RALES study gets the fast track
On-line publication makes study details official
Over the past year, you may have heard good news about spironolactone — but now, it’s official: A team of international investigators from the Randomized Aldactone Evaluation Study (RALES) have found the drug lowers morbidity and mortality in patients with advanced CHF.
Spironolactone had been on the market for decades, long before the new buzz began on what it can do for CHF patients. But its success in RALES sparked several early announcements. First, the trial was stopped early.
The study was originally scheduled to follow patients from 15 countries for three years. But after two years had passed, interim analysis showed the spironolactone group had a treatment advantage over the controls: a 30% reduction in risk of death from both progression of heart failure and sudden death from cardiac causes. (See CHF Disease Management, November 1998, pp. 78-79.) Patients on the drug also had improved CHF symptoms and reduced hospitalization.
Doctors began to hear about the RALES results and learned more about the new use for spironolactone at the American Heart Association meeting in November 1998. Some cardiologists, such as Americo Simonini, MD, of the new CHF clinic at Cedars-Sinai Medical Center in Los Angeles, told CHF Disease Management that discovering new uses for old drugs is like finding "buried treasure." (See CM, April 1999, p. 45.)
The report on RALES was due to be published Sept. 2 in The New England Journal of Medicine. But the journal’s editors broke their own embargo on the story and made it available on their Web site in July. The success (and surrounding excitement) may take spironolactone from virtual obscurity in cardiovascular circles to the established ranks of standard CHF medicines such as ACE inhibitors, beta-blockers, diuretics and digitalis.
It may take more than an initial look at a drug before its usefulness is established, says lead RALES researcher Bertram Pitt, MD, from the University of Michigan Medical Center in Ann Arbor. Beta-blockers also have been around for decades, he says, and were first believed not to be useful for treating CHF. Doctors once were too concerned with the initial worsening of CHF symptoms to think that the drugs could help these patients. Then studies of these drugs proved otherwise; they can be helpful in treating the disease and increasing survivability.
In the same way, Pitt says, doctors may have been reluctant to put patients on both an ACE inhibitor and a drug like spironolactone to add to aldosterone blockade because of the concern for hyperkalemia.
Initial safety studies were needed to show spironolactone used with the other CHF drugs did not contribute to significantly high potassium levels, defined as 6.0 mmol/L or higher. (Spironolactone was given in a daily dose of 12.5 mg to 25 mg along with the CHF patient’s other medications.)
Pitt says he first became interested in studying spironolactone during the time he had been lecturing on diuretics. Doctors knew that aldosterone contributed to fibrosis and the cardiovascular decline CHF patients experience. In addition, they knew that ACE inhibitors did not suppress aldosterone completely.
Studies continued to come in showing that spironolactone not only acted like a diuretic, but it also had effects on the endothelium and had other vascular benefits. Pitt talked with manufacturer Searle of Skokie, Il, and began to test the drug’s safety in patients. "All these things gave us increasing enthusiasm," he says.
RALES details
The double-blinded study recruited over 1,600 patients with severe CHF at nearly 200 centes. Patients could be in the study if they fit these criteria:
ª had a left-ventricular ejection fraction less than 35% within six months of enrollment;
ª were in NYHA class IV disease within 6 months before the enrollment and were in class III or IV during enrollment;
ª were diagnosed with heart failure at least 6 weeks prior to enrollment;
ª were not receiving potassium-sparing diuretics;
ª did not have operable disease of the heart valves (other than mitral or tricuspid regurgitation with clinical symptoms due to left-ventricular systolic heart failure);
ª did not have congenital heart disease, unstable angina, primary hepatic failure, active cancer, or life-threatening disease other than CHF;
ª were not transplant candidates or recipients;
ª did not have a serum creatinine concentration more than 2.5 mg/dL (221 micromol/L);
ª did not have a serum potassium concentration of more than 5.0 mmol/L.
Patients were also receiving ACE inhibitors and a loop diuretic, and some patients also were being treated with digoxin. In the control group, 841 patients received a placebo and were compared with a group of 822 patients that received 25 mg of spironolactone each day.
Doctors compared the death rate from all causes in these groups. By the mean follow-up of two years into the study, 35% of the patients in the spironolactone group had died, compared to 46% of the participants in the placebo group. The drug group also had 35% lower rates of rehospitalization for worsening CHF symptoms, and the CHF symptoms among the patients in the spironolactone group improved in NYHA class.
Patients in the spironolactone group took 25 mg of the drug (Aldactone) once a day for two months. The dose could be doubled after that time if it appeared the CHF was getting worse as long as there was no sign of hyperkalemia. If high potassium developed, the treating physician was encouraged to adjust the other medications first, but if that didn’t help, the dose of spironolactone could be reduced to 25 mg once every other day.
A need to monitor patients
Cardiologist Karl T. Weber, MD, from the University of Missouri Health Sciences Center in Columbia, says the drug has many benefits: It’s cheap; it’s effective; and when used appropriately, it’s safe. "It’s an old friend," says Weber, author of the New England Journal companion editorial on aldosterone and spironolactone in heart failure.
But the drug must be used properly. The RALES investigators permitted patients to participate in the study only if the baseline renal serum creatinine was less than 2.5 mg/dL. Weber says he prefers patients to have a level lower than 2.0. The risk of hyperkalemia can be minimal, he notes, "but it has to be monitored."
Patients often are on a diuretic such as Lasix, so doctors may be in the mode of thinking about replacing the potassium often lost through diuresis. But spironolactone keeps the body from losing potassium, so supplementation may no longer be needed or a patient may need less of it.
The physician also may be able to reduce the loop diuretic, depending on how the patient is responding to therapy.
Pitt also warns that potassium levels can get too high. Overall, his group reported the incidence of serious hyperkalemia was minimal in both the drug and placebo groups.
Applying RALES to clinical practice
Other observers note it’s important to remember the conditions of the RALES participants are not always going to match the patients doctors treat every day.
Remember that if the participants had a serum creatinine concentration of more than 2.5 mg/dL, they were eliminated from the study, says David S. Roffman, PharmD, BCPS, associate professor at the University of Maryland School of Pharmacy in Baltimore and CCU therapeutic consultant with the university’s medical system. Most patients with advanced CHF don’t have normal renal function.
Roffman says it’s also important to recognize that nearly a third of the RALES patients who received spironolactone, on top of using ACE inhibitors, still needed potassium supplementation.
"You would think that this cohort would have too much potassium," he says, "But 29% still needed extra." Since patients are probably on substantial doses of loop diuretics, that’s the most likely reason for why they still are losing potassium.
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