What are the differences among angiotensin‑converting enzyme inhibitors and which agents are best suited for specific clinical scenarios?

Differences Among ACE Inhibitors and Clinical Selection

All ACE inhibitors demonstrate equivalent efficacy for reducing mortality and morbidity in heart failure and cardiovascular disease, but preference should be given to agents proven in landmark trials (captopril, enalapril, lisinopril, perindopril, ramipril, and trandolapril) because these have clearly defined target doses that modify disease progression. 1, 2, 3

Structural and Pharmacokinetic Differences

ACE inhibitors differ in three key structural categories based on their zinc-binding moiety:

• Sulfhydryl-containing agents (captopril): Active in parent form, rapid onset, short duration of action, primarily renal elimination 4, 5, 6
• Carboxyl-containing agents (enalapril, lisinopril, ramipril, perindopril, trandolapril, benazepril): Most require hepatic activation except lisinopril, which is absorbed as active drug but slowly 4, 5, 6
• Phosphinyl-containing agents (fosinopril): Dual elimination (50% renal, 50% hepatic), highest lipophilicity, greatest tissue ACE penetration 7, 5, 6

Lipophilicity and Tissue Penetration

• Most lipophilic: Fosinopril, ramipril, trandolapril—better tissue ACE inhibition 5
• Least lipophilic: Lisinopril—minimal tissue penetration 5
• Clinical significance of tissue ACE inhibition remains under investigation, though theoretical advantages exist for cardiac and vascular remodeling 5, 8

Duration of Action and Dosing

For once-daily dosing in hypertension, trough-to-peak ratios matter clinically:

• Suitable for once-daily dosing (trough-to-peak ratio ≥50%): Fosinopril, ramipril, trandolapril 5
• Requires twice-daily dosing: Captopril (short half-life) 4
• Once-daily capable: Enalapril, lisinopril (though some patients benefit from twice-daily enalapril) 4, 5

Clinical Scenario-Specific Selection

Heart Failure with Reduced Ejection Fraction (HFrEF)

Use captopril, enalapril, or lisinopril as these have the strongest mortality reduction data from landmark trials (CONSENSUS, SOLVD, ATLAS). 1, 3

• Start at low doses: captopril 6.25 mg three times daily, enalapril 2.5 mg twice daily, or lisinopril 2.5-5 mg once daily 2
• Titrate every 1-2 weeks to target doses used in trials: captopril 50 mg three times daily, enalapril 10-20 mg twice daily, lisinopril 20-40 mg once daily 1, 2
• Must be used with beta-blockers unless contraindicated 1, 3
• ACE inhibitors are second-line after ARNIs (sacubitril/valsartan) for HFrEF 9

Post-Myocardial Infarction

Initiate captopril, lisinopril, ramipril, or trandolapril within 24 hours of ST-elevation MI in patients with left ventricular dysfunction (EF ≤40%), heart failure, hypertension, or diabetes. 2, 9

• Continue indefinitely for secondary prevention 2
• Ramipril specifically demonstrated 25% reduction in composite endpoint of MI, stroke, or death in the HOPE trial 3
• ACE inhibitors are preferred over ARBs for secondary prevention of MI 9

Hypertension with Diabetes and Chronic Kidney Disease

Choose an ACE inhibitor (any agent) as first-line therapy when albuminuria is present (ACR ≥30 mg/g), titrating to the highest tolerated dose. 1

• ACE inhibitors slow progression of diabetic nephropathy in both type 1 and type 2 diabetes 1, 3, 8
• Monitor serum creatinine and potassium within 2-4 weeks of initiation 1, 2
• Continue therapy unless creatinine rises >30% within 4 weeks 1, 2
• ACE inhibitors are preferred over ARBs for primary prevention of diabetic kidney disease and reducing major cardiovascular/renal outcomes in type 2 diabetes 9

Renal Impairment

Select fosinopril when creatinine clearance is significantly reduced, as it maintains dual elimination pathways (50% hepatic, 50% renal). 7, 5, 6

• All other ACE inhibitors require dose reduction with declining renal function due to predominantly renal elimination 4, 5, 6
• Lisinopril has no hepatic metabolism and is entirely renally eliminated—avoid in severe renal dysfunction 4, 5

Hepatic Impairment

Use lisinopril or captopril, as these do not require hepatic activation. 4, 5

• Enalapril, ramipril, perindopril, trandolapril, and benazepril are prodrugs requiring hepatic conversion to active metabolites 4, 5, 6
• Fosinopril requires hepatic metabolism but has renal backup elimination 7, 5

Hypertension Requiring Once-Daily Dosing

Choose fosinopril, ramipril, trandolapril, lisinopril, or enalapril for reliable 24-hour blood pressure control. 5

• These agents maintain trough-to-peak ratios ≥50%, ensuring consistent antihypertensive effect 5
• Captopril requires three-times-daily dosing and is unsuitable for once-daily regimens 4

Primary Prevention of Stroke

ACE inhibitors and ARBs show equivalent efficacy—either class is appropriate. 9

Secondary Prevention of Stroke

Prefer ACE inhibitors over ARBs based on superior evidence. 9

Critical Monitoring and Safety Considerations

Absolute Contraindications

• History of angioedema with prior ACE inhibitor exposure 2, 3
• Pregnancy or women planning pregnancy (teratogenic in second/third trimesters) 2, 3, 10
• Bilateral renal artery stenosis or stenosis of solitary kidney 2, 3
• Anuric renal failure 1, 2

Relative Contraindications (Use with Extreme Caution)

• Systolic blood pressure <80 mmHg 1, 2
• Serum creatinine >3 mg/dL 1, 2
• Serum potassium >5.0-5.5 mEq/L 1, 2

Mandatory Monitoring Protocol

• Obtain baseline metabolic panel before initiation 2
• Recheck creatinine and potassium within 1-2 weeks after starting therapy 1, 2, 10
• Repeat monitoring 1-2 weeks after each dose increase 1, 2
• Accept up to 30% creatinine increase within 4 weeks; discontinue only if rise exceeds 30% or continues beyond 4 weeks 1, 2, 3

Managing Hyperkalemia

Rather than immediately stopping the ACE inhibitor when potassium rises:

• Review concurrent medications (NSAIDs, potassium-sparing diuretics, potassium supplements) 1, 10
• Moderate dietary potassium intake 1
• Correct volume depletion 1
• Discontinue or reduce dose only if hyperkalemia is refractory to these measures 1, 2

Common Pitfalls and Caveats

The Cough Dilemma

• ACE inhibitor-induced cough occurs in up to 20% of patients due to bradykinin accumulation 3, 10
• The incidence is frequently overestimated in clinical practice 9
• Consider switching to a more lipophilic ACE inhibitor or combining with a calcium channel blocker before abandoning the class 9
• Switch to an ARB only if cough is truly intolerable and confirmed to be ACE inhibitor-related 1, 9

Underdosing in Clinical Practice

• Physicians commonly prescribe ACE inhibitors at initiation doses rather than titrating to target doses proven in trials 1
• Always attempt to reach target doses from landmark trials unless limited by hypotension, hyperkalemia, or creatinine rise >30% 1, 2
• Intermediate doses are acceptable if target doses cannot be tolerated, but this represents suboptimal therapy 1

Food and Absorption

• Fosinopril absorption is unaffected by food, though rate may be slowed 7
• Captopril absorption is reduced by 30-40% when taken with food—administer 1 hour before meals 4

Drug Interactions

• NSAIDs (including COX-2 inhibitors) blunt antihypertensive effects and increase risk of acute kidney injury 10
• Potassium-sparing diuretics, potassium supplements, and salt substitutes increase hyperkalemia risk 1, 10
• Lithium toxicity can occur—monitor lithium levels closely 10
• Dual RAAS blockade (ACE inhibitor + ARB, or either + aliskiren) increases risks of hypotension, hyperkalemia, and renal dysfunction without additional benefit—avoid this combination 10