For an adult with uncontrolled hypertension despite hydrochlorothiazide therapy, what is the preferred next antihypertensive medication to add?

Next Antihypertensive After HCTZ Failure

Add either a calcium channel blocker (amlodipine 5-10mg daily) or an ACE inhibitor/ARB (e.g., lisinopril 10-20mg or losartan 50-100mg daily) to the existing HCTZ regimen to achieve guideline-recommended dual therapy. 1

Preferred Second Agent Selection

For Most Patients (Age <55, Non-Black)

• Add an ACE inhibitor (lisinopril 10-20mg daily) or ARB (losartan 50-100mg daily) as the second agent, creating the combination of RAS blocker + thiazide diuretic that targets both volume reduction and renin-angiotensin system blockade. 1
• If an ACE inhibitor causes cough (occurs in ~10-15% of patients), switch to an ARB rather than abandoning the class entirely. 1

For Patients Age ≥55 or Black Patients of Any Age

• Add a calcium channel blocker (amlodipine 5-10mg daily) as the preferred second agent, creating the combination of CCB + thiazide diuretic. 1
• This combination is particularly effective in elderly and Black patients due to the predominance of volume-dependent and low-renin hypertension in these populations. 1

Critical Step Before Adding Medication

• Replace HCTZ with chlorthalidone 12.5-25mg daily or indapamide 1.5mg daily before adding a second agent, as these thiazide-like diuretics provide superior 24-hour blood pressure control and stronger cardiovascular outcome data compared to HCTZ. 1, 2, 3
• Chlorthalidone produces significantly greater overnight and 24-hour ambulatory BP reduction than HCTZ at equipotent doses (chlorthalidone 25mg vs HCTZ 50mg). 1, 3
• If the patient is already stable on HCTZ with good control, continuation is acceptable, but for uncontrolled hypertension, substitution is preferred. 1

Progression to Triple Therapy

• If BP remains ≥140/90 mmHg after optimizing dual therapy, add the third agent from the remaining class (ACE inhibitor/ARB + CCB + thiazide diuretic) to achieve guideline-recommended triple therapy. 1, 2
• This triple combination targets three complementary mechanisms: renin-angiotensin system blockade, vasodilation, and volume reduction. 1, 2

Fourth-Line Agent for Resistant Hypertension

• Add spironolactone 25-50mg daily as the preferred fourth-line agent if BP remains ≥140/90 mmHg despite optimized triple therapy (ACE inhibitor/ARB + CCB + thiazide diuretic at maximal tolerated doses). 1, 2, 4
• Spironolactone produces additional reductions of approximately 20-25 mmHg systolic and 10-12 mmHg diastolic when added to triple therapy. 1, 2, 4
• Monitor serum potassium and creatinine 2-4 weeks after initiating spironolactone due to hyperkalemia risk, especially when combined with ACE inhibitors or ARBs. 1, 2, 4

Blood Pressure Targets and Monitoring

• Target BP <140/90 mmHg minimum, ideally <130/80 mmHg for most patients; higher-risk patients (diabetes, CKD, established CVD) should aim for <130/80 mmHg. 1, 2, 4
• Reassess BP within 2-4 weeks after adding each new agent, with the goal of achieving target BP within 3 months of therapy modification. 1, 2, 4

Essential Pre-Treatment Steps

• Verify medication adherence first, as non-adherence is the most common cause of apparent treatment resistance—use direct questioning, pill counts, or pharmacy refill records. 1, 2, 4
• Confirm true hypertension with home BP monitoring (≥135/85 mmHg) or 24-hour ambulatory monitoring (≥130/80 mmHg) to exclude white-coat hypertension before escalating therapy. 1, 2, 4
• Review for interfering medications: NSAIDs, decongestants, oral contraceptives, systemic corticosteroids, and herbal supplements (ephedra, licorice) can all elevate BP and undermine treatment. 1, 2

Lifestyle Modifications (Additive to Pharmacotherapy)

• Sodium restriction to <2g/day yields a 5-10 mmHg systolic reduction and enhances the efficacy of all antihypertensive classes, especially diuretics and RAS blockers. 1, 2, 4
• DASH dietary pattern reduces BP by approximately 11.4/5.5 mmHg (systolic/diastolic). 1
• Weight loss of ~10kg in overweight patients decreases BP by roughly 6.0/4.6 mmHg. 1
• Regular aerobic exercise (≥30 minutes most days) lowers BP by approximately 4/3 mmHg. 1
• Limit alcohol to ≤2 drinks/day for men, ≤1 drink/day for women. 1

Common Pitfalls to Avoid

• Do not add a beta-blocker as the second or third agent unless there are compelling indications (angina, post-MI, heart failure with reduced ejection fraction, atrial fibrillation requiring rate control), as beta-blockers are less effective than CCBs or diuretics for stroke prevention and cardiovascular events in uncomplicated hypertension. 1, 2
• Do not combine an ACE inhibitor with an ARB (dual RAS blockade), as this increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular benefit. 1, 2, 4
• Do not delay treatment intensification when BP remains ≥140/90 mmHg; prompt action within 2-4 weeks is required to reduce cardiovascular risk. 1, 2, 4
• Do not rely solely on dose escalation of HCTZ (e.g., increasing from 12.5mg to 25mg or 50mg) as the primary strategy; combination therapy with agents from different classes is more effective than monotherapy dose increases. 1

Special Populations

Black Patients

• The combination of CCB + thiazide diuretic may be more effective than CCB + ACE inhibitor/ARB in Black patients due to the higher prevalence of low-renin, volume-dependent hypertension. 1

Patients with CKD (eGFR <30 mL/min)

• Loop diuretics (furosemide 20-80mg twice daily or torsemide 5-10mg daily) may be necessary instead of thiazides for effective volume and BP control. 1
• Chlorthalidone maintains efficacy down to eGFR 30 mL/min/1.73m², making it preferable to HCTZ in moderate CKD. 2

Patients with Heart Failure

• If a CCB is required, use only dihydropyridines (amlodipine or felodipine); avoid non-dihydropyridines (diltiazem, verapamil) due to negative inotropic effects. 1