Entresto (Sacubitril/Valsartan) Use in Chronic Kidney Disease
Primary Recommendation
Entresto can be safely used in patients with CKD and should be considered particularly for those with heart failure, but requires careful monitoring of renal function, potassium, and blood pressure, with dose adjustments based on tolerability rather than eGFR alone. 1
Indications for Entresto in CKD Patients
Heart Failure with Reduced Ejection Fraction (HFrEF)
- Entresto is indicated for patients with heart failure and reduced ejection fraction who have CKD, as it provides cardiovascular mortality benefit beyond traditional ACE inhibitors or ARBs 2
- The drug has demonstrated safety and efficacy across a broad range of kidney disease stages, including patients with significant renal impairment 2
Heart Failure with Preserved Ejection Fraction (HFpEF)
- In patients with both CKD and HFpEF, Entresto slows the decline of eGFR more effectively than ACEI/ARB therapy and reverses myocardial remodeling 3
- Even low-dose Entresto provides renal protective benefits in this population 3
Renal Function Considerations
eGFR Thresholds and Monitoring
- No dose adjustment is required based solely on eGFR level - dosing should be guided by tolerability (hypotension, hyperkalemia, symptomatic side effects) rather than a specific eGFR cutoff 1
- In patients with eGFR 20-60 mL/min/1.73 m², Entresto has similar effects on kidney function compared to irbesartan, with no significant difference in measured GFR at 12 months 4
- After 6 months of treatment in CKD patients (mean baseline eGFR 50 mL/min/1.73 m²), renal function remains stable with initial improvement at one month 5
Expected Renal Effects
- Monitor serum creatinine closely and down-titrate or interrupt Entresto if clinically significant decrease in renal function occurs 1
- The drug may cause transient increases in serum creatinine and blood urea, particularly in patients with bilateral renal artery stenosis 1
- Meta-analysis shows Entresto significantly increases eGFR compared to RAS inhibitors (MD = 1.90 mL/min/1.73 m²) 6
Initiation and Titration Protocol
Starting Dose
- Begin with sacubitril/valsartan 24/26 mg or 49/51 mg twice daily, particularly in volume-depleted patients or those with significant renal impairment 1
- Correct volume or salt depletion prior to initiation 1
Dose Escalation
- Increase to target dose of 97/103 mg twice daily as tolerated over several weeks 4, 5
- Check serum creatinine, potassium, and blood pressure within 2-4 weeks of initiation or dose increase 7
- In real-world practice, even low doses provide renal and cardiac benefits if maximum doses cannot be tolerated 3, 5
Critical Monitoring Parameters
Renal Function
- Monitor serum creatinine at baseline, 2-4 weeks after initiation, and with each dose increase 1
- Discontinue or down-titrate if serum creatinine rises >30% within 4 weeks of starting or increasing dose 7
- Continue monitoring periodically during maintenance therapy 1
Potassium Management
- Check serum potassium at baseline and within 2-4 weeks of initiation or dose increase 7, 1
- Hyperkalemia is a key risk - monitor especially in patients with severe renal impairment, diabetes, or those on high-potassium diets 1
- Manage hyperkalemia with dietary restriction, potassium binders, or diuretic adjustment rather than immediately stopping Entresto 7
- Dosage reduction or interruption may be required for persistent hyperkalemia 1
Blood Pressure
- Monitor for symptomatic hypotension, particularly in volume-depleted patients or those on high-dose diuretics 1
- Entresto reduces systolic BP by approximately 4-5 mm Hg and diastolic BP by 2-3 mm Hg compared to ARBs alone 4, 6
- If hypotension occurs, adjust diuretics and other antihypertensives before reducing Entresto dose 1
Contraindications and Precautions
Absolute Contraindications
- History of angioedema with prior ACE inhibitor or ARB therapy 1
- Hereditary or idiopathic angioedema 1
- Concomitant use with ACE inhibitors (36-hour washout period required) 1
- Pregnancy (causes fetal toxicity and death) 1
Relative Contraindications and Cautions
- Bilateral renal artery stenosis requires close monitoring of renal function 1
- Black patients have higher rates of angioedema (2.4% vs 0.5% with enalapril) 1
- Patients with prior angioedema history are at increased risk 1
Drug Interactions
- Never combine with ACE inhibitors, other ARBs, or direct renin inhibitors - dual RAS blockade increases risks of hyperkalemia, hypotension, and acute kidney injury 7
- Avoid potassium supplements and potassium-sparing diuretics unless carefully monitored 1
Comparative Benefits in CKD
Cardiovascular Outcomes
- Reduces NT-proBNP by 18% compared to irbesartan 4
- Decreases troponin I by 16% 4
- Improves left ventricular ejection fraction from 31% to 39% over 6 months 5
- Reduces left atrial width more effectively than ACEI/ARB 3
Renal Outcomes
- Provides stability in CKD progression over 6 months 5
- Slows eGFR decline more effectively than ACEI/ARB in HFpEF patients with CKD 3
- No significant difference in albuminuria compared to irbesartan, though ACEI/ARB may have superior proteinuria reduction 3, 4
Common Pitfalls to Avoid
Premature Discontinuation
- Do not stop Entresto solely based on eGFR decline if the patient is otherwise tolerating therapy well 2
- Temporary creatinine elevations <30% are acceptable and do not require discontinuation 7
Inadequate Monitoring
- Failure to check potassium and creatinine within 2-4 weeks of initiation is a common error that can lead to undetected hyperkalemia or acute kidney injury 1
Inappropriate Combination Therapy
- Combining Entresto with ACE inhibitors or other ARBs is contraindicated and dangerous 7
- Ensure adequate washout period (36 hours) when switching from ACE inhibitors 1
Volume Depletion
- Starting Entresto in volume-depleted patients without correction leads to symptomatic hypotension 1
- Optimize volume status and reduce diuretic doses if needed before initiation 1
Special Populations
Advanced CKD (eGFR <20 mL/min/1.73 m²)
- Limited data exist for patients with eGFR <20 mL/min/1.73 m², but real-world experience suggests benefits may extend to this population 2
- Use with extreme caution and more frequent monitoring in this group 1