What is the recommended dose of Isosorbide dinitrate (ISDN) plus Hydralazine (HYZ) for the treatment of heart failure?

Isosorbide Dinitrate plus Hydralazine Dosing for Heart Failure

Start with isosorbide dinitrate 20 mg plus hydralazine 37.5 mg three times daily, then titrate to the target dose of isosorbide dinitrate 40 mg plus hydralazine 75 mg three times daily (total daily: 120 mg isosorbide dinitrate and 225 mg hydralazine). 1

Initial Dosing

• Begin with the fixed-dose combination tablet containing 20 mg isosorbide dinitrate and 37.5 mg hydralazine, administered three times daily. 1
• When using the medications separately (not as fixed-dose combination), start with isosorbide dinitrate 20-30 mg and hydralazine 25-50 mg, both given 3-4 times daily. 1

Target Dosing

• Titrate to the maximum dose of 40 mg isosorbide dinitrate and 75 mg hydralazine three times daily (equivalent to 2 tablets of the fixed-dose combination three times daily). 1
• This achieves a total daily dose of 120 mg isosorbide dinitrate and 225 mg hydralazine. 1
• When using separate formulations, the maximum target is 120 mg isosorbide dinitrate total daily in divided doses and 300 mg hydralazine total daily in divided doses. 1

Titration Strategy

• Increase the dose gradually over several weeks to enhance tolerance and minimize adverse effects. 1
• The mean doses achieved in clinical trials were approximately 90 mg isosorbide dinitrate and 175 mg hydralazine total daily, indicating that many patients may not tolerate the full target dose. 1
• Slower titration is warranted given the high incidence of adverse reactions, particularly headache, dizziness, and gastrointestinal complaints. 1

Clinical Context for Use

• This combination is specifically indicated for self-identified Black patients with HFrEF (NYHA class III-IV) who remain symptomatic despite optimal therapy with ACE inhibitors/ARBs, beta-blockers, and aldosterone antagonists. 1
• The combination can also be used in patients who cannot tolerate ACE inhibitors or ARBs due to drug intolerance, hypotension, or renal insufficiency. 1
• Do not substitute this combination for ACE inhibitor/ARB therapy in patients tolerating those medications without difficulty. 1

Mortality Benefit

• This combination provides a 43% relative risk reduction in mortality with a number needed to treat of 7 (standardized to 36 months) and a 33% reduction in heart failure hospitalizations. 1
• In the African-American Heart Failure Trial (A-HeFT), the combination reduced all-cause mortality by 43% and first hospitalizations for heart failure by 39%. 2, 3
• Benefits emerge early (approximately 50 days of treatment) and are sustained throughout therapy. 4

Important Caveats

• Adherence is typically poor due to the three-times-daily dosing schedule, large pill burden, and frequent adverse effects. 1
• Common side effects include headache (49.5% vs 21.1% placebo), dizziness (30.1% vs 13.7%), nausea/vomiting (9.7% vs 6.1%), and hypotension (7.9% vs 4.4%). 3
• The combination is effective even in patients with low baseline systolic blood pressure (<126 mmHg) and does not further reduce blood pressure in this population. 5
• Asymptomatic low blood pressure should not be considered a contraindication to use. 5

Dosing Across Blood Pressure Ranges

• Patients with baseline systolic blood pressure below 126 mmHg experience similar relative benefit from this combination as those with higher blood pressure, despite having more severe heart failure and higher baseline risk. 5
• The medication reduces blood pressure in patients with systolic BP above the median but not in those with lower baseline pressures. 5