What is the next best step for a patient with uncontrolled hypertension (blood pressure 160/90) already on amlodipine (5mg) and olmesartan (40mg)?

Add a Thiazide or Thiazide-Like Diuretic as the Third Agent

For this patient with uncontrolled hypertension (BP 160/90) on amlodipine 5mg and olmesartan 40mg, add a thiazide or thiazide-like diuretic as the third antihypertensive agent. 1, 2

Rationale for Adding a Diuretic

• The patient is already on a calcium channel blocker (amlodipine) and an ARB (olmesartan 40mg, which is the maximum dose), representing two complementary drug classes 3
• The 2024 ESC guidelines recommend a three-drug combination of RAS blocker + calcium channel blocker + thiazide diuretic for uncontrolled hypertension 1
• This combination targets different mechanisms: volume reduction (diuretic), vasodilation (CCB), and renin-angiotensin system blockade (ARB) 1, 2

Specific Diuretic Recommendations

• Chlorthalidone 12.5-25mg daily is preferred over hydrochlorothiazide due to its longer duration of action and superior 24-hour ambulatory blood pressure reduction 4
• Hydrochlorothiazide 25-50mg daily is an acceptable alternative if chlorthalidone is not available 2
• Adding HCTZ to olmesartan 20mg provides dose-dependent BP reductions, with HCTZ 25mg providing significantly greater 24-hour BP control than 12.5mg 5

Before Adding the Diuretic: Critical Steps

• Verify medication adherence first, as non-adherence is the most common cause of apparent treatment resistance 2
• Consider increasing amlodipine from 5mg to 10mg before adding a third agent, as the patient is not yet on maximum doses of both current medications 6
• Rule out secondary causes of hypertension, particularly if the patient has features suggesting resistant hypertension 2

Expected Outcomes

• The combination of olmesartan/HCTZ achieved BP goals of <140/90 mmHg in 66.3% of patients with stage 2 hypertension 7
• Adding HCTZ to olmesartan approximately doubles response rates, with HCTZ 25mg achieving 69.5% response rates versus monotherapy 5
• Target BP should be <140/90 mmHg minimum, ideally <130/80 mmHg for higher-risk patients 1, 2

Monitoring After Adding Diuretic

• Check serum potassium and creatinine within 2-4 weeks after initiating diuretic therapy to detect hypokalemia, hyponatremia, or renal function changes 2, 4
• Reassess BP within 2-4 weeks after adding the diuretic, with the goal of achieving target BP within 3 months 2
• Monitor for hyperuricemia and glucose intolerance, which are known thiazide-related adverse effects 2

If Triple Therapy Fails: Fourth-Line Agent

• Add spironolactone 25-50mg daily as the preferred fourth-line agent if BP remains uncontrolled despite optimized triple therapy (ARB + CCB + thiazide diuretic) 1, 4
• The 2024 ESC guidelines specifically recommend spironolactone for resistant hypertension, with evidence showing additional BP reductions of 25/12 mmHg systolic/diastolic 1, 4
• Monitor potassium closely when adding spironolactone to olmesartan, as the combination significantly increases hyperkalemia risk 2, 4
• Alternative fourth-line agents include eplerenone, amiloride, bisoprolol, or doxazosin if spironolactone is not tolerated 1

Important Caveats

• Reinforce lifestyle modifications, especially sodium restriction to <2g/day, which can provide additive BP reduction of 10-20 mmHg 1, 2
• Do not combine olmesartan with an ACE inhibitor, as this increases adverse events without additional BP benefit 2, 4
• For Black patients specifically, the combination of CCB + thiazide diuretic may be more effective than CCB + ARB, though the patient is already on the ARB 1, 2