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

Resistant Hypertension Workup and Management

The workup for resistant hypertension must include confirmation of true resistance, screening for secondary causes, and a stepwise pharmacologic approach with spironolactone as the preferred fourth agent for most patients. 1

Confirming True Resistant Hypertension

Before initiating extensive workup, confirm true resistant hypertension:

• Definition: BP remaining above goal (>140/90 mmHg) despite concurrent use of 3 antihypertensive agents of different classes at optimal doses, including a diuretic 2
• Rule out pseudo-resistance:
  • Ensure proper BP measurement technique (patient seated quietly for 5 minutes, correct cuff size, arm at heart level) 2
  • Confirm with out-of-office measurements (24-hour ambulatory BP monitoring preferred) 2
  • Assess medication adherence through direct questioning and consider objective evaluation (blood/urine drug levels) 2
  • Review medication list for interfering substances (NSAIDs, stimulants, certain antidepressants) 1

Diagnostic Workup

Medical History

• Duration, severity, and progression of hypertension
• Response to prior medications and adverse events
• Current medications (including OTC and herbal supplements)
• Symptoms of secondary causes:
  • Sleep apnea: daytime sleepiness, loud snoring, witnessed apnea
  • Renal artery stenosis: history of peripheral/coronary atherosclerotic disease
  • Pheochromocytoma: episodic hypertension, palpitations, diaphoresis, headaches
  • Primary aldosteronism: muscle weakness, polyuria 2

Physical Examination

• Fundoscopic exam (retinopathy)
• Carotid, abdominal, or femoral bruits (renal artery stenosis)
• Diminished femoral pulses or arm/thigh BP discrepancy (aortic coarctation)
• Cushing's syndrome signs: moon facies, central obesity, abdominal striae 2

Laboratory and Diagnostic Testing

• Basic metabolic panel (renal function, electrolytes)
• Urinalysis and albumin-to-creatinine ratio
• Plasma aldosterone/renin ratio (screen for primary aldosteronism) 1
• Consider sleep study for suspected sleep apnea
• Additional testing based on suspected secondary causes 1

Management Approach

Step 1: Optimize Current Regimen

• Ensure optimal doses of initial 3-drug regimen:
  • Long-acting thiazide-like diuretic (chlorthalidone preferred over hydrochlorothiazide)
  • RAS blocker (ACE inhibitor or ARB)
  • Long-acting calcium channel blocker 1, 3
• For patients with eGFR <30 mL/min/1.73m², substitute loop diuretic for thiazide 2, 1
• Reinforce lifestyle modifications:
  • Sodium restriction (<2400 mg/day)
  • Weight loss if indicated
  • Regular physical activity
  • DASH diet
  • Limited alcohol intake 1

Step 2: Add Fourth Agent

• Spironolactone is the preferred fourth agent (12.5-50 mg daily) 1, 3, 4, 5
  • Monitor potassium and renal function
  • Consider eplerenone if spironolactone causes side effects (gynecomastia)
• If spironolactone is contraindicated or not tolerated:
  • Amiloride (alternative potassium-sparing diuretic)
  • Beta-blocker (especially if heart rate ≥70 beats/min)
  • Alpha-blocker (doxazosin) 1, 5

Step 3: Further Intensification

• Add hydralazine (start 25 mg three times daily, titrate upward to maximum dose) 1, 6
• Consider minoxidil if BP still not controlled 1
• For patients with continued uncontrolled BP despite optimal medical therapy, refer to hypertension specialist 2

Special Considerations

Secondary Causes

Primary aldosteronism, chronic kidney disease, and obstructive sleep apnea are the most common secondary causes of resistant hypertension 1, 7:

• Primary aldosteronism: Screen with plasma aldosterone/renin ratio
• Chronic kidney disease: Monitor renal function and adjust medications accordingly
• Obstructive sleep apnea: Consider sleep study and CPAP therapy if diagnosed

Medication Adherence

• Poor adherence is a major cause of treatment failure
• Consider single-pill combinations to improve adherence
• Discuss barriers to adherence (cost, side effects, dosing complexity) 2, 1

Referral Criteria

Refer to hypertension specialist if:

• BP remains uncontrolled after 6 months of treatment
• Secondary cause is suspected
• Complex medication regimen is needed 2

Common Pitfalls to Avoid

• Failing to confirm true resistant hypertension with out-of-office measurements
• Inadequate diuretic therapy (insufficient dose or inappropriate choice)
• Overlooking medication nonadherence
• Neglecting to screen for common secondary causes
• Therapeutic inertia (not intensifying treatment despite persistently elevated BP) 1, 3