Is a combination of chlorthalidone, olmesartan (angiotensin II receptor blocker), and lisinopril (angiotensin-converting enzyme inhibitor) appropriate for a patient with hypertension and dizziness, previously on amlodipine (calcium channel blocker)/olmesartan?

Combining Chlorthalidone, Olmesartan, and Lisinopril is NOT Appropriate

This combination is explicitly contraindicated because it combines two renin-angiotensin system (RAS) blockers—olmesartan (an ARB) and lisinopril (an ACE inhibitor)—which significantly increases risks of hypotension, hyperkalemia, and acute renal failure without providing additional cardiovascular benefit. 1, 2, 3

Why This Combination is Harmful

Dual RAS Blockade is Contraindicated

• The ESH/ESC guidelines explicitly state that the only combination that cannot be recommended is that between two different blockers of the RAS 1
• The ONTARGET trial demonstrated that combining an ACE inhibitor with an ARB resulted in a significant excess of end-stage renal disease (ESRD) without cardiovascular benefit 1
• The ALTITUDE trial was prematurely terminated due to excess ESRD and stroke when a renin inhibitor was added to existing ACE inhibitor or ARB therapy 1
• FDA labeling for both lisinopril and olmesartan explicitly warns that dual blockade of the RAS is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy 2, 3

Specific Risks of This Combination

• Hyperkalemia risk is substantially elevated when combining olmesartan with lisinopril, particularly when also using chlorthalidone (though chlorthalidone causes hypokalemia, the dual RAS blockade effect predominates) 2, 3
• Acute kidney injury occurs more frequently with dual RAS blockade 2, 3
• Hypotension is more common, especially when initiating lisinopril in patients already on diuretics like chlorthalidone 2
• Most patients receive no additional benefit from combining two RAS inhibitors compared to monotherapy 2, 3

What Should Be Done Instead

For Uncontrolled Hypertension on Olmesartan/Amlodipine

The appropriate third agent is chlorthalidone alone—NOT lisinopril. 4, 5

• The guideline-recommended triple therapy is: ARB (olmesartan) + calcium channel blocker (amlodipine) + thiazide-like diuretic (chlorthalidone) 1, 5
• Start chlorthalidone 12.5-25mg once daily 4, 5
• Chlorthalidone is preferred over hydrochlorothiazide due to its longer half-life and superior cardiovascular outcomes 4

If Patient Has Dizziness

• Dizziness may indicate orthostatic hypotension from the current regimen, particularly if amlodipine dose is high 6, 7
• Consider optimizing olmesartan dose to 40mg before adding a third agent 5
• Check blood pressure in standing position to rule out orthostatic hypotension before intensifying therapy 5
• If dizziness persists, consider reducing amlodipine dose rather than adding lisinopril 5

Critical Monitoring When Adding Chlorthalidone

• Check serum potassium and creatinine within 2-4 weeks of initiating chlorthalidone 4, 5
• Monitor for hypokalemia (chlorthalidone increases this risk significantly, with adjusted HR 3.06 vs hydrochlorothiazide) 4
• Reassess blood pressure within 2-4 weeks, targeting <140/90 mmHg minimum, ideally <130/80 mmHg 5

If Blood Pressure Remains Uncontrolled on Triple Therapy

• Add spironolactone 25-50mg daily as the preferred fourth-line agent for resistant hypertension 5, 8
• Spironolactone provides additional BP reductions of 20-25/10-12 mmHg when added to triple therapy 5, 8
• Monitor potassium closely when adding spironolactone to olmesartan, as hyperkalemia risk is significant 5, 8

Common Pitfall to Avoid

Do not assume that "more drugs = better control"—the combination of olmesartan + lisinopril violates fundamental hypertension management principles and exposes the patient to serious harm without benefit. 1, 2, 3