What should be added to the regimen of a 75-year-old patient with uncontrolled hypertension despite maximal doses of irbesartan 300 mg, amlodipine 10 mg, and bisoprolol 10 mg, with normal renal function?

Add a Thiazide-Like Diuretic as the Fourth Agent

For this 75-year-old patient with uncontrolled hypertension on maximal doses of irbesartan 300mg, amlodipine 10mg, and bisoprolol 10mg, the next step is to add a thiazide-like diuretic—preferably chlorthalidone 12.5-25mg daily or indapamide, as this represents the guideline-recommended fourth drug class for resistant hypertension. 1

Critical First Steps Before Adding Medication

Before prescribing additional therapy, you must address these common causes of apparent treatment resistance:

• Verify medication adherence using direct questioning about prescription fills, pill counts, or chemical adherence testing, as non-adherence is the most common cause of treatment resistance 1
• Confirm true hypertension with 24-hour ambulatory blood pressure monitoring (preferred) or home blood pressure monitoring to exclude white-coat effect 1
• Review interfering substances: NSAIDs, decongestants, oral contraceptives, systemic corticosteroids, excessive alcohol (>2 drinks/day for men), and herbal supplements can significantly elevate blood pressure 1
• Assess sodium intake: dietary sodium should be restricted to <2400 mg/day (<2g/day ideally), as excessive sodium is a major contributor to treatment resistance 1

Why Add a Diuretic Now

The patient is already on the three foundational drug classes for resistant hypertension (RAS blocker, calcium channel blocker, and beta-blocker), but notably missing a diuretic—the most critical component for resistant hypertension management:

• The American Heart Association's algorithm for resistant hypertension explicitly states that Step 1 requires ensuring adherence to three antihypertensive agents including a RAS blocker, CCB, and diuretic at maximal doses 1
• Your patient has a beta-blocker instead of a diuretic in the initial three-drug regimen, which is less optimal for resistant hypertension 1
• Occult volume expansion underlies treatment resistance in most cases, making diuretic therapy essential 1

Specific Diuretic Selection

Chlorthalidone is the preferred thiazide-like diuretic for several reasons:

• Start chlorthalidone 12.5-25mg once daily in the morning 1, 2
• Chlorthalidone maintains efficacy down to eGFR 30 mL/min/1.73m² and has superior 24-hour blood pressure control compared to hydrochlorothiazide 1
• If chlorthalidone is unavailable, use indapamide (preferred alternative) or hydrochlorothiazide 25mg daily 1, 2

Monitoring After Adding Diuretic

• Check serum potassium and creatinine 2-4 weeks after initiating diuretic therapy to detect hypokalemia or changes in renal function 1
• Reassess blood pressure within 2-4 weeks, with the goal of achieving target BP <140/90 mmHg (minimum) or <130/80 mmHg (optimal for high-risk patients) within 3 months 1, 3
• Monitor for hypokalemia, hyperuricemia, and glucose intolerance as potential adverse effects 2

If Blood Pressure Remains Uncontrolled on Four-Drug Therapy

If target blood pressure is not achieved after optimizing the diuretic dose:

• Add spironolactone 25-50mg daily as the preferred fifth agent for resistant hypertension, which provides additional blood pressure reductions of 20-25/10-12 mmHg 1, 3
• Monitor potassium closely when adding spironolactone to irbesartan, as hyperkalemia risk is significant with dual RAS blockade and mineralocorticoid receptor antagonism 1
• Alternative fifth-line agents if spironolactone is contraindicated include eplerenone, amiloride, doxazosin, or hydralazine 1, 3

Essential Lifestyle Modifications

Reinforce these interventions, which provide additive blood pressure reductions of 10-20 mmHg:

• Sodium restriction to <2g/day (most important) 1, 3
• Weight loss if overweight (BMI goal 20-25 kg/m²) 1
• DASH dietary pattern 1
• Regular aerobic exercise (minimum 30 minutes most days) 1
• Alcohol limitation to ≤2 drinks/day for men, ≤1 drink/day for women 1, 3

Screen for Secondary Hypertension

Given the severity of treatment resistance, evaluate for secondary causes:

• Primary aldosteronism (most common secondary cause in resistant hypertension) 1
• Obstructive sleep apnea (especially if obese, snoring, daytime somnolence) 1
• Renal artery stenosis (especially if age >55, atherosclerotic disease, or abdominal bruit) 1
• Check thyroid function, serum calcium, and consider 24-hour urinary metanephrines if clinically indicated 1

Critical Pitfalls to Avoid

• Do not add a second beta-blocker or increase bisoprolol dose—beta-blockers are less effective than diuretics for stroke prevention and cardiovascular outcomes in hypertension 1
• Do not combine irbesartan with an ACE inhibitor—dual RAS blockade increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit 1, 2
• Do not delay treatment intensification—this patient has uncontrolled hypertension requiring prompt action to reduce cardiovascular risk 1, 3
• Do not assume treatment failure without confirming adherence and ruling out secondary causes first 1

Referral Considerations

• Consider referral to a hypertension specialist if blood pressure remains ≥160/100 mmHg despite four-drug therapy at optimal doses, or if there are concerning features suggesting secondary hypertension 1, 3