What is the initial treatment approach for a patient with hypertension, considering angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs)?

Initial Treatment for Hypertension with ACE Inhibitors or ARBs

For most patients with confirmed hypertension (BP ≥140/90 mmHg), start with combination therapy using a RAS blocker (either an ACE inhibitor or ARB) plus a dihydropyridine calcium channel blocker or thiazide/thiazide-like diuretic, preferably as a single-pill combination. 1

Confirming the Diagnosis

• Confirm hypertension using out-of-office blood pressure measurements (home monitoring ≥135/85 mmHg or 24-hour ambulatory monitoring ≥130/80 mmHg) before initiating treatment, rather than relying solely on office readings 2
• Once confirmed hypertension is diagnosed (sustained BP ≥140/90 mmHg), start both lifestyle interventions and pharmacological therapy simultaneously 1

Initial Pharmacologic Approach

For BP 140-150/90 mmHg (Most Patients)

Start with two-drug combination therapy as initial treatment: 1

• Preferred combinations: ACE inhibitor or ARB + dihydropyridine calcium channel blocker, OR ACE inhibitor or ARB + thiazide/thiazide-like diuretic 1
• Use fixed-dose single-pill combinations to improve adherence 1
• This approach provides more effective BP control than monotherapy 1

For BP ≥160/100 mmHg

• Initiate two antihypertensive medications immediately, preferably as a single-pill combination 1
• Follow the same preferred combinations as above 1

Exceptions to Combination Therapy

Consider monotherapy for: 1

• Patients aged ≥85 years
• Those with symptomatic orthostatic hypotension
• Moderate-to-severe frailty
• Elevated BP (systolic 120-139 mmHg or diastolic 70-89 mmHg) with a concomitant indication for treatment

Choosing Between ACE Inhibitors and ARBs

ACE Inhibitors Are Preferred When:

• Patient has coronary artery disease: ACE inhibitors are first-line therapy 1
• Patient has type 2 diabetes: Evidence favors ACE inhibitors for BP control, primary prevention of diabetic kidney disease, and reducing major cardiovascular and renal outcomes 3
• For primary prevention of heart failure: ACE inhibitors should be considered first choice 3
• Post-myocardial infarction: Start ACE inhibitor within 24 hours in patients with heart failure, left ventricular systolic dysfunction, and/or diabetes 3

ARBs Are Indicated When:

• Patient cannot tolerate ACE inhibitors (primarily due to cough or angioedema) 1, 4
• Black patients: Initial therapy should include ARB + dihydropyridine calcium channel blocker or calcium channel blocker + thiazide-like diuretic, as ACE inhibitors show reduced response as monotherapy in this population 2

Equivalent Efficacy Between ACE Inhibitors and ARBs:

• Albuminuria (UACR ≥30 mg/g): Either ACE inhibitor or ARB is appropriate to reduce risk of progressive kidney disease 1
• Primary prevention of stroke: Both classes show equivalent efficacy 3
• Blood pressure lowering: No difference in efficacy for the surrogate endpoint of BP reduction 4, 5

Specific Clinical Scenarios

Chronic Kidney Disease or Albuminuria

• UACR ≥300 mg/g: ACE inhibitor or ARB at maximum tolerated dose is strongly recommended as first-line treatment 1
• UACR 30-299 mg/g: ACE inhibitor or ARB is recommended 1
• Proteinuria >0.5 g/day: Initial therapy should be ACE inhibitor or ARB 1
• Continue ACE inhibitor or ARB even as eGFR declines to <30 mL/min/1.73 m² for cardiovascular benefit 1
• Lower proteinuria threshold: The 2021 KDIGO guideline lowered the proteinuria threshold from 1 g/day to 0.5 g/day for initiating ACE inhibitor or ARB therapy 1

Diabetes with Hypertension

• Use ACE inhibitor or ARB as first-line therapy to reduce risk of progressive kidney disease 1, 2
• For children and adolescents ≥13 years with diabetes and BP ≥90th percentile or ≥120/80 mmHg, start ACE inhibitor or ARB after 6 months of lifestyle modification 1
• For adolescents with BP consistently ≥95th percentile or ≥140/90 mmHg, consider pharmacologic treatment immediately in addition to lifestyle modification 1

Advanced Chronic Kidney Disease (GFR <30 mL/min/1.73 m²)

• ACE inhibitor or ARB should be used as first-line agent for hypertension 1
• Monitor BP at every clinic visit (at least every 3 months) 1
• If BP remains elevated (systolic ≥130 mmHg or diastolic ≥80 mmHg), intensify antihypertensive therapy 1

Dosing Strategy

Starting Doses

• Losartan (ARB example): Start with 50 mg once daily; can increase to 100 mg once daily as needed 6
• Patients with possible intravascular depletion (e.g., on diuretic therapy): Start with 25 mg losartan 6
• Hepatic impairment: Start with 25 mg losartan once daily in mild-to-moderate hepatic impairment 6

Titration Approach

• Recheck BP in 1 month after initiating therapy 2
• Adjust dose every 2-4 weeks until BP is controlled 1
• BP should be controlled preferably within 3 months 1

Escalation to Three-Drug Therapy

If BP is not controlled with two-drug combination: 1

• Increase to three-drug combination: RAS blocker + dihydropyridine calcium channel blocker + thiazide/thiazide-like diuretic
• Preferably use single-pill combination
• If still uncontrolled, consider adding spironolactone 1

Important Contraindications and Cautions

Do NOT Combine:

• Two RAS blockers together (ACE inhibitor + ARB): This combination is not recommended due to lack of added benefit and increased risk of hyperkalemia, syncope, and acute kidney injury 1, 7
• ACE inhibitor or ARB + direct renin inhibitor: Contraindicated due to increased adverse events 1

Monitoring Requirements

• Monitor serum creatinine/eGFR and potassium within 7-14 days after initiation or dose adjustment of ACE inhibitor, ARB, or diuretic 1, 2
• Continue monitoring at least annually 1
• Watch for hyperkalemia with ACE inhibitors/ARBs and hypokalemia with diuretics 2

Adverse Effects Profile

ACE Inhibitors

• Associated with dry cough (most common reason for discontinuation) 4, 5
• Very low risk of angioedema and fatalities 4
• Overall withdrawal rates due to adverse events are higher than with ARBs 4, 5

ARBs

• Slightly lower incidence of withdrawal due to adverse events compared to ACE inhibitors (absolute risk reduction 1.8%, NNT 55 over 4.1 years) 5
• Well tolerated with good safety profile 8
• Primarily indicated as alternative for ACE inhibitor-intolerant patients 4

Blood Pressure Targets

• Most adults <65 years: Target <130/80 mmHg 2
• Adults ≥65 years: Systolic <130 mmHg if well-tolerated 2
• Patients with diabetes, CKD, or established CVD: Target <130/80 mmHg 2

Common Pitfalls to Avoid

• Do not delay pharmacologic therapy while attempting lifestyle modifications alone in confirmed hypertension ≥140/90 mmHg 1
• Do not start with monotherapy in most patients with confirmed hypertension, as combination therapy is more effective 1
• Do not assume ACE inhibitor cough incidence is prohibitively high—the risk tends to be overestimated and can be reduced by using a lipophilic ACE inhibitor or combining with a calcium channel blocker 3
• Do not use dual RAS blockade (ACE inhibitor + ARB) as it provides no additional benefit and increases adverse events 1