What are the indications, dosing regimen, common adverse effects, contraindications, and alternative therapies for Isolazine (hydralazine 37.5 mg/isosorbide dinitrate 20 mg)?

Isolazine (Hydralazine 37.5 mg/Isosorbide Dinitrate 20 mg)

Primary Indication

The fixed-dose combination of hydralazine/isosorbide dinitrate is specifically recommended for self-identified African American patients with NYHA class III-IV heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%) who remain symptomatic despite optimal therapy with ACE inhibitors/ARBs (or ARNI), beta-blockers, and aldosterone antagonists. 1

• This represents a Class I, Level A recommendation from the ACC/AHA guidelines 1
• The combination provides a remarkable 43% relative risk reduction in mortality with a number needed to treat of only 7 patients (standardized to 36 months) 1, 2
• It also reduces heart failure hospitalizations by 33% 1, 2

Secondary Indication

For patients with symptomatic HFrEF who cannot tolerate ACE inhibitors or ARBs due to drug intolerance, hypotension, or renal insufficiency, this combination may be considered as an alternative therapy, regardless of race. 1, 3

• This is a Class IIa, Level B recommendation 1
• However, this combination should never be substituted for ACE inhibitors/ARBs in patients who are tolerating those medications without difficulty 1, 3
• It should not be used as first-line therapy in patients who have never received standard neurohormoral antagonist therapy 1

Dosing Regimen

Initial Dosing

Start with 1 tablet (37.5 mg hydralazine/20 mg isosorbide dinitrate) three times daily. 1, 2, 3

Target Dosing

Titrate to 2 tablets (75 mg hydralazine/40 mg isosorbide dinitrate) three times daily for a total daily dose of 225 mg hydralazine and 120 mg isosorbide dinitrate. 1, 2, 3

Titration Strategy

Increase the dose gradually over several weeks to enhance tolerance and minimize adverse effects. 2

• In clinical trials, the mean doses actually achieved were approximately 90 mg isosorbide dinitrate and 175 mg hydralazine total daily, indicating many patients cannot tolerate the full target dose 2
• When using separate formulations (not the fixed-dose combination), start with isosorbide dinitrate 20-30 mg and hydralazine 25-50 mg, both given 3-4 times daily 2

Common Adverse Effects

Adherence to this combination is generally poor due to the high frequency of adverse reactions, three-times-daily dosing schedule, and large pill burden. 1, 2

Most Frequent Side Effects:

• Headache (very common) 1, 4
• Dizziness 1
• Gastrointestinal complaints (nausea, diarrhea) 1, 4

Clinical Trial Data:

• In the HIDE trial, nausea occurred at 1.90 events/patient-year with hydralazine/isosorbide dinitrate versus 0.50 events/patient-year with placebo (p=0.03) 4
• Headache and diarrhea were numerically more frequent but not statistically significant 4
• Overall adverse events were more frequent: 11.4 events/patient-year versus 6.31 events/patient-year with placebo 4

Tolerance Strategy:

A slower titration schedule can substantially enhance tolerance to therapy despite the high incidence of adverse effects. 1

Contraindications and Critical Warnings

Absolute Contraindication:

Do not use concomitantly with phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil) due to risk of profound hypotension. 3

Monitoring Requirements:

Monitor blood pressure and heart rate closely, especially during dose titration, to detect hypotension. 3

• Interestingly, in dialysis patients, recurrent intradialytic hypotension was actually less frequent with hydralazine/isosorbide dinitrate (0.47 events/patient-year) compared to placebo (1.83 events/patient-year, p=0.04) 4

Mechanism of Benefit

The combination functions as a nitric oxide enhancer and antioxidant, helping to prevent tolerance to prolonged nitrate use. 5

• Hemodynamic effects include increased cardiac output by 17-25% 6
• Hydralazine increases renal blood flow by 19% and limb blood flow by 17% 6
• The combination produces regression of left ventricular remodeling: LVEF increased by 2.8% versus 0.8% with placebo (p<0.01), LV mass index decreased by 7.4 g/m² versus an increase of 1.4 g/m² with placebo (p<0.05) 7
• B-type natriuretic peptide (BNP) fell by 39 pg/mL in the treatment group versus 8 pg/mL in placebo (p=0.05) 7

Alternative Therapies

When hydralazine/isosorbide dinitrate cannot be used or is not tolerated in African American patients with HFrEF:

• Optimize existing guideline-directed medical therapy (ACE inhibitors/ARBs/ARNI, beta-blockers, aldosterone antagonists) to maximum tolerated doses 1
• Consider SGLT2 inhibitors (though not mentioned in these specific guidelines, they represent contemporary standard of care)
• Digoxin can be beneficial to decrease hospitalizations for heart failure (Class IIa recommendation) 1
• Ivabradine for patients in sinus rhythm with heart rate ≥70 bpm despite beta-blocker therapy
• Vericiguat or omecamtiv mecarbil for patients with recent worsening heart failure

Critical Clinical Pitfalls

1. Do not use this combination as a substitute for ACE inhibitors/ARBs in patients tolerating those medications well - it is an add-on therapy for African Americans or an alternative for those with intolerance 1, 3

2. Do not use as first-line therapy - patients must first be on standard neurohormonal antagonist therapy unless contraindicated 1

3. Anticipate poor adherence - counsel patients extensively about the three-times-daily dosing and expected side effects, emphasizing the substantial mortality benefit 1, 2

4. The benefit in non-African American populations remains uncertain - the landmark A-HeFT trial was conducted exclusively in self-identified African American patients 1, 5, 8