Is Entresto (sacubitril/valsartan) a good choice for treatment of Congestive Heart Failure (CHF) in patients with hepatic disease?

Entresto Use in Heart Failure with Hepatic Disease

Entresto (sacubitril/valsartan) can be used cautiously in patients with CHF and mild hepatic impairment without dose adjustment, but requires dose reduction in moderate hepatic impairment and is not recommended in severe hepatic disease. 1

Dosing Recommendations by Hepatic Function

Mild Hepatic Impairment (Child-Pugh A)

• No dose adjustment required when administering Entresto to patients with mild hepatic impairment 1
• Standard initiation at 49/51 mg twice daily can proceed as in patients without liver disease 1

Moderate Hepatic Impairment (Child-Pugh B)

• Start with half the standard starting dose in adult and pediatric patients with moderate hepatic impairment 1
• This translates to initiating at 24/26 mg twice daily rather than the standard 49/51 mg twice daily 1
• Titrate more cautiously with close monitoring of blood pressure and renal function 2

Severe Hepatic Impairment (Child-Pugh C)

• Use is not recommended in patients with severe hepatic impairment, as no studies have been conducted in this population 1
• The lack of safety and efficacy data makes risk assessment impossible in this group 1

Heart Failure Management in Hepatic Disease Context

Standard CHF Treatment in Liver Disease

• Patients with high-output heart failure from hepatic vascular malformations respond to standard CHF therapy including ACE inhibitors, beta-blockers, diuretics, and digoxin 3
• The traditional approach with ACE inhibitors and beta-blockers remains the foundation of therapy in patients with liver disease 3

Considerations for Entresto vs. Traditional Therapy

In patients with mild-moderate hepatic impairment and HFrEF:

• Entresto is recommended as a replacement for ACE inhibitors in ambulatory patients who remain symptomatic despite optimal therapy with ACE inhibitor, beta-blocker, and MRA 3
• The 2022 AHA/ACC/HFSA guidelines support Entresto use to reduce cardiovascular mortality and hospitalization in HFrEF 3, 2
• However, hepatic impairment was not specifically studied in PARADIGM-HF, the pivotal trial establishing Entresto's superiority over enalapril 4

Critical Monitoring Requirements

Baseline Assessment

• Measure baseline liver function tests, renal function (eGFR), electrolytes (potassium, magnesium), and blood pressure before initiating Entresto 2
• Document Child-Pugh classification to determine appropriate dosing 1

Ongoing Monitoring

• Monitor liver enzymes more frequently in patients with pre-existing hepatic disease, as rare cases of sacubitril/valsartan-induced liver injury have been reported 5
• Check electrolytes and renal function within 1-2 weeks after initiation and with each dose increase 6
• Monitor for symptomatic hypotension, which occurs more frequently with Entresto than with ACE inhibitors 4

Special Precautions in Hepatic Disease

Drug Interactions and Contraindications

• Avoid triple combination of Entresto with ACE inhibitors and MRAs due to significantly increased risk of hyperkalemia and electrolyte disturbances 2
• Ensure 36-hour washout period when transitioning from ACE inhibitors to avoid angioedema 6
• Exercise caution with concomitant use of NSBBs (non-selective beta-blockers) in decompensated cirrhosis, particularly in patients with refractory ascites 3

Renal-Hepatic Considerations

• Patients with both hepatic and renal impairment require half the starting dose if either moderate hepatic impairment OR severe renal impairment (eGFR <30) is present 1
• The valsartan component can worsen electrolyte abnormalities in patients with renal dysfunction, which is common in advanced liver disease 2

Clinical Decision Algorithm

For CHF patients with hepatic disease considering Entresto:

1. Assess hepatic function using Child-Pugh classification

   • Child-Pugh A: Standard dosing acceptable
   • Child-Pugh B: Reduce starting dose by 50%
   • Child-Pugh C: Do not use Entresto

2. Evaluate concurrent renal function

   • If eGFR <30 mL/min/1.73m² AND moderate hepatic impairment: Use lowest starting dose (24/26 mg BID) 1

3. Optimize traditional GDMT first

   • Ensure patient is on maximally tolerated ACE inhibitor, beta-blocker, and MRA before considering switch 3
   • Verify patient remains symptomatic (NYHA class II-IV) despite optimization 7

4. Monitor closely after initiation

   • Liver enzymes at 2 weeks, 1 month, then quarterly 5
   • Electrolytes and renal function at 1-2 weeks and with each dose increase 2
   • Blood pressure monitoring for symptomatic hypotension 4

Common Pitfalls to Avoid

• Do not assume all patients with cirrhosis have severe hepatic impairment—use Child-Pugh scoring to guide dosing rather than avoiding Entresto entirely 1
• Do not continue ACE inhibitors when starting Entresto—this increases angioedema risk and requires the mandatory washout period 6
• Do not overlook electrolyte monitoring—patients with liver disease often have baseline electrolyte abnormalities that can be exacerbated 2
• Do not use in patients with biliary symptoms or active hepatic necrosis—these patients are at higher risk for hepatotoxicity 3, 5