What is the next step in managing a patient's hypertension who is already on indapamide (Indapamide) 2.5mg, amlodipine (Amlodipine) 5mg, and perindopril ( Coversyl, ACE inhibitor) 8mg?

Management of Uncontrolled Hypertension on Triple Therapy

Add spironolactone 25 mg once daily as the fourth-line agent for this patient with resistant hypertension who is already on maximal triple therapy (perindopril 8 mg, indapamide 2.5 mg, amlodipine 5 mg). 1

Current Regimen Assessment

Your patient is already on the guideline-recommended triple combination for hypertension:

• ACE inhibitor (perindopril 8 mg) - at maximum dose 1
• Thiazide-like diuretic (indapamide 2.5 mg) - at maximum effective dose 1, 2
• Calcium channel blocker (amlodipine 5 mg) - can be increased to 10 mg 1, 3

Recommended Next Steps

Option 1: Optimize Current Regimen First (Preferred Initial Step)

Increase amlodipine from 5 mg to 10 mg once daily before adding a fourth agent. 1, 3

• The 2024 ESC guidelines recommend optimizing the three-drug combination before adding a fourth medication 1
• Amlodipine can be safely titrated to 10 mg daily, which provides additional blood pressure reduction 3, 4
• Wait 7-14 days between titration steps to assess response, though more rapid titration is acceptable with frequent monitoring 3
• This approach maintains the proven triple combination of RAS blocker + thiazide-like diuretic + dihydropyridine CCB at maximal doses 1, 5

Option 2: Add Fourth-Line Agent (If BP Remains Uncontrolled After Amlodipine Optimization)

Add spironolactone 25-50 mg once daily as the mineralocorticoid receptor antagonist. 1

• The 2024 ESC guidelines give a Class IIa, Level B recommendation for adding spironolactone when BP is not controlled with optimal triple therapy 1
• Start at 25 mg once daily and titrate to 50 mg if needed and tolerated 1
• Spironolactone is the preferred fourth-line agent in resistant hypertension, superior to adding other drug classes 1

Critical Monitoring Requirements

Check serum potassium and creatinine within 1-2 weeks after any medication adjustment involving the ACE inhibitor or adding spironolactone. 1

• The combination of perindopril + spironolactone significantly increases hyperkalemia risk 1
• Monitor for acute kidney injury, especially with eGFR <45 mL/min 1
• Avoid spironolactone if baseline potassium >5.0 mEq/L or eGFR <30 mL/min 1

Alternative Fourth-Line Options (If Spironolactone Not Tolerated or Contraindicated)

If spironolactone causes hyperkalemia, gynecomastia, or is otherwise not tolerated:

• Eplerenone 50-100 mg once daily - alternative mineralocorticoid receptor antagonist with less hormonal side effects 1
• Beta-blocker (e.g., metoprolol succinate, bisoprolol) if heart rate >70 bpm and no contraindications 1
• Alpha-blocker, centrally acting agent, or hydralazine as subsequent options 1

Important Caveats

Do NOT add another ACE inhibitor or ARB - dual RAS blockade is explicitly contraindicated and increases risk of hypotension, hyperkalemia, and acute kidney injury without cardiovascular benefit. 1

Confirm true resistant hypertension before escalating therapy:

• Verify medication adherence 1
• Exclude white coat hypertension with home or ambulatory BP monitoring 1
• Ensure proper BP measurement technique 1
• Screen for secondary causes of hypertension if not already done 1

Assess for target organ damage including left ventricular hypertrophy, proteinuria, and reduced eGFR to guide urgency of treatment intensification. 1

Evidence Supporting This Approach

The PIANIST and PETRA studies demonstrated that the triple combination of perindopril/indapamide/amlodipine achieved BP control in 72-81% of high-risk hypertensive patients, with mean BP reductions of 28/14 mmHg. 5, 6 For the remaining patients requiring fourth-line therapy, spironolactone has the strongest evidence base for resistant hypertension. 1