Is Entresto (sacubitril/valsartan) safe to use in a patient with severe renal impairment (creatinine level of 11.10)?

Entresto is contraindicated in severe renal impairment with a creatinine of 11.10 mg/dL

A creatinine level of 11.10 mg/dL indicates end-stage renal disease (ESRD), likely requiring dialysis. While Entresto (sacubitril/valsartan) is not absolutely contraindicated in severe renal impairment, it requires extreme caution with mandatory dose reduction and close monitoring, and alternative therapies should be strongly considered.

Dosing Requirements in Severe Renal Impairment

Half of the starting dose is required for patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), which corresponds to your patient's creatinine level 1. The FDA label explicitly states this dose reduction is mandatory, not optional 1.

• Start with sacubitril/valsartan 24/26 mg twice daily (half the usual starting dose of 49/51 mg) 1
• Titration must be slower and more cautious than in patients with normal renal function 1
• No studies have been conducted in patients on dialysis, creating significant uncertainty about safety 1

Pharmacokinetic Concerns

The active neprilysin inhibitor metabolite (sacubitrilat) accumulates dramatically in severe renal impairment:

• Sacubitrilat exposure increases 2.70-fold in severe renal impairment compared to normal kidney function 2
• Half-life extends from 12 hours to 38.5 hours in severe renal impairment 2
• Peak concentrations increase by approximately 60% regardless of renal impairment severity 2
• Sacubitril and valsartan themselves show unchanged exposure, but the active metabolite accumulation is the primary concern 2

Evidence for Efficacy and Safety

The evidence base for Entresto in severe renal impairment is limited but suggests potential benefit:

• A meta-analysis of 17,335 patients with eGFR <60 mL/min/1.73 m² showed sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization (OR: 0.65,95%CI: 0.54-0.78) 3
• The UK HARP-III trial included patients with eGFR 20-60 mL/min/1.73 m² and found no worsening of kidney function over 12 months compared to irbesartan 4
• However, patients with eGFR <20 mL/min/1.73 m² (which your patient likely has) were excluded from most trials 4
• Hyperkalemia rates were not significantly increased (OR: 1.31,95%CI: 0.79-2.17), though confidence intervals are wide 3

Critical Monitoring Requirements

If Entresto is initiated despite severe renal impairment, mandatory monitoring includes:

• Serum creatinine and eGFR weekly for the first month, then biweekly for 2 months 1
• Serum potassium every 3-7 days initially, as hyperkalemia risk is substantial 1
• Blood pressure monitoring for symptomatic hypotension 1
• Watch for signs of drug accumulation (dizziness, hypotension, hyperkalemia) 2

Alternative Considerations

Given the creatinine of 11.10 mg/dL, strongly consider:

• Whether the patient is on dialysis or needs urgent dialysis initiation (creatinine >10 mg/dL typically indicates ESRD)
• Standard ACE inhibitors or ARBs may be safer alternatives with more established dosing in ESRD 4
• The risk-benefit ratio is uncertain in this population as Entresto is unlikely to be removed by hemodialysis due to high protein binding 1

Common Pitfalls to Avoid

• Do not use standard starting doses - this will lead to excessive drug accumulation 1, 2
• Do not assume dialysis will clear the drug - high protein binding prevents effective removal 1
• Do not initiate without baseline potassium <5.0 mEq/L - hyperkalemia risk is already elevated in ESRD 3
• Do not continue if creatinine rises >26.5 μmol/L or eGFR drops >20% from baseline 5

Clinical Decision Algorithm

1. Confirm actual eGFR - a creatinine of 11.10 mg/dL suggests eGFR <10 mL/min/1.73 m² (ESRD)
2. If eGFR <15 mL/min/1.73 m²: Consider alternative therapy (standard ACE-I/ARB) as evidence is insufficient 1
3. If eGFR 15-30 mL/min/1.73 m²: May use Entresto at half starting dose with intensive monitoring 1
4. Check baseline potassium: Must be <5.0 mEq/L before initiation 3
5. Assess dialysis status: If on dialysis, risk-benefit is highly uncertain 1

Bottom line: With a creatinine of 11.10 mg/dL, this patient is at the extreme end of renal impairment where Entresto has minimal safety data. If used at all, start at 24/26 mg twice daily with weekly monitoring, but strongly consider whether standard ACE-I/ARB therapy is more appropriate given the lack of evidence in ESRD.