What can be added to lisinopril (angiotensin-converting enzyme inhibitor) 40 mg for a patient with uncontrolled hypertension?

Adding a Third Agent to Lisinopril 40 mg for Uncontrolled Hypertension

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

Preferred Add-On Options

The 2024 ESC guidelines explicitly state that when blood pressure is not controlled with a two-drug combination, increasing to a three-drug combination is recommended, usually a RAS blocker (your patient's lisinopril) with a dihydropyridine calcium channel blocker and a thiazide/thiazide-like diuretic, preferably in a single-pill combination. 1

Option 1: Add a Calcium Channel Blocker (Preferred for Most Patients)

• Start amlodipine 5 mg once daily, which can be titrated to 10 mg if needed. 1, 2
• This combination provides complementary mechanisms: ACE inhibition (lisinopril) plus vasodilation through calcium channel blockade (amlodipine). 2
• The ACE inhibitor + calcium channel blocker combination has demonstrated superior blood pressure control compared to either agent alone and may reduce peripheral edema that occurs with amlodipine monotherapy. 2
• This approach is particularly beneficial for patients with chronic kidney disease, heart failure, coronary artery disease, or diabetes. 2

Option 2: Add a Thiazide/Thiazide-Like Diuretic

• Start hydrochlorothiazide 12.5-25 mg once daily OR chlorthalidone 12.5-25 mg once daily (chlorthalidone preferred due to longer duration of action). 1, 3, 4
• The FDA label for lisinopril specifically states: "If blood pressure is not controlled with lisinopril tablets alone, a low dose of a diuretic may be added (e.g., hydrochlorothiazide, 12.5 mg)." 3
• A direct comparison study demonstrated that adding bendrofluazide (a thiazide) to amlodipine and lisinopril caused a significant fall in blood pressure compared with placebo and a significantly greater fall than adding atenolol. 4
• This combination is particularly effective for volume-dependent hypertension, elderly patients, and Black patients. 2

Clinical Decision Algorithm

Choose calcium channel blocker if:

• Patient has coronary artery disease, angina, or diabetes 2
• Patient has chronic kidney disease with proteinuria 2
• Patient is Black (though both options are effective) 2

Choose thiazide diuretic if:

• Patient has volume-dependent hypertension 2
• Patient is elderly 2
• Cost is a major concern (generics are less expensive) 4

Add BOTH if blood pressure remains uncontrolled:

• If adding one agent doesn't achieve target BP, progress to triple therapy with lisinopril + calcium channel blocker + thiazide diuretic. 1

Target Blood Pressure and Monitoring

• Target systolic BP of 120-129 mmHg if well tolerated, or at minimum <140/90 mmHg. 1
• Reassess blood pressure within 2-4 weeks after adding the second agent. 2
• Goal is to achieve target blood pressure within 3 months of treatment modification. 2
• Monitor serum potassium and creatinine 2-4 weeks after initiating diuretic therapy to detect potential hypokalemia or changes in renal function. 2

If Blood Pressure Remains Uncontrolled on Triple Therapy

• Add spironolactone 25-50 mg daily as the preferred fourth-line agent for resistant hypertension. 1, 2
• The 2024 ESC guidelines specifically recommend spironolactone for resistant hypertension, with evidence showing additional blood pressure reductions. 2
• Monitor potassium closely when adding spironolactone to an ACE inhibitor, as hyperkalemia risk is significant. 2

Critical Pitfalls to Avoid

• Do NOT combine lisinopril with an ARB - this increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit. 1, 2
• Do NOT add a beta-blocker as the third agent unless there are compelling indications such as angina, post-myocardial infarction, heart failure with reduced ejection fraction, or need for heart rate control. 1
• Do NOT delay treatment intensification - prompt action is required to reduce cardiovascular risk in uncontrolled hypertension. 1
• Verify medication adherence first - non-adherence is the most common cause of apparent treatment resistance. 1, 2
• Consider ruling out secondary causes of hypertension (primary aldosteronism, renal artery stenosis, obstructive sleep apnea) if blood pressure remains severely elevated despite appropriate therapy. 2

Lifestyle Modifications to Reinforce

• Sodium restriction to <2 g/day 1, 2
• Weight management (target BMI 20-25 kg/m²) 1
• Regular aerobic exercise 1
• Alcohol limitation to <100 g/week 1
• These lifestyle measures provide additive blood pressure reductions of 10-20 mmHg. 2