What is the first‑line treatment for stage 2 hypertension (systolic ≥160 mm Hg or diastolic ≥100 mm Hg)?

First-Line Treatment for Stage 2 Hypertension

For stage 2 hypertension (≥140/90 mm Hg or ≥160/100 mm Hg), initiate combination therapy with two antihypertensive agents from different classes immediately at the first visit, along with lifestyle modifications. 1, 2, 3

Recommended Two-Drug Combinations

The preferred initial combinations are:

• ACE inhibitor (or ARB) + calcium channel blocker, OR 3
• ACE inhibitor (or ARB) + thiazide/thiazide-like diuretic 1, 3

Use single-pill combination formulations whenever possible to improve medication adherence. 3

Specific Agent Selection

For the thiazide component, chlorthalidone (12.5-25 mg daily) is preferred over hydrochlorothiazide due to its prolonged half-life and superior cardiovascular outcomes in clinical trials. 1, 4

Why Combination Therapy Over Monotherapy

Monotherapy fails to achieve blood pressure goals in up to 75% of patients with stage 2 hypertension and should not be used as initial treatment. 3, 4 Combination therapy provides:

• Greater systolic blood pressure reduction (approximately 8 mm Hg more than monotherapy at 6 weeks) 5
• Higher rates of blood pressure control (44.5% vs 29.1% reaching goal with combination vs monotherapy) 5
• Faster achievement of blood pressure targets 3
• Reduced therapeutic inertia and healthcare costs 4

Concurrent Lifestyle Modifications

Start lifestyle changes simultaneously with medications—do not delay pharmacotherapy while attempting lifestyle modifications alone. 3 Implement:

• Weight loss targeting BMI 20-25 kg/m² and waist circumference <94 cm (men) or <80 cm (women) 3
• DASH or Mediterranean diet with reduced saturated fat, increased fruits, vegetables, and low-fat dairy 3
• Sodium restriction and increased potassium intake 6
• Alcohol limitation to maximum 100 g/week of pure alcohol 3
• Physical activity: 150 minutes/week moderate-intensity aerobic exercise plus resistance training 2-3 times/week 3
• Tobacco cessation 6

Blood Pressure Target

Target systolic blood pressure of 120-129 mm Hg if well tolerated, or at minimum <140/90 mm Hg. 3 For patients with diabetes or chronic kidney disease, target <130/80 mm Hg. 1

Follow-Up Schedule

• Recheck blood pressure in 1 month after initiating therapy 1, 3
• Monitor electrolytes and renal function 2-4 weeks after starting ACE inhibitor, ARB, or diuretic 1, 3
• Continue monthly follow-up until blood pressure is controlled 1
• Achieve blood pressure control within 3 months of initial diagnosis 3

Escalation Strategy if Uncontrolled

If blood pressure remains ≥140/90 mm Hg on two-drug combination after 1 month, add a third agent to create triple therapy: ACE inhibitor/ARB + calcium channel blocker + thiazide diuretic. 3 Continue follow-up every 1-3 months until controlled. 2

For resistant hypertension (uncontrolled on three drugs), add spironolactone as the fourth agent. 2

Special Population Considerations

For patients with coronary artery disease: Prioritize ACE inhibitor or ARB as one of the initial agents. 2, 3

For patients with diabetes, chronic kidney disease, or albuminuria (UACR ≥30 mg/g): Include ACE inhibitor or ARB in the initial combination to reduce progressive kidney disease risk. 2, 3

For pregnant women or those planning pregnancy: Completely avoid ACE inhibitors, ARBs, mineralocorticoid receptor antagonists, and direct renin inhibitors due to fetal injury and death risk. 2, 3

For patients ≥85 years or with moderate-to-severe frailty: Consider single-agent therapy instead of combination therapy. 3

For black patients: Combination therapy shows particularly robust efficacy, with 41.8% achieving blood pressure goals versus only 19.1% with monotherapy. 5

For obese patients (BMI ≥30 kg/m²): Combination therapy achieves significantly better blood pressure reduction than monotherapy (-23.6 vs -15.9 mm Hg). 5

Critical Pitfalls to Avoid

Never combine two RAS blockers (ACE inhibitor + ARB + renin inhibitor)—this is potentially harmful. 3

Do not use monotherapy for stage 2 hypertension, as it delays blood pressure control and leaves patients at unnecessary cardiovascular risk. 3, 4

Avoid beta-blocker + thiazide diuretic combinations as initial therapy, as this may cause more adverse effects than other combinations. 4

For patients with very high blood pressure (≥180/110 mm Hg): Initiate prompt treatment with careful monitoring and be prepared for upward dose adjustment as necessary. 1

Tolerability

Combination therapy is generally well tolerated, with the main adverse effect being increased dizziness (8.5% vs 4.7% with monotherapy), though this difference is modest. 5 The combination of ACE inhibitor/ARB with calcium channel blocker may have similar or fewer adverse effects than other combinations. 4