What other angiotensin‑converting enzyme inhibitors are available besides lisinopril and enalapril, and what are their usual starting doses and contraindications?

Available ACE Inhibitors Beyond Lisinopril and Enalapril

Six ACE inhibitors have demonstrated mortality reduction in large randomized trials and should be preferentially selected: captopril, enalapril, lisinopril, perindopril, ramipril, and trandolapril. 1, 2 Two additional agents—fosinopril and quinapril—are FDA-approved but lack extensive outcomes data. 1

Evidence-Based ACE Inhibitors with Proven Mortality Benefit

Captopril

• Starting dose: 6.25 mg three times daily 3, 1, 2
• Target dose: 50 mg three times daily (mean trial dose ≈123–127 mg/day) 3, 1, 2
• Key characteristics: Sulfhydryl-containing compound; active in parent form; rapid onset with short duration of action; primarily renal elimination 4, 5
• Evidence base: Proven mortality benefit in post-MI patients (SAVE trial) 3

Ramipril

• Starting dose: 1.25–2.5 mg once daily 3, 1, 2
• Target dose: 5 mg twice daily or 10 mg once daily 3, 1, 2
• Key characteristics: Prodrug requiring hepatic conversion; dual renal and hepatic elimination 4, 6
• Evidence base: 22% reduction in cardiovascular death, MI, and stroke in high-risk patients (HOPE trial) 2

Trandolapril

• Starting dose: 1 mg once daily 3, 1, 2
• Target dose: 4 mg once daily 3, 1, 2
• Key characteristics: Prodrug with lowest oral bioavailability (11%); dual renal and hepatic elimination 4
• Evidence base: Proven mortality benefit post-MI (TRACE trial) 3

Perindopril

• Starting dose: 2 mg once daily 1, 2
• Target dose: 8–16 mg once daily 1, 2
• Key characteristics: Prodrug with medium half-life; primarily renal elimination 4
• Evidence base: 20% reduction in cardiovascular death, MI, or cardiac arrest in stable CAD (EUROPA trial) 2

Additional FDA-Approved ACE Inhibitors (Limited Outcomes Data)

Fosinopril

• Starting dose: Not specified in mortality trials 1
• Key characteristics: Unique phosphoryl-containing ACE inhibitor; dual renal and hepatic elimination (approximately 50% each route) 7, 4, 8
• Advantage: Dose adjustment not required in renal insufficiency until creatinine clearance <30 mL/min due to compensatory hepatic elimination 4
• Evidence base: Demonstrated hemodynamic benefit in heart failure but lacks large-scale mortality trials 7

Quinapril

• Key characteristics: Prodrug with hepatic metabolism; primarily renal excretion of active metabolite 4, 8
• Evidence base: Approved for clinical use but lacks extensive morbidity-mortality outcome data 1

Benazepril

• Key characteristics: Prodrug with dual renal and hepatic elimination; earlier peak time and slightly shorter half-life than enalapril 4, 8
• Evidence base: No large-scale mortality trials 9

Critical Dosing Principles

• All ACE inhibitors are therapeutically equivalent when prescribed at evidence-based target doses; no agent shows superiority for symptoms or survival in heart failure. 2
• Underdosing is the most common clinical pitfall—many patients receive initiation doses rather than maintenance target doses, diminishing expected outcome benefits. 2
• Titrate doses no more frequently than every 2 weeks to reach target or maximally tolerated doses. 3
• If the full target dose is not tolerated, use an intermediate dose rather than switching agents unnecessarily. 2

Pharmacokinetic Considerations for Agent Selection

Renal Impairment

• Preferred agents with dual elimination: Fosinopril, benazepril, ramipril, spirapril, and trandolapril have hepatic metabolic routes and require less dose adjustment in renal failure. 4
• Dose adjustment required below creatinine clearance 30 mL/min for renally eliminated agents (captopril, enalapril, lisinopril, perindopril). 4

Hepatic Impairment

• Preferred agent: Lisinopril (renally excreted, no hepatic metabolism required). 4
• Avoid prodrugs requiring hepatic activation (enalapril, ramipril, perindopril, trandolapril) in severe liver disease. 4

Dosing Frequency

• Short half-life (requires TID dosing): Captopril (t½ ≈1 hour) 4, 5
• Medium half-life (once or twice daily): Enalapril, lisinopril, ramipril, perindopril 4
• Long half-life (once daily): Trandolapril, spirapril (t½ up to 30 hours) 4

Absolute Contraindications (All ACE Inhibitors)

• Pregnancy (all trimesters)—serious fetal toxicity including renal dysfunction, oligohydramnios, skull hypoplasia, and fetal death 2, 4
• History of angioedema with any ACE inhibitor 2, 10
• Bilateral renal artery stenosis—risk of acute renal failure 2
• Concurrent use with ARBs or direct renin inhibitors—dual RAAS blockade increases hyperkalemia, syncope, and acute kidney injury 2–3-fold without added benefit 11, 2

Monitoring Requirements

• Check serum creatinine/eGFR and potassium within 1–2 weeks after initiation or dose increase, then at least annually. 3, 2
• More frequent monitoring required in patients with baseline hypotension (SBP <80 mmHg), hyponatremia, diabetes, azotemia, or chronic kidney disease. 2
• Acceptable laboratory changes: Creatinine rise up to 50% and potassium up to 5.5 mmol/L; larger increases require discontinuation. 11

Common Adverse Effects (Class-Wide)

• Cough (10–15% of patients)—mechanism-based, not dose-dependent 4, 6
• Hypotension—especially in volume-depleted patients or those on high-dose diuretics 3, 7, 6
• Hyperkalemia—particularly with concurrent potassium-sparing diuretics, supplements, or renal impairment 2, 7
• Angioedema (0.1–0.5%)—higher incidence in Black patients; requires immediate discontinuation 3, 2
• Renal dysfunction—modest creatinine elevation (0.1–0.3 mg/dL) is expected and does not mandate discontinuation unless acute tubular necrosis is evident 11, 2

Special Considerations

• Approximately 85–90% of heart failure patients tolerate long-term ACE inhibitor therapy, with most adverse events being mild and transient. 2
• Initiate with low doses in severe heart failure and maintain or add diuretic therapy to prevent fluid retention. 3, 4
• ACE inhibitors should always be combined with diuretics in patients with current or recent fluid overload. 3, 2