What are the criteria for selecting among ACE (Angiotensin-Converting Enzyme) inhibitors, ARBs (Angiotensin Receptor Blockers), calcium channel blockers, and thiazide diuretics as first-line monotherapy for hypertension?

Selecting First-Line Monotherapy for Hypertension

Primary Decision Framework

The choice among ACE inhibitors, ARBs, calcium channel blockers, and thiazide diuretics as first-line monotherapy depends primarily on the presence of specific comorbidities—particularly chronic kidney disease with albuminuria, diabetes, coronary artery disease, and patient race. 1

Algorithm for Drug Selection

Step 1: Assess for Chronic Kidney Disease and Albuminuria

For patients with albuminuria (UACR ≥300 mg/g creatinine):

• ACE inhibitors or ARBs are the mandatory first-line choice because they reduce progression to end-stage renal disease 1
• This recommendation holds regardless of blood pressure level 1
• Either class provides similar benefits and risks; choose based on tolerability 1

For patients with moderate albuminuria (UACR 30-299 mg/g):

• ACE inhibitors or ARBs are preferred to prevent progression to more severe albuminuria and reduce cardiovascular events 1
• This applies even without established CKD (eGFR >60 mL/min/1.73 m²) 1

For patients without albuminuria and normal kidney function:

• ACE inhibitors and ARBs offer no superiority over thiazide diuretics or calcium channel blockers 1
• Proceed to Step 2 for selection 1

Step 2: Consider Coronary Artery Disease

For patients with established coronary artery disease:

• ACE inhibitors or ARBs are recommended as first-line therapy 1
• This recommendation applies regardless of albuminuria status 1

Step 3: Evaluate Patient Race (in absence of CKD or CAD)

For Black patients without CKD or heart failure:

• Thiazide diuretics or calcium channel blockers are preferred initial agents 1
• ACE inhibitors and ARBs produce smaller blood pressure reductions in Black patients as monotherapy 1, 2
• The combination of a calcium channel blocker plus thiazide diuretic may be more effective than calcium channel blocker plus ACE inhibitor/ARB in this population 3

For non-Black patients without CKD or CAD:

• All four drug classes (thiazide diuretics, calcium channel blockers, ACE inhibitors, ARBs) are equally acceptable first-line options 1
• Thiazide diuretics may provide optimal cardiovascular protection, particularly long-acting agents like chlorthalidone 1

Step 4: Consider Diabetes Mellitus

For patients with diabetes and hypertension:

• If albuminuria is present (any level ≥30 mg/g), ACE inhibitors or ARBs are first-line 1
• If no albuminuria, all four major classes are acceptable, but ACE inhibitors/ARBs are not superior to thiazide diuretics or calcium channel blockers for cardiovascular protection 1

Specific Drug Class Characteristics

ACE Inhibitors

• Reduce cardiovascular events and slow CKD progression in patients with albuminuria 1
• Metabolically neutral 4
• Monitor serum creatinine and potassium at baseline and within 2-4 weeks of initiation 1
• Common side effect: dry cough (switch to ARB if intolerable) 1
• Contraindicated in pregnancy 2

Angiotensin Receptor Blockers (ARBs)

• Equivalent efficacy to ACE inhibitors for renal and cardiovascular protection 1
• Better tolerated than ACE inhibitors (no cough) 5
• Monitor serum creatinine and potassium at baseline and within 2-4 weeks 1
• Contraindicated in pregnancy 6

Calcium Channel Blockers (Dihydropyridine)

• Particularly effective in Black patients 1, 3
• Effective in older adults and those with isolated systolic hypertension 1
• No adverse metabolic effects 4
• May cause peripheral edema (reduced when combined with ACE inhibitor/ARB) 3

Thiazide Diuretics

• Long-acting thiazide-like agents (chlorthalidone, indapamide) preferred over hydrochlorothiazide for cardiovascular event reduction 1
• Particularly effective in Black patients 1
• May cause hypokalemia, hyperuricemia, and glucose intolerance 3
• Monitor serum potassium and creatinine 2-4 weeks after initiation 1
• Effective even in advanced CKD (eGFR <30 mL/min/1.73 m²), contrary to common perception 1

Critical Contraindications

Never combine ACE inhibitors with ARBs:

• This combination increases adverse events (hyperkalemia, acute kidney injury) without additional cardiovascular or renal benefit 1

Avoid ACE inhibitors/ARBs in patients without hypertension:

• These agents do not prevent development of CKD in normotensive patients and may increase cardiovascular events 1

When Monotherapy is Insufficient

For blood pressure 140-159/90-99 mmHg:

• Start with single-agent monotherapy and titrate 1

For blood pressure ≥160/100 mmHg:

• Initiate with two antihypertensive agents simultaneously (either as separate agents or fixed-dose combination) to achieve blood pressure control more rapidly 1

Preferred two-drug combinations:

• ACE inhibitor or ARB + calcium channel blocker 1, 3
• ACE inhibitor or ARB + thiazide diuretic 1
• Calcium channel blocker + thiazide diuretic (especially for Black patients) 1