Washout Period for Benazepril Before Starting Entresto

Rationale for the 36-Hour Washout

A 36-hour washout period is required after the last dose of benazepril (or any ACE inhibitor) before initiating Entresto to prevent life-threatening angioedema, as recommended by the American College of Cardiology and American Heart Association 1, 2
The 36-hour washout period is critical because both ACE inhibitors and neprilysin (inhibited by sacubitril) break down bradykinin, and dual inhibition dramatically increases bradykinin accumulation, which directly causes angioedema 1
Historical data from omapatrilat (a combined ACE inhibitor/neprilysin inhibitor) demonstrated unacceptably high rates of angioedema, leading to termination of its development, highlighting the importance of the washout period 1
Concomitant use of Entresto with ACE inhibitors or administration within 36 hours of the last ACE inhibitor dose is contraindicated (Class III: Harm recommendation) by the American College of Cardiology 1, 2

Stop benazepril and document the exact time of the last dose, then wait a full 36 hours before administering the first dose of Entresto, as recommended by the American College of Cardiology and American Heart Association 1, 2
Any history of angioedema (with ACE inhibitors, ARBs, or any other cause) precludes Entresto use, according to the American College of Cardiology 2
Verify systolic blood pressure ≥100 mm Hg, as symptomatic hypotension is more common with Entresto, and check baseline renal function (eGFR should be >30 mL/min/1.73 m²) and potassium levels, as recommended by the American College of Cardiology 1, 3
The starting dose of Entresto depends on prior ACE inhibitor dose: if on ≤10 mg daily enalapril equivalent (benazepril ≤10 mg), start Entresto 24/26 mg twice daily, and if on >10 mg daily enalapril equivalent (benazepril >10 mg), start Entresto 49/51 mg twice daily, according to the American College of Cardiology 3
Increase dose every 2-4 weeks to target dose of 97/103 mg twice daily, as tolerated, and monitor blood pressure, renal function, and electrolytes after initiation and during each titration, as recommended by the American College of Cardiology 3

Angioedema risk is highest during the transition period and early treatment phase, and patients with prior angioedema to any cause should never receive Entresto, according to the American College of Cardiology 1, 2
Black patients and smokers have higher angioedema risk based on historical neprilysin inhibitor data, and patients should be educated about angioedema symptoms (lip/tongue/throat swelling, difficulty breathing) and instructed to seek emergency care immediately if these occur, as recommended by the American College of Cardiology 1