Angiotensin Receptor Neprilysin Inhibitors

Angiotensin receptor neprilysin inhibitors combine an angiotensin receptor blocker with a neprilysin inhibitor. Sacubitril-valsartan is the only member. It reduces cardiovascular death and heart failure hospitalisation more than enalapril in heart failure with reduced ejection fraction, and is a first choice in that setting.

Mechanism. Sacubitril is a prodrug converted to sacubitrilat, which inhibits neprilysin. This raises natriuretic peptides (ANP, BNP), bradykinin and adrenomedullin, causing natriuresis, vasodilation and anti-fibrotic effects. Valsartan blocks the AT1 receptor and offsets the rise in angiotensin II that neprilysin inhibition would cause.

Biomarkers. BNP is a neprilysin substrate and rises on treatment, so NT-proBNP is the marker to use for monitoring.

Pharmacokinetics. Sacubitril peaks within 0.5 hours and sacubitrilat within 2 hours. Valsartan in this formulation is more bioavailable than in tablet form, so 51 mg of valsartan here is equivalent to 80 mg of ordinary valsartan. Elimination is mainly renal for sacubitrilat. Sacubitril inhibits OATP1B1 and OATP1B3 transporters.

Pregnancy risk. The valsartan component carries foetal toxicity in the second and third trimesters.

• Sacubitril-valsartan: fixed combination in 24/26 mg, 49/51 mg and 97/103 mg tablets, taken twice daily. Also licensed in some regions for paediatric heart failure and for heart failure with LVEF below normal.

• Reduced ejection fraction: start 49/51 mg twice daily if the patient takes an ACE inhibitor or angiotensin receptor blocker at moderate or high dose. Start 24/26 mg twice daily if treatment-naive, on low doses, systolic pressure 100 to 110 mmHg, eGFR under 30 mL/min/1.73 m2, moderate hepatic impairment, or older age. Double the dose every 2 to 4 weeks to a target of 97/103 mg twice daily.
• Switching from an ACE inhibitor: stop the ACE inhibitor 36 hours before the first dose. Switching from an angiotensin receptor blocker needs no gap.
• Mildly reduced or low-normal preserved ejection fraction: benefit is greatest at the lower end of the range and in women. Use after SGLT2 inhibitor and diuretic.
• Acute decompensation: may be started in hospital once stable and off intravenous vasodilators or inotropes.
• Selection: use in place of an ACE inhibitor or angiotensin receptor blocker in reduced ejection fraction. Where cost or supply limits access, an ACE inhibitor or angiotensin receptor blocker remains a sound choice.

Contraindications. Use of an ACE inhibitor within 36 hours, previous angioedema with an ACE inhibitor or angiotensin receptor blocker, hereditary or idiopathic angioedema, pregnancy, severe hepatic impairment or biliary cirrhosis, and use with aliskiren in diabetes or kidney impairment.

Adverse effects. Hypotension (most frequent, including symptomatic), hyperkalaemia, rise in creatinine, cough, dizziness, and angioedema, which is more frequent in patients of African ancestry.

Interactions. ACE inhibitors, aliskiren, potassium supplements, potassium-sparing diuretics, trimethoprim and NSAIDs. Atorvastatin exposure rises through OATP inhibition. Sildenafil and other vasodilators add hypotension. Lithium levels rise. Loop diuretic doses often need to fall.

Monitoring. Blood pressure, potassium and creatinine at 1 to 2 weeks after each change, then at regular intervals, and NT-proBNP.

Referral and escalation. Lip, tongue or throat swelling needs emergency care and permanent withdrawal.

Special groups. Renal impairment: lower starting dose when eGFR is under 30. Hepatic impairment: moderate disease needs the lower dose, and severe disease contraindicates use. Older adults: higher hypotension risk. Pregnancy: stop. Breastfeeding: avoid. Region: cost limits access in many low-resource settings.