When should hydralazine be started in a patient with hypertension, particularly those with heart failure or resistant hypertension, who is already on a combination of antihypertensive medications, including Angiotensin-Converting Enzyme (ACE) inhibitors, beta blockers, and diuretics?

When to Start Hydralazine in Heart Failure with Reduced Ejection Fraction

Hydralazine should be started when hypertension persists despite treatment with an ACE inhibitor (or ARB), beta-blocker, mineralocorticoid receptor antagonist (MRA), and diuretic in patients with heart failure with reduced ejection fraction (HFrEF). 1

Stepwise Algorithm for Initiating Hydralazine

Step 1: Optimize Guideline-Directed Medical Therapy First

• Ensure the patient is on maximally tolerated doses of ACE inhibitor (or ARB), beta-blocker, and MRA before considering hydralazine 1, 2
• Verify adequate diuretic therapy (thiazide or loop diuretic depending on renal function) 1
• In patients with CKD stage 3B or worse, loop diuretics are preferred over thiazides 2

Step 2: Add Amlodipine Before Hydralazine

• If blood pressure remains uncontrolled after Step 1, amlodipine is recommended as the preferred third-line agent (Class I, Level A recommendation) 1
• Amlodipine is safe in HFrEF and neither improves nor worsens survival 1
• Felodipine is an alternative dihydropyridine calcium channel blocker (Class IIa, Level B recommendation) 1

Step 3: Add Hydralazine for Persistent Hypertension

• Hydralazine is recommended when hypertension persists despite ACE inhibitor (or ARB), beta-blocker, MRA, diuretic, and amlodipine (Class I, Level A recommendation) 1
• This represents fourth-line therapy for resistant hypertension in HFrEF 1

Special Population: African American Patients with Persistent Symptoms

Earlier Initiation for Symptom Control

• In self-described African American patients with HFrEF and persistent NYHA class III or IV symptoms despite ACE inhibitor (or ARB), beta-blocker, and MRA, hydralazine combined with isosorbide dinitrate should be added earlier (Class I, Level A recommendation) 1
• This combination reduces morbidity and mortality in African American patients, independent of blood pressure control 1
• The A-HeFT trial demonstrated increased survival and reduced healthcare costs with this combination 1

Dosing for Symptom Management

• When used for symptom control in African Americans, hydralazine/isosorbide dinitrate is added as third-line therapy after ACE inhibitor and beta-blocker, not reserved for resistant hypertension 1

Alternative Indication: ACE Inhibitor/ARB Intolerance

When First-Line Agents Cannot Be Used

• Hydralazine combined with isosorbide dinitrate might be considered in patients who cannot tolerate ACE inhibitors or ARBs due to drug intolerance, hypotension, or renal insufficiency (Class IIb, Level C recommendation) 1
• This represents a weaker recommendation with lower quality evidence for non-African American patients 1
• Referral to a heart failure specialist is recommended before using this alternative approach 1

Practical Dosing Considerations

Initial Dosing Protocol

• Start with 10 mg four times daily for the first 2-4 days 3
• Increase to 25 mg four times daily for the remainder of the first week 3
• For the second and subsequent weeks, increase to 50 mg four times daily 3
• Adjust to the lowest effective maintenance dose 3

Maximum Dosing

• In resistant cases, up to 300 mg daily may be required, though this increases the risk of lupus-like syndrome 3
• When combining with other antihypertensives, individual titration is essential to ensure the lowest therapeutic dose of each drug 3

Critical Pitfalls to Avoid

Do Not Use Hydralazine as First-Line Therapy

• Hydralazine should never replace ACE inhibitors, beta-blockers, or MRAs as these agents reduce mortality in HFrEF 1
• The exception is African American patients with persistent symptoms, where hydralazine/isosorbide dinitrate is added to (not instead of) guideline-directed medical therapy 1

Avoid Intravenous Hydralazine for Non-Urgent Hypertension

• Intravenous hydralazine is commonly misused in hospitalized patients without urgent hypertensive conditions 4
• It causes highly variable blood pressure responses and is associated with hypotension in hospitalized patients 4
• Reserve intravenous formulations for acute heart failure with severely elevated blood pressure requiring immediate reduction 1

Monitor for Lupus-Like Syndrome

• The incidence of drug-induced lupus increases with higher doses and prolonged use 3, 5
• Risk is higher in slow acetylators 5
• Regular monitoring is essential, particularly when doses exceed 200 mg daily 3

Contraindicated Medications to Avoid

• Do not use moxonidine (increased mortality, Class III recommendation) 1
• Avoid alpha-adrenergic blockers like doxazosin (cause neurohumoral activation, fluid retention, and worsening heart failure, Class III recommendation) 1
• Never use non-dihydropyridine calcium channel blockers (diltiazem, verapamil) in HFrEF (Class III recommendation) 1

Evidence Quality Considerations

The 2022 ACC/AHA/HFSA guidelines 1 and 2012 ESC guidelines 1 provide the most recent and highest quality recommendations. Both consistently place hydralazine as fourth-line therapy for resistant hypertension in HFrEF, with the important exception of earlier use in African American patients for symptom control. The evidence for mortality benefit in African Americans is strong (Level A), while evidence for use in ACE inhibitor-intolerant patients is weaker (Level C) and based on older trials conducted before modern heart failure therapy 1.