Initial Management of Primary Hypertension in Adults
Start with Two Medications Immediately for Stage 2 Hypertension
For adults with blood pressure ≥140/90 mmHg, initiate combination therapy with two first-line agents from different classes at the first visit, preferably as a single-pill formulation. 1, 2 This approach achieves faster blood pressure control, reduces cardiovascular events more rapidly than sequential monotherapy, and improves medication adherence. 2, 3
First-Line Drug Selection by Population
General (Non-Black) Adult Population
Chlorthalidone 12.5–25 mg daily is the optimal first-line agent because the ALLHAT trial (>50,000 participants) demonstrated superior prevention of heart failure compared with amlodipine and superior stroke prevention compared with lisinopril. 1, 2, 4 Chlorthalidone provides 24-hour blood pressure control due to its 40–60 hour half-life and has the strongest cardiovascular outcome evidence among all antihypertensive classes. 2, 4
For Stage 2 hypertension (≥140/90 mmHg), combine:
- Chlorthalidone 12.5–25 mg + amlodipine 5 mg daily, or 2, 4
- Chlorthalidone 12.5–25 mg + lisinopril 10 mg daily 2, 4
Both combinations are delivered preferably as single-pill formulations. 2, 3
Black Patients Without Heart Failure or CKD
Initiate a thiazide diuretic (chlorthalidone) + calcium-channel blocker (amlodipine) rather than an ACE inhibitor or ARB. 1, 2 ACE inhibitors are approximately 30–36% less effective than thiazides and CCBs for stroke prevention in Black patients due to lower renin activity. 1, 3 ARBs cause less cough and angioedema than ACE inhibitors but offer no additional cardiovascular benefit over thiazide/CCB combinations in this population. 1
Patients with Diabetes Mellitus
Start an ACE inhibitor (lisinopril 10 mg daily) or ARB (losartan 50 mg daily) as the initial agent to protect renal function, especially when albuminuria ≥30 mg/g is present. 2, 3, 4 Target blood pressure <130/80 mmHg. 2, 3
Patients with Chronic Kidney Disease (Stage 3+ or Albuminuria ≥300 mg/day)
An ACE inhibitor or ARB is mandatory as first-line therapy to slow eGFR decline and reduce proteinuria. 2, 3 Thiazide diuretics remain effective even when eGFR <30 mL/min/1.73 m² and should not be avoided. 2
Post-Myocardial Infarction or Stable Ischemic Heart Disease
Combine a beta-blocker with an ACE inhibitor or ARB as foundational therapy; continue the beta-blocker for at least 3 years post-MI. 2, 3 If angina persists and blood pressure remains uncontrolled, add amlodipine. 2, 3 Target <130/80 mmHg. 2, 3
Monotherapy Strategy for Stage 1 Hypertension
For blood pressure 130–139/80–89 mmHg, start single-agent therapy only if the patient has established cardiovascular disease or 10-year ASCVD risk ≥10% (ACC/AHA Pooled Cohort Equations). 2, 3, 4 Begin with chlorthalidone 12.5 mg daily, titrate upward, and add a second agent from a different class if blood pressure remains uncontrolled after 2–4 weeks. 2, 4
For patients with Stage 1 hypertension and ASCVD risk <10%, implement lifestyle modifications alone for 3–6 months before considering pharmacotherapy. 2, 3
Lifestyle Modifications (All Patients with BP ≥120/80 mmHg)
Lifestyle changes enhance drug efficacy and should be initiated concurrently with pharmacotherapy, not sequentially. 2, 5
- Weight loss to BMI 20–25 kg/m²: A 10-kg reduction lowers blood pressure by approximately 6/5 mmHg. 2, 5
- DASH diet (8–10 servings fruits/vegetables, 2–3 servings low-fat dairy daily): Reduces blood pressure by 11/5 mmHg. 2, 5, 6
- Sodium restriction to <2,300 mg/day (≈5 g salt): Achieves a 5–10 mmHg systolic reduction. 2, 5, 6
- Potassium supplementation through diet (fruits/vegetables): Enhances blood pressure lowering. 2, 6
- Aerobic exercise ≥150 minutes/week (moderate intensity): Decreases blood pressure by ~4/3 mmHg. 2, 5, 6
- Alcohol restriction (≤2 drinks/day for men, ≤1 drink/day for women): Prevents interference with blood pressure control. 2, 5, 6
- Smoking cessation: Independently reduces cardiovascular mortality. 2, 7
Blood Pressure Targets
Target <130/80 mmHg for most adults <65 years, including those with diabetes, CKD, or established cardiovascular disease. 2, 3, 5 For adults ≥65 years, aim for systolic <130 mmHg if tolerated. 2, 3 The European Society of Cardiology recommends an optimal range of 120–129/70–79 mmHg for most adults when treatment is well tolerated. 2, 3
Avoid lowering diastolic pressure below 60–70 mmHg in high-risk patients (especially those with coronary artery disease), as excessive reduction may increase adverse cardiovascular events. 2, 3
Expected Blood Pressure Reduction by Drug Class
Each first-line drug class (thiazide diuretics, ACE inhibitors, ARBs, long-acting dihydropyridine CCBs) produces comparable office blood pressure reductions of approximately 9/5 mmHg and ambulatory reductions of 5/3 mmHg when used as monotherapy. 3, 5 A 10 mmHg systolic reduction decreases cardiovascular events by 20–30%. 5
Combination therapy using two submaximal doses from different classes yields larger blood pressure reductions with fewer adverse effects than maximal dosing of a single agent. 2, 3
Monitoring and Follow-Up
- Recheck blood pressure 1 month after initiating or adjusting therapy. 2, 3, 4
- Check serum creatinine, eGFR, sodium, and potassium within 7–14 days when starting ACE inhibitors, ARBs, or diuretics. 2, 3
- An increase in serum creatinine up to 50% above baseline or to 3 mg/dL (whichever is greater) is acceptable when starting ACE inhibitors or ARBs. 3
- Continue monthly follow-up until blood pressure target is achieved, then every 3–5 months for maintenance. 2, 3, 4
- Dose adjustments should be spaced at least 4 weeks apart to allow full blood pressure response. 3
Escalation to Triple Therapy
If blood pressure remains ≥130/80 mmHg on two optimized agents, add a third first-line drug (ACE inhibitor/ARB + CCB + thiazide diuretic), preferably as a single-pill combination. 2, 3 For apparent resistant hypertension (uncontrolled on three drugs including a diuretic), verify adherence, switch to chlorthalidone if not already used, and add spironolactone 25 mg daily (expected additional reduction ≈20/10 mmHg). 2, 3
Critical Pitfalls to Avoid
- Do not delay pharmacotherapy for lifestyle modification trials in patients with BP ≥140/90 mmHg; start medications concurrently with lifestyle changes. 2, 3
- Do not use monotherapy for Stage 2 hypertension (≥140/90 mmHg); dual therapy is required. 2, 3, 4
- Never combine an ACE inhibitor with an ARB (or add a direct renin inhibitor); this increases hyperkalemia and acute kidney injury without added cardiovascular benefit. 2, 3
- Do not use beta-blockers as first-line therapy in uncomplicated hypertension, especially in patients >60 years; they are 36% less effective than CCBs and 30% less effective than thiazides for stroke prevention. 1, 2, 3
- Avoid alpha-blockers (doxazosin) as first-line agents; they are less effective for cardiovascular disease prevention than thiazide diuretics. 1, 2
- Prefer chlorthalidone over hydrochlorothiazide when available for superior 24-hour blood pressure control and cardiovascular outcomes. 1, 2, 4
- Confirm medication adherence before labeling treatment as failure. 2, 3
- Exclude white-coat hypertension with out-of-office monitoring (home BP ≥135/85 mmHg or 24-hour ambulatory BP ≥130/80 mmHg) before initiating therapy in low-risk patients. 2, 3
Special Populations
Pregnancy
Switch to methyldopa, extended-release nifedipine, or labetalol immediately. 2, 3 ACE inhibitors, ARBs, and direct renin inhibitors are absolutely contraindicated due to fetal toxicity and death. 2, 3
Older Adults (≥85 years)
Continue blood pressure-lowering therapy lifelong if well tolerated; asymptomatic orthostatic hypotension alone should not prompt withdrawal. 2, 3