July 20, 1999 ANN ARBOR -- A new study---led by a leading University of Michigan heart researcher and made public today by the New England Journal of Medicine---shows that adding an established medication to standard treatment regimens for heart failure reduced deaths by 30 percent. While the article will not appear in the journal until later this year, the life-saving potential of the information caused the editorial staff to post the findings on its Internet site, http://www.nejm.org.
The NEJM posts an early release of a manuscript on its Web site only two or three times a year in accordance with its Ingelfinger Rule, which allows the early release of findings determined to have immediate clinical implications. Such is the case in this heart failure study, where researchers observed a substantial reduction in mortality for a disease that, in the United States alone, affects as many as 4.7 million people and results in approximately 250,000 deaths annually, according to the American Heart Association.
The study looked at the effect of adding Aldactone (spironolactone), a drug that has been used for decades to treat a variety of conditions (see indications below) but had not been tested previously as therapy for reducing deaths in heart failure patients.
Known as the Randomized Aldactone Evaluation Study (RALES), the trial defies current thinking that spironolactone and other drugs that block the action of a hormone known as aldosterone should not be administered in conjunction with an ACE (angiotensin-converting-enzyme) inhibitor. "Not only was combination therapy with Aldactone and ACE inhibitors well tolerated by patients in the most severe stages of heart failure, but the decrease in cardiac death and hospitalization was dramatic," said lead investigator Bertram Pitt, M.D., professor in the Division of Cardiology at the U-M Medical School. "These findings suggest that the gold standard treatment for severe heart failure should include an aldosterone receptor antagonist."
In the RALES study, investigators compared a standard treatment regimen of an ACE inhibitor and a diuretic, with or without digoxin added to this regimen, plus Aldactone or placebo in patients with severe heart failure. Patients were followed for a mean of 24 months.
"The research led by Dr. Pitt demonstrates our commitment to targeting the mechanisms behind serious and complex diseases," said Dr. Holly Kleinert, global vice president of the Cardiovascular/Metabolic and Oncology Franchises at Searle, which sponsored the study. "The RALES trial helps to define the important role of aldosterone in heart failure and opens the door to the research and development of more effective treatment options based on its blockade."
Aldosterone Blockade in Treating Heart Failure
This study confirms that aldosterone plays an important role in the pathophysiology of heart failure. Under the conditions of the RALES trial, aldosterone blockade was shown to be a key factor to greater reduction of mortality associated with heart failure, according to Dr. Pitt. "Many physicians assume that by using an ACE inhibitor, aldosterone will be as effectively blocked as angiotensin II," he says. Angiotensin II, the molecule targeted by ACE inhibitors, increases blood pressure and stimulates the secretion of aldosterone. Continues Pitt, "Other studies have shown that, although inhibition of angiotensin II by an ACE inhibitor can reduce aldosterone levels, there is a significant amount that can 'escape,' or is not suppressed, and aldosterone has been associated with increased mortality in heart failure patients."
RALES Study Results
The RALES study, conducted in 15 countries, was a multi-center, randomized, double-blind, placebo-controlled trial, which enrolled 1,663 severe heart failure patients with systolic left ventricular dysfunction. These patients were classified as Class III or IV, the most severe levels of heart failure defined by the New York Heart Association (NYHA).
Originally scheduled to conclude in December 1999, the RALES trial was halted a full 18 months early. The Data Safety Monitoring Board (DSMB), an independent oversight committee, concluded that the results were so statistically and clinically significant that it would have been unethical to continue the trial.
Among the 1,663 patients randomized, there were 386 deaths (46 percent, n=841) in the placebo group and 284 deaths (35 percent, n=822) in the spironolactone group; this figure represents a 30 percent decrease in mortality, applying the Kaplan-Meier method, which analyzes mortality in relation to duration of treatment. Also observed during the trial were 336 placebo-treated and 260 spironolactone-treated patients who had at least one non-fatal cardiac hospitalization, representing 753 hospitalizations for the placebo group and 515 for the spironolactone group. This represents a 30 percent decrease in non-fatal cardiac hospitalizations. Spironolactone was well tolerated, with only gynecomastia, or breast pain, in the male sub-group achieving statistical significance.
According to the label approved by the U.S. Food and Drug Administration, Aldactone is indicated in the management of primary hyperaldosteronism; edematous conditions for patients with congestive heart failure; cirrhosis of the liver accompanied by edema and/or ascites; essential hypertension and hypokalemia. It is not indicated for adjunctive therapy of heart failure as used in the RALES study. Spironolactone is a pharmacologic aldosterone receptor antagonist. It has been shown to be a tumorigen in chronic toxicity studies in rats. Aldactone is contraindicated for patients with anuria, acute renal insufficiency, significant impairment of renal excretory function, or hyperkalemia.
Impact of Heart Failure
American Heart Association statistics indicate that an estimated 400,000 new cases of heart failure are diagnosed each year. Worldwide, it is estimated that 20 million people suffer from this condition. For people with heart failure, the five-year mortality rate is estimated at 50-60 percent. In addition to the number of deaths directly attributed to heart failure, this serious and prevalent illness is an indirect, contributing cause of more than one million deaths. For heart failure patients, sudden death occurs at six to nine times the rate expected in the general population. Even patients with mild symptoms face an annual mortality rate of 10-20 percent.
There are many known causes leading to heart failure, including coronary heart disease, high blood pressure and cardiomyopathy. While treatment varies depending on the etiology and stage of heart failure, most therapeutic protocols include lifestyle changes as well as drug therapy.
The RALES study, sponsored by Searle, was conducted in Belgium, Brazil, Canada, France, Germany, Japan, Mexico, the Netherlands, New Zealand, South Africa, Spain, Switzerland, Venezuela, the United Kingdom and the United States. Because of the global nature of the RALES study, and the large number of study sites in Europe, the Aldactone used in the trial was the formulation approved in many European countries.
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