Is combining losartan (angiotensin II receptor antagonist) and hydralazine (vasodilator) effective and safe for treating hypertension, particularly in African American patients with heart failure or resistant hypertension?

Combining Losartan and Hydralazine: Evidence-Based Recommendation

Combining losartan with hydralazine alone is not recommended and should be avoided; however, combining losartan with the fixed-dose combination of hydralazine-isosorbide dinitrate is appropriate and beneficial in specific clinical contexts, particularly for African American patients with heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite optimal therapy. 1

Key Clinical Context: Hydralazine Must Be Combined with a Nitrate

Hydralazine should never be used as monotherapy or without isosorbide dinitrate in heart failure patients, as this is associated with harm (Class III recommendation). 2, 3 The combination with a nitrate is essential because:

• Hydralazine alone causes reflex tachycardia and sodium/water retention, requiring concurrent beta-blocker and diuretic therapy 3
• The nitrate component (isosorbide dinitrate) provides venous vasodilation to complement hydralazine's arterial effects and prevents nitrate tolerance 1
• All clinical trials demonstrating mortality benefit used the combination, not hydralazine alone 1

When the Combination IS Appropriate

Primary Indication: African American Patients with HFrEF

For self-identified African American patients with NYHA class III-IV HFrEF who remain symptomatic despite optimal therapy with ACE inhibitors (or ARBs like losartan), beta-blockers, and mineralocorticoid receptor antagonists, adding hydralazine-isosorbide dinitrate is strongly recommended (Class I, Level A). 1

• This combination provides a 43% relative risk reduction in mortality and 33% reduction in heart failure hospitalizations 1
• The benefit was demonstrated specifically when added to background ARB therapy (along with beta-blockers and aldosterone antagonists) 1
• Target dosing: hydralazine 75 mg three times daily plus isosorbide dinitrate 40 mg three times daily 1, 3

Secondary Indication: ACE Inhibitor/ARB Intolerance

For patients with HFrEF who cannot tolerate ACE inhibitors or ARBs due to hypotension, renal insufficiency, or drug intolerance, hydralazine-isosorbide dinitrate may be considered as an alternative (Class IIa, Level B). 1, 4

• This indication has substantially weaker evidence than the African American population 4
• Recent observational datasets have not confirmed benefit in this population 1
• Referral to a heart failure specialist is strongly recommended when first-line agents cannot be tolerated 1, 4

Hypertension Management Context

Not Recommended for Primary Hypertension

For treating hypertension without heart failure, combining losartan with hydralazine is not recommended as a standard approach. 1, 2

• Losartan combined with hydrochlorothiazide (a diuretic) is the evidence-based combination for hypertension, providing superior blood pressure control 5, 6, 7
• Hydralazine monotherapy is not recommended for chronic hypertension due to reflex tachycardia and fluid retention 3
• For African Americans with hypertension and diastolic dysfunction, thiazide diuretics or calcium channel blockers are first-line, not hydralazine 2

Resistant Hypertension Consideration

If hydralazine is considered for resistant hypertension (fifth-line agent), it must be combined with a beta-blocker and diuretic to counteract reflex tachycardia and sodium retention, and total daily doses should remain below 150 mg to avoid drug-induced lupus. 3

Critical Monitoring and Safety Considerations

Renal Function Monitoring

• Hydralazine is renally excreted and accumulates when GFR falls below 30 mL/min, requiring dose reduction 4
• Check creatinine and potassium at 2-3 days after initiation, then monthly for 3 months, then every 3 months 4
• Do not confuse drug accumulation with direct nephrotoxicity—hydralazine does not damage kidneys through toxic mechanisms in most patients 4

Common Adverse Effects

• Headache, dizziness, and gastrointestinal complaints are frequent and may limit adherence 1, 3
• Slower titration enhances tolerance 1
• Risk of hydralazine-induced lupus increases with prolonged use and doses above 150 mg daily 4, 3

Absolute Contraindications

Avoid hydralazine in patients with advanced aortic stenosis due to unpredictable blood pressure effects. 3

Practical Algorithm for Decision-Making

Step 1: Identify the primary indication

• Heart failure with reduced ejection fraction? → Proceed to Step 2
• Hypertension without HFrEF? → Use losartan + hydrochlorothiazide instead 5, 6

Step 2: Assess current HFrEF therapy

• Already on ACE inhibitor/ARB + beta-blocker + MRA? → Proceed to Step 3
• Not on optimal therapy? → Optimize first-line agents before considering hydralazine-isosorbide dinitrate 1

Step 3: Determine patient population

• Self-identified African American with persistent NYHA class III-IV symptoms? → ADD hydralazine-isosorbide dinitrate (Class I recommendation) 1
• Non-African American with ACE inhibitor/ARB intolerance? → CONSIDER hydralazine-isosorbide dinitrate after specialist consultation (Class IIa recommendation) 1, 4
• Tolerating ACE inhibitor/ARB well? → Do not substitute with hydralazine-isosorbide dinitrate 1

Step 4: Ensure proper formulation

• Always use hydralazine WITH isosorbide dinitrate, never hydralazine alone 2, 3
• Fixed-dose combination preferred for adherence 1