What is the preferred additional antihypertensive agent for a patient with uncontrolled hypertension already on the maximum dose of lisinopril (Angiotensin-Converting Enzyme inhibitor)?

Preferred Additional Antihypertensive Agent After Maximum-Dose Lisinopril

Add a calcium channel blocker (amlodipine 5-10 mg daily) or a thiazide/thiazide-like diuretic (chlorthalidone 12.5-25 mg or hydrochlorothiazide 12.5-25 mg daily) as the second agent to achieve guideline-recommended dual combination therapy. 1

Algorithmic Approach to Selection

First Choice: Calcium Channel Blocker (Amlodipine)

• For most patients, add amlodipine 5-10 mg once daily as it provides complementary vasodilation through calcium channel blockade while the ACE inhibitor blocks the renin-angiotensin system 1, 2
• This combination (ACE inhibitor + calcium channel blocker) is explicitly recommended as first-line dual therapy by the 2024 ESC Guidelines 1
• Amlodipine combined with an ACE inhibitor demonstrates superior blood pressure control compared to either agent alone, particularly in patients with diabetes, chronic kidney disease, or heart failure 2
• An additional benefit: adding an ACE inhibitor or ARB to amlodipine may attenuate the peripheral edema commonly seen with calcium channel blockers alone 2

Alternative Choice: Thiazide/Thiazide-Like Diuretic

• Add chlorthalidone 12.5-25 mg daily (preferred) or hydrochlorothiazide 12.5-25 mg daily if calcium channel blockers are contraindicated or not tolerated 1, 3
• Chlorthalidone is preferred over hydrochlorothiazide due to its longer duration of action and superior 24-hour blood pressure control 3
• This combination is particularly effective for volume-dependent hypertension, elderly patients, or Black patients 2
• Thiazide diuretics demonstrate significant additive antihypertensive benefit when combined with ACE inhibitors, and lisinopril attenuates the hypokalemia induced by thiazides 1, 4

Race-Specific Considerations

• For Black patients specifically, the combination of calcium channel blocker + thiazide diuretic may be more effective than calcium channel blocker + ACE inhibitor 1, 2
• However, if the patient is already on maximum-dose lisinopril, adding a calcium channel blocker first followed by a diuretic as the third agent remains the recommended sequence 1

Monitoring After Adding Second Agent

• Check blood pressure within 1 month (preferred) or at least within 1-3 months after adding the second agent 1
• Target blood pressure is <140/90 mmHg minimum, ideally <130/80 mmHg for higher-risk patients 2, 3
• When adding a diuretic, check serum potassium and creatinine 2-4 weeks after initiation to detect hypokalemia or changes in renal function 2
• When adding a calcium channel blocker, monitor for peripheral edema, headache, and flushing 2

If Blood Pressure Remains Uncontrolled on Dual Therapy

Step to Triple Therapy

• Add the third agent from the remaining major drug class (if on ACE inhibitor + calcium channel blocker, add thiazide diuretic; if on ACE inhibitor + diuretic, add calcium channel blocker) 1
• The combination of ACE inhibitor + calcium channel blocker + thiazide diuretic represents guideline-recommended triple therapy with complementary mechanisms targeting volume reduction, vasodilation, and renin-angiotensin system blockade 1, 2, 5
• Optimize doses of all three agents to their maximum tolerated levels before considering a fourth agent 1

Resistant Hypertension (Uncontrolled on Triple Therapy)

• Add spironolactone 12.5-50 mg daily as the preferred fourth-line agent for resistant hypertension 1, 3
• Spironolactone provides an average additional blood pressure reduction of 25/12 mmHg systolic/diastolic when added to triple therapy 1, 3
• Before adding spironolactone, verify medication adherence and rule out secondary causes of hypertension (primary aldosteronism, renal artery stenosis, obstructive sleep apnea) 1
• Monitor potassium closely (every 1-2 weeks initially) when combining spironolactone with an ACE inhibitor due to hyperkalemia risk 3, 6

Alternative Fourth-Line Agents

• If spironolactone is not tolerated, consider eplerenone 50-200 mg daily (may need twice-daily dosing), or a vasodilating beta-blocker (labetalol, carvedilol, or nebivolol) if not already indicated 1
• Beta-blockers are less potent than spironolactone for resistant hypertension but are appropriate if compelling indications exist (angina, post-MI, heart failure, heart rate control) 1

Critical Pitfalls to Avoid

• Never combine lisinopril with an ARB—this increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit 1, 3, 6
• Do not add a beta-blocker as the second or third agent unless there are compelling indications (angina, post-MI, heart failure with reduced ejection fraction, heart rate control) 1, 2
• Do not delay treatment intensification—prompt action is required for stage 2 hypertension (≥160/100 mmHg) to reduce cardiovascular risk 1
• Verify medication adherence before escalating therapy, as non-adherence is the most common cause of apparent treatment resistance 1, 3
• Confirm elevated readings with home blood pressure monitoring (target <135/85 mmHg) or 24-hour ambulatory monitoring (target <130/80 mmHg) if not already done 2, 6

Lifestyle Modifications to Reinforce

• Sodium restriction to <2 g/day can provide additive blood pressure reductions of 10-20 mmHg, particularly critical in resistant hypertension 1, 6
• Weight management (target BMI 20-25 kg/m²), regular aerobic exercise (≥150 min/week moderate intensity), and alcohol limitation (<100 g/week) provide additional benefit 1, 6