What is the role of Hydralazine (HYD) and Isosorbide dinitrate (ISDN) in treating heart failure?

From the Guidelines

Hydralazine and Isosorbide Dinitrate combination therapy is recommended for self-identified African American patients with NYHA class III-IV heart failure with reduced ejection fraction (HFrEF) who are receiving optimal medical therapy, to improve symptoms and reduce morbidity and mortality. This recommendation is based on the most recent and highest quality study, the 2022 AHA/ACC/HFSA guideline for the management of heart failure 1. The combination of hydralazine and isosorbide dinitrate works through complementary mechanisms, with hydralazine acting as a direct vasodilator and isosorbide dinitrate increasing nitric oxide availability, promoting venous and arterial dilation.

Key Points

• The standard dosing regimen is hydralazine 37.5 mg with isosorbide dinitrate 20 mg taken three times daily, titrated up to hydralazine 75 mg with isosorbide dinitrate 40 mg three times daily as tolerated.
• This combination has shown particular benefit in African American patients due to differences in nitric oxide pathway biology.
• Common side effects include headache, dizziness, and hypotension, so blood pressure should be monitored regularly.
• HYD-ISDN is typically added to standard heart failure therapy including ACE inhibitors, beta-blockers, and diuretics rather than replacing these medications.
• Patients should take the medication consistently with meals to improve absorption and minimize side effects.

Clinical Considerations

• The combination of hydralazine and isosorbide dinitrate may also be considered in patients with current or previous symptomatic HFrEF who cannot be given first-line agents, such as ARNi, ACEi, or ARB, because of drug intolerance or renal insufficiency 1.
• The economic value of this combination is high, particularly in African American patients with NYHA class III to IV HFrEF who are receiving optimal medical therapy with ACEi or ARB, beta blockers, and MRA 1.

From the FDA Drug Label

Although the precise mechanism of action of hydrALAZINE is not fully understood, the major effects are on the cardiovascular system. The peripheral vasodilating effect of hydrALAZINE results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The benefits of immediate-release oral isosorbide dinitrate in patients with acute myocardial infarction or congestive heart failure have not been established.

The role of Hydralazine (HYD) and Isosorbide dinitrate (ISDN) in treating heart failure is to act as vasodilators, with Hydralazine directly relaxing vascular smooth muscle and Isosorbide dinitrate providing benefits that have not been established in congestive heart failure.

• Hydralazine increases cardiac output by decreasing peripheral vascular resistance and arterial blood pressure.
• Isosorbide dinitrate has not been established as beneficial in congestive heart failure, and its use in this setting requires careful monitoring to avoid hypotension and tachycardia 2 3.

From the Research

Role of Hydralazine and Isosorbide Dinitrate in Treating Heart Failure

The combination of Hydralazine (HYD) and Isosorbide Dinitrate (ISDN) plays a significant role in the treatment of heart failure, particularly in certain patient populations. Key aspects of their role include:

• Mortality and Morbidity Reduction: The combination of ISDN and HYD has been shown to reduce mortality and morbidity in patients with heart failure, especially in African-American patients with symptomatic heart failure and reduced ejection fraction 4, 5.
• Vasodilating Properties: The HYD and ISDN combination has arterial and venous vasodilating properties, which can decrease preload and afterload, improve left ventricular ejection fraction, and induce left ventricular reverse remodeling 6.
• Regression of Left Ventricular Remodeling: Studies have demonstrated that the fixed-dose combination of ISDN and HYD can produce further regression of left ventricular remodeling when added to background therapy with renin-angiotensin and sympathetic inhibitors in black patients with heart failure 7.
• Benefits in Specific Patient Populations: The combination has been found to be particularly beneficial in self-identified black patients with heart failure, who may have a reduced ability to produce endogenous nitric oxide and thus may be more responsive to drugs that increase nitric oxide delivery, such as nitrates 5.
• Efficacy in Elderly Patients: Analysis from the African-American Heart Failure Trial (A-HeFT) indicates that fixed-dose combined ISDN/HYD improves outcomes in both younger and elderly patients with heart failure, despite baseline differences between these age groups 8.

Mechanism of Action and Clinical Implications

The mechanism by which HYD and ISDN exert their beneficial effects in heart failure involves:

• Vasodilation: ISDN acts as a nitrate, providing vasodilatory effects, while HYD may mitigate nitrate tolerance and contribute to sustained vasodilation 4, 6.
• Antioxidant Properties: HYD has antioxidant properties that can affect endothelial dysfunction beneficially and improve NO bioavailability, contributing to the therapeutic effects of the combination 6.
• Clinical Implications: The use of HYD and ISDN in combination is guideline-recommended for certain patient groups, including African-American patients with symptomatic heart failure and reduced ejection fraction, and those who cannot receive angiotensin-converting enzyme inhibitors or angiotensin receptor blockers due to intolerance or contraindication 4, 6.