After 5 months of data collection, 60% of patients in the eplerenone group were on the higher dosage (50 mg/d), as were 65% of the patients receiving placebo. At the conclusion of the trial, the study drug had been discontinued in 16% of patients in the eplerenone group and 17% of the controls.
The primary outcome (death from a cardiovascular cause or hospitalization for heart failure) occurred in 18% of patients in the eplerenone group vs 26% of those on placebo. The number needed to treat to prevent one primary outcome was estimated to be 19 per year of follow-up, and 51 per year of follow-up to postpone one death. The study was terminated early (after a median follow-up of 21 months) due to the clear benefits that were evident in the eplerenone group.
WHAT’S NEW?: We have another way to help Class II patients
Previously, mineralocorticoid-receptor antagonists were recommended only for carefully selected patients—those with a history of MI and heart failure, diabetes and heart failure, or more severe (Class III or IV) heart failure.4,7 This study shows that heart failure patients with milder symptoms can benefit from eplerenone, as well.
CAVEATS: Cost differential means it pays to try spironolactone first
Eplerenone is expensive (approximately $100 for 30 25-mg tablets at Drugstore.com compared with $4 for the same quantity of spironolactone at Walmart.com). Because eplerenone’s beneficial effects are likely due to its action as a mineralocorticoid-receptor antagonist, it makes sense to use spironolactone as a first-line agent and reserve eplerenone for patients who cannot tolerate it.
Risk of hyperkalemia
Both spironolactone and eplerenone can cause hyperkalemia and should not be used in patients with a baseline potassium level >5.0 mmol/L. Patients who are started on either of these medications should have their potassium levels checked after 3 days, 7 days, and 1 month, then periodically, whenever the dosage is changed.4 If the potassium level is >5.0 mmol/L, the dose should be decreased by 50%—and the drug should be stopped if the potassium level is >5.5 mmol/L.1
In this study, serum potassium levels were >5.5 mmol/L in 12% of patients in the eplerenone group and 7% of those on placebo—a statistically significant difference. Eplerenone therapy was reduced or discontinued in hyperkalemic patients. No one suffered from the significant, but rare, sequelae associated with hyperkalemia, including arrhythmias and sudden death.
Only 2.4% of the patients included in this study were African American (the majority were white, but there was a significant number [11.5%] of Asians). We cannot be sure that African Americans with less severe heart failure would reap the same benefits from treatment with a mineralocorticoid-receptor antagonist.
This was a well-done RCT, which found a significant benefit of eplerenone over placebo. It was a relatively small study, however, and it would help if the findings were replicated in larger studies. It is noteworthy, too, that this study was supported by Pfizer, which manufactures eplerenone, and 2 of the authors were employed by the pharmaceutical company.
CHALLENGES TO IMPLEMENTATION: Close follow-up, lab work is crucial
Hyperkalemia can be a significant side effect of both spironolactone and eplerenone. Patients started on either medication will need close follow-up and frequent lab monitoring of potassium levels. Patients who are unable or unwilling to comply with this strict follow-up are not good candidates for either drug.
Overall, this is a straightforward change to implement. In many cases, convincing patients of the benefits of taking yet another pill will be the greatest challenge. For the right patient population, however, both eplerenone and spironolactone appear to be medications we should encourage more often.
Acknowledgement
The PURLs Surveillance System is supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.