What to do when blood pressure remains elevated despite increased dose of lisinopril (angiotensin-converting enzyme inhibitor)?

Management of Persistent Hypertension Despite Increased Lisinopril Dose

When blood pressure remains elevated despite increased doses of lisinopril, add a thiazide-like diuretic as the next step in therapy, followed by a calcium channel blocker if needed, to achieve target blood pressure control. 1

Assessment of Current Situation

First, verify that the patient is truly experiencing resistant hypertension by:

• Confirming medication adherence to lisinopril
• Ensuring proper blood pressure measurement technique
• Ruling out white coat hypertension with home or ambulatory BP monitoring
• Checking for lifestyle factors that may elevate BP (high sodium intake, alcohol, NSAIDs)

Step-by-Step Management Algorithm

Step 1: Optimize Current Therapy

• Ensure lisinopril is at maximum tolerated dose (typically up to 40 mg daily)
• Verify patient is taking medication correctly (once daily, consistently)
• Review for potential interfering medications or substances

Step 2: Add Second Agent

• Add a thiazide-like diuretic (chlorthalidone 12.5-25 mg or indapamide 1.5-2.5 mg daily) 1
• For Black patients, a calcium channel blocker may be more effective as the second agent 1

Step 3: Add Third Agent (if needed)

• Add a calcium channel blocker (amlodipine 5-10 mg daily) if not already added 1
• This creates the optimal triple therapy combination of ACE inhibitor + thiazide diuretic + calcium channel blocker

Step 4: Consider Resistant Hypertension

If BP remains elevated despite optimal doses of three medications:

• Add spironolactone 25 mg daily (if eGFR adequate and potassium <4.6 mmol/L) 1
• If spironolactone is contraindicated or not tolerated, consider adding:
  • Eplerenone
  • Amiloride
  • Alpha-blocker (doxazosin)
  • Beta-blocker

Evidence-Based Rationale

The 2024 ESC guidelines strongly recommend a stepwise approach to hypertension management when initial therapy is insufficient 1. The International Society of Hypertension guidelines (2020) similarly support this approach, recommending combination therapy with complementary mechanisms of action 1.

Multiple studies have shown that most hypertensive patients will require two or more antihypertensive medications to achieve their BP goals 1. The combination of an ACE inhibitor (lisinopril), a thiazide-like diuretic, and a calcium channel blocker provides complementary mechanisms that effectively lower blood pressure through different pathways.

Special Considerations

• Medication adherence: Poor adherence is a common cause of apparent treatment resistance. Consider once-daily dosing and fixed-dose combinations to improve compliance 1.

• Secondary hypertension: Consider screening for secondary causes if BP remains poorly controlled despite multiple medications at optimal doses.

• Comorbidities: Tailor therapy based on compelling indications:

  • For diabetes: Target SBP to 130 mmHg and <130 mmHg if tolerated 1
  • For chronic kidney disease: Target SBP to 130-139 mmHg 1

• Monitoring: After adding a new agent, reassess BP within 2-4 weeks to determine effectiveness and adjust therapy accordingly 1.

Common Pitfalls to Avoid

1. Therapeutic inertia: Failing to intensify therapy when BP remains above target
2. Overlooking non-adherence: Up to 50% of patients may not take medications as prescribed
3. Suboptimal dosing: Using inadequate doses before adding new agents
4. Ignoring lifestyle factors: Sodium restriction, weight loss, and physical activity remain important adjuncts to pharmacotherapy
5. Inappropriate combinations: Using multiple drugs with similar mechanisms (e.g., two RAS blockers)

The evidence clearly shows that a systematic, stepwise approach to adding complementary antihypertensive agents is the most effective strategy when lisinopril monotherapy fails to control blood pressure 1.