The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure

Department of Internal Medicine, Division of Cardiology, University of Michigan, Ann Arbor, USA.
New England Journal of Medicine (Impact Factor: 55.87). 09/1999; 341(10):709-717. DOI: 10.1056/NEJM199909023411001


Aldosterone is important in the pathophysiology of heart failure. In a doubleblind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting-enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes.
The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P<0.001). This 30 percent reduction in the risk of death among patients in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes. The frequency of hospitalization for worsening heart failure was 35 percent lower in the spironolactone group than in the placebo group (relative risk of hospitalization, 0.65; 95 percent confidence interval, 0.54 to 0.77; P<0.001). In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure, as assessed on the basis of the New York Heart Association functional class (P<0.001). Gynecomastia or breast pain was reported in 10 percent of men who were treated with spironolactone, as compared with 1 percent of men in the placebo group (P<0.001). The incidence of serious hyperkalemia was minimal in both groups of patients.
Blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of both morbidity and death among patients with severe heart failure.

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Available from: Janet Wittes, Sep 20, 2014
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    • "Chronically elevated plasma aldosterone levels are linked to the development and progression of certain cardiovascular diseases such as hypertension, congestive heart failure, and myocardial fibrosis [1]. In clinical studies, the mineralocorticoid receptor (MR) antagonists like spironolactone and eplerenone reduce mortality in patients with congestive heart failure and post acute myocardial infarction [2], thereby showing the detrimental role of aldosterone in the pathophysiology of cardiovascular diseases and the therapeutic benefit of blocking its action. However, the influence of the unaffected elevated plasma aldosterone levels leading to an up-regulation of mineralocorticoid receptor expression [3] and to nongenomic aldosterone effects is not yet fully explained [4]. "
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    ABSTRACT: 1-Phenylsulfinyl-3-(pyridin-3-yl)naphthalen-2-ols and related compounds were synthesized and evaluated for inhibition of aldosterone synthase (CYP11B2), a potential target for cardiovascular diseases associated with elevated plasma aldosterone levels like congestive heart failure and myocardial fibrosis. Introduction of substituents at the phenylsulfinyl moiety and changes of the substitution pattern at the naphthalene core were examined. Potent compounds were further examined for selectivity versus other important steroidogenic CYP enzymes, i.e. the highly homologous 11 beta-hydroxylase (CYP11B1), CYP17 and CYP19. The most potent compound (IC50 = 14 nM) discovered was the meta-trifluoromethoxy derivative 11, which also exhibited excellent selectivity toward CYP11B1 (SF = 415), and showed no inhibition of CYP17 and CYP19.
    European Journal of Medicinal Chemistry 01/2015; 89. DOI:10.1016/j.ejmech.2014.10.027 · 3.45 Impact Factor
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    • "4.1.7. 7-(Isoquinolin-4-yl)-2H-benzo[b][1] [4] "
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    ABSTRACT: Aldosterone synthase (CYP11B2) catalyzes the conversion of 11-deoxycorticosterone to aldosterone via corticosterone and 18-hydroxycorticosterone. CYP11B2 is regarded as a new target for several cardiovascular diseases which are associated with chronically elevated aldosterone levels such as hypertension, congestive heart failure and myocardial fibrosis. In this paper, we optimized heterocycle substituted 3,4-dihydropyridin-2(1H)-ones as CYP11B inhibitors by systematic introduction of heteroatoms and by bioisosteric exchange of the lactame moiety by a sultame moiety. The most promising compounds regarding inhibition of human CYP11B2 and selectivity versus human enzymes CYP11B1, CYP17, and CYP19 were tested for inhibition of rat CYP11B2. Thus, we discovered compounds 4 and 9 which show potent inhibition of hCYP11B2 (IC50 < 1 nM) and the corresponding rat enzyme (4: 64%, 9: 51% inhibition, at 2 μM). Copyright © 2014. Published by Elsevier Masson SAS.
    European Journal of Medicinal Chemistry 12/2014; 90C:788-796. DOI:10.1016/j.ejmech.2014.12.022 · 3.45 Impact Factor
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    • "Despite that, addition of potassium supplements or potassium-sparing diuretics, including aldosterone receptor blockers (such as spironolactone and eplerenone) or epithelial sodium channel blockers (such as amiloride and triamterene) can sometimes be necessary, depending on the clinical characteristics of the patient.94 Combination with an aldosterone receptor blocker may be particularly beneficial in hypertensive patients with heart failure.95–97 "
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    ABSTRACT: Combined therapy is required in the majority of patients with hypertension to achieve blood pressure (BP) targets. Although different antihypertensive drugs can be combined, not all combinations are equally effective and safe. In this context, the combination of a renin angiotensin system inhibitor with a diuretic, usually a thiazide, particularly hydrochlorothiazide (HCTZ) or thiazide-like diuretics, such as chlorthalidone or indapamide, is recommended. However, not all diuretics are equal. Although HCTZ, chlorthalidone, and indapamide as add-on therapy effectively reduce BP levels, the majority of studies have obtained greater BP reductions with chlorthalidone or indapamide than with HCTZ. Moreover, there are data showing benefits with chlorthalidone or indapamide beyond BP. Thus, chlorthalidone seems to have pleiotropic effects beyond BP reduction. Moreover, compared with placebo, chlorthalidone has small effects on fasting glucose and total cholesterol, and compared with HCTZ, chlorthalidone achieves significantly lower total cholesterol and low-density lipoprotein cholesterol levels. Similarly, indapamide has demonstrated no negative impact on glucose or lipid metabolism. More importantly, although head-to-head clinical trials comparing the effects of indapamide or chlorthalidone with HCTZ are not available, indirect comparisons and post hoc analyses suggest that the use of chlorthalidone or indapamide is associated with a reduction in cardiovascular events. Despite this, the most frequent diuretic used in clinical practice as add-on therapy for hypertension is HCTZ. The purpose of this review is to update the published data on the efficacy and safety of HCTZ, chlorthalidone, and indapamide as add-on therapy in patients with hypertension.
    Integrated Blood Pressure Control 07/2014; 7(1):35-47. DOI:10.2147/IBPC.S40248
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