What are the guidelines for using eplerenone (an aldosterone antagonist) in patients with impaired renal function, specifically those with a glomerular filtration rate (GFR) under 30 milliliters per minute (ml/min)?

Eplerenone Use in Patients with GFR Under 30 ml/min

Eplerenone is contraindicated in patients with a GFR less than 30 ml/min due to high risk of life-threatening hyperkalemia. 1, 2

Rationale for Contraindication

• Mineralocorticoid receptor antagonists (MRAs) like eplerenone significantly increase the risk of hyperkalemia in patients with severely impaired renal function 1
• The American Heart Association/American College of Cardiology guidelines explicitly recommend MRAs only if estimated glomerular filtration rate is >30 mL/min/1.73 m² and serum potassium is <5.0 mEq/L 1
• Rates of hyperkalemia with eplerenone increase dramatically with decreasing renal function, with 32% of patients with creatinine clearance ≤30 mL/min developing hyperkalemia (>5.5 mEq/L) in clinical trials 3
• The FDA drug label for eplerenone shows that hyperkalemia rates are significantly higher in patients with lower baseline creatinine clearance 3

Risk Assessment in Severe Renal Impairment

• In patients with creatinine clearance ≤30 mL/min, the rate of hyperkalemia (>5.5 mEq/L) was 32% with eplerenone versus 23% with placebo 3
• Severe hyperkalemia (≥6.0 mEq/L) occurred in 5.5% of eplerenone-treated patients versus 3.9% of placebo-treated patients in the EPHESUS trial 3
• The risk of hyperkalemia increases further when eplerenone is combined with ACE inhibitors and/or ARBs, which are common medications in patients with heart failure 3, 1
• Patients with proteinuria, diabetes, or both have even higher rates of hyperkalemia when treated with eplerenone 3

Alternative Approaches

• For patients with heart failure and GFR <30 ml/min, other evidence-based therapies should be prioritized, including SGLT2 inhibitors, which have proven mortality benefits in heart failure regardless of the presence of diabetes 1
• Beta-blockers with proven mortality benefits (bisoprolol, carvedilol, sustained-release metoprolol succinate) should be continued as they do not have renal clearance restrictions 1
• Loop diuretics can be used for volume management in patients with severe renal impairment 1
• If potassium levels are normal and the patient has heart failure with reduced ejection fraction, ACE inhibitors or ARBs should be continued with close monitoring 1

Recent Evidence Challenging the Contraindication

• A 2024 pooled analysis of RALES and EMPHASIS-HF trials suggests that patients who experience a decline in eGFR to <30 mL/min/1.73 m² while on MRA therapy may still derive significant benefit 4
• This analysis showed that the risk reduction in cardiovascular death or HF hospitalization with MRA therapy was similar in those who experienced a decrease in eGFR to <30 mL/min/1.73 m² (HR: 0.65) compared with those who did not (HR: 0.63) 4
• However, this evidence applies to patients who develop worsening renal function while on therapy, not to patients who already have GFR <30 ml/min at baseline 4
• Current guidelines have not yet been updated to reflect this recent evidence, and the contraindication remains in place 1, 2

Monitoring Requirements if Used Despite Contraindication

• If a clinical decision is made to use eplerenone despite severe renal impairment (which is against guidelines):
  • Check potassium and renal function within 2-3 days of initiation 1, 2
  • Recheck at 7 days and then weekly for the first month 2
  • Continue monthly monitoring for at least 3 months 2
  • Use significantly reduced doses (12.5 mg every other day as starting dose) 2
  • Discontinue immediately if potassium rises above 6.0 mmol/L 1, 2
  • Avoid concomitant use of NSAIDs, potassium supplements, and high-potassium foods 2
  • Temporarily stop during episodes of diarrhea, dehydration, or when loop diuretic therapy is interrupted 2

Conclusion

Based on current guidelines and evidence, eplerenone should not be used in patients with GFR <30 ml/min due to the significantly increased risk of potentially life-threatening hyperkalemia. While recent research suggests continued benefit in patients who develop worsening renal function while on therapy, this does not override the contraindication for initiating therapy in patients with baseline severe renal impairment.