What is the role of hydralazine in managing hypertension?

Hydralazine for Hypertension

Primary Role and Positioning

Hydralazine is not recommended as monotherapy for primary hypertension and should only be used as an add-on agent in specific clinical contexts: combined with isosorbide dinitrate in Black patients with heart failure, or as a late-line agent (typically fifth-line) in resistant hypertension after optimizing other drug classes. 1

Clinical Context and Appropriate Use

Heart Failure with Reduced Ejection Fraction

• The combination of hydralazine plus isosorbide dinitrate is specifically recommended (Class I, Level A) for Black patients with NYHA class III-IV heart failure who remain symptomatic despite optimal therapy with ACE inhibitors/ARBs, beta-blockers, and aldosterone antagonists. 1
• This combination reduced mortality by 43% (10.2% vs 6.2%, P=0.02) in the A-HeFT trial, which was stopped early due to benefit. 1
• For non-Black patients with heart failure who are intolerant to ACE inhibitors or ARBs, hydralazine plus isosorbide dinitrate may be considered as an alternative, though compliance is often poor due to high pill burden and adverse effects. 1

Resistant Hypertension

• Hydralazine should only be considered as a fifth-line agent after maximizing a three-drug regimen (RAS inhibitor, calcium channel blocker, and thiazide-like diuretic) and adding a mineralocorticoid receptor antagonist. 1, 2
• The 2017 ACC/AHA guidelines note that hydralazine or minoxidil can be effective in achieving blood pressure control in patients resistant to usual combination therapy, but these are reserved for refractory cases. 1

Why Hydralazine Is Not First-Line

Lack of Outcomes Data

• A 2011 Cochrane review found zero randomized controlled trials comparing hydralazine to placebo for mortality, morbidity, or cardiovascular outcomes in primary hypertension. 3
• There is no randomized trial evidence supporting the prevention of cardiovascular events with hydralazine monotherapy in primary hypertension. 1

Mechanism-Related Limitations

• Hydralazine causes reflex sympathetic activation, leading to increased heart rate and sodium retention, which counteracts its blood pressure-lowering effect. 4, 5
• This reflex tachycardia can provoke anginal attacks and myocardial ischemia, making hydralazine particularly problematic in patients with coronary artery disease. 1, 5
• The drug requires concurrent use with beta-blockers and diuretics to mitigate these compensatory mechanisms. 2, 4

Unpredictable Response and Safety Concerns

• Blood pressure response to hydralazine is highly variable and unpredictable, with changes in systolic BP ranging widely (mean reduction 24/9 ± 29/15 mmHg in one study). 6
• Hypotension is a common adverse event, occurring in 11 of 94 patients (12%) in one hospitalized cohort. 6
• The drug has a prolonged duration of action (2-4 hours), making overshoot hypotension difficult to reverse. 4

Serious Adverse Effects

• Total daily doses should be kept below 150 mg to avoid drug-induced systemic lupus erythematosus. 4, 5
• Other serious adverse effects include hemolytic anemia, vasculitis, glomerulonephritis, peripheral neuritis, and blood dyscrasias. 5, 3
• Slow acetylators have higher plasma levels, better blood pressure control, but significantly more side effects. 7, 8

Appropriate Combination Therapy When Hydralazine Is Used

Essential Concurrent Medications

• Beta-blockers (metoprolol, carvedilol, or labetalol) must be added to control reflex tachycardia. 2, 4
• Thiazide or thiazide-like diuretics (chlorthalidone or indapamide) should be included to counteract sodium retention and fluid accumulation. 2, 4

Alternative Add-On Options

• If beta-blockers are contraindicated, calcium channel blockers (amlodipine) can provide additional vasodilation. 2
• In resistant hypertension, mineralocorticoid receptor antagonists (spironolactone or eplerenone) should be optimized before adding hydralazine. 2

Common Pitfalls to Avoid

Inappropriate Hospital Use

• A retrospective review found that 36% of PRN hydralazine doses were given for blood pressures below the threshold for acute severe hypertension (SBP <180 mmHg and DBP <110 mmHg). 9
• Only 2% of patients receiving intravenous hydralazine in one study had evidence of a true hypertensive emergency. 6
• Instead of using PRN hydralazine, providers should optimize scheduled home antihypertensive regimens—yet 40.8% of patients were not continued on their home medications during hospitalization. 9

Monotherapy Errors

• Hydralazine should never be used as monotherapy for primary hypertension due to lack of outcomes data and problematic compensatory mechanisms. 1, 3
• The combination with isosorbide dinitrate should not be substituted for ACE inhibitors in patients tolerating ACE inhibitors without difficulty. 1

Dosing Considerations

• Hydralazine exhibits polymorphic acetylation—slow acetylators require lower doses but have better blood pressure control. 5, 7
• Twice-daily dosing is adequate; once-daily conventional hydralazine is unsatisfactory as its effect wanes at 24 hours, particularly in rapid acetylators. 7