What is the role of isosorbide dinitrate (ISDN) plus hydralazine (HYD) in heart failure management?

Isosorbide Dinitrate Plus Hydralazine in Heart Failure Management

The combination of isosorbide dinitrate and hydralazine is a Class I recommendation for self-identified African American patients with symptomatic HFrEF (NYHA class III-IV) who remain symptomatic despite optimal guideline-directed medical therapy with ACE inhibitors/ARBs, beta blockers, and mineralocorticoid receptor antagonists. 1, 2

Primary Indications

African American Patients with HFrEF (Strongest Evidence)

• This combination provides a 43% reduction in mortality risk and 33% reduction in heart failure hospitalizations when added to standard neurohormonal blockade therapy 2, 3
• The number needed to treat for mortality reduction is only 7 when standardized to 36 months, making this one of the most effective interventions in heart failure 2
• The A-HeFT trial demonstrated significant improvements in composite outcomes including death, hospitalization, and quality of life in self-identified Black patients 1, 3
• This benefit appears related to enhanced nitric oxide bioavailability in this population 1

Alternative Therapy for ACE Inhibitor/ARB Intolerance

• For patients of any race who cannot tolerate ACE inhibitors or ARBs due to hypotension, renal insufficiency, or drug intolerance, hydralazine-isosorbide dinitrate may be considered as an alternative (Class IIa recommendation) 1, 2
• The evidence for non-African American patients is less robust, derived primarily from the V-HeFT I trial conducted before modern neurohormoral therapy was standard 1
• Referral to a heart failure specialist is recommended when considering this option for ACE inhibitor/ARB-intolerant patients 1

Mechanism and Physiologic Benefits

The combination provides complementary vasodilatory effects 4, 5:

• Isosorbide dinitrate acts primarily as a venodilator, reducing preload through peripheral venous pooling and decreasing left ventricular end-diastolic pressure 4
• Hydralazine acts as an arterial vasodilator, reducing afterload by decreasing systemic vascular resistance 1, 5
• The combination produces favorable left ventricular reverse remodeling, with studies showing increased ejection fraction (2.8% vs 0.8% with placebo), decreased LV mass index, and improved sphericity indices 6
• Hydralazine may prevent nitrate tolerance that typically develops with continuous nitrate therapy 1, 2
• Both agents have antioxidant properties and improve endothelial function and nitric oxide bioavailability 5

Dosing Strategy

Start with one tablet containing 37.5 mg hydralazine and 20 mg isosorbide dinitrate three times daily 2:

• Target dose is 2 tablets three times daily (total daily dose: 225 mg hydralazine and 120 mg isosorbide dinitrate) 2
• Implement a nitrate-free interval of at least 10-14 hours to minimize tolerance development 1, 2, 4
• If side effects are problematic, consider slower titration to enhance tolerance 2
• The longer dose-free interval (14 hours) compared to nitroglycerin (10-12 hours) reflects the longer half-lives of isosorbide dinitrate and its active metabolites 4

Common Pitfalls and Adverse Effects

Tolerability Challenges

• Headache and gastrointestinal complaints are the most common side effects, often limiting dose escalation 1
• Hypotension and dizziness can occur, particularly when combined with other vasodilators 7, 4
• Patient adherence is challenging due to three-times-daily dosing and side effect profile 2
• Many patients in clinical trials could not continue treatment at target doses due to adverse reactions 1

Critical Contraindications

• Absolute contraindication with concurrent sildenafil or other PDE-5 inhibitors due to risk of severe hypotension 4
• Not recommended in acute myocardial infarction or acute decompensated heart failure due to difficulty rapidly terminating effects 4
• Careful hemodynamic monitoring required if used in these acute settings 4

Important Clinical Caveats

When NOT to Use This Combination

• Should not be used as first-line therapy in patients who have not tried ACE inhibitors or ARBs 1, 2
• Should not be substituted for ACE inhibitors in patients tolerating them without difficulty 1
• Insufficient data exists for concomitant use with angiotensin receptor-neprilysin inhibitors (ARNi) 1

Evidence Limitations

• The benefit in non-African American patients remains uncertain, with observational datasets showing inconsistent results 1
• The V-HeFT II trial showed ACE inhibitors produced more favorable survival effects than hydralazine-isosorbide dinitrate in the overall cohort, though mortality was similar in Black patients 1, 8
• Most robust evidence predates widespread use of modern guideline-directed medical therapy including SGLT2 inhibitors and ARNi 1

Economic Considerations

The A-HeFT economic analysis demonstrated this combination is cost-effective 1:

• Increased survival and reduced healthcare costs over the 12.8-month trial period 1
• Cost per life-year gained was less than $60,000 when extrapolated over a lifetime 1
• Reduction in hospitalizations contributes significantly to cost-effectiveness 8