Hydralazine: Clinical Overview
Primary Indication
Hydralazine is primarily used in combination with isosorbide dinitrate for heart failure with reduced ejection fraction (HFrEF), particularly in self-identified Black or African American patients with NYHA class III-IV symptoms who remain symptomatic despite optimal therapy with ACE inhibitors/ARBs and beta-blockers. 1
Adult Dosing Recommendations
Heart Failure (with Isosorbide Dinitrate)
Fixed-Dose Combination:
- Initial dose: 1 tablet (37.5 mg hydralazine + 20 mg isosorbide dinitrate) three times daily 1
- Target dose: 2 tablets three times daily (total daily: 225 mg hydralazine + 120 mg isosorbide dinitrate) 1
Separate Formulations:
- Both medications must be administered at least three times daily 1
- Titrate slowly from initial low doses to target similar to fixed-dose combination 1
- Slower titration enhances tolerance and adherence 1
Hypertension
- Hydralazine produces unpredictable blood pressure responses with prolonged duration of action (2-4 hours), making it less favorable as first-line therapy 2, 3
- Onset of action is approximately 15 minutes with challenging dose titration 2
Indications
Class I Recommendation (Strongest Evidence)
- Self-identified Black or African American patients with HFrEF (LVEF ≤40%) and NYHA class III-IV symptoms who are already receiving ACE inhibitors/ARBs and beta-blockers 1
- This combination reduced mortality by 43% (NNT=7 for mortality reduction over 36 months) 1
Class IIa Recommendation (Reasonable Alternative)
- Patients intolerant of ACE inhibitors or ARBs, though data is limited 1
- Should NOT be used as first-line therapy without prior neurohormonal antagonist therapy 1
- Should NOT be substituted for ACE inhibitors/ARBs in patients tolerating them without difficulty 1
Contraindications
Absolute Contraindications
- Concurrent use of phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) when combined with isosorbide dinitrate 4
- Hypertrophic cardiomyopathy with outflow obstruction 4
Relative Contraindications
- Severe anemia (may worsen tissue hypoxia) 4
- Cardiovascular disease with concern for tachycardia (hydralazine causes reflex tachycardia) 4, 2, 3
Pediatric Populations
- Avoid in children: No established safety profiles or dosing guidelines exist 4
Adverse Effects
Common Adverse Effects
- Headache (very common) 1, 2
- Gastrointestinal complaints (nausea, vomiting, diarrhea) 1, 2
- Dizziness 1
- Reflex tachycardia (due to arterial vasodilation triggering baroreceptor-mediated sympathetic activation) 4, 2, 3
Serious Adverse Effects
Adherence Challenges
- Poor adherence is common due to large pill burden, three-times-daily dosing, and high incidence of adverse reactions 1
- Many patients cannot continue treatment at target doses 1
Monitoring Parameters
When Combined with Isosorbide Dinitrate
Cardiovascular Monitoring:
- Heart rate: Monitor for reflex tachycardia, particularly in patients with underlying cardiovascular disease 4, 2, 3
- Blood pressure: Assess for unpredictable responses and hypotension 2, 3
Nitrate Tolerance Prevention:
- Ensure nitrate-free interval of 10-12 hours daily to prevent complete loss of anti-ischemic effects 4
- Hydralazine prevents nitrate tolerance by maintaining persistent hemodynamic effects on pulmonary artery and left ventricular filling pressures 6
Symptom Assessment:
- Monitor for headache, dizziness, and gastrointestinal symptoms 1
- Assess NYHA functional class and heart failure symptoms 1
Laboratory Monitoring:
- Complete blood count: Screen for hemolytic anemia 5
- Autoimmune markers: If lupus-like symptoms develop (arthralgia, fever, rash) 5
- Renal function: Assess for glomerulonephritis if indicated 5
Clinical Pearls and Pitfalls
Mechanism of Action
- Hydralazine: Direct arterial vasodilator with minimal venous effect, reducing afterload 2
- Isosorbide dinitrate: Preferentially dilates veins, reducing preload 2
- Synergistic effect: Combined therapy enhances cardiac output while reducing both preload and afterload 2
Race-Specific Efficacy
- Post hoc analysis of V-HeFT trials demonstrated particular efficacy in African American patients, presumed related to enhanced nitric oxide bioavailability 1, 7
- The A-HeFT trial confirmed mortality benefit in self-identified Black patients, leading to early trial termination 7
- Efficacy in non-African American patients with HFrEF remains uninvestigated 1
Real-World Utilization Gap
- Only 22.4% of eligible African American patients receive hydralazine-isosorbide dinitrate despite Class I guideline recommendation 8
- Treatment rates have increased from 16% to 24% among African Americans between 2008-2012, but remain suboptimal 8
Post-Stroke Hypertension
- Not recommended as first-line for post-stroke blood pressure management due to unpredictable response and reflex tachycardia 3
- Calcium channel blockers (nicardipine, clevidipine) are preferred alternatives 3