Published on October 16, 2016
1. EPHESUS OVMC LANDMARK TRIALS SERIES 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 and EMPHASIS-HF trials showed that aldosterone antagonists reduced mortality in heart failure patients with reduced EF (HFrEF) Mechanism of Aldosterone blockade for Mortality: Likely through preventing ventricular remodeling and collagen formation in patients with LV dysfunction after MI Eplerenone is an aldosterone blocker that selectively blocks mineralocorticoid NOT glucocorticoid receptors Benefit over Spironolactone is lower rates of Gynecomastia However, it is unknown if post-acute MI, the role of aldosterone antagonist can still apply
4. CLINICAL QUESTION After a patient has an acute MI complicated by HFrEF <40%, does addition of epelrenone (aldosterone antagonist) help reduce mortality?
5. DESIGN Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial N=6,642 Eplerenone (n=3,313) Placebo (n=3,319) Setting: 674 centers in 37 countries Enrollment: 1999-2001 Median follow-up: 16 months Primary outcomes: All-cause mortality CV mortality or hospitalization for CV events
6. POPULATION Inclusion Criteria MI in prior 3-14 days LVEF <40% HF (defined as pulmonary crackles, CXR with pulmonary venous congestion, or S3 heart sound) No symptoms required in diabetic patients Exclusion Criteria Use of potassium-sparing diuretics Creatinine >2.5 before randomization Serum potassium >5 before randomization
7. 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
8. 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 by
9. 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.
10. 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?
11. DISCUSSION QUESTIONS/ANSWERS What is the benefit of Eplerenone over Spironolactone? Disadvantage? ANSWER: Benefit: Lower rates of Gynecomastia 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%)
12. 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 stop Ticagrelol E. No Changes
13. 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 stop Ticagrelol E. No Changes
14. 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)