ACE Inhibitors and ARNIs in HFpEF Patients with Liver Failure
ACE inhibitors and ARNIs should be avoided in patients with heart failure with preserved ejection fraction (HFpEF) who have liver failure due to increased risk of adverse events and lack of proven mortality benefit in this specific population. 1, 2
Risks of ACE Inhibitors in Liver Failure
ACE inhibitors require careful consideration in patients with liver disease for several reasons:
- Hepatic Metabolism: Most ACE inhibitors are prodrugs requiring hepatic activation, which may be impaired in liver failure 3
- Risk of Hepatic Failure: ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice or hepatitis that can progress to fulminant hepatic necrosis and death 2
- Hypotension Risk: Patients with liver failure often have baseline hypotension, which can be exacerbated by ACE inhibitors 2
- Renal Considerations: Hepatorenal syndrome is common in liver failure, and ACE inhibitors can further compromise renal function 2
Risks of ARNIs in Liver Failure
ARNIs (specifically sacubitril/valsartan) carry similar concerns:
- Valsartan Component: The ARB component undergoes hepatic metabolism
- Hypotension: ARNIs cause symptomatic hypotension in 14% of patients even without liver disease 4
- Lack of Evidence: No clinical trials have specifically evaluated ARNIs in patients with liver failure
Evidence for HFpEF Treatment
The evidence for using these medications in HFpEF (regardless of liver function) is limited:
ACE Inhibitors: According to a 2021 Cochrane review, ACE inhibitors likely have little to no effect on cardiovascular mortality (RR 0.93), all-cause mortality (RR 1.04), or heart failure hospitalization (RR 0.86) in HFpEF patients 5
ARNIs: In HFpEF, ARNIs may result in a slight reduction in heart failure hospitalization (RR 0.89) but have little to no effect on cardiovascular mortality (RR 0.96) or all-cause mortality (RR 0.97) 5
Alternative Approaches for HFpEF with Liver Failure
Given these considerations, alternative approaches should be prioritized:
Mineralocorticoid Receptor Antagonists (MRAs): These probably reduce heart failure hospitalization in HFpEF (RR 0.82) 5, but require careful monitoring of potassium and renal function
Volume Management: Careful diuresis while monitoring electrolytes and renal function
Treatment of Underlying Causes: Address contributing factors like hypertension, atrial fibrillation, or coronary disease with liver-safe medications
Special Considerations for Medication Selection
If renin-angiotensin system blockade is absolutely necessary despite liver failure:
Lisinopril: Among ACE inhibitors, lisinopril may be safer as it's not a prodrug and has primarily renal elimination 3
Fosinopril: Has dual elimination routes (hepatic and renal), potentially making it safer in patients with mixed hepatorenal dysfunction 3
Dosing: Start at the lowest possible dose with very close monitoring of blood pressure, renal function, and liver enzymes
Monitoring Recommendations
If any of these medications must be used despite the risks:
- Monitor liver function tests weekly initially, then biweekly
- Check renal function and electrolytes frequently
- Monitor blood pressure closely, especially after initial dosing
- Discontinue immediately if worsening liver function, significant hypotension, or acute kidney injury occurs
The risk-benefit ratio strongly favors avoiding these medications in patients with HFpEF and liver failure, as the potential harms likely outweigh the limited benefits demonstrated in the HFpEF population.