What is the role of Angiotensin-Converting Enzyme (ACE) inhibitors in managing hypertension?

ACE Inhibitors for Blood Pressure Management

ACE inhibitors are highly effective first-line antihypertensive agents that reduce blood pressure by 3-5/2 mmHg systolic/diastolic through suppression of the renin-angiotensin-aldosterone system, and they should be strongly considered as initial therapy particularly in patients with diabetes, heart failure, post-myocardial infarction, or chronic kidney disease. 1, 2, 3

Mechanism and Hemodynamic Effects

ACE inhibitors work by blocking the conversion of angiotensin I to angiotensin II, leading to decreased vasoconstriction and reduced aldosterone secretion 4, 5. They reduce blood pressure primarily by decreasing peripheral arterial resistance while maintaining cardiac output and heart rate, unlike beta-blockers 3. The antihypertensive effect typically begins within 1 hour of administration, peaks at 6 hours, and provides 24-hour coverage with once-daily dosing for most agents 4.

Blood Pressure Targets and Treatment Initiation

For patients with diabetes or chronic kidney disease, target blood pressure is <130/80 mmHg 1, 2. For the general hypertensive population, the target is <140/90 mmHg 1.

Treatment Algorithm by Blood Pressure Level:

• Blood pressure 130-139/80-89 mmHg: Initiate lifestyle modifications for up to 3 months maximum; if target not achieved, add ACE inhibitor pharmacotherapy 1, 2
• Blood pressure ≥140/90 mmHg: Immediately start ACE inhibitor plus lifestyle modifications without delay 1, 2
• Blood pressure ≥160/100 mmHg: Begin treatment immediately without waiting for confirmatory measurements 1

Specific Patient Populations Where ACE Inhibitors Excel

ACE inhibitors demonstrate superior cardiovascular outcomes compared to other antihypertensive classes in several high-risk populations 1, 2:

Diabetes Mellitus

• ACE inhibitors are the preferred initial agent for all diabetic patients with hypertension 1, 2
• They reduce cardiovascular events including myocardial infarction, stroke, and heart failure even in diabetic patients without hypertension who have other cardiovascular risk factors 1, 2
• For patients ≥55 years with diabetes and any additional cardiovascular risk factor (history of CVD, dyslipidemia, microalbuminuria, smoking), an ACE inhibitor should be initiated regardless of blood pressure 1
• Type 1 diabetic nephropathy: ACE inhibitors are first-line for prevention and progression 6

Coronary Artery Disease and Post-MI

• ACE inhibitors reduce mortality by 15-27% in post-MI patients, with greater benefit (41% reduction) in hypertensive versus normotensive patients 1
• The HOPE trial demonstrated a 22% reduction in cardiovascular death, MI, and stroke with ramipril in high-risk vascular disease patients 1
• The EUROPA trial showed a 20% relative risk reduction in cardiovascular events with perindopril 1

Heart Failure

• ACE inhibitors reduce mortality across the entire spectrum from asymptomatic to severe heart failure 1, 6
• They should be prescribed to all heart failure patients with reduced ejection fraction unless contraindicated 1
• The TRACE trial showed a 7% absolute mortality reduction, and the AIRE trial demonstrated a 27% relative mortality reduction 1

Chronic Kidney Disease

• ACE inhibitors slow progression of both diabetic and non-diabetic nephropathy 1
• They are particularly beneficial in patients with albuminuria or proteinuria 1

Comparative Efficacy: Important Caveats

While ACE inhibitors are highly effective, they were less effective than thiazide diuretics and calcium channel blockers in lowering blood pressure in the general population 3. In Black patients specifically, ACE inhibitors were notably less effective than calcium channel blockers in preventing heart failure and stroke 3. However, when combined with a thiazide diuretic, racial differences in blood pressure response disappear 4.

Practical Dosing Recommendations

Commonly Used ACE Inhibitors for Hypertension 3:

• Lisinopril: Start 2.5-5 mg once daily, maximum 20-40 mg once daily
• Enalapril: Start 2.5 mg twice daily, maximum 10-20 mg twice daily
• Ramipril: Start 1.25-2.5 mg once daily, maximum 10 mg once daily
• Trandolapril: Start 1 mg once daily, maximum 4 mg once daily

For heart failure patients, use agents with proven mortality benefits: enalapril, lisinopril, or ramipril 3.

Combination Therapy Strategy

Most patients require more than one drug to achieve blood pressure control 1. When ACE inhibitor monotherapy is insufficient:

• Add a thiazide diuretic (hydrochlorothiazide or chlorthalidone) as second-line agent 2
• The ADVANCE trial demonstrated that perindopril plus indapamide significantly reduced microvascular and macrovascular outcomes, as well as cardiovascular and total mortality 2
• If eGFR <30 mL/min/m², substitute a loop diuretic for thiazides 2
• Consider administering at least one antihypertensive medication at bedtime, which reduced cardiovascular events and mortality in diabetic patients 2

Critical Monitoring Requirements

Monitor renal function and serum potassium levels when initiating ACE inhibitors 1, 2:

• Check within 1-2 weeks after initiation
• Recheck within 3 months of any medication changes 2
• Expect a mean serum potassium increase of approximately 0.1 mEq/L; 15% of patients may have increases >0.5 mEq/L 4
• When combined with hydrochlorothiazide, expect a mean decrease of 0.1 mEq/L 4

Absolute Contraindications

Do not prescribe ACE inhibitors in the following situations 1:

• Pregnancy (all trimesters)
• History of angioedema with previous ACE inhibitor exposure
• Anuric renal failure

Use With Extreme Caution

Exercise caution and consider specialist consultation in 1:

• Systolic blood pressure <80 mmHg
• Serum creatinine >3 mg/dL
• Bilateral renal artery stenosis or stenosis of a solitary kidney
• Serum potassium >5.5 mEq/L
• Severe volume depletion (risk of functional acute renal failure)

Common Pitfalls to Avoid

Never combine ACE inhibitors with ARBs 6. This combination offers no added cardiovascular benefit but significantly increases risks of hyperkalemia, syncope, and acute kidney injury 6.

If ACE inhibitor is not tolerated due to cough (occurs more frequently than with ARBs), switch to an ARB 1, 6, 3. ARBs produce similar blood pressure reduction and mortality benefits in heart failure patients who cannot tolerate ACE inhibitors 6.

Do not initiate ACE inhibitors in patients at immediate risk of cardiogenic shock; stabilize first with other therapies, then re-evaluate 1.

Avoid excessive initial dosing—captopril's side effects (skin rashes, proteinuria, neutropenia) are dose-dependent, and doses should not exceed 150 mg/day 7.

Tolerability Profile

ACE inhibitors cause slightly more withdrawals due to adverse effects compared to ARBs (absolute risk increase 1.8%, number needed to harm 55 over 4.1 years), primarily due to dry cough 8. However, they remain well-tolerated overall with relatively low incidence of adverse effects 9.

ACE inhibitors do not cause metabolic disturbances, lipid abnormalities, CNS effects, or orthostatic hypotension, making them particularly suitable for elderly patients 9.