DOCTOR'S VIEW ARCHIVE
The New England Journal of Medicine removed the embargo on an unpublished article (1999) and accompanying editorial about the clinical implications of an advance in the treatment of heart failure. The advance involves a drug called spironolactone (pronounced spi-ro-no-lac-tone) that has been manufactured by G.D. Searle & Co. for some years under the brand name of Aldactone and is available as a generic drug. The news about spironolactone is twofold:
- Spironolactactone is a major help in treating congestive heart failure; and very importantly
- Its beneficial effects are additive to those from ACE inhibitors, another class of drugs commonly relied on in treating heart failure.
The research was reported by Bernard Pitt and colleagues in what was called the Randomized Aldactone Evaluation Study (RALES). The RALES study was unusually far-flung. It took place on 5 continents in 15 countries -- Belgium, Brazil, Canada, France, Germany, Japan, Mexico, The Netherlands, New Zealand, South Africa, Spain, Switzerland, the United Kingdom, the U.S. and Venezuela. At 195 medical centers, a grand total of 1663 patients with symptomatic heart failure were studied. All received standard care and, in addition, they were assigned randomly (by chance alone) to receive spironolactone or a placebo, a blank that looked just like spironolactone.
Results of the research
The overall risks of death, death due to progressive heart failure, and sudden death from cardiac causes were all found to be lowered by about 30% among the patients treated with spironolactone. This remarkable result prompted the RALES study to be ended early so that all of the patients could receive spironolactone and benefit from it.
The RALES study demonstrated that patients who received spironolactone had a sizable reduction in the chance of being hospitalized for heart problems and they had significant improvement in functional status. These healthy responses were evident within several months after enrollment in the RALES study and persisted throughout the two-year duration of the study.
Congestive heart failure and aldosterone
Congestive heart failure occurs gradually. It tends to occur frequently after the heart has been damaged by a prior heart attack or after the heart has been subjected to long-standing high blood pressure (hypertension). The heart is unable to eject or receive the normal quantities of blood. This results in characteristic symptoms and signs. If a person with heart failure is able to compensate for it, they may feel breathless and easily tired with moderate or greater levels of exertion. Symptoms with only minimal exertion or at rest accompanied by swelling (edema) of the legs reflect decompensation. The failing heart can not keep up with the demands put upon it.
Congestive heart failure is a syndrome that arises from under- oxygenated tissues and congested tissues. By retaining salt, the kidneys work counter to the heart, lungs, and liver in heart failure. There is a "dysfunctional relationship" between the kidney and these other organs that normally cooperate to preserve circulatory balance. This dysfunctional relationship involves a substance called aldosterone.
Spironolactone blocks the action of aldosterone, a hormone that is released by the adrenal glands into the blood stream. Aldosterone acts upon the kidneys to encourage the retention of sodium in the blood and promote the loss of magnesium and potassium into the urine. Since the blockade of aldosterone receptors by spironolactone substantially reduces the risk of both morbidity and death among patients with severe heart failure, it is becoming abundantly clear that aldosterone plays an important role in the events leading up to and surrounding heart failure.
Implications for care
The discovery of the value of spironolactone for heart failure is an "important therapeutic advance," commented Dr. Karl T. Weber in the New England Journal editorial. The research "suggests that the standard of care for the treatment of patients with moderate or severe symptomatic heart failure" will change and "should be broadened to include spironolactone."
If kidney function is all right, the use of a combination of a diuretic (water pill) and spironolactone allows the dose of the diuretic and the amount of supplemental potassium to be reduced. Dr. Weber adds that: "When properly monitored, this therapeutic approach should reduce the risk of death among patients with this common and serious disorder."
Just as old dogs occasionally do learn new tricks, old drugs like spironolactone sometimes show new therapeutic potential.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, , for the Randomized Aldactone Evaluation Study Investigators: The effect of spironolactone on morbidity and mortality in patients with severe heart failure. New Engl J Med, in press, 1999. (Original report)
Weber KT: Aldosterone and Spironolactone in Heart Failure. New Engl J Med, in press, 1999. (Editorial)