CHICAGO—The addition of eplerenone to recommended medical therapy was well tolerated, and had a 37 percent reduced combined risk of death and hospitalization in patients with systolic heart failure (HF) and mild symptoms, compared with placebo, based on the findings of the EMPHASIS-HF trial presented today as a late-breaking paper at the American Heart Association (AHA) Scientific Sessions.
Aldosterone antagonists, the class of drugs to which eplerenone (Inspra, Pfizer) belongs, improve survival among patients with chronic, severe systolic HF and HF after MI. Under the current guidelines, aldosterone antagonists, including eplerenone and the older spironolactone, are recommended only for patients with moderate to severe HF and reduced heart functions.
|Slideshow | Eplerenone in Patients with Systolic Heart Failure and Mild Symptoms|
|Falez Zannad, MD, PhD et al. for the EMPHASIS-HF Study Group
In the double-blind EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization And SurvIval Study in HF) trial, the researchers randomly assigned 2,737 patients (average age 69 years, 78 percent were male) with N.Y. Heart Association class II HF and an ejection fraction of no more than 35 percent to receive eplerenone (up to 50 mg daily) or placebo, in addition to recommended therapy. Patient enrollment began in March 2006 at 270 centers in 29 countries.
The primary endpoint was a composite of death from cardiovascular causes or hospitalization for HF. The adjudicated secondary endpoint was death from any cause, hospitalization from any cause and hospitalization from HF.
The trial was stopped prematurely in May 2010, after eplerenone showed an overwhelming benefit in reducing HF deaths and hospitalizations, with a median follow-up period of 21 months. The primary outcome occurred in 18.3 percent of patients in the eplerenone group compared with 25.9 percent in the placebo group.
A total of 12.5 percent of patients receiving eplerenone and 15.5 percent of those receiving placebo died; 10.8 percent and 13.5 percent, respectively, died of cardiovascular causes. Hospitalizations for HF and for any cause were also reduced with eplerenone. A serum potassium level exceeding 5.5 mmol per liter occurred in 11.8 percent of patients in the eplerenone group and 7.2 percent of those in the placebo group.
Principal investigator Faiez Zannad, MD, PhD, from the Nancy University Hospital Center in Nancy, France, who presented the trial at this morning’s press conference, also pointed out that eplerenone reduced the number of deaths due to any cause and hospitalizations for any reason by one-third compared with placebo. “We hit all the secondary endpoints, including mortality from all causes,” he added.
Based on the “robustness of these findings, in conjunction with the consistent results from the earlier RALES and EMPHASIS trials,” the researchers concluded that there is “compelling evidence to change medical practice.”
Zanand added that the “treatment is certainly going to change the guidelines for mild HF.”
In an accompanying editorial in the New England Journal of Medicine, where EMPHASIS HF was published simultaneous to its presentation, Paul W. Armstrong, MD, from the University of Alberta in Edmonton, commends the trial for adding “real value to the management of HF,” but questions whether cost considerations would affect its adoption rates.
“Since spironolactone is available for pennies a day, one might reasonably ask whether the greater cost of eplerenone is warranted or whether it is reasonable to simply assume that the current findings also apply to spironolactone and reserve the newer, more expensive therapy for those few patients in whom the side effects of spironolactone are disabling,” wrote Armstrong, adding that this would be “a reasonable tactic.”
Also, Mariell L. Jessup, MD, from the University of Pennsylvania School of Medicine in Philadelphia, who commented on EMPASIS-HF at this morning’s press conference, noted that prior to expanding the population to receive aldosterone antagonists, “we need to learn how to use them without causing life-threatening hyperkalemia.”
Also, Jessup noted that while the trial showed a “clear benefit of aldosterone antagonism in mild HF,” these questions still remain:
- Who are the patients who will benefit?
- How should aldosterone antagonists be prescribed and monitored?
- Why does it work?
The New York City-based Pfizer funded EMPHASIS-HF.