What is the recommended first‑line antihypertensive therapy for an adult with primary hypertension, taking into account common comorbidities and demographic factors?

First-Line Antihypertensive Therapy for Primary Hypertension

For adults with primary hypertension, initiate treatment with a thiazide or thiazide-like diuretic (preferably chlorthalidone), ACE inhibitor, ARB, or long-acting dihydropyridine calcium channel blocker, with thiazide diuretics offering the strongest evidence for cardiovascular outcomes including superior heart failure and stroke prevention. 1, 2

Treatment Initiation Strategy Based on Blood Pressure Stage

Stage 1 Hypertension (130–139/80–89 mm Hg)

• Start with single-agent monotherapy and titrate upward before adding a second drug from a different class. 1, 2
• Initiate pharmacologic therapy when the patient has:
  • Established atherosclerotic cardiovascular disease (ASCVD), or
  • 10-year ASCVD risk ≥10% using the ACC/AHA Pooled Cohort Equations, or
  • Diabetes mellitus, or
  • Chronic kidney disease (CKD) stage 3 or higher. 2

Stage 2 Hypertension (≥140/90 mm Hg or >20/10 mm Hg Above Goal)

• Begin with two-drug combination therapy from different first-line classes, preferably as a single-pill formulation to improve adherence. 1, 2
• Preferred two-drug combinations:
  • Thiazide diuretic + ACE inhibitor or ARB, or
  • Calcium channel blocker + ACE inhibitor or ARB. 2

First-Line Drug Class Selection by Population

General Adult Population (Non-Black, No Compelling Indications)

• Thiazide diuretics (especially chlorthalidone) are optimal first-line agents based on the highest-quality evidence from trials involving >50,000 patients. 1, 3
• In the ALLHAT trial, chlorthalidone was superior to lisinopril in preventing stroke and superior to amlodipine in preventing heart failure. 1, 3
• A 2025 real-world cohort study of 97,639 patients confirmed thiazides had the lowest risk for the composite outcome of MI, ACS, stroke, or heart failure compared to all other classes. 4
• ACE inhibitors, ARBs, and calcium channel blockers are acceptable alternatives when thiazides cannot be used, with similar cardiovascular outcomes. 2, 5

Black Patients Without Heart Failure or CKD

• Initiate with a thiazide diuretic or calcium channel blocker as first-line therapy. 1, 2
• ACE inhibitors and ARBs are less effective in Black patients for stroke prevention and blood pressure reduction due to lower renin activity. 1
• ARBs may be better tolerated than ACE inhibitors (less cough and angioedema) but offer no proven cardiovascular advantage in this population. 1

Patients with Diabetes Mellitus

• Prefer an ACE inhibitor or ARB as initial therapy. 1, 2
• All four first-line classes (thiazides, ACE inhibitors, ARBs, CCBs) are effective and appropriate. 1
• In the presence of albuminuria ≥300 mg/day, ACE inhibitors or ARBs should be considered to reduce kidney disease progression. 1

Patients with Chronic Kidney Disease (Stage 3+ or Albuminuria)

• ACE inhibitor or ARB is first-line to slow eGFR decline and reduce proteinuria. 1, 2
• Thiazide diuretics remain effective in advanced CKD (eGFR <30 mL/min/1.73m²) and should not be avoided based solely on reduced eGFR. 1

Patients with Stable Ischemic Heart Disease or Post-MI

• Combine a β-blocker with an ACE inhibitor or ARB as initial therapy. 2
• Target blood pressure <130/80 mm Hg. 1, 2

Patients with Heart Failure with Reduced Ejection Fraction

• Use a three-drug regimen: ACE inhibitor or ARB + β-blocker + diuretic. 2

Older Adults (≥65 Years, Ambulatory, Non-Institutionalized)

• Target systolic blood pressure <130 mm Hg when baseline systolic is ≥130 mm Hg. 2
• Exercise caution when initiating combination therapy in those at risk for orthostatic hypotension. 2
• Virtually all adults ≥70 years have 10-year ASCVD risk ≥10% and qualify for pharmacologic treatment at stage 1 hypertension. 2

Blood Pressure Treatment Targets

• General adult population: <130/80 mm Hg. 1, 2
• Diabetes mellitus: <130/80 mm Hg. 1, 2
• Chronic kidney disease: <130/80 mm Hg. 1
• Stable ischemic heart disease: <130/80 mm Hg. 1, 2
• Post-stroke or TIA: <130/80 mm Hg may be reasonable. 1
• Avoid excessive diastolic lowering: Do not reduce diastolic pressure below 60–70 mm Hg in high-risk patients; optimal diastolic range is 70–79 mm Hg. 2

Drugs to Avoid as First-Line Therapy

• β-blockers should not be used as first-line therapy in uncomplicated hypertension, especially in patients >60 years, because they are 36% less effective than calcium channel blockers and 30% less effective than thiazides for stroke prevention. 1, 2
• β-blockers are reserved for compelling indications: post-MI, stable ischemic heart disease, or heart failure with reduced ejection fraction. 2
• Alpha-blockers are not first-line agents because they are less effective for cardiovascular disease prevention than thiazide diuretics. 1
• Clonidine should never be used as initial therapy due to significant CNS adverse effects, rebound hypertension risk, and lack of guideline support; it is reserved only for resistant hypertension after failure of first-line agents. 6

Monitoring and Follow-Up

• Review patients monthly after initiating or adjusting antihypertensive therapy until the blood pressure target is achieved. 2
• Once at target, conduct follow-up every 3–5 months. 2
• Baseline laboratory evaluation: serum creatinine, eGFR, potassium, fasting glucose, and lipid panel. 2
• When prescribing ACE inhibitors, ARBs, or diuretics, repeat creatinine, eGFR, and potassium within 1–2 weeks of initiation, after each dose increase, and annually thereafter. 2
• An increase in serum creatinine up to 50% above baseline or to 3 mg/dL (whichever is greater) is acceptable. 2
• Out-of-office blood pressure monitoring (home or ambulatory) is essential to assess treatment response, detect white-coat effect, and identify masked uncontrolled hypertension. 2

Critical Pitfalls to Avoid

• Delaying combination therapy in stage 2 hypertension (≥140/90 mm Hg) increases cardiovascular risk; always start with two drugs. 2
• Using β-blockers as first-line agents in patients >60 years without a compelling indication leads to inferior stroke prevention. 2
• Combining an ACE inhibitor with an ARB (or adding a direct renin inhibitor) should be avoided due to increased risk of hyperkalemia and acute kidney injury without added cardiovascular benefit. 1, 2
• Prescribing clonidine as initial therapy violates all major hypertension guidelines and exposes patients to unnecessary CNS adverse effects and rebound hypertension risk. 6
• Never prescribe clonidine PRN for blood pressure control; this creates life-threatening rebound hypertension risk. 6
• Continuing ACE inhibitors or ARBs during pregnancy is absolutely contraindicated due to fetal toxicity; switch to methyldopa, nifedipine, or labetalol. 2
• Excessive diastolic lowering below 60 mm Hg in high-risk patients may increase adverse cardiovascular events. 2
• Failing to employ out-of-office blood pressure monitoring can miss white-coat or masked hypertension, compromising management. 2