What is the next step in managing resistant hypertension that is not controlled with three antihypertensive (blood pressure lowering) medications?

Management of Resistant Hypertension

The next step in managing resistant hypertension that is not controlled with three antihypertensive medications is to add spironolactone (25-50 mg daily) as the fourth agent. 1

Confirming True Resistant Hypertension

Before adding a fourth medication, ensure the patient truly has resistant hypertension:

1. Verify diagnosis: Resistant hypertension is defined as BP ≥130/80 mmHg despite adherence to 3 or more antihypertensive agents from different classes at optimal doses, including a diuretic 1

2. Exclude pseudoresistance:

   • Confirm medication adherence
   • Perform 24-hour ambulatory BP monitoring or home BP monitoring to exclude white-coat effect 2
   • Ensure proper BP measurement technique (appropriate cuff size)

3. Optimize current regimen:

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

4. Address lifestyle factors:

   • Sodium restriction (<2,300 mg/day)
   • DASH diet implementation
   • Weight loss if overweight/obese
   • Regular physical activity
   • Alcohol limitation
   • Adequate sleep (≥6 hours uninterrupted) 1

Fourth-Line Treatment: Spironolactone

After confirming true resistant hypertension and optimizing the current regimen, the evidence strongly supports adding spironolactone:

• Dosage: Start with 25 mg daily, can be titrated up to 50 mg daily 1
• Monitoring: Check serum potassium and renal function within 1-2 weeks of starting spironolactone 1
• Caution: Use with particular care when adding to ARB therapy due to increased risk of hyperkalemia 1

The FDA label confirms spironolactone is indicated as add-on therapy for the treatment of hypertension in patients not adequately controlled on other agents 3.

Alternative Fourth-Line Options

If spironolactone is contraindicated or not tolerated, consider these alternatives:

1. Eplerenone: Alternative mineralocorticoid receptor antagonist with fewer anti-androgenic side effects 1
2. Amiloride: Potassium-sparing diuretic 1
3. Doxazosin: Alpha-1 blocker 1
4. Beta-blockers: Consider if heart rate is not <70 beats/min 2

Fifth and Sixth-Line Options

If blood pressure remains uncontrolled after adding a fourth agent:

1. Fifth step: Add hydralazine (starting at 25 mg three times daily and titrating upward) 2
2. Sixth step: Substitute minoxidil for hydralazine (starting at 2.5 mg two to three times daily) 2

Screening for Secondary Causes

Consider screening for secondary causes of resistant hypertension, particularly:

• Primary aldosteronism: Present in 10-20% of resistant hypertension cases 1
• Obstructive sleep apnea: High prevalence in resistant hypertension 1
• Chronic kidney disease: Can cause volume overload 1
• Renal artery stenosis: Especially in patients with peripheral arterial disease 1

When to Consider Specialist Referral

Consider referral to a hypertension specialist if:

• BP remains uncontrolled after adding spironolactone 1
• Secondary causes are suspected
• Complex comorbidities exist

Important Caveats

• Mineralocorticoid receptor antagonists like spironolactone have shown substantial benefit even in patients without demonstrable aldosterone excess 4
• Patients with resistant hypertension have higher rates of cardiovascular events and mortality compared to those with more easily controlled hypertension 5
• Device-based therapies like renal denervation are not first-line interventions and should only be considered after pharmacological options have been exhausted 1