What is the recommended initial treatment for a patient with uncontrolled hypertension, particularly considering the use of ACE (Angiotensin-Converting Enzyme) inhibitors?

ACE Inhibitors for Uncontrolled Hypertension

ACE inhibitors are recommended as one of four equally effective first-line medication classes for initial treatment of uncontrolled hypertension, and should be combined with either a calcium channel blocker or thiazide-like diuretic as initial therapy for most patients with confirmed hypertension (BP ≥140/90 mmHg). 1, 2

First-Line Medication Classes

The four major drug classes are equally effective and include: 1, 3

• ACE inhibitors
• Angiotensin receptor blockers (ARBs)
• Dihydropyridine calcium channel blockers (CCBs)
• Thiazide or thiazide-like diuretics

All four classes have demonstrated reduction in cardiovascular morbidity and mortality, with a 10 mmHg reduction in systolic BP decreasing cardiovascular events by 20-30%. 3

Initial Treatment Strategy

For most patients with confirmed hypertension (BP ≥140/90 mmHg), start with combination therapy using two drugs from different classes, preferably as a single-pill combination. 1, 2 The recommended combinations are:

• ACE inhibitor + calcium channel blocker, OR
• ACE inhibitor + thiazide-like diuretic 1

For stage 2 hypertension (BP ≥160/100 mmHg), immediately initiate two medications from different classes plus lifestyle modifications. 3

For stage 1 hypertension (BP 130-139/80-89 mmHg) with high cardiovascular risk (≥10% 10-year ASCVD risk, diabetes, CKD, or established CVD), start both lifestyle modifications and a single first-line medication immediately. 3

When ACE Inhibitors Are Mandatory First-Line

ACE inhibitors (or ARBs if ACE inhibitors are not tolerated) are the required first-line choice in these specific populations: 1, 2, 3, 4

• Patients with albuminuria (UACR ≥30 mg/g) - ACE inhibitors reduce proteinuria and slow kidney disease progression beyond BP reduction alone 1, 2, 3
• Patients with coronary artery disease 2, 3, 4
• Patients with diabetes and chronic kidney disease 1, 3
• Patients with heart failure 1, 5

Special Population Considerations

For Black patients, calcium channel blockers or thiazide diuretics are more effective than ACE inhibitors or ARBs when used as monotherapy. 1, 2, 3 However, combination therapy with a diuretic and CCB, either with each other or with an ACE inhibitor or ARB, is recommended for initial treatment in most Black patients. 1

Dosing and Titration

Starting dose for ACE inhibitors (using enalapril as example): 5

• 5 mg once daily for patients not on diuretics with normal renal function
• 2.5 mg once daily for patients currently on diuretics (discontinue diuretic 2-3 days before if possible)
• 2.5 mg once daily for patients with creatinine clearance ≤30 mL/min

Usual dosage range: 10-40 mg daily in single or divided doses. 5 Titrate every 2-4 weeks until BP target is achieved. 4

Blood Pressure Targets

• <130/80 mmHg for most adults <65 years 2, 4
• Systolic BP 120-129 mmHg in most adults if well tolerated 1, 4
• Systolic BP <130 mmHg for adults ≥65 years 1, 2, 4

Escalation Algorithm

If BP is not controlled with initial therapy: 1, 2, 4

1. Two-drug combination not at target → Progress to three-drug combination (ACE inhibitor + CCB + thiazide-like diuretic)
2. Three-drug combination not at target → Add spironolactone and refer to specialist with expertise in BP management 1

Critical Monitoring Requirements

Monitor serum creatinine and potassium within 7-14 days after initiating ACE inhibitors, then at least annually. 2, 3, 4

Accept creatinine increases up to 30% from baseline after ACE inhibitor initiation - this reflects beneficial reduction in intraglomerular pressure. 3

Follow-up within 7-14 days after medication initiation or dose changes, with goal of achieving BP target within 3 months. 2, 4

Absolute Contraindications and Critical Caveats

Never combine ACE inhibitors with ARBs - this increases adverse effects (hyperkalemia, syncope, acute kidney injury) without added cardiovascular benefit. 1, 2, 3, 4

ACE inhibitors are contraindicated in pregnancy and should be avoided in sexually active individuals of childbearing potential not using reliable contraception. 4

Discontinue or reduce ACE inhibitor dose if: 3

• Potassium >5.5 mEq/L or increases to >6.0 mEq/L
• Creatinine increases >30% from baseline
• Acute kidney injury suspected

Common side effect: dry cough occurs in 5-20% of patients. 6 If intolerable, switch to an ARB, which has equal efficacy but lower adverse event rates. 6

Risk of angioedema is very low but potentially fatal - educate patients to seek immediate care for lip/tongue swelling or difficulty breathing. 6

Essential Lifestyle Modifications (Additive to Pharmacotherapy)

All patients should implement: 2, 3, 4

• Sodium restriction to <2,300 mg/day
• Weight loss if BMI >25 kg/m² targeting BMI 20-25 kg/m²
• Moderate-intensity aerobic exercise ≥150 minutes/week plus resistance training 2-3 times/week
• Mediterranean or DASH dietary pattern with increased potassium intake
• Alcohol limitation to <100g/week (complete avoidance preferred)
• Smoking cessation