EPHESUS

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. 2003 Eplerenone Post–Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)

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 Exclusion Criteria Use of potassium-sparing diuretics Creatinine >2.5 before randomization Serum potassium >5 before randomization • 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)

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. Rate of death from any cause RR = 0.85, p = 0.008

12. Rate of death from CV Cause RR = 0.87, p = 0.002

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 EPHESUS Trial 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 EPHESUS Trial 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? • Get repeat Echo is 3 months • Add Eplerenone • Increase Metoprolol • Start Clopidogrel and stop Ticagrelol • 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? • Get repeat Echo is 3 months • Add Eplerenone • Increase Metoprolol • Start Clopidogrel and stop Ticagrelol • 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