What's the next step for a patient with uncontrolled hypertension, currently on lisinopril (angiotensin-converting enzyme inhibitor), with blood pressure readings still elevated?

Management of Uncontrolled Hypertension on Lisinopril Monotherapy

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

Stepwise Treatment Algorithm

First Priority: Add a Second Agent

• The combination of an ACE inhibitor plus a calcium channel blocker provides complementary mechanisms of action (vasodilation plus renin-angiotensin system blockade), and is particularly beneficial for patients with chronic kidney disease, heart failure, or coronary artery disease. 1

• Alternatively, adding a thiazide-like diuretic to lisinopril is highly effective, particularly for patients with volume-dependent hypertension, elderly patients, or Black patients. 1

• The guideline-recommended sequence for non-Black patients is: ACE inhibitor → add calcium channel blocker → optimize doses → add thiazide/thiazide-like diuretic if needed. 1

• For Black patients specifically, the combination of calcium channel blocker plus thiazide diuretic may be more effective than ACE inhibitor-based regimens. 1

Before Adding: Confirm True Hypertension

• Arrange home blood pressure monitoring or 24-hour ambulatory monitoring to confirm sustained hypertension, as clinic readings may overestimate true blood pressure. 1

• Home BP ≥135/85 mmHg or 24-hour ambulatory BP ≥130/80 mmHg confirms true hypertension requiring treatment intensification. 1

• Verify medication adherence before escalating therapy, as non-adherence is the most common cause of apparent treatment resistance. 1

Dosing Considerations for Lisinopril

• The FDA-approved dosing for hypertension is 10mg initially, with a usual dosage range of 20-40mg daily administered once daily. 2

• Before adding a second agent, ensure lisinopril is at an adequate dose (at least 20mg daily, up to 40mg daily if tolerated). 2

• Doses up to 80mg have been used but do not appear to give greater effect than 40mg. 2

Specific Add-On Recommendations

Option 1: Calcium Channel Blocker (Preferred for Most)

• Start amlodipine 5mg once daily, which can be increased to 10mg if needed. 1

• This combination (ACE inhibitor + calcium channel blocker) has demonstrated superior blood pressure control compared to either agent alone in patients with diabetes, chronic kidney disease, or heart failure. 1

• Monitor for peripheral edema, which is more common with amlodipine but may be attenuated by the ACE inhibitor. 1

Option 2: Thiazide-Like Diuretic

• Start chlorthalidone 12.5-25mg daily or hydrochlorothiazide 25-50mg daily, with chlorthalidone preferred due to its longer duration of action. 1

• When adding a diuretic to lisinopril, the FDA recommends starting with a low dose (e.g., hydrochlorothiazide 12.5mg), and after the addition of a diuretic, it may be possible to reduce the dose of lisinopril. 2

• Check serum potassium and creatinine 2-4 weeks after initiating diuretic therapy to detect potential hypokalemia, hyperuricemia, or changes in renal function. 1

Target Blood Pressure and Monitoring

• Target blood pressure should be <140/90 mmHg minimum, ideally <130/80 mmHg for higher-risk patients. 1

• Reassess blood pressure within 2-4 weeks after adding the second agent, with the goal of achieving target BP within 3 months of treatment modification. 1

If Blood Pressure Remains Uncontrolled on Dual Therapy

• Add a third agent from the remaining class to achieve guideline-recommended triple therapy (ACE inhibitor + calcium channel blocker + thiazide diuretic). 1

• The combination of ACE inhibitor + calcium channel blocker + thiazide diuretic represents the evidence-based triple therapy for uncontrolled hypertension. 1

• 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

If Triple Therapy Fails: Fourth-Line Agent

• Add spironolactone 25-50mg daily as the preferred fourth-line agent for resistant hypertension if blood pressure remains uncontrolled despite optimized triple therapy. 1

• Monitor potassium closely when adding spironolactone to an ACE inhibitor, as hyperkalemia risk is significant. 1

• Consider referral to a hypertension specialist if blood pressure remains uncontrolled (≥160/100 mmHg) despite four-drug therapy at optimal doses. 1

Critical Pitfalls to Avoid

• Do not combine lisinopril with an ARB (dual RAS blockade), as this increases adverse events without additional benefit. 1

• Do not add a third drug class before maximizing doses of the current two-drug regimen—this violates guideline-recommended stepwise approaches and may expose patients to unnecessary polypharmacy. 1

• Do not delay treatment intensification for stage 2 hypertension (BP >160/100 mmHg), as prompt action is required to reduce cardiovascular risk. 1

• Avoid NSAIDs during lisinopril treatment as they reduce efficacy and increase renal dysfunction risk. 3

Special Monitoring for ACE Inhibitors

• Check baseline serum creatinine, eGFR, and potassium before initiating or escalating lisinopril, with repeat monitoring 1-2 weeks after dose changes. 3

• An up to 30% increase in creatinine is expected and acceptable when starting or increasing ACE inhibitors, which typically returns toward baseline in most patients. 3

• If hyperkalemia develops, consider adding an SGLT2 inhibitor (if diabetic or heart failure), which reduces hyperkalemia risk and allows continuation of ACE inhibitors. 4, 3

Lifestyle Modifications (Additive Effect)

• Reinforce sodium restriction to <2g/day, weight management, regular aerobic exercise, and alcohol limitation to <100g/week, as these provide additive blood pressure reductions of 10-20 mmHg. 1