Should sacubitril/valsartan (Entresto) be initiated in a female patient with stage 4 chronic kidney disease (eGFR 15–29 mL/min/1.73 m²)?

Starting Entresto in Stage 4 CKD Female

Direct Recommendation

Sacubitril/valsartan (Entresto) can be safely initiated in a female patient with stage 4 chronic kidney disease (eGFR 15–29 mL/min/1.73 m²) if she has heart failure with reduced ejection fraction, starting at half the usual dose (24/26 mg twice daily) and titrating every 2–4 weeks to the target dose of 97/103 mg twice daily as tolerated. 1

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Dosing Algorithm for Stage 4 CKD

Initial Dose Adjustment

• Start sacubitril/valsartan at 24/26 mg twice daily (half the usual starting dose) in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²). 1

• After initiation, increase the dose every 2–4 weeks following the standard dose escalation: 24/26 mg → 49/51 mg → 97/103 mg twice daily. 1

• The FDA label explicitly permits use in severe renal impairment with dose adjustment, making this a guideline-supported approach. 1

Pre-Initiation Requirements

• Confirm the patient is not taking an ACE inhibitor; if she is, discontinue it and wait 36 hours before starting sacubitril/valsartan. 1

• Assess for history of angioedema related to previous ACE inhibitor or ARB therapy, which is an absolute contraindication. 1

• Evaluate volume status and blood pressure; ensure systolic BP is adequate to tolerate the medication (generally >100 mmHg). 2

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Evidence Supporting Use in Advanced CKD

Renal Function Stability

• The UK HARP-III trial randomized 414 patients with eGFR 20–60 mL/min/1.73 m² to sacubitril/valsartan 97/103 mg twice daily versus irbesartan 300 mg daily and found no difference in measured GFR at 12 months (29.8 vs 29.9 mL/min/1.73 m²), demonstrating renal safety. 3

• A meta-analysis of 6,217 CKD patients showed sacubitril/valsartan prevented serum creatinine elevation (OR 0.79,95% CI 0.67–0.95) and reduced the risk of >50% eGFR decline with long-term follow-up (OR 0.52,95% CI 0.32–0.84). 4

• A Japanese prospective study in CKD stage G4-5 patients (mean eGFR 21.1 mL/min/1.73 m²) showed renal function improved after one month (eGFR 53 mL/min/1.73 m²) and remained stable through 6 months, with no patients experiencing ≥30% creatinine increase. 2, 5

Cardiovascular Benefits Preserved

• Sacubitril/valsartan reduced cardiovascular death or heart failure hospitalization by 32% (OR 0.68,95% CI 0.61–0.76) in CKD patients across multiple trials. 4

• The UK HARP-III trial demonstrated additional blood pressure reduction of 5.4/2.1 mmHg and lowered troponin I by 16% and NT-proBNP by 18% compared to irbesartan, indicating superior cardiac biomarker improvement. 3

• Left ventricular ejection fraction improved from 31% to 39% (P <0.001) in a real-world CKD cohort after 6 months of sacubitril/valsartan. 5

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Safety Profile in Stage 4 CKD

Hyperkalemia Risk

• The meta-analysis found no increased risk of hyperkalemia with sacubitril/valsartan versus ACE inhibitors/ARBs (OR 1.09,95% CI 0.75–1.60). 4

• In the Japanese CKD G4-5 study, no potassium values exceeded 6.0 mmol/L after sacubitril/valsartan initiation. 2

• A retrospective analysis of CKD stages III–V patients showed only 12% experienced potassium >5.0 mEq/L and 4% >5.5 mEq/L. 6

Hypotension Monitoring

• Sacubitril/valsartan was associated with increased hypotension (OR 1.71,95% CI 1.15–2.56) but this was generally manageable and did not lead to excess discontinuation. 4

• The UK HARP-III trial reported similar rates of serious adverse events between sacubitril/valsartan and irbesartan (29.5% vs 28.5%). 3

• Only 10.6% of CKD patients withdrew from treatment in a 6-month real-world study, indicating good tolerability. 5

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Monitoring Protocol After Initiation

Renal Function Assessment

• Recheck serum creatinine and potassium 1–2 weeks after initiation and after each dose escalation. 2

• An initial eGFR dip of 2–5 mL/min/1.73 m² is expected within the first month and should not prompt discontinuation unless accompanied by symptomatic hypotension or hyperkalemia. 3, 2

• Continue monitoring renal function every 3 months once the target dose is achieved. 5

Blood Pressure Monitoring

• Measure sitting and standing blood pressure at each visit to detect orthostatic hypotension. 2

• If systolic BP falls below 90 mmHg or the patient develops symptomatic hypotension, reduce the dose by one step rather than discontinuing. 1

Cardiac Biomarkers

• Consider measuring NT-proBNP or BNP at baseline and 3 months to assess treatment response, as sacubitril/valsartan significantly lowers these markers. 3

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Common Pitfalls to Avoid

• Do not withhold sacubitril/valsartan solely because eGFR is <30 mL/min/1.73 m²; the FDA label and clinical trials support use with dose adjustment in severe renal impairment. 1, 3

• Do not discontinue for modest creatinine rises up to 30% within the first 4 weeks, as this reflects hemodynamic adaptation rather than kidney injury. 3, 2

• Do not combine with ACE inhibitors; ensure a 36-hour washout period to prevent angioedema risk. 1

• Do not use in patients on dialysis; sacubitril/valsartan is contraindicated in end-stage renal disease requiring renal replacement therapy. 1

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Integration with Other CKD Therapies

SGLT2 Inhibitors

• Consider adding dapagliflozin 10 mg daily if eGFR is ≥20 mL/min/1.73 m² for additional renal and cardiovascular protection, as SGLT2 inhibitors provide complementary benefits to sacubitril/valsartan. 7

• The combination of sacubitril/valsartan and SGLT2 inhibitors is safe and provides additive renal protection without requiring dose adjustments of either agent. 7

Diuretic Management

• Loop diuretics (not thiazides) should be used for volume management in stage 4 CKD, as thiazides are ineffective when eGFR <30 mL/min/1.73 m². 8

• Consider reducing loop diuretic doses when initiating sacubitril/valsartan to prevent excessive volume depletion, especially in elderly patients. 2