What is the initial step in managing resistant hypertension?

Initial Management of Resistant Hypertension

The first step in managing resistant hypertension is to confirm true treatment resistance by performing 24-hour ambulatory blood pressure monitoring to exclude white-coat effect and verify medication adherence, as approximately 50% of apparent resistant hypertension cases are pseudoresistance. 1, 2

Step 1: Exclude Pseudoresistance

Before proceeding with additional interventions, you must systematically rule out false resistance:

Confirm Diagnosis with Ambulatory Monitoring

• Perform 24-hour ambulatory BP monitoring as the gold standard to exclude white-coat hypertension, which accounts for roughly half of apparent resistant cases 1, 2
• If ambulatory monitoring is unavailable, use home BP monitoring as an alternative 1
• Ensure proper BP measurement technique using appropriate cuff size and correct patient positioning 2

Verify Medication Adherence

• Directly question patients about medication-taking behavior, perform pill counts, or review pharmacy refill records, as nonadherence is responsible for approximately 50% of treatment resistance 2
• Consider blood or urine drug level testing if available and adherence remains uncertain 3

Review Interfering Substances

• Identify and discontinue medications that elevate BP: NSAIDs, oral contraceptives, decongestants, stimulants, immunosuppressive agents, and excessive alcohol 3, 4

Step 2: Optimize Current Three-Drug Regimen

Once true resistance is confirmed, maximize the foundation therapy before adding agents:

Ensure Appropriate Drug Classes

• Verify the regimen includes a renin-angiotensin system blocker (ACE inhibitor or ARB), a long-acting calcium channel blocker, and a diuretic at maximal or maximally tolerated doses 1, 2

Optimize Diuretic Selection

• Substitute thiazide-like diuretics (chlorthalidone or indapamide) for standard thiazides, as they are more effective in resistant hypertension 1, 2
• Switch to loop diuretics if eGFR <30 mL/min/1.73m² or clinical volume overload is present, as unrecognized volume overload is a common cause of treatment failure 1, 2

Maximize Lifestyle Interventions

• Restrict sodium intake to <2400 mg/day (ideally <1500 mg/day), as high sodium significantly contributes to treatment resistance 1, 2, 3
• Encourage weight loss if overweight/obese, which can produce significant BP reductions 2, 5
• Limit alcohol to ≤2 drinks/day for men and ≤1 drink/day for women 2
• Implement regular physical activity with a structured exercise program 2, 5
• Ensure at least 6 hours of uninterrupted sleep nightly 1, 5

Step 3: Screen for Secondary Causes

Evaluate for underlying conditions that perpetuate resistance:

Essential Screening Tests

• Screen for primary aldosteronism even with normal potassium levels, particularly in young patients (<30 years) 2, 3
• Evaluate for obstructive sleep apnea using Berlin Questionnaire or Epworth Sleepiness Score, confirming with polysomnography if suspected 3, 4
• Assess renal function including baseline eGFR and screen for renal artery stenosis with kidney ultrasound followed by renal artery imaging if clinically indicated 2, 3
• Check TSH to evaluate for thyroid dysfunction 1, 2

Target Organ Damage Assessment

• Perform funduscopic exam for ocular damage 1, 5
• Evaluate for left ventricular hypertrophy and coronary artery disease 1, 5
• Check for proteinuria and reduced glomerular filtration rate 1, 5
• Measure ankle-brachial index to assess for peripheral arterial disease 1

Step 4: Add Fourth-Line Agent

If BP remains uncontrolled after optimizing the three-drug regimen and addressing secondary causes:

Mineralocorticoid Receptor Antagonist as Preferred Fourth Agent

• Add spironolactone 25 mg daily as the fourth-line agent, as it has demonstrated superior efficacy in resistant hypertension 5, 6, 4, 7
• Monitor serum potassium and renal function 1-2 weeks after initiation, especially when combining with RAS blockade 5, 6
• Use caution if eGFR <30 mL/min/1.73m² due to hyperkalemia risk 1, 6
• Consider eplerenone as an alternative if spironolactone is not tolerated 1, 8

Alternative Fourth-Line Agents

• If spironolactone is contraindicated or not tolerated, consider amiloride, doxazosin, beta-blockers (if heart rate >70 bpm), or alpha-agonists like clonidine 1, 4

Step 5: Monitor and Reassess

Follow-Up Timeline

• Reassess BP response within 2-4 weeks of any medication adjustment 2, 5
• Check serum potassium and renal function regularly, particularly after adding spironolactone 2, 5
• Continue home BP monitoring to guide medication titration and improve adherence 2

Critical Pitfalls to Avoid

• Do not proceed to additional agents without first confirming true resistance through ambulatory monitoring 1, 2
• Do not overlook volume overload as a cause of treatment failure—ensure appropriate diuretic type and dose for kidney function 1, 2
• Do not add spironolactone without checking baseline potassium and renal function, and monitoring closely thereafter 5, 6
• Do not delay screening for secondary causes, particularly in young patients (<30 years) where secondary hypertension is highly prevalent 3

When to Refer

Refer to a hypertension specialist if BP remains uncontrolled despite optimization of a four-drug regimen including spironolactone, or if complex secondary causes require specialized management 2, 5, 3, 9