Recommendations for Using Isolazine in Treating Cardiovascular Diseases
The combination of hydralazine and isosorbide dinitrate (often referred to as "Isolazine") is strongly 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, as it significantly reduces morbidity and mortality. 1
Specific Indications and Recommendations
For African American Patients with Heart Failure
- Recommended for self-identified African American patients with NYHA class III-IV HFrEF who are receiving optimal medical therapy with ACEi/ARB, beta-blockers, and MRA 1
- Provides high economic value in this population with a cost per life-year <$60,000 1
- The benefit is presumed to be related to enhanced nitric oxide bioavailability 1, 2
- The combination has been shown to reduce mortality by 43% compared to placebo in this specific population 3
For Non-African American Patients with Heart Failure
- May be considered in patients with HFrEF who cannot tolerate first-line agents such as ARNi, ACEi, or ARB due to drug intolerance or renal insufficiency 1
- Should not be used as first-line therapy or substituted for ACE inhibitors in patients who tolerate ACE inhibitors without difficulty 1
- Should not be used for HF treatment in patients with no prior use of an ACE inhibitor 1
For Hypertension in Cardiovascular Disease
- Can be added to the regimen of diuretic, ACE inhibitor or ARB, and beta-blocker in patients with hypertension and heart failure 1
- Listed as a second-line or "add-on" therapy for stable angina with hypertension 1
Mechanism of Action and Benefits
- Provides both arterial and venous vasodilation, decreasing preload and afterload 4
- Decreases left ventricular end-diastolic diameter and mitral regurgitation volume 4
- Reduces left atrial and ventricular wall tension 4
- Decreases pulmonary artery pressure and pulmonary arterial wedge pressure 4
- Increases stroke volume and improves left ventricular ejection fraction 4
- Has antioxidant properties that affect endothelial dysfunction beneficially 4
- Hydralazine prevents the development of nitrate tolerance when used with isosorbide dinitrate 3
Dosing and Administration
- The benefit in clinical trials was seen only at higher doses than typically used in clinical practice 1
- In A-HeFT trial, the fixed-dose combination of ISDN/hydralazine 40/75 mg TID was used 3
- In V-HeFT trials, ISDN 40 mg QID and hydralazine 75 mg QID were used 3
- Short-acting nitrate therapy was used in the successful trials 1
Potential Adverse Effects and Cautions
- Produces frequent adverse reactions, primarily headache (49.5% vs 21.1% for placebo) and gastrointestinal complaints 1, 3
- Other common side effects include dizziness (30.1%), nausea and vomiting (9.7%), hypotension (7.9%), and tachycardia (4.1%) 3
- Many patients cannot continue treatment at target doses due to side effects 1
- Uptake of this regimen has been modest due to the complexity of the medical regimen and array of drug-related adverse effects 1
- Marked underusage based on very low prescription refill rates 1
- Nitrate component is contraindicated with phosphodiesterase inhibitors (e.g., sildenafil, tadalafil) due to risk of profound hypotension 2
- Should be avoided in patients with severe hypotension (systolic BP <90 mmHg) 2
- Use with caution in patients with aortic stenosis due to risk of marked hypotension 2
Clinical Pearls and Implementation Strategies
- A nitrate-free interval of at least 10 hours can minimize tolerance and side effects 2, 5
- Referral to a heart failure specialist is recommended for patients who cannot receive first-line agents, as the use of hydralazine and isosorbide dinitrate in these patients is uncertain 1
- There are insufficient data to guide the use of hydralazine-isosorbide dinitrate with ARNi 1
- When prescribed, ensure patients understand the importance of adherence despite side effects, as the mortality benefit is significant in appropriate populations 3