What are the considerations for using Isordil (isosorbide dinitrate) and hydralazine in an older patient with heart failure with preserved ejection fraction (HFpEF), hypertension, and diabetes?

Hydralazine and Isosorbide Dinitrate Should NOT Be Used in HFpEF

The combination of hydralazine and isosorbide dinitrate is not recommended for patients with heart failure with preserved ejection fraction (HFpEF), as there is no evidence of benefit and emerging data suggest potential harm in this population. 1, 2

Evidence-Based Rationale

Lack of Indication in HFpEF

• Guideline recommendations for hydralazine-isosorbide dinitrate are specific to HFrEF (heart failure with reduced ejection fraction), not HFpEF. The American Heart Association and American College of Cardiology guidelines explicitly recommend this combination only for patients with reduced ejection fraction (EF ≤35-40%), not preserved ejection fraction. 1, 3

• The Class I recommendation applies exclusively to self-identified African American patients with NYHA class III-IV HFrEF who remain symptomatic despite optimal therapy with ACE inhibitors, beta-blockers, and aldosterone antagonists. 1, 3, 4

Direct Evidence of Harm in HFpEF

• A 2017 randomized controlled trial specifically tested isosorbide dinitrate with and without hydralazine in HFpEF patients and found concerning results: 2

  • ISDN+hydralazine increased wave reflection magnitude (worsening hemodynamics)
  • Reduced 6-minute walk distance (decreased functional capacity)
  • Increased native myocardial T1 on cardiac MRI (suggesting worsening myocardial remodeling)
  • High adverse event rates: 60-61.5% with active therapy vs. 12.5% with placebo 2

• Neither ISDN alone nor ISDN+hydralazine reduced left ventricular mass, myocardial fibrosis, or improved wave reflections in HFpEF patients. 2

Appropriate Management of HFpEF with Hypertension and Diabetes

Guideline-Directed Therapy for HFpEF

For patients with HFpEF, hypertension, and diabetes, the recommended approach includes: 1, 5

• Beta-blockers, ACE inhibitors, or ARBs are reasonable for blood pressure control in HFpEF (Class IIa recommendation). 1

• ARBs may be considered to decrease hospitalizations in HFpEF patients. 1

• SGLT2 inhibitors represent emerging guideline-directed therapy for HFpEF, particularly beneficial in patients with diabetes. 5

• Mineralocorticoid receptor antagonists (MRAs) can be considered for most older adults with HFpEF. 5

• Loop diuretics for symptom management when volume overload is present. 1, 5

Blood Pressure Management Specifics

• Hypertension control is particularly important in HFpEF, as these patients often have left ventricular hypertrophy that may regress with adequate blood pressure control. 1

• Thiazide or thiazide-like diuretics are more effective than loop diuretics for blood pressure control in HFpEF (Class IIa). 1

Critical Pitfalls to Avoid

Do Not Extrapolate HFrEF Data to HFpEF

• The mortality and morbidity benefits demonstrated in HFrEF trials (43% mortality reduction, 33% hospitalization reduction) do not apply to HFpEF. 3, 4, 6, 7

• All major trials supporting hydralazine-isosorbide dinitrate (V-HeFT I, V-HeFT II, A-HeFT) enrolled patients with reduced ejection fraction, not preserved ejection fraction. 7, 8

Medication Tolerance Issues

• Even in appropriate HFrEF populations, adherence is challenging due to three-times-daily dosing and side effects (headache, dizziness, gastrointestinal complaints). 1, 4, 9

• In older adults with HFpEF, the risk-benefit ratio is particularly unfavorable given age-related pharmacokinetic changes and increased susceptibility to adverse effects. 5

Specific Contraindications Relevant to This Patient

• Hydralazine causes reflex tachycardia and requires concurrent beta-blocker therapy, which may complicate management. 3, 10

• The combination can cause severe hypotension, particularly problematic in elderly patients who may already be volume depleted or have autonomic dysfunction. 9, 10