View source for Eplerenone Post-Ami Heart Failure Efficacy And Survival Study

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==Acronym==
EPHESUS stands for Eplerenone Post-AMI Heart Failure Efficacy and Survival Trial.

==Background==
[[Eplerenone]] is an [[aldosterone antagonist]] that blocks the mineralocorticoid receptor.  In contrast to [[spironolactone]], it does  not block the glucocorticoid, progesterone, or androgen receptors and for that reason it may may be associated with fewer side effects than [[spironolactone]].  Pre clinical studies have demonstrated that aldosterone antagonism may improve ventricular remodeling and collagen formation among patients who sustain LV dysfunction following an MI.

The EPHESUS study builds upon the [[RALES]] study ([[Randomized Aldactone Evaluation Study]]) which demonstrated that aldosterone inhibition with the older agent [[spironolactone]] reduced mortality when added to an ACE inhibitor among patients with severe [[congestive heart failure]].  In the older [[RALES study]], only 10% of patients were on a beta blocker, and the benefit of an [[aldosterone antagonist]] on top of beta blockade was not adequately tested.

==Methods==
Entry criteria included a left ventricular ejection fraction <40% or diabetes a range of 3 to 14 days following MI (median = 7 days). Patients (n=6632) were randomized to administration of either eplerenone at a starting dose of 25 mg (titrated to a maximum of 50 mg q day, mean dose 43 mg) versus placebo.  Exclusion criteria included a baseline K+ of > meq/li and a baseline Cr of > 2.5 mg/dl.  This was an event driven trial that was continued until there were 1012 deaths.  There was a median of 16 months of follow-up.

==Results==

All cause death, and cardiovascular death, and cardiovascular death plus rehospitalization were all significantly reduced over 16 months of follow-up.


{| border="0" cellspacing="1" cellpadding="4"
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End point

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| '''

Eplerenone, No. (%)

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| '''

Placebo, No. (%)

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| '''

Relative risk (95% CI)

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| '''

p

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|-
| Mortality (Prim Endpt)
| 478 (14.4)
| 554 (16.7)
| 0.85 <br />(0.75-0.96)
| 0.008
|-
| Cardiovascular mortality
| 407 (12.3)
| 483 (14.6)
| 0.83 <br />(0.72-0.94)
| 0.005
|-
| CV mortality or hospitalization for CV events*
| 885 (26.7)
| 993 (30.0)
| 0.87 <br />(0.79-0.95)
| 0.002
|}

[[Sudden death]] from cardiac causes was reduced (p=0.03).  Among those patients who would qualify for an AICD by MADIT II criteria (an LVEF <30%), there was a 33% reduction in [[sudden cardiac death]].  When the analysis was restricted to those patients who were treated with optimal evidence based therapy with an ACE/ARB, aspirin, statin, beta-blockade and reperfusion therapy there was still a 26% reduction in all cause mortality.

Number Needed to Treat (NNT) = 50 patients to save one life, and 33 to prevent one cardiovascular death or rehospitalization.

==Adverse Events==
As might be expected from an [[aldosterone inhbitor]], the risk of [[hyperkalemia]] was significantly increased among those patients with a Cr clearance < 50 cc / minute on entry into the trial.  There were no deaths attributable to hyperkalemia.  As a result, potassium levels should be monitored in patients on [[eplerenone]].  Interestingly, the risk of [[hypokalemia]] was actually twice as high as the risk of [[hyperkalemia]].  It is notable that [[eplerenone]] reduced the risk of [[hypokalemia]].  The investigators hypothesized that reducing the risk of [[hypokalemia]] was important in so far as the presence of [[hypokalemia]] reversed any benefit from antihypertensive therapy in the [[SHEP]] trial.

     {| border="0" cellspacing="1" cellpadding="4"
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End point

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Eplerenone (%)

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Placebo (%)

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p

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|-
| Serious hyperkalemia
| 5.5
| 3.9
| 0.002
|-
| Hypokalemia
| 8.4
| 13.1
| <0.001
|}

Consistent with the improved specificity of the agent, there was no increase in the risk of gynecomastia, or menstrual disorders with [[eplerenone]].

==Summary==
Among MI patients with LV dysfunction, the administration of eplerenone (Inspra®, Pharmacia) in addition to evidence based therapy is associated with a 15% reduction in all cause mortality.  In addition, cardiovascular death, and CV death and hospitalization were also significantly reduced.

==References==
{{Reflist|2}}

[[Category:Cardiology]]
[[Category:Clinical trials]]