What is the recommended dose and indication for Isosorbide dinitrate (ISDN) with Hydralazine (HYZ)?

Isosorbide Dinitrate with Hydralazine: Dosing and Indications

The combination of isosorbide dinitrate and hydralazine is indicated primarily for self-identified African American patients with NYHA class III-IV heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal guideline-directed medical therapy with ACE inhibitors/ARBs, beta blockers, and aldosterone antagonists. 1

Primary Indication (Class I Recommendation)

• African American patients with symptomatic HFrEF (NYHA class III-IV) already on optimal therapy with ACE inhibitors, beta blockers, and aldosterone antagonists should receive this combination to reduce mortality and morbidity 1
• This represents a 43% relative risk reduction in mortality with a number needed to treat of only 7 patients to prevent one death over 36 months 1
• The A-HeFT trial demonstrated a 43% reduction in overall mortality (6.2% vs 10.2%, p=0.02) and 33% reduction in first HF hospitalization 2

Secondary Indication (Class IIa Recommendation)

• Patients with symptomatic HFrEF who cannot tolerate ACE inhibitors or ARBs due to drug intolerance, hypotension, or renal insufficiency may benefit from this combination as an alternative 1
• This is based on weaker evidence but represents a reasonable option when first-line neurohormonal blockade is not feasible 1

Dosing Regimen

Fixed-Dose Combination (Preferred)

Initial dose: 1 tablet (37.5 mg hydralazine/20 mg isosorbide dinitrate) three times daily 1

Target dose: 2 tablets (75 mg hydralazine/40 mg isosorbide dinitrate) three times daily 1

Maximum daily dose: 225 mg hydralazine/120 mg isosorbide dinitrate total 1

Separate Components (When Fixed-Dose Unavailable)

Initial dose: Isosorbide dinitrate 20-30 mg three times daily + Hydralazine 25-50 mg three times daily 1

Target dose: Isosorbide dinitrate 40 mg three times daily + Hydralazine 100 mg three times daily 1

• Both medications must be administered at least three times daily to maintain therapeutic effect 1
• Titrate slowly from initial to target doses to enhance tolerance 1
• Mean doses achieved in clinical trials were approximately 90 mg isosorbide dinitrate and 175 mg hydralazine daily 1, 3

Critical Prescribing Considerations

Important Contraindications and Warnings

• Never use with phosphodiesterase-5 inhibitors (sildenafil, tadalafil) due to risk of profound hypotension 3
• Do not substitute for ACE inhibitors/ARBs in patients tolerating those medications well 1
• Do not use as first-line therapy in patients without prior neurohormoral antagonist therapy 1

Common Adverse Effects Requiring Slow Titration

• Headache (49.5% vs 21.1% placebo) is the most common side effect 4
• Dizziness (30.1% vs 13.7% placebo) 4
• Hypotension (7.9% vs 4.4% placebo) 4
• Gastrointestinal complaints, sinus congestion, and tachycardia also occur 1, 4

Adherence Challenges

• Poor adherence is common due to three-times-daily dosing, large pill burden, and frequent adverse effects 1
• Slower titration improves tolerance despite the substantial mortality benefit 1
• Fixed-dose combination shows superior outcomes compared to off-label separate generic components in adherent patients (87.9% vs 83.0% 1-year survival, p=0.0024) 5

Monitoring Parameters

• Blood pressure and heart rate should be monitored, especially during dose titration 3
• Watch for signs of hypotension, particularly in elderly patients or those on multiple antihypertensive medications 3

Evidence Quality Note

The benefit in non-African American populations remains uninvestigated in prospective trials 1. The pharmacogenetic basis for differential response may relate to reduced endogenous nitric oxide production in African Americans 4. While ACE inhibitors showed superior survival compared to this combination in the general V-HeFT II population, mortality rates were similar between treatments specifically in self-identified Black patients 6, 4.