What are the best oral Angiotensin-Converting Enzyme (ACE) inhibitors?

Best Oral ACE Inhibitors

For heart failure with reduced ejection fraction and post-myocardial infarction, use captopril, enalapril, lisinopril, or ramipril at target doses proven in clinical trials, as these four agents have the strongest evidence for reducing mortality and morbidity. 1, 2

Evidence-Based ACE Inhibitor Selection

The ACC/AHA guidelines specifically identify four ACE inhibitors with proven mortality benefit in landmark trials 1:

• Captopril: 6.25 mg three times daily initially, titrate to 50 mg three times daily 1
• Enalapril: 2.5 mg twice daily initially, titrate to 10-20 mg twice daily 1
• Lisinopril: 2.5-5 mg once daily initially, titrate to 20-40 mg once daily 1, 3
• Ramipril: 1.25-2.5 mg once daily initially, titrate to 10 mg once daily 1

These four agents should be prioritized because clinical trials have clearly defined effective doses that modify disease progression and reduce mortality. 2

Clinical Context for Selection

For Heart Failure

• High-dose lisinopril (32.5-35 mg/day) demonstrated significantly lower mortality compared to low-dose lisinopril (2.5-5 mg/day) in the ATLAS trial, emphasizing the importance of titrating to target doses 1
• Ramipril reduced relative mortality risk by 27% overall in post-MI patients with LV dysfunction, with a 41% reduction specifically in hypertensive patients 1
• Trandolapril showed a 7% absolute mortality reduction in the TRACE trial 1

For Hypertension with Diabetes

• ACE inhibitors are first-line therapy for diabetic patients with microalbuminuria or clinical nephropathy 1
• The MICRO-HOPE study demonstrated cardiovascular benefits with ramipril that may extend beyond blood pressure reduction alone 1

Practical Dosing Considerations

Start low and titrate to target doses used in clinical trials 1:

• Begin with the initial doses listed above, particularly in patients at risk for hypotension 4
• Double doses at each titration step, monitoring blood pressure (including orthostatic measurements), renal function, and potassium within 1-2 weeks after each change 1, 4
• Target the maximum doses proven in trials rather than stopping at lower doses 1, 2

Pharmacokinetic Distinctions

While clinical outcomes are similar among the four preferred agents, some pharmacokinetic differences may guide selection in specific situations 5, 6:

• Lisinopril provides consistently better 24-hour blood pressure control than captopril or enalapril and requires no hepatic activation 6, 7
• Captopril has rapid onset and short duration, making it preferable for initiating therapy in severe heart failure patients at risk of first-dose hypotension 6
• Ramipril has dual renal and hepatic elimination, potentially advantageous in renal impairment 5

Critical Safety Monitoring

Monitor for these ACE inhibitor-related adverse effects 1, 3:

• Hypotension: Especially with initial dosing or in volume-depleted patients
• Worsening renal function: Particularly when combined with diuretics or in pre-existing renal disease
• Hyperkalemia: Risk increases with aldosterone antagonists or renal impairment
• Cough: Occurs in a minority but may require switching to an ARB if persistent and troublesome 1
• Angioedema: Rare (<1%) but life-threatening; permanently contraindicate all ACE inhibitors if it occurs 1

When ARBs Are Appropriate Alternatives

If ACE inhibitors cause intolerable cough or angioedema, candesartan and valsartan have demonstrated equivalent mortality and hospitalization benefits 1. However, ACE inhibitors remain first-line therapy when tolerated 1, 8.

Never exceed the maximum recommended dose of 40 mg once daily for lisinopril; if blood pressure control is inadequate, add a different antihypertensive class rather than exceeding maximum doses 3.