What is the appropriate third agent in a triple‑therapy antihypertensive regimen when a thiazide diuretic is contraindicated (e.g., because of gout)?

Third Agent in Triple Therapy When Diuretics Are Contraindicated

When a thiazide diuretic cannot be used in triple therapy (e.g., due to gout), a beta-blocker should be added as the third agent to the combination of an ACE inhibitor (or ARB) and a calcium channel blocker. 1

Standard Triple Therapy Framework

The foundation of triple antihypertensive therapy consists of three complementary mechanisms 1:

• Renin-angiotensin system (RAS) blocker: ACE inhibitor or ARB
• Calcium channel blocker (CCB): Preferably a dihydropyridine (e.g., amlodipine)
• Diuretic: Thiazide or thiazide-like agent (chlorthalidone, indapamide)

This combination is recommended because each class targets different pathophysiological mechanisms, providing additive blood pressure reduction 1, 2.

When Diuretics Are Contraindicated

Primary Alternative: Beta-Blocker

Beta-blockers represent the most evidence-based third agent when diuretics must be avoided 1. The 2018 AHA Scientific Statement on Resistant Hypertension explicitly includes beta-blockers in the treatment algorithm as Step 4 therapy, and the 2007 AHA guidelines support their use in triple combinations 1.

Preferred beta-blockers include 1:

• Metoprolol succinate (long-acting formulation)
• Bisoprolol
• Carvedilol or labetalol (combined alpha-beta blockers for additional vasodilation)

Clinical Considerations for Beta-Blocker Selection

Beta-blockers are particularly indicated when patients have 1:

• Coronary artery disease or stable angina
• History of myocardial infarction
• Heart failure with reduced ejection fraction
• Atrial fibrillation requiring rate control

Important contraindications and cautions 1:

• Avoid in patients with bradycardia (heart rate <60 bpm)
• Contraindicated with left ventricular dysfunction when using non-dihydropyridine CCBs (diltiazem, verapamil)
• Must be tapered rather than stopped abruptly to avoid rebound hypertension 1

Alternative Third Agents in Specific Scenarios

Mineralocorticoid Receptor Antagonist (MRA)

Spironolactone or eplerenone can serve as the third agent, particularly in patients with 1, 3:

• Obesity-related hypertension (aldosterone-mediated sodium retention)
• Low-renin hypertension
• Gout or hyperuricemia (spironolactone has minimal gout risk with OR 1.06) 3, 4

Dosing for spironolactone: 25-50 mg daily 1, 5

Critical monitoring requirements 1:

• Check potassium and creatinine at 2-4 weeks after initiation
• Avoid if eGFR <30 mL/min/1.73 m² without close monitoring
• Risk of hyperkalemia increases when combined with ACE inhibitors or ARBs

Non-Dihydropyridine Calcium Channel Blockers

Diltiazem or verapamil can substitute for beta-blockers only if 1:

• Beta-blockers are contraindicated or cause intolerable side effects
• Patient does NOT have bradycardia
• Patient does NOT have left ventricular dysfunction

This combination (RAS blocker + dihydropyridine CCB + non-dihydropyridine CCB) is less commonly used but physiologically rational 1.

Special Consideration: Gout as the Contraindication

When gout specifically contraindicates diuretic use, the optimal regimen becomes 3, 4:

1. Losartan (preferred ARB with uricosuric properties, 100 mg daily)
2. Calcium channel blocker (amlodipine 5-10 mg daily)
3. Spironolactone (25-50 mg daily) OR beta-blocker

Losartan uniquely lowers serum uric acid by 20-47 μmol/L while controlling blood pressure, making it the preferred RAS blocker in this scenario 3, 4.

Common Pitfalls to Avoid

• Do not combine beta-blockers with non-dihydropyridine CCBs (diltiazem, verapamil) due to excessive bradycardia and heart block risk 1
• Do not use hydralazine or minoxidil as third agents without first optimizing standard triple therapy; these require concomitant beta-blocker and diuretic to prevent reflex tachycardia and fluid retention 1
• Do not assume all CCBs are interchangeable; dihydropyridines (amlodipine) can be safely combined with beta-blockers, while non-dihydropyridines cannot 1
• Monitor heart rate before adding beta-blockers; if baseline heart rate is <70 bpm, consider MRA instead 1

Practical Algorithm

Step 1: Confirm ACE inhibitor/ARB + dihydropyridine CCB are at maximum tolerated doses 1

Step 2: Assess for compelling indications 1:

• If coronary disease, prior MI, or heart failure → Add beta-blocker
• If obesity, low-renin state, or gout → Add spironolactone
• If neither → Beta-blocker is preferred based on broader evidence base

Step 3: Monitor response at 2-4 weeks with home blood pressure readings and assess for adverse effects 1