Entresto (Sacubitril/Valsartan) in Chronic Kidney Disease
Entresto is recommended for patients with CKD and heart failure with reduced or mildly reduced ejection fraction (HFrEF/HFmrEF), and should be initiated at standard or reduced doses depending on baseline eGFR, with close monitoring of renal function, potassium, and blood pressure within 2-4 weeks of initiation. 1, 2
Primary Indications in CKD
Entresto is preferred over ACE inhibitors or ARBs in patients with CKD who have heart failure with ejection fraction up to 55-60%. 1 This represents a Class 1A recommendation for patients with HFrEF and extends to those with HFmrEF (EF 41-49%). 1
For patients with CKD and heart failure with preserved ejection fraction (HFpEF, EF ≥50%), Entresto may be considered as part of the treatment regimen. 1 Real-world data demonstrates that even low-dose Entresto can slow eGFR decline more effectively than ACEI/ARB in CKD patients with HFpEF. 3
Renal Function Considerations and Dosing
Patients with eGFR ≥30 mL/min/1.73 m² can be initiated on standard dosing with routine monitoring. 4 The FDA label indicates that decreases in renal function may be anticipated in susceptible individuals, particularly those whose renal function depends on RAAS activity. 2
For patients with moderate renal impairment (eGFR 20-30 mL/min/1.73 m²), start at lower doses and titrate gradually with more frequent electrolyte monitoring. 4 Consultation with nephrology is recommended before initiating therapy in patients on dialysis. 4
Continue Entresto even when eGFR falls below 30 mL/min/1.73 m², unless specific contraindications develop. 5, 1 This mirrors the guidance for RAS inhibitors in advanced CKD. 5
Monitoring Requirements
Check serum creatinine, potassium, and blood pressure within 2-4 weeks of initiation or dose increase. 1, 2 This timing is critical for detecting early adverse effects.
Managing eGFR Changes:
Tolerate acute eGFR decreases of ≤30% after initiation—do not discontinue therapy prematurely. 1 Meta-analysis data shows no significant difference in measured GFR at 12 months compared to irbesartan (29.8 vs 29.9 mL/min/1.73 m²). 6
If >30% decline in eGFR occurs, ensure euvolemia, discontinue nonessential nephrotoxic agents, and evaluate alternative etiologies before stopping Entresto. 1 The FDA label mandates close monitoring and potential down-titration in patients who develop clinically significant decreases in renal function. 2
Consider reducing dose or discontinuing only in cases of symptomatic hypotension or uncontrolled hyperkalemia despite medical treatment. 1, 2 Permanent discontinuation is usually not required for hypotension. 2
Hyperkalemia Management
Monitor serum potassium periodically, especially in patients with severe renal impairment, diabetes, or high potassium diet. 2 The risk of hyperkalemia increases with advanced CKD stages. 1
Hyperkalemia Treatment Algorithm:
- Implement low potassium diet as first-line intervention. 1
- Consider potassium binders to facilitate ongoing use of Entresto rather than discontinuing therapy. 1
- Initiate diuretics or sodium bicarbonate in those with metabolic acidosis and hyperkalemia. 1
- Avoid triple combination of Entresto with ACE inhibitors and mineralocorticoid receptor antagonists due to significantly increased risk of hyperkalemia. 4
Real-world data shows hyperkalemia >5.0 mEq/L occurs in approximately 12% of patients, with only 4% experiencing levels >5.5 mEq/L. 7
Special Monitoring Considerations
Patients with eGFR <30 mL/min/1.73 m² are at highest risk for developing hypermagnesemia when taking Entresto due to reduced renal clearance. 4 Baseline assessment of serum magnesium is recommended before initiation, with regular monitoring especially in CKD stages 3B-5. 4
Concomitant use of magnesium-containing medications, supplements, or mineralocorticoid receptor antagonists increases the risk of electrolyte imbalances. 4 Patient education on avoiding over-the-counter potassium supplements, potassium-based salt substitutes, and high-magnesium foods is essential. 4
Contraindications in CKD
Do not use Entresto within 36 hours of switching from or to an ACE inhibitor. 2 This washout period is critical to prevent angioedema, which occurs at higher rates in Black patients. 2
Entresto is contraindicated with concomitant use of aliskiren in patients with diabetes. 2 This applies regardless of CKD stage.
Clinical Outcomes in CKD
Entresto demonstrates cardiovascular benefits beyond renal effects in CKD patients. 6 Compared to irbesartan, Entresto reduces systolic blood pressure by 5.4 mmHg, diastolic blood pressure by 2.1 mmHg, troponin I by 16%, and NT-proBNP by 18%. 6
Ejection fraction improves significantly with Entresto in CKD patients. 8, 7 Studies show LVEF improvement from 31% to 39% at 6 months 8 and from median 22.5% to 30% at 180 days. 7
Renal function remains stable or improves slightly with Entresto in CKD. 8, 9 Meta-analysis demonstrates that Entresto significantly increases eGFR compared to RAS inhibitors (MD = 1.90 mL/min/1.73 m², P = 0.02). 9
Common Pitfalls to Avoid
Do not discontinue Entresto for modest creatinine increases (<30%) without first assessing volume status and other nephrotoxic exposures. 1 This premature discontinuation denies patients proven cardiovascular benefits.
Do not withhold Entresto in advanced CKD (stages 3B-4) based solely on eGFR. 5, 1 Evidence supports use down to eGFR 20 mL/min/1.73 m² with appropriate monitoring.
Do not assume proteinuria protection is equivalent to ACEI/ARB. 3 While Entresto slows eGFR decline more effectively, ACEI/ARB may provide superior proteinuria reduction in some patients.