What is the appropriate workup and management for a patient with resistant hypertension?

Workup for Resistant Hypertension

Before pursuing an extensive workup, confirm true resistant hypertension by performing 24-hour ambulatory blood pressure monitoring to exclude white-coat effect (which accounts for approximately 50% of apparent resistant cases) and verify medication adherence through direct questioning, pill counts, or pharmacy records (responsible for roughly half of treatment resistance). 1

Confirm the Diagnosis

Verify Blood Pressure Measurement Technique

• Use proper technique: patient seated with back supported for 5 minutes, correct cuff size (air bladder encircling ≥80% of arm), arm supported at heart level 1
• Take minimum of 2 readings at 1-minute intervals and average them 1
• Measure BP in both arms; use the arm with higher readings for future measurements 1
• Check supine and upright BP to detect orthostatic complications 1

Confirm Resistant Hypertension Criteria

• Office BP ≥140/90 mmHg (or ≥130/80 mmHg per newer guidelines) despite adherence to maximum tolerated doses of 3 antihypertensive agents from different classes, including a diuretic 1
• The regimen must include: a long-acting calcium channel blocker, a renin-angiotensin system blocker (ACE inhibitor or ARB), and an appropriate diuretic 1, 2
• Confirm uncontrolled BP with out-of-office measurements using ABPM or home BP monitoring 1

Exclude Pseudo-Resistance

• Perform 24-hour ambulatory BP monitoring as the gold standard to exclude white-coat hypertension 1, 2, 3
• Assess medication adherence through nonjudgmental questioning about missed doses, adverse effects, out-of-pocket costs, and dosing inconvenience 1
• Consider objective adherence evaluation (directly observed treatment or detecting prescribed drugs in blood/urine samples) if resources allow 1
• Involve family members for more objective adherence assessments when appropriate 1

Screen for Secondary Causes

Laboratory Evaluation

• Measure serum creatinine, eGFR, and urine albumin-creatinine ratio in all patients 1
• Screen for primary aldosteronism by measuring aldosterone-to-renin ratio (ARR), even with normal potassium levels 1, 3
• Check serum potassium (though hypokalaemia is absent in most primary aldosteronism cases) 1
• Measure TSH to evaluate for thyroid dysfunction 2

Clinical Assessment for Secondary Causes

• Obstructive sleep apnea: Ask about daytime sleepiness, loud snoring, and witnessed apnea 1, 2
• Renal artery stenosis: Look for history of peripheral or coronary atherosclerotic disease, presence of carotid/abdominal/femoral bruits 1, 2
• Pheochromocytoma: Assess for episodic hypertension, palpitations, diaphoresis, headache, and labile BP 1
• Cushing's syndrome: Examine for moon facies, central obesity, pigmented abdominal striae, interscapular fat deposition 1
• Aortic coarctation: Check for differential in brachial/femoral pulses, diminished femoral pulses, discrepancy between arm and thigh BP, systolic bruit 1

Physical Examination

• Perform fundoscopic examination to document presence and severity of retinopathy 1
• Auscultate for carotid, abdominal, and femoral bruits (suggests renal artery stenosis) 1
• Palpate femoral pulses and compare arm-to-thigh BP (diminished suggests coarctation or aortoiliac disease) 1

Cardiac Evaluation

• Obtain 12-lead ECG in all patients with hypertension 1
• Perform echocardiography if ECG abnormalities present or signs/symptoms of cardiac disease 1

Additional Testing When Indicated

• Fundoscopy if BP >180/110 mmHg to evaluate for hypertensive emergency and malignant hypertension 1
• Consider coronary artery calcium scoring when likely to change management 1

Identify Contributing Factors

Medication and Substance Review

• Discontinue or minimize interfering substances: NSAIDs (most common), stimulants, oral contraceptives, certain antidepressants, decongestants, sympathomimetics, adrenal steroids, VEGF pathway antineoplastic drugs 1, 2, 3
• Review all current medications including herbal and over-the-counter products 1

Lifestyle Factors

• Assess for obesity (measure BMI and waist circumference) 1, 2
• Evaluate alcohol consumption (recommend <100 g/week of pure alcohol) 1
• Document smoking status 1
• Assess dietary sodium intake (recommend restriction to approximately 2 g/day, equivalent to 5 g salt) 1, 2

Optimize Current Antihypertensive Regimen

Maximize Diuretic Therapy

• Switch from hydrochlorothiazide to thiazide-like diuretics (chlorthalidone 12.5-25 mg daily or indapamide 1.5-2.5 mg daily) for superior efficacy 2, 4
• Use loop diuretics instead of thiazides if eGFR <30 mL/min/1.73m² or clinical volume overload present, as thiazides become ineffective at lower GFR 1, 2, 4

Consider Fourth-Line Agent

• Add low-dose spironolactone (25-50 mg daily) as the most effective fourth-line agent if serum potassium <4.5 mEq/L and eGFR >45 mL/min/1.73m² 2, 5
• Monitor serum potassium and renal function within 1-2 weeks after initiation 2, 4
• Alternative agents if spironolactone contraindicated: eplerenone (50-200 mg daily), amiloride, doxazosin, or vasodilating beta-blockers (nebivolol, carvedilol, labetalol) 1, 2, 6

Monitoring Strategy

• Reassess BP response within 2-4 weeks of any medication adjustment 2, 4
• If moderate-to-severe CKD diagnosed, repeat serum creatinine, eGFR, and urine ACR at least annually 1
• Use home BP monitoring to guide medication titration and improve adherence 2, 4

Specialist Referral

Refer to a hypertension specialist if BP remains uncontrolled after 6 months of optimized treatment or if complications arise (severe hyperkalemia, progressive renal dysfunction, difficulty managing regimen). 1, 2, 3

• Hypertension specialists achieve BP control in approximately 52-53% of resistant hypertension patients with average BP reduction of 18/9 mmHg at 1-year follow-up 3
• Refer to appropriate specialist for known or suspected secondary causes requiring specific intervention 1

Common Pitfalls to Avoid

• Do not continue hydrochlorothiazide—switch to chlorthalidone or indapamide for superior 24-hour BP control 2
• Do not use thiazide diuretics when eGFR <30 mL/min/1.73m²; switch to loop diuretics 2, 4
• Do not add spironolactone without checking baseline potassium and ensuring adequate monitoring capability 2, 5
• Do not assume adherence—specifically ask patients in a nonjudgmental fashion about missed doses 1
• Do not rely solely on office BP measurements—confirm with ABPM or home monitoring 1