Spironolactone For Congestive Heart Failure

Journal of Family Practice, Oct, 1999 by Erik J. Lindbloom, Clint J. Koenig

Clinical question Does the addition of spironolactone to the usual regimen for severe congestive heart failure (CHF) reduce morbidity and mortality?

Background Aldosterone plays an important role in CHF, causing harmful electrolyte, autonomic, and vascular changes. Angiotensin-converting enzyme (ACE) inhibitors only transiently suppress aldosterone production. Spironolactone is an aldosterone receptor antagonist that may produce a more lasting inhibition of aldosterone's effects.

Population studied The investigators prospectively enrolled patients with New York Heart Association (NYHA) class III or IV heart failure who had class IV heart failure within the 6 months before enrollment. By this classification, these were all patients with marked limitation of physical activity, having all recently experienced a period when any activity caused discomfort. All patients were taking an ACE inhibitor (if tolerated) and a loop diuretic, and had a left ventricular ejection fraction of no more than 35% within the previous 6 months. Exclusion criteria were primary operable valvular heart disease, congenital heart disease, unstable angina, primary hepatic failure, creatinine [is greater than] 2.5 mg/dL, potassium [is greater than] 5.0 mmol/L, active cancer, or other life-threatening disease (other than heart failure). A total of 1663 patients were randomized: 86% were white; 73% were men; and the mean age was 65 years.

Study design and validity This was a multicenter randomized double-blind placebo-controlled trial using spironolactone 25 mg orally each day. After 8 weeks, the dose could be increased to 50 mg daily, if the patient showed signs of worsening CHF without hyperkalemia. If hyperkalemia developed, the dosage could be lowered to 25 mg every other day. Potassium, creatinine, and other laboratory measurements were monitored throughout the trial. A total of 414 patients discontinued treatment during the trial, 102 because of adverse effects, and 312 because of administrative reasons or a poorly defined lack of response. Aside from these unclear reasons for discontinuation, the study design appears sound. The trial was stopped earlier than anticipated because of a significant survival difference discovered on interim analysis.

Outcomes measured The primary end point was death from any cause. Secondary end points included death from cardiac causes, hospitalization for cardiac causes, and change in NYHA class. Adverse effects were also recorded.

Results Spironolactone use was associated with a 30% reduction in death over 2 years (95% confidence interval, 18% - 40%). The number needed to treat (NNT) is 9, meaning that approximately 9 patients on usual therapy for severe CHF would need to be placed on spironolactone to prevent one death during a 2-year period. There was also a significant 32% reduction in cardiac deaths (NNT = 11) and cardiac hospitalizations (NNT = 12), and a significant improvement in NYHA class. Creatinine and potassium levels did increase slightly in the spironolactone group, but this was not clinically significant. Gynecomastia or breast pain occurred in 10% of the men taking spironolactone.

Recommendations for clinical practice Patients with severe CHF and reasonable renal function should be prescribed spironolactone 25 mg orally every day. At this low dose, the diuretic effects are minimal, but monthly potassium checks for 3 months and electrolyte and creatinine monitoring 2 to 4 times per year would be reasonable. The medication is inexpensive; locally, 30 spironolactone 25 mg tablets cost less than $4.

Pitt B, Zannad F, Remme W J, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341:709-17.

Erik J. Lindbloom, MD, MSPH
Clint J. Koenig, MD
Columbia, Missouri
E-mail: LindbloomE@health.missouri.edu