How is refractory hypertension managed?

Management of Refractory Hypertension

Refractory hypertension requires aggressive pharmacological escalation with spironolactone as the preferred fourth-line agent, followed by hydralazine or minoxidil if blood pressure remains uncontrolled on five or more antihypertensive medications, while simultaneously addressing medication adherence, volume overload, and secondary causes. 1

Definition and Confirmation

Refractory hypertension is defined as failure to control blood pressure despite use of at least 5 antihypertensive agents of different classes, including a long-acting thiazide-type diuretic (such as chlorthalidone) and a mineralocorticoid receptor antagonist (such as spironolactone), at maximal or maximally tolerated doses. 1

Before proceeding with aggressive treatment:

• Perform 24-hour ambulatory blood pressure monitoring to exclude white-coat effect, which accounts for approximately 50% of apparent resistant cases. 2, 3, 4
• Verify medication adherence through direct questioning, pill counts, or pharmacy records, as nonadherence is responsible for roughly half of treatment resistance. 2, 3
• Ensure proper BP measurement technique using appropriate cuff size and correct patient positioning. 2, 4

Optimize the Foundation Regimen

The baseline regimen must include:

• A renin-angiotensin system blocker (ACE inhibitor or ARB) at maximal tolerated dose 1, 3
• A long-acting calcium channel blocker (dihydropyridine class) 1, 3
• Chlorthalidone as the preferred thiazide-like diuretic, which is superior to standard thiazides in resistant hypertension 1, 3
• Switch to loop diuretics if eGFR <30 mL/min/1.73m² or clinical volume overload is present, as unrecognized volume overload is a common cause of treatment failure 2, 3, 4

Fourth-Line Agent: Spironolactone

Add spironolactone 25 mg daily as the fourth-line agent, as it has demonstrated superior efficacy compared to alpha and beta blockers in the PATHWAY-2 trial. 1, 3, 4, 5

Eligibility criteria for spironolactone:

• Serum potassium <4.5 mmol/L 3
• eGFR >45 mL/min/1.73m² (use caution if eGFR <30 mL/min/1.73m²) 3, 4

Monitoring requirements:

• Check serum potassium and renal function 1-2 weeks after initiation, especially when combining with RAS blockade 3, 4
• Continue monitoring at least annually thereafter 3

Fifth-Line and Beyond: Potent Vasodilators

If blood pressure remains uncontrolled despite the above four-drug regimen (meeting the definition of refractory hypertension):

Add hydralazine or minoxidil as clinical trial evidence demonstrates effectiveness in achieving BP control in patients resistant to usual combination therapy. 1

• These potent vasodilators cause fluid retention and reflex tachycardia, which is why they must be combined with adequate diuretic therapy and beta-blockade 1
• The dosing of these multidrug regimens, occasionally including nighttime dosing, may be best optimized by hypertension specialists 1

Important caveat: In patients with heart failure with reduced ejection fraction (HFrEF), minoxidil should be avoided due to renin-related salt and fluid-retaining effects. 1

Address Secondary Causes

Screen for and treat reversible causes:

• Primary aldosteronism even with normal potassium levels, particularly in young patients (<30 years) 2, 4
• Obstructive sleep apnea using Berlin Questionnaire or Epworth Sleepiness Score, confirming with polysomnography if suspected 2, 4
• Renal artery stenosis with kidney ultrasound followed by renal artery imaging if clinically indicated 2, 4
• Thyroid dysfunction by checking TSH 2, 4
• Chronic kidney disease including baseline eGFR assessment 2, 4

Lifestyle Interventions

These remain critical even in refractory cases:

• Restrict sodium intake to <2400 mg/day (ideally <1500 mg/day), as high sodium significantly contributes to treatment resistance 2, 3, 4
• Encourage weight loss if overweight/obese, which can produce significant BP reductions 2, 3, 4
• Limit alcohol to ≤2 drinks/day for men, ≤1 drink/day for women 2, 4
• Implement regular physical activity with a structured exercise program 2, 4

Device-Based Therapies

Do not use device-based interventions (carotid baroreceptor pacing, catheter ablation of renal sympathetic nerves) as these studies have not provided sufficient evidence to recommend their use in managing resistant hypertension. 1 In particular, two RCTs of renal sympathetic nerve ablation have been negative, including the SYMPLICITY HTN-3 trial. 1

Monitoring and Reassessment

• Reassess BP response within 2-4 weeks of any medication adjustment 2, 3, 4
• Check serum potassium and renal function regularly, particularly after adding spironolactone 2, 3, 4
• Continue home BP monitoring to guide medication titration and improve adherence 3, 4

Specialist Referral

Refer to a hypertension specialist if BP remains uncontrolled after optimizing the five-drug regimen, as these patients experience high rates of cardiovascular complications including left ventricular hypertrophy, heart failure, and stroke. 1, 2

Common Pitfalls to Avoid

• Never combine ACE inhibitors with ARBs, as this does not reduce cardiovascular events and increases adverse effects 3
• Do not use standard thiazides when thiazide-like diuretics (chlorthalidone, indapamide) are available, as they are superior for resistant hypertension 3
• Never add spironolactone without checking potassium and renal function due to hyperkalemia risk 3
• Avoid nondihydropyridine calcium channel blockers (diltiazem, verapamil) in patients with HFrEF due to negative inotropic effects 1