Is Entresto (sacubitril/valsartan) contraindicated with lisinopril, an Angiotensin-Converting Enzyme (ACE) inhibitor?

Yes, Entresto (sacubitril/valsartan) and lisinopril are absolutely contraindicated when used together.

Concomitant use of Entresto with any ACE inhibitor, including lisinopril, is contraindicated due to significantly increased risk of life-threatening angioedema. 1

Critical Safety Requirements

Mandatory Washout Period

• A minimum 36-hour washout period is required between the last dose of an ACE inhibitor (lisinopril) and the first dose of Entresto. 2, 1
• This washout period is non-negotiable and must be strictly observed to prevent overlapping inhibition of both ACE and neprilysin, which dramatically increases angioedema risk. 2

Mechanism of Harm

• Both ACE inhibitors and neprilysin break down bradykinin; when both pathways are blocked simultaneously, bradykinin accumulates to dangerous levels, directly causing angioedema. 2
• The combination drug omapatrilat (which inhibited both ACE and neprilysin) was terminated from development specifically because it caused unacceptably high rates of angioedema—3-fold higher than enalapril alone. 2
• Black patients and smokers face particularly elevated angioedema risk with dual inhibition. 2

Switching Protocol from Lisinopril to Entresto

Step 1: Discontinue Lisinopril

• Stop lisinopril completely and document the exact time of the last dose. 1

Step 2: Wait 36 Hours

• Do not administer Entresto until at least 36 hours have elapsed since the last lisinopril dose. 2, 1
• This washout allows ACE inhibitor activity to clear sufficiently to minimize angioedema risk. 2

Step 3: Initiate Entresto

• Start Entresto at 49/51 mg twice daily (or 24/26 mg twice daily if the patient has severe renal impairment, hypotension, or was on low-dose ACE inhibitor). 1
• Titrate to target dose of 97/103 mg twice daily after 2-4 weeks as tolerated. 1

Step 4: Monitor Closely

• Check blood pressure within 2-3 days after initiation (hypotension is common). 3, 4
• Check renal function and potassium within 2-3 days and during titration. 3, 4
• Educate the patient about angioedema symptoms (facial/tongue/throat swelling, difficulty breathing) and instruct them to seek emergency care immediately if these occur. 2

Absolute Contraindications to Entresto

Never initiate Entresto in patients with: 2, 1

• History of angioedema from any cause (Class III: Harm recommendation)
• Current ACE inhibitor use or <36 hours since last ACE inhibitor dose
• Pregnancy or planned pregnancy
• Concomitant aliskiren use in diabetic patients

Why This Matters for Mortality and Morbidity

• Entresto reduced cardiovascular death or heart failure hospitalization by 20% compared to enalapril in the PARADIGM-HF trial. 2, 4, 5
• Entresto is now preferred over ACE inhibitors as first-line renin-angiotensin system inhibition in eligible HFrEF patients. 6, 3
• However, this mortality benefit is completely negated if angioedema occurs, which can be fatal and requires mechanical airway support in severe cases. 2
• The 36-hour washout period is the critical safety measure that allows patients to access Entresto's superior efficacy while minimizing life-threatening risk. 2, 1

Common Pitfall to Avoid

Do not attempt to "bridge" therapy by overlapping lisinopril and Entresto even briefly. 2, 1 The temptation to avoid a gap in renin-angiotensin system blockade must be resisted—the 36-hour washout is based on the pharmacokinetics needed to prevent dangerous bradykinin accumulation and is supported by the PARADIGM-HF trial design, which incorporated two washout periods and resulted in low angioedema rates (0.45% with Entresto vs 0.24% with enalapril). 7