What is the best course of action for a patient with uncontrolled hypertension after being taken off lisinopril (angiotensin-converting enzyme inhibitor) 40mg?

Management of Uncontrolled Hypertension After Discontinuation of Lisinopril

Restart lisinopril immediately and add a second antihypertensive agent, as discontinuation of guideline-directed medical therapy (GDMT) is associated with poorer clinical outcomes and the patient's high blood pressure readings indicate inadequate control. 1

Immediate Action Required

• Reinitiate lisinopril at the previous dose of 40mg daily, as abrupt withdrawal of ACE inhibitors is not associated with rebound hypertension but leaves the patient unprotected from cardiovascular risk. 2

• The 2025 American Journal of Kidney Diseases guidelines emphasize that GDMT withdrawal is associated with poorer clinical outcomes, and clinicians should try hard to not stop or to quickly restart GDMT whenever possible. 1

Add a Second Antihypertensive Agent

Add a dihydropyridine calcium channel blocker (amlodipine 5-10mg daily) as the preferred second agent to achieve guideline-recommended dual therapy for uncontrolled hypertension. 3, 4

• The combination of ACE inhibitor plus calcium channel blocker provides complementary mechanisms of action: renin-angiotensin system blockade plus vasodilation. 3

• This combination is particularly beneficial for patients with chronic kidney disease, heart failure, or coronary artery disease. 3

• The 2024 ESC guidelines explicitly recommend this two-drug combination as standard therapy for uncontrolled hypertension. 1

Alternative Second Agent Option

If calcium channel blockers are contraindicated or not tolerated, add a thiazide-like diuretic (chlorthalidone 12.5-25mg daily or hydrochlorothiazide 25mg daily) as the second agent. 3, 5

• When given together with thiazide-type diuretics, the blood pressure lowering effects are approximately additive. 2

• Chlorthalidone is preferred over hydrochlorothiazide due to its longer duration of action. 3

Target Blood Pressure and Monitoring

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

• Reassess blood pressure within 2-4 weeks after restarting lisinopril and adding the second agent. 3, 4

• Aim to achieve target blood pressure within 3 months of treatment modification. 3, 4

If Blood Pressure Remains Uncontrolled on Dual Therapy

Add a third agent from the remaining class (thiazide diuretic if on ACE inhibitor + calcium channel blocker, or calcium channel blocker if on ACE inhibitor + thiazide diuretic) to achieve guideline-recommended triple therapy. 1, 3

• The 2024 ESC guidelines recommend that when blood pressure is not controlled with a two-drug combination, increasing to a three-drug combination is recommended, usually a RAS blocker with a dihydropyridine calcium channel blocker and a thiazide/thiazide-like diuretic. 1

Special Consideration: SGLT2 Inhibitor Co-Administration

Consider adding an SGLT2 inhibitor together with lisinopril, particularly if the patient has diabetes, heart failure, or chronic kidney disease, as this strategy can facilitate GDMT optimization. 1

• In a meta-analysis of randomized controlled trials in patients with type 2 diabetes with high cardiovascular risk and/or CKD, SGLT2 inhibitors reduced the risk of serious hyperkalemia (hazard ratio 0.84; 95% CI 0.76-0.93), which is a common limiting adverse effect when titrating GDMT. 1

• This becomes an opportunity for simultaneous reintroduction of further components of GDMT to help improve not only cardiovascular but also kidney outcomes. 1

Critical Pitfalls to Avoid

• Do not leave the patient without ACE inhibitor therapy, as the patient was previously controlled on lisinopril 40mg and discontinuation exposes them to increased cardiovascular risk. 1

• Do not add a beta-blocker as the second agent unless there are compelling indications such as angina, post-myocardial infarction, heart failure with reduced ejection fraction, or need for heart rate control. 3

• Do not combine two RAS blockers (ACE inhibitor plus ARB), as this increases adverse events without additional benefit. 1, 3

• Verify medication adherence before assuming treatment failure, as non-adherence is the most common cause of apparent treatment resistance. 3

Lifestyle Modifications to Reinforce

• Sodium restriction to <2g/day can provide additive blood pressure reduction of 10-20 mmHg. 3

• Weight management (target BMI 20-25 kg/m²), regular aerobic exercise, and alcohol limitation to <100g/week should be reinforced. 3

• These lifestyle measures are mandatory and provide substantial additive benefit to pharmacologic therapy. 1

Monitoring Parameters After Restarting Lisinopril

• Check serum potassium and creatinine 2-4 weeks after reinitiating lisinopril to detect potential hyperkalemia or changes in renal function. 3

• Monitor for cough (occurs in approximately 10-15% of patients on ACE inhibitors), hyperkalemia, and acute kidney injury. 3

• If hyperkalemia develops, consider switching to an angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) or using a potassium binder (patiromer) to maintain GDMT. 1