What second antihypertensive should be added to an adult patient on Losartan 100 mg daily with uncontrolled blood pressure and no severe renal impairment, gout, or sulfonamide allergy?

Second Antihypertensive to Add to Losartan 100 mg

Add either a calcium channel blocker (amlodipine 5–10 mg once daily) or a thiazide-like diuretic (chlorthalidone 12.5–25 mg once daily or hydrochlorothiazide 25 mg once daily) to achieve guideline-recommended dual therapy for uncontrolled hypertension. 1

Preferred Add-On Options

Calcium Channel Blocker (First Choice for Most Patients)

• Amlodipine 5–10 mg once daily provides complementary vasodilation through calcium channel blockade combined with losartan's renin-angiotensin system inhibition, creating an evidence-based dual therapy regimen. 1, 2
• This combination is particularly beneficial for patients with chronic kidney disease, diabetes, coronary artery disease, or heart failure, and may reduce amlodipine-related peripheral edema when paired with an ARB. 2
• The ARB + calcium channel blocker combination has demonstrated superior blood pressure control compared to either agent alone in patients with diabetes, chronic kidney disease, or heart failure. 2

Thiazide-Like Diuretic (Alternative First Choice)

• Chlorthalidone 12.5–25 mg once daily is preferred over hydrochlorothiazide due to its longer duration of action (24–72 hours versus 6–12 hours) and superior cardiovascular outcome data from the ALLHAT trial. 1, 2
• Hydrochlorothiazide 25 mg once daily is an acceptable alternative if chlorthalidone is unavailable, though it remains inferior to chlorthalidone for 24-hour blood pressure control. 2
• The ARB + thiazide diuretic combination is especially effective in elderly patients, Black patients, and those with volume-dependent hypertension. 2

Special Population Considerations

• For Black patients specifically, the combination of a calcium channel blocker plus a thiazide diuretic may be more effective than a calcium channel blocker plus an ARB. 1, 2
• For patients with compelling cardiovascular indications (heart failure with reduced ejection fraction, post-myocardial infarction, coronary artery disease), the ARB + calcium channel blocker combination is preferred. 2

Blood Pressure Targets and Monitoring

• Target blood pressure is <130/80 mmHg for most patients, with a minimum acceptable goal of <140/90 mmHg. 1, 2
• Reassess blood pressure within 2–4 weeks after adding the second agent, with the goal of achieving target blood pressure within 3 months of therapy modification. 1, 2
• Check serum potassium and creatinine 2–4 weeks after initiating a thiazide diuretic to detect hypokalemia or changes in renal function. 1, 2

Escalation to Triple Therapy (If Needed)

• If blood pressure remains uncontrolled after optimizing dual therapy, add the third agent from the remaining class (ARB + calcium channel blocker + 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, achieving blood pressure control in >80% of patients. 2

Fourth-Line Agent for Resistant Hypertension

• If blood pressure remains ≥140/90 mmHg despite optimized triple therapy, add spironolactone 25–50 mg daily as the preferred fourth-line agent, which provides additional reductions of approximately 20–25 mmHg systolic and 10–12 mmHg diastolic. 1, 2

Critical Pitfalls to Avoid

• Do not combine losartan with an ACE inhibitor (dual renin-angiotensin system blockade), as this increases adverse events such as hyperkalemia and acute kidney injury without additional cardiovascular benefit. 1, 2
• Do not add a beta-blocker as the second agent unless there are compelling indications (angina, post-myocardial infarction, heart failure with reduced ejection fraction, atrial fibrillation requiring rate control), as beta-blockers are less effective than calcium channel blockers or diuretics for stroke prevention and cardiovascular events. 1, 2
• Do not delay treatment intensification when blood pressure remains uncontrolled; prompt action within 2–4 weeks is required to reduce cardiovascular risk. 2
• Do not assume treatment failure without first confirming medication adherence and ruling out secondary causes of hypertension (primary aldosteronism, renal artery stenosis, obstructive sleep apnea) or interfering medications (NSAIDs, decongestants, oral contraceptives, systemic corticosteroids). 2

Verification Before Escalation

• Confirm true hypertension with home blood pressure monitoring (≥135/85 mmHg) or 24-hour ambulatory monitoring (≥130/80 mmHg) before adding a second agent to exclude white-coat hypertension. 2
• Verify medication adherence first, as non-adherence is the most common cause of apparent treatment resistance. 2

Adjunctive Lifestyle Modifications

• Sodium restriction to <2 g/day provides a 5–10 mmHg systolic reduction and enhances the efficacy of both ARBs and diuretics. 2
• Weight loss of approximately 10 kg reduces blood pressure by about 6.0/4.6 mmHg (systolic/diastolic). 2
• The DASH dietary pattern reduces blood pressure by roughly 11.4/5.5 mmHg. 2
• Regular aerobic exercise (≥30 minutes most days, approximately 150 minutes/week moderate intensity) lowers blood pressure by approximately 4/3 mmHg. 2
• Limit alcohol intake to ≤2 drinks/day for men and ≤1 drink/day for women. 2