Eplerenone vs Spironolactone: which is preferred for treatment?

Eplerenone vs Spironolactone: Treatment Preference

For heart failure and resistant hypertension, eplerenone should be the preferred first-line mineralocorticoid receptor antagonist, particularly in male patients, due to its significantly lower risk of sexual side effects while maintaining equivalent cardiovascular efficacy. 1, 2

Efficacy: Equivalent Cardiovascular Outcomes

• Both agents are equally effective for treating heart failure with reduced ejection fraction, resistant hypertension, and primary aldosteronism 1, 2
• Both medications improve morbidity and mortality in heart failure when added to standard therapy 3
• The antihypertensive effect is independent of baseline renin or aldosterone levels, making either agent appropriate regardless of renin profile 4

Side Effect Profile: Critical Differentiator

Spironolactone carries substantially higher risk of hormone-related adverse effects:

• Gynecomastia and impotence occur commonly with spironolactone due to non-selective binding to progesterone and androgen receptors 1, 2, 5
• Eplerenone was specifically engineered with a 9,11-epoxide group to eliminate these sexual side effects while maintaining mineralocorticoid receptor blockade 1, 3
• Male patients particularly benefit from eplerenone's selective receptor binding, avoiding gynecomastia and sexual dysfunction 2

Hyperkalemia Risk: Similar Between Agents

• Both medications carry equal risk of hyperkalemia requiring identical monitoring protocols 1, 5
• Serum potassium and creatinine must be checked before initiation and monitored regularly during treatment 1
• The concern that eplerenone causes more hyperkalemia than spironolactone is unfounded—clinical trials show no difference in hyperkalemia-induced drug withdrawals 5
• Spironolactone's active metabolites have very long half-lives, potentially increasing cumulative hyperkalemia risk over time 3

Dosing Considerations

• Eplerenone: Start 25-50 mg once daily, titrate to target 50-100 mg daily; may require twice-daily dosing for adequate blood pressure control 1, 2
• Spironolactone: 25-100 mg once daily for hypertension; 25-50 mg daily for resistant hypertension 1, 6
• Eplerenone's shorter half-life and lack of active metabolites provide more predictable pharmacokinetics 3

Clinical Decision Algorithm

Start with eplerenone in:

• All male patients (to avoid gynecomastia and impotence) 2
• Patients concerned about sexual side effects or menstrual irregularities 5, 3
• Patients requiring twice-daily dosing for better blood pressure control 1

Consider spironolactone only when:

• Cost is prohibitive (though price difference is now negligible after eplerenone patent expiration) 1
• Patient has already tolerated spironolactone without side effects 1

Common Pitfalls and Monitoring

• Contraindications for both agents: Concurrent use of potassium supplements, other potassium-sparing diuretics, potent CYP3A4 inhibitors, or combined ACE inhibitor plus ARB therapy 1
• Avoid in pregnancy 1
• Renal dysfunction: Use caution when GFR <45 mL/min; avoid in severe renal impairment 1
• Combining either agent with adequate-dose thiazide diuretics (particularly chlorthalidone) maximizes efficacy while reducing hyperkalemia risk in resistant hypertension 6
• Monitor potassium at baseline, 1 week after initiation, then monthly with dose adjustments per protocol 1