When is isosorbide dinitrate (isosorbide dinitrate) used in the treatment of heart failure?

When to Use Isosorbide Dinitrate in Heart Failure

Isosorbide dinitrate combined with hydralazine should be added to guideline-directed medical therapy in self-identified Black or African American patients with NYHA class III-IV heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%) who remain symptomatic despite optimal treatment with ACE inhibitors (or ARBs), beta-blockers, and mineralocorticoid receptor antagonists. 1

Primary Indication: African American Patients with Advanced HFrEF

The 2022 AHA/ACC/HFSA guidelines provide a Class 1 recommendation for the hydralazine/isosorbide dinitrate combination specifically in this population to reduce both morbidity and mortality. 1, 2 This recommendation is based on the A-HeFT trial, which demonstrated significant survival benefit and reduced healthcare costs when this combination was added to standard therapy including ACE inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. 1

Specific Criteria for Use:

• Age: ≥18 years (no upper age limit) 1, 2
• Race/Ethnicity: Self-identified as Black or African American 1
• NYHA Class: III or IV symptoms 1
• LVEF: Current or prior ≤40% 1
• Background therapy: Already receiving ACE inhibitor (or ARB) AND beta-blocker 1

Secondary Indication: ACE Inhibitor/ARB Intolerance

Isosorbide dinitrate with hydralazine may be considered (Class 2b) in patients of any race who cannot tolerate first-line agents (ACE inhibitors, ARBs, or ARNi) due to drug intolerance, symptomatic hypotension, renal insufficiency, hyperkalemia, cough, rash, or angioedema. 1

This is a weaker recommendation because the evidence predates modern ACE inhibitor use (V-HeFT I trial), and recent observational data have not confirmed benefit in this setting. 1 The 1995 ACC/AHA guidelines noted this as an alternative when ACE inhibitors cannot be tolerated. 1 However, referral to a heart failure specialist is strongly recommended before using this approach, as the benefit is uncertain in contemporary practice. 1

Critical Contraindications and Precautions

Absolute Contraindications:

• Concurrent phosphodiesterase-5 inhibitor use (sildenafil, tadalafil, vardenafil) - can cause severe hypotension 2, 3
• Hypertrophic cardiomyopathy with outflow obstruction 2
• Pediatric patients - no established safety profile or dosing guidelines 2, 4

Relative Contraindications:

• Severe anemia - may worsen tissue hypoxia 2
• Acute myocardial infarction or acute decompensated heart failure - FDA labeling notes benefits are not established in these settings, and effects are difficult to terminate rapidly 3

Dosing and Administration Considerations

A nitrate-free interval of at least 10-12 hours daily is essential to prevent complete loss of anti-ischemic effects due to nitrate tolerance. 1, 2 The 1995 guidelines specifically recommend achieving a minimal 10-hour "nitrate-free" period at night. 1

Important Monitoring Points:

• Reflex tachycardia: Hydralazine can cause reflex tachycardia, requiring careful monitoring in patients with cardiovascular disease 2, 5
• Unpredictable response: Hydralazine has variable blood pressure effects and prolonged duration of action 5
• Hypotension risk: The FDA warns that amplification of vasodilatory effects can result in severe hypotension, particularly with concurrent PDE-5 inhibitor use 3

When NOT to Use

Do not use isosorbide dinitrate alone without hydralazine in heart failure - the evidence base specifically supports the combination therapy, not monotherapy. 1 The guidelines specify that formulations of nitrates other than isosorbide dinitrate do not meet quality measure requirements. 1

Insufficient data exists for concomitant use with ARNi (sacubitril/valsartan), so this combination should be approached cautiously. 1

Clinical Context and Evidence Strength

The evidence for use in African American patients is robust (Level of Evidence A), while use in ACE inhibitor-intolerant patients of other races is based on older data (Level of Evidence B-R) and carries more uncertainty. 1 The economic analysis from A-HeFT showed cost-effectiveness with cost per life-year <$60,000, making this a high-value intervention in the appropriate population. 1

Resistance to isosorbide dinitrate occurs in approximately 46% of patients with severe chronic heart failure, particularly those with baseline right atrial pressure ≥10 mmHg, who may require higher doses (80-120 mg). 6 Patients with lower systemic vascular resistance and larger, more compliant ventricles may experience decreased cardiac output with high-dose therapy. 7