PharmacologyTier 1Medical Sciences concept

Neprilysin inhibition mechanism in heart failure (sacubitril)

Core concept

Neprilysin (neutral endopeptidase, NEP) degrades a family of vasoactive peptides
- ANP, BNP, CNP, adrenomedullin, substance P, bradykinin, and angiotensin II
Inhibiting neprilysin raises natriuretic peptides -> natriuresis, diuresis, vasodilatation, dec sympathetic tone, dec RAAS activation, dec fibrosis and dec remodelling
But it also raises angiotensin II - so neprilysin inhibition alone is ineffective and must be paired with RAS blockade
Sacubitril/valsartan (ARNI) - a single-crystal complex
- Sacubitril -> LBQ657, the active neprilysin inhibitor
- Valsartan blocks AT1, countering the rise in angiotensin II
The bradykinin problem - both neprilysin and ACE degrade bradykinin
- Blocking both simultaneously -> bradykinin accumulation -> angioedema
- Therefore: never combine an ARNI with an ACE inhibitor; a 36-hour washout is mandatory when switching

PARADIGM-HF - sacubitril/valsartan vs enalapril in HFrEF: dec 20% CV death or HF hospitalisation, dec all-cause mortality; trial stopped early
Practical prescribing
- 36-hour washout from any ACE inhibitor; no washout needed from an ARB
- Start 24/26 mg or 49/51 mg bd depending on prior dose and BP, double every 2-4 weeks to target 97/103 mg bd
- Contraindicated: previous angioedema, pregnancy, bilateral renal artery stenosis, eGFR <30 (caution), symptomatic hypotension
Adverse effects: hypotension (commonest limiting factor), hyperkalaemia, renal impairment, angioedema (higher in Black patients), cough (less than ACEi)
BNP rises on an ARNI - because it is a neprilysin substrate
- NT-proBNP is NOT a neprilysin substrate and remains interpretable - the diagnostic point
- Use NT-proBNP, not BNP, to monitor a patient on sacubitril/valsartan
Neprilysin also degrades amyloid-beta - the theoretical cognitive concern, not borne out in PERSPECTIVE
Neprilysin inhibition is the reason omapatrilat (a dual ACE/NEP inhibitor) failed - unacceptable angioedema

HFrEF: an ARNI replaces the ACE inhibitor or ARB as the preferred RAS-acting pillar, alongside a beta-blocker, an MRA and an SGLT2 inhibitor
- Switch rather than sequence where blood pressure allows; up-titrate all four rapidly (STRONG-HF approach) rather than one at a time
- Also beneficial started in-hospital after stabilisation of acute decompensation (PIONEER-HF)
HFpEF/HFimpEF - modest and less certain benefit (PARAGON-HF was neutral overall, with signal at lower EF and in women)
Practical monitoring: U&E and BP at 1-2 weeks after each dose change
Angioedema on an ACE inhibitor is a contraindication to an ARNI, not just a caution
Do not measure BNP in an ARNI patient and conclude the heart failure is worse

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