What are the usual adult target doses for isosorbide dinitrate (or isosorbide mononitrate) and hydralazine in patients with heart failure?

Target Doses for Isosorbide Dinitrate and Hydralazine in Heart Failure

The target dose for isosorbide dinitrate is 40 mg three times daily (120 mg total daily) and for hydralazine is 75 mg three times daily (300 mg total daily) when used separately, or as a fixed-dose combination of 40 mg isosorbide dinitrate/75 mg hydralazine three times daily. 1

Dosing Regimens

Fixed-Dose Combination

• Starting dose: 20 mg isosorbide dinitrate/37.5 mg hydralazine three times daily 1
• Target dose: 40 mg isosorbide dinitrate/75 mg hydralazine three times daily 1
• Mean dose achieved in clinical trials: 90 mg isosorbide dinitrate and approximately 175 mg hydralazine total daily 1

Separate Prescriptions

• Isosorbide dinitrate:

  • Starting: 20-30 mg three to four times daily 1
  • Target: 120 mg total daily in divided doses 1

• Hydralazine:

  • Starting: 25-50 mg three to four times daily 1
  • Target: 300 mg total daily in divided doses 1
  • Critical safety limit: Keep total daily doses below 150 mg to avoid drug-induced systemic lupus erythematosus 2

Clinical Context and Evidence

The combination demonstrated a 43% relative risk reduction in all-cause mortality with a number needed to treat of 25 over 10 months in the African-American Heart Failure Trial 1, 3. This mortality benefit was established in patients with NYHA class III-IV heart failure already receiving optimal medical therapy including ACE inhibitors/ARBs and beta-blockers 3.

Important Clinical Considerations

Tolerability challenges are substantial:

• Headache occurs in approximately 50% of patients on the combination versus 21% on placebo 4
• Dizziness affects 30% versus 14% on placebo 4
• These adverse effects are the primary reason many patients cannot continue treatment at target doses 1

The combination should be used with background therapy:

• Beta-blockers help mitigate reflex tachycardia caused by hydralazine's arterial vasodilation 2, 5
• Diuretics counteract sodium and water retention 5

Dosing Strategy

Titration approach:

• Start at the lower fixed-dose combination (20/37.5 mg three times daily) 1
• Uptitrate every 1-2 weeks as tolerated toward target doses 1
• Monitor blood pressure and heart rate, especially during titration 6
• Watch for hypotension, particularly in elderly patients or those on multiple antihypertensives 6

Common pitfall to avoid: Do not use phosphodiesterase inhibitors (sildenafil, tadalafil) concurrently due to risk of profound hypotension 6

The mean compliance in clinical trials was 87% with an average of 3.7 tablets taken per day, though only 6% discontinued for adverse events in the extension trial 7. Despite the high target doses, the actual achieved doses in practice often fall short due to side effects, but even submaximal dosing provided significant mortality benefit in the pivotal trials 1, 3.