What is the treatment for resistant hypertension?

Management of Resistant Hypertension

For resistant hypertension, a stepwise approach starting with optimization of the three-drug regimen followed by addition of spironolactone as the fourth agent is the most effective treatment strategy. 1

Definition and Confirmation

Resistant hypertension is defined as blood pressure that remains above goal (>130/80 mmHg) despite concurrent use of 3 antihypertensive agents of different classes at optimal doses, including a diuretic. It also includes patients whose BP is controlled but requires 4 or more medications. 1, 2

Before initiating treatment, confirm true resistance by:

• Excluding pseudoresistance (white coat effect, poor measurement technique)
• Confirming adherence with 24-hour ambulatory BP monitoring or home BP monitoring
• Assessing for target organ damage
• Screening for secondary causes of hypertension

Stepwise Treatment Algorithm

Step 1: Optimize Current Regimen

• Ensure adherence to 3 antihypertensive agents of different classes:
  • RAS blocker (ACE inhibitor or ARB)
  • Long-acting calcium channel blocker
  • Diuretic at appropriate dose for kidney function
• Maximize lifestyle interventions:
  • Sodium restriction (<2400 mg/day)
  • Weight loss
  • Regular physical activity
  • DASH diet
  • Limited alcohol intake
  • Adequate sleep (≥6 hours uninterrupted) 1, 2

Step 2: Optimize Diuretic Therapy

• Substitute a thiazide-like diuretic (chlorthalidone or indapamide) for the prior diuretic
• For eGFR <30 mL/min/1.73m², use loop diuretics 1, 2

Step 3: Add Mineralocorticoid Receptor Antagonist

• Add spironolactone (most effective fourth-line agent) at 12.5-50 mg daily
• Monitor potassium and renal function
• Alternative: eplerenone if spironolactone causes side effects
• For patients with low potassium (<4.5 mmol/L) and adequate renal function (eGFR >45 mL/min/1.73m²), spironolactone is particularly effective 1, 2

Step 4: Add Additional Agents Based on Heart Rate

• If heart rate ≥70 beats/min, add β-blocker (metoprolol succinate, bisoprolol) or combined α-β-blocker (labetalol, carvedilol)
• If β-blocker is contraindicated, consider central α-agonist (clonidine patch weekly or guanfacine at bedtime)
• If these are not tolerated, consider once-daily diltiazem 1

Step 5: Add Vasodilator

• Add hydralazine 25 mg three times daily and titrate upward to maximum dose
• For patients with heart failure with reduced ejection fraction, combine hydralazine with isosorbide mononitrate 1

Step 6: Consider Advanced Options

• Substitute minoxidil for hydralazine if BP still not controlled
• Consider referral to hypertension specialist 1

Special Considerations

Secondary Causes

Screen for common secondary causes:

• Primary aldosteronism (present in ~20% of resistant hypertension cases)
• Renal parenchymal disease
• Renovascular hypertension
• Obstructive sleep apnea
• Medication-induced hypertension 2

Medication Interference

• Withdraw or minimize medications that may interfere with BP control:
  • NSAIDs
  • Stimulants
  • Decongestants
  • Certain antidepressants
  • Oral contraceptives 1

Population-Specific Considerations

• In Black patients, initial therapy should emphasize calcium channel blockers and diuretics
• Adjust treatment based on comorbidities (diabetes, CKD, heart failure) 2

Monitoring

• Use ambulatory or home BP monitoring to confirm diagnosis and monitor treatment response
• Monitor serum creatinine/eGFR and potassium levels regularly, especially when using ACE inhibitors, ARBs, or diuretics 2

Common Pitfalls

• Failing to confirm true resistant hypertension
• Inadequate diuretic therapy
• Overlooking medication adherence issues
• Neglecting secondary causes
• Inappropriate medication timing
• Overlooking interfering substances 2

Remember that approximately 50% of patients diagnosed with resistant hypertension have pseudoresistance rather than true resistant hypertension, highlighting the importance of thorough evaluation before escalating therapy. 2