In a 64-year-old man with hypertension on lisinopril 40 mg daily and atorvastatin, whose blood pressure remains in the 140 mm Hg range, what medication should be added next?

Add a Calcium Channel Blocker or Thiazide Diuretic to Lisinopril

For this 64-year-old man with uncontrolled hypertension (BP in the 140s) on lisinopril 40 mg daily, add either a calcium channel blocker (amlodipine 5-10 mg daily) or a thiazide-like diuretic (chlorthalidone 12.5-25 mg daily) as the second agent to achieve guideline-recommended dual therapy. 1

Rationale for Dual Therapy

• The patient is already on maximum-dose lisinopril (40 mg daily per FDA labeling), so adding a second agent from a different class is more effective than further dose escalation 2
• All major guidelines (JNC 8, ESH/ESC, AHA/ACC/CDC, NICE) recommend adding either a calcium channel blocker (CCB) or thiazide diuretic to an ACE inhibitor when blood pressure remains uncontrolled 1
• Combination therapy targeting complementary mechanisms (renin-angiotensin blockade + vasodilation or volume reduction) achieves blood pressure control faster and more effectively than monotherapy dose increases 3

First Choice: Calcium Channel Blocker

Adding amlodipine 5-10 mg once daily provides complementary vasodilation through calcium channel blockade alongside the renin-angiotensin inhibition from lisinopril. 3

• The ACE inhibitor + CCB combination is particularly beneficial for patients with chronic kidney disease, diabetes, heart failure, or coronary artery disease 3
• This combination may reduce amlodipine-related peripheral edema when paired with an ACE inhibitor 3
• The lisinopril + amlodipine regimen has demonstrated superior blood pressure control compared to either agent alone 3

Alternative Choice: Thiazide-Like Diuretic

Adding chlorthalidone 12.5-25 mg once daily (preferred) or hydrochlorothiazide 25 mg daily creates an ACE inhibitor + diuretic combination that addresses volume-dependent hypertension. 3, 4

• Chlorthalidone is preferred over hydrochlorothiazide due to its longer duration of action (24-72 hours vs 6-12 hours) and superior cardiovascular outcome data from the ALLHAT trial 3, 5
• The ACE inhibitor + thiazide combination is particularly effective in elderly patients, Black patients, and those with volume-dependent hypertension 3
• In patients with advanced chronic kidney disease (stage 4), chlorthalidone at 12.5-50 mg daily reduced 24-hour ambulatory systolic blood pressure by 11.0 mm Hg compared to placebo 4

Monitoring After Adding Second Agent

• Check serum potassium and creatinine 2-4 weeks after initiating a thiazide diuretic to detect hypokalemia or changes in renal function 3
• Reassess blood pressure within 2-4 weeks after adding the second agent, with the goal of achieving target BP within 3 months 3
• Target blood pressure is <140/90 mm Hg minimum, ideally <130/80 mm Hg for higher-risk patients 3

If Blood Pressure Remains Uncontrolled on Dual Therapy

Add the third agent from the remaining class (CCB + thiazide + ACE inhibitor) to achieve guideline-recommended triple therapy. 1, 3

• All major guidelines (JNC 8, ESH/ESC, France, NICE, Taiwan, China) specify CCB + thiazide + ACE inhibitor/ARB as the standard three-drug combination 1
• If blood pressure remains ≥140/90 mm Hg after optimized triple therapy, add spironolactone 25-50 mg daily as the preferred fourth-line agent for resistant hypertension 3

Critical Pitfalls to Avoid

• Do not increase lisinopril beyond 40 mg daily, as this is the maximum recommended dose for hypertension and provides minimal additional benefit 2
• Do not add a beta-blocker as the second agent unless there are compelling indications (angina, post-MI, heart failure with reduced ejection fraction, atrial fibrillation), as beta-blockers are less effective than CCBs or diuretics for stroke prevention 1, 3
• Do not combine lisinopril with an ARB (dual RAS blockade), as this increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit 3
• Verify medication adherence before escalating therapy, as non-adherence is the most common cause of apparent treatment resistance 3, 6

Lifestyle Modifications to Reinforce

• Sodium restriction to <2 g/day provides 5-10 mm Hg systolic reduction and enhances the efficacy of both ACE inhibitors and diuretics 3
• Weight loss if overweight (10 kg reduction associated with 6.0/4.6 mm Hg reduction) 3
• Regular aerobic exercise (≥30 minutes most days) reduces blood pressure by approximately 4/3 mm Hg 3
• Alcohol limitation to ≤2 drinks/day for men contributes additional blood pressure reduction 3