Hydralazine in Heart Failure with Reduced Ejection Fraction
Hydralazine combined with isosorbide dinitrate (H-ISDN) should be prescribed for self-identified Black or African American patients with HFrEF (LVEF ≤40%) who have NYHA class III-IV symptoms despite optimal therapy with ACE inhibitors/ARBs/ARNI and beta-blockers, as this combination reduces mortality by 43% in this population. 1
Primary Indication: Self-Identified Black or African American Patients
The 2022 ACC/AHA guidelines provide a Class I recommendation for adding H-ISDN to standard GDMT (ACEi/ARB/ARNI plus beta-blocker) in self-identified Black or African American patients with symptomatic HFrEF (NYHA class III-IV). 1
This recommendation is based on the African-American Heart Failure Trial (A-HeFT), which demonstrated a 43% reduction in mortality when H-ISDN was added to contemporary guideline-based therapy in Black patients with advanced heart failure. 2, 3
The 2020 ACC/AHA performance measures specifically track prescribing of H-ISDN in this population as a quality metric, emphasizing that this therapy remains significantly underutilized despite strong evidence. 1
Secondary Indication: ACE Inhibitor/ARB/ARNI Intolerance
H-ISDN serves as an alternative when renin-angiotensin system inhibitors cannot be used due to intolerance (such as angioedema, severe hyperkalemia, or renal dysfunction) or contraindications. 1, 3
The 1995 ACC/AHA guidelines established H-ISDN as a Class I recommendation for patients who cannot tolerate ACE inhibitors, based on the original V-HeFT I trial showing 34% mortality reduction at 2 years. 1, 3
The 2016 ESC guidelines include H-ISDN in their treatment algorithm specifically for patients where ACE inhibitors, ARBs, or ARNI are not tolerated or contraindicated. 1
Mechanism and Hemodynamic Effects
Hydralazine acts as a direct arterial vasodilator by relaxing vascular smooth muscle through interference with calcium metabolism, resulting in decreased afterload and increased cardiac output. 4
Isosorbide dinitrate provides venous vasodilation and improves nitric oxide bioavailability, reducing preload and left ventricular wall tension. 5
The combination decreases left ventricular end-diastolic diameter, reduces mitral regurgitation volume, lowers pulmonary artery pressures, and induces left ventricular reverse remodeling. 5
Hydralazine specifically mitigates nitrate tolerance that develops with continuous isosorbide dinitrate use, maintaining therapeutic efficacy during long-term treatment. 2, 6
Dosing and Titration
Target dosing is hydralazine 75 mg three times daily plus isosorbide dinitrate 40 mg three times daily, as used in the A-HeFT trial. 2
Start with lower doses (hydralazine 25 mg three times daily plus isosorbide dinitrate 20 mg three times daily) and titrate upward based on blood pressure tolerance and symptom response. 1
A fixed-dose combination formulation is available, which may improve adherence compared to separate medications. 2
Important Caveats and Monitoring
Hydralazine undergoes polymorphic acetylation, meaning slow acetylators have higher plasma levels and may require lower doses to avoid side effects like headache, tachycardia, and hypotension. 4
Monitor for drug-induced lupus syndrome with long-term hydralazine use, particularly at doses >200 mg daily and in slow acetylators. 4
Reflex tachycardia from hydralazine increases myocardial oxygen demand; ensure adequate beta-blocker therapy is established before initiating H-ISDN. 7
Nitrate tolerance can develop despite hydralazine co-administration; if symptoms worsen after initial improvement, consider dose adjustment or alternative therapies. 6
Clinical Context and Underutilization
H-ISDN remains significantly underused in eligible Black patients, with studies showing prescription rates well below 50% even in those meeting guideline criteria. 3
The combination is often overlooked due to three-times-daily dosing complexity, side effects (particularly headache from nitrates), and polypharmacy concerns in patients already on multiple HF medications. 6
Despite being superseded by ACE inhibitors, ARBs, and ARNI as first-line therapy in non-Black populations, H-ISDN fills a critical gap for Black patients who have persistently higher HF mortality rates even on standard GDMT. 3
The 2022 ACC/AHA guidelines position H-ISDN as part of comprehensive quadruple therapy for HFrEF, which can extend life expectancy by approximately 6 years compared to dual therapy alone. 8
When NOT to Use Hydralazine-Isosorbide Dinitrate
Do not use in patients with severe hypotension (systolic BP <90 mmHg) or those unable to tolerate vasodilator therapy. 1
Avoid in patients with severe aortic stenosis, as afterload reduction can precipitate hemodynamic collapse. 7
Use caution in patients with coronary artery disease, as reflex tachycardia may precipitate myocardial ischemia despite improved hemodynamics. 7