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

Workup and Management of Resistant Hypertension

Confirm True Resistance First

Before pursuing an extensive workup, confirm true resistant hypertension by performing 24-hour ambulatory blood pressure monitoring, as white-coat hypertension accounts for approximately 50% of apparent resistant cases. 1, 2 Medication nonadherence represents another 50% of apparent treatment resistance and is the single most common cause. 1 Address these pseudoresistance factors before proceeding with costly secondary cause evaluations. 1, 3

Verify Proper BP Measurement Technique

• Ensure the patient is seated with back supported for 5 minutes, using correct cuff size, taking minimum 2 readings at 1-minute intervals 3
• Incorrect technique leads to falsely elevated readings that trigger unnecessary workups 1

Assess Medication Adherence

• Question directly in a nonjudgmental fashion about missed doses, adverse effects, out-of-pocket costs, and dosing inconvenience 2
• Simplify regimens to once-daily dosing with combination products to improve adherence 4

Systematic Screening for Secondary Causes

Screen all patients with confirmed resistant hypertension for the following secondary causes, as they are highly prevalent and often coexist: 1, 2

Laboratory Evaluation

• Serum creatinine, eGFR, and urine albumin-creatinine ratio to screen for chronic kidney disease/renal parenchymal disease 3, 1
• Aldosterone-to-renin ratio (ARR) even with normal potassium levels, as primary aldosteronism affects 17-23% of resistant hypertension patients and hypokalemia is a late manifestation 1, 2, 5
• 24-hour urine metanephrines or plasma metanephrines if pheochromocytoma is suspected based on clinical presentation 4
• 24-hour urine collection (with non-salt acid preservative) to estimate dietary sodium/potassium intake, calculate creatinine clearance, and measure aldosterone excretion 4

Clinical Screening

• Obstructive sleep apnea assessment, as it affects 83% of resistant hypertension patients and induces sustained sympathetic activation 1, 2
• Screen for Cushing's syndrome if clinical features suggest hypercortisolism 4, 2

Imaging Studies

• Reserve renal artery stenosis imaging for high-suspicion patients: young patients (particularly women suggesting fibromuscular dysplasia) or older patients with atherosclerotic risk factors and sudden BP deterioration 4, 1
• Do not perform abdominal CT for adrenal adenomas without biochemical confirmation of hormonally active tumors (hyperaldosteronism, pheochromocytoma, Cushing's syndrome), as specificity is poor 4
• Do not perform diagnostic renal arteriograms without suspicious noninvasive imaging first 4

Identify and Remove Contributing Factors

Interfering Medications and Substances

• Discontinue or minimize NSAIDs, which are among the most common interfering medications 1, 3
• Review and discontinue when possible: oral contraceptives, certain antidepressants, decongestants, corticosteroids, and herbal supplements 1, 3

Lifestyle Factors

• Excessive sodium intake: Restrict to <1500-2400 mg/day (ideally <100 mEq/24-hour), producing 5-10 mmHg systolic reductions with greater benefit in African-American and elderly patients 4, 2
• Obesity: 10-kg weight loss reduces systolic BP by 6.0 mmHg and diastolic by 4.6 mmHg 4, 2
• Excessive alcohol: Limit to ≤2 drinks/day for men, ≤1 drink/day for women 4
• Physical inactivity: Encourage minimum 30 minutes of aerobic exercise on most days 4
• DASH diet: High in fruits, vegetables, low-fat dairy, potassium, magnesium, calcium; low in saturated fats 4

Optimize Pharmacologic Regimen

Foundation Three-Drug Regimen

Ensure the patient is on a long-acting calcium channel blocker, a renin-angiotensin system blocker, and an appropriate diuretic at maximum tolerated doses. 2, 6

Critical Diuretic Optimization

• Switch from hydrochlorothiazide to thiazide-like diuretics (chlorthalidone 12.5-25 mg or indapamide 1.5-2.5 mg daily) for superior 24-hour BP control 2, 3
• Use loop diuretics instead of thiazides when eGFR <30 mL/min/1.73m² or clinical volume overload is present 2, 3
• Inadequate diuretic therapy is extremely common and volume overload must be addressed before adding additional agents 1, 3

Fourth-Line Agent

Add spironolactone 25-50 mg daily as the preferred fourth-line agent, as it is the most effective medication for resistant hypertension. 2, 7, 6, 5

• Check serum potassium and renal function before initiation and regularly during treatment 2, 3
• In patients with eGFR 30-50 mL/min/1.73m², consider initiating at 25 mg every other day due to hyperkalemia risk 7
• Spironolactone is particularly effective given the high prevalence of primary aldosteronism in this population 5

Additional Agents if Needed

• Consider beta-blockers, alpha-blockers, centrally acting agents (e.g., clonidine), or direct vasodilators (e.g., hydralazine) as fifth-line options 6, 8
• Dual renin-angiotensin system blockade or dual calcium channel blockade may be attempted 8

Monitoring and Follow-Up

• 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, 3
• Check serum potassium and renal function regularly, particularly after adding mineralocorticoid receptor antagonists 2, 3
• Use home BP monitoring to guide medication titration and improve adherence 3

When to Refer

Refer to a hypertension specialist if BP remains uncontrolled after 6 months of optimized treatment, as specialists achieve control in 52-53% of resistant cases. 1, 3 Also refer if complications arise or if secondary causes require specialized management (e.g., primary aldosteronism, pheochromocytoma, renovascular disease). 4, 3

Critical Pitfalls to Avoid

• Do not pursue extensive secondary hypertension workup before confirming true resistance with ambulatory BP monitoring and verifying medication adherence 1, 3
• Do not overlook volume overload—optimize diuretic therapy before adding additional agents 1, 3
• Screen for primary aldosteronism even when potassium is normal, as hypokalemia is a late manifestation 1, 2
• Do not use hydrochlorothiazide when thiazide-like diuretics (chlorthalidone, indapamide) are superior 2, 3