What medication should be added next for resistant hypertension in a patient already taking losartan 100 mg daily, carvedilol (Coreg) 50 mg twice daily, amlodipine 10 mg daily, and doxazosin 4 mg at bedtime?

Add Spironolactone 25 mg Daily as the Fourth-Line Agent

For this patient with resistant hypertension on maximally-dosed losartan, carvedilol, amlodipine, and doxazosin, spironolactone 25 mg daily is the next medication to add. 1

Why Spironolactone is the Preferred Choice

Spironolactone has demonstrated superior efficacy in resistant hypertension, producing additional blood pressure reductions of approximately 20-25 mmHg systolic and 10-12 mmHg diastolic when added to triple therapy. 1 The American College of Cardiology and European Society of Cardiology both recommend spironolactone as the preferred fourth-line agent for resistant hypertension. 1

The underlying mechanism addresses a common cause of treatment resistance: occult volume expansion and aldosterone excess frequently underlie persistent hypertension despite multidrug regimens. 2, 1 Studies at Mayo Clinic found that patients with resistant hypertension often had unrecognized volume expansion, and blood pressure control improved primarily through increased diuresis. 2

Critical Steps Before Adding Spironolactone

1. Optimize the Diuretic Component First

Replace any standard thiazide with chlorthalidone 12.5-25 mg daily before adding a fourth agent. 1 Chlorthalidone provides significantly greater 24-hour ambulatory blood pressure reduction compared to hydrochlorothiazide and has superior cardiovascular outcome data. 2, 1 If the patient is not currently on a diuretic or is on suboptimal dosing, this must be corrected first—lack of adequate diuretic therapy is the most common modifiable factor in resistant hypertension. 2

2. Verify True Treatment Resistance

Perform 24-hour ambulatory blood pressure monitoring to exclude white-coat hypertension, which accounts for approximately 50% of apparent resistant cases. 1, 3 If ambulatory monitoring is unavailable, use home blood pressure monitoring (target <135/85 mmHg). 1

Confirm medication adherence—non-adherence is the single most common cause of apparent treatment resistance. 1 Use direct questioning, pill counts, or pharmacy refill records. 1

3. Address Lifestyle and Interfering Factors

Restrict dietary sodium to <2400 mg/day (ideally <1500 mg/day), as high sodium intake significantly contributes to treatment resistance and can produce 5-10 mmHg systolic reductions when corrected. 2, 1

Review for interfering medications: NSAIDs, decongestants, oral contraceptives, systemic corticosteroids, and herbal supplements (ephedra, St. John's wort) can all elevate blood pressure. 1

Assess alcohol intake—limit to ≤2 drinks/day for men and ≤1 drink/day for women. 1

4. Screen for Secondary Hypertension

Screen for primary aldosteronism using aldosterone-to-renin ratio, even with normal potassium levels. 1, 3 This is particularly important in younger patients (<30 years). 1

Evaluate for obstructive sleep apnea using Berlin Questionnaire or Epworth Sleepiness Score, confirming with polysomnography if suspected. 1, 3

Check baseline eGFR and TSH to evaluate renal function and thyroid dysfunction. 1, 3

Spironolactone Dosing and Monitoring

Start spironolactone 25 mg once daily. 1 The target dose is 25-50 mg daily. 1

Check serum potassium and creatinine 1-2 weeks after initiation, then regularly thereafter. 1 The combination of spironolactone with losartan (an ARB) significantly increases hyperkalemia risk. 1

Use caution if eGFR <45 mL/min/1.73m² due to heightened hyperkalemia risk. 1 Contraindications include baseline potassium ≥4.5 mmol/L or eGFR <45 mL/min/1.73m². 1

Alternative Fourth-Line Agents (If Spironolactone Contraindicated)

If spironolactone cannot be used due to hyperkalemia risk or renal dysfunction:

• Amiloride 5-10 mg daily as an alternative potassium-sparing diuretic 1
• Clonidine 0.1-0.3 mg twice daily (centrally acting agent, though higher adverse-effect profile) 1
• Hydralazine 25 mg three times daily, titrating upward as needed 1

Note that doxazosin is already part of this patient's regimen, so it cannot serve as an add-on option. 4

Blood Pressure Targets and Reassessment

Target blood pressure is <130/80 mmHg for most patients, with a minimum acceptable goal of <140/90 mmHg. 1

Reassess blood pressure within 2-4 weeks of adding spironolactone, with the goal of achieving target blood pressure within 3 months. 1

Common Pitfalls to Avoid

Do not add a fifth agent before optimizing the diuretic to chlorthalidone and ensuring adequate dosing. 2, 1 Evaluations of resistant hypertension consistently find that treatment resistance is often related to underuse of diuretic therapy. 2

Do not skip screening for secondary causes when blood pressure remains severely elevated despite four medications. 1, 3 Primary aldosteronism, renal artery stenosis, and obstructive sleep apnea are common and treatable. 1

Do not initiate spironolactone without confirming acceptable baseline potassium (<4.5 mmol/L) and renal function (eGFR ≥45 mL/min/1.73m²). 1

When to Refer to a Hypertension Specialist

Refer if blood pressure remains >130/80 mmHg after at least six months of optimized four-drug therapy, or if blood pressure remains ≥160/100 mmHg despite four drugs at optimal doses. 1 Hypertension specialists achieve blood pressure control in approximately 52-53% of resistant cases. 1