In a stable patient with chronic kidney disease and heart failure with reduced or mildly reduced ejection fraction, how should sacubitril/valsartan be initiated, what starting dose and titration schedule should be used, and what monitoring and safety precautions are required?

Sacubitril/Valsartan in CKD Patients with Heart Failure

Starting Dose and Initiation Strategy

In stable CKD patients with heart failure and reduced ejection fraction, initiate sacubitril/valsartan at 24/26 mg twice daily if the patient has severe renal impairment (eGFR <30 mL/min/1.73 m²) or is not currently on an ACE inhibitor/ARB, then titrate to the target dose of 97/103 mg twice daily over 2-4 weeks as tolerated. 1

Dose Selection Based on Prior Therapy

• Patients on high-dose ACE inhibitor or ARB: Start at 49/51 mg twice daily, as these patients have demonstrated tolerance to renin-angiotensin system blockade 2, 1

• Patients on low/medium-dose ACE inhibitor or ARB: Start at 24/26 mg twice daily to minimize hypotension risk, particularly important in CKD where hemodynamic changes are more pronounced 2, 1

• ACE inhibitor/ARB-naïve patients: Start at 24/26 mg twice daily, which is half the usual recommended starting dose 2, 1

• Severe renal impairment (eGFR <30 mL/min/1.73 m²): Start at 24/26 mg twice daily regardless of prior therapy 2, 1

Critical Pre-Initiation Requirements

• Mandatory 36-hour washout from ACE inhibitors: This strict interval prevents life-threatening angioedema; no washout is required when switching from an ARB 2, 1

• Assess volume status before initiation: In patients with low blood pressure, start SGLT2 inhibitors and mineralocorticoid receptor antagonists first (as they do not lower BP), then add sacubitril/valsartan at the lowest dose 2

• Review and reduce diuretics if appropriate: Excessive diuresis can precipitate hypotension; assess for congestion and cautiously decrease diuretics in euvolemic patients before initiating sacubitril/valsartan 2

Titration Schedule

Double the dose every 2-4 weeks to reach the target maintenance dose of 97/103 mg twice daily, monitoring blood pressure, renal function, and potassium at each step. 2, 1

Structured Titration Protocol

• Week 0: Start 24/26 mg or 49/51 mg twice daily (based on criteria above) 1

• Week 2-4: Increase to 49/51 mg twice daily (if started at 24/26 mg) or 97/103 mg twice daily (if started at 49/51 mg) 2, 1

• Week 4-8: Advance to target dose of 97/103 mg twice daily if not yet achieved 2, 1

• Gradual titration approach: A 6-week titration maximizes attainment of target dose compared to condensed 3-week approaches, particularly in patients previously on low-dose ACE inhibitor/ARB 2

Special Considerations in Low Blood Pressure

• In patients with baseline low blood pressure, initiate at the lowest dose and up-titrate slowly with small increments every 1-2 weeks, one drug at a time with close observation 2

• If blood pressure is very low, consider starting low-dose ACE inhibitor first and up-titrating, then shifting to sacubitril/valsartan once adequate ACE inhibitor dose is tolerated 2

• Cardiac output improvement over time may allow easier up-titration as heart failure improves 2

Monitoring Parameters and Frequency

Check blood pressure, serum creatinine, and serum potassium within 2-4 weeks of initiation or each dose increase, with timing dependent on baseline eGFR and potassium levels. 2, 3

Renal Function Monitoring

• Acceptable creatinine rise: Continue therapy if serum creatinine rises ≤30% within 4 weeks of initiation or dose increase, as this reflects hemodynamic changes from reduced intraglomerular pressure 2, 4, 5

• Significant deterioration: Stop treatment if renal function deteriorates substantially (>30% creatinine rise) 2

• Long-term stability: After initial hemodynamic adjustment, renal function typically stabilizes; in one study of CKD patients, eGFR improved from 50 to 53 mL/min/1.73 m² at 1 month and remained stable at 51 mL/min/1.73 m² at 6 months 6

• Continue despite declining eGFR: Do not discontinue sacubitril/valsartan even when eGFR falls below 30 mL/min/1.73 m², as cardiovascular and renal protection persists 2, 4, 5, 3

Potassium Monitoring

• Check within 2-4 weeks of each dose change, with more frequent monitoring if baseline potassium is elevated or eGFR is low 2, 3

• Manage hyperkalemia medically: Use potassium-lowering measures (dietary restriction, potassium binders, diuretic adjustment) rather than stopping sacubitril/valsartan 2, 4, 5

• Discontinuation threshold: Only reduce dose or discontinue for uncontrolled hyperkalemia despite medical treatment 2, 3

Blood Pressure Monitoring

• Hypotension is common but often asymptomatic: Low blood pressure during guideline-directed medical therapy does not always indicate poor tolerance 2

• Symptomatic hypotension management: Mild dizziness upon standing can usually be managed through patient education without reducing heart failure pharmacotherapy 2

• Discontinuation threshold: Only reduce dose or discontinue for symptomatic hypotension that persists despite conservative measures 2, 3, 1

• Evaluate alternative causes: In stable patients with low BP on optimal therapy, investigate other cardiovascular (valvular disease, ischemia) or non-cardiovascular causes (alpha-blockers for benign prostatic hyperplasia) before reducing heart failure medications 2

Safety Precautions and Contraindications

Absolute Contraindications

• Concomitant ACE inhibitor use: Contraindicated due to angioedema risk; requires 36-hour washout 2, 1

• History of angioedema with prior ACE inhibitor or ARB therapy 1

• Pregnancy: Discontinue immediately when pregnancy is detected due to fetal toxicity 1

• Concomitant aliskiren in diabetes: Contraindicated due to increased adverse events 1

Critical Safety Warnings

• Never combine with dual RAS blockade: Do not use sacubitril/valsartan with ACE inhibitor + ARB combinations, as this increases hyperkalemia and acute kidney injury without benefit 2, 3

• Avoid NSAIDs: Non-steroidal anti-inflammatory drugs increase risk of renal deterioration and hyperkalemia 2

• Severe hepatic impairment: Not recommended in Child-Pugh Class C; start at 24/26 mg twice daily in moderate hepatic impairment (Child-Pugh Class B) 2, 1

Expected Clinical Outcomes in CKD

Cardiovascular Benefits

• Reduced cardiovascular death and heart failure hospitalization: Meta-analysis of 6,217 CKD patients showed 32% reduction in cardiovascular death or heart failure hospitalization (OR 0.68,95% CI 0.61-0.76) 7

• Improved ejection fraction: In CKD patients, LVEF improved from 31% to 39% over 6 months, with improvement evident as early as 12 weeks 2, 6

• Quality of life improvement: CKD patients' quality of life scores increased from 45.15 to 57.57 over 12 months, independent of ejection fraction changes 8

Renal Outcomes

• Preserved renal function: Meta-analysis showed sacubitril/valsartan increased eGFR by 1.90 mL/min/1.73 m² compared to RAS inhibitors alone 9

• Reduced creatinine elevation: 21% reduction in incidence of serum creatinine elevation (OR 0.79,95% CI 0.67-0.95) 7

• Long-term protection: With extended follow-up, 48% reduction in patients experiencing >50% eGFR decline (OR 0.52,95% CI 0.32-0.84) 7

• Trend toward reduced ESRD: 41% reduction in end-stage renal disease incidence, though not statistically significant (OR 0.59,95% CI 0.29-1.20) 7

Safety Profile in CKD

• Hypotension: Increased risk (OR 1.71,95% CI 1.15-2.56), but often manageable with patient education and conservative measures 7

• Hyperkalemia: No significant increase compared to ACE inhibitors/ARBs (OR 1.09,95% CI 0.75-1.60) 7

• Low discontinuation rate: Only 10.6% of CKD patients withdrew from treatment in real-world practice 6

Common Pitfalls and How to Avoid Them

Pitfall 1: Premature Discontinuation for Creatinine Rise

• Error: Stopping sacubitril/valsartan when creatinine rises by 15-25%
• Correct approach: Continue therapy unless creatinine rises >30% within 4 weeks, as modest increases reflect beneficial hemodynamic effects 2, 4, 5

Pitfall 2: Inadequate Washout from ACE Inhibitors

• Error: Starting sacubitril/valsartan within 24 hours of last ACE inhibitor dose
• Correct approach: Strictly observe 36-hour washout period to prevent angioedema 2, 1

Pitfall 3: Stopping for Asymptomatic Hypotension

• Error: Reducing dose when blood pressure is low but patient is clinically stable
• Correct approach: Educate patients that low blood pressure is expected with life-prolonging therapy; only reduce for symptomatic hypotension 2

Pitfall 4: Stopping for Hyperkalemia Without Medical Management

• Error: Immediately discontinuing sacubitril/valsartan when potassium rises to 5.5-6.0 mEq/L
• Correct approach: Implement dietary restriction, potassium binders, or diuretic adjustment before reducing dose 2, 4, 5

Pitfall 5: Failing to Titrate to Target Dose

• Error: Maintaining patients on starting dose of 24/26 mg or 49/51 mg indefinitely
• Correct approach: Proven benefits in trials were achieved at target dose of 97/103 mg twice daily; titrate every 2-4 weeks as tolerated 2, 1

Pitfall 6: Discontinuing When eGFR Falls Below 30

• Error: Stopping sacubitril/valsartan when eGFR declines to <30 mL/min/1.73 m²
• Correct approach: Continue therapy even as eGFR declines, only considering discontinuation at eGFR <15 mL/min/1.73 m² if symptomatic 2, 4, 5, 3