Entresto in ESRD Patients on Hemodialysis with HFrEF
Direct Answer
Entresto (sacubitril/valsartan) can be used in patients with end-stage renal disease on hemodialysis who have HFrEF, starting at a reduced dose of 24/26 mg twice daily, with careful monitoring of blood pressure and potassium. 1, 2
Evidence Base and Guideline Context
FDA Approval and Renal Dosing
The FDA label specifies that patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) should start at the reduced dose of 24/26 mg twice daily rather than the standard 49/51 mg dose. 1, 2 This is the only formal guidance for advanced kidney disease, as ESRD patients on hemodialysis were excluded from the pivotal PARADIGM-HF trial. 1
The drug is unlikely to be removed by hemodialysis due to high protein binding, meaning dialysis timing does not significantly affect drug levels. 2
Guideline Limitations
Current ACC/AHA/HFSA guidelines provide a Class I recommendation for sacubitril/valsartan in NYHA class II-IV HFrEF, but this is based on trial data that explicitly excluded patients with eGFR ≤30 mL/min/1.73 m². 1 This creates an evidence gap where FDA approval extends beyond the studied population. 1
Clinical Evidence in ESRD Patients
Despite exclusion from major trials, real-world evidence supports both safety and efficacy in this population:
Mortality Benefit
A retrospective cohort study of 2,860 HFrEF patients with ESRD demonstrated that sacubitril/valsartan treatment for ≥9 months reduced 5-year all-cause mortality from 54.7% to 39.3% (HR 0.46; 95% CI 0.25-0.82; P=0.0094) compared to candesartan or valsartan. 3 This represents a 46% relative risk reduction in mortality, comparable to the benefit seen in patients with preserved renal function.
Functional Improvement
Multiple studies show consistent improvements in cardiac function:
- LVEF improvement after 3 years was significantly greater with sacubitril/valsartan (14.51±18.98%) versus ARB alone (6.91±18.44%) (P=0.0408). 3
- After 1 year of treatment, LVEF improved from 31.3% to 45.1% (P<0.0001), with corresponding improvements in left ventricular end-systolic volume and diameter. 4
- In a 12-week study, NYHA class III prevalence decreased from 60.71% to 32.14% (P<0.05), and LVEF improved from 44.29±8.92% to 53.32±7.88% (P<0.001). 5
Symptomatic Benefit
Quality of life measures showed substantial improvement: Physical Component Summary scores increased from 40.0±6.41 to 56.20±9.86 (P<0.001) and Mental Component Summary scores from 39.99±6.14 to 52.59±11.0 (P<0.001) after 12 weeks. 5
Initiation Protocol
Step 1: Verify Eligibility
Before initiating sacubitril/valsartan in ESRD patients on hemodialysis:
- Confirm HFrEF diagnosis (LVEF ≤40%) with NYHA class II-IV symptoms. 1, 6
- Check systolic blood pressure ≥100 mmHg (though lower pressures may be tolerated with careful monitoring). 1
- Verify serum potassium <5.2 mmol/L. 1
- Ensure no history of angioedema with ACE inhibitors or ARBs. 1, 6
Step 2: Washout Period
If the patient is currently on an ACE inhibitor, a mandatory 36-hour washout is required to prevent angioedema. 1, 6 No washout is needed when switching from an ARB. 1
Step 3: Starting Dose
Initiate at 24/26 mg twice daily in ESRD patients on hemodialysis, regardless of prior ACE inhibitor or ARB dose. 1, 2 This reduced starting dose accounts for the inability to clear the drug renally.
Step 4: Titration Strategy
Titrate to 49/51 mg twice daily after 2-4 weeks if tolerated, assessing blood pressure, symptoms, and potassium at each visit. 1, 7 The case report literature suggests that many ESRD patients tolerate 49/51 mg twice daily as a maintenance dose, though the target 97/103 mg dose may not be achievable. 7, 5
One case report documented successful use of 49/51 mg twice daily in a patient with baseline systolic blood pressure in the low range, demonstrating feasibility even with borderline hemodynamics. 7
Monitoring Requirements
Blood Pressure Management
Asymptomatic hypotension (SBP 80-100 mmHg) with adequate perfusion should not prompt dose reduction or discontinuation. 1 The evidence shows that GDMT maintains efficacy and safety even with baseline SBP <110 mmHg. 1
If symptomatic hypotension occurs (SBP <80 mmHg or major symptoms), first address reversible non-HF causes such as excessive ultrafiltration during dialysis, then consider spacing out medication administration. 1
Electrolyte Monitoring
Check potassium and renal function within 1-2 weeks after initiation and with each dose increase. 1 Importantly, sacubitril/valsartan actually reduces hyperkalemia risk compared to ACE inhibitors when combined with mineralocorticoid receptor antagonists (HR 0.63; 95% CI 0.45-0.87 in the DIAMOND trial). 1
Studies in ESRD patients confirm that serum potassium did not increase with sacubitril/valsartan treatment. 4 If hyperkalemia develops, consider potassium binders (patiromer or sodium zirconium cyclosilicate) rather than discontinuing life-saving therapy. 1
Cardiac Function Assessment
Reassess LVEF and symptoms at 3-6 months to document response, as improvements in systolic and diastolic function typically manifest within this timeframe. 4
Integration with Comprehensive HFrEF Therapy
Quadruple Therapy in ESRD
While sacubitril/valsartan is one component of modern HFrEF management, all four foundational drug classes should be considered:
- SGLT2 inhibitors (empagliflozin ≥20 mL/min/1.73 m² or dapagliflozin ≥25 mL/min/1.73 m²) can be used in ESRD patients on dialysis, though evidence is limited. 1, 6
- Evidence-based beta-blockers (carvedilol, metoprolol succinate, or bisoprolol) provide mortality reduction and should be titrated to target doses. 6
- Mineralocorticoid receptor antagonists are contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²) per guidelines, though some ESRD patients may tolerate low doses with careful potassium monitoring. 1
Diuretic Management
Loop diuretics should be titrated to maintain euvolemia (no edema, no orthopnea, no jugular venous distension), using the lowest dose that achieves this state. 6 In ESRD patients on hemodialysis, coordinate diuretic dosing with dialysis schedules to optimize volume management.
Critical Pitfalls to Avoid
Do Not Withhold Due to ESRD Diagnosis Alone
The absence of ESRD patients from PARADIGM-HF does not constitute a contraindication. 1 Real-world evidence demonstrates both safety and substantial mortality benefit in this population. 3, 4
Do Not Discontinue for Modest Creatinine Changes
Changes in kidney function during GDMT optimization must be interpreted in the context of decongestion. 1 In ESRD patients already on dialysis, modest fluctuations in residual renal function should not prompt discontinuation unless accompanied by clinical deterioration.
Do Not Accept Suboptimal Dosing Without Attempting Titration
While the 24/26 mg twice daily starting dose is appropriate, attempt titration to 49/51 mg twice daily unless limited by hypotension or other adverse effects. 7, 5 The case literature suggests this dose is frequently achievable.
Do Not Delay Initiation for "Optimization" of Other Therapies
Start sacubitril/valsartan as soon as eligibility criteria are met, rather than waiting for target doses of other medications. 1, 6 The mortality benefit is time-dependent, and each month of delay represents lost therapeutic opportunity.
Safety Profile in ESRD
The most common adverse effects are hypotension and hyperkalemia, but rates in ESRD patients appear comparable to the general HFrEF population. 7, 5, 4 No increase in serious adverse events was reported in the available case series and cohort studies.
Angioedema risk exists but appears low, with no cases reported in the published ESRD literature. 7, 5, 4 The 36-hour washout from ACE inhibitors remains mandatory to minimize this risk. 1, 6