What are the next steps for a patient with uncontrolled hypertension on carvedilol (beta blocker), hydrochlorothiazide (HCTZ) (thiazide diuretic), amlodipine (calcium channel blocker), and olmesartan (angiotensin II receptor blocker) with blood pressures consistently above 170/100?

Management of Resistant Hypertension on Four-Drug Regimen

Immediate Next Step: Add Spironolactone

Add spironolactone 25-50 mg daily as the fifth antihypertensive agent, as this patient has resistant hypertension (BP ≥170/100 mmHg despite four medications including a diuretic). 1, 2, 3

This patient meets the definition of resistant hypertension—blood pressure above goal despite adherence to three or more antihypertensive medications of different classes at optimal doses, including a diuretic. 4 The current regimen already includes:

• Beta-blocker (carvedilol)
• Thiazide diuretic (HCTZ)
• Calcium channel blocker (amlodipine)
• ARB (olmesartan)

Rationale for Spironolactone

• The 2024 ESC guidelines explicitly recommend spironolactone as the preferred fourth-line agent when BP is not controlled with three-drug combinations, or in this case, as the fifth agent when a non-standard four-drug regimen has failed. 1

• Spironolactone is FDA-approved as add-on therapy for treatment of hypertension in patients not adequately controlled on other agents. 3

• If spironolactone is not tolerated, eplerenone can be substituted, followed by consideration of centrally acting agents, alpha-blockers, hydralazine, or other potassium-sparing diuretics. 1

Critical Actions Before Adding Spironolactone

Verify Medication Adherence

• Non-adherence is the most common cause of apparent treatment resistance and must be ruled out before escalating therapy. 2, 4

Rule Out White-Coat Hypertension

• Confirm sustained hypertension with home BP monitoring (≥135/85 mmHg) or 24-hour ambulatory monitoring (≥130/80 mmHg), as clinic readings may overestimate true BP. 2

Optimize Current Regimen First

• Ensure HCTZ is dosed at 25-50 mg daily (not 12.5 mg), as inadequate diuretic dosing is observed in nearly half of patients with resistant hypertension. 2, 5
• Consider switching HCTZ to chlorthalidone 12.5-25 mg daily, which has longer duration of action and may be more effective. 2
• Verify olmesartan is at maximum dose of 40 mg daily. 2

Screen for Secondary Causes

• Evaluate for chronic kidney disease, obstructive sleep apnea, and primary hyperaldosteronism—the three most common causes of truly drug-resistant hypertension, all of which lead to fluid retention. 4, 5
• Assess for interfering substances, particularly NSAIDs, which are major contributors to resistant hypertension. 4, 5
• Review for other contributors: obesity, heavy alcohol intake (>100 g/week), and high dietary sodium (target <2 g/day). 1, 4

Monitoring After Adding Spironolactone

• Check serum potassium and creatinine 2-4 weeks after initiating spironolactone, as hyperkalemia risk is significant when combined with an ARB. 2

• Monitor for hyperkalemia and hold or reduce dose if potassium rises significantly or creatinine increases substantially. 2

• Reassess BP within 2-4 weeks, targeting <140/90 mmHg minimum, ideally 120-129/<80 mmHg if well tolerated. 1, 2

If BP Remains Uncontrolled After Spironolactone

• Consider referral to a hypertension specialist if BP remains ≥160/100 mmHg despite five-drug therapy at optimal doses. 2

• Next medication options include centrally acting agents (clonidine), alpha-blockers, or direct vasodilators (hydralazine), though evidence is limited. 1, 5

Reinforce Lifestyle Modifications

• Sodium restriction to <2 g/day can provide additive BP reductions of 10-20 mmHg. 1, 2

• Target BMI 20-25 kg/m² and waist circumference <94 cm (men) or <80 cm (women). 1

• Regular aerobic exercise ≥150 minutes/week of moderate intensity or 75 minutes/week of vigorous intensity, complemented with resistance training 2-3 times/week. 1

• Limit alcohol to <100 g/week (<14 units/week for men, <8 units/week for women). 1

Important Caveats

• Do not combine olmesartan with an ACE inhibitor, as dual RAS blockade increases adverse events without additional benefit. 2

• The current regimen includes carvedilol (beta-blocker), which is not part of standard triple therapy but may have been added for compelling indications—verify if this is appropriate or if it should be discontinued to simplify the regimen. 1, 2

• Device-based therapies (renal denervation) are not recommended for routine treatment outside of clinical trials. 1