Hydralazine and Isosorbide Dinitrate Combination Therapy in Heart Failure

Indications for Combination Therapy

The American College of Cardiology recommends the combination of hydralazine and isosorbide dinitrate as Class I (Level of Evidence A) therapy for self-identified African American patients with NYHA class III-IV heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal therapy with ACE inhibitors, beta blockers, and aldosterone antagonists 1, 3
The American College of Cardiology also recommends this combination as Class IIa (Level of Evidence B) for patients with current or prior symptomatic HFrEF who cannot tolerate ACE inhibitors or ARBs due to drug intolerance, hypotension, or renal insufficiency 1, 4

The combination therapy has demonstrated a 43% reduction in mortality risk and a 33% reduction in heart failure hospitalizations, with a number needed to treat (NNT) for mortality reduction of only 7 when standardized to 36 months 1

The American College of Cardiology recommends starting with 1 tablet containing 37.5 mg hydralazine and 20 mg isosorbide dinitrate three times daily, with the option to increase to 2 tablets three times daily for a total daily dose of 225 mg hydralazine and 120 mg isosorbide dinitrate 1, 4
A nitrate-free interval of at least 10 hours may help minimize nitrate tolerance 5, 6

Patient adherence can be challenging due to the multiple daily dosing and side effect profile, and consider slower titration to enhance tolerance if side effects are problematic 1, 5

For non-African American patients with HFrEF, the benefit remains to be fully investigated, but the combination may be considered for those who cannot tolerate ACE inhibitors or ARBs 1, 7
The combination should not be used as first-line therapy in patients who have not tried standard neurohumoral antagonist therapy (ACE inhibitors, ARBs) 1, 4