What are the differences between various Angiotensin-Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs)?

Differences Between ACE Inhibitors and ARBs

ACE inhibitors and ARBs differ primarily in their mechanism of action, side effect profiles, and specific clinical indications, with ARBs being better tolerated but ACE inhibitors having more robust mortality benefit evidence in certain cardiovascular conditions. 1

Mechanism of Action

ACE Inhibitors

• Inhibit angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I to angiotensin II 2
• Decrease plasma angiotensin II levels, reducing vasopressor activity and aldosterone secretion 2
• Also inhibit kininase II (identical to ACE), which degrades bradykinin, leading to increased bradykinin levels 2
• This bradykinin effect contributes to vasodilation but also causes cough in some patients 3

ARBs

• Selectively block angiotensin II from binding to AT1 receptors 4, 5
• Do not affect bradykinin metabolism (do not inhibit kininase II) 4, 5
• Action is independent of angiotensin II synthesis pathways 4
• Have much greater affinity for AT1 receptors than AT2 receptors 4, 5

Side Effect Profiles

ACE Inhibitors

• Dry cough occurs in up to 20% of patients due to bradykinin accumulation 3
• Angioedema occurs in <1% of patients but more frequently in Black patients and women 3
• Can cause hypotension, hyperkalemia, and renal dysfunction 3

ARBs

• Significantly lower incidence of cough and angioedema 1
• Similar rates of hypotension, hyperkalemia, and renal dysfunction 1
• Overall better tolerated than ACE inhibitors with 17% fewer withdrawals due to adverse effects 6

Clinical Indications and Efficacy

Heart Failure

• ACE inhibitors are recommended as first-line therapy for heart failure with reduced ejection fraction (HFrEF) 3
• ARBs are recommended for patients who cannot tolerate ACE inhibitors due to cough or angioedema 3
• In advanced heart failure (NYHA III-IV), aldosterone antagonists are recommended in addition to ACE inhibitors 3

Hypertension

• Both are effective first-line treatments for hypertension 3, 1
• ARBs may be preferred in patients who cannot tolerate ACE inhibitors 3
• No significant differences in blood pressure reduction between the classes 6

Post-Myocardial Infarction

• ACE inhibitors should be started within 24 hours of ST-elevation MI and continued long-term in patients with heart failure, LV dysfunction, or diabetes 7
• ARBs can be used as alternatives in ACE inhibitor-intolerant patients 3

Diabetic Nephropathy

• Both ACE inhibitors and ARBs are recommended for patients with diabetes, hypertension, and albuminuria 3
• ACE inhibitors may have preferential effects in reducing the risk of major cardiovascular and renal outcomes in diabetic patients 7

Specific Drugs and Dosing

Common ACE Inhibitors

• Lisinopril: Initial 10 mg once daily, target 20-40 mg once daily
• Ramipril: Initial 2.5 mg once daily, target 10 mg once daily
• Enalapril: Initial 5 mg twice daily, target 10-20 mg twice daily
• Perindopril: Initial 4 mg once daily, target 8 mg once daily

Common ARBs

• Valsartan: Initial 40-80 mg once daily, target 160-320 mg once daily 4
• Candesartan: Initial 4-8 mg once daily, target 32 mg once daily 5
• Losartan: Initial 25-50 mg once daily, target 50-100 mg once daily 1
• Telmisartan: Initial 40 mg once daily, target 80 mg once daily 1

Important Clinical Considerations

• Combination therapy: Dual RAS blockade with both ACE inhibitor and ARB is not recommended due to increased risk of hyperkalemia, hypotension, and renal dysfunction without significant additional benefits 3, 1

• Pregnancy: Both ACE inhibitors and ARBs are contraindicated in pregnancy (category D) 1

• Monitoring: For both classes, monitor renal function, serum potassium, and blood pressure, especially when initiating therapy 1

• Cost considerations: ACE inhibitors are generally less expensive than ARBs, with many available as generics

• Ethnic differences: ACE inhibitors may be less effective in Black hypertensive patients compared to non-Black patients 2

Clinical Decision Making

When choosing between an ACE inhibitor and ARB:

1. For most cardiovascular indications, start with an ACE inhibitor unless contraindicated 7, 8

2. Switch to an ARB if the patient develops intolerable cough or angioedema on ACE inhibitor 3

3. Consider starting with an ARB in patients with a history of ACE inhibitor-induced cough or angioedema, or those at higher risk (e.g., history of idiopathic angioedema) 3

4. For specific conditions like heart failure with reduced ejection fraction, follow the sequence: ARNI (sacubitril/valsartan) first, ACE inhibitor second, ARB as alternative if both are not tolerated 3