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  1. 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.
  2. 2. 2003 Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)
  3. 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. 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. 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. 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. 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. 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. 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. 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
  11. 11. RATE OF DEATH FROM ANY CAUSE RR = 0.85, p = 0.008
  12. 12. RATE OF DEATH FROM CV CAUSE RR = 0.87, p = 0.002
  13. 13. RATE OF SUDDEN DEATH FROM CARDIAC CAUSE RR = 0.79, p = 0.03
  14. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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