ACE Inhibitor with Longest Duration of Action
Trandolapril and ramipril are the ACE inhibitors with the longest duration of action, both demonstrating trough-to-peak ratios exceeding 50% and allowing true once-daily dosing with sustained 24-hour ACE inhibition. 1
Primary Recommendations
Trandolapril is dosed at 1 mg once daily initially, with a target dose of 4 mg once daily, and provides the most sustained ACE inhibition throughout a 24-hour period. 2, 1
Ramipril is dosed at 1.25-2.5 mg once daily initially, with a target dose of 10 mg once daily (or 5 mg twice daily), and similarly maintains trough-to-peak ratios exceeding 50%. 2, 1, 3
Perindopril represents another long-acting option, with maximal ACE inhibition occurring 4-6 hours after dosing and substantial inhibition persisting beyond 24 hours, despite the active metabolite (perindoprilat) being barely detectable by 24 hours. 4, 5 It is dosed at 2 mg once daily initially, with a target of 8-16 mg once daily. 2, 1
Comparison with Shorter-Acting Agents
In contrast, captopril has a half-life of approximately 1 hour and requires three-times-daily dosing (6.25 mg initially, target 50-100 mg three times daily), making it the shortest-acting ACE inhibitor. 1
Enalapril and quinapril require twice-daily dosing due to intermediate duration of action. 2, 1
Lisinopril and fosinopril allow once-daily dosing but have less robust trough-to-peak ratios compared to trandolapril and ramipril. 1
Renal Adjustment Considerations
Trandolapril
- No specific renal adjustment guidelines are provided in major heart failure trials, but caution is advised when creatinine exceeds 3 mg/dL. 2
Ramipril
- Dose reduction required in renal impairment, though specific adjustments vary by indication. 3
- Monitor renal function and electrolytes within 1-2 weeks of initiation or dose changes. 3
Perindopril
- Dose reduction is required in elderly subjects and those with renal impairment. 4
- The area under the curve of perindoprilat increases dramatically from 93 ng·ml⁻¹·h in normal renal function to 1106 ng·ml⁻¹·h in severe renal failure, with half-life extending from 5.0 to 27.4 hours. 6
- The extent and duration of ACE inhibition is markedly augmented in renal failure, with the area under the inhibition-time curve increasing from 2490%·h in normal function to 42,241%·h in severe impairment. 6
- Perindoprilat is dialyzable. 6
General Renal Precautions
All ACE inhibitors should be used with caution when serum creatinine exceeds 2.5 mg/dL (221 μmol/L) or potassium exceeds 5.0 mEq/L. 2
Elderly Patient Considerations
Perindopril demonstrates greater blood pressure reductions in elderly compared to young subjects due to pharmacokinetic differences, necessitating dose reduction. 4
Moexipril also requires dosage reduction in elderly patients. 1
Age alone should not preclude ACE inhibitor use, but elderly patients require more cautious titration and monitoring. 7
Clinical Efficacy Evidence
All ACE inhibitors with proven mortality benefit in heart failure trials (captopril, enalapril, lisinopril, perindopril, ramipril, and trandolapril) should be preferred over those without such evidence. 2, 1
The available data suggest no differences among ACE inhibitors in their effects on symptoms or survival when used at appropriate doses. 2
Higher doses of ACE inhibitors are better than low doses in reducing hospitalization risk, though they show similar effects on symptoms and mortality. 2