Is isosorbide mononitrate (ISMN) appropriate for a patient with chronic heart failure (any ejection fraction) who does not have angina?

ISMN in Heart Failure Without Angina

Isosorbide mononitrate (ISMN) is explicitly NOT recommended for heart failure management and should not be used in patients with chronic heart failure regardless of ejection fraction or angina status. 1, 2

Why ISMN is Inappropriate for Heart Failure

The FDA drug label explicitly states that the benefits of ISMN in patients with congestive heart failure have not been established, and because its effects are difficult to terminate rapidly, this drug is not recommended in heart failure settings. 3

Guideline-Based Recommendations

The evidence is clear and consistent across multiple ACC/AHA guidelines:

• Only isosorbide dinitrate (ISDN), not mononitrate, has proven mortality benefit in heart failure trials and is the recommended nitrate formulation 1, 2
• ISDN must be used in combination with hydralazine to achieve mortality benefit, particularly in African American patients with symptomatic heart failure on optimal therapy 4, 1
• The target dose is isosorbide dinitrate 40 mg three times daily (not mononitrate) 4, 1

Why the Distinction Matters

The pharmacologic differences between ISDN and ISMN are clinically significant:

• ISDN undergoes hepatic first-pass metabolism to produce active metabolites with proven efficacy in heart failure trials 2
• ISDN's three-times-daily dosing naturally provides the necessary 10-14 hour nitrate-free interval to prevent tolerance 2, 5
• ISMN has never demonstrated mortality benefit in heart failure patients 1, 2
• The NICE study showed only a trend toward improved exercise time with ISMN in heart failure, which was not statistically significant for the overall group 6

What Should Be Used Instead

For Patients Who Cannot Tolerate ACE Inhibitors/ARBs

Hydralazine plus isosorbide dinitrate (not mononitrate) is the Class I recommendation for patients who cannot take ACE inhibitors due to contraindications 4

• Start ISDN at 20 mg three times daily and titrate to target dose of 40 mg three times daily 1
• Combine with hydralazine (target dose typically 75-100 mg three times daily) 4

For African American Patients on Optimal Therapy

The combination of hydralazine and isosorbide dinitrate should be added to standard therapy (ACE inhibitor/ARB and beta-blocker) in African American patients with NYHA class III-IV heart failure 4, 1

• This combination demonstrated significant mortality benefit in this population 4
• The benefit is presumed related to enhanced nitric oxide bioavailability 4

Critical Pitfalls to Avoid

Do not substitute ISMN for ISDN thinking they are interchangeable - they are fundamentally different drugs with different evidence bases for heart failure 1, 2

Never use nitrates (ISDN or ISMN) concurrently with phosphodiesterase-5 inhibitors (sildenafil, tadalafil) due to risk of profound hypotension, myocardial infarction, and death 1, 5, 3

Compliance with ISDN is often poor due to the large number of tablets required (three times daily dosing) and high incidence of adverse reactions, particularly headache 4

• Approximately 46% of patients with severe heart failure may not respond to standard doses of ISDN 7
• Patients with baseline right atrial pressure <10 mmHg are more likely to respond to ISDN 7