In a patient with resistant hypertension (blood pressure ~140 mm Hg) despite a calcium‑channel blocker, an ACE inhibitor, and a beta‑blocker, which laboratory tests should be ordered to screen for primary hyperaldosteronism and other secondary causes, and what fourth antihypertensive agent should be added?

Management of Resistant Hypertension: Laboratory Workup and Fourth-Line Agent Selection

Add spironolactone 25 mg daily as your fourth antihypertensive agent if serum potassium is <4.5 mmol/L and eGFR is >45 mL/min/1.73m², as this is the most effective option supported by the PATHWAY-2 trial. 1, 2, 3

Laboratory Tests to Order

Before adding a fourth agent, obtain the following labs to screen for secondary causes and ensure safe medication addition:

Essential Screening Labs

• Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) - Screen for primary aldosteronism, which accounts for 8-20% of resistant hypertension cases. An aldosterone/renin ratio >20-30 is suggestive. 2, 3, 4

• Serum potassium - Must be <4.5 mmol/L before adding spironolactone to minimize hyperkalemia risk. 1, 2, 3

• Serum creatinine with eGFR calculation - Must be >45 mL/min/1.73m² for safe spironolactone use. 2, 3

• TSH - Screen for thyroid dysfunction as a secondary cause. 2

• Urine albumin-to-creatinine ratio - Assess for hypertensive/diabetic nephropathy. 3

Additional Considerations

• Sleep apnea screening (STOP-BANG questionnaire) - Obstructive sleep apnea is present in 25-50% of resistant hypertension cases. 2, 3

• 24-hour ambulatory blood pressure monitoring - Exclude white-coat effect, which accounts for approximately 50% of apparent resistant hypertension. 2, 3

Optimizing Current Regimen Before Adding Fourth Agent

Critical First Step: Switch to More Effective Diuretic

Replace your current thiazide with chlorthalidone 12.5-25 mg daily or indapamide 1.5-2.5 mg daily, as thiazide-like diuretics are significantly more effective than hydrochlorothiazide for resistant hypertension. 1, 2, 3

• If eGFR <30 mL/min/1.73m² or clinical volume overload is present, use a loop diuretic instead, as thiazides become ineffective at lower GFR. 2, 3

Verify Adequate Dosing

• Ensure your ACE inhibitor, CCB, and beta-blocker are at maximal tolerated doses before adding a fourth agent. 1

• Inadequate diuretic therapy is the most common reason for treatment failure in resistant hypertension. 2

Fourth-Line Agent Selection Algorithm

First Choice: Spironolactone

Add spironolactone 25 mg once daily if the following criteria are met: 1, 2, 3

• Serum potassium <4.5 mmol/L (some guidelines use <4.6 mmol/L)
• eGFR >45 mL/min/1.73m²
• Patient can undergo regular laboratory monitoring

Increase to 50 mg daily if BP remains uncontrolled after 4 weeks and medication is well-tolerated. 2, 3

Monitor potassium and creatinine within 1-4 weeks after initiation, as hyperkalemia risk is significant when combined with ACE inhibitors. 2, 3

Alternative Agents (If Spironolactone Contraindicated)

If potassium ≥4.5 mmol/L or eGFR <45 mL/min/1.73m², use the following hierarchy:

1. Eplerenone 50-200 mg daily (may need twice-daily dosing) - Less gynecomastia than spironolactone but requires higher doses for equivalent BP reduction. 2, 3

2. Amiloride - One trial found it more effective than spironolactone for resistant hypertension. 2

3. Vasodilating beta-blockers (nebivolol, carvedilol, or labetalol) - Safest option for patients who cannot undergo regular laboratory monitoring, as they don't require potassium checks. 2, 3

4. Alpha-blocker (doxazosin) - Consider if diuretic therapy is not tolerated or contraindicated. 1

Agents Reserved for Refractory Cases

• Hydralazine - Only after other agents prove ineffective. 2

• Minoxidil - Last resort due to multiple side effects; reserve for cases where all other agents have failed. 1, 2

Common Pitfalls to Avoid

• Don't continue hydrochlorothiazide - Switch to chlorthalidone or indapamide for superior efficacy. 2, 3

• Don't add spironolactone without checking potassium and renal function first - Hyperkalemia risk is substantial, especially with concurrent ACE inhibitor use. 2, 3

• Don't assume true resistant hypertension without confirming medication adherence - Nonadherence accounts for roughly half of treatment resistance. 2, 3

• Don't overlook volume overload - This is a common unrecognized cause of treatment failure. 2

• Don't forget to assess for interfering substances - NSAIDs, stimulants, oral contraceptives, and certain antidepressants can interfere with BP control. 2, 3

When to Refer to Specialist

Refer to a hypertension specialist if: 2, 3

• BP remains >130/80 mmHg after optimizing a four-drug regimen with lifestyle modifications
• Severe hyperkalemia or progressive renal dysfunction develops
• Secondary cause requiring specialized management is identified
• Difficulty managing the complex medication regimen

Target Blood Pressure

Aim for BP <130/80 mmHg, though individualize for elderly patients based on frailty and comorbidity burden. 2, 3