Some question study results on spironolactone treatment for CHF
Trial finds new drug reduces mortality, morbidity rates
Despite promising news for patients, there are concerns that cloud the unconditional acceptance of the new CHF drug spironolactone. Some physicians call into question the conclusions of a recent study of the drug, challenging the significance of the findings and their impact on CHF treatment. Some argue that the study participants are not representative of CHF patient profiles, while others say the dosing level of ACE inhibitors was too low.
However, not all feedback on the Randomized Aldactone Evalua-tion Study (RALES) of spironolactone, also called Aldactone, is negative. In support of RALES, many clinicians enthusiastically embrace the positive implications of the study and are optimistic about the drug that has been shown to reduce mortality and morbidity rates.
In a double-blind study following 1,600 patients from 15 countries, RALES results found that spironolactone reduced CHF patient mortality by 30% and re-hospitalization by 35% as compared to a CHF placebo group. By blocking the chemical signal aldosterone, which causes the heart muscle to lose its ability to pump, spironolactone keeps the heart muscle from becoming stiff and fibrotic.
Lead RALES researcher Bertram Pitt, MD, associate chair of internal medicine and professor of cardiology at the University of Michigan Medical Center in Ann Arbor, first became interested in studying spironolactone while lecturing on diuretics. In continuous studies, spironolactone proved to act not only as a diuretic, but also had effects on the endothelium as well as other vascular benefits. Prompted by the knowledge that ACE inhibitors did not suppress aldosterone completely and that aldosterone contributed significantly to fibrosis, Pitt approached G.D. Searle & Co. of Skokie, IL, and began to test spironolactone’s safety.
In what was meant to be a three-year study, RALES was cut short after only two years because of the overwhelmingly positive results in respect to CHF patient mortality and morbidity. Although the report was due to be published in the New England Journal of Medicine (NEJM) on Sept. 2, 1999, the journal’s editors surprised everyone by making details of the study available on their Web site in July.
As a treatment option for CHF, spironolactone is usually prescribed as the fourth or fifth drug for most CHF patients. (See CHF Disease Manage-ment, September 1999, pp. 102-105.) According to David S. Roffman, PharmD, BCPS, associate professor at the University of Maryland School of Pharmacy in Baltimore, current standard CHF treatment options are an ACE inhibitor, a diuretic, a beta-blocker, and digitalis.
The medications that were taken in the study included loop diuretics, ACE inhibitors, digitalis, aspirin, potassium supplements, and beta-blockers. At baseline, the drug doses of ACE inhibitors given daily to the placebo group were Captopril 62.1 mg, Enalapril 16.5 mg, and Lisinopril 13.1 mg. At baseline, the drug doses of ACE inhibitors given daily to the spironolactone group were Captopril 63.4 mg, Enalapril 13.5 mg, and Lisinopril 15.5 mg.
Are older patients at risk?
Rosanne M. Leipzig, MD, PhD, clinical associate professor at Mount Sinai School of Medicine and the department of geriatrics and adult development at Mount Sinai Medical Center in New York City, responded to the findings of the RALES study in a letter to the editor of the NEJM.
Leipzig says she was particularly concerned for older patients and cautious about adding more drugs to a treatment plan before it was absolutely necessary. "My biggest concern is we don’t maximize what folks are on before we add another drug. When you add another drug, you add all the possibilities of drug interactions. Spironolactone is for people who are on the usual three drugs who are still not responding at maximum doses of those."
"These are not benign drugs," Leipzig emphasizes. Referring to the traditional CHF drug therapy regimen, she explains her philosophy. "Give them the maximal dose and make sure they get the maximum benefit before adding other drugs to those."
She admits, however, that "spironolactone is a much more benign drug than beta-blockers, which have all sorts of potential complications. Compared to other drugs, spironolactone is cheap."
In another letter to NEJM, Karl T. Weber, MD, a cardiologist at the University of Missouri Health Services Center, said that when properly monitored, spironolactone should reduce the risk of death among patients with CHF. "The importance of aldosterone in CHF has been overlooked in recent years because ACE-inhibitor-related reductions in angiotensin were thought to eliminate aldosterone production."
Some physicians caution against the broad use of spironolactone when treating CHF patients. Also responding in a letter to the editor of NEJM, Robert J. Larkin, MD; Stephen A. Atlas, MD; and Thomas J. Donohue, MD; staff members at Hospital of St. Raphael in New Haven, CT, pointed out that the average blood pressure reported in the study was 122/75, which they claim indicates that the dose of ACE inhibitors was too low.
They reason that patients with diabetes may be at a greater risk for hyperkalemia when treated with the combination of spironolactone and a high dose of an ACE inhibitor, which is considered standard. Hyperkalemia is a condition caused by excessive amounts of potassium in the blood. (See related story, p. 27.) Another point of contention with the RALES results, as pointed out in their letter, asserts that although Type 2 diabetes is common in CHF patients, potassium levels in diabetic patients were not considered in the subgroup analysis.
In a follow-up letter to the NEJM editor, lead RALES researcher Pitt claims that the data revealed no difference in the effect of spironolactone on mortality between patients on higher doses and those on lower doses of ACE inhibitors.
Regarding CHF patients who also suffer from diabetes mellitus, Pitt explains that nearly 25% of RALES study patients had a history of diabetes mellitus at baseline. He also notes that none of the patients receiving spironolactone died of hyperkalemia.
Two practicing geriatricians from the Universite Catholique de Louvain in Belgium question the mean age of the RALES population. In their letter to NEJM, Dominique Vanpee, MD, and Christian Swine, MD, write that the mean age of the study population (65 ± 12 years) is very different from that of the patients (83 ± 8 years) in their own practice. Because the prevalence and incidence of heart failure increases with age, the physicians challenge the study’s implications for a much older population.
Adding to the age factor, the Belgium physicians point out that older patients have lower levels of aldosterone as well as impaired renal function, despite apparently normal levels of serum creatinine. The Belgium doctors also caution that hyperkalemia may develop in these patients after only a single dose of ACE inhibitors or spironolactone.
Pitt counters that out of the 24 patients in the study developing hyperkalemia, nine of those patients were diabetic and four were 80 or older. He concludes that there was no significant difference in the occurrence of serious hyperkalemia between the treatment groups and the subgroup of patients with diabetes.
Pitt warns clinicians "to monitor potassium and not to give spironolactone to people with renal dysfunction using a 2.5 mg per deciliter cutoff." Despite challenges to the RALES findings, "the data are still very valid. I see a big change in people’s thinking."
Gerald Glick, MD, professor of medicine at Rush Medical College in Chicago, applauded the RALES findings in a letter to NEJM as a major breakthrough in the understanding of the pathogenesis and therapy of CHF.
"In patients with congestive heart failure, the beneficial effects of spironolactone and beta-blockade are produced by means of the same final common pathway of suppressed aldosterone effects: Spironolactone blocks aldosterone at its effector site, and beta-blockade decreases the production of aldosterone. Such a formulation would help to explain the apparently counterintuitive finding that beta-blockade, which is a negative inotropic intervention, has salutary effects in patients with congestive heart failure," he wrote.
Glick prefers the use of spironolactone. "It may be preferred to use spironolactone rather than starting with a beta-blocker to get to the same culprit, namely aldosterone, and avoid bad side effects," he says.
Glick reports no problems in the short term in prescribing spironolactone for CHF patients. "It’s a valuable addition to usual drug therapy."
To clarify the debate over population concerns expressed by physicians who questioned the study’s participants as not representative of typical CHF profiles, those excluded from RALES were patients with these conditions:
- primary operable valvular disease;
- congenital heart disease;
- unstable angina;
- primary hepatic failure;
- active cancer, or any life threatening disease (other than heart failure);1
- a serum creatinine concentration of more than 2.5 mg per deciliter (221 mmol per liter);
- a serum potassium concentration of more than 5.0 mmol per liter.
Reference
1. Pitt B, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341:709-717.
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