Spironolactone versus eplerenone for the treatment of idiopathic hyperaldosteronism

The aim of this prospective, randomised, open-label, blinded-end point study was to compare the efficacy and safety of eplerenone versus spironolactone in patients with bilateral idiopathic hyperaldosteronism (IHA). After a 2-week washout period, 34 patients with IHA were assigned to receive either spironolactone 25 mg b.i.d. (n = 17) or eplerenone 25 mg b.i.d. (n = 17) for 24 weeks. If the patients' blood pressure (BP) was not < 140/90 mmHg, the doses were gradually increased up to 400 mg for spironolactone and 200 mg for eplerenone. If the patients' BP remained uncontrolled, a daily dose of hydrochlorothiazide 12.5 mg was added at week 16. The primary outcome was the percentage of patients with BP < 140/90 mmHg at 16 weeks (i.e., with aldosterone antagonist monotherapy). The patients' BP was normalised in 13 out of 17 (76.5%) and 14 out of 17 (82.4%) patients in the spironolactone and eplerenone groups, respectively (p = 1.00). Systolic BP decreased more rapidly with eplerenone. Serum potassium levels were normalised (> 3.5 mmol/l) in all patients at 4 weeks. Mild hyperkalaemia was observed in two patients receiving 400 mg of spironolactone and in three patients receiving 150 mg of eplerenone. Two patients presented with bilateral painful gynaecomastia at the end of week 16 while receiving 400 mg of spironolactone. Switching spironolactone to 150 mg of eplerenone daily resulted in resolution of gynaecomastia and also maintained BP control. At the end of the study, 19 patients were on eplerenone and 15 were on spironolactone. However, this did not affect the primary end point, because the switch from spironolactone to eplerenone (in two patients) occurred at the end of week 16. It was concluded that eplerenone was as effective as spironolactone in reducing BP in patients with IHA. The risk of mild hyperkalaemia was similar with both drugs.     

Eplerenone in hypertension

Appreciation of the role of aldosterone in cardiovascular and renal disease has increased in the last 50 years. The use of spironolactone was limited by adverse sexual effects, including gynaecomastia. Eplerenone is a newer aldosterone antagonist that is much more selective, with minimal affinity for progesterone and androgenic receptors; therefore, there are very few reports of adverse sexual effects. A review of published trials shows that eplerenone reduces blood pressure (BP) in a dose-dependent manner, from 50 to 200 mg/day, and to a similar degree as enalapril. It has an additive effect when given to patients inadequately controlled on an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. Eplerenone performs better than losartan in African-American patients and lowers BP regardless of initial plasma renin activity. The risk of hyperkalaemia is low, similar to that of enalapril, and < 1% of patients have had to be withdrawn from studies because of elevated serum potassium levels. Eplerenone is an effective, well-tolerated antihypertensive agent that may be used alone or in conjunction with other agents; apart from the risk of hyperkalaemia, adverse effects are similar to placebo.     

Eplerenone in hypertension

Appreciation of the role of aldosterone in cardiovascular and renal disease has increased in the last 50 years. The use of spironolactone was limited by adverse sexual effects, including gynaecomastia. Eplerenone is a newer aldosterone antagonist that is much more selective, with minimal affinity for progesterone and androgenic receptors; therefore, there are very few reports of adverse sexual effects. A review of published trials shows that eplerenone reduces blood pressure (BP) in a dose-dependent manner, from 50 to 200 mg/day, and to a similar degree as enalapril. It has an additive effect when given to patients inadequately controlled on an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. Eplerenone performs better than losartan in African-American patients and lowers BP regardless of initial plasma renin activity. The risk of hyperkalaemia is low, similar to that of enalapril, and < 1% of patients have had to be withdrawn from studies because of elevated serum potassium levels. Eplerenone is an effective, well-tolerated antihypertensive agent that may be used alone or in conjunction with other agents; apart from the risk of hyperkalaemia, adverse effects are similar to placebo.     

Should the aldosterone-receptor antagonist – eplerenone – be used after acute myocardial infarction with left ventricular dysfunction?

Eplerenone is a more selective aldosterone-receptor antagonist than spironolactone. Patients who had evidence of left ventricular (LV) dysfunction, were enrolled for treatment with eplerenone or placebo within 3 – 14 days of acute myocardial infarction (MI). During the mean follow-up of 16 months, the primary end point of death from any cause occurred in fewer patients in the eplerenone group than in the placebo group. The other primary end point of death from cardiovascular causes or hospitalisations for cardiovascular events also occurred to a lesser extent in the eplerenone than placebo group. Eplerenone should probably be added to the optimal therapy for use after acute MI with LV dysfunction, provided care is taken to avoid hyperkalaemia.     

Spironolactone in severe heart failure: enhances efficacy of diuretic + ACE inhibitor combinations

(1) In patients with heart failure who remain symptomatic despite combination therapy with a diuretic and an angiotensin-converting-enzyme (ACE) inhibitor, a strictly conducted trial has shown that adding spironolactone at a mean dose of 25 mg/day reduces overall mortality by approximately 5% per year, and reduces the incidence of hospitalisation for heart disease and disability. (2) There is a risk of gynaecomastia (9%) and potentially severe hyperkalaemia. (3) It is crucial to follow the protocol used in the clinical trial, i.e. this treatment is contraindicated in severe renal failure or hyperkalaemia; creatinine and potassium levels must be monitored strictly; and spironolactone must be combined with a loop diuretic.     

Eplerenone: new drug. Recent myocardial infarction with heart failure: a spironolactone me too

(1) Heart failure is diagnosed on the basis of both clinical symptoms and evaluation of cardiac function (preferably measured by echocardiography). Left ventricular dysfunction is defined as a left ventricular ejection fraction (LVEF) below 40%. The drugs of choice for chronic heart failure are certain angiotensin-converting-enzyme (ACE) inhibitors, some diuretics, some betablockers, and spironolactone. In one trial, spironolactone greatly reduced mortality at 24 months (35%, compared with 46% on placebo, p <0.001). (2) Eplerenone, a spironolactone derivative, is marketed for the treatment of left ventricular dysfunction in heart failure patients with recent myocardial infarction. (3) The EPHESUS study, a double-blind, placebo-controlled trial involving 6632 patients, showed a significant reduction in the overall mortality rate among patients with heart failure and recent myocardial infarction treated with eplerenone for 16 months (16.7% versus 14.4%; p = 0.008). This improvement was mainly due to a reduction in mortality during the first month of treatment. Eplerenone has not been compared with spironolactone, although the latter was known to be effective before the EPHESUS trial was conducted. (4) Severe hyperkalemia is frequent with eplerenone, occurring in 5.5% of patients. The risk of hyperkalaemia increases with renal failure and co-administration of potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists and nonsteroidal antiinflammatory drugs. (5) In the short term, the incidence of gynecomastia in patients taking eplerenone seems to be low. (6) In patients who develop heart failure after myocardial infarction, an indirect comparison of available data favours spironolactone over eplerenone (better efficacy, lower risk of hyperkalemia). (7) In France, treatment with eplerenone is about 9 times more expensive than spironolactone. (8) Spironolactone remains the treatment of choice for patients with heart failure and incapacitating dyspnea despite ACE inhibitor and diuretic therapy. Eplerenone may possibly be useful for patients who have non severe heart failure after recent myocardial infarction.     

Upper gastrointestinal bleeding and spironolactone

Spironolactone is a potassium-sparing diuretic marketed since the 1960s that is known to cause the same adverse effects as other diuretics as well as some effects of its own, such as hyperkalaemia, gynaecomastia and menstrual disturbances. A cohort study and 2 case-control studies concurred to show an approximately twofold, dose-dependent increase in the incidence of upper gastrointestinal bleeding in patients receiving spironolactone. The postulated mechanism is that spironolactone's aldosterone antagonist activity delays gastroduodenal healing. However, gastrointestinal bleeding is not a common adverse effect of aldosterone antagonists. In practice, although these studies have a low level of evidence, the role of spironolactone should be suspected in the event of a gastrointestinal bleed and caution should be exercised with spironolactone in patients who have predisposing factors to gastrointestinal bleeding.     

氢氯噻嗪与螺内酯长期联用对高血压患者左室重量指数的影响

目的:探讨氢氯噻嗪(HCTZ)与螺内酯长期联用对高血压患者左室重量指数的影响。方法:采用多中心双盲研究设计,选择9所开滦矿区医院,筛选出轻、中度高血压患者。入选患者经安慰剂洗脱2周,HCTZ(12.5mg,qd)导入6周后加服螺内酯(20mg,qd),共服药36个月。治疗期间每月随访1次,监测血压。洗脱期末和治疗12、24、36个月末行超声心动图测量并计算左室重量指数(LVMI),采静脉血行实验室检查。结果:治疗12个月末患者血压及LVMI出现明显下降;36个月末与12个月末比较,舒张压、LVMI进一步下降(P<0.05)。结论:HCTZ与螺内酯长期联用有效降低血压的同时,显著降低LVMI,且随治疗时间延长疗效更显著。     

Eplerenone : a pharmacoeconomic review of its use in patients with post-myocardial infarction heart failure

Eplerenone (Inspra) is a selective aldosterone blocker. When added to standard medical therapy, eplerenone significantly improved morbidity and mortality in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI), in a well designed, placebo-controlled trial known as EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study). Although eplerenone was generally well tolerated, it was associated with a higher incidence of hyperkalaemia than placebo.Cost-effectiveness analyses based on this trial have been performed in the US, The Netherlands, Germany, France and Spain. Direct medical costs were analysed based on prospectively collected resource-use data with local costs applied; modelling was conducted to calculate incremental costs per life-year or QALY gained, with survival curves assumed to remain parallel after treatment ended. Eplerenone was associated with a gain of 0.0304 life-years (approximately 11 days) compared with placebo during the study period.Based on these analyses, eplerenone was cost effective compared with placebo in patients with LV systolic dysfunction and heart failure after an MI when added to standard therapy for 16 months. The incremental cost per life-year gained for eplerenone versus placebo (for a range of three different life-expectancy projections) was 10,402-21,876 US dollars in the US (year 2001 costs, except for eplerenone [2004]) [equivalent to 12,274-25,814 euro; mid-2001 exchange rate], 5,365-12,795 euro for The Netherlands (year 2003 costs), 6,956-14,628 euro for Germany, 5,432-11,423 euro for France and 8,626-18,141 euro for Spain (year of costing not reported). The US, Dutch, French and Spanish analyses estimated that >90% of observations for incremental cost per life-year gained were below a threshold of 50,000 US dollars or 50,000 euro. Incremental costs per QALY gained for eplerenone versus placebo in the US, Dutch, French and Spanish analyses were 15,330-32,405 US dollars (18,089-38,238 euro), 12,148, 8,005-16,922 euro and 12,713-26, 873 euro, respectively.Clinical and pharmacoeconomic data comparing eplerenone with another active drug, such as spironolactone, in this patient population are not available.In conclusion, when added to standard therapy in patients with LV systolic dysfunction and heart failure after an acute MI, eplerenone was associated with significant reductions in mortality and morbidity compared with placebo. Despite some inherent limitations, available pharmacoeconomic data from Europe and the US indicate that eplerenone is a cost-effective treatment compared with placebo in terms of incremental cost per life-year gained in this patient population.     

Multiple dose kinetics of spironolactone and canrenoate-potassium in cardiac and hepatic failure

Summary Plasma concentrations of canrenone and canrenoate were measured in 43 patients treated with spironolactone 50–400 mg/day, and in one patient treated with canrenoate-K 3×200 mg/day. The cumulation of canrenone and canrenoate was followed in 9 patients recovering from myocardial infarction, without congestive heart failure or cirrhosis, who received spironolactone 2×100 mg/day. The cumulation half-life was 1–4 days, which may partly explain the delayed clinical action of spironolactone. The plasma elimination half-life of canrenone and canrenoate in six of these patients lay between 13.5 and 24 h. After 10 doses it was unchanged in three patients and had decreased only slightly in three others. Steady state minimum plasma levels of canrenone and canrenoate were measured in 33 patients with congestive heart failure or cirrhosis who received spironolactone 50–400 mg/day for at least three weeks. There was up to 15 fold inter-individual variation in the plasma levels of canrenone amongst those receiving spironolactone 200 mg/day. No statistically significant correlation was found between steady state levels of canrenone and plasma creatinine or the results of bromsulphalein liver function tests. In one patient with severe congestive heart failure given canrenoate-K 3×200 mg/day, cumulation of canrenone and canrenoate occurred for seven days, followed by a gradual decline in their plasma levels until the eleventh day of therapy. A loading dose is recommended for initiation of spironolactone therapy.     

The risks and benefits of therapy with aldosterone receptor antagonist therapy

Spironolacotone and eplerenone are mineralocorticoid-blocking agents. These compounds block both the epithelial and non-epithelial actions of aldosterone with the latter assuming increasing clinical importance. Spironolactone and eplerenone both effectively reduce blood pressure either as mono- or add-on therapy; moreover, they each offer survival benefits in diverse circumstances of heart failure and the potential for renal protection in proteinuric chronic kidney disease. However, as the use of mineralocorticoid-blocking agents has increased the hazards inherent to use of such drugs has become more apparent. Whereas; the endocrine side-effects of spironolactone are in most cases little more than a cosmetic annoyance the potassium-sparing effects of both spironolactone and eplerenone can prove fatal if sufficient degrees of hyperkalemia develop. However, for most patients the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered as a possibility in any patient receiving one or the other of these medications. As such, steps should be taken to lessen the likelihood of its occurring if therapy is being contemplated with agents in this class.     

Detection of spironolactone-associated hyperkalaemia following the Randomized Aldactone Evaluation Study (RALES).

INTRODUCTION: A population-based analysis has suggested that the publication of the RALES (Randomized Aldactone Evaluation Study) in late 1999 was associated with both the wider use of spironolactone to treat heart failure and a corresponding increase in hyperkalaemia-associated morbidity and mortality in patients also being treated with ACE inhibitors. OBJECTIVES: To gain further insight into the reporting of spironolactone-associated hyperkalaemia in an independent dataset by analysing the spontaneous reporting experience in relation to the publication of RALES, and to determine whether the implementation of a commonly used data mining algorithm (DMA) might have directed the attention of safety reviewers to the spironolactone/hyperkalaemia association in advance of epidemiological findings. METHODS: We calculated the reporting rate of spironolactone-associated hyperkalaemia per 1,000 reports per year from 1970 through to the end of 2005 by identifying relevant cases in the US FDA Adverse Event Reporting System. We did this for reports of spironolactone-associated hyperkalaemia (where spironolactone was listed as a suspect drug) and according to whether the reports listed an ACE inhibitor as a co-suspect or concomitant medication. A further statistical analysis of the overall reporting of spironolactone (suspect drug)-associated hyperkalaemia was also performed. We also performed 3-dimensional (3-D; drug-drug-event) disproportionality analyses using a DMA known as the multi-item gamma-Poisson shrinker, which allows the calculation and display of a 3-D disproportionality metric known as the 'interaction signal score' (INTSS). This metric is a measure of the strength of a higher order reporting relationship of a triplet (i.e. drug-drug-event) association above and beyond what would be expected from the largest disproportionalities associated with the individual 2-way associations. RESULTS: Visual inspection of a graph of the reporting frequency of spironolactone (suspect drug)-associated hyperkalaemia per 1,000 reports was highly suggestive of a change point. The t-test on the arcsine-transformed data showed a significant difference in reporting of spironolactone-hyperkalaemia combination through 1999 compared with 2000 onwards (p < 0.001). When examining the reporting time trends according to the presence or absence of an ACE inhibitor, the change point seemed to be mostly attributable to an increase in the number of spironolactone (suspect drug)-associated hyperkalaemia reports with ACE inhibitors listed as a co-suspect drug. No obvious change points in INTSSs for spironolactone-ACE inhibitor-hyperkalaemia reports were observed. DISCUSSION: Although we could not pinpoint the relative contribution of many possible artifacts in the reporting process, as well as increased drug exposure, increased adverse event incidence and/or a change in patient monitoring practices, to our findings, we observed a notable change in reporting frequency of spironolactone-associated hyperkalaemia in temporal proximity to the publication of RALES. Evidence of this was provided by a trend analysis depicted in a simple graph that was supported by statistical analysis. The observed trend was in large part due to increased reporting of spironolactone-associated hyperkalaemia with reported co-medication with ACE inhibitors. CONCLUSION: These findings are consistent with those originally reported in an epidemiological analysis. In this retrospective exercise, a simple graph was more illuminating than more complex data mining analyses.     

Aldosterone receptor antagonists and cardiovascular disease: do we need a change of the guard?

Aldosterone is a mineralocorticoid primarily produced in the zona glomerulosa of the adrenal gland. For many years, aldosterone (Aldo) was thought to have its sole site of action in the kidney, where it regulated sodium excretion and potassium reabsorption. It is now known that Aldo is produced in cardiovascular tissues, and has been implicated in the development of ventricular hypertrophy and cardiac fibrosis. The precise mechanisms whereby Aldo acts in cardiac tissues are diverse. It was assumed that Aldo production could be limited by angiotensin-converting enzyme (ACE) inhibition, but serial measurements during therapy reveal only a transient decrease in Aldo levels. Moreover, the effects of Aldo on cardiac tissues occur even when angiotensin II (Ang II) has been suppressed or eliminated. Multiple investigators have examined effects of Aldo receptor blockade in human subjects and various animal models using the two Aldo receptor antagonists (ARAs), spironolactone and eplerenone. Major clinical trials involving spironolactone (RALES) and eplerenone (EPHESUS) ARAs have shown significant benefits in the treatment of congestive heart failure (CHF). In RALES, patients with New York Heart Association (NYHA) Class III or IV systolic heart failure treated with spironolactone had a 30% relative risk decrease in mortality. Although spironolactone is an effective competitive inhibitor of the mineralocorticoid receptor (MR), progestational and antiandrogenic side effects limit its use in some patients. Eplerenone, a more selective ARA, lacks these undesirable side effects. Although eplerenone is 20-fold less potent at the MR, it demonstrates efficacy similar to spironolactone, possibly due to decreased protein binding. Eplerenone has fewer side effects than spironolactone, which has been attributed to the low cross-reactivity with androgen and progesterone receptors. In EPHESUS, patients with left ventricular systolic dysfunction [Ejection Fraction (EF) <40%] and CHF following an acute myocardial infarction (AMI), were treated with eplerenone, resulting in a 17% reduction in cardiovascular mortality. However, these studies were limited in that diastolic function was not evaluated, although approximately 1/2 of CHF is due to diastolic dysfunction alone. To date, neither ARA has been studied for the treatment of diastolic dysfunction in a major clinical trial. However, numerous animal studies employing ARAs have shown a decrease in cardiac hypertrophy and fibrosis, indicating the potential benefits of these agents in the treatment of diastolic heart failure. In this review, we discuss possible underlying mechanisms responsible for Aldo effects on cardiovascular function and compare the beneficial effects of spironolactone and eplerenone in the treatment of heart disease.     

Aldosterone antagonists in the treatment of heart failure.

PURPOSE: The clinical benefits, adverse effects, pharmacokinetics, and recommendations for the appropriate use of the aldosterone antagonists spironolactone and eplerenone in patients with heart failure are reviewed. SUMMARY: Heart failure is a clinical syndrome characterized by the functional inability of the ventricle to meet the metabolic demands of the body. Renal hypoperfusion occurs as a result of reduced cardiac output, resulting in the activation of the renin-angiotensin-aldosterone system, which compensates for the hypoperfusion. However, this contributes to the pathology of the disease by, among other actions, increasing the release of aldosterone. Aldosterone has been shown to cause coronary inflammation, cardiac hypertrophy, myocardial fibrosis, ventricular arrhythmias, and ischemic and necrotic lesions. There are currently two aldosterone antagonists commercially available in the United States, spironolactone and eplerenone. Spironolactone is a nonselective aldosterone antagonist, and eplerenone is selective to the aldosterone receptor. Although numerous clinical trials have evaluated the efficacy of each drug, no studies have directly compared spironolactone and eplerenone. Both have been shown to improve morbidity and mortality in patients with advanced heart failure. Adverse effects of both spironolactone and eplerenone include potentially life-threatening hyperkalemia, which can be induced by renal insufficiency, diabetes mellitus, advanced heart failure, advanced age, and concurrent drug therapy. CONCLUSION: Spironolactone and eplerenone are life-saving agents in patients with advanced heart failure and may benefit patients with mild heart failure. Potassium and renal function must be routinely assessed to minimize the risk of life-threatening hyperkalemia.     

Eplerenone : a review of its use in left ventricular systolic dysfunction and heart failure after acute myocardial infarction

Eplerenone (Inspra) is a selective aldosterone blocker. Oral eplerenone is approved for use in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI) in the US and in European countries (e.g. the UK and The Netherlands).The addition of eplerenone to standard medical therapy significantly improved mortality and morbidity in patients with LV systolic dysfunction and clinical evidence of heart failure following acute MI in the large, well designed EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study) trial. The beneficial effects of eplerenone on all-cause mortality and cardiovascular mortality were seen within 30 days of randomisation. Eplerenone was generally well tolerated. Although a higher incidence of hyperkalaemia occurred with eplerenone than with placebo, the incidence of hypokalaemia was significantly lower with eplerenone treatment. Thus, the addition of eplerenone to standard medical therapy is an important new strategy for further improving mortality and morbidity in post-MI patients with LV systolic dysfunction and heart failure.     

Lercanidipine : a review of its efficacy in the management of hypertension

Lercanidipine (Zanidip) is a vasoselective dihydropyridine calcium channel antagonist that causes systemic vasodilation by blocking the influx of calcium ions through L-type calcium channels in cell membranes. It is a highly lipophilic drug that exhibits a slower onset and longer duration of action than other calcium channel antagonists. Furthermore, lercanidipine may have antiatherogenic activity unrelated to its antihypertensive effect.In two large, nonblind, noncomparative studies involving approximately 16 000 patients with mild-to-moderate hypertension, systolic blood pressure (BP) [SBP] and diastolic BP (DBP) were significantly reduced after 12 weeks' treatment with lercanidipine 10-20 mg/day. Furthermore, in the largest study, 64% of patients were responders (DBP <90 mm Hg) after 12 weeks of treatment and an additional 32% had their BP normalised (BP <140/90 mm Hg). In comparative trials, lercanidipine 10-20 mg/day was as effective as nifedipine slow release (SR) 20-40 mg twice daily, amlodipine 10 mg/day, felodipine 10-20 mg/day, nifedipine gastrointestinal therapeutic system (GITS) 30-60 mg once daily or verapamil SR 240 mg/day at reducing SBP and DBP in patients with mild-to-moderate hypertension after 2-16 weeks of therapy. In addition, 4 weeks of lercanidipine therapy (10 mg/day) was as effective as captopril 25mg twice daily, atenolol 50 mg/day or hydrochlorothiazide 12.5 mg/day.Lercanidipine 5-30 mg/day effectively decreased BP in elderly patients (aged >60 years) with mild-to-moderate hypertension or isolated systolic hypertension to the same extent as amlodipine 5-10 mg/day, nifedipine GITS 30-60 mg/day or lacidipine 2-4 mg/day after 24-26 weeks of therapy. In addition, a limited number of studies suggest that lercanidipine may have antihypertensive efficacy in patients with severe or resistant hypertension, in hypertensive patients with type 2 diabetes mellitus and in postmenopausal women with mild-to-moderate essential hypertension. Lercanidipine is well tolerated, with most treatment-emergent events related to vasodilation. Common adverse events included headache, flushing and peripheral oedema. Importantly, the incidence of vasodilatory oedema was significantly lower in patients receiving lercanidipine than in those receiving some other calcium channel antagonists. CONCLUSION: Once-daily lercanidipine is an effective and well tolerated antihypertensive agent in patients with mild-to-moderate hypertension.     

基于FAERS数据库醛固酮受体拮抗剂不良反应信号挖掘与分析

目的 基于美国食品药品监督管理局不良事件报告系统（FAERS）数据库挖掘醛固酮受体拮抗剂依普利酮和螺内酯的不良反应（ADR）信号,对比和分析两者ADR的相关情况,为临床安全用药提供参考依据。方法 基于FAERS数据库,利用Open Vigil FDA分析工具提取2004年1月1日—2022年11月4日上报的目标药物依普利酮与螺内酯相关的不良事件情况数据。采用报告比值比法进行数据挖掘,按国际医学用语词典25.1版中的首选系统器官分类（SOC）和首选术语（PT）对不良事件进行统计分类并分析。结果 共检索到醛固酮受体拮抗剂依普利酮和螺内酯相关的ADR报告112 518份,其中依普利酮ADR报告8 516份,风险信号50个,信号累及12个系统/器官;螺内酯ADR报告104 002份,风险信号60个,信号累及13个系统器官分类;其中36个为重叠信号。依普利酮说明书未提及的有13个风险信号,主要涉及呼吸、胃肠等系统器官分类;螺内酯说明书未提及的有19个风险信号,主要涉及血液及淋巴系统疾病、精神病类等系统器官分类。结论 临床应用醛固酮受体拮抗剂时,除重点关注说明书提及的ADR,还需对未提及的风险信号和原有疾病进展情况引起重视。     

New strategies for treatment of heart failure with aldosterone antagonists and the risk of hyperkalaemia

Since the publication of The Randomized Aldactone Study (RALES) in 1999, the association of angiotensin-converting enzyme (ACE) inhibitors and spironolactone has been largely used for the treatment of congestive heart failure (CHF). Although this study had shown a diminished morbimortality in patients with CHF that are treated with spironolactone and ACE inhibitors and a low risk (2%) of development of severe hyperkalaemia, other clinical studies have shown higher rates of hyperkalaemia and serious adverse clinical events culminating in death. Therefore, the identification of risk factors for the development of hyperkalaemia in CHF patients, close monitoring of serum potassium and determination of renal function before and after the initiation of combined therapy or after a dose increment, should be routinely performed. It is strongly recommended that these drugs be initiated in low doses and that the increment in dose should only occur after considering all safety issues.     

Eplerenone: the evidence for its place in the treatment of heart failure after myocardial infarction

INTRODUCTION: Heart failure is a frequent complication after acute myocardial infarction (MI) and carries a poor prognosis. Current treatments inhibit the renin-angiotensin-aldosterone system but suppression of aldosterone may be incomplete. The aldosterone antagonist spironolactone has been shown to improve survival in patients with chronic, severe heart failure. Eplerenone is a selective aldosterone antagonist expected to have a lower incidence of hormonal side effects than spironolactone. AIMS: To assess the evidence on the therapeutic value of eplerenone for treatment of heart failure in adults. EVIDENCE REVIEW: The evidence base consists of one large double-blind placebo-controlled multicenter randomized trial in over 6000 patients with postmyocardial infarction (MI) heart failure, comparing eplerenone plus standard therapy with placebo plus standard therapy. All the main outcomes were patient-oriented. Evidence from this trial shows that eplerenone improves survival and reduces cardiovascular hospitalization/mortality, compared with standard treatment alone. The incidence of hormonal side effects is no greater than with placebo. The risk of hyperkalemia is significantly increased, especially in patients with low creatinine clearance. Eplerenone was both more effective and more costly than standard treatment alone. The cost-effectiveness ratio has been estimated at $US10 402-21 876 per life-year gained. PLACE IN THERAPY: Eplerenone reduces mortality compared with current treatment alone in patients with post-MI heart failure, at additional cost. Direct comparative evidence is needed to assess its efficacy versus spironolactone. It may be valuable in patients who are intolerant to the hormonal side effects of spironolactone.     

New strategies for treatment of heart failure with aldosterone antagonists and the risk of hyperkalaemia

Since the publication of The Randomized Aldactone Study (RALES) in 1999, the association of angiotensin-converting enzyme (ACE) inhibitors and spironolactone has been largely used for the treatment of congestive heart failure (CHF). Although this study had shown a diminished morbimortality in patients with CHF that are treated with spironolactone and ACE inhibitors and a low risk (2%) of development of severe hyperkalaemia, other clinical studies have shown higher rates of hyperkalaemia and serious adverse clinical events culminating in death. Therefore, the identification of risk factors for the development of hyperkalaemia in CHF patients, close monitoring of serum potassium and determination of renal function before and after the initiation of combined therapy or after a dose increment, should be routinely performed. It is strongly recommended that these drugs be initiated in low doses and that the increment in dose should only occur after considering all safety issues.