Eplerenone Post-Ami Heart Failure Efficacy And Survival Study
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
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.
|
End point
|
Eplerenone, No. (%)
|
Placebo, No. (%)
|
Relative risk (95% CI)
|
p
|
| Mortality (Prim Endpt) | 478 (14.4) | 554 (16.7) | 0.85 (0.75-0.96) |
0.008 |
| Cardiovascular mortality | 407 (12.3) | 483 (14.6) | 0.83 (0.72-0.94) |
0.005 |
| CV mortality or hospitalization for CV events* | 885 (26.7) | 993 (30.0) | 0.87 (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.
|
End point
|
Eplerenone (%)
|
Placebo (%)
|
p
|
| 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.