Should lisinopril be added to a patient with resistant hypertension (BP 182/81 mm Hg) who is already taking hydrochlorothiazide, carvedilol (beta‑blocker) and nifedipine (calcium‑channel blocker)?

Adding Lisinopril for Resistant Hypertension

Yes, add lisinopril to this patient's regimen, but only after first optimizing the existing three-drug foundation by replacing hydrochlorothiazide with chlorthalidone 12.5–25 mg daily, which is significantly more effective for resistant hypertension. 1, 2

Current Regimen Assessment

Your patient has resistant hypertension (BP 182/81 mmHg on three agents) and is already taking:

• Carvedilol (beta-blocker)
• Nifedipine/Procardia (calcium-channel blocker)
• Hydrochlorothiazide (thiazide diuretic)

Critical problem: This regimen lacks a renin-angiotensin system (RAS) blocker, which is a mandatory component of the guideline-recommended three-drug foundation for resistant hypertension. 1, 2, 3

Step 1: Optimize the Three-Drug Foundation FIRST

Before adding a fourth agent, the 2024 ESC guidelines mandate that the regimen must include: 1

1. A RAS blocker (ACE inhibitor or ARB) — currently missing
2. A long-acting dihydropyridine calcium-channel blocker — already present (nifedipine)
3. A thiazide-like diuretic — needs optimization (see below)

Replace Hydrochlorothiazide with Chlorthalidone

Switch from HCTZ to chlorthalidone 12.5–25 mg once daily because thiazide-like diuretics (chlorthalidone or indapamide) provide superior 24-hour blood pressure control and are markedly more effective than hydrochlorothiazide in resistant hypertension. 2, 4, 3 This single change is often the most impactful intervention in apparent treatment failure. 2

Add Lisinopril as the Missing RAS Blocker

Start lisinopril 10–20 mg once daily to complete the guideline-mandated three-drug foundation. 1, 5 Lisinopril demonstrates superior systolic blood pressure reduction compared to hydrochlorothiazide and is approximately equivalent to beta-blockers for diastolic control. 5, 6, 7

• Lisinopril produces blood pressure reduction that begins within 2 hours, peaks at 6 hours, and lasts at least 24 hours, making once-daily dosing appropriate. 6, 7
• Titrate to a maximum of 40 mg daily if needed for blood pressure control. 5, 7
• Lisinopril is less effective in Black patients, so anticipate potentially needing higher doses or earlier addition of a fourth agent in this population. 5

Step 2: Reassess Carvedilol's Role

Important caveat: Beta-blockers are explicitly not recommended as first-, second-, or third-line agents in uncomplicated resistant hypertension—they are fourth-line only. 1, 2 The 2024 ESC guidelines state that beta-blockers should be combined with other major drug classes only when there are compelling indications (angina, post-MI, heart failure with reduced ejection fraction, or heart rate control). 1

• If the patient has a compelling indication (e.g., coronary disease, heart failure, heart rate >70 bpm), continue carvedilol.
• If no compelling indication exists, consider discontinuing carvedilol and optimizing the three-drug foundation (RAS blocker + CCB + thiazide-like diuretic) before adding a fourth agent. 1, 2

Step 3: If Blood Pressure Remains Uncontrolled After Optimization

After 2–4 weeks on the optimized three-drug regimen (lisinopril + nifedipine + chlorthalidone), if BP remains ≥130/80 mmHg: 1, 4, 3

Add Spironolactone as the Preferred Fourth-Line Agent

Add spironolactone 25 mg once daily if: 2, 4, 3

• Serum potassium <4.5 mmol/L
• eGFR >45 mL/min/1.73 m²

Spironolactone is the most effective fourth-line agent, reducing office systolic BP by approximately 13 mmHg in the PATHWAY-2 trial. 2, 4 Monitor serum potassium and creatinine 1–2 weeks after initiation, then every 3–6 months. 2, 4

Alternative Fourth-Line Agents

If spironolactone is contraindicated: 2, 4

• Eplerenone 50–100 mg daily (up to 200 mg, possibly divided twice daily)
• Vasodilating beta-blocker (if not already on carvedilol)—safest option for patients unable to undergo regular potassium monitoring

Step 4: Confirm True Resistant Hypertension

Before intensifying therapy, exclude pseudoresistance: 2, 4, 3

• Perform 24-hour ambulatory blood pressure monitoring to rule out white-coat hypertension, which accounts for approximately 50% of apparent resistant cases. 2, 4, 3
• Verify medication adherence through direct questioning, pill counts, or pharmacy refill records—nonadherence causes roughly half of treatment resistance. 2, 4, 3
• Ensure proper BP measurement technique using an appropriately sized cuff. 2, 4

Step 5: Screen for Secondary Causes

Obtain: 2, 4, 3

• Morning plasma aldosterone-to-renin ratio to screen for primary aldosteronism (even with normal potassium)
• Sleep history and consider polysomnography for obstructive sleep apnea
• Serum creatinine and eGFR to assess for chronic kidney disease
• TSH to exclude thyroid dysfunction

Step 6: Lifestyle Optimization

Mandate: 2, 4, 3

• Sodium restriction to <2,400 mg/day (ideally <1,500 mg/day)—high sodium is a major contributor to treatment resistance
• Weight loss if BMI >25 kg/m²
• Alcohol limitation to ≤1 drink/day for women, ≤2 drinks/day for men
• Discontinue NSAIDs and other interfering substances (decongestants, stimulants)
• Regular moderate-intensity physical activity

Step 7: Blood Pressure Target and Monitoring

• Target BP <130/80 mmHg for most adults with resistant hypertension. 1, 4, 3
• The 2024 ESC guidelines recommend targeting systolic BP 120–129 mmHg if well tolerated. 1
• Reassess BP within 2–4 weeks after any medication adjustment. 2, 4, 3
• Use home BP monitoring to guide titration and improve adherence. 2, 3

Step 8: Specialist Referral

Refer to a hypertension specialist if: 2, 4, 3

• BP remains >130/80 mmHg after optimizing a four-drug regimen with lifestyle modifications
• Complications arise (severe hyperkalemia, progressive renal dysfunction, difficulty managing the regimen)
• Secondary causes require expert evaluation

Common Pitfalls to Avoid

• Do not continue hydrochlorothiazide—switching to chlorthalidone or indapamide is the single most critical optimization step. 2, 4, 3
• Do not add a fourth agent before establishing the proper three-drug foundation (RAS blocker + CCB + thiazide-like diuretic). 2, 3
• Do not combine two RAS blockers (ACE inhibitor + ARB)—this is explicitly not recommended. 1, 3
• Do not use beta-blockers as routine third-line therapy unless a compelling indication exists. 1, 2
• Do not add spironolactone without checking potassium and renal function first. 2, 4, 3
• If eGFR <30 mL/min/1.73 m², switch to a loop diuretic (furosemide or torsemide) instead of thiazide-like agents, as they lose efficacy below this threshold. 2, 3