Posted on 01/07/2011 10:36:22 PM PST by neverdem
Vitals
Major Finding: Eplerenone reduced the risk of cardiovascular death or heart failure hospitalization by 37%, compared with placebo.
Data Source: Phase III randomized trial in 2,737 patients with NYHA class II heart failure.
Disclosures: EMPHASIS-HF was funded by Pfizer. Dr. Zannad reported receiving grants from and consulting for Pfizer. Two coauthors are Pfizer employees, and several others reported Pfizer grants and consultancy.
CHICAGO — Adding eplerenone to standard therapy significantly cut the risk of cardiovascular death and heart failure hospitalization by more than one-third in patients with mild heart failure in the phase III EMPHASIS-HF trial.
The primary composite end point of death from cardiovascular causes or first hospitalization for heart failure occurred in 18% of patients receiving eplerenone (Inspira) and 26% of those given placebo.
This translates into a significant 37% reduction in the primary end point; furthermore, the number of patients needed to treat to prevent one such outcome per year of follow-up was 19, Dr. Faiez Zannad reported in a late-breaking clinical trial report at the meeting. The trial was stopped early, at a median follow-up of 21 months of the planned 48 months, when an interim analysis showed an “overwhelming benefit” with eplerenone.
The use of eplerenone, an aldosterone antagonist, also significantly reduced all-cause mortality by 24%, hospitalization from any cause by 23%, and heart failure hospitalization by 42%.
The benefits were consistent across 20 prespecified subgroups analyzed in the New York Heart Association (NYHA) class II cohort of 2,737 patients.
“We believe that the robustness of these findings, in conjunction with the consistent results from the earlier RALES and EPHESUS trials, provides compelling evidence to change medical practice,” said Dr. Zannad, a cardiologist and professor of therapeutics at Henri Poincaré University of Nancy (France).
Current guidelines recommend the use of aldosterone antagonists in moderate to severe heart failure (NYHA class III and IV) and in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure.
The Randomized Aldactone Evaluation Study (RALES) demonstrated a survival advantage with the aldosterone antagonist spironolactone (Aldactone) plus standard therapy in moderate to severe heart failure patients, while the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) did so in the post–MI/heart failure setting.
The current findings have the potential to greatly expand the use of aldosterone antagonists, which are now utilized by fewer than two-thirds of patients with heart failure in the United States with a current indication.
“We have three trials in three distinct groups of heart failure severity which essentially have shown the same results,” Dr. Zannad said in an interview. “This puts this class of drugs on equal ground and if anything, the benefit comes on top of the benefit of angiotensin-converting enzyme inhibitors and beta-blockers.”
The bottom line, he said, is that all patients with a low ejection fraction, provided they have a normal estimated glomerular filtration rate or an EGFR above 30, should be on the three drugs now.
At a press briefing on the study, Dr. Clyde Yancy, immediate past president of the AHA, said that he was enthusiastic about the potential for these drugs to include patients with mild heart failure, but that his enthusiasm is tempered by the risk of hyperkalemia.
“You need to always watch for the presence of hyperkalemia with these drugs, but having said that, the benefit is not modest,” Dr. Yancy said. “This is a very real benefit. And again, two-thirds of patients with an indication are not getting these drugs, and that is what I hope will change.”
Hyperkalemia was reported in 8% of patients treated with eplerenone, compared with 3.7% given placebo, Dr. Zannad said. Treatment discontinuation due to hyperkalemia was reported in 1.1% of eplerenone patients and 0.9% of placebo patients, with hospitalization due to hyperkalemia occurring in 0.3% and 0.2% of patients.
In all, 171 of the 1,364 patients randomized to eplerenone and 213 of the 1,373 patients in the placebo group died. Of these, 147 deaths in the eplerenone group and 185 in the placebo group were due to cardiovascular causes.
Invited discussant Dr. Lynne Warner Stephenson, director of the heart failure program at Brigham and Women's Hospital in Boston, said that EMPHASIS-HF bridges an “awkward gap in our evidence,” but that clinicians need a better understanding of how best to prescribe eplerenone, how the drug works, and how to reduce the life-threatening hyperkalemia associated with these agents before widespread adoption.
She noted that hyperkalemia rates associated with spironolactone in general use have reached 12% in Texas and 10% in Denmark and Norway, and that in Canada the number needed to treat to get one case of hyperkalemia was 13. This led to the recent PEARL-HF trial (Evaluation of RLY5016 in Heart Failure Patients) in which the addition of a new potassium-binding resin (RLY5016) to spironolactone helped lower potassium levels and prevent hyperkalemia in patients with heart failure.
“We have the opportunity and the responsibility to learn from these experiences about how to use aldosterone antagonists safely before we recommend expanding this to the population at risk,” she said.
When asked by reporters whether the data support the use of spironolactone in mild heart failure, Dr. Zannad said that it's possible to extrapolate the results to spironolactone, but that the findings are limited to eplerenone at a dose of 50 mg in patients with NYHA class II heart failure and an ejection fraction of no more than 35%.
During a panel discussion of the study, Dr. Zannad said now that eplerenone has demonstrated efficacy in all symptomatic patients, the next step will be to evaluate the drug in asymptomatic patients and in those with preserved ejection fractions.
The EMPHASIS-HF results were also published in the New England Journal of Medicine (2010 Nov. 14; doi:10.1056/NEJMoa1009492).
Hyperkalemia means elevated blood potassium. The suffix "emia" refers to blood, e.g. anemia refers to low blood counts.
Heart failure is often refered to as congestive heart failure. Systolic Heart Failure means the contraction of the heart is weak. Diasystolic Heart Failure is abnormal relaxation and filling between contractions. Ejection fraction is a measure of pumping efficiency. Normal is about 55 - 60 %, IIRC.
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I once took care of an old guy with a <15% ejection fraction. He couldn’t run a marathon, but was somehow still alive.
Wow! I'm not sure how, but you come across these anomalies from time to time.
I have an EF of 25%. My electrophysiologist and cardiologist both prescribed an implanted defibrillator.
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