What is the next step in managing a patient's blood pressure (BP) who is already on amlodipine (calcium channel blocker) and remains uncontrolled?

Managing Uncontrolled Blood Pressure on Amlodipine

Add either an ACE inhibitor/ARB or a thiazide-like diuretic to the amlodipine regimen, with the choice depending on patient-specific factors such as race, comorbidities, and presence of volume overload. 1

First-Line Add-On Options

ACE Inhibitor or ARB Addition

• Adding an ACE inhibitor or ARB to amlodipine provides complementary mechanisms of action through renin-angiotensin system blockade combined with vasodilation. 1
• This combination is particularly beneficial for patients with chronic kidney disease, heart failure, diabetes, or coronary artery disease. 1
• The amlodipine plus ACE inhibitor combination has demonstrated superior blood pressure control compared to either agent alone in patients with diabetes, chronic kidney disease, or heart failure. 1, 2
• A notable advantage is that ACE inhibitors or ARBs may attenuate the peripheral edema commonly associated with amlodipine monotherapy. 1

Thiazide-Like Diuretic Addition

• Adding a thiazide-like diuretic to amlodipine is highly effective, particularly for patients with volume-dependent hypertension, elderly patients, or Black patients. 1, 3
• Chlorthalidone should be preferentially used over hydrochlorothiazide in patients with resistant hypertension, as it provides greater 24-hour ambulatory blood pressure reduction with the largest difference occurring overnight. 3
• Chlorthalidone 12.5-25 mg daily is more effective than hydrochlorothiazide 50 mg daily in blinded comparisons. 3
• Thiazide diuretics significantly improve blood pressure control when combined with most other antihypertensive classes, making them essential for maximizing blood pressure control. 3

Race-Specific Considerations

• For Black patients, the combination of amlodipine plus a thiazide diuretic may be more effective than amlodipine plus an ACE inhibitor/ARB. 1
• For non-Black patients, either combination is appropriate as initial dual therapy. 1

Monitoring After Adding Second Agent

• Target blood pressure should be <140/90 mmHg for most patients. 1
• Reassess blood pressure within 2-4 weeks after adding the second agent, with the goal of achieving target blood pressure within 3 months of treatment modification. 1
• When adding an ACE inhibitor or ARB, monitor for cough, hyperkalemia, and acute kidney injury. 1
• When adding a thiazide diuretic, check serum potassium and creatinine 2-4 weeks after initiation to detect potential hypokalemia, hyperuricemia, or changes in renal function. 1, 3

Progression to Triple Therapy

• If blood pressure remains uncontrolled after adding a second agent at optimal dose, add a third agent from the remaining class to create the guideline-recommended triple therapy of ACE inhibitor/ARB + calcium channel blocker + thiazide diuretic. 1, 3
• This triple regimen targets different mechanisms: volume reduction, vasodilation, and renin-angiotensin system blockade. 1
• The triple combination can be accomplished with 2 pills using various fixed-dose combinations. 3

Resistant Hypertension Management

• If blood pressure remains uncontrolled despite optimized triple therapy, add spironolactone 25-50 mg daily as the preferred fourth-line agent for resistant hypertension. 1, 3
• Spironolactone provides significant antihypertensive benefit when added to existing multidrug regimens, lowering blood pressure by an average of 25 mm Hg systolic and 12 mm Hg diastolic in patients on multiple medications including a diuretic and ACE inhibitor or ARB. 3
• Monitor potassium closely when adding spironolactone to an ACE inhibitor or ARB, as hyperkalemia risk is significant. 1, 3
• Amiloride combined with hydrochlorothiazide is an alternative aldosterone antagonist option, particularly in patients with low-renin hypertension, reducing systolic and diastolic blood pressure by 31 and 15 mm Hg respectively. 3

Critical Pitfalls to Avoid

• Never combine an ACE inhibitor with an ARB, as this increases adverse effects without additional benefit. 1
• Do not add a third drug class before maximizing doses of the current two-drug regimen, as this violates guideline-recommended stepwise approaches and may expose patients to unnecessary polypharmacy. 1
• Confirm medication adherence and rule out secondary causes of hypertension before assuming treatment failure, as non-adherence is the most common cause of apparent treatment resistance. 1
• Avoid or withdraw NSAIDs in patients with resistant hypertension, as these medications interfere with blood pressure control; if clinically necessary, use the lowest effective dose with close blood pressure monitoring. 3

Special Considerations for Chronic Kidney Disease

• In patients with chronic kidney disease (creatinine clearance <30 mL/min), loop diuretics may be necessary for effective volume and blood pressure control instead of thiazide diuretics. 3
• Furosemide requires at least twice-daily dosing due to its short duration of action, while longer-acting loop diuretics such as torsemide can be used as alternatives. 3