What are the indications for Spironolactone (potassium-sparing diuretic)?

Indications for Spironolactone

Spironolactone is FDA-approved for heart failure with reduced ejection fraction (NYHA Class III-IV), hypertension (as add-on therapy), edema associated with hepatic cirrhosis or nephrotic syndrome, and primary hyperaldosteronism. 1

FDA-Approved Indications

Heart Failure with Reduced Ejection Fraction

• Spironolactone is indicated for NYHA Class III-IV heart failure with reduced ejection fraction to increase survival, manage edema, and reduce hospitalization. 1
• The drug should be used in conjunction with other heart failure therapies including ACE inhibitors and beta-blockers. 2
• In the landmark RALES trial, spironolactone (25-50 mg daily) reduced mortality by 30% and heart failure hospitalizations by 35% when added to conventional therapy in patients with LVEF ≤35%. 2
• The number needed to treat for 2 years to prevent one death is 9 in patients with severe heart failure. 2
• Post-myocardial infarction patients with LVEF ≤40% and heart failure or diabetes also benefit, with a 15% reduction in mortality (EPHESUS trial with eplerenone). 2

Hypertension

• Spironolactone is indicated as add-on therapy for hypertension in patients not adequately controlled on other agents. 1
• Effective doses range from 25-100 mg daily for blood pressure control. 3
• Particularly effective in three-drug-resistant hypertension at modest dosages. 4
• Lowering blood pressure reduces fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. 1

Edema Associated with Hepatic Cirrhosis

• Spironolactone is the first-line diuretic for ascites in cirrhosis, with a 95% response rate compared to 52% for furosemide alone. 2
• Starting dose is typically 100 mg daily, with potential titration up to 400 mg daily to achieve adequate natriuresis. 3
• The drug works by antagonizing secondary aldosteronism, which plays a major role in renal sodium retention in cirrhosis. 2
• Target weight loss should not exceed 0.5 kg/day without peripheral edema, or 1 kg/day with peripheral edema. 2
• There is a 3-5 day lag between treatment initiation and full natriuretic effect. 3

Edema Associated with Nephrotic Syndrome

• Indicated when treatment of underlying disease, fluid/sodium restriction, and other diuretics produce inadequate response. 1
• Particularly useful when other diuretics have caused hypokalemia, as spironolactone conserves potassium. 1

Primary Hyperaldosteronism

• Indicated for short-term preoperative treatment and long-term maintenance therapy in patients with aldosterone-producing adenomas who are not surgical candidates. 1
• Doses of 25-400 mg daily effectively control blood pressure and hypokalemia in the majority of cases. 5
• Considered the drug of first choice in idiopathic hyperaldosteronism. 5

Off-Label Uses with Evidence

Central Serous Chorioretinopathy

• Small prospective studies show potential benefit with improved visual acuity, reduced choroidal thickness, and reduced subretinal fluid. 3
• However, large randomized controlled trials (SPECTRA and VICI) with eplerenone did not demonstrate significant benefit, suggesting insufficient evidence for routine use. 2
• Doses studied include 25-50 mg daily, with some studies showing 44-71% complete subretinal fluid resolution. 2

Chronic Kidney Disease and Diabetic Nephropathy

• Low-dose spironolactone decreases albuminuria when added to maximal ACE inhibitor therapy. 4
• This represents a nongenomic effect independent of sodium excretion. 4

Critical Monitoring and Safety Considerations

Mandatory Monitoring Parameters

• Check renal function and serum electrolytes at baseline, 1 week, 4 weeks, then at 1,2,3, and 6 months, and every 6 months thereafter. 2
• Hyperkalemia risk is significant, particularly in elderly patients, those with diabetes, kidney disorders, or liver disease. 2, 3

Dose Adjustments for Adverse Events

• If potassium rises to >5.5 mmol/L: halve the dose (e.g., 25 mg on alternate days). 2
• If potassium rises to ≥6.0 mmol/L: stop spironolactone immediately and monitor closely; specific treatment may be needed. 2
• If creatinine rises to >220 μmol/L (2.5 mg/dL): halve the dose. 2
• If creatinine rises to >310 μmol/L (3.5 mg/dL): stop spironolactone immediately. 2

Contraindications

• Concomitant use of potassium supplements or other potassium-sparing diuretics. 3, 6
• Potent CYP3A4 inhibitors. 3, 6
• Combined use of ACE inhibitor with angiotensin receptor blocker. 3, 6

Common Side Effects (>10% of patients)

• Headache, diarrhea, fatigue. 3, 6
• Gynecomastia and decreased libido in men (10% in RALES trial). 2, 6
• Menstrual disruption and decreased arousal in women. 6
• These anti-androgenic effects result from competitive inhibition of testosterone and dihydrotestosterone binding to androgen receptors. 6

Serious Adverse Events in Heart Failure Patients

• Hepatic encephalopathy occurs in up to 25% of hospitalized patients on diuretics. 2
• Renal impairment occurs in 14-20%, especially without peripheral edema, but is usually reversible. 2
• Hyponatremia occurs in 8-30%. 2
• Adverse event prevalence ranges from 19-33%, with almost half requiring dose reduction or discontinuation. 2