Angiotensin receptor-neprilysin inhibitor (ARNI): sacubitril/valsartan
FMT in HFrEF · Class IAMT in HFpEF · Class IIbRemoval by dialysis
What each drug's prescribing information says about removal by (haemo)dialysis. Where the label is silent, this page says so rather than inferring from protein binding.
- Sacubitril/valsartanNot removed (or not meaningfully removed)
“ENTRESTO is unlikely to be removed by hemodialysis because of high protein binding.”
After starting: what a change in creatinine, eGFR or potassium means
Same thresholds as for an ACE-I: eGFR fall under 30% and potassium up to 5.5 mmol/L acceptable; larger persisting rises, halve the dose and re-check within 1–2 weeks. Reducing the diuretic when not congested matters especially on an SGLT2 inhibitor.
“Some rise in urea (BUN), creatinine, and potassium is to be expected after an ARNI; if an increase is small, no action is necessary.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 Source“A decrease in eGFR of <30% is acceptable.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 Source“An increase in potassium up to ≤5.5 mmol/L is acceptable.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 Source“This is particularly true in those patients on an SGLT2-I.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 Source
A hemodynamic eGFR dip of up to 30% after starting an SGLT2 inhibitor, RAAS inhibitor, MRA or ARNI is expected and should not lead to discontinuation; above 30%, look for other causes of AKI (KDIGO). ESC accepts a creatinine rise of less than 50% above baseline as long as eGFR stays above 15.
“Hemodynamic fluctuations in eGFR up to 30% can be seen and should not lead to discontinuation”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 10“If >30%, other causes of AKI should be evaluated”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 10“An increase in serum creatinine of <50% above baseline, as long as eGFR remains >15 mL/min/1.73 m2, is considered acceptable.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 66, Section 10.3 Source“Worsening kidney function alone is not an independent determinant of outcomes in patients with acute HF.”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 11
Drugs and doses
| Drug | Brands | Start | Target | Kidney dosing |
|---|---|---|---|---|
| Sacubitril/valsartan | Entresto | 49/51 mg b.i.d. (optional 24/26 mg b.i.d.: ACE-I/ARB-naive or low-dose ACE-I/ARB, history of symptomatic hypotension or SBP 100-110 mmHg, eGFR <30 (FDA) or eGFR 30-60 (ESC option), moderate hepatic impairment) | 97/103 mg b.i.d. | FDA: no starting-dose adjustment for eGFR 30-90; start at half dose (24/26 mg b.i.d.) if eGFR <30, then titrate every 2-4 weeks as tolerated. ESC 2026 allows an optional 24/26 mg start for eGFR 30-60 and advises caution if eGFR <30; EMA SmPC suggests considering half dose for eGFR 30-60 and does not recommend use in end-stage renal disease. Not removed by haemodialysis (high protein binding). Washout 36 h after the last ACE-I dose. |
Status by kidney stage
| Stage | Initiate | Continue |
|---|---|---|
| G1 | Recommended HFrEF: ESC 2026 Class I (de novo or switch from ACE-I/ARB); standard 49/51 mg b.i.d. start, no renal dose adjustment. HFpEF: Class IIb only. | Recommended Continue and uptitrate to 97/103 mg b.i.d. as tolerated. |
| G2 | Recommended Class I in HFrEF; standard 49/51 mg b.i.d. start (FDA: no adjustment for eGFR 60-90). | Recommended Continue and uptitrate to target. |
| G3a | Recommended Class I in HFrEF with CKD and eGFR >=30. FDA: no starting-dose adjustment; ESC 2026 offers an optional 24/26 mg b.i.d. start for eGFR 30-60. | Recommended Continue and uptitrate; benefit consistent in CKD, with slower eGFR decline than enalapril. |
| G3b | Recommended Class I in HFrEF (eGFR >=30); consider the optional 24/26 mg b.i.d. start (ESC/EMA) with closer monitoring; FDA requires no adjustment. | Recommended Continue; PARADIGM-HF benefit maintained down to CKD stage 3b. |
| G4 | Use with caution Not studied in PARADIGM-HF (eGFR <30 excluded). FDA permits use: start at half dose (24/26 mg b.i.d.) and titrate; ESC 2026 says use with caution; ESC CVD-CKD 2026 limits its Class I to eGFR >=30 and notes that data are lacking below 30. | Use with caution If eGFR falls below 30 on therapy, continuation under close monitoring should be considered (ESC CVD-CKD 2026 Class IIa; PARADIGM/PARAGON post hoc data show persistent benefit). |
| G5 | Not recommended No trial data at eGFR <15. The FDA label sets no lower eGFR limit beyond half-dose start for eGFR <30, but the EMA SmPC does not recommend use in end-stage renal disease, and ESC CVD-CKD 2026 finds no data for RAS inhibitors in kidney failure. Proposed: do not initiate except by specialist decision. | Use with caution Individualise: ESC 2026 says temporary discontinuation may be needed at eGFR <15 and accepts a creatinine rise only while eGFR stays >15; Beldhuis 2022 suggests considering stopping at eGFR <20. Continue only with specialist input and close K+/creatinine/BP monitoring. |
| dialysis | Not recommended Dialysis patients were excluded from the outcome trials. EMA does not recommend use in ESRD, and ESC CVD-CKD finds no supporting data. Observational cohorts (USRDS 2024; a 2026 meta-analysis) suggest lower all-cause mortality and less hyperkalaemia than ACE-I/ARB. Specialist decision only. | Use with caution Patients already on an ARNI who start dialysis: no guideline guidance. Continuation is reasonable only with specialist input (monitor for intradialytic hypotension and K+). The drug is not removed by haemodialysis. |
| aki | Not recommended Defer initiation until kidney function and volume status have stabilised. The label advises correcting volume depletion first and down-titrating or interrupting the drug when renal function falls significantly. | Use with caution Do not stop for a transient eGFR dip (creatinine rise <50% with eGFR >15 is acceptable). Halve the dose for a larger persistent rise. Temporarily hold for AKI with eGFR <15, a creatinine rise >100% or >3.5 mg/dL, K+ >5.5-6.0, or haemodynamic instability. Restart at the prior dose if held for <14 days. |
| transplant | No data No source makes a kidney-transplant-specific statement about sacubitril/valsartan. Use the eGFR stage of the graft. | No data No transplant-specific guidance found; follow the eGFR-stage rules. |
Cutoffs recorded from the sources
- egfr < 30 mL/min/1.73m2 → caution (dose_reduce; sacubitril-valsartan)“Half of the starting dose is recommended in adult and pediatric patients with heart failure and with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).” — fda-sacubitril-valsartan, Section 8.7 Renal Impairment
- egfr < 30 mL/min/1.73m2 → caution (initiate; sacubitril-valsartan)“Treatment with ACE-Is or ARNIs is indicated, but should be given with caution, to patients with low blood pressures (systolic blood pressure <100 mmHg), kidney insufficiency (eGFR <30 mL/min/1.73 m2), or elevated serum potassium (>5.2 mEq/L).” — esc2026, p. 33, Section 6.1.4.1
- egfr < 30 mL/min/1.73m2 → caution (initiate; sacubitril-valsartan)“Significant hyperkalaemia (K+ >5.2 mmol/L). (3) (4) eGFR <30 mL/min/1.73 m2.” — esc2026-supp, p. 12, Table S5 (Cautions/seek specialist advice)
- egfr <= 60 mL/min/1.73m2 → allowed (dose_reduce; sacubitril-valsartan)“Sacubitril–valsartan may have an optional lower starting dose of 24/26 mg twice daily for those with a history of symptomatic hypotension, ACE-I naïve patients and patients with eGFR 30–60 mL/min/1.73 m2.” — esc2026, p. 37, Table 11 footnote c
- egfr <= 60 mL/min/1.73m2 → caution (dose_reduce; sacubitril-valsartan)“Half of the starting dose should be considered in patients with moderate renal impairment (eGFR 30-60 ml/min/1.73 m2).” — ema-entresto, p. 4, Section 4.2 Renal impairment
- egfr >= 30 mL/min/1.73m2 → recommended (initiate; sacubitril-valsartan)“Treatment with either ACEI, ARNI, or ARB (if ACEI or ARNI not tolerated) is recommended in patients with HFrEF and CKD with an eGFR ≥30 mL/min/1.73 m2 to reduce the risk of HF hospitalization and death.” — esc2026-ckd, p. 39, Recommendation Table 15
- egfr < 30 mL/min/1.73m2 → caution (continue; sacubitril-valsartan)“Similar findings were observed with ARNIs, and continuation may also be considered if eGFR declines to <30 mL/min/1.73 m2, provided generally that overall eGFR does not drop >50% from baseline.” — esc2026-ckd, p. 44, Section 6.4.1
- egfr < 15 mL/min/1.73m2 → not-recommended (initiate; sacubitril-valsartan)“There is no experience in patients with end-stage renal disease and use of Entresto is not recommended.” — ema-entresto, p. 4, Section 4.2 Renal impairment
- egfr < 15 mL/min/1.73m2 → caution (hold; sacubitril-valsartan)“However, temporary discontinuation of MRAs/ARNIs/ACE-Is/ARBs and SGLT2-Is may be needed in cases with acute kidney injury and eGFR <15 mL/min/1.73 m2.” — esc2026, p. 35, Section 6.1.6
- creatinine_rise_pct < 50 % above baseline → allowed (continue; sacubitril-valsartan)“An increase in serum creatinine of <50% above baseline, as long as eGFR remains >15 mL/min/1.73 m2, is considered acceptable.” — esc2026, p. 66, Section 10.3
- other < 30 % eGFR decrease from baseline → allowed (continue; sacubitril-valsartan)“Hemodynamic fluctuations in eGFR up to 30% can be seen and should not lead to discontinuation” — kdigo2026-hf, p. 10, Table 2
- creatinine_rise_pct >= 50 % above baseline (50-100%) → caution (dose_reduce; sacubitril-valsartan)“Evaluate clinical status and other 50-100 3.5 mg/dL 20 5.5 causes of WRF. Consider halving ARNI and re-evaluate” — beldhuis2022, p. 9, Figure 2E
- creatinine_rise_pct > 100 % above baseline → not-recommended (hold; sacubitril-valsartan)“Evaluate clinical status and other > 100 > 3.5 mg/dL < 20 > 5.5 causes of WRF. Consider stopping ARNI and re-evaluate” — beldhuis2022, p. 9, Figure 2E
- egfr < 20 mL/min/1.73m2 → caution (hold; sacubitril-valsartan)“Evaluate clinical status and other > 100 > 3.5 mg/dL < 20 > 5.5 causes of WRF. Consider stopping ARNI and re-evaluate” — beldhuis2022, p. 9, Figure 2E
- creatinine_rise_pct > 50 % above baseline (or creatinine >3.5 mg/dL) → not-recommended (hold; sacubitril-valsartan)“In contrast, only if serum creatinine rises by >50% or above 3.5 mg/dl treatment should be discontinued with re-challenge when possible” — mullens2022, p. 13
- creatinine_abs < 3 mg/dL (with creatinine rise up to 50% and eGFR >25) → allowed (uptitrate; sacubitril-valsartan)“Therefore, practice guidelines and a previous position paper from this working group propose to tolerate an increase of serum creatinine up to 50% if serum creatinine remains below 3.00 mg/dl and eGFR above >25 ml/min/1.73 m2 when titrating ACE-I/ARB/ARNI.” — mullens2022, p. 13
- potassium > 5.2 mmol/L → caution (initiate; sacubitril-valsartan)“Treatment with ACE-Is or ARNIs is indicated, but should be given with caution, to patients with low blood pressures (systolic blood pressure <100 mmHg), kidney insufficiency (eGFR <30 mL/min/1.73 m2), or elevated serum potassium (>5.2 mEq/L).” — esc2026, p. 33, Section 6.1.4.1
- potassium > 5.4 mmol/L → not-recommended (initiate; sacubitril-valsartan)“Treatment should not be initiated in patients with serum potassium level >5.4 mmol/l or with SBP <100 mmHg (see section 4.4).” — ema-entresto, p. 3, Section 4.2
- potassium <= 5.5 mmol/L → allowed (continue; sacubitril-valsartan)“An increase in potassium up to ≤5.5 mmol/L is acceptable.” — esc2026-supp, p. 13, Table S5 (PROBLEM SOLVING)
- potassium > 5.5 mmol/L → caution (dose_reduce; sacubitril-valsartan)“Severe hyperkalaemia (potassium >5.5 or >6 mmol/L) should lead to temporary down-titration or discontinuation of MRAs and/or ARNIs/ACE-Is/ARBs (see Supplementary data online, Tables S4, S5 and S9).” — esc2026, p. 35, Section 6.1.6
- potassium > 6 mmol/L → not-recommended (hold; sacubitril-valsartan)“Generally, dose reduction of these agents is advised if potassium is between 5.5 mEq/L and 6 mEq/L and temporarily termination if potassium is above 6 mEq/L, with reinstitution of the drug only when the potassium drops below 5.5 mEq/L.” — mullens2022, p. 13
- potassium > 5.4 mmol/L → caution (hold; sacubitril-valsartan)“If serum potassium level is >5.4 mmol/l discontinuation should be considered.” — ema-entresto, p. 6, Section 4.4 Hyperkalaemia
- sbp < 100 mmHg → caution (initiate; sacubitril-valsartan)“Treatment with ACE-Is or ARNIs is indicated, but should be given with caution, to patients with low blood pressures (systolic blood pressure <100 mmHg), kidney insufficiency (eGFR <30 mL/min/1.73 m2), or elevated serum potassium (>5.2 mEq/L).” — esc2026, p. 33, Section 6.1.4.1
- sbp < 90 mmHg → contraindicated (initiate; sacubitril-valsartan)“Symptoms of hypotension or a systolic blood pressure <90 mmHg (PARADIGM-HF enrolled patients with a systolic blood pressure >95 mmHg at randomization).” — esc2026-supp, p. 12, Table S5 (Contraindications)
- sbp < 100 mmHg → not-recommended (initiate; sacubitril-valsartan)“Treatment should not be initiated unless SBP is ≥100 mmHg for adult patients or ≥5th percentile SBP for the age of the paediatric patient.” — ema-entresto, p. 5, Section 4.4 Hypotension
- sbp <= 110 mmHg (100-110) → caution (dose_reduce; sacubitril-valsartan)“In some patients, one may consider a reduced starting dose (24/26 mg b.i.d.), namely in those with systolic blood pressure 100–110 mmHg, ACE-I/ARB naïve patients, and in those with CKD.” — esc2026-supp, p. 13, Table S5 (HOW TO USE?)
- sbp <= 95 mmHg → caution (dose_reduce; sacubitril-valsartan)“If patients experience tolerability issues (systolic blood pressure [SBP] ≤95 mmHg, symptomatic hypotension, hyperkalaemia, renal dysfunction), adjustment of concomitant medicinal products, temporary down–titration or discontinuation of Entresto is recommended (see section 4.4).” — ema-entresto, p. 3, Section 4.2
- other >= 36 hours since last ACE-I dose → contraindicated (initiate; sacubitril-valsartan)“If switching from an ACE inhibitor to ENTRESTO allow a washout period of 36 hours between administration of the two drugs” — fda-sacubitril-valsartan, Section 2.1 General Considerations
- egfr < 60 mL/min/1.73m2 → not-recommended (initiate; sacubitril-valsartan)“Avoid use with aliskiren in patients with renal impairment (eGFR less than 60 mL/min/1.73 m2).” — fda-sacubitril-valsartan, Section 7.1 Dual Blockade of the Renin-Angiotensin-Aldosterone System
Trial evidence (informational)
- PARADIGM-HF · HFrEF (LVEF <=40%), NYHA II-IV, on ACE-I/ARB; eGFR <30 and SBP <100 excludedCV death or HF hospitalization (vs enalapril): HR 0.80 (95% CI 0.73-0.87)“At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001).” — mcmurray2014, Abstract
- PARADIGM-HF · HFrEFAll-cause death (vs enalapril): HR 0.84 (95% CI 0.76-0.93)“ENTRESTO also improved overall survival (HR 0.84; 95% CI [0.76, 0.93], p = 0.0009) (Table 4).” — fda-sacubitril-valsartan, Section 14.1 Adult Heart Failure
- PARADIGM-HF (renal analysis) · HFrEF, 33% with CKD at screeningeGFR slope (vs enalapril): -1.61 vs -2.04 mL/min/1.73m2/year“The effect of sacubitril/valsartan on cardiovascular death or heart failure hospitalization was not modified by eGFR, UACR (p interaction = 0.70 and 0.34, respectively), or by change in UACR (p interaction = 0.38).” — damman2018, Abstract
- PARADIGM-HF + PARAGON-HF (post hoc) · Patients whose eGFR fell to <30 during follow-upPrimary outcome with continued ARNI vs RASi: Benefit maintained (P-interaction 0.50 and 0.64); no incremental safety risk“Continuation of sacubitril/valsartan was associated with persistent clinical benefit and no incremental safety risk.” — chatur2024-egfr, Abstract
- PARAGON-HF · HF with LVEF >=45%, structural heart disease, elevated NPs; SBP <110 excludedTotal HF hospitalizations and CV death (vs valsartan): RR 0.87 (95% CI 0.75-1.01), P=0.06 (neutral)“There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06).” — solomon2019, Abstract
- PARAGON-HF · HF with LVEF >=45%Worsening renal function (secondary): 1.4% vs 2.7%, HR 0.50 (95% CI 0.33-0.77)“renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77).” — solomon2019, Abstract
- PIONEER-HF · HFrEF hospitalized for ADHF after haemodynamic stabilizationTime-averaged change in NT-proBNP (vs enalapril): Ratio of change 0.71 (95% CI 0.63-0.81)“Rates of worsening renal function, hyperkalemia, symptomatic hypotension, and angioedema did not differ significantly between the two groups.” — velazquez2019, Abstract
- UK HARP-III · CKD, eGFR 20-60 (HF not required)Measured GFR at 12 months (vs irbesartan): No difference (-0.1 mL/min/1.73m2); lower BP and NT-proBNP“At 12 months, there was no difference in measured GFR: 29.8 (SE 0.5) among those assigned sacubitril/valsartan versus 29.9 (SE, 0.5) mL/min/1.73 m2 among those assigned irbesartan; difference, -0.1 (0.7) mL/min/1.73 m2.” — haynes2018, Abstract
- Vaduganathan 2026 (cross-trial modelling) · HFmrEF/HFpEF with LVEF <60%CV death or first worsening HF event with SGLT2i + nsMRA + ARNI: HR 0.61 (95% CI 0.48-0.77)“In individuals with an LVEF below normal (<60%), the combined use of SGLT2i, nsMRA and ARNI was estimated to reduce risk by 39% (HR 0.61; 95% CI 0.48–0.77)” — vaduganathan2026, p. 3
- Le 2024 (USRDS, observational) · HFrEF on in-centre haemodialysisAll-cause mortality, new ARNI vs ACE-I/ARB: HR 0.82 (95% CI 0.73-0.92)“There was a decrease in hyperkalemia (HR, 0.71 [95% CI, 0.62-0.81]) and no difference in hypotension (HR, 0.99 [95% CI, 0.83-1.19]).” — le2024, Abstract
Acute kidney injury
Do not start an ARNI during AKI; wait until the patient is euvolaemic and creatinine is stable. On therapy, a transient eGFR dip (creatinine rise <50%, eGFR >15; or eGFR fall <30%) is expected and should not prompt interruption. Persistent larger rises: first stop nephrotoxins and K+-retaining drugs and reduce the diuretic if not congested, then halve the ARNI and recheck in 1-2 weeks. Hold temporarily for AKI with eGFR <15, creatinine >100% above baseline or >3.5 mg/dL, K+ >5.5-6.0, or severe haemodynamic instability. Rechallenge after recovery, at the previous dose if held <14 days.
“Temporary discontinuation of beta-blockers and ARNIs/ACE-Is/ARBs is advised in patients with severe haemodynamic instability.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 35, Section 6.1.6 Source“If greater rises in creatinine or potassium than those outlined above persist despite adjustment of concomitant medications, the dose of the ARNI should be halved and blood chemistry rechecked within 1–2 weeks; if there is still an unsatisfactory response, specialist advice should be sought.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 (PROBLEM SOLVING) Source“When WRF develops during initiation of ARNI, therapy should be continued (and uptitrated) unless the increase in serum creatinine (and potassium) is large (Figure 2E).”
Beldhuis 2022 Circulation: Evidence-based medical therapy in HFrEF patients with CKD (2022)· p. 13 Source“Hemodynamic fluctuations in eGFR up to 30% can be seen and should not lead to discontinuation”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 10, Table 2“Correct volume or salt depletion prior to administration of ENTRESTO or start at a lower dose.”
Dialysis
No outcome RCT. PARADIGM-HF and PARAGON-HF excluded eGFR <30, so dialysis patients were not studied. The FDA label is silent apart from noting the drug is not dialysable. EMA does not recommend use in ESRD. ESC CVD-CKD 2026 finds no data for RAS inhibitors in kidney failure or dialysis. Observational data favour the ARNI: USRDS/Medicare 2024 (n=2868 matched) showed lower all-cause mortality and less hyperkalaemia vs ACE-I/ARB, and a 2026 meta-analysis found pooled all-cause mortality HR 0.78 but no significant CV-mortality effect. Small PK studies in HD and PD support 100 mg b.i.d. (49/51 mg b.i.d.). Proposed: initiation not recommended outside specialist care; continuation with caution.
Trials: Sacubitril/valsartan in PD (Silva 2026 meta-analysis), HD cohort, 2868 HFrEF patients (cited by Li 2025), Guo 2026 HD cohort (dose reduction/discontinuation)
“No studies have been performed in patients undergoing dialysis. However, LBQ657 and valsartan are highly bound to plasma protein and therefore unlikely to be effectively removed by dialysis.”
“Sacubitril-valsartan (vs ACEI or ARB) therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.82 [95% CI, 0.73-0.92]) and all-cause hospitalization (HR, 0.86 [95% CI, 0.79-0.93]) but not cardiovascular mortality (HR, 1.01 [95% CI, 0.86-1.19]) or HF hospitalization (HR, 0.91 [95% CI, 0.82-1.02]).”
Le D, Grams ME, Coresh J, Shin JI. Sacubitril-valsartan in patients requiring hemodialysis. JAMA Netw Open 2024;7:e2429237 (USRDS/Medicare propensity-matched cohort). PubMed abstract (2024)· Abstract Source“These findings suggest a potential overall benefit of RAS blockade in this population; however, they are derived predominantly from observational studies, remain susceptible to residual confounding and should not be interpreted as demonstrating causal treatment effects.”
Sritharan A et al. Renin-angiotensin system inhibition in dialysis-dependent patients with chronic HFrEF: a systematic review and meta-analysis. Nephrol Dial Transplant 2026 (online ahead of print, gfag184). PubMed abstract (2026)· Abstract Source“Safety analysis indicated no differences in incidence of hyperkalemia (pooled odds ratio [OR] 0.72; 95% CI: 0.38, 1.36) or hypotension (pooled risk ratio [RR] 1.03; 95% CI: 0.36, 2.98).”
Charkviani M et al. Systematic review of cardiovascular benefits and safety of sacubitril-valsartan in end-stage kidney disease. Kidney Int Rep 2024;9:39-51. PubMed abstract (2024)· Abstract Source“HD did not remove the SAC metabolite LBQ657 or VAL in patients with HF. However, SAC/VAL 100 mg BID was safe and effective in patients undergoing HD.”
Feng Z et al. Pharmacokinetics and pharmacodynamics of sacubitril/valsartan in maintenance hemodialysis patients with heart failure. Blood Purif 2022;51:270-279. PubMed abstract (2022)· Abstract Source“Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF.”
He Y et al. Pharmacokinetics and pharmacodynamics of sacubitril/valsartan in peritoneal dialysis patients. Nephrol Dial Transplant 2023;38:1880-1889. PubMed abstract (2023)· Abstract Source“Efficacy and safety of GDMT in end-stage renal disease or in patients with eGFR <30 mL/min/1.73 m 2 .”
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure (2022)· p. 107, evidence gaps table Source“There is no experience in patients with end-stage renal disease and use of Entresto is not recommended.”
“Treatment of HF with an ARNI may slow the rate of kidney function decline compared with ACEIs, making them an attractive option in patients at high risk of progressive kidney dysfunction; however, data are lacking in patients with eGFR <30 mL/ min/1.73 m2.”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 36, Section 6.2.2.1.1 Source“Sacubitril/valsartan may benefit ESRD patients with heart failure by improving ventricular remodeling and cardiac function while reducing mortality and hospitalization risks, without major safety concerns. However, larger studies are needed for confirmation.”
Li P et al. Efficacy and safety of sacubitril/valsartan in ESRD patients with heart failure: a review. Ann Med 2025 (PMC12422042) (2025)· Abstract, Conclusion Source“Sacubitril-valsartan is generally contraindicated or not recommended in patients with ESRD or severe renal impairment (eGFR <30 ml/min/1.73 m²) due to several concerns, including mainly the risk of hyperkalaemia and hypotension [74].”
Touzot M et al. Prescription of off-label medications in patients on dialysis. Clin Kidney J 2026 (PMC13184690) (2026)· Sacubitril/valsartan Source
Kidney transplant
No ARNI-specific data or guidance for kidney transplant recipients; apply the graft's eGFR stage. (KDIGO 2026 HF notes that HF therapy is poorly studied in kidney failure treated with dialysis or transplantation; text not quotable because of two-column extraction.)
“Further, while there is emerging data supporting the efficacy of ARNI among patients undergoing dialysis [63] and those with advanced non-dialysis CKD [64], this drug class has not been studied in the kidney transplant population to date.”
Ghimire A et al. Heart Failure in Kidney Transplant Recipients: Narrative Review of Risk Factors, Therapy, and Current Gaps. Cardiol Ther 2026 (PMC12988941) (2026)· RAS inhibitors Source“Despite the lack of interventional studies for HF therapy specifically targeting KTR, it is generally recommended to treat HF the same as would be indicated in the general population [18, 21].”
Ghimire A et al. Heart Failure in Kidney Transplant Recipients: Narrative Review of Risk Factors, Therapy, and Current Gaps. Cardiol Ther 2026 (PMC12988941) (2026)· Section: Heart failure therapy in KTR Source
Albuminuria
Albuminuria does not change ARNI eligibility. Sacubitril/valsartan slightly raises UACR versus enalapril (attributed to neprilysin effects on the glomerular barrier and tubules, not to nephron loss) while slowing eGFR decline. UK HARP-III showed no clear UACR difference vs irbesartan. Benefit was consistent across KDIGO GFR/albuminuria risk categories in PARADIGM-HF.
“Sacubitril–valsartan, compared with enalapril, led to a slower decline in kidney function, despite a slight increase in the UACR, and improved CV outcomes to a similar extent in patients with CKD vs other patients in the PARADIGM-HF trial.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 66, Section 10.3 Source“Sacubitril/valsartan exhibited consistent CV and kidney protective benefits as well as safety across the spectrum of baseline kidney risk.”
Chatur S et al. Effects of sacubitril/valsartan across the spectrum of renal impairment in patients with heart failure (PARADIGM-HF, KDIGO risk). J Am Coll Cardiol 2024;83:2148-2159. PubMed abstract (2024)· Abstract Source“There was also no significant difference in estimated GFR at 3, 6, 9, or 12 months and no clear difference in urinary albumin:creatinine ratio between treatment arms (study average difference, -9%; 95% CI, -18 to 1).”
Haynes R et al. Effects of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease (UK HARP-III). Circulation 2018;138:1505-1514. PubMed abstract (2018)· Abstract Source
Monitoring
Check creatinine/eGFR and K+ before starting. Recheck 1-2 weeks after initiation and after the final titration step, then every 4-6 months (the trials checked at ~14 days and every 4 months). Monitor more often in CKD G4-G5 and until creatinine and K+ plateau. Monitor BP during titration. The label calls for periodic K+ checks, especially with severe renal impairment, diabetes, or MRA/K+ supplements. (ESC Table S5 also says to monitor blood chemistry every 4-6 months; that wording is identical in Table S4 and is not quoted separately.)
“Aim for the target dose (see above) or, failing that, the highest tolerated dose. • Recheck blood chemistry (urea/BUN, creatinine, K+) 1–2 weeks after initiation and 1–2 weeks after final dose titration.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 (HOW TO USE?) Source“Monitor serum potassium periodically and treat appropriately, especially in patients with risk factors for hyperkalemia such as severe renal impairment, diabetes, hypoaldosteronism, or a high potassium diet.”
“In the ACE-I/ARB/ARNI and SGLT2 inhibitor trials, laboratory assessment of creatinine, urea, eGFR and electrolytes was typically done after 14 days during drug titration and every 4 months thereafter.”
“However, in clinical practice, individualization according to the KDIGO stage should be considered, with more frequent analysis in CKD stage 5 or stage 4 with macro-albuminuria.”
In-hospital initiation
Continue an existing ARNI during a decompensation unless there is hypoperfusion or severe haemodynamic instability. Start de novo (or switch from ACE-I/ARB) once the patient is haemodynamically stable and decongested, ideally before discharge (PIONEER-HF, TRANSITION). Exclude volume depletion. Hypotension is the main risk: up to 25% in PIONEER-HF. Rapid in-hospital uptitration is acceptable with close monitoring.
“In patients already receiving FMT, continuation and/or rapid reintroduction as soon as possible is recommended.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 45, Section 7.4.1 Source“Data from recent RCTs have demonstrated that initiating MRAs, SGLT2-Is, or ARNIs is feasible and safe in this phase of DHF.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 46, Section 7.4.2 Source“In patients hospitalized with DHF—after stabilizing, relieving congestion, and if possible, restoring ‘euvolaemia’ (but ideally before discharge).”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 (WHERE?) Source“An intensive strategy of rapid initiation and uptitration of FMT before discharge and during frequent follow-up visits in the first 6 weeks following an HFH is recommended to reduce the risk of HF rehospitalization or death.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 47, Recommendation Table 8 Source“In patients with HFrEF, GDMT should be initiated during hospitalization after clinical stability is achieved”
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure (2022)· p. 80, recommendations for GDMT during hospitalization, rec 3 (COR 1, LOE B-NR) Source“in PIONEER-HF, up to 25% of patients developed hypotension when treated with sacubitril/valsartan.”
“Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks.”
Wachter R et al. Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study. Eur J Heart Fail 2019;21:998-1007. PubMed abstract (2019)· Abstract Source
Outpatient
Start in stable outpatients; refer NYHA IV, advanced HF, or recent exacerbation for specialist input. Double the dose every 2-4 weeks (label; ESC Table S5 advises intervals of at least 2 weeks when close monitoring is not possible). Switch from ACE-I with a 36-h washout. Avoid NSAIDs and K+-rich salt substitutes. Do not stop for asymptomatic low BP.
“target dose 97/103 mg b.i.d. WHERE? • In the community in stable patients (NYHA class IV/patients with advanced HF and those with a current/recent exacerbation should be referred for specialist advice).”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 (WHERE?) Source“Double the dose of ENTRESTO after 2 to 4 weeks to the target maintenance dose of 97/103 mg twice daily, as tolerated by the patient.”
“Asymptomatic or tolerable hypotension should not lead to downtitration or discontinuation of FMT but may require re-evaluation of diuretic use.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 35, Section 6.1.6 Source“It is very rarely necessary to stop an ARNI, and clinical deterioration is likely if treatment is withdrawn.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 (HOW TO USE?) Source
Where sources disagree
Starting dose at eGFR 30-60
“No starting dose adjustment is needed for mild or moderate renal impairment.”
ENTRESTO (sacubitril/valsartan) PI, Novartis (2026)· Section 2.7 Dose Adjustment for Severe Renal Impairment Source“Sacubitril–valsartan may have an optional lower starting dose of 24/26 mg twice daily for those with a history of symptomatic hypotension, ACE-I naïve patients and patients with eGFR 30–60 mL/min/1.73 m2.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 37, Table 11 footnote c Source“Half of the starting dose should be considered in patients with moderate renal impairment (eGFR 30-60 ml/min/1.73 m2).”
Tool uses fda-sacubitril-valsartan: Label > guideline: default start 49/51 mg b.i.d. at eGFR >=30. Show the ESC/EMA option of 24/26 mg as an allowed alternative, as both are optional ('may', 'should be considered').
Initiation at eGFR <30 (CKD G4)
“Half of the starting dose is recommended in adult and pediatric patients with heart failure and with severe renal impairment (eGFR less than 30 mL/min/1.73 m2).”
“Treatment with ACE-Is or ARNIs is indicated, but should be given with caution, to patients with low blood pressures (systolic blood pressure <100 mmHg), kidney insufficiency (eGFR <30 mL/min/1.73 m2), or elevated serum potassium (>5.2 mEq/L).”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 33, Section 6.1.4.1 Source“Treatment of HF with an ARNI may slow the rate of kidney function decline compared with ACEIs, making them an attractive option in patients at high risk of progressive kidney dysfunction; however, data are lacking in patients with eGFR <30 mL/min/1.73 m2.”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 36, Section 6.2.2.1.1 Source“4. Known allergic reaction/other adverse reaction (drug-specific). 5. eGFR <30 mL/min/1.73 m2.”
2021 ESC HF Guidelines Supplementary Data (2021)· p. 13, Supplementary Table 5 (Contraindications) Source
Tool uses fda-sacubitril-valsartan: Label > guideline, and ESC 2026 also permits it with caution: status 'caution' with a 24/26 mg b.i.d. start. The 2021 ESC 'contraindication' was dropped in the 2026 Table S5, which lists eGFR <30 under cautions.
End-stage kidney disease / dialysis
“ENTRESTO is unlikely to be removed by hemodialysis because of high protein binding.”
“There is no experience in patients with end-stage renal disease and use of Entresto is not recommended.”
“There are no data to support the use of these agents in patients with HFrEF with kidney failure (eGFR <15 mL/min/1.73 m2 or dialysis).”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 36, Section 6.2.2.1.1 Source“In this comparative effectiveness study of patients with HFrEF requiring hemodialysis, sacubitril-valsartan therapy was associated with beneficial effects in all-cause mortality and all-cause hospitalization.”
Le D, Grams ME, Coresh J, Shin JI. Sacubitril-valsartan in patients requiring hemodialysis. JAMA Netw Open 2024;7:e2429237 (USRDS/Medicare propensity-matched cohort). PubMed abstract (2024)· Abstract Source
Tool uses ema-entresto: The FDA label has no ESRD/dialysis statement, so the next regulatory source (EMA) and ESC CVD-CKD decide. Conservative choice per the brief: initiation 'not-recommended' (specialist only), continuation 'caution'. Observational benefit is shown as information. Owner to confirm.
Continuation when eGFR falls below 30
“Continuation of an ARNI should be considered in patients with HF and CKD in whom the eGFR progresses to <30 mL/min/1.73 m2,c to avoid worsening of HF.”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 44, Recommendation Table 18 (Class IIa, Level C) Source“Continuation of therapy, under close monitoring, if eGFR falls below 30 mL/min/1.73 m2 might therefore be appropriate.”
2026 ESC Guidelines for the management of cardiovascular disease and chronic kidney disease, in collaboration with the ERA (2026)· p. 36, Section 6.2.2.1.1 Source“Evaluate clinical status and other > 100 > 3.5 mg/dL < 20 > 5.5 causes of WRF. Consider stopping ARNI and re-evaluate”
Beldhuis 2022 Circulation: Evidence-based medical therapy in HFrEF patients with CKD (2022)· p. 9, Figure 2E Source
Tool uses esc2026-ckd: The ESC 2026 guideline outranks the 2022 review: continue with caution below 30; consider stopping below 20 (Beldhuis) or if eGFR drops >50% from baseline (ESC CVD-CKD p. 44).
Potassium ceiling for initiation
“Treatment with ACE-Is or ARNIs is indicated, but should be given with caution, to patients with low blood pressures (systolic blood pressure <100 mmHg), kidney insufficiency (eGFR <30 mL/min/1.73 m2), or elevated serum potassium (>5.2 mEq/L).”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 33, Section 6.1.4.1 Source“Treatment should not be initiated in patients with serum potassium level >5.4 mmol/l or with SBP <100 mmHg (see section 4.4).”
Tool uses esc2026: The FDA label gives no K+ cutoff; ESC 2026 (primary guideline) gives >5.2 = caution. Optionally show >5.4 (EMA) as the hard 'do not initiate' level.
Systolic blood pressure floor for initiation
“Symptoms of hypotension or a systolic blood pressure <90 mmHg (PARADIGM-HF enrolled patients with a systolic blood pressure >95 mmHg at randomization).”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 12, Table S5 (Contraindications) Source“Treatment with ACE-Is or ARNIs is indicated, but should be given with caution, to patients with low blood pressures (systolic blood pressure <100 mmHg), kidney insufficiency (eGFR <30 mL/min/1.73 m2), or elevated serum potassium (>5.2 mEq/L).”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 33, Section 6.1.4.1 Source“Treatment should not be initiated unless SBP is ≥100 mmHg for adult patients or ≥5th percentile SBP for the age of the paediatric patient.”
“Patients with a systolic blood pressure of less than 100 mmHg at screening were excluded.”
Tool uses esc2026: The FDA label sets no SBP cutoff (trial exclusion only). Use ESC: SBP <90 or symptomatic hypotension = do not start; SBP 90-99 = caution; SBP 100-110 = consider a 24/26 mg start.
ARNI in HFpEF / LVEF range
“ENTRESTO is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in adult patients with chronic heart failure. Benefits are most clearly evident in patients with left ventricular ejection fraction (LVEF) below normal.”
“A meta-analysis of the PARADIGM-HF and PARAGON-HF trials showed a benefit of sacubitril–valsartan compared with valsartan in patients with an LVEF below 60-65%.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 36, Section 6.1.7.1 Source“All patients with HF and persisting symptoms (NYHA classes II–IV), irrespective of LVEF.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 12, Table S5 (IN WHOM AND WHEN?) Source
Tool uses esc2026: Per the brief, ESC 2026 is the frame: HFpEF = AMT, Class IIb (main Rec Table 5). Table S5's 'irrespective of LVEF' conflicts with the main recommendation and should not raise the class. Show the FDA 'LVEF below normal' indication and the ACC 2026 HFpEF ECDP as US context.
Acceptable kidney-function change during titration
“An increase in serum creatinine of <50% above baseline, as long as eGFR remains >15 mL/min/1.73 m2, is considered acceptable.”
2026 ESC Guidelines for the diagnosis and treatment of heart failure (2026)· p. 66, Section 10.3 Source“Some rise in urea (BUN), creatinine, and potassium is to be expected after an ARNI; if an increase is small, no action is necessary.”
2026 ESC Guidelines for the management of heart failure: Supplementary data (Tables S1-S26) (2026)· p. 13, Table S5 (PROBLEM SOLVING) Source“Therefore, practice guidelines and a previous position paper from this working group propose to tolerate an increase of serum creatinine up to 50% if serum creatinine remains below 3.00 mg/dl and eGFR above >25 ml/min/1.73 m2 when titrating ACE-I/ARB/ARNI.”
“Hemodynamic fluctuations in eGFR up to 30% can be seen and should not lead to discontinuation”
Lam CSP, Bozkurt B, Cherney DZI, et al. Kidney Disease and Heart Failure: Recent Advances and Current Challenges. Conclusions From a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. JACC: Heart Failure 2026 (KDIGO Executive Conclusions) (2026)· p. 10, Table 2
Tool uses esc2026: Main ESC 2026 text: creatinine rise <50% with eGFR >15 is acceptable. Table S5 and KDIGO use eGFR fall <30%, roughly equivalent to a creatinine rise of ~40-50%. Expose both as user-adjustable thresholds.
ARNI in HFpEF: ESC 2026 (Class IIb) versus the ACC 2026 HFpEF pathway
“ACE-I/ARB/ARNI may be considered in patients with symptomatic HFpEF to reduce the risk of HFH.”
“Although no strong recommendation is given to start these agents in patients with HFpEF, many have coexisting indications for ACE-I/ARB therapy (hypertension/diabetes/CKD).”
“Therefore, sacubitril-valsartan may be a reasonable choice for women or those with LVEF of <57%, particularly if additional blood pressure control is warranted.”
Kittleson MM, et al. Management of Heart Failure With Preserved Ejection Fraction: 2026 ACC Expert Consensus Decision Pathway. JACC 2026 (2026)· p. 17 Source“Sacubitril-valsartan offers a reduction in HF hospitalizations in subgroups of women and those with LVEF of <55% to 60%.”
Kittleson MM, et al. Management of Heart Failure With Preserved Ejection Fraction: 2026 ACC Expert Consensus Decision Pathway. JACC 2026 (2026)· p. 17 Source“ARBs provide a modest benefit in reducing the risk of HF hospitalizations and should be considered when angiotensin receptor–neprilysin inhibitors are contraindicated or unaffordable.”
Kittleson MM, et al. Management of Heart Failure With Preserved Ejection Fraction: 2026 ACC Expert Consensus Decision Pathway. JACC 2026 (2026)· p. 17 Source“Angiotensin-converting enzyme inhibitors are not considered a suitable alternative due to a lack of benefit with perindopril in the PEP-CHF (Perindopril in Elderly People with Chronic Heart Failure) trial.”
Kittleson MM, et al. Management of Heart Failure With Preserved Ejection Fraction: 2026 ACC Expert Consensus Decision Pathway. JACC 2026 (2026)· p. 17 Source
Tool uses esc2026: ESC 2026 frames the tool: ARNI is AMT (Class IIb) in HFpEF. The ACC 2026 pathway does include sacubitril-valsartan as a reasonable choice for women or LVEF <57% (an ARB when ARNI is contraindicated or unaffordable; ACE inhibitors not suitable). The tool's explanation shows both.
Open questions
- Dialysis: initiation set to 'not-recommended' and continuation to 'caution' (EMA ESRD statement + ESC CVD-CKD 'no data'), despite consistent observational mortality benefit (Le 2024, Sritharan 2026) and an FDA label that is silent. Owner to confirm, or relax to 'caution' for both.
- G5 (eGFR <15, not on dialysis): initiation 'not-recommended' and continuation 'caution'. The FDA label technically permits a half-dose start at any eGFR <30.
- eGFR 30-60 starting dose: default to the FDA 49/51 mg with ESC's optional 24/26 mg shown as an alternative, or default to 24/26 mg (more conservative; EMA/ESC)?
- KDIGO 2026 HF Figure (p. 11) appears to list ARNI/ACEi/ARB for HFrEF only in the eGFR 30-59 and >=60 columns (extraction scrambled, not quoted). This would be another source not endorsing ARNI initiation at eGFR 15-29; verify visually in the PDF.
- ESC 2026 Table S5 lists symptomatic hypotension/SBP <90 as a 'contraindication' (expert opinion), while main text says 'caution' at SBP <100. Use SBP <90 as the hard stop?
- Beldhuis 2022 Figure 2E thresholds are quoted from a column-scrambled table extraction; a visual check of the PDF figure is advised before using them as defaults.