Apresoline

The familiar diuretic spironolactone has taken on new life as a treatment for left-sided congestive heart failure. Spironolactone has been shown to decrease mortality in such patients who are New York Heart Association class IV. It can be used in addition to agents such as angiotensin-converting enzyme inhibitors and beta blockers, which also decrease mortality, and diuretics and digoxin, which are useful in treating symptoms. Spironolactone is safe, easy to use and reasonably priced. More research is necessary to determine the order and combinations of these medications in slowing the progression of this disease. (Am Fam Physician 2001;64:1393-8,1399.)

Spironolactone (Aldactone) is a potassium-sparing diuretic that was approved many years ago. Until recently, it was used primarily to treat edema resulting from liver cirrhosis, primary hyperaldosteronism and nephrotic syndrome. It has been used in combination with potassium-wasting diuretics to prevent hypokalemia.

Recent research on this older diuretic has focused on its effect in patients with left-sided congestive heart failure (CHF). As an aldosterone-blocking agent, spironolactone is postulated to work synergistically with angiotensin-converting enzyme (ACE) inhibitors to provide more thorough blockade of the renin-angiotensin-aldosterone (RAA) system.

Pharmacology

The RAA system is the complex mechanism by which the kidneys control the cardiovascular system. The system goes awry in patients with heart failure; in these persons, the decreased renal blood flow is not due to low blood volume but to a heart pump that is not working efficiently. ACE inhibitors block the conversion of vasoconstrictor angiotensin I to the much more potent angiotensin II, also blocking the production of the sodium-retaining hormone aldosterone. This production is only transiently suppressed, thus allowing aldosterone production to "escape" the effects of the ACE inhibitors.(1)

Spironolactone is a specialized antagonist of aldosterone. It acts as a competitive binding agent at the aldosterone receptor site in the distal convoluted renal tubules, preventing the formation of a protein important in the sodium-potassium exchange in the kidneys. This action causes increased amounts of water and sodium to be excreted while potassium is conserved.

Evidence of Benefit in Heart Failure

Based on earlier work suggesting a benefit of therapy,(2) the Randomized Aldactone Evaluation Study (RALES) was undertaken to evaluate the role of spironolactone when used in addition to standard therapy for CHF. Standard therapy in this study did not include beta blockers.(3) The investigators prospectively enrolled 1,663 patients with severe (New York Heart Association [NYHA] class IV) CHF (Table 1).(4) Most of the enrolled patients were white men averaging 65 years of age. These patients had a left ventricular ejection fraction of 35 percent or less and marked physical limitations related to CHF. Patients were excluded if they had unstable angina or moderate renal failure, and if they were hyperkalemic.

All patients who could tolerate the drug were given an ACE inhibitor and a loop diuretic, and 70 percent were taking digoxin. Only 10 percent were taking beta blockers. Patients were randomly assigned to receive placebo or 25 mg of spironolactone daily in addition to their current regimen. After eight weeks, if the patient showed worsening CHF and had a stable potassium level, the dosage was increased to 50 mg daily. The dosage was decreased to 25 mg every other day if at any time the patient became hyperkalemic.

Even with a 25 percent dropout rate (414 patients) among the two groups, related to adverse effects or lack of response, the results in the remaining patients in the study indicated a 30 percent reduction in death (35 versus 46 percent) over two years. During the study period, one death was avoided for every nine patients receiving spironolactone (number needed to treat [NNT] = 9).

The number of hospitalizations related to worsening CHF was lowered by 35 percent. NYHA classification improved in the spironolactone group more than in the placebo group. The primary adverse effect causing discontinuation of this agent in 10 percent of the men taking spironolactone was gynecomastia or breast pain. The incidence of serious hyperkalemia (5 versus 8 percent) was small.

Spironolactone in Left Ventricular CHF

Left ventricular CHF is a problem commonly seen in family practice, with a prevalence close to 2 percent. In a typical panel of 2,500 patients, about 50 will have heart failure. In mild failure, the annual mortality is 5 to 10 percent annually; in severe cases, it increases to 30 to 40 percent annually.(5)

The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS)6 trial in 1987 was the first to show that ACE inhibitors could decrease mortality related to heart failure. ACE inhibitors are generally well tolerated except in patients with an elevated creatinine level (usually greater than 3 mg per dL [265 [micro]mol per L]). The angiotensin-II receptor antagonist losartan has also been shown to decrease mortality in patients with heart failure.(7)

Loop diuretics have been universally used to reduce the symptoms of heart failure, but they have not been shown to reduce mortality.(8) Digoxin has recently had a resurgence of use in patients with severe CHF; it does not reduce mortality but has been shown to reduce symptoms and hospitalizations.(9)

In stark contrast to previous conventional wisdom, beta blockers have been shown to reduce mortality in patients with heart failure who can tolerate them. In the Cardiac Insufficiency Bisoprolol Study (CIBIS-II),(10) patients taking bisoprolol, a beta1 selective blocker, had fewer hospital admissions (NNT = 17.5) and cardiovascular deaths (NNT = 31) than the control group. All patients had NYHA class III or IV failure, were taking ACE inhibitors and diuretics, and had been clinically stable for at least six weeks.

Numerous other studies have demonstrated the benefit of beta blockers in patients with heart failure, with a 31 percent reduction in mortality overall. The benefit occurs primarily in reductions in non-sudden rather than sudden cardiac death and is similar in patients with ischemic and nonischemic cardiomyopathy.(11)

Carvedilol (Coreg) is the only beta blocker specifically labeled for treatment of patients with heart failure. However, studies of metoprolol, bisoprolol and propranolol have shown them to be effective in decreasing mortality, hospitalizations and hospitalizations related to heart failure. Carvedilol was found to be more effective than the other agents in patients without ischemic heart disease.(12)

The combination of hydralazine and isosorbide dinitrate has been shown to decrease mortality by 25 to 30 percent (Veterans Administration Cooperative Study [V-HEFT I]).(13) This combination of agents has been supplanted by ACE inhibitors, which are easier to use and more effective. However, the combination would be appropriate to consider in a patient who cannot tolerate ACE inhibitors.

Given the wide variety of choices, how do physicians decide which agents to use and when? Table 2(2,13-16) shows the NNT for each of these agents, and Table 3 gives an indication for each agent's use, as some guidance for this complicated decision.

Cardiac Medications for Prevention

The prescribing of ACE inhibitors, beta blockers and spironolactone in patients with heart failure presents the physician with challenges because while these agents do slow long-term decline related to heart failure, they have little or no effect on symptoms. In addition, it is not clear how quickly therapy should be started, whether all three approaches should be combined at once or which drugs should be added first. Research to date suggests benefit from all of the options in patients with an ejection fraction of less than 30 percent. A prudent approach would be to begin with an ACE inhibitor (or an angiotensin-II receptor blocker) and spironolactone in most patients (Table 4), slowly adding a beta blocker after the patient is stabilized on the first two drugs.

Specific Use of Spironolactone

Spironolactone is contraindicated in patients with anuria, acute renal insufficiency, significant renal insufficiency or hyperkalemia. Potassium supplementation should not be combined with spironolactone. Other drug interactions include errors in measurement of and an increase in the half-life of digoxin, decreased effectiveness when used with salicylates and variable effects or side effects (i.e., increased potassium) with use of nonsteroidal anti-inflammatory drugs. Gynecomastia and hyponatremia can occur, along with metabolic acidosis, which is usually associated with hyperkalemia. Other side effects are rare and include drug fever, drowsiness, lack of coordination, lethargy and gastrointestinal signs and symptoms.

Dosages range from 25 to 50 mg per day in patients with heart failure, although much higher dosages are used to treat other disorders. Patients pay less than $10 per month for typical dosages. This cost compares with that of other medications used for CHF, such as $31 to $33 per month for generic metoprolol, $97 for carvedilol and $22 to $87 for low to moderate doses of ACE-inhibitor therapy.

Spironolactone absorption is increased significantly when taken with food, but the clinical significance of this effect is not known. The metabolites are excreted primarily in the urine and secondarily in the bile, with half-lives of approximately 14 to 16 hours.

Final Comment

One study(3) has shown that spironolactone improves morbidity and mortality in patients with severe heart failure. The particular advantages of spironolactone for prevention are that it is inexpensive, is taken once daily and has relatively few side effects. This study suggests that all patients with class IV heart failure should be given a trial of spironolactone. Further research is needed to understand its usefulness in patients with less severe heart failure and whether its benefit is present in patients who are also taking beta blockers. Research is also necessary to determine which order and combinations of medications are the most beneficial in slowing the progression of this disease.

The authors indicate that they do not have any conflicts of interest. Sources of funding: none reported.

Richard W. Sloan, M.D., R.Ph., coordinator of this series, is chairman and residency program director of the Department of Family Medicine at York (Pa.) Hospital and clinical associate professor in family and community medicine at the Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa.

KATHERINE L. MARGO, M.D., is associate professor of family medicine at the University of Pennsylvania School of Medicine, Philadelphia. She completed medical training at the SUNY Health Science Center, Syracuse, N.Y., and served a residency at St. Joseph's Hospital in Syracuse. Dr. Margo was formerly the associate residency director for the Harrisburg Family Practice Residency and medical director of the Harrisburg and Kline Family Practice Centers, Harrisburg, Pa.

GARY LUTTERMOSER, M.D., is in practice at the Mechanicsburg Family Practice Center in Mechanicsburg, Pa., and a member of the Harrisburg Family Practice Residency faculty. Dr. Luttermoser completed medical training at the Medical College of Ohio, Toledo, and a residency at the Family Practice Residency at Akron City Hospital, Akron, Ohio. He has certificates of added qualification in geriatrics and sports medicine.

ALLEN F. SHAUGHNESSY, PHARM.D., is director of research and associate director of the Harrisburg Family Practice Residency. He received his undergraduate degree in pharmacy from Temple University, Philadelphia, and obtained a doctor of pharmacy degree and fellowship training at the Medical University of South Carolina, Charleston.

Address correspondence to Allen F. Shaughnessy, Pharm.D., Harrisburg Family Practice Residency, 111 S. Front St., Harrisburg, PA 17101 (e-mail: Ashaughnessy@PinnacleHealth.org). Reprints are not available from the authors.

REFERENCES

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(2.) Effectiveness of spironolactone added to an angiotensin-converting enzyme inhibitor and a loop diuretic for severe chronic congestive heart failure (the Randomized Aldactone Evaluation Study [RALES]). Am J Cardiol 1996;78:902-7.

(3.) Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.

(4.) Criteria Committee, New York Heart Association. Diseases of the heart and blood vessels. Nomenclature and criteria for diagnosis. 6th ed. Boston: Little, Brown, 1964:114.

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(8.) Konstam MA. Heart failure: evaluation and care of patients with left-ventricular systolic dysfunction. Rockville, Md.: U.S. Dept. of Health and Human Services, Agency for Health Care Policy and Research, 1994; Clinical Practice Guideline no. 11, AHCPR publication no. 94-0612.

(9.) The effect of digoxin on mortality and morbidity in patients with heart failure. The Digitalis Investigation Group. N Engl J Med 1997:336:525-33.

(10.) The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13.

(11.) Heidenreich PA, Lee TT, Massie BM. Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials. J Am Coll Cardiol 1997;30:27-34.

(12.) Bonet S, Agusti A, Arnau JM, Vidal X, Diogene E, Galve E, et al. Beta-adrenergic blocking agents in heart failure: benefits of vasodilating and non-vasodilating agents according to patients' characteristics: a meta-analysis of clinical trials. Arch Intern Med 2000;160:621-7.

(13.) Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-52.

(14.) NNTs for cardiac interventions. Retrieved June 2001, from: http://www.jr2.ox.ac.uk/bandolier/band17/ b17-7.html.

(15.) Lechat P, Packer M, Chalon S, Cucherat M, Arab T, Boissel JP. Clinical effects of beta-adrenergic blockade in chronic heart failure: a meta-analysis of double-blind, placebo-controlled, randomized trials. Circulation 1998;98:1184-91.

(16.) Comparative effects of therapy with captopril and digoxin in patients with mild to moderate heart failure. The Captopril-Digoxin Multicenter Research Group. JAMA 1988;259:539-44.

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