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Angiotensin Receptor-Neprilysin Inhibitor (ARNi) Pregnancy: Contraindicated in 2nd and 3rd trimester (valsartan — fetal renal toxicity); avoid in 1st trimester; switch to alternative before conception

Sacubitril/Valsartan

Brand names: Entresto

Adult dose

Dose: Start 24/26 mg twice daily; titrate to 49/51 mg twice daily, then target 97/103 mg twice daily
Route: Oral
Frequency: Twice daily
Max: 97/103 mg twice daily (194/206 mg/day total)
HFrEF (EF ≤40%) — replaces ACE inhibitor or ARB; must not be combined with ACEi; 36-hour washout required when switching FROM ACEi (angioedema risk); start at low dose if hospitalised for acute HF

Paediatric dose

Dose: Weight-based dosing ≥1 year (specialist use) mg/kg
Route: Oral
Frequency: Twice daily
Max: Weight-based
Paediatric HF: specialist cardiology prescribing only

Dose adjustments

Renal

eGFR ≥30: start 24/26 mg twice daily; eGFR <30: use with caution, start lowest dose; avoid in severe renal impairment

Hepatic

Mild: start 24/26 mg twice daily; moderate (Child-Pugh B): start 24/26 mg twice daily; severe: contraindicated

Paediatric weight-based calculator

Paediatric HF: specialist cardiology prescribing only

Clinical pearls

  • PARADIGM-HF (McMurray et al. NEJM 2014): sacubitril/valsartan reduced CV death and HF hospitalisation by 20% vs enalapril in HFrEF — trial stopped early due to overwhelming benefit; 16% relative risk reduction in all-cause mortality; transformed HF management
  • Dual mechanism: valsartan blocks angiotensin II (as standard ARB) + sacubitril inhibits neprilysin (neutral endopeptidase) — neprilysin inhibition prevents degradation of natriuretic peptides (BNP, ANP), bradykinin, and angiotensin II; net effect: vasodilation, natriuresis, anti-fibrotic, anti-hypertrophic
  • 36-hour ACEi washout: combining sacubitril/valsartan with ACEi causes dangerous additive angioedema (both increase bradykinin) — MHRA requirement; when switching from ramipril/lisinopril, stop ACEi and wait 36 hours before starting first sacubitril/valsartan dose; no washout needed switching from ARB
  • BNP vs NT-proBNP monitoring: sacubitril inhibits BNP degradation — BNP levels RISE on treatment (not indicative of worsening HF); use NT-proBNP for monitoring (sacubitril does not affect NT-proBNP metabolism); important to avoid misinterpretation
  • NICE TA506: first-line recommendation for HFrEF with EF ≤35% in patients already on ACEi/ARB + beta-blocker; should replace ACEi/ARB in all eligible patients; significant under-prescribing in clinical practice

Contraindications

  • Concurrent ACE inhibitor use (36-hour washout required)
  • History of ACEi/ARB-related angioedema
  • Severe hepatic impairment
  • 2nd/3rd trimester pregnancy

Side effects

  • Hypotension (especially first doses)
  • Hyperkalaemia
  • Renal impairment
  • Angioedema (risk elevated with prior ACEi angioedema)
  • Dizziness
  • Cough (less than ACEi — valsartan component, not bradykinin)

Interactions

  • ACE inhibitors — NEVER combine; 36-hour washout mandatory when switching (risk of serious angioedema)
  • Potassium-sparing diuretics/potassium supplements — additive hyperkalaemia
  • Lithium — valsartan component increases lithium levels; monitor

Monitoring

  • Blood pressure (each visit)
  • Potassium and eGFR (at 1-2 weeks after each titration, then 3-6 monthly)
  • NT-proBNP (NOT BNP — unreliable on sacubitril)
  • Symptoms of HF (NYHA class)
  • Signs of angioedema (especially early)

Reference: BNFc; BNF 90; PARADIGM-HF (McMurray et al. NEJM 2014); NICE TA506; MHRA SPC Entresto; ESC HF Guidelines (2021). Verify against your local formulary and the latest BNF before prescribing.

Related

Curated clinical cross-links plus same-class fallbacks.

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