What is a suitable replacement medication for a patient taking lisinopril (Angiotensin-Converting Enzyme (ACE) inhibitor) who requires an alternative due to side effects or other considerations?

Replacement Medication for Lisinopril

Angiotensin Receptor Blockers (ARBs) are the preferred first-line replacement for lisinopril, with valsartan, candesartan, or losartan being the most appropriate choices depending on the clinical indication. 1

Primary Alternative: Angiotensin Receptor Blockers (ARBs)

ARBs represent the most direct replacement for ACE inhibitors like lisinopril because they target the same renin-angiotensin system through a different mechanism. 1

Specific ARB Selection by Indication:

For Hypertension:

• Start with valsartan 80-160 mg once daily, candesartan 8-16 mg once daily, or losartan 50 mg once daily 2, 1
• Candesartan demonstrates higher AT1 receptor affinity and insurmountable antagonism compared to losartan's competitive antagonism, potentially offering superior blood pressure control 3
• Target doses proven effective in trials: valsartan 160 mg twice daily, candesartan 32 mg daily, losartan 100 mg daily 2

For Heart Failure (NYHA Class II-IV):

• Valsartan is the preferred ARB with proven mortality benefit, starting at 40 mg twice daily and titrating to target dose of 160 mg twice daily 2, 4
• Candesartan is an alternative, starting at 4-8 mg once daily and titrating to 32 mg daily 2
• ARBs should be combined with beta-blockers and aldosterone antagonists for optimal heart failure management 2, 1

For Post-Myocardial Infarction with LV Dysfunction:

• Valsartan 20 mg twice daily, titrating to 160 mg twice daily, has demonstrated non-inferiority to captopril 2, 4
• Losartan showed a trend toward increased mortality compared to captopril in OPTIMAAL, likely due to inadequate dosing, making it a less preferred option 2

Critical Safety Considerations with ARBs:

If the reason for switching is angioedema:

• Exercise extreme caution as cross-reactivity occurs in 2-17% of patients 1, 5
• Mandatory 6-week washout period before initiating any ARB 5, 6
• Start at the lowest possible dose with close monitoring 5
• Consider alternative drug classes first (see below) 5

If the reason for switching is cough or rash:

• ARBs are excellent alternatives with minimal cross-reactivity for these side effects 2, 1
• Can initiate immediately without washout period 1

Monitoring requirements:

• Check blood pressure, renal function (creatinine), and potassium within 1-2 weeks of initiation 2, 1
• Avoid in bilateral renal artery stenosis 2
• Use caution if creatinine >2.5 mg/dL or potassium >5.0 mEq/L 2

Second-Line Alternatives (When ARBs Are Contraindicated)

Calcium Channel Blockers (CCBs):

• Amlodipine 5-10 mg once daily or felodipine 2.5-10 mg once daily are preferred dihydropyridine CCBs 2, 1
• Particularly useful in patients with angioedema history where ARBs pose risk 1, 5
• Avoid non-dihydropyridines (diltiazem, verapamil) in heart failure with reduced ejection fraction 2

Thiazide or Thiazide-Like Diuretics:

• Chlorthalidone 12.5-25 mg once daily is preferred over hydrochlorothiazide due to longer half-life and proven cardiovascular benefit 2, 1
• Effective for hypertension, particularly in patients with volume overload 1
• Monitor for hypokalemia, hyponatremia, and hyperuricemia 2

Beta-Blockers:

• Reserve primarily for patients with coronary artery disease or heart failure 2, 1
• Metoprolol succinate 25-200 mg once daily or carvedilol 6.25-25 mg twice daily for heart failure 2
• Not recommended as first-line for uncomplicated hypertension 2

Critical Pitfalls to Avoid

Never combine ACE inhibitors with ARBs:

• Combination therapy increases cardiovascular and renal risk without additional mortality benefit 2, 1
• The VALIANT trial showed increased adverse events with captopril plus valsartan combination 2

Never use ARBs with neprilysin inhibitors (ARNI) simultaneously:

• Must allow 36-hour washout when switching between ACE inhibitors/ARBs and sacubitril-valsartan 2
• Concomitant use dramatically increases angioedema risk 2

Avoid aldosterone antagonists without careful monitoring:

• Risk of life-threatening hyperkalemia, especially with creatinine clearance <50 mL/min 2
• Contraindicated if baseline potassium >5.0 mEq/L or creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women) 2

Practical Titration Strategy

1. Initiate ARB at low dose (e.g., valsartan 40 mg daily, candesartan 4 mg daily, losartan 25 mg daily) 2, 1
2. Double dose every 2 weeks as tolerated, monitoring blood pressure and labs 2
3. Target trial-proven doses for maximum cardiovascular benefit 2
4. Accept highest tolerated dose if target dose causes adverse effects—some ARB is better than none 2