Effectiveness of ACE Inhibitors and ARBs When Taken in Lower Doses Twice Daily
For most ACE inhibitors and ARBs, splitting the total daily dose into twice-daily administration is effective and appropriate when patients cannot tolerate the full dose at once, as the therapeutic benefit is primarily related to achieving at least 50% of the target daily dose rather than the dosing frequency. 1
Dosing Considerations for ACE Inhibitors and ARBs
Evidence Supporting Split Dosing
- ACE inhibitors and ARBs are recommended for patients with heart failure with reduced ejection fraction (HFrEF) and should be titrated to maximally tolerated doses to reduce morbidity and mortality 1
- For most ACE inhibitors and ARBs, the total daily dose is more important than the dosing frequency, with guidelines specifying that achieving at least 50% of the target total daily dose is a key performance measure 1
- Several ACE inhibitors are already designed for twice-daily administration in their standard dosing regimens, including captopril (three times daily), enalapril (twice daily), and quinapril (twice daily) 1
Target Doses and Flexibility in Administration
- According to ACC/AHA guidelines, the minimum effective dose is considered to be 50% of the target dose for both ACE inhibitors and ARBs 1
- For example, enalapril's target dose is 10 mg twice daily (20 mg total), with 10 mg daily (50% of target) considered clinically effective 1
- Valsartan's target dose is 160 mg twice daily (320 mg total), with 160 mg daily (50% of target) still providing clinical benefit 1
Clinical Implications and Recommendations
Benefits of Split Dosing
- Split dosing may improve tolerability for patients who experience adverse effects with once-daily full dosing 2
- For patients with low blood pressure, starting with lower doses and gradually titrating up with small increments is recommended, which may include twice-daily administration of smaller doses 1
- Twice-daily administration may provide more consistent 24-hour coverage for some agents with shorter half-lives 3
Important Considerations
- Most ACE inhibitors demonstrate a flat dose-response curve for blood pressure reduction, meaning increased doses primarily extend duration of action rather than increasing potency 4
- Perindopril is noted as an exception, showing a true dose-response curve for blood pressure reduction 4
- The 2022 AHA/ACC/HFSA guidelines emphasize that clinical trials of ACE inhibitors, ARBs, and other heart failure medications typically initiated therapy at low doses and gradually titrated to target doses, regardless of symptomatic improvement at lower doses 1
Practical Application
- When initiating ACE inhibitors or ARBs, start with low doses and gradually increase to target doses while monitoring for adverse effects 1
- For patients who cannot tolerate once-daily target doses, splitting into twice-daily administration of lower doses is a reasonable approach to achieve the total daily target dose 1
- Monitor renal function and serum potassium within 1-2 weeks of initiation and periodically thereafter, especially in high-risk patients 1
Special Populations and Considerations
Elderly and Frail Patients
- The International Society of Hypertension guidelines recommend simplifying regimens with once-daily dosing when possible, but acknowledge that dose adjustments may be needed in elderly or frail patients 1
- In patients aged >80 years or who are frail, starting with lower doses and potentially using split dosing may improve tolerability 1
Patients with Low Blood Pressure
- For patients with low blood pressure who need ACE inhibitors or ARBs for heart failure, starting with the lowest dose and titrating slowly with small increments is recommended 1
- Split dosing may help minimize hypotensive episodes in these patients 1
Remember that the primary goal is to achieve at least 50% of the target daily dose to obtain significant clinical benefits in reducing morbidity and mortality, regardless of whether this is accomplished through once-daily or split dosing 1.