What is the best approach to treat resistant hypertension?

Treatment of Resistant Hypertension

The most effective treatment for resistant hypertension is adding spironolactone 25mg daily as a fourth-line agent after optimizing a three-drug regimen (ACE inhibitor/ARB + long-acting calcium channel blocker + thiazide-like diuretic) at maximal tolerated doses, combined with aggressive lifestyle modifications including sodium restriction to <2400 mg/day. 1, 2, 3, 4, 5

Step 1: Confirm True Resistant Hypertension

Before escalating therapy, you must exclude pseudoresistance:

• Perform 24-hour ambulatory blood pressure monitoring to exclude white-coat hypertension (clinic BP >130/80 mmHg but controlled on ambulatory monitoring). 1, 2, 3
• Assess medication adherence directly, as nonadherence accounts for approximately 50% of apparent treatment resistance. 2, 3
• Verify proper BP measurement technique using validated automated upper arm cuff devices with appropriate cuff size. 6
• Identify interfering substances: NSAIDs, oral contraceptives, stimulants, certain antidepressants, and decongestants can all impair BP control. 1, 3

Step 2: Optimize Lifestyle Modifications

These interventions are critical and often overlooked:

• Sodium restriction to <2400 mg/day is essential, as volume overload is a primary driver of treatment resistance. 1, 2, 3
• Weight loss for overweight/obese patients can produce significant BP reductions. 2, 3
• Structured exercise program with regular physical activity. 3
• Alcohol limitation to ≤2 drinks/day for men, ≤1 drink/day for women. 3
• DASH dietary pattern to facilitate weight management. 3

Step 3: Optimize Three-Drug Foundation Regimen

Ensure the patient is on maximal or maximally tolerated doses of:

• A blocker of the renin-angiotensin system (ACE inhibitor or ARB). 1, 2, 3
• A long-acting dihydropyridine calcium channel blocker (amlodipine, nifedipine). 1, 2, 3
• An appropriate diuretic for kidney function:
  • Substitute chlorthalidone or indapamide for hydrochlorothiazide if not already done, as thiazide-like diuretics are more effective. 1, 2
  • Use loop diuretics (furosemide, torsemide) if eGFR <30 mL/min/1.73m². 1

Common pitfall: Inadequate diuretic therapy leading to volume overload is the most frequent cause of treatment failure. 2, 3

Step 4: Add Spironolactone as Fourth-Line Agent

Spironolactone 25mg daily is the most effective fourth-line agent, demonstrating superior efficacy compared to all other options in network meta-analysis. 5

• Monitor serum potassium and renal function 1-2 weeks after initiation, particularly with existing RAS blockade. 3
• Titrate upward if needed and tolerated to achieve BP control. 4
• If spironolactone is not tolerated (gynecomastia, hyperkalemia), use eplerenone as an alternative mineralocorticoid receptor antagonist. 1, 2

The FDA label indicates spironolactone is approved for treatment of hypertension as add-on therapy in patients not adequately controlled on other agents. 4

Step 5: Additional Agents if Needed

If BP remains uncontrolled after spironolactone:

• Check heart rate: If ≥70 beats/min, add a β-blocker (metoprolol succinate, bisoprolol) or combined α-β-blocker (labetalol, carvedilol). 1
• If β-blocker is contraindicated: Consider central α-agonist (clonidine patch weekly or guanfacine at bedtime), or once-daily diltiazem. 1
• If still uncontrolled: Add hydralazine 25mg three times daily and titrate upward. 1

Step 6: Screen for Secondary Causes

All patients with resistant hypertension require evaluation for:

• Primary aldosteronism (even with normal potassium levels) - most common secondary cause. 3
• Obstructive sleep apnea - highly prevalent in this population. 3
• Chronic kidney disease - assess eGFR and proteinuria. 3
• Renal artery stenosis - particularly in patients with abdominal bruits or asymmetric kidney size. 3
• Other endocrine disorders (pheochromocytoma, Cushing's syndrome, thyroid disease). 3

Population-Specific Considerations

• Black patients: Ensure regimen includes a diuretic or calcium channel blocker, as these are more effective in this population. 2, 3
• Heart failure patients: Include ACE inhibitor/ARB, β-blocker, and mineralocorticoid receptor antagonist. 2, 3
• Chronic kidney disease (eGFR >30): Target SBP 120-129 mmHg. 2

Critical Pitfalls to Avoid

• Failing to confirm true resistant hypertension before escalating therapy leads to unnecessary polypharmacy. 3
• Not addressing volume overload with adequate diuretic therapy is the most common reversible cause. 2, 3
• Missing primary aldosteronism as a secondary cause, which is highly prevalent in resistant hypertension. 3
• Overlooking medication nonadherence rather than assuming true resistance. 2, 3
• Using suboptimal medication combinations or inadequate doses of the foundation regimen. 3

Monitoring Strategy

• Assess BP response within 2-4 weeks of medication adjustment. 3
• Monitor serum potassium and renal function regularly, especially after initiating spironolactone. 3
• Use home BP monitoring to guide medication titration and improve adherence. 3
• Simplify regimen with single-pill combinations when possible to enhance adherence. 2, 6