguishable from or superior to captopril 100 mg/d, enalapril 10 or 20 mg/d, hydrochlorothiazide (HCTZ) 25 mg/d, nifedipine ER 30 or 40 mg/d, nitrendipine 20 mg/d, perindopril 4 mg/d, and verapamil ER 120 to 240 mg/d. In the Trandolapril Cardiac Evaluation, trandolapril also significantly reduced all-cause mortality, cardiovascular mortality, sudden death, and progression to severe chronic heart failure in patients with evidence of LV systolic dysfunction after AMI. In comparative trials in the management of hypertension, the combination of trandolapril 1 or 2 mg/d and verapamil ER 180 mg/d was statistically indistinguishable from or superior to the combinations of atenolol 50 or 100 mg/d plus chlorthalidone 12.5 or 25 mg/d, captopril 50 mg/d plus HCTZ 25 mg/d, lisinopril 20 mg/d plus HCTZ 12.5 mg/d, and metoprolol 100 mg/d plus HCTZ 12.5 mg/d. The most common adverse effects of trandolapril monotherapy in clinical trials of < or = 1 year's duration included cough, dizziness, and diarrhea (frequency < or = 1.9%). The most common adverse effects of trandolapril/verapamil ER therapy in clinical trials of < or = 1 year's duration included first-degree atrioventricular block, bradycardia, constipation, cough, diarrhea, dizziness, fatigue, and dyspnea (frequency < or = 4.6%). Based on the literature search, there are no published pharmacoeconomic evaluations of trandolapril alone or combined with verapamil ER in the US health care setting. CONCLUSIONS: Based on the literature, trandolapril is a well-tolerated and effective antihypertensive agent, whether used alone or in combination with verapamil ER. These products may be valuable in patients with LV systolic dysfunction after AMI, although the combination product is approved for the management of hypertension only.     

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.     

Management of hypertension in chronic heart failure

Chronic heart failure (CHF) is associated with frequent hospitalizations and high mortality. It affects more than 5 million individuals in the USA, and another 660,000 new cases are diagnosed each year; overall, heart failure (HF) now accounts for 7% of all deaths from cardiovascular disease. Hypertension (HTN) increases the risk of development of HF and it precedes it in 75% of cases. HF patients are nearly evenly divided between those with reduced left ventricular (LV) function or systolic dysfunction and those with preserved LV systolic function or diastolic dysfunction. The management of HTN in patients with CHF is challenging. Drugs such as β-blockers, angiotensin-converting enzyme inhibitiors, angiotensin receptor blockers, aldosterone receptor blockers, hydralazine and nitrates, which have shown mortality benefit in CHF and exert antihypertensive effects, should be used as first-line agents to control HTN in CHF. In addition, antihypertensive drugs such as α-receptor blockers that can increase mortality in HF should be avoided. The dihydropyridine group of calcium channel blockers are good antihypertensive medications with a neutral effect on mortality in patients with CHF. These may be used in CHF patients with refractory HTN. In patients with HF with reduced ejection fraction, HTN is treated differently in comparison to patients with HF with normal ejection fraction. This article reviews the treatment of essential HTN in patients at risk for developing HF, in the presence of HF and the latest developments in treatment that might benefit both HTN and HF management.     

依普利酮对慢性心力衰竭患者血浆转化生长因子β1水平的影响

目的 观察依普利酮对慢性心力衰竭患者血浆转化生长因子β1（TGF-β1）水平的影响,探讨其治疗心力衰竭的可能机制.方法 将85例慢性心力衰竭患者随机分为依普利酮组（n=43）和常规治疗组（n=42）,常规治疗组为基础治疗,依普利酮组在常规治疗基础上加服依普利酮25 mg/d,持续1个月后,无明显不良反应者增至50 mg/d,治疗1年后复查心脏超声,ELISA法测外周血脑钠肽（BNP）、TGF-β1水平,比较两组治疗前后各指标变化,分析TGF-β1水平与BNP及心功能的相关性.结果 依普利酮治疗1年后,患者左心室射血分数（LVEF）及6 min步行距离增加,左心室后壁厚度（LVP）、左心室舒张末期内径（LVEDD）、室间隔厚度（IVS）、TGF-β1水平、BNP水平均减少,血压降低,且各项指标改善均优于常规治疗组,差异有统计学意义（P〈0.05）;TGF-β1水平与BNP呈正相关,与LVEF呈负相关（P〈0.05）.结论 在常规抗心力衰竭治疗基础上,加用依普利酮能降低心力衰竭患者血浆TGF-β1水平,逆转心肌重构,改善心功能.     

The role of aldosterone in heart failure and the clinical benefits of aldosterone blockade

Aldosterone has a variety of detrimental effects on the heart and vasculature and is increasingly recognized as an important target in chronic heart failure, as illustrated by the Randomized Aldactone Evaluation Study. In this article, the evidence supporting the cardiovascular effects of aldosterone in humans and the proven benefits of aldosterone-receptor antagonists in heart failure shall be discussed.     

The role of aldosterone in heart failure and the clinical benefits of aldosterone blockade

Aldosterone has a variety of detrimental effects on the heart and vasculature and is increasingly recognized as an important target in chronic heart failure, as illustrated by the Randomized Aldactone Evaluation Study. In this article, the evidence supporting the cardiovascular effects of aldosterone in humans and the proven benefits of aldosterone-receptor antagonists in heart failure shall be discussed.     

依普利酮联合依那普利叶酸治疗H型高血压合并慢性心衰的疗效及对血清NT-proBNP、Hcy水平的影响

[目的]探讨探讨依普利酮联合依那普利叶酸片治疗H型高血压并慢性心衰患者的疗效及对血清氨基末端B型脑钠肽前体(NT-proBNP)和同型半胱氨酸(Hcy)水平的影响.[方法]选取2016年1月至2019年1月本院收治的104例H型高血压合并慢性心衰的患者为研究对象,根据随机数表法将其分为观察组和对照组,每组各52例.对照...     

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.     

Use of Left Ventricular Ejection Fraction or Wall-Motion Score Index in Predicting Arrhythmic Death in Patients Following an Acute Myocardial Infarction

All-cause mortality and morbidity following an acute myocardial infarction (AMI) are correlated to LV systolic dysfunction. The correlation is closest with mortality and morbidity associated with congestive heart failure (CHF). Prediction of arrhythmic death in patients with AMI relies on the correlation between arrhythmic death and "sudden unexpected death" defined as death within 1 hour of onset of new symptoms. Assessment of late potentials, heart rate variability (HRV), T wave alternans, arrhythmias seen on Holter monitoring or during exercise testing, electrophysiological testing, and baroreceptor assessment have all proven to be useful in the prediction of sudden death even when LV systolic function is known. In selected populations HRV is superior to LV systolic function assessment in predicting sudden death and/or arrhythmic events, and may even predict all-cause mortality with the same precision. Comparisons of other methods with LV function assessment should be interpreted with care because most methods have been evaluated in subgroups of infarct patients with a low risk of death. Results from a large series of high risk patients with AMI (the TRAndolapril Cardiac Evaluation study) have shown that even in patients with severe depressed LV systolic function around one-third of the patients will die suddenly. The current situation is that LV function appears to be the best method of predicting death whereas other methods appear very promising for detecting arrhythmic death in more selected populations. The optimal method for selecting patients at high risk of arrhythmic death has not yet been developed, but a combination of LV function and another method, i.e., HRV, appears promising. This may ensure that the enrolled patients have an increased risk of death and that this risk will be due to arrhythmic events. Patients with LVEF of 10% or less can be excluded as they will most likely not die suddenly.