For a patient with heart failure with reduced ejection fraction, which ACE inhibitor (angiotensin‑converting enzyme inhibitor) is appropriate to initiate?

Which ACE Inhibitor for Heart Failure with Reduced Ejection Fraction

For patients with HFrEF, the appropriate ACE inhibitors are enalapril, lisinopril, captopril, or ramipril—all have proven mortality benefit in clinical trials and are listed in the 2022 AHA/ACC/HFSA guidelines. 1

Specific ACE Inhibitor Options with Dosing

The 2022 AHA/ACC/HFSA guidelines 1 provide explicit dosing for the following ACE inhibitors proven to reduce mortality in HFrEF:

• Enalapril: Start 2.5 mg twice daily → Target 10-20 mg twice daily
• Lisinopril: Start 2.5-5 mg once daily → Target 20-40 mg once daily
• Captopril: Start 6.25 mg three times daily → Target 50 mg three times daily
• Ramipril: Start 1.25-2.5 mg once daily → Target 5 mg twice daily
• Trandolapril: Start 1 mg once daily → Target 4 mg once daily

Critical Implementation Strategy

Start at the low dose listed above and uptitrate to target doses regardless of symptom improvement. 1 The clinical trials that established ACE inhibitor efficacy used protocol-driven uptitration to these specific target doses. Even when patients felt better at lower doses, the trials continued dose escalation because the mortality benefit is dose-dependent. 2

Mortality Benefit

ACE inhibitors reduce all-cause mortality by 17% in HFrEF patients. 1 The number needed to treat (NNT) to prevent one death is 77 at 12 months and 26 at 36 months. 1 Discontinuing or failing to initiate ACE inhibitors during heart failure hospitalization increases 30-day mortality to 8.8% (vs 3.5% for continued therapy) and 1-year mortality to 41.6% (vs 28.2%). 3

When ACE Inhibitors Are NOT First-Line

ACE inhibitors should only be used when ARNI (sacubitril/valsartan) is not feasible. 4 The 2022 guidelines give ARNI a Class 1A recommendation as preferred first-line therapy for NYHA class II-III HFrEF, as it provides an additional 16% relative risk reduction in mortality beyond ACE inhibitors. 1, 4

Use ACE inhibitors specifically when:

• ARNI is contraindicated (history of angioedema, pregnancy)
• Cost barriers prevent ARNI access
• Patient has not yet been transitioned to ARNI

Common Pitfalls to Avoid

Under-dosing is the most critical error. 5 Real-world data shows only 14.6% of patients receive optimal ACE inhibitor doses, with 61.8% receiving less than 75% of target doses. 6 This under-dosing directly compromises survival benefit.

Do not stop uptitration when symptoms improve. The target doses from clinical trials are what established efficacy—lower doses may provide less mortality benefit even if symptoms seem controlled. 1

Monitor for adverse effects but manage them rather than discontinuing:

• Cough: Number needed to harm = 12 7 (switch to ARB if intolerable)
• Hypotension: Number needed to harm = 20 7 (reduce diuretics first)
• Hyperkalemia: Number needed to harm = 31 7 (adjust MRA dose, dietary counseling)
• Creatinine elevation: Number needed to harm = 49 7 (acceptable up to 30% increase)

The Four-Pillar Framework

ACE inhibitors (or ARNI) represent one of four essential medication classes that should be initiated simultaneously or in rapid sequence: 4, 8

1. ACE inhibitor/ARNI
2. Beta-blocker (bisoprolol, carvedilol, or metoprolol succinate)
3. Mineralocorticoid receptor antagonist
4. SGLT2 inhibitor

Do not wait to achieve target dose of one medication before starting the next. 1 Start all four pillars at low doses and uptitrate each independently.