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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    • "4.1.7. 7-(Isoquinolin-4-yl)-2H-benzo[b][1] [4] "
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    • "Increasing evidence links aldosterone excess and/or chronic activation of mineralocorticoid receptors to the development and progression of various cardiovascular disease processes in humans (Pitt et al., 1999, 2003; Suzuki et al., 2002). Both direct and indirect evidence of the harmful effects of RAAS activation are evident in veterinary cardiac patients (The COVE Study Group, 1995; Hamlin & Nakayama, 1998; Ettinger et al., 1999; The BENCH Study Group, 1999; Amberger et al., 2004; Bernay et al., 2010; Hezzell et al., 2010). "
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