13th January 2011
The EMPHASIS-HF study found that adding eplerenone▼ to recommended therapy for heart failure (HF) with left ventricular systolic dysfunction (LVSD) reduced the risk of a composite of death from cardiovascular (CV) causes or hospitalisation for HF compared with placebo in patients with mild symptoms. However, this was in a very specific patient group (e.g. with additional CV risk factors, recent CV hospitalisation) and the results may not be applicable to all patients with ‘mild symptoms’. Furthermore, it is unclear if adding in the other aldosterone antagonist spironolactone instead may have produced similar results in these patients at significantly lower cost.
Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.
Health professionals should continue to follow the recently updated NICE guidance on the management of heart failure. ACE inhibitors and beta-blockers licensed for heart failure should be considered as first-line treatments in patients with HF due to LVSD, using clinical judgement to decide which drug to start first. Aldosterone antagonists (spironolactone, eplerenone) can be considered as a second-line option, within licensed indications for patients whose symptoms persist despite optimal first-line treatment. Eplerenone is currently only licensed as an adjunct in LVSD and evidence of HF post-myocardial infarction (MI). Specialist advice should be sought before offering any second-line treatment.
What is the background to this?
The new NICE guideline on heart failure (CG108) was published in August 2010. As we reviewed previously, there are significant changes from the previous 2003 guidance, including new recommendations on drug treatment. As previously, the guidance recommends ACE inhibitors and beta-blockers licensed for heart failure first-line in patients with HF due to LVSD.
There have also been changes to the guidance on second-line drug treatments, which should be started only after specialist advice. Aldosterone antagonists, within licensed indications, are recommended as a second-line option for patients who remain symptomatic. Evidence for spironolactone is mainly derived from an RCT of patients with moderate to severe symptoms (NYHA class III–IV) and for eplerenone evidence is based on an RCT of post-MI patients with LVSD (see ‘How does this relate to other studies’ below).
An overview of the recommendations on all drug treatment options is available in the NICE quick reference guide. More information on heart failure can be found in a 2008 MeReC Bulletin, and on the heart failure section of NPC, which will be updated to reflect the changes outlined in the new NICE guidance in 2011.
This new study (EMPHASIS-HF) evaluated the effect of adding eplerenone to standard treatment for systolic HF in patients with mild symptoms (NYHA class II), compared with placebo.
What does this study claim?
This study was a double blind RCT which compared eplerenone (up to 50mg daily; n=1364) with placebo (n=1373) in patients with HF (NYHA class II symptoms) aged 55 years or over. The primary outcome (a composite of death from CV causes or first hospitalisation for HF) occurred in 18.3% of patients in the eplerenone group, compared with 25.9% in the placebo group (adjusted hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54 to 0.74, P<0.001, number needed to treat [NNT] 13 over 21 months).
Eplerenone also significantly reduced all cause death, death from CV causes, hospitalisations for HF, for CV causes, and for any reason, compared with placebo (see ‘Study details’). There were no significant differences in the occurrence of all adverse events between groups, although there was a significant increase in hyperkalaemia in the eplerenone group (8.0% vs. 3.7%, P<0.001).
How does this relate to other studies?
In the RALES study (n=1,663) spironolactone 25mg daily significantly reduced deaths from any cause (34.5% vs. 45.9%, relative risk [RR] 0.70, 95%CI 0.60 to 0.82, P<0.001, NNT 9) and hospitalisation for worsening heart failure (45.2% vs. 52.1%, RR 0.65, 95%CI 0.54 to 0.77, P<0.001, NNT 14 over 2 years), compared with placebo in patients with moderate to severe (NYHA class III and IV, LVEF<35%) HF symptoms. Patients received ACEI and diuretics but treatment with beta blockers was not optimised (only about 10% of patients), although this study was conducted over ten years ago.
In the EPHESUS study (n=6,632), eplerenone improved mortality compared with placebo when added to existing medical therapy within 3–14 days following acute MI (14.4% vs. 16.7%, RR 0.85, 95%CI 0.75 to 0.96, P=0.008, NNT 43 over 16 months). Patients had reduced LVEF (<40%) and diabetes or clinical signs of HF.
This study adds to the evidence base supporting the use of aldosterone antagonists in HF with LVSD by evaluating their use in patients with mild symptoms (NYHA class II). The results support NICE guidance — aldosterone antagonists are an appropriate option to consider in patients who are symptomatic despite optimal treatment with an ACEI and a beta blocker licensed for HF. However, neither this placebo-controlled study, nor indeed any other RCTs have compared eplerenone with spironolactone. While comparing the results of different studies is problematic, the relative benefits (as seen by the RRs) provided by spironolactone and eplerenone are similar in both studies. This may suggest that using either drug would provide a similar degree of benefit and that the differences in the absolute risks seen in the studies were due to the different baseline risks of the populations included in the studies.
What is known is that spironolactone is available at a significantly lower cost than eplerenone. A 28-day supply of spironolactone 25mg costs £1.50, compared with £42.72 for eplerenone 25/50mg. An accompanying editorial comments that “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 who the side effects of spironolactone are disabling”.
Although eplerenone, in addition to recommended therapy significantly reduced the risk of death and hospitalisation compared with placebo, there are a number of important limitations to the study which limit its applicability to all patients with NYHA class II HF. Firstly, the patients selected had many additional CV risk factors — around half of patients had a previous MI, a similar number had a previous hospitalisation for HF, and hypertension and angina were common. All patients had a recent (last 6 months) hospitalisation for any CV reason and about a quarter had left bundle-branch block. They also had a marked reduction in LVEF (mean 26%), a figure similar to the RALES study in moderate to severely symptomatic patients. Symptoms can fluctuate and the severity of symptoms (NYHA class) does not always reflect the severity of the underlying heart problem — people with severe heart disease can have mild symptoms, and vice versa. Given the characteristics of the patients in the study, clinicians should be cautious about extrapolating these results to all patients with HF and mild symptoms.
Finally, the trial was stopped early after a mean duration of 21 months according to prespecified rules. As the authors point out, this may have resulted in an overestimation of the effect of eplerenone — but the results are consistent with those seen with spironolactone in the RALES study.
Aldosterone antagonists, if used appropriately and within licensed indications, have an important role in the management of heart failure. Spironolactone is licensed for congestive HF, while eplerenone is only licensed for LVSD and evidence of heart failure post-MI. Advice on their use in the NICE guidance should be followed e.g. careful monitoring of potassium levels to ensure that renal function is not deteriorating.
Zannad F, et al. Eplerenone in patients with systolic heart failure and mild symptoms. NEJM 2011;364:11–21
Double blind RCT. Allocation concealed. Study was stopped early after a median of 21 months.
2737 patients aged >55 years (average age 69 years) with NYHA class II HF (mild symptoms) and a LVEF of <30% (or if >30 to 35%, a QRS duration of >130msec on electrocardiography). Some patients were also enrolled on the basis of B-type natriuretic peptide (BNP) measures. Exclusion criteria included acute MI, NYHA class III or IV HF and serum potassium level >5mmol/L. Patients were recruited from 30th March 2006 to 25th May 2010.
Intervention and comparison
Eplerenone (up to 50mg daily) versus placebo. All patients without contraindications were receiving ACEI or ARB (or both – over 90% of patients in both groups), and beta blockers (around 86% in both groups), at the recommended or maximum tolerated dose.
Outcomes and results
Primary outcome was a composite of death from CV causes or a first hospitalisation for HF — 18.3% of patients in the eplerenone group, compared with 25.9% in the placebo group (adjusted HR 0.63, 95% CI 0.54 to 0.74, P<0.001, NNT 13 over 21 months).
Selected secondary outcomes (all adjusted HRs):
All cause death — 12.5% for eplerenone vs. 15.5% for placebo, HR 0.76, 95%CI 0.62 to 0.93
Death from CV causes — 10.8% vs. 13.5%, HR 0.76, 95%CI 0.61 to 0.94
Any hospitalisation — 29.9 % vs. 35.8%, HR 0.77, 95%CI 0.67 to 0.88
Hospitalisation for HF — 12.0% vs. 18.4%, HR 0.58, 95%CI 0.47 to 0.70
Hospitalisation for CV causes — 22.3% vs. 29.1%, HR 0.69 95%CI 0.60 to 0.81
Fatal or non-fatal MI — 3.3% vs. 2.4%, HR 1.32 95%CI 0.84 to 2.06
All adverse events — 72.0% vs. 73.6%, P=0.37
Adverse events leading to discontinuation — 13.8% vs. 16.2%, P=0.09
Hyperkalaemia — 8.0% vs. 3.7%, P<0.001
Hypokalaemia — 1.2% vs. 2.2%, P=0.05
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