What is the workup for treatment-resistant hypertension?

Workup for Treatment-Resistant Hypertension

The workup for treatment-resistant hypertension requires a systematic three-step approach: first confirm true resistance by excluding pseudoresistance with ambulatory blood pressure monitoring and assessing medication adherence; second, screen for common secondary causes including primary aldosteronism (with aldosterone-to-renin ratio), obstructive sleep apnea, chronic kidney disease, and renal artery stenosis; and third, document target-organ damage while optimizing the medication regimen with maximally-dosed triple therapy including a diuretic. 1

Step 1: Confirm True Treatment Resistance

Define Resistant Hypertension

• Office BP >140/90 mmHg (or >130/80 mmHg in patients with diabetes or CKD) despite use of 3 antihypertensive medications at optimal doses, including a diuretic, RAS blocker, and calcium channel blocker 1
• Alternatively, BP at goal but requiring 4 or more medications 1
• All uncontrolled BP values must be confirmed by out-of-office measurements (home BP monitoring or 24-hour ambulatory BP monitoring) 1

Exclude Pseudoresistance

Assess medication adherence:

• Ask patients directly in a nonjudgmental manner about success in taking prescribed doses, discussing adverse effects, out-of-pocket costs, and dosing inconvenience 1
• Poor adherence accounts for approximately 50% of apparent treatment resistance 1, 2
• Consider objective evaluation with directly observed treatment or detecting prescribed drugs in blood/urine samples if resources allow 1

Exclude white-coat hypertension:

• Obtain 24-hour ambulatory BP monitoring to document out-of-office values 1
• Mean ambulatory daytime BP of 135/85 mmHg is considered elevated 1
• Suspect white-coat effect when clinic BP is consistently higher than out-of-office measurements, patients show signs of overtreatment (orthostatic symptoms), or chronically high office BP exists without target-organ damage 1

Ensure proper BP measurement technique:

• Patient sits quietly with back supported for 5 minutes before measurement 1
• Use correct cuff size with air bladder encircling at least 80% of arm (adult large cuff for most patients) 1
• Support arm at heart level during measurement 1
• Take minimum of 2 readings at 1-minute intervals and average them 1
• Measure BP in both arms; use arm with higher pressures for future measurements 1

Step 2: Screen for Secondary Causes of Hypertension

Medical History - Key Clinical Clues

Obstructive sleep apnea (most common):

• Snoring, witnessed apnea, excessive daytime sleepiness 1

Primary aldosteronism (most common secondary cause):

• May present without hypokalemia in majority of cases 3
• Prevalence up to 12% in patients with BP >180/110 mmHg 1

Renal artery stenosis:

• Young female (suggests fibromuscular dysplasia) 1
• Known atherosclerotic disease, history of peripheral or coronary disease 1
• Worsening renal function 1
• History of "flash" or episodic pulmonary edema with preserved systolic function 1

Pheochromocytoma:

• Episodic/labile hypertension, palpitations, diaphoresis, headache 1

Cushing's syndrome:

• Moon facies, central obesity, abdominal striae (particularly if pigmented), interscapular fat deposition 1

Chronic kidney disease:

• Creatinine clearance <30 mL/min 1

Current medications:

• Document all medications including herbal and over-the-counter products 1
• NSAIDs, certain antidepressants, and stimulants can interfere with BP control 2

Physical Examination - Specific Findings

Fundoscopic examination:

• Document presence and severity of retinopathy 1

Vascular examination:

• Carotid, abdominal, or femoral bruits increase likelihood of renal artery stenosis 1
• Diminished femoral pulses or discrepancy between arm and thigh BP suggests aortic coarctation or aortoiliac disease 1

Cushing's disease signs:

• Abdominal striae (particularly if pigmented), moon facies, prominent interscapular fat deposition 1

Orthostatic BP:

• Measure supine and upright BP to detect orthostatic complications with treatment 1

Biochemical Evaluation

Routine metabolic profile:

• Sodium, potassium, chloride, bicarbonate, glucose, blood urea nitrogen, creatinine 1
• Urinalysis 1
• Calculate creatinine clearance or use validated urine-free formulae 1

Screen for primary aldosteronism (ALL patients with resistant hypertension):

• Obtain paired morning plasma aldosterone and plasma renin activity (aldosterone-to-renin ratio) 1, 3
• ARR can be performed even while patient is on antihypertensive medications (except potassium-sparing diuretics and aldosterone antagonists) 1
• High ratio (generally 20-30 when aldosterone in ng/dL and renin activity in ng/mL/h) suggests primary aldosteronism 1
• For positive ARR: plasma aldosterone should be ≥10-15 ng/dL AND plasma renin activity ≥0.5 ng/mL/h improves specificity 1, 3
• Confirmatory testing required (IV saline suppression test or oral salt-loading test) when ARR elevated 3
• Mineralocorticoid receptor antagonists should be withdrawn at least 4 weeks before testing 3

24-hour urine collection (if feasible):

• Estimate dietary sodium and potassium intake 1
• Calculate creatinine clearance 1
• Measure aldosterone excretion (requires non-salt acid preservative like acetic acid) 1

Screen for pheochromocytoma (if clinically suspected):

• 24-hour urinary metanephrines or plasma metanephrines 1

Noninvasive Imaging

Renal artery stenosis imaging (reserve for high clinical suspicion):

• Young patients (particularly women) suggesting fibromuscular dysplasia 1
• Older patients at increased risk of atherosclerotic disease 1
• Modalities include duplex ultrasound, MRA, CT angiography, or renal scintigraphy 1
• MRA is highly sensitive but has low specificity; minimal lesions often characterized as moderate/high grade 1
• For patients with CKD, prefer modalities without iodinated contrast over CT angiography 1
• Negative imaging warrants additional examinations if high clinical suspicion and revascularization being considered 1

Adrenal imaging:

• Abdominal CT not recommended to screen for adrenal adenomas without biochemical confirmation of hormonally active tumors 1
• If primary aldosteronism confirmed, adrenal venous sampling may be needed to determine unilateral vs bilateral source 3

Step 3: Document Target-Organ Damage

Assess for end-organ complications:

• Retinopathy (fundoscopic exam) 1
• Chronic kidney disease (creatinine clearance, proteinuria) 1
• Left ventricular hypertrophy (ECG or echocardiography) 1
• Target-organ damage supports diagnosis of poorly controlled hypertension and influences treatment goals 1

Step 4: Referral Considerations

Refer to hypertension specialist (nephrologist, cardiologist, or endocrinologist):

• BP remains uncontrolled after 6 months of treatment 1
• Known or suspected secondary causes of hypertension 1
• Patients with suspected resistant hypertension should be considered for referral to clinical centers with expertise in hypertension management 1
• The workup is complex and often requires technologies not available to general practitioners 1

Common Pitfalls to Avoid

• Do not diagnose resistant hypertension based solely on office BP measurements without confirming with ambulatory or home BP monitoring 1
• Do not overlook medication non-adherence as the cause—it accounts for 50% of apparent resistance 1, 2
• Do not skip screening for primary aldosteronism even if potassium is normal—hypokalemia is absent in most cases 3
• Do not assume low renin alone confirms primary aldosteronism—it can occur in low-renin essential hypertension, CKD, Cushing's syndrome, or high sodium intake 3
• Do not order renal artery imaging routinely—reserve for patients with high clinical suspicion based on history and exam 1
• Do not forget to assess for volume overload due to insufficient diuretic therapy—this is a common cause of treatment failure 2