In patients with ischemic heart disease who have had a recent myocardial infarction and reduced left‑ventricular ejection fraction (≤40%) or heart‑failure symptoms/type‑2 diabetes, should eplerenone be added to standard therapy, and what are the recommended dose and monitoring?

Eplerenone in Ischemic Heart Disease Post-Myocardial Infarction

Eplerenone should be added to standard therapy (ACE inhibitor/ARB and beta-blocker) in patients with recent myocardial infarction who have LVEF ≤40% AND either clinical heart failure symptoms OR diabetes mellitus, starting at 25 mg daily and titrating to 50 mg daily after 4 weeks if potassium remains <5.0 mEq/L. 1

Patient Selection Criteria

You must verify ALL of the following before prescribing eplerenone:

• LVEF ≤40% documented after the acute MI 1
• Clinical heart failure symptoms (pulmonary congestion on exam/chest x-ray, S3 gallop, Killip class II or higher) OR diabetes mellitus 1, 2
• Already receiving optimized ACE inhibitor (or ARB) AND beta-blocker therapy at target doses 1, 3
• Timing: 3-14 days post-MI when patient is clinically stable 1, 2

This recommendation is based on the landmark EPHESUS trial, which demonstrated a 15% reduction in all-cause mortality and 13% reduction in cardiovascular death or hospitalization in 6,632 patients meeting these criteria, with benefits appearing within 30 days of initiation. 1, 2

Absolute Contraindications (Do Not Prescribe If Present)

• Serum potassium >5.0 mEq/L at baseline 1, 2
• Serum creatinine >2.5 mg/dL in men or >2.0 mg/dL in women 1, 2
• eGFR <30 mL/min/1.73m² 3
• Concomitant use of potassium supplements or potassium-sparing diuretics 4

These exclusion criteria were strictly enforced in EPHESUS to prevent life-threatening hyperkalemia. 2

Dosing Protocol

Starting dose: 25 mg once daily 1, 2

Target dose: 50 mg once daily after 4 weeks if serum potassium remains <5.0 mEq/L 1, 2

Dose adjustments during therapy: 2

• If potassium 5.0-5.4 mEq/L: Reduce dose from 50 mg to 25 mg daily, or from 25 mg to every other day
• If potassium 5.5-5.9 mEq/L: Withhold eplerenone until potassium <5.0 mEq/L, then restart at 25 mg every other day
• If potassium ≥6.0 mEq/L: Discontinue eplerenone permanently

Mandatory Monitoring Protocol

The monitoring schedule is critical to prevent hyperkalemia-related mortality:

Before initiation: Check serum potassium and creatinine 3

After starting eplerenone: 3, 5

• Within 3 days of initiation
• At 1 week
• At 1 month
• At 2 months
• At 3 months
• At 6 months
• Then every 3 months thereafter

If creatinine rises: 3

• To >220 μmol/L (2.5 mg/dL): Halve the dose immediately
• To >310 μmol/L (3.5 mg/dL): Stop eplerenone completely

Evidence Quality and Magnitude of Benefit

The 2025 ACC/AHA guidelines assign eplerenone a Class I recommendation (should be given) with Level of Evidence B for this specific population. 1 The EPHESUS trial showed that 86% of patients were already on ACE inhibitor/ARB and 75% on beta-blockers, demonstrating that eplerenone provides additional mortality benefit beyond standard therapy. 1

A post-hoc analysis demonstrated that earlier initiation (<7 days post-MI) significantly reduced sudden cardiac death and cardiovascular mortality compared to later initiation (≥7 days), supporting prompt use once the patient is stabilized. 1

Patients with LVEF = 40% ("Mid-Range")

Recent evidence suggests that patients with LVEF exactly 40% derive similar benefit to those with LVEF <40%. 6 In this subgroup analysis of EPHESUS, eplerenone reduced the composite endpoint of cardiovascular death or hospitalization homogeneously regardless of whether LVEF was 40% or <40% (interaction p=0.21). 6 Therefore, do not withhold eplerenone from patients with LVEF = 40% who meet other criteria. 6

Common Pitfalls to Avoid

Never use eplerenone as monotherapy—it must be added to optimized ACE inhibitor/ARB and beta-blocker therapy, not used instead of these agents. 3, 5

Do not combine ACE inhibitor + ARB + eplerenone—the 2025 guidelines explicitly state that concomitant use of ACE inhibitor and ARB should be avoided due to increased adverse events without added benefit. 1

Do not prescribe in patients with advanced chronic kidney disease—the EPHESUS trial excluded patients with creatinine >2.5 mg/dL, and real-world use in this population carries unacceptable hyperkalemia risk. 1, 2

Monitor more frequently in high-risk patients—those with diabetes, reduced renal function, or on other medications that increase potassium are at highest risk for hyperkalemia and require closer surveillance. 7

Economic Considerations

Eplerenone reduces mean length of heart failure hospitalization by 1.6 days (9.2 vs 10.8 days with placebo, p=0.019) and total days spent hospitalized for heart failure by 3.6 days (13.3 vs 16.9 days, p=0.0006). 8 Given the high cost of heart failure hospitalizations, this translates into substantial economic benefit beyond the mortality reduction. 8