What is the recommended washout period for benzapril (Angiotensin-Converting Enzyme (ACE) inhibitor) before starting Entresto (sacubitril/valsartan)?

Washout Period for Benazepril Before Starting Entresto

A mandatory 36-hour washout period is required after the last dose of benazepril (or any ACE inhibitor) before initiating Entresto (sacubitril/valsartan). 1, 2

Rationale for the 36-Hour Washout

The 36-hour washout period is critical to prevent life-threatening angioedema. 1

• 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. 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). 1, 2

Practical Implementation Algorithm

Step 1: Discontinue Benazepril

• Stop benazepril and document the exact time of the last dose. 1
• Wait a full 36 hours before administering the first dose of Entresto. 1, 2

Step 2: Screen for Contraindications During Washout

• Absolute contraindication: Any history of angioedema (with ACE inhibitors, ARBs, or any other cause) precludes Entresto use. 1
• Verify systolic blood pressure ≥100 mm Hg, as symptomatic hypotension is more common with Entresto. 1
• Check baseline renal function (eGFR should be >30 mL/min/1.73 m²) and potassium levels. 1

Step 3: Initiate Entresto After 36 Hours

• Starting dose depends on prior ACE inhibitor dose: 1, 2
  • If on ≤10 mg daily enalapril equivalent (benazepril ≤10 mg): Start Entresto 24/26 mg twice daily
  • If on >10 mg daily enalapril equivalent (benazepril >10 mg): Start Entresto 49/51 mg twice daily
• The standard starting dose for most patients is 49/51 mg twice daily. 2

Step 4: Uptitration Schedule

• Increase dose every 2-4 weeks to target dose of 97/103 mg twice daily, as tolerated. 1, 2
• Monitor blood pressure, renal function, and electrolytes after initiation and during each titration. 1

Critical Safety Considerations

Angioedema risk is highest during the transition period and early treatment phase. 1

• Patients with prior angioedema to any cause should never receive Entresto. 1
• Black patients and smokers have higher angioedema risk based on historical neprilysin inhibitor data. 1
• Educate patients about angioedema symptoms (lip/tongue/throat swelling, difficulty breathing) and instruct them to seek emergency care immediately if these occur. 1

The 36-hour washout is non-negotiable—shorter intervals significantly increase angioedema risk. 1, 2

Special Populations

• Severe renal impairment (eGFR <30 mL/min/1.73 m²): Start at half the usual starting dose (24/26 mg twice daily), then uptitrate as tolerated. 2
• Patients not previously on ACE inhibitors/ARBs: Can initiate Entresto de novo without washout concerns, though starting at lower doses may improve tolerability. 3, 4
• Recently hospitalized heart failure patients: Entresto can be initiated pre-discharge or within 1-14 days post-discharge after hemodynamic stabilization, following the same 36-hour ACE inhibitor washout rule. 4