1. EPHESUS
ISABELLA LAI
Pitt B, et al. "Eplerenone, a selective aldosterone
blocker, in patients with left ventricular dysfunction after
myocardial infarction". The New England Journal of
Medicine. 2003. 348(14):1309-21.
3. BACKGROUND
The RALES 1999 showed that aldosterone
antagonists reduce mortality for patients with heart
failure with reduced EF (HFrEF)
Mechanism of Aldosterone blockade for Mortality:
Likely through decreasing inflammation preventing ventricular
remodeling and collagen formation in patients with LV
dysfunction after MI
RALES studied spironolactone in patients with HFrEF 35%,
NYHA III-IV symptoms
4. BACKGROUND
Eplerenone is an aldosterone blocker that selectively blocks mineralocorticoid NOT
androgenic/progesterone/glucocorticoid receptors
Benefit over Spironolactone is lower rates of Gynecomastia
Prior to EPHESUS, it was unknown if post-acute MI, the role of aldosterone antagonist can have similar
benefits
5. CLINICAL QUESTION
After a patient has an acute MI
complicated by HFrEF <40%, how does
addition of eplerenone (aldosterone
antagonist) effect morbidity/mortality?
6. DESIGN
Trial Design: Multicenter, double-blind, international,parallel-group, randomized, placebo-controlled trial
N=6,642 (88% power to detect 18% difference between the two groups)
Eplerenone (n=3,313)
Placebo (n=3,319)
Mean follow-up: 16 months
7. DESIGN
Primary outcomes:
1) Time to death from ANY cause
2) Time to death from CV events or complications
3) First hospitalization from CV event
Secondary outcomes:
Death from CV events and death from any cause OR any hospitalization
8. INTERVENTIONS
Randomized to a group:
Eplerenone
25mg for 4 weeks
Then, if tolerated, 50mg qday, HOLD for hyperkalemia >5.5
Placebo
All patients received optimal medical therapy, including ACE inhibitors,ARBs, diuretics, beta-blockers, and
coronary revascularization
9. POPULATION
Inclusion Criteria
MI in prior 3-14 days
LVEF <40%
Symptoms of heart failures (defined as pulmonary
crackles, CXR with pulmonary venous congestion,
or S3 heart sound)
Exclusion Criteria
Use of potassium-sparing diuretics
Creatinine >2.5 before randomization
Serum potassium >5 before randomization
10. RESULTS
During 16 month follow-up
478 deaths in eplerenone group
407 attributed to CV cause
554 deaths in placebo group
483 attributed to CV causes
13. RATE OF SUDDEN DEATH FROM CARDIAC CAUSE RR = 0.79, p = 0.03
14. SIDE EFFECTS
Hyperkalemia
3.4 vs. 2.0% (p<0.001)
Serious hyperkalemia (>6)
5.5 vs. 3.9% (p = 0.002)
Hypokalemia
0.5 vs. 1.5% (0<0.001)
Serious hypokalemia (<3.5)
8.4% vs. 13.1% (p<0.001)
GI Disorder
19.9% vs. 17.7 (p = 0.02)
Gynecomastia
0.5 vs 0.6% (p = non-significant)
15. DISCUSSION
• Adding eplerenone at maximal dose of 50mg once daily in patients 3-14 days (mean 7 days) post-MI
resulted in reduced overall mortality and rate of death from CV causes or hospitalization from CV causes
16. DISCUSSION (CONT.)
• However, of note, mortality rate in control group of this trial was 13.6% (those who received both ACEi and
Beta blockers) This is HIGHER than in CAPRICORN (Carvedilol) trial and OPTIMAAL trial (Losartan) post-
MI
• Thought to be due to high number of patients in heart failure
• Mortality in Eplerenone group HIGHER than in Spironolactone group of RALES trial
• Mean EF in Ephesus 33%, EF in RALES was 25%)
17. BOTTOM LINE
Among patients with acute MI complicated by LV
dysfunction with reduced EF<40%, the addition
of eplerenone to optimal medical therapy showed a
15% REDUCTION in morbidity and mortality.
Number needed to treat of 50 patients to save
one life in 1 year
Number needed to treat of 33 to prevent one
death from CV causes or one hospitalization
for CV event in 1 year
18. CRITICISMS
This study was funded by Pharmacia, the makers
of Inspra (Eplerenone)
Beta-blockers was established as the standard of
care and used widely during the study period, as
opposed to when RALES study was performed
(RALES study only showed 10% improvement in
benefits)
The RALES trial used Spironolactone.The cost of
Eplerenone is significantly higher.
19. DISCUSSION QUESTIONS
What is the benefit of Eplerenone over
Spironolactone? Disadvantage?
How is the EPHESUSTrial different than the
RALES trial?
According to the EPHESUS trial, in patients
after an acute MI, should aldosterone
antagonist be started? If so, when?
20. DISCUSSION QUESTIONS/ANSWERS
What is the benefit of Eplerenone over Spironolactone? Disadvantage?
ANSWER:
Benefit: Lower rates of Gynecomastia
Disadvantage: Cost--Eplerenone is more expensive
How is the EPHESUSTrial different than the RALES trial?
ANSWER: The RALES trial showed that aldosterone blockade reduces mortality in severe systolic
heart failure.The EPHESUS trial showed that mineralcorticoid antagonist after an acute MI is beneficial
According to the EPHESUS trial, in patients after an acute MI, should aldosterone antagonist be started? If so,
when?
ANSWER: Yes,Aldosterone antagonist should be started in patients after an acute MI if HFrEF is
present (LVEF <40%)
21. BOARD-LIKE QUESTION
A 61 yo women, with hx DM2, HTN, HLD, is 5 days
s/p DES in LAD for STEMI For the past few days, she
is chest pain free.
Meds include Aspirin 81,Ticagrelor, Metoprolol,
Lisinopril, atorvastatin, and sublingual nitroglycerin
PRN.
Physical examination:
HR 78, BP 121, 72. BMI 22.
Lungs clear
Heart: RRR, normal S1/S2, no S3/S4/gallops/murmurs
Labs: K 4.5, Creatinine 1.7 (baseline)
Echo: LVEF 25%
(ADAPTED from MKSAP 17)
QUESTION
Which of the following is the most appropriate
adjustment to his discharge medications?
A. Get repeat Echo is 3 months
B. Add Eplerenone
C. Increase Metoprolol
D. Start Clopidogrel and stopTicagrelol
E. No Changes
22. BOARD-LIKE QUESTION
Educational Objective:
How to manage patients post-ACS and PCI.
Key Point:
- Optimal medical therapy: Lifestyle changes and
pharmacologic therapy -- Aspirin, BB,ACEi, Statin.
Additionally, post-PCI patients should be on a
P2Y12 inhibitors (clopidogrel, prasugrel, ticagrelor)
for at least 1 year
- Aldosterone antagonist to be added in patients
with reduced EF <40% after MI; however, <35% if
has HFrEF not post MI.
- This patient’s EF is reduced so Eplerenone should
be started
ANSWER
Which of the following is the most appropriate
adjustment to his discharge medications?
A. Get repeat Echo is 3 months
B. Add Eplerenone
C. Increase Metoprolol
D. Start Clopidogrel and stopTicagrelol
E. No Changes
23. AHA/ACCF HEART FAILURE RECOMMENDATIONS
Aldosterone antagonists recommended if NYHA class II-IV,
LVEF ≤35% unless contraindicated (class I, level A)
If NYHA class II, should have prior CV hospitalization or
elevated BNP (or analogous test)
Aldosterone antagonists recommended after MI if LVEF
≤40% with HF symptoms or DM unless contraindicated
(class I, level B)
Aldosterone antagonists harmful if creatinine >2.5 mg/dL
in men or >2.0 mg/dL in women (GFR <30 mL/min/1.73
m2) or potassium ≥5.0 mEq/L (class III, level B)
24. REFERENCES
Pitt B, et al. "Eplerenone, a selective aldosterone
blocker, in patients with left ventricular dysfunction
after myocardial infarction". The New England Journal
of Medicine. 2003. 348(14):1309-21.
Brain, P. EPHESUS.
https://www.wikijournalclub.org/wiki/EPHESUS