Should hydralazine (Hydralazine) and Isordil (Isosorbide dinitrate) be continued in a patient with a history of heart failure with preserved ejection fraction (HFpEF), hypertension, and diabetes, who has now recovered their ejection fraction (EF)?

Discontinuation of Hydralazine-Isosorbide Dinitrate After EF Recovery

In patients who have recovered their ejection fraction (EF ≥45%) after previously having HFrEF, hydralazine-isosorbide dinitrate should be discontinued, as these medications are specifically indicated only for symptomatic HFrEF (EF <40%) and have no proven benefit—and potential harm—in patients with preserved ejection fraction. 1, 2

Evidence-Based Rationale for Discontinuation

Indication-Specific Therapy

• Hydralazine-isosorbide dinitrate combination received Class I recommendation specifically for African-American patients with NYHA class III-IV HFrEF who remain symptomatic despite optimal therapy with ACE inhibitors, beta-blockers, and diuretics 1, 2
• The Class IIa recommendation for non-African American patients applies only to those with reduced LVEF already taking an ACE inhibitor and beta-blocker who have persistent symptoms 2
• Once EF recovers to ≥45%, the patient no longer meets the indication criteria for this therapy 3

Evidence of Harm in Preserved EF

• A 2017 randomized controlled trial specifically tested isosorbide dinitrate with or without hydralazine in HFpEF patients and found deleterious effects: the combination increased wave reflections (reflection magnitude increased from 0.39 to 0.44, P=0.03), reduced 6-minute walk distance (343.3 to 277.0 meters, P=0.022), and increased native myocardial T1 suggesting worsening myocardial remodeling (1016.2 to 1054.5, P=0.021) 4
• High adverse event rates occurred with active therapy (60-61.5%) compared to placebo (12.5%, P=0.007) in HFpEF patients 4
• The study concluded these vasodilators should not be routinely used in patients with HFpEF 4

Improved Prognosis After EF Recovery

• Patients with recovered heart failure (baseline EF <45% recovering to ≥45%) demonstrate significantly improved mortality and morbidity compared to both persistent HFrEF and HFpEF patients 3
• Using HF-recovered patients as reference, HFrEF patients had HR 1.99 (95% CI 1.50-2.65, P<0.001) for the composite endpoint of CV death or HF hospitalization 3
• All-cause, cardiovascular, HF-related, and sudden death were significantly lower in HF-recovered subjects relative to persistent HFrEF (all P<0.01) 3

Appropriate Medication Management After EF Recovery

Continue Foundational Neurohormonal Therapy

• ACE inhibitors or ARBs should be continued for blood pressure control and to prevent recurrent LV dysfunction, as hypertension control is critical in patients with recovered EF 1
• Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) should be continued as they provide ongoing benefit for hypertension, coronary disease, and prevention of recurrent dysfunction 1, 5
• Mineralocorticoid receptor antagonists may be continued or discontinued based on blood pressure control needs, potassium levels, and renal function 1

Discontinue HFrEF-Specific Therapies

• Hydralazine-isosorbide dinitrate should be discontinued as the indication no longer exists and evidence shows potential harm in preserved EF 4, 2
• The combination has no Class I or IIa recommendation for patients with preserved EF or recovered EF 1, 2

Optimize for Comorbidities

• Given the patient's hypertension and diabetes, focus should shift to optimal blood pressure control with guideline-directed therapy for these conditions 1
• For hypertension in patients with history of HF, target BP <140/90 mmHg, with consideration for <130/80 mmHg 1
• Thiazide or thiazide-like diuretics should be used for BP control if needed 1

Critical Pitfalls to Avoid

Do Not Continue Medications Without Current Indication

• Continuing hydralazine-isosorbide dinitrate "just because the patient was on it" is inappropriate when the indication (symptomatic HFrEF) no longer exists 2, 4
• The 2017 trial demonstrated that continuing these medications in preserved EF patients causes harm, not benefit 4

Monitor for Recurrent LV Dysfunction

• Serial echocardiographic monitoring is essential as some patients may experience recurrent decline in EF 3
• If EF declines back to <40% with symptoms, hydralazine-isosorbide dinitrate could be reconsidered at that time 2

Avoid Medication Inertia

• One in four treated HFrEF patients show recovery of systolic function, and their medication regimen should be appropriately adjusted 3
• Recovered patients have fundamentally different pathophysiology and prognosis compared to persistent HFrEF 3

Maintain Appropriate Monitoring

• Continue monitoring blood pressure, renal function, and electrolytes after medication adjustments 1, 5
• Daily weight monitoring remains important to detect early signs of volume overload if LV function deteriorates 5