What is the drug of choice for initial treatment of hypertension?

Drug of Choice for Hypertension

Thiazide-type diuretics, specifically chlorthalidone 12.5-25 mg daily, are the optimal first-line drug for initial treatment of hypertension in most patients, with calcium channel blockers (CCBs) as the preferred alternative when diuretics are not tolerated. 1

Initial Treatment Strategy Based on Blood Pressure Stage

For Stage 1 Hypertension:

• Initiate with a single antihypertensive agent and titrate dosage before adding sequential agents to reach BP target <130/80 mmHg 1

For Stage 2 Hypertension (BP >20/10 mmHg above target):

• Start with 2 first-line agents of different classes, either as separate medications or fixed-dose combination 1
• This approach is particularly important in older patients, though careful BP monitoring is needed to avoid hypotension 1

First-Line Medication Classes: The Evidence Hierarchy

Thiazide-Type Diuretics (Preferred):

• Chlorthalidone 12.5-25 mg daily is superior to other first-line agents based on the largest head-to-head trial (ALLHAT) 1
• Chlorthalidone demonstrated superiority over amlodipine for heart failure prevention (38% lower risk) and over lisinopril for stroke prevention (15% lower risk) 1, 2
• Diuretics are significantly more effective than CCBs for preventing heart failure and more effective than beta-blockers for preventing stroke and cardiovascular events 1
• Chlorthalidone is more potent than hydrochlorothiazide, particularly for 24-hour BP control and nighttime BP reduction 3, 4, 2
• Low-dose chlorthalidone (even 6.25 mg daily) significantly reduces 24-hour ambulatory BP, while hydrochlorothiazide 12.5 mg does not provide adequate 24-hour coverage 4

Calcium Channel Blockers (Alternative First-Line):

• CCBs are as effective as diuretics for all cardiovascular events except heart failure 1
• Amlodipine is the preferred CCB and should be used when thiazide diuretics are not tolerated 1
• Previous safety concerns about CCBs have been definitively resolved; they do not increase cancer or gastrointestinal bleeding risk 1

ACE Inhibitors and ARBs (Conditional First-Line):

• These agents are generally equivalent to diuretics and CCBs for most cardiovascular outcomes but with important exceptions 1
• ACE inhibitors are less effective than thiazide diuretics and CCBs for stroke prevention 1
• ACE inhibitors are less effective than CCBs for heart failure prevention 1

Population-Specific Recommendations

Black Patients Without Comorbidities:

• Initiate with thiazide diuretic (especially chlorthalidone) or CCB 1, 5
• ACE inhibitors are notably less effective than CCBs and thiazides for stroke prevention (15% higher stroke risk) and heart failure prevention (19% higher risk) in this population 1, 5
• ARBs may be better tolerated than ACE inhibitors (less cough and angioedema) but offer no proven advantage over ACE inhibitors for cardiovascular outcomes 1

Patients With Diabetes:

• ACE inhibitors or ARBs are preferred initial agents, particularly when albuminuria or established coronary artery disease is present 1, 5
• However, a low-dose thiazide diuretic should generally be one of the first two drugs used regardless of initial choice 1
• Multiple drug classes (thiazides, ACE inhibitors, ARBs, CCBs, beta-blockers) have demonstrated cardiovascular benefits in diabetic patients 1

Patients With Chronic Kidney Disease:

• ACE inhibitors or ARBs are preferred to reduce progressive kidney disease, especially with albuminuria 5
• Monitor serum creatinine, eGFR, and potassium within 7-14 days after initiation 5

Patients With Heart Failure:

• Thiazide diuretics and ACE inhibitors are more effective than CCBs for heart failure prevention 1
• Low-dose diuretics have been shown more effective than ACE inhibitors, beta-blockers, or CCBs for preventing heart failure development 1

Medications to Avoid as First-Line Therapy

Beta-Blockers:

• Not recommended for uncomplicated hypertension due to inferior efficacy 1, 5
• 36% less effective than CCBs and 30% less effective than thiazides for stroke prevention 1, 5
• Significantly less effective than diuretics for preventing stroke and cardiovascular events overall 1

Alpha-Blockers:

• Not used as first-line therapy due to inferior cardiovascular disease prevention 1, 5
• In ALLHAT, doxazosin doubled heart failure risk compared to chlorthalidone and showed 20% higher rates of cardiovascular disease and stroke 1

Critical Pitfalls and Monitoring

Chlorthalidone vs. Hydrochlorothiazide:

• Most clinicians incorrectly assume these are interchangeable 3
• Chlorthalidone has a 40-60 hour half-life compared to hydrochlorothiazide's shorter duration 2
• Hydrochlorothiazide 12.5 mg monotherapy does not provide adequate 24-hour BP control and converts sustained hypertension into masked hypertension 4
• If using hydrochlorothiazide, doses of 25-50 mg are needed, but chlorthalidone 12.5-25 mg remains superior 3, 2

Electrolyte Monitoring:

• Maintain potassium >3.5 mmol/L when using thiazide diuretics to avoid increased ventricular ectopy 5
• Monitor potassium and renal function within 7-14 days after starting diuretics, ACE inhibitors, or ARBs 1, 5
• Thiazide-induced hypokalemia is associated with increased blood glucose; treating hypokalemia may reverse glucose intolerance 2

Drug Interactions:

• NSAIDs blunt thiazide effectiveness 2
• Combining thiazides with beta-blockers may increase fatigue, lethargy, and glucose levels 2
• Never combine ACE inhibitors with ARBs due to lack of added benefit and increased adverse events 5

Uric Acid Considerations:

• Thiazide-induced hyperuricemia does not contraindicate thiazide use, especially if allopurinol is being used 2

Why This Recommendation Prioritizes Morbidity and Mortality

The recommendation for thiazide diuretics, particularly chlorthalidone, is based on superior outcomes in the largest head-to-head trial (ALLHAT with 42,418 participants) showing reduced heart failure, stroke, and combined cardiovascular disease compared to newer agents 1, 6. Extended follow-up (8-13 years) confirmed these benefits persist beyond the active treatment period 6. This mortality and morbidity benefit, combined with low cost and proven efficacy across diverse populations, makes thiazide diuretics the evidence-based first choice for most patients with hypertension 1.