Hydralazine and Isosorbide Dinitrate Dosing in Heart Failure with Angioedema History
In a patient with heart failure and a history of angioedema, start with hydralazine 37.5 mg plus isosorbide dinitrate 20 mg three times daily (using the fixed-dose combination tablet), and titrate every 2 weeks to the target dose of hydralazine 75 mg plus isosorbide dinitrate 40 mg three times daily. 1, 2
Critical Context: Why This Combination is Particularly Appropriate
This patient's history of angioedema makes hydralazine/isosorbide dinitrate an essential therapeutic option, as ACE inhibitors and ARNIs (sacubitril/valsartan) are contraindicated due to angioedema risk. 3 The 2021 ACC guidelines explicitly state that neprilysin inhibitors cannot be combined with ACE inhibitors due to higher angioedema risk, and patients with a history of angioedema were excluded from the PARADIGM-HF trial. 3
Specific Dosing Algorithm
Initial Dosing
- Start with 1 tablet of the fixed-dose combination (37.5 mg hydralazine/20 mg isosorbide dinitrate) three times daily 1, 2
- If prescribing separately: hydralazine 25 mg three times daily plus isosorbide dinitrate 20 mg three times daily 1
Titration Schedule
- Increase dose every 2 weeks until reaching maximum tolerated or target dose 3
- Target dose: 2 tablets three times daily (75 mg hydralazine/40 mg isosorbide dinitrate per dose) 1, 2
- Maximum daily dose: 225 mg hydralazine/120 mg isosorbide dinitrate total 2
Monitoring During Titration
- Check blood pressure at each dose escalation to avoid hypotension 3, 2
- Monitor heart rate, particularly in elderly patients or those on multiple antihypertensive medications 1
Evidence Supporting This Approach
The combination of hydralazine and isosorbide dinitrate provides a 43% relative risk reduction in mortality with a number needed to treat of only 7 patients to prevent one death over 36 months. 2 In the original V-HeFT I trial, patients receiving this combination had a 34% reduction in mortality risk compared with placebo. 4
The mean dose achieved in clinical trials was approximately 90 mg isosorbide dinitrate daily when used in fixed-dose combination with hydralazine. 1 This represents roughly 2 tablets three times daily of the fixed-dose combination.
Critical Safety Considerations
Absolute Contraindication
Never prescribe this combination with phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) due to risk of profound, life-threatening hypotension. 5, 2 This is an absolute contraindication that must be verified before initiating therapy.
Dosing Interval Requirements
The FDA label specifies that isosorbide dinitrate requires a daily dose-free interval of at least 14 hours to minimize tolerance development. 6 However, the three-times-daily regimen used in heart failure trials (dosing at 0800,1400, and 1800 hours) provides effective coverage while allowing overnight nitrate-free interval. 6
Blood Pressure Considerations
Low baseline systolic blood pressure should not be considered a contraindication to this therapy. 7 In the A-HeFT trial, patients with systolic blood pressure below 126 mm Hg had similar relative benefit from hydralazine/isosorbide dinitrate as those with higher blood pressure, and the combination did not reduce blood pressure in patients with low baseline values. 7
Common Pitfalls and How to Avoid Them
Tolerance Development
- The three-times-daily dosing schedule (rather than four times daily) provides the necessary nitrate-free interval overnight 6
- Do not dose at bedtime, as this eliminates the dose-free interval needed to prevent tolerance 6
Adverse Effects Management
- Headache occurs in approximately 49.5% of patients but typically improves with continued therapy 4
- Dizziness affects 30% of patients 4
- Only 6% of patients discontinue due to adverse events in extension studies 8
- These side effects were less common with continued use in the X-A-HeFT extension trial 8
Compliance Optimization
- Average compliance in clinical trials was 87%, with patients taking an average of 3.7 tablets per day 8
- The fixed-dose combination tablet improves adherence compared to separate prescriptions 2
Alternative Dosing if Fixed-Dose Combination Unavailable
If prescribing separately: