What is the recommended workup and treatment for a patient with resistant hypertension?

Resistant Hypertension Workup

Before pursuing an extensive workup, confirm true resistant hypertension with 24-hour ambulatory blood pressure monitoring and verify medication adherence, as approximately 50% of apparent resistant cases are actually pseudoresistance from white-coat effect or nonadherence. 1, 2

Step 1: Confirm True Resistant Hypertension

Definition Verification

• Ensure BP remains ≥140/90 mmHg despite maximum tolerated doses of three specific drug classes: a thiazide or thiazide-like diuretic, a RAS blocker (ACE inhibitor or ARB), and a long-acting calcium channel blocker 1
• Confirm elevated BP with out-of-office measurements using 24-hour ambulatory BP monitoring (ABPM) or home BP monitoring—this is mandatory, not optional 1, 3
• For patients with eGFR <30 mL/min/1.73 m², a loop diuretic (not thiazide) must be used to meet the definition 1

Exclude Pseudoresistance (Accounts for ~50% of Cases)

• Perform 24-hour ABPM to exclude white-coat hypertension, which represents approximately 50% of apparent resistant cases 2, 3
• Verify proper BP measurement technique: patient seated with back supported for 5 minutes, correct cuff size encircling ≥80% of arm, arm supported at heart level, minimum 2 readings 1 minute apart 1
• Assess medication adherence through direct, nonjudgmental questioning about missed doses, adverse effects, out-of-pocket costs, and dosing inconvenience—this is the single most common cause of apparent resistance 2, 4
• Consider objective adherence testing (directly observed treatment or drug detection in blood/urine) if resources allow 1

Step 2: Optimize Current Regimen Before Further Testing

Medication Optimization

• Switch from hydrochlorothiazide to chlorthalidone 12.5-25 mg or indapamide 1.5-2.5 mg daily for superior 24-hour BP control 2
• For eGFR <30 mL/min/1.73 m², switch to loop diuretics 1, 4
• Ensure all three foundation drugs are at maximum tolerated doses 3
• Simplify to once-daily dosing with combination pills to improve adherence 4

Identify and Eliminate Interfering Substances

• Discontinue NSAIDs, oral contraceptives, decongestants, corticosteroids, certain antidepressants, stimulants, and herbal supplements 4, 3
• Limit alcohol to ≤2 drinks/day for men, ≤1 drink/day for women 4

Step 3: Screen for Secondary Causes

Secondary hypertension occurs in 10-35% of all hypertensive patients and up to 50% of those with resistant hypertension—screening is essential, not optional. 1

Primary Aldosteronism (Most Common—Prevalence 17-23% in Resistant HTN)

• Check aldosterone-to-renin ratio (ARR) in ALL patients with resistant hypertension, even with normal potassium levels, as hypokalemia is absent in most cases 1, 2, 4
• This condition increases CVD risk independent of BP levels 1

Obstructive Sleep Apnea (Affects 83% of Resistant HTN Patients)

• Screen for daytime sleepiness, loud snoring, and witnessed apneas 1
• Refer for polysomnography if clinical suspicion exists 4

Chronic Kidney Disease/Renal Parenchymal Disease

• Measure serum creatinine and calculate eGFR 4, 3
• Check urinalysis for proteinuria 4

Renal Artery Stenosis

• Consider in patients with: peripheral or coronary atherosclerotic disease, sudden BP deterioration, abdominal/femoral bruits, or discrepancy between arm and thigh BP 1, 4
• Reserve imaging for high-suspicion patients only—do not perform diagnostic renal arteriograms without suspicious noninvasive imaging first 4

Pheochromocytoma

• Suspect with: episodic/labile hypertension, palpitations, diaphoresis, headache 1
• Perform 24-hour urine metanephrines or plasma metanephrines if suspected 4

Cushing's Syndrome

• Look for: moon facies, central obesity, pigmented abdominal striae, interscapular fat deposition 1
• Screen if clinical features suggest hypercortisolism 4

Aortic Coarctation

• Check for: diminished femoral pulses, differential in brachial/femoral pulses, systolic bruit 1

Step 4: Physical Examination Findings

• Fundoscopic exam for retinopathy severity 1
• Carotid, abdominal, femoral bruits (suggest renal artery stenosis) 1
• Measure BP in both arms; use arm with higher readings for future measurements 1
• Check supine and upright BP to detect orthostatic complications 1

Step 5: Laboratory and Diagnostic Testing

Essential Tests

• Serum creatinine and eGFR 4, 3
• Serum potassium (before and after adding mineralocorticoid antagonists) 2, 5
• Aldosterone-to-renin ratio 1, 2
• 24-hour urine collection for sodium/potassium intake, creatinine clearance, and aldosterone excretion 4
• Urinalysis 4

Conditional Tests Based on Clinical Suspicion

• Sleep study for obstructive sleep apnea 4
• Renal artery imaging only if high clinical suspicion 4
• Plasma or urine metanephrines for pheochromocytoma 4
• Do not perform abdominal CT for adrenal adenomas without biochemical confirmation of hormonally active tumors 4

Step 6: Referral Criteria

Refer to a hypertension specialist if BP remains >130/80 mmHg after 6 months of optimized three-drug therapy, as specialists achieve control in 52-53% of resistant cases with average BP reduction of 18/9 mmHg. 2, 3

When to Refer

• BP uncontrolled after 6 months of optimized treatment 1, 3
• Suspected or confirmed secondary causes requiring specialized management 1
• Complex cases requiring technologies not available in primary care 1

Treatment After Workup Completion

Fourth-Line Agent

• Add spironolactone 25-50 mg daily as the preferred fourth-line agent, as demonstrated by the PATHWAY-2 trial 2, 5, 6
• Check serum potassium and renal function before initiation and regularly during treatment 2, 5
• For patients with serum potassium ≤5.0 mEq/L and eGFR >50 mL/min/1.73 m², initiate at 25 mg once daily 5
• Consider 25 mg every other day for eGFR 30-50 mL/min/1.73 m² 5

Lifestyle Modifications (Produce Significant BP Reductions)

• Restrict sodium to <1500-2400 mg/day (produces 5-10 mmHg systolic reduction, greater in African-Americans and elderly) 2, 4
• Achieve 10-kg weight loss (reduces systolic BP by 6.0 mmHg, diastolic by 4.6 mmHg) 2, 4
• Minimum 30 minutes aerobic exercise most days 4
• DASH diet high in fruits, vegetables, low-fat dairy, potassium, magnesium, calcium 4

Monitoring

• Target BP <130/80 mmHg for most adults <65 years; <130 mmHg systolic for adults ≥65 years 2
• Reassess BP within 2-4 weeks of any medication adjustment 2
• Monitor serum potassium and renal function regularly, particularly with mineralocorticoid antagonists 2, 5

Critical Pitfalls to Avoid

• Do not pursue extensive secondary hypertension workup before confirming true resistance with ABPM and verifying adherence 4, 3
• Do not overlook volume overload—optimize diuretic therapy before adding additional agents 4
• Do not assume normal potassium excludes primary aldosteronism 1, 2, 4
• Do not use hydrochlorothiazide when chlorthalidone or indapamide provide superior control 2