What is the preferred Angiotensin-Converting Enzyme Inhibitor (ACEI)?

Preferred ACE Inhibitors Based on Clinical Guidelines

For most patients requiring an ACE inhibitor, captopril, enalapril, lisinopril, perindopril, ramipril, or trandolapril should be selected as they have demonstrated mortality and morbidity benefits in large clinical trials. 1

Selection Criteria by Clinical Condition

Heart Failure

• First choice: Enalapril, lisinopril, captopril, ramipril, or trandolapril
• These ACEIs have been specifically shown to reduce morbidity and mortality in heart failure trials 1
• Target doses should be those proven in clinical trials rather than lower doses 1, 2
• In the ATLAS trial, high-dose lisinopril (32.5-35 mg daily) showed 12% lower risk of death or hospitalization compared to low-dose (2.5-5.0 mg) therapy 2

Hypertension

• First choice: Any ACE inhibitor is appropriate for initial therapy
• ACE inhibitors, β-blockers, and diuretics have been repeatedly shown to be particularly beneficial in reducing cardiovascular events 1
• For patients >55 years with hypertension or with another cardiovascular risk factor, an ACE inhibitor should be considered to reduce cardiovascular events 1

Diabetic Nephropathy

• First choice: Any ACE inhibitor at maximally tolerated dose
• For patients with diabetes and urinary albumin-to-creatinine ratio ≥300 mg/g creatinine, an ACE inhibitor is strongly recommended 1
• For patients with diabetes and urinary albumin-to-creatinine ratio 30-299 mg/g creatinine, an ACE inhibitor is suggested 1

Chronic Kidney Disease

• First choice: Any ACE inhibitor at appropriate dose
• Target blood pressure <130/80 mmHg for patients with CKD 1
• ACE inhibitors are preferred for patients with albuminuria 1

Pharmacological Considerations

Pharmacokinetic Differences

• Prodrugs vs. Active Drugs: Captopril and lisinopril are the only ACEIs that are not prodrugs requiring hepatic activation 3
• Elimination: Most ACEIs are eliminated mainly by kidneys; lisinopril is the only ACE inhibitor that does not require hepatic metabolism 3
• Lipophilicity: Fosinopril has the greatest lipophilicity, lisinopril the least 3

Dosing Considerations

• Once-daily dosing: Fosinopril, ramipril, and trandolapril have minimum trough-peak ratios of 50% or greater, making them suitable for once-daily dosing 3
• Titration: Start with low doses and gradually increase to target doses proven effective in clinical trials 1
• Target doses for heart failure:
  • Captopril: 50 mg three times daily
  • Enalapril: 10-20 mg twice daily
  • Lisinopril: 20-40 mg once daily
  • Ramipril: 5 mg twice daily
  • Trandolapril: 4 mg once daily 1

Safety and Monitoring

Common Adverse Effects

• Hypotension, cough, hyperkalemia 4, 3
• Renal insufficiency, particularly in patients with bilateral renal artery stenosis 1
• Angioedema (rare but serious) 5

Monitoring Requirements

• Serum creatinine/eGFR and potassium levels should be monitored:
  • Within 1-2 weeks of initiation
  • After any dose change
  • At least annually thereafter 1

Common Pitfalls and Caveats

1. Underdosing: Many patients are prescribed doses lower than those proven effective in clinical trials. Target doses should be achieved when possible 2, 6

2. Inappropriate discontinuation: Despite initial side effects, more than 90% of patients can be successfully titrated to and maintained on high doses of ACE inhibitors 6

3. Failure to monitor: Not checking renal function and potassium after initiation can lead to undetected hyperkalemia or renal dysfunction 1

4. Drug interactions: ACE inhibitors combined with potassium-sparing diuretics or potassium supplements can cause hyperkalemia 5

5. Racial differences in response: Black patients may have a smaller average response to ACE inhibitor monotherapy compared to non-black patients 5, 7

6. Combination therapy errors: Combining an ACE inhibitor with an ARB increases adverse effects without additional benefits and should be avoided 1

7. Pregnancy risk: ACE inhibitors are contraindicated during pregnancy 5

In conclusion, while all ACE inhibitors work through the same mechanism, preference should be given to those with proven mortality benefits in large clinical trials. The choice between these agents should be based on the specific clinical condition being treated, dosing convenience, and patient-specific factors such as renal function and comorbidities.