What is the next step in managing a patient with stage 2 hypertension on losartan, hydrochlorothiazide (HCTZ), and amlodipine at maximum doses?

Add Spironolactone as the Fourth Antihypertensive Agent

The next step is to add spironolactone 25 mg daily to your current regimen of losartan, HCTZ, and amlodipine at maximum doses. 1, 2

Confirming Resistant Hypertension

Your blood pressure of 158/96 mmHg meets criteria for resistant hypertension—defined as BP remaining above goal despite adherence to three appropriately dosed medications from different classes, including a diuretic. 1, 2 Before adding a fourth agent, you must:

• Confirm true treatment resistance with 24-hour ambulatory BP monitoring (target <130/80 mmHg) or home BP monitoring (target <135/85 mmHg) to exclude white-coat hypertension 1
• Verify medication adherence, as nonadherence affects 10-80% of hypertensive patients and is the most common cause of apparent treatment resistance 1, 2
• Ensure dietary sodium restriction to <2.3g (100 mEq) per day, as excess sodium intake commonly undermines treatment efficacy 1, 2

Spironolactone as Preferred Fourth-Line Agent

Spironolactone 25-50 mg daily is the preferred fourth-line agent for resistant hypertension, with strong evidence showing additional BP reductions when added to triple therapy. 1, 2 The American Heart Association's 2018 resistant hypertension algorithm specifically recommends adding a mineralocorticoid receptor antagonist (MRA) at this step. 1

Dosing and Monitoring

• Start with spironolactone 25 mg daily 1, 2
• Monitor serum potassium and renal function within 1-2 weeks of initiation, as hyperkalemia risk is significant when combining spironolactone with losartan (an ARB) 1, 2
• Use caution if eGFR <30 mL/min/1.73m², as risk of hyperkalemia increases substantially 1
• Titrate to 50 mg daily if BP remains uncontrolled and potassium remains safe 1

Alternative Fourth-Line Agents

If spironolactone is not tolerated or contraindicated (hyperkalemia, renal dysfunction, gynecomastia), consider these alternatives in order: 1, 2

• Eplerenone (alternative MRA with less gynecomastia)
• Beta-blocker (bisoprolol or metoprolol succinate) if heart rate >70 bpm
• Doxazosin (alpha-blocker)
• Clonidine patch (central alpha-agonist) if beta-blockers contraindicated

Target Blood Pressure and Timeline

Your target BP should be <130/80 mmHg for most patients, though <140/90 mmHg is acceptable minimum. 1, 2 Reassess BP within 2-4 weeks after adding spironolactone, with the goal of achieving target within 3 months of treatment modification. 2

Critical Lifestyle Reinforcement

Even with four medications, lifestyle modifications provide additive BP reduction of 10-20 mmHg: 2

• Sodium restriction to <2.3g/day (most impactful in resistant hypertension) 1, 2
• Weight loss if BMI >25 2
• Regular aerobic exercise (150 minutes moderate-intensity weekly) 2
• Alcohol limitation (<14 units/week for men, <8 for women) 2
• DASH diet pattern (high in fruits, vegetables, whole grains) 2

When to Refer to Specialist

Consider referral to a hypertension specialist if: 1, 2

• BP remains ≥160/100 mmHg despite four optimally dosed medications
• Multiple drug intolerances occur
• Suspicion for secondary hypertension (young age, sudden onset, hypokalemia, resistant to multiple agents)
• eGFR <30 mL/min/1.73m² complicating medication choices

Common Pitfalls to Avoid

• Do not add a fifth agent before optimizing spironolactone dosing to 50 mg daily (if tolerated) 1
• Do not assume treatment failure without confirming adherence—use pill counts, pharmacy refill records, or directly observed therapy if needed 1, 2
• Do not overlook secondary causes: screen for primary aldosteronism (especially given resistant hypertension), renal artery stenosis, obstructive sleep apnea, and pheochromocytoma 1
• Do not continue HCTZ if eGFR <30 mL/min/1.73m²—switch to loop diuretic instead 1

Evidence Supporting This Approach

The 2018 AHA Scientific Statement on resistant hypertension provides the most comprehensive algorithm, explicitly recommending spironolactone as the preferred fourth agent after optimized triple therapy (RAS blocker + CCB + diuretic). 1 This is reinforced by the 2020 ISH guidelines and European Society of Cardiology recommendations. 1, 2 Research evidence demonstrates that adding spironolactone to losartan/HCTZ/amlodipine combinations produces significant additional BP reductions with acceptable tolerability. 3, 4