When should spironolactone be added to a hypertensive regimen?

When to Add Spironolactone to a Hypertensive Regimen

Add low-dose spironolactone (25-50 mg daily) as the fourth-line agent when blood pressure remains ≥140/90 mmHg despite optimal doses of three antihypertensive medications (including a diuretic, ACE inhibitor or ARB, and typically a calcium channel blocker), after confirming true resistant hypertension and ensuring serum potassium is <4.5 mmol/L and eGFR is >45 mL/min/1.73m² 1.

Definition of Resistant Hypertension

Before adding spironolactone, confirm true resistant hypertension by excluding pseudoresistance 1:

• Verify proper blood pressure measurement technique - ensure appropriate cuff size and positioning 1
• Rule out white coat hypertension - use home or ambulatory blood pressure monitoring to confirm elevated readings outside the office 2
• Assess medication adherence - approximately 50% of patients diagnosed with resistant hypertension have pseudoresistance rather than true resistance 1
• Exclude substance-induced hypertension - review NSAIDs, decongestants, alcohol, and other interfering substances 1

Optimize Current Regimen First

Before adding spironolactone, maximize the existing three-drug regimen 1:

• Ensure optimal doses - all three medications should be at maximally tolerated doses 1
• Optimize diuretic choice - use thiazide-like diuretics (chlorthalidone, indapamide) rather than hydrochlorothiazide for superior 24-hour blood pressure control 1, 3
• Switch to loop diuretics - if eGFR <30 mL/min/1.73m² or clinical volume overload is present 1
• Address lifestyle factors - reinforce dietary sodium restriction, weight loss, and exercise 1

Specific Criteria for Adding Spironolactone

Add spironolactone when all of the following are met 1:

• Blood pressure remains >140/90 mmHg on three optimized medications
• Serum potassium <4.5 mmol/L (some guidelines allow <5.0 mmol/L) 1
• eGFR >45 mL/min/1.73m² 1
• Serum creatinine <2.5 mg/dL in men or <2.0 mg/dL in women 1

Dosing and Monitoring

Initial dosing 2, 4:

• Start with 25 mg once daily 1, 2, 5
• May increase to 50 mg daily if tolerated and blood pressure remains uncontrolled 1, 2, 6
• Doses of 12.5-50 mg are typically sufficient; higher doses rarely provide additional benefit 2, 5

Monitoring requirements 2:

• Check serum potassium and creatinine 5-7 days after initiation
• Recheck every 5-7 days until stable
• Then monitor every 3-6 months thereafter

Expected Blood Pressure Reduction

Spironolactone provides substantial additional blood pressure lowering in resistant hypertension 5, 7, 6:

• Average reduction of 21-26/8-12 mmHg when added to three-drug regimens 5, 7, 6
• Effect is additive to ACE inhibitors, ARBs, and diuretics 5
• Benefit occurs regardless of primary aldosteronism status 5
• Superior to renal denervation for 24-hour blood pressure control 8

Special Populations

Heart failure with reduced ejection fraction 1, 4:

• Spironolactone is indicated for NYHA Class II-IV heart failure with ejection fraction <40%
• Provides mortality benefit in addition to blood pressure lowering
• Should be included in the regimen regardless of blood pressure if heart failure is present

Renal impairment 1, 3:

• If eGFR 30-50 mL/min/1.73m², consider initiating at 25 mg every other day due to hyperkalemia risk 4
• Switch from thiazide to loop diuretic for volume control when eGFR <30 mL/min/1.73m² 3
• Avoid if eGFR <30 mL/min/1.73m² unless under specialist supervision 1

Alternative Agents if Spironolactone Contraindicated

If spironolactone cannot be used, consider these alternatives in order of preference 1, 2:

1. Eplerenone (50-100 mg daily) - lower risk of gynecomastia 2
2. Amiloride (5-10 mg daily) - potassium-sparing alternative 1, 2
3. Doxazosin - alpha-blocker option 1
4. Beta-blockers - if not already in use 1
5. Clonidine - centrally acting agent 1

Critical Safety Considerations

Hyperkalemia risk 1, 2, 6:

• Occurs in approximately 4% of patients 6
• Risk increased when combined with ACE inhibitors or ARBs (which most resistant hypertension patients are taking) 1
• Discontinue if potassium rises above 5.5-6.0 mmol/L 1, 7

Other adverse effects 6, 9:

• Gynecomastia in approximately 5% of males 6
• Overall adverse effects leading to discontinuation in approximately 10% 6
• May cause decline in eGFR, particularly in those with baseline renal impairment 8

When to Refer to Specialist

Resistant hypertension should be managed in specialist centers when 1:

• Blood pressure remains uncontrolled despite spironolactone addition
• Secondary causes of hypertension are suspected
• Significant adverse effects occur requiring alternative management strategies
• Complex comorbidities complicate medication selection