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

Workup and Treatment of Resistant Hypertension

The recommended workup for resistant hypertension should first exclude pseudoresistance causes, then screen for secondary causes, followed by treatment optimization with spironolactone as the preferred fourth-line agent for most patients. 1

Definition and Initial Assessment

Resistant hypertension is defined as:

• Blood pressure >140/90 mmHg despite treatment with ≥3 antihypertensive medications at optimal doses, including a diuretic 1
• Or controlled BP requiring ≥4 antihypertensive agents 2

Step 1: Exclude Pseudoresistance

Before confirming true resistant hypertension, rule out:

• Poor BP measurement technique
• White coat effect (confirm with 24-hour ambulatory or home BP monitoring)
• Medication nonadherence
• Suboptimal medication choices or dosing 1

Step 2: Identify Contributing Factors

• Medications/substances that interfere with BP control:

  • NSAIDs
  • Oral contraceptives
  • Sympathomimetics
  • Alcohol
  • Licorice
  • Cocaine 1

• Lifestyle factors:

  • High sodium intake
  • Obesity
  • Physical inactivity
  • Excessive alcohol consumption 1

Secondary Causes Workup

Screen for secondary causes, particularly in patients with:

• Early-onset hypertension (<30 years)
• Sudden BP deterioration
• Hypertensive urgency/emergency
• Strong clinical clues suggesting secondary cause 1

Common Secondary Causes to Evaluate:

1. Primary aldosteronism (present in ~20% of resistant hypertension)

   • Screen with plasma aldosterone/renin ratio or 24-hour urinary aldosterone 3

2. Chronic kidney disease

   • Serum creatinine, eGFR, urinalysis, albumin-to-creatinine ratio 1

3. Renal artery stenosis

   • Duplex ultrasonography, CT or MR angiography in high-risk patients 1

4. Obstructive sleep apnea

   • Sleep study for patients with symptoms (snoring, daytime sleepiness) 4

5. Pheochromocytoma

   • Plasma or 24-hour urinary metanephrines in patients with episodic symptoms 1

Treatment Algorithm

Step 1: Optimize Lifestyle Modifications

• Sodium restriction (especially important in resistant hypertension)
• Weight loss if overweight/obese
• Regular physical activity
• DASH diet
• Alcohol limitation 1

Step 2: Optimize Current Medication Regimen

• Ensure appropriate dosing of current medications
• Consider switching to longer-acting agents
• Use fixed-dose combinations to improve adherence 5
• Replace hydrochlorothiazide with chlorthalidone (more effective long-acting thiazide-like diuretic) 1
• Use loop diuretics (e.g., torsemide) if eGFR <30 mL/min/1.73m² 1

Step 3: Implement Optimal Three-Drug Combination

The most effective three-drug combination includes:

• ACE inhibitor or ARB
• Long-acting calcium channel blocker (CCB)
• Thiazide-like diuretic (preferably chlorthalidone) 1

Step 4: Add Fourth-Line Agent

• First choice: Spironolactone 25-50 mg daily (if eGFR >45 mL/min/1.73m² and K+ <4.5 mmol/L) 1
• Monitor potassium levels closely, especially in patients with CKD, diabetes, or those on ACE inhibitors/ARBs 1

Step 5: Alternative Fourth-Line Options (if spironolactone contraindicated/not tolerated)

• Eplerenone (less risk of gynecomastia)
• Amiloride
• Beta-blocker (especially if tachycardia present)
• Alpha-blocker (doxazosin)
• Centrally-acting agent (clonidine)
• Vasodilator (hydralazine, minoxidil) 1

Special Considerations

Ethnic Differences

• In Black patients, initial treatment should include a CCB and/or thiazide diuretic 1, 6
• When using multiple agents, race should not exclude any class of antihypertensive 6

Chronic Kidney Disease

• Target systolic BP 120-129 mmHg if eGFR >30 mL/min/1.73m² 1
• Use loop diuretics instead of thiazides if eGFR <30 mL/min/1.73m² 1
• Monitor potassium closely when using spironolactone 1

Device-Based Therapies

For patients with truly resistant hypertension despite optimal medical therapy:

• Renal denervation may be considered if performed at experienced centers 1, 2
• Should only be considered after thorough evaluation and optimization of pharmacological therapy 1

Common Pitfalls to Avoid

1. Failing to confirm true resistant hypertension

   • Always rule out pseudoresistance before escalating therapy

2. Inadequate diuretic therapy

   • Volume expansion is common in resistant hypertension; ensure appropriate diuretic type and dose

3. Overlooking medication adherence

   • Consider simplified regimens, single-pill combinations

4. Neglecting secondary causes

   • Primary aldosteronism and sleep apnea are particularly common in resistant hypertension

5. Inappropriate medication timing

   • Consider administering at least one antihypertensive at bedtime for better 24-hour control 1

6. Overlooking interfering substances

   • NSAIDs are particularly problematic; recommend acetaminophen when analgesic needed 1