What is the first line of treatment for an adult patient with uncontrolled hypertension?

First-Line Treatment for Uncontrolled Hypertension

For most adults with uncontrolled hypertension, initiate treatment with a thiazide or thiazide-like diuretic, specifically chlorthalidone 12.5-25 mg once daily, as this agent has the strongest evidence for reducing cardiovascular mortality, stroke, and heart failure. 1, 2, 3

Treatment Stratification by Blood Pressure Stage

Stage 1 Hypertension (130-139/80-89 mmHg)

• For patients with 10-year ASCVD risk ≥10%, established cardiovascular disease, diabetes, or chronic kidney disease: Start single-agent pharmacotherapy immediately alongside lifestyle modifications 1, 3

• For patients with 10-year ASCVD risk <10%: Begin with lifestyle modifications alone for up to 3 months, then add pharmacotherapy if blood pressure remains uncontrolled 1

Stage 2 Hypertension (≥140/90 mmHg)

• Initiate two-drug combination therapy immediately from different first-line classes, preferably as a single-pill combination to improve adherence 1, 4

• Effective combinations include: ACE inhibitor/ARB + thiazide diuretic, ACE inhibitor/ARB + calcium channel blocker, or calcium channel blocker + thiazide diuretic 1, 4

Hypertensive Emergency (≥180/110 mmHg)

• Requires prompt evaluation and immediate antihypertensive drug treatment, typically with two agents 1

First-Line Medication Classes

The four evidence-based first-line classes are equally acceptable, but thiazide diuretics hold the strongest overall evidence 1, 5:

Thiazide/Thiazide-Like Diuretics (Preferred for Most Patients)

• Chlorthalidone 12.5-25 mg once daily is superior to hydrochlorothiazide due to longer half-life and stronger cardiovascular outcome data from the ALLHAT trial 1, 2, 4, 6

• Chlorthalidone demonstrated superiority over lisinopril for stroke prevention and over amlodipine for heart failure prevention in head-to-head trials 2, 6

• Monitor for hypokalemia, hyponatremia, hyperuricemia, and hyperglycemia 1

ACE Inhibitors

• Lisinopril 10-40 mg once daily or other ACE inhibitors are appropriate alternatives 1, 7

• Monitor serum creatinine and potassium within 7-14 days of initiation 2, 3

• Contraindicated in pregnancy and history of angioedema 1, 2

Angiotensin Receptor Blockers (ARBs)

• Losartan 50-100 mg once daily or other ARBs provide similar efficacy to ACE inhibitors 1

• Preferred over ACE inhibitors if patient has ACE inhibitor-induced cough 1

Long-Acting Dihydropyridine Calcium Channel Blockers

• Amlodipine 5-10 mg once daily is equally effective as thiazides for all cardiovascular events except heart failure 1, 2

Special Population Considerations

Black Patients Without Heart Failure or CKD

• Start with calcium channel blocker or thiazide diuretic rather than ACE inhibitor or ARB as monotherapy, as these are more effective in this population 2, 3, 7

• ACE inhibitors and ARBs remain appropriate as part of combination therapy 1

Patients With Albuminuria or Chronic Kidney Disease

• ACE inhibitor or ARB is mandatory first-line therapy to provide renoprotection beyond blood pressure reduction alone 1, 2, 3

• These agents slow progression of kidney disease and reduce proteinuria 1, 2

Patients With Diabetes

• All four first-line classes are equally effective 1, 2

• If albuminuria is present, ACE inhibitor or ARB becomes mandatory 1, 2

• Target blood pressure is <130/80 mmHg 1

Patients With Established Coronary Artery Disease

• ACE inhibitor or ARB is preferred first-line therapy 2

Blood Pressure Targets

• General population: <140/90 mmHg (strong recommendation) 1

• Patients with known cardiovascular disease: <130/80 mmHg (strong recommendation) 1, 3

• High-risk patients (diabetes, CKD, 10-year ASCVD risk ≥10%): <130/80 mmHg (conditional recommendation) 1, 3

• Adults ≥65 years: systolic <130 mmHg 3, 5

Critical Contraindications and Pitfalls

• Never combine ACE inhibitor + ARB + renin inhibitor simultaneously, as this increases adverse effects without cardiovascular benefit 1, 2

• Avoid ACE inhibitors and ARBs in pregnancy and women of childbearing potential not using reliable contraception 1, 2

• Discontinue or reduce ACE inhibitor/ARB if potassium >5.5 mEq/L or creatinine increases >30% from baseline 2

• Ensure adequate diuretic dosing before declaring treatment resistance—inadequate diuretic therapy is a common cause of apparent resistant hypertension 1, 8

Follow-Up Protocol

• Reassess monthly after medication initiation or dose changes until target blood pressure is achieved 1, 3

• Check electrolytes and renal function within 7-14 days when starting ACE inhibitors, ARBs, or diuretics 2, 3

• Once controlled, follow up every 3-5 months 1, 3

• Confirm diagnosis with out-of-office blood pressure measurements (home or ambulatory monitoring) to exclude white coat hypertension 1

Lifestyle Modifications (Essential Adjunct to All Pharmacotherapy)

• Dietary sodium restriction to <2,300 mg/day 2

• Weight loss if overweight (target BMI <25 kg/m²) 2, 5

• DASH dietary pattern with increased potassium intake 2, 4, 5

• Aerobic exercise (150 minutes/week of moderate-intensity activity) 2, 5

• Alcohol limitation (≤14 drinks/week for men, ≤9 drinks/week for women) 2

• Smoking cessation 2

When to Escalate Therapy

• If blood pressure remains uncontrolled after 2-4 weeks on monotherapy at optimal dose, add a second agent from a different class rather than continuing to wait 2

• If blood pressure remains uncontrolled on two-drug therapy, add a third agent, typically a mineralocorticoid receptor antagonist (spironolactone) for resistant hypertension 1, 8

• Consider referral to hypertension specialist if blood pressure remains uncontrolled on three or more agents at optimal doses 1, 9