Anti-aldosterone therapy in severe heart failure]

The mortality rate among patients with severe heart failure is still very high despite treatment with loop diuretics and angiotensin-converting enzyme (ACE) inhibitors. The 'randomized aldactone evaluation study' (RALES) has shown that 25 mg spironolactone added to this treatment was safe and reduced all-cause mortality by 30% in patients with severe (previous New York Heart Association (NYHA) functional class IV) heart failure due to systolic left ventricular dysfunction. Blockade of aldosterone in these patients may be necessary to overcome so-called aldosterone escape during chronic ACE-inhibition. The beneficial effects of spironolactone may relate to enhanced diuresis, anti-arrhythmogenic properties and direct effects on the myocardium and blood vessels. At present, addition of spironolactone may be appropriate for patients with severe heart failure, whereas patients with moderate heart failure may benefit more from beta-blockade.     

The role of aldosterone-antagonists in the treatment of congestive heart failure

The role of aldosterone-antagonists in the treatment of congestive heart failure. Despite the advances of the treatment of congestive heart failure, nearly half of the patients diagnosed with this disease five years ago are alive today. Experimental and human studies have demonstrated, that under special pathologic condition, the heart extracts aldosterone, and aldosterone extraction in the heart stimulates increased collagen turnover culminating in ventricular remodeling. Aldosterone blockade has been shown to be effective in reducing total mortality and hospitalization for heart failure in patients with systolic left ventricular dysfunction due to chronic heart failure (RALES study with spironolactone) and in patients with systolic left ventricular dysfunction post acute myocardial infarction (EPHESUS study with eplerenone). These clinical studies have shown that mineralocorticoid receptor activation remains important despite the use of angiotensin converting enzyme inhibitor or angiotensin receptor blocking agent and a beta blocker. In the ACC/AHA (and in the European and Hungarian) guidelines for the evolution and management of chronic heart failure, the indication of spironolactone was defined of Class Ila, Level of Evidence: B in CHF of stage C. The eplerenone (in US: INSPRA) was approved for the management of CHF patients after myocardial infarction with ejection fraction < 40%. Eplerenone, compared with spironolactone, is associated with a lower incidence of gynecomastia and other sex hormone-related adverse effect (breast pain, menstrual abnormalities). The spironolactone should not be used in patients with a creatinine above 220 mikromol/l. Despite the guidelines recommendation, spironolactone has been widely used in patients without consideration of their functional class or ejection fraction, without optimization of background treatment with ACE inhibitors and beta-blockers.     

Aldosterone antagonism in heart failure

Aldosterone, a neurohormone known to affect electrolytes, has recently been implicated as playing a major role in the progression of heart failure, particularly in patients with systolic dysfunction. Major clinical trials designed to analyze clinical outcomes using an aldosterone antagonist have been done in two groups with heart failure. The first was the Randomized Aldactone Evaluation Study, which was done in symptomatic chronic advanced heart failure patients and showed that an aldosterone antagonist, spironolactone, reduced mortality significantly compared with placebo. Very few of these patients were on standard therapy with beta blockade. Another study, the Eplerenone Post myocardial infarction Heart failure Efficacy and SUrvival Study (EPHESUS), done in post-myocardial infarction patients with heart failure, demonstrated a significant reduction in mortality and hospitalizations for patients randomized to the aldosterone antagonist eplerenone. These trial results provide the background for aldosterone antagonist therapy in chronic advanced heart failure patients as well as post-myocardial infarction heart failure patients with reduced ejection.     

Treatment of diastolic dysfunction in hypertension

Diastolic dysfunction is present in half of patients with hypertension and has been shown to be associated with increased cardiovascular morbidity and mortality, as well as the development of heart failure. With the high prevalence of hypertension and its associated complications, treatment of diastolic dysfunction in hypertension is an important and desirable goal. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers have been shown to be effective in improvement of measures of diastolic function and are recommended as first-line agents in the control of hypertension in patients with diastolic heart failure. Beta-blockers, calcium channel blockers, and diuretics have also shown some efficacy in improved indices of diastolic filling. However, the independent impact of these pharmacologic interventions on prognosis and outcome in diastolic dysfunction has yet to be clarified. The Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) study, Candesartan in Heart Failure: Assessment in Reduction of Mortality and Morbidity (CHARM-Preserved) trial and the Losartan Intervention For End-point Reduction in Hypertension (LIFE) Study all failed to show improved morbidity and mortality with these drugs although, the LIFE study showed reduced heart failure hospitalization in hypertensive patients with normal in-treatment diastolic function. The Trial Of Preserved Cardiac function heart failure with an Aldosterone anTagonist (TOPCAT) is an on-going large, international study evaluating the effect of spironolactone on cardiovascular mortality, aborted cardiac arrest, or hospitalization for diastolic heart failure. This and other studies will provide further insight into the pathophysiology and management of patients with diastolic dysfunction.     

Valsartan in the treatment of heart failure or left ventricular dysfunction after myocardial infarction

The physiological role of the renin angiotensin aldosterone system (RAAS) is to maintain the integrity of the cardiovascular system. The effect of angiotensin II is mediated via the angiotensin type I receptor (AT1 ) resulting in vasoconstriction, sodium retention and myocyte growth changes. This causes myocardial remodeling which eventually leads to left ventricular hypertrophy, dilation and dysfunction. Inhibition of the RAAS with angiotensin converting enzyme (ACE) inhibitors after acute myocardial infarction has been shown to reduce cardiovascular morbidity and mortality. Angiotensin receptor blockers (ARBs) specifically inhibit the AT1 receptor. It has not been known until the performance of the VALIANT (valsartan in acute myocardial infarction trial) whether blockade of the angiotensin receptor with an ARB or combination of an ACE inhibitor and ARB leads to similar outcomes as an ACE inhibitor. The VALIANT trial demonstrated equal efficacy and non-inferiority of the ARB valsartan 160 mg bid compared with captopril 50 mg tds, when administered to high risk patients with left ventricular dysfunction or heart failure in the immediate post myocardial infarction period. The combination therapy showed no incremental benefit over ACE inhibition or an ARB alone and resulted in increased adverse effects. This review examines the role of valsartan in left ventricular dysfunction post myocardial infarction. We also discuss pharmacokinetics, dosing, side effects, and usage in the elderly.     

No advantage of the combination of ACE-inhibition and angiotensin receptor blockade in patients with high cardiovascular risk

The results of the 'Ongoing telmisartan alone and in combination with ramipril global eendpoint trial' (ONTARGET) have recently been published. In this trial, which was performed in patients with a high cardiovascular risk, it was investigated whether angiotensin II receptor blockade with telmisartan is equally effective as angiotensin converting enzyme (ACE) inhibition with ramipril and whether the combination oftelmisartan and ramipril (dual blockade) is more effective than ACE-inhibition alone to reduce cardiovascular morbidity and mortality and hospitalization for heart failure. On the basis of the ONTARGET results it can be concluded that dual blockade has no place in the treatment of high cardiovascular risk patients without heart failure, because this approach gives no additional reduction of cardiovascular risk and may even be associated with increased mortality. It also has more side effects. Since telmisartan was equally effective and safe as ramipril, one can choose from both agents in the treatment of patients with a high cardiovascular risk.     

依那普利、呋噻米、螺内酯治疗慢性充血性心力衰竭35例临床疗效观察

目的观察依那普利、呋噻米、螺内酯联合治疗心力衰竭的有效性和安全性。方法 35例心力衰竭患者给予联合服用依那普利5~10mg每日1~2次,螺内酯20～80mg每日1次,每日口服呋噻米20～100mg。治疗3个月后,观察治疗前后心功能的改善情况,测定左室射血分数(EF值)、观察6分钟步行距离(6MWD)。结果心功能改善总有效率92.5%,其中显效67%,有效25.5%,未发现严重低、高血钾患者。6MWD增加128米～217.5米,平均(172.7±45.5)米。结论依那普利、呋噻米、螺内酯联合治疗心力衰竭可以明显减轻患者的症状,提高生活质量,安全有效。     

Profibrotic effects of aldosterone

Animal studies have shown that during high sodium intake aldosterone induces cardiac fibrosis and renal nephrosclerosis through activation of mineralocorticoid receptors. In the human heart mineralocorticoid receptors and activity of the enzyme 11beta-hydroxysteroid-dehydrogenase type 2, which is required for the activation of mineralocorticoid receptors by aldosterone, are both present. In clinical medicine the profibrotic effect of aldosterone has been related to diastolic dysfunction, arrhythmia and progression of cardiac and renal failure. The addition of an aldosterone receptor antagonist to optimal treatment in patients with heart failure causes a decrease in serum markers of collagen turnover and a decline in cardiac morbidity and mortality. These findings are a strong indication of a profibrotic effect of aldosterone in cardiac failure. Studies concerning the profibrotic effect of aldosterone in patients with primary hyperaldosteronism are contradictory and at the moment no data are available about a potential antifibrotic effect of aldosterone receptor antagonists in patients with impaired renal function.     

Cost-Effectiveness of Aldosterone Antagonists for the Treatment of Post–Myocardial Infarction Heart Failure

ObjectiveTo assess the cost-effectiveness of eplerenone versus spironolactone as an adjunctive therapy to standard care in patients with heart failure (HF) following a myocardial infarction (post-MI) from the perspective of the National Health Service in the United Kingdom.MethodsA systematic review was conducted, and a Bayesian meta-regression approach was used to establish the relative effectiveness of eplerenone and spironolactone by using evidence from randomized controlled trials. A decision analytic model was developed to assess the costs and consequences associated with the primary outcome of the trials over a lifetime time horizon.ResultsThe incremental cost-effectiveness ratio of eplerenone compared with that of standard care alone was £4457 and £7893 for each additional quality-adjusted life-year when 2-year and lifetime treatment duration was assumed, respectively. In both scenarios, spironolactone did not appear cost-effective compared with eplerenone. The results were sensitive to the higher relative effectiveness estimated for eplerenone compared with spironolactone from the meta-regression. When a class effect was assumed for the effect on mortality and hospitalizations, spironolactone emerged as the most cost-effective treatment.ConclusionsEplerenone appears more cost-effective than spironolactone for the treatment of post-MI HF. These findings, however, remain subject to important uncertainties regarding the effects of treatment on major clinical events. An adequately powered, well-conducted randomized controlled trial that directly compares spironolactone and eplerenone may be required to provide more robust evidence on the optimal management of post-MI HF. Despite these uncertainties, the use of an aldosterone antagonist was consistently demonstrated to be a highly cost-effective strategy for the management of post-MI HF in the National Health Service.     

Diastolic heart failure

Diastolic heart failure is predominantly a disease of the elderly: at the age of 70 years, almost half of all patients with heart failure have diastolic heart failure. Hypertension and obesity are common underlying disorders in patients with diastolic heart failure. Patients with diastolic heart failure have an equal, or only slightly better, prognosis in terms of mortality compared to patients with systolic heart failure. Echocardiography can distinguish diastolic heart failure from systolic heart failure. Patients with heart failure and a normal ejection fraction almost certainly have a diastolic dysfunction. There is a lack of reliable data about the optimal medicinal treatment strategy for patients with diastolic heart failure. Angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and (non-dihydropyridine) calcium antagonists have therapeutic potential. Digoxin may be contraindicated.     

Moexipril and left ventricular hypertrophy

Angiotensin-converting enzyme (ACE) inhibitors today are the standard therapy of patients with myocardial infarction and heart failure due to their proven beneficial effects in left ventricular remodeling and left ventricular function. ACE inhibitors have also been demonstrated to lead to regression of left ventricular hypertrophy (LVH). It is believed that the mechanism of action of LVH regression with ACE inhibitors arises from more than simple blood pressure reduction. LVH is an important risk factor for cardiovascular disease morbidity and mortality independent of blood pressure. Moexipril hydrochloride is a long-acting, non-sulfhydryl ACE inhibitor that can be taken once daily for the treatment of hypertension. Moexipril has now also been demonstrated to have beneficial effects on LVH and can lead to LVH regression.     

ACE inhibitors in congestive heart failure.

Despite improved understanding of both disease mechanisms and the quality of care, congestive heart failure (CHF) remains a serious clinical problem. The traditional treatments, diuretics and digitalis, continue to play a major role in the management of many patients with CHF; however, in the last decade, angiotensin-converting enzyme (ACE) inhibitors have been added as an important treatment option. These agents counteract the overstimulation effects of diuretics on the renin-angiotensin-aldosterone system. In addition, some studies indicate that ACE inhibitors may improve symptoms and survival. Recent evidence suggests that in patients with mild to moderate CHF, ACE inhibitor and a diuretic should be administered with or without digitalis to achieve the maximum clinical benefit.     

Short-Term Aggressive Disease Management Programs for Heart Failure

Cardiovascular disease is the leading cause of death in developed countries. It is estimated that about 15 million people worldwide die every year from heart disease, with a substantial proportion of these deaths occurring in developing nations. Congestive heart failure (CHF) is a condition that develops as a late complication from a variety of heart disease states. CHF remains a devastating disease. It exacts a high toll in terms of mortality and morbidity and carries a high price burden. As the population ages and treatments for conditions such as acute coronary syndrome and hypertension improve, the prevalence of heart failure can be expected to increase, because survivors of hypertension and myocardial infarction live long enough to develop complications such as congestive heart failure.Recent advances have clearly shown that treatment strategies including ACE inhibitors, β-adrenoceptor antagonists, and aldosterone inhibitors improve morbidity and survival. However, even among patients treated with recommended therapy at recommended doses, mortality remains high. Opportunities exist for further improvement of prognosis beyond current guidelines for heart failure. As new evidence emerges, it is evident that survival can be further improved by using other strategies such as angiotensin receptor antagonists as alternative or add-on therapy and ventricular resynchronization for qualifying candidates.The management of heart failure patients in the community presents unique challenges. Patients who are managed in community hospitals are often elderly and/or very ill, with several comorbidities and clinical characteristics that may be different from patients who qualify for clinical trials. Furthermore, there appears to be a delay in incorporating scientific evidence into practice and studies continue to show that many heart failure patients do not receive recommended medications at adequate doses.Disease management programs have evolved as a way of improving heart failure care. Different models have been established and some institutions have published the results of their specific programs. The consistent findings include reductions in hospitalization rates, improvements in quality of life, and reductions in cost. However, to date, such studies have not compared different models and until large prospective trials are available, the true benefits of these programs will continue to be debated.     

依那普利联合螺内酯治疗高血压性心力衰竭临床疗效及安全性分析

目的探讨高血压性心力衰竭的治疗方法,分析依那普利联合螺内酯治疗高血压性心力衰竭的临床疗效及安全性。方法36例高血压性心脏病所致的心力衰竭患者,在强心、利尿、扩张血管的基础上,用依那普利5～10mg,每日1～2次,螺内酯20～100mg,每日2次,联合治疗8周后观察血压和心功能的改善情况。结果全部患者收缩压和舒张压均显著下降（P均〈0．01）,36例患者经2个疗程治疗后心力衰竭改善显效19例（52．8％）,有效15例（41．6％）,无效2例（5．6％）;临床治疗期间无严重高血钾及其他严重不良反应发生。结论依那普利联合螺内酯治疗高血压性心力衰竭可降低血压、改善心功能和临床症状,降低病死率,是有效和安全的。     

Drug therapy for hypertension in the elderly

Essential hypertension is a major health care problem in the elderly and requires effective treatment to reduce morbidity and mortality. The traditional stepped-care approach to therapy consisted of diuretics; sympatholytic agents, or beta-blockers for all age groups. Indeed, initial therapy with these agents is effective in 50 to 60 percent of elderly patients but may produce adverse effects. A high incidence of adverse responses, including sexual dysfunction and central nervous system impairment, has been reported with diuretic or beta-blocker therapy, and a reduction in several measures of quality of life has been noted during therapy with methyldopa or propranolol. Administration of an angiotensin-converting enzyme (ACE) inhibitor is as effective as the traditional stepped-care approach without producing the ill effects associated with diuretics, sympatholytics, or beta-blockers. The combination of an ACE inhibitor with a diuretic produces additive antihypertensive effects while minimizing diuretic-induced metabolic alterations. Orthostatic hypotension with the first dose can be minimized by making sure that patients are not hypovolemic from previous diuretic therapy. Nevertheless, in controlled trials, the combination of ACE inhibitor and diuretic has been effective in up to 85 percent of patients. In addition, the use of ACE inhibitors may be beneficial in the hypertensive patient with concomitant congestive heart failure. Most important, the patient's quality of life is maintained during therapy with an ACE inhibitor alone or in combination with a diuretic. Thus, an ACE inhibitor plus a diuretic is a valuable alternative to traditional antihypertensive therapy in elderly patients.     

A four-part regimen for clinical heart failure

Combination therapy with a diuretic, digoxin, ACE inhibitor, and beta-blocker can help patients with heart failure caused by severe systolic dysfunction feel better and live longer. Especially with ACE inhibitors and beta-blockers, the key to success is starting at low doses and titrating carefully to proven target doses. The demanding complexity of the four-drug regimen is well worth the results.     

No reason to start treatment with statins in patients with moderate to severe heart failure

The 'Controlled rosuvastatin multinational trial in heart failure' (CORONA) recently reported that treatment with 10 mg of rosuvastatin per day has no significant effect on primary endpoints cardiovascular death, non-fatal myocardial infarction and non-fatal stroke in older patients with ischaemic systolic heart failure, despite a reduction in LDL-cholesterol of 45% to a level of 2.0 mmol/l. High sensitivity C-reactive protein was also reduced by 37%. The number of hospitalizations for cardiovascular disorders was significantly reduced. There were no more side effects in the rosuvastatin group than in the placebo group, even though the population consisted of elderly people with comorbidity and at risk for adverse drug interactions due to polypharmacy. There were no signs of any pleiotropic effects of statins in patients with heart failure. There seems to be no indication to start treatment with statins in patients with moderate to severe heart failure.     

螺内酯对醛固酮诱导的大鼠肾小球系膜细胞氧化应激的影响

目的 观察螺内酯对醛固酮诱导的大鼠肾小球系膜细胞(mesangial cells,MCs)氧化应激的影响,探讨其肾脏保护机制.方法 体外培养大鼠MCs,设正常对照组、醛固酮(10-7 mol/L)刺激组、不同浓度螺内酯(10-7、10-8、10-9mol/L)干预组.以2',7'-二氯双氢荧光素二乙酸酯(2',7'-dichlorofluorescein diacetate,DCFH-DA)为细胞内H2O2的荧光探针标记细胞,采用流式细胞术检测系膜细胞内活性氧(reactive oxygen species,ROS)水平;采用比色法检测培养细胞上清液中丙二醛(malondialdehyde,MDA)的含量和超氧化物歧化酶(superoxide dismutase,SOD)活性.结果 与正常对照组比较,醛固酮刺激系膜细胞48 h后,细胞内ROS水平明显增加,上清液中MDA含量增高、SOD活性下降,差异均有统计学意义(均有P＜0.05).螺内酯干预可明显抑制醛固酮刺激下的系膜细胞的上述反应,差异均有统计学意义(均有P＜0.05),且呈浓度依赖性.结论 螺内酯可呈浓度依赖性地抑制醛固酮诱导的大鼠MCs氧化应激,该作用可能是其肾脏保护机制之一.     

贝那普利联合螺内酯治疗扩张型心肌病心力衰竭的临床分析

目的观察贝那普利和螺内酯治疗扩张型心肌病心力衰竭的有效性。方法将60例扩张型心肌病心力衰竭患者随机分成2组。对照组30例予以地高辛、氢氯噻嗪、倍他乐克等药物治疗,治疗组30例在此基础上加用贝那普利和螺内酯,两组均治疗6个月。结果两组比较,治疗组心功能、左心室射血分数有明显改善,心胸比、BNP下降,治疗组总有效率93%,对照组的总有效率为66%,两组差异有统计学意义(p<0.05)。结论贝那普利联合螺内酯治疗扩张型心肌病心力衰竭疗效显著且安全,并能改善心室重构。     

Treatment of systolic and diastolic heart failure in the elderly

Underlying causes, risk factors, and precipitating causes of heart failure (HF) should be treated. Drugs known to precipitate or aggravate HF should be stopped. Patients with HF and an abnormal left ventricular ejection fraction (LVEF) (systolic heart failure) or normal LVEF (diastolic HF) should be treated with diuretics if fluid retention is present; with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker if the patient cannot tolerate an ACE inhibitor because of cough, angioneurotic edema, rash, or altered taste sensation; and with a beta blocker unless contraindicated. If severe systolic HF persists, an aldosterone antagonist should be added. If HF persists, isosorbide dinitrate plus hydralazine should be added. Calcium channel blockers should be avoided if systolic HF is present. Digoxin should be avoided in men and women with diastolic HF if sinus rhythm is present and in women with systolic HF. Digoxin should be given to men with systolic HF if symptoms persist, but the serum digoxin level should be maintained between 0.5 and 0.8 ng/mL. A multidisciplinary approach should be used with nurse monitoring of the condition. In a home-bound patient, a homemaker should be hired.