What is the best approach to manage a patient with resistant hypertension who is already on multiple antihypertensive medications, including an Angiotensin-Converting Enzyme (ACE) inhibitor, a calcium channel blocker, and a diuretic?

Management of Resistant Hypertension

Add a mineralocorticoid receptor antagonist (spironolactone 25-50 mg daily) as the fourth antihypertensive agent, provided serum potassium is <4.5 mEq/L and eGFR is >45 mL/min/1.73m², as this is the most effective intervention for resistant hypertension. 1

Confirm True Resistant Hypertension

Before escalating therapy, exclude pseudoresistance:

• Perform ambulatory or home blood pressure monitoring to rule out white-coat hypertension, which accounts for approximately 50% of apparent resistant cases 1, 2
• Verify medication adherence through direct questioning, pill counts, or pharmacy records, as nonadherence causes roughly half of treatment resistance 1, 2
• Ensure proper BP measurement technique using appropriate cuff size and correct arm positioning 1, 2
• Confirm BP remains ≥140/90 mmHg (or ≥130/80 mmHg per newer guidelines) despite adherence to three antihypertensive agents from different classes at adequate doses, including a diuretic 1

Optimize the Current Three-Drug Regimen

Before adding a fourth agent, maximize the existing regimen:

• Switch from hydrochlorothiazide to chlorthalidone (12.5-25 mg daily) or indapamide (1.5-2.5 mg daily), as thiazide-like diuretics provide superior 24-hour BP control and cardiovascular outcomes 1, 2
• Ensure the regimen includes an ACE inhibitor (or ARB), a long-acting dihydropyridine calcium channel blocker, and a thiazide-like diuretic at maximally tolerated doses 1
• Use loop diuretics instead of thiazides if eGFR <30 mL/min/1.73m² or clinical volume overload is present, as thiazides become ineffective at lower GFR 1, 2

Address Contributing Factors

• Restrict dietary sodium to <2400 mg/day, as high sodium intake significantly contributes to treatment resistance 1, 2
• Encourage weight loss if overweight or obese, which can produce significant BP reductions 1, 2
• Limit alcohol to ≤2 drinks/day for men, ≤1 drink/day for women 1
• Discontinue or minimize interfering substances: NSAIDs, stimulants, oral contraceptives, certain antidepressants 1, 2
• Implement regular exercise with a structured program 1

Screen for Secondary Causes

Before diagnosing true resistant hypertension, evaluate for:

• Primary aldosteronism by obtaining morning plasma aldosterone and plasma renin activity (aldosterone/renin ratio >20-30 is suggestive) 1, 2
• Obstructive sleep apnea through clinical screening or sleep study 1, 2
• Renal artery stenosis, particularly in young patients or those with sudden onset resistant hypertension 1, 2
• Chronic kidney disease by assessing baseline eGFR 1, 2
• Thyroid dysfunction by checking TSH 2

Add Mineralocorticoid Receptor Antagonist

Spironolactone is the preferred fourth-line agent:

• Start with spironolactone 25 mg once daily, which can be increased to 50 mg daily if BP remains uncontrolled and the medication is well-tolerated 1, 2
• This is effective even in patients without biochemical evidence of aldosterone excess 1
• Spironolactone also reduces albuminuria and provides additional cardiovascular benefits 1
• Approximately 70% of adults with resistant hypertension are candidates based on serum potassium and eGFR criteria 2

Critical Monitoring Requirements

• Check serum potassium and renal function within 1-2 weeks after initiation, especially in patients already on ACE inhibitors or ARBs 1, 2
• Monitor regularly thereafter, as adding a mineralocorticoid receptor antagonist to a regimen including an ACE inhibitor or ARB increases hyperkalemia risk 1
• Continue monitoring serum creatinine and potassium at least annually in all patients on these combinations 1

Alternative Fourth-Line Agents

If spironolactone is contraindicated or not tolerated:

• Eplerenone (50-200 mg daily) causes less gynecomastia but requires higher dosing for equivalent BP reduction 2
• Amiloride has shown effectiveness in one trial, potentially more effective than spironolactone 2
• Vasodilating beta-blockers (labetalol, carvedilol, or nebivolol) are the safest option for patients who cannot undergo regular laboratory monitoring 2
• Doxazosin or clonidine can be considered 2

Fifth-Line Options

If BP remains uncontrolled on four agents:

• Hydralazine should only be considered after other agents prove ineffective, starting at 10 mg four times daily and titrating up 2
• Minoxidil should be reserved as a last resort due to side effects (requires concomitant beta-blocker and loop diuretic) 1, 2

Monitoring Strategy

• Reassess BP response within 2-4 weeks of any medication adjustment 2
• Target BP <130/80 mmHg per current guidelines, though individualize for elderly patients based on frailty 1, 2
• Use home BP monitoring to guide medication titration and improve adherence 2

Specialist Referral

Refer to a hypertension specialist if:

• BP remains uncontrolled (>130/80 mmHg) after optimizing the four-drug regimen with lifestyle modifications 2
• Complications arise such as severe hyperkalemia, progressive renal dysfunction, or difficulty managing the regimen 2
• Secondary causes are suspected but require specialized evaluation 1, 2

Common Pitfalls to Avoid

• Do not continue hydrochlorothiazide when chlorthalidone or indapamide are superior options 1, 2
• Do not combine ACE inhibitors with ARBs or use direct renin inhibitors with either, as these combinations increase adverse events without additional benefit 1
• Do not use thiazides when eGFR <30 mL/min/1.73m² as they become ineffective; switch to loop diuretics 1, 2
• Do not add spironolactone if serum potassium is ≥4.5 mEq/L or eGFR <45 mL/min/1.73m² without close monitoring 2
• Do not diagnose resistant hypertension without first confirming adherence and excluding white-coat effect 1, 2