Should Entresto (sacubitril/valsartan) be prescribed for a patient with chronic kidney disease without heart failure, and what dosing and monitoring are recommended?

Entresto in CKD Without Heart Failure

Entresto (sacubitril/valsartan) should NOT be prescribed for patients with chronic kidney disease who do not have heart failure, as there is no approved indication, no evidence of benefit, and current guidelines do not support its use in this population.

Current Approved Indications

Entresto is FDA-approved exclusively for heart failure management, not for CKD alone 1:

• Adult heart failure: Reduces cardiovascular death and hospitalization in chronic heart failure, with benefits most evident in patients with left ventricular ejection fraction below normal 1
• Pediatric heart failure: Treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in patients aged one year and older 1

The FDA label contains no indication for CKD without heart failure 1.

Guideline Recommendations for CKD Without Heart Failure

The 2024 KDIGO guidelines provide a clear treatment hierarchy for CKD that does not include sacubitril/valsartan as monotherapy 2:

• First-line RAS inhibition: ACE inhibitors or ARBs are recommended for CKD patients with specific indications including hypertension or albuminuria 2
• SGLT2 inhibitors: Strongly recommended (1A) for patients with CKD and eGFR ≥20 mL/min/1.73 m² with urine ACR ≥200 mg/g, or for those with heart failure 2
• Nonsteroidal MRAs: Suggested for type 2 diabetes patients with eGFR >25 mL/min/1.73 m² and persistent albuminuria despite maximum tolerated RAS inhibitor 2

Notably, sacubitril/valsartan is never mentioned in the KDIGO CKD guidelines as a treatment option for CKD without heart failure 2.

Why This Matters: Evidence Limitations

The evidence base for sacubitril/valsartan specifically excludes CKD-only patients:

• PARADIGM-HF trial exclusions: Patients with eGFR <30 mL/min/1.73 m² were excluded from the landmark trial that established Entresto's efficacy 3
• Heart failure requirement: All major trials of sacubitril/valsartan enrolled patients with heart failure as the primary condition 4, 3
• Research focus: Meta-analyses examining renal outcomes consistently studied heart failure patients with concomitant CKD, not CKD alone 5, 6

Alternative Approach for CKD Without Heart Failure

For patients with CKD but no heart failure, follow this evidence-based algorithm 2:

1. Assess for specific indications:

   • Hypertension → ACE inhibitor or ARB 2
   • Type 2 diabetes with eGFR ≥20 mL/min/1.73 m² → SGLT2 inhibitor (1A recommendation) 2
   • Albuminuria ≥200 mg/g with eGFR ≥20 mL/min/1.73 m² → SGLT2 inhibitor (1A recommendation) 2

2. Optimize RAS inhibition first: Use maximum tolerated doses of ACE inhibitor or ARB before considering additional agents 2

3. Add SGLT2 inhibitor: This has the strongest evidence (1A) for kidney protection in CKD 2

4. Consider nonsteroidal MRA: Only if type 2 diabetes, persistent albuminuria >30 mg/g despite RAS inhibitor, eGFR >25 mL/min/1.73 m², and normal potassium 2

Critical Pitfalls to Avoid

• Do not substitute sacubitril/valsartan for standard ACE inhibitor/ARB therapy in CKD without heart failure - there is no evidence supporting this practice and it contradicts FDA labeling 1
• Do not assume renal benefits from heart failure trials apply to CKD-only patients - the research specifically studied heart failure populations with concomitant CKD, not isolated CKD 7, 5, 6
• Do not overlook SGLT2 inhibitors - these have the strongest evidence (1A) for kidney protection in CKD and should be prioritized over experimental approaches 2

If Heart Failure Is Subsequently Diagnosed

Only if heart failure is confirmed should sacubitril/valsartan be considered 4, 1:

• Start at 49/51 mg twice daily in most patients 1
• Reduce starting dose to 24/26 mg twice daily if severe renal impairment (eGFR <30 mL/min/1.73 m²) 1
• Allow 36-hour washout from ACE inhibitors before initiating 1
• Monitor blood pressure, serum creatinine, and potassium within 2-4 weeks 2, 4