What is the treatment approach for resistant hypertension?

Treatment Approach for Resistant Hypertension

For patients with resistant hypertension, treatment should include maximization of diuretic therapy (preferably chlorthalidone or indapamide instead of hydrochlorothiazide), addition of a mineralocorticoid receptor antagonist (spironolactone as the preferred fourth agent), and consideration of additional agents with different mechanisms of action if blood pressure remains uncontrolled. 1, 2

Definition and Diagnosis

Resistant hypertension is defined as:

• Blood pressure ≥130/80 mmHg despite adherence to 3 or more antihypertensive agents from different classes at optimal doses, including a diuretic, OR
• Blood pressure controlled but requiring 4 or more medications 1, 2

Before initiating treatment for resistant hypertension, confirm the diagnosis by:

• Ensuring accurate office BP measurements with proper technique
• Assessing medication adherence
• Obtaining home or ambulatory BP readings to rule out white coat effect
• Identifying contributing lifestyle factors
• Discontinuing or minimizing substances that interfere with therapy (NSAIDs, stimulants, oral contraceptives)
• Excluding secondary causes of hypertension 1, 2

Treatment Algorithm

Step 1: Optimize Current Therapy

• Ensure patient is on optimal doses of a three-drug regimen including:
  • ACE inhibitor or ARB
  • Long-acting calcium channel blocker (CCB)
  • Thiazide-like diuretic (preferably chlorthalidone or indapamide instead of hydrochlorothiazide) 1, 2

Step 2: Add Fourth Agent

• Spironolactone is the preferred fourth agent at 25-50 mg daily 2, 3, 4
• Monitor serum potassium and renal function within 1-2 weeks of starting spironolactone 2
• For patients who cannot tolerate spironolactone, alternatives include:
  • Eplerenone
  • Amiloride
  • Doxazosin
  • Beta-blockers 2, 4

Step 3: Additional Agents if Needed

• If BP remains uncontrolled after adding spironolactone:
  • Consider adding other agents with different mechanisms of action
  • For patients with CKD, consider loop diuretics
  • Hydralazine (100-200 mg/day divided into 2-3 doses) may be used as a third-line agent, combined with a beta-blocker to counteract reflex tachycardia 2
  • Referral to a hypertension specialist is recommended if BP remains uncontrolled 1, 2

Lifestyle Modifications

Essential adjuncts to pharmacotherapy include:

• Dietary sodium restriction (<2,300 mg/day)
• DASH diet implementation
• Weight loss if overweight/obese
• Regular physical activity
• Alcohol limitation
• Adequate sleep (≥6 hours uninterrupted)
• Increased fluid intake (target urine volume >2.5 L/day) 2

Special Considerations

Older Adults

• For adults aged ≥65 years with resistant hypertension:
  • Treatment goal remains <130 mmHg systolic
  • Careful titration and close monitoring are essential, especially with high comorbidity burden
  • For frail older adults, a team-based approach considering risk-benefit tradeoffs is reasonable 1

Chronic Kidney Disease

• For patients with CKD:
  • Consider loop diuretics instead of thiazide diuretics
  • Monitor renal function and electrolytes closely, especially when using RAS blockers 1, 2

Monitoring and Follow-up

• Check BP within 1 month of medication changes
• Monitor electrolytes and renal function 1-2 weeks after initiation of RAS blockers or diuretics
• Schedule follow-up at least every 3-6 months once BP is controlled
• Pay particular attention to potassium levels when using spironolactone, especially in combination with ACE inhibitors or ARBs 2

Clinical Implications

Resistant hypertension is associated with 2-6 fold higher risk for myocardial infarction, stroke, end-stage renal disease, and death compared to non-resistant hypertension 1. Aggressive management is therefore essential to reduce cardiovascular morbidity and mortality.