November 16th, 2010
Putting the EMPHASIS on Eplerenone for HF
Paul Armstrong, MD
In the EMPHASIS-HF study, aldosterone inhibition with eplerenone reduced the rate of death from cardiovascular causes or heart-failure (HF) hospitalizations by about 37% (compared with placebo) in patients with functional NHYA class II HF. CardioExchange welcomes Paul Armstrong, Professor of Medicine in the Division of Cardiology at the University of Alberta, to answer our questions about this study. His editorial on the EMPHASIS-HF study appears in the New England Journal of Medicine.
The Data Safety and Monitoring Committee terminated the study early. How would you respond to those that point out that this often exaggerates the treatment effects?
The results of EMPHASIS-HF are so clearly positive and consistent with prior work that I suspect this was a minimal issue in the decision to end the study early.
Few patients (about 20%) in EMPHASIS-HF were treated with an implantable cardiodefibrillator (ICD) or cardiac resynchronization therapy (CRT). Would you expect such therapy to blunt the benefits of eplerenone? Should we restrict aldosterone inhibitor therapy to patients without ICD or CRT therapy?
Device implantation might have blunted some of the effect, but by no means all in my view. A future study might usefully explore whether device therapy can improve outcomes on top of eplerenone.
Although the trial purportedly studied patients with “mild” (NHYA class II) HF, they appeared to have advanced disease (mean LVEF, 26%). Should patients with moderately reduced EF (30-50%) be treated with an aldosterone inhibitor?
We will need to see from additional analysis the extent to which baseline EF interacted with treatment effect, but I would guess that anyone with a depressed EF would benefit from this therapy. I recall that the EPHESUS trial showed a benefit for post-MI HF patients with an EF mean of 33%. The diastolic dysfunction among patients with normal EFs are the subject of ongoing studies.
Following the RALES trial, widespread use of spironolactone in HF patients resulted in an increased incidence of hyperkalemia and cardiac-related death. Should we expect the same with eplerenone?
It has recently been shown that careful monitoring of renal function and electrolytes is warranted and this results in safer general use. I believe the Ontario data published in NEJM may have overstated the safety issue.
In the editorial that accompanied the study, you recommended that spironolactone be used in HF patients and the more expensive eplerenone be reserved for the rare patient who has disabling side effects from spironolactone. Are there any differences in efficacy or safety between the two?
The principal side effect of aldosterone is painful gynecomastia, which occurs in about 10% of men and can be avoided with eplerenone. There is not a direct head-to-head comparison of these antagonists: However, based on what literature is available, I believe they are otherwise very similar regarding their safety and efficacy.
10 Responses to “Putting the EMPHASIS on Eplerenone for HF”
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I am comparing mortality benefits with eplerenone Vs other aldosterone antagonists(namely spironolactone and canrenone) compared with placebo by looking at different meta-analyses.The mortality benefit with eplerenone looks to be abt 15% while that with the other aldosterone antagonists is about 25%(compared with placebo/control)…Also there is the cost factor….Now the trials have been heterogenous in many aspects and a meta-analysis can often be suspect in terms of the findings…however such a drastic difference can scarcely be disregarded….Any thoughts?
EMPHASIS-HF studied a different patient population than RALES and EPHESUS did. RALES studied NYHA Class III and IV patients with an average EF of about 25%, while EPHESUS studied post-MI patients with an average EF of 33%. Until the drugs are compared head to head in an identical population, I don’t know how much can be extrapolated about the degree of mortality benefit difference. The take home point from this trial for me is that there is a role for aldosterone antagonists in the the treatment of mild (NYHA II) heart failure.
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so thats more reason for emphasis to have a greater mortality benefit as they studied a less sick population-right??
Mortality benefit that we have been discussing it is in terms of relative risk, not absolute. If you look at the absolute difference in RALES, mortality was 46% in the placebo group and 35% in the spironolactone group (RR, 0.70, p<0.001). In contrast, EMPHASIS-HF the all-cause mortality was lower (12.5% vs. 15.5%, HR 0.76, 95% CI 0.62-0.93, p = 0.008), as was CV mortality (10.8% vs. 13.5%, HR 0.76, 95% CI 0.61-0.94, p = 0.01).
So overall the absolute mortality in the eplerenone study was much better than the spironolactone study (both in the treatment and placebo arms), but the relative improvement was less dramatic.
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From what I understand absolute risk reduction in RALES trial was 11% and EMPHASIS-HF 3%. I am inclind to think that sprironolactone is probably more effective. However, it is also correctly noted that baseline characteristics of the two study populations were different. Thus, it is not reasonable to reach a conclusion unless head to head trial is done.
Of course-a head to head trial is the way to go-however my point is that pending a direct comparison-still the absolute numbers are much more in favorable for the actually cheaper spironolactone……….
and the question at this time unfortunately is also whether a more cost effective way remains for treating heart failure and not just if aldosterone antagonists have a role(which I think is amply proven by now)…..
Also can’t ignore the fact that only 13% of the patients in each group had an ICD at baseline. In current practice essentially all patients with EF < 35% should have an ICD. The subgroup analysis, however, did suggest benefit even in the group with ICD/CRT. Something to keep in mind, but I think it is definitely reasonable to add an aldosterone antagonist in patients with class II systolic HF on optimal doses of ACEI/ARB and beta-blocker.
Cant disagree-only question is should it be the more expensive eplerenone or the one with slightly more side effect profile like spironolactone and canrenone…..
Dr. Malm,
I agree…based on current guidelines these patients definitely _should_ have ICDs. However, recent surveys demonstrated that this is sadly not the case. Even for secondary prevention, only 30.7% received devices in one study. I think the EMPHASIS-HF trial is pretty helpful in guiding treatment for these patients!