Correspondence
Spironolactone in Patients with Heart Failure
N Engl J Med 2000; 342:132-134January 13, 2000
- Article
To the Editor:
The study by Pitt and colleagues (Sept. 2 issue)1 of the effect of spironolactone on morbidity and mortality in patients with severe heart failure addresses a very important issue. Spironolactone, a relatively inexpensive and safe agent, has not previously been shown to increase the value of triple therapy with an angiotensin-converting–enzyme (ACE) inhibitor, furosemide, and digoxin. We have not used it because of concern that it may precipitate serious hyperkalemia.
We are concerned, however, that the practical message of this study — that is, that spironolactone can decrease morbidity and mortality in patients with severe heart failure who are already receiving triple therapy — is undercut by the failure of the investigators to maximize the effect of triple therapy. For example, at base line, the mean daily doses of ACE inhibitors in the placebo and spironolactone groups were 62.1 and 63.4 mg of captopril, 16.5 and 13.5 mg of enalapril, and 13.1 and 15.5 mg of lisinopril, respectively. These doses are considerably lower than the target doses used in other studies and suggested by the American College of Cardiology and American Heart Association.2
Pitt et al. do not report the mean doses of digoxin or furosemide. They state that “the investigator was encouraged first to adjust the doses” of ACE inhibitors, digoxin, and diuretics before changing the dose of spironolactone. If so, what effect did this approach have? Could the favorable outcome with respect to morbidity and mortality be the result of maximizing the effects of these medications rather than adding spironolactone?
2 ReferencesHelen M. Fernandez, M.D.
Rosanne M. Leipzig, M.D., Ph.D.
Mt. Sinai Medical Center, New York, NY 10029-65741
Pitt B ,Zannad F ,Remme WJ , et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-717
Full Text | Web of Science | Medline2
Guidelines for the evaluation and management of heart failure: report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
Web of Science | Medline
To the Editor:
Caution may be necessary with respect to the broad use of spironolactone in the treatment of patients with congestive heart failure. The small but statistically significant elevation in serum potassium levels in the spironolactone group in the study by Pitt et al. must not be dismissed, since the prescribed doses of the ACE inhibitors were low in terms of the current standard of care. The fact that the average blood pressure was 122/75 mm Hg suggests that the dose of ACE inhibitors was less than optimal. The results of another recently completed study1 provide evidence that higher doses of ACE inhibitors may result in larger reductions in combined end points and rates of hospitalization.
Patients with diabetes, who are prone to have hyporeninemic hypoaldosteronism, may be at particular risk for hyperkalemia when they are treated with the combination of spironolactone and a high dose of an ACE inhibitor. Half of patients with long-standing diabetes mellitus have subclinical abnormalities of the renin–aldosterone axis.2 Treatment with ACE inhibitors alone can cause hyperkalemia in patients with diabetes,3 and it is recommended that the serum potassium level be checked within 7 to 10 days after the initiation of such treatment.4 Additional blockade of aldosterone receptors and subsequent down-regulation of the Na+/K+–ATPase pump could further increase this risk. Treatment with beta-blockers, which is now standard in many patients with New York Heart Association class III symptoms, also has the potential to increase the incidence of hyperkalemia.
Patients with diabetes mellitus were not excluded from the study, but they were not mentioned in the subgroup analysis. Since type 2 diabetes is common among patients with congestive heart failure, the data on potassium levels in the diabetic patients would be of considerable interest. Since the standard of care is to use high doses of ACE inhibitors in the treatment of congestive heart failure, we wish to reinforce that close monitoring of the serum potassium level after the initiation of spironolactone therapy is particularly important in patients with congestive heart failure that is complicated by diabetes.
4 ReferencesRobert J. Larkin, M.D.
Stephen A. Atlas, M.D.
Thomas J. Donohue, M.D.
Hospital of Saint Raphael, New Haven, CT 065111
Hobbs RE . Results of the ATLAS Study: high or low doses of ACE inhibitors for heart failure? Cleve Clin J Med 1998;65:539-542
Web of Science | Medline2
DeFronzo RA . Hyperkalemia and hyporeninemic hypoaldosteronism. Kidney Int 1980;17:118-134
CrossRef | Web of Science | Medline3
Halperin ML ,Bear RA ,Hannaford MC ,Goldstein MB . Selected aspects of the pathophysiology of metabolic acidosis in diabetes mellitus. Diabetes 1981;30:781-787
CrossRef | Web of Science | Medline4
Bennett PH ,Haffner S ,Kasiske BL , et al. Screening and management of microalbuminuria in patients with diabetes mellitus. Am J Kidney Dis 1995;25:107-112
CrossRef | Web of Science | Medline
To the Editor:
Pitt and coworkers report that blockade of aldosterone receptors by spironolactone, in addition to treatment with loop diuretics, ACE inhibitors, and other drugs, in patients with severe heart failure reduces the risk of both morbidity and death, with a minimal incidence of serious hyperkalemia. The authors warn about the risk of this complication in patients with an increased creatinine level and recommend a maximal dose of spironolactone of 25 mg.
As geriatricians, we are concerned by the mean age of the study population (65±12 years), which is very different from that of the patients in our practice (mean, 83±8 years). Indeed, because the prevalence and incidence of heart failure increase exponentially with age, a high proportion of patients with heart failure are frail elderly persons. This proportion will further increase as a result of the doubling of the number of octogenarians in the next three decades. Therefore, if the warnings of the authors are appropriate for the population studied, we want to emphasize that for frail elderly patients, the combination of spironolactone with standard therapy including ACE inhibitors should be considered with more caution. This concern is based on clinical experience and on several physiologic factors.1 Older patients have lower levels of aldosterone as well as impaired renal function, despite apparently normal levels of serum creatinine,2 and hyperkalemia may develop in these patients after even a single use of ACE inhibitors or spironolactone.3
3 ReferencesDominique Vanpee, M.D.
Christian Swine, M.D.
Université Catholique de Louvain, B5530 Yvoir, Belgium1
Perazella MA . Hyperkalemia in the elderly: a group at high risk. Conn Med 1996;60:195-198
Medline2
Beck LH . Changes in renal function with aging. Clin Geriatr Med 1998;14:199-209
Web of Science | Medline3
Perazella MA ,Mahnensmith RL . Hyperkalemia in the elderly: drugs exacerbate impaired potassium homeostasis. J Gen Intern Med 1997;12:646-656
CrossRef | Web of Science | Medline
To the Editor:
The study by Pitt et al. demonstrating the importance of administering spironolactone and the consequent blocking of the action of aldosterone in the treatment of congestive heart failure is a major breakthrough in our understanding of the pathogenesis and therapy of this disease. In my view, the results of this study allow us to reevaluate our interpretation of many of the investigations of the effects of beta-adrenergic–receptor blockade in patients with congestive heart failure.1,2
The beneficial effects of beta-blockade that have been demonstrated in these studies have been attributed to blockade of the sympathetic nervous system, which produces harmful effects as a result of overcompensation. The tachycardia that is frequently present may well be an example of such overcompensation.
What does not seem to have been appreciated, however, is the fact that beta-blockade markedly reduces the secretion of renin from the juxtaglomerular apparatus of the kidney, an effect that has been known for several decades.3 With the suppression of renin secretion, angiotensin levels fall and the stimulation of aldosterone production is minimized. Thus, in patients with congestive heart failure, the beneficial effects of spironolactone and beta-blockade are produced by means of the same final common pathway of suppressed aldosterone effects: spironolactone blocks aldosterone at its effector site, and beta-blockade decreases the production of aldosterone.
Such a formulation would help to explain the apparently counterintuitive finding that beta-blockade, which is a negative inotropic intervention, has salutary effects in patients with congestive heart failure.
3 ReferencesGerald Glick, M.D.
Rush Medical College, Chicago, IL 606121
Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure
CrossRef | Web of Science | Medline2
The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial
CrossRef | Web of Science | Medline3
Morganti A ,Pickering TG ,Lopez-Ovejero JA ,Laragh JH . Contrasting effects of acute beta blockade with propranolol on plasma catecholamines and renin in essential hypertension: a possible basis for delayed antihypertensive response. Am Heart J 1979;98:490-494
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: In our study, we added spironolactone or placebo to the treatment regimen of patients with heart failure. Drs. Fernandez and Leipzig suggest that the use of maximal doses of ACE inhibitors might have negated the benefits of spironolactone. Although the mean daily doses of ACE inhibitors in our study were lower than target doses, they are reflective of current practice.1 Furthermore, among all randomized patients, the final mean daily dose of enalapril used in the Studies of Left Ventricular Dysfunction (SOLVD)2 was 11.2 mg, whereas in our study the mean daily dose was 15.0 mg at base line. A retrospective analysis of our data revealed no difference in the effect of spironolactone on mortality between patients who received higher doses of ACE inhibitors and those who received lower doses. In addition, there is no evidence that the use of either higher doses of ACE inhibitors or a combination of an ACE inhibitor and an angiotensin-receptor blocker effectively suppresses aldosterone production in the long term,3 since factors other than angiotensin II, such as serum potassium, are important.4
Drs. Vanpee and Swine and Dr. Larkin and his colleagues are concerned about the risk of hyperkalemia in the elderly and in patients with type 2 diabetes mellitus. In our study, 9 percent of the patients were 80 years of age or older and nearly 25 percent of patients had a history of diabetes mellitus at base line. None of the patients who were randomly assigned to receive spironolactone died of hyperkalemia. Among elderly patients (age, 67 to 91 years) and patients with diabetes, the risk of death from any cause was reduced by 32 percent and 30 percent, respectively — values that were similar to those in the population as a whole. Similar reductions were also observed in the secondary end points (Table 1Table 1
Relative Risks of Death and Hospitalization among the Subgroups of 861 Elderly Patients and 389 Patients with Diabetes.). Interestingly, an analysis of data from SOLVD revealed that mortality was lower among patients receiving a potassium-sparing diuretic than among those receiving a non–potassium-sparing diuretic.5 Of the 24 patients in our study in whom serious hyperkalemia developed, 9 patients had diabetes (5 in the placebo group and 4 in the spironolactone group) and 4 (2 in each group) were at least 80 years old; there was no significant difference in the incidence of serious hyperkalemia between the treatment groups in either the study group as a whole or the subgroup of patients with diabetes. However, we recommend careful monitoring of the serum potassium level in patients who are receiving combination therapy.Dr. Glick is correct that beta-blockers act on renin and that there may be an important additive or synergistic effect when a beta-blocker is combined with spironolactone in the treatment of heart failure. However, the benefits of the use of such a combination remain to be confirmed in large, well-controlled clinical trials.
5 ReferencesBertram Pitt, M.D.
University of Michigan, Ann Arbor, MI 48109-0366Alfonso Perez, M.D.
Searle, Skokie, IL 60077for the Randomized Aldactone Evaluation Study Investigators
1
Consensus recommendations for the management of chronic heart failure
CrossRef | Web of Science | Medline2
The SOLVD Investigators
Full Text | Web of Science | Medline3
McKelvie RS ,Yusuf S ,Pericak D , et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) Pilot Study. Circulation 1999;100:1056-1064
Web of Science | Medline4
Weber KT ,Villarreal D . Aldosterone and antialdosterone therapy in congestive heart failure. Am J Cardiol 1993;71:3A-11A
CrossRef | Web of Science | Medline5
Cooper HA ,Dries DL ,Davis CE ,Shen YL ,Domanski MJ . Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation 1999;100:1311-1315
Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Michael R. MacDonald, Mark C. Petrie, Miles Fisher, John J. V. McMurray. (2009) Pharmacologic management of patients with both heart failure and diabetes. Current Heart Failure Reports 6:2, 126-132
CrossRef2
T.S. Dharmarajan, Tuan Nguyen, Robin O. Russell. (2005) Life-Threatening, Preventable Hyperkalemia in a Nursing Home Resident: Case Report and Literature Review. Journal of the American Medical Directors Association 6:6, 400-405
CrossRef3
T. S. Dharmarajan, Tuan Nguyen, Robin O. Russell. (2005) Life-Threatening, Preventable Hyperkalemia in a Nursing Home Resident. Journal of the American Medical Directors Association 6:6, 400???405
CrossRef
