What are the interventions for resistant hypertension?

Interventions for Resistant Hypertension

The management of resistant hypertension requires a stepwise approach starting with confirmation of true resistance, followed by optimization of lifestyle factors, evaluation for secondary causes, and sequential medication adjustments, with spironolactone being the preferred fourth-line agent for most patients. 1, 2

Confirming True Resistant Hypertension

Before initiating treatment, confirm that the patient has true resistant hypertension:

• Definition: BP >130/80 mm Hg despite concurrent use of 3 antihypertensive agents of different classes at optimal doses, including a diuretic 1, 2
• Rule out pseudoresistance:
  • Perform 24-hour ambulatory BP monitoring (or home BP monitoring if unavailable) to exclude white coat effect
  • Assess medication adherence
  • Ensure proper BP measurement technique 1, 2

Step 1: Optimize Lifestyle Modifications

• Sodium restriction (<2400 mg/day)
• Implementation of DASH diet
• Weight loss if overweight/obese
• Regular physical activity
• Alcohol limitation
• Adequate sleep (≥6 hours uninterrupted) 1, 2

Step 2: Evaluate for Secondary Causes

Common secondary causes to screen for include:

• Obstructive sleep apnea (snoring, witnessed apnea, excessive daytime sleepiness)
• Primary aldosteronism (elevated aldosterone/renin ratio)
• Chronic kidney disease (creatinine clearance <30 ml/min)
• Renal artery stenosis (young female, known atherosclerotic disease, worsening renal function)
• Pheochromocytoma (episodic hypertension, palpitations, diaphoresis, headache)
• Cushing's syndrome (moon facies, central obesity, abdominal striae)
• Thyroid disorders 1

Step 3: Optimize Medication Therapy

Base Regimen Optimization

Ensure patients are on optimal doses of:

• RAS blocker (ACE inhibitor or ARB)
• Long-acting calcium channel blocker
• Appropriate diuretic for kidney function 1, 2

Sequential Medication Adjustments

1. Optimize diuretic therapy:

   • Substitute chlorthalidone or indapamide for hydrochlorothiazide
   • For patients with CKD (eGFR <30 ml/min), use loop diuretics 1, 2

2. Add mineralocorticoid receptor antagonist (MRA):

   • Spironolactone (12.5-25 mg daily) is the preferred 4th agent 1, 2, 3
   • Particularly effective in patients with serum potassium <4.5 mmol/L and eGFR >45 ml/min/1.73m² 2
   • Eplerenone is an alternative if spironolactone is not tolerated 1, 2

3. If BP remains uncontrolled, add:

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

4. For persistent uncontrolled BP:

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

5. For refractory cases:

   • Substitute minoxidil for hydralazine (start 2.5 mg two to three times daily and titrate upward) 1
   • Consider referral to hypertension specialist 1, 2

Monitoring and Safety Precautions

• Monitor electrolytes (potassium, sodium, magnesium) 1-2 weeks after initiation and every 3-6 months thereafter
• Monitor kidney function (creatinine, eGFR) before starting treatment, 1-2 weeks after initiation, and periodically thereafter
• More frequent monitoring in patients with reduced kidney function
• Watch for hyperkalemia with MRAs, especially in patients with:
  • CKD (eGFR <45 mL/min/1.73m²)
  • Concomitant use of ACE inhibitors or ARBs
  • Potassium supplements
  • Advanced age 2

Common Pitfalls to Avoid

1. Failing to confirm true resistant hypertension
2. Inadequate diuretic therapy for volume status
3. Overlooking medication non-adherence
4. Neglecting to screen for secondary causes
5. Inappropriate medication timing
6. Failing to address interfering substances (NSAIDs, stimulants, oral contraceptives)
7. Not maximizing lifestyle modifications
8. Therapeutic inertia (not intensifying treatment despite persistently elevated BP) 2

Emerging Therapies

While device-based therapies like renal denervation and baroreceptor stimulation have been investigated, their role remains unclear as validation of true benefit has not been confirmed in rigorous, double-blind comparisons with sham intervention 1, 4. Newer pharmacological approaches under investigation include non-steroidal mineralocorticoid receptor antagonists (finerenone, esaxerenone), selective aldosterone synthase inhibitors (baxdrostat), and dual endothelin antagonists (aprocitentan) 5, 4.