When to switch a patient from lisinopril (Angiotensin-Converting Enzyme Inhibitor) to Entresto (sacubitril/valsartan)?

When to Switch from Lisinopril to Entresto (Sacubitril/Valsartan)

Patients with heart failure with reduced ejection fraction (HFrEF) should be switched from lisinopril to sacubitril/valsartan (Entresto) if they have LVEF ≤40% and remain symptomatic (NYHA class II-IV) despite optimal ACE inhibitor therapy. 1

Indications for Switching

The primary indications for switching from lisinopril to sacubitril/valsartan include:

• LVEF ≤40% (most evidence is for LVEF ≤35%)
• Persistent NYHA class II-IV symptoms despite optimal ACE inhibitor therapy
• Systolic blood pressure ≥100 mmHg
• eGFR ≥30 mL/min/1.73m²
• Serum potassium ≤5.2 mmol/L

Evidence Supporting the Switch

The PARADIGM-HF trial demonstrated that sacubitril/valsartan was superior to enalapril (another ACE inhibitor similar to lisinopril) with:

• 20% reduction in cardiovascular death
• 21% reduction in heart failure hospitalizations
• 16% reduction in all-cause mortality
• Number needed to treat of 21 to prevent one primary endpoint over 27 months 1

Additionally, sacubitril/valsartan has been shown to improve:

• Left ventricular ejection fraction (median increase from 28.2% to 37.8% after 12 months)
• Cardiac remodeling parameters
• Quality of life 1, 2

Switching Protocol

When switching from lisinopril to sacubitril/valsartan:

1. Mandatory washout period: Discontinue lisinopril for at least 36 hours before starting sacubitril/valsartan to reduce risk of angioedema 3

2. Starting dose:

   • For most adults: 49/51 mg twice daily
   • For patients not currently on ACE inhibitor/ARB or on low doses: 24/26 mg twice daily
   • For elderly patients (≥75 years): Consider starting at 24/26 mg twice daily 3

3. Dose titration:

   • Double the dose every 2-4 weeks as tolerated
   • Target maintenance dose: 97/103 mg twice daily 3

4. Monitoring:

   • Blood pressure (watch for symptomatic hypotension)
   • Renal function and electrolytes
   • Signs/symptoms of angioedema

Special Considerations

Contraindications to Switching

• History of angioedema with ACE inhibitors
• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Hypotension (systolic BP <100 mmHg)
• Severe hepatic impairment (Child-Pugh C)
• Pregnancy (sacubitril/valsartan has fetal toxicity warnings) 3

Potential Challenges

• Symptomatic hypotension (14.0% with sacubitril/valsartan vs. 9.2% with enalapril in clinical trials)
• In patients with borderline blood pressure, consider reducing diuretic dose if not congested 1

Broader Treatment Context

Sacubitril/valsartan is part of the quadruple therapy for HFrEF, which includes:

1. ARNI (sacubitril/valsartan) or ACE inhibitor/ARB
2. Beta-blocker
3. Mineralocorticoid receptor antagonist (MRA)
4. SGLT2 inhibitor

The 2021 ACC Expert Consensus and 2024 ESC guidelines recommend sacubitril/valsartan as a replacement for ACE inhibitors in eligible patients with HFrEF to reduce the risk of heart failure hospitalization and cardiovascular death 1.

Real-World Implementation

Real-world data suggests that approximately 38% of patients with HFrEF on guideline-directed medical therapy may be eligible for switching to sacubitril/valsartan 4. The benefits of switching appear consistent regardless of heart failure duration, with improvements in biomarkers, health status, and cardiac remodeling observed even in patients with long-standing heart failure 2.