What are the guidelines for managing resistant hypertension?

Management of Resistant Hypertension

For patients with resistant hypertension, treatment should include confirmation of true resistance, optimization of a three-drug regimen (RAS blocker, calcium channel blocker, and appropriate diuretic), followed by addition of spironolactone as the preferred fourth-line agent. 1

Definition and Diagnosis

Resistant hypertension is defined as:

• Blood pressure remaining above goal (>140/90 mmHg or >130/80 mmHg) despite concurrent use of 3 antihypertensive agents of different classes at optimal doses, including a diuretic 1
• OR controlled hypertension requiring 4 or more medications 2

Distinguishing True Resistance from Pseudoresistance

Before intensifying therapy, confirm true resistance by:

1. Proper BP measurement technique:

   • Patient seated quietly for 5 minutes
   • Correct cuff size
   • Arm at heart level 1

2. Out-of-office confirmation:

   • 24-hour ambulatory BP monitoring or home BP monitoring 1

3. Exclude pseudoresistance causes:

   • White coat effect
   • Poor medication adherence
   • Improper BP measurement 1

Step-by-Step Management Algorithm

Step 1: Optimize Lifestyle Modifications

• Sodium restriction (<2400 mg/day)
• DASH diet implementation
• Weight loss if overweight/obese
• Regular physical activity
• Alcohol limitation
• Adequate sleep (≥6 hours uninterrupted) 1

Step 2: Screen for Secondary Causes

Common secondary causes to evaluate:

• Obstructive sleep apnea
• Primary aldosteronism
• Chronic kidney disease
• Renal artery stenosis
• Pheochromocytoma
• Cushing's syndrome
• Thyroid disorders 1

Step 3: Optimize Three-Drug Regimen

Ensure patients are on optimal doses of:

1. RAS blocker (ACE inhibitor or ARB)
2. Long-acting calcium channel blocker
3. Appropriate diuretic based on kidney function:
   • Consider substituting chlorthalidone or indapamide for hydrochlorothiazide
   • Use loop diuretics for patients with CKD (eGFR <30 ml/min) 1

Step 4: Add Fourth-Line Agent

• Spironolactone (12.5-25 mg daily) is the preferred fourth agent 1, 3
• Spironolactone has demonstrated superior efficacy in resistant hypertension regardless of aldosterone levels 4

Step 5: Consider Alternative Agents if Spironolactone is Contraindicated

Options include:

• Eplerenone (alternative MRA with fewer anti-androgenic side effects)
• Amiloride
• Doxazosin
• Clonidine
• Beta-blockers
• Hydralazine 1, 5, 2

Monitoring and Follow-up

Laboratory Monitoring

• Electrolytes: Check potassium, sodium, and magnesium 1-2 weeks after initiation and every 3-6 months thereafter
• Kidney function: Monitor serum creatinine and eGFR before starting treatment, 1-2 weeks after initiation, and periodically thereafter 1

Special Monitoring Considerations

• Hyperkalemia risk: Increased with combination of chlorthalidone and spironolactone, especially in:

  • Patients with CKD (eGFR <45 mL/min/1.73m²)
  • Concomitant use of ACE inhibitors or ARBs
  • Potassium supplements
  • Advanced age 1

• Hyponatremia: Monitor especially in elderly patients 1

Emerging Therapies

While device-based therapies like renal denervation and baroreceptor stimulation are being studied, their role remains unclear due to lack of validation in rigorous, double-blind comparisons with sham intervention 1, 6

Newer pharmacological approaches under investigation include:

• Selective non-steroidal mineralocorticoid receptor antagonists (finerenone, esaxerenone)
• Selective aldosterone synthase inhibitors (baxdrostat)
• Dual endothelin antagonist (aprocitentan) 6

Common Pitfalls to Avoid

• Failing to confirm true resistant hypertension
• Inadequate diuretic therapy
• Overlooking medication adherence issues
• Neglecting to screen for secondary causes
• Inappropriate medication timing
• Overlooking interfering substances 1

Barriers to Treatment Success

• Medication cost and complexity
• Side effects
• Therapeutic inertia (not intensifying treatment despite persistently elevated BP) 1
• Consider single-pill combinations to improve adherence 1, 2