ARNI Dosing in HFrEF with Advanced CKD
For patients with HFrEF and severe renal impairment (eGFR <30 mL/min/1.73 m²), start sacubitril/valsartan at 24/26 mg twice daily, then uptitrate every 2-4 weeks to the target dose of 97/103 mg twice daily as tolerated. 1, 2
Initial Dosing Strategy
The starting dose must be adjusted based on kidney function:
- Severe renal impairment (eGFR <30 mL/min/1.73 m²): Start at 24/26 mg twice daily 1, 3, 2
- Moderate renal impairment (eGFR 30-60 mL/min/1.73 m²): No dose adjustment needed; start at standard 49/51 mg twice daily 3
- Normal renal function (eGFR >60 mL/min/1.73 m²): Start at 49/51 mg twice daily 1
The FDA-approved labeling explicitly states that patients with severe renal impairment should initiate therapy at the lower 24/26 mg dose 2. This recommendation is consistent across the 2021 ACC Expert Consensus Decision Pathway and 2022 AHA/ACC/HFSA guidelines 1.
Critical Pre-Initiation Requirements
Before starting ARNI, ensure a 36-hour washout period if switching from an ACE inhibitor to avoid angioedema risk 1, 2. No washout is required when switching from an ARB 1.
Verify the patient is hemodynamically stable with adequate blood pressure, as hypotension is a common concern in advanced CKD 4.
Uptitration Protocol
Double the dose every 2-4 weeks toward the target of 97/103 mg twice daily, unless not tolerated 1, 2:
- Week 0: 24/26 mg twice daily
- Week 2-4: 49/51 mg twice daily
- Week 4-8: 97/103 mg twice daily (target dose)
The 2022 AHA/ACC/HFSA guidelines emphasize that titration as frequently as every 1-2 weeks can be useful depending on symptoms, vital signs, and laboratory findings 1.
Monitoring Requirements
Check renal function and potassium within 1-2 weeks after initiation or any dose increase 3. This is particularly critical in advanced CKD where hyperkalemia and worsening renal function are more common 4, 5.
Key monitoring thresholds:
- eGFR decline >30%: Consider dose reduction 3
- Hyperkalemia: May require dose adjustment or discontinuation 4, 5
- Symptomatic hypotension: Reduce diuretics first if volume depleted; may need ARNI dose reduction 3
Real-world data from the TRANSITION study showed that 42% of patients with moderate-to-severe renal dysfunction achieved target dose by week 10, compared to 54% without renal dysfunction 4. Importantly, sacubitril/valsartan improved eGFR in the renal dysfunction group (mean increase 4.1 mL/min/1.73 m²) 4.
Common Pitfalls and Practical Considerations
Do not discontinue ARNI for transient eGFR declines of ≤15%, as these changes are not consistently associated with adverse outcomes and typically partially recover 6. The treatment benefits of sacubitril/valsartan are retained even in patients experiencing moderate eGFR decline during initiation 6.
Hyperkalemia occurred in 16.3% of patients with renal dysfunction versus 6.5% without in the TRANSITION study 4. Monitor potassium closely and adjust mineralocorticoid receptor antagonists if needed before discontinuing ARNI 4.
Very low dose initiation (25 mg twice daily) is feasible in patients considered intolerant, with similar NT-proBNP reductions and LVEF improvements compared to standard dosing 7. However, this is below FDA-approved dosing and should be reserved for exceptional circumstances 2.
Evidence from advanced CKD (stages 4-5, including dialysis patients) demonstrates that ARNI can be used effectively with careful monitoring, showing significant reductions in hospitalization, NYHA class, and NT-proBNP levels without significant eGFR decline 5. However, 8 of 34 patients (24%) required discontinuation due to hyperkalemia or >30% eGFR decline within the first month 5.