Sacubitril Valsartan

Sacubitril valsartan is a fixed combination of a neprilysin inhibitor (sacubitril, a prodrug) and an angiotensin receptor blocker (valsartan). It reduces cardiovascular death and heart failure admission compared with enalapril in heart failure with reduced ejection fraction. It replaces an angiotensin converting enzyme inhibitor or angiotensin receptor blocker in selected patients. It is expensive and limited in East Africa.

Classification. Angiotensin receptor neprilysin inhibitor.

Mechanism. Sacubitrilat inhibits neprilysin, which breaks down natriuretic peptides, bradykinin and other peptides, raising natriuresis and vasodilation. Valsartan blocks the AT1 receptor. Neprilysin inhibition alone would raise angiotensin II, so the angiotensin receptor blocker is essential.

Pharmacodynamics. Lowers blood pressure and natriuretic peptide effects within hours; raises BNP (not NT-proBNP) because neprilysin degrades BNP; use NT-proBNP to monitor. Increases cyclic GMP.

Pharmacokinetics. Sacubitril is converted by esterases to sacubitrilat (peak 2 hours; half life about 11 hours). Valsartan in this product is more bioavailable than standalone tablets, so 26, 51 and 103 mg valsartan equal 40, 80 and 160 mg of other valsartan products. Valsartan half life about 10 hours.

Heart failure with reduced ejection fraction, adult.

• Usual start 49 mg sacubitril with 51 mg valsartan (49/51 mg) twice daily.

• Start 24/26 mg twice daily if not on an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, on a low dose of either (enalapril 10 mg daily or less, or equivalent), with eGFR under 30 mL/min, with moderate hepatic impairment, or in older or frail patients.

• Double the dose every 2 to 4 weeks as tolerated to the target of 97/103 mg twice daily.

• Maximum 97/103 mg twice daily (194/206 mg daily).

• Washout: stop any angiotensin converting enzyme inhibitor 36 hours before the first dose.

Heart failure in children aged 1 year and over (licensed in some markets). Weight based dosing: under 40 kg start 1.6 mg/kg twice daily; 40 to under 50 kg start 24/26 mg twice daily; titrate every 2 to 4 weeks; specialist.

Symptomatic heart failure with mildly reduced or preserved ejection fraction (selected patients). Use the doses given for reduced ejection fraction; benefit is greatest at the lower end of the ejection fraction range.

Contraindications. History of angioedema (hereditary, idiopathic or related to an angiotensin converting enzyme inhibitor or angiotensin receptor blocker); concurrent angiotensin converting enzyme inhibitor or use within 36 hours; pregnancy; severe hepatic impairment (Child-Pugh C), biliary cirrhosis and cholestasis; aliskiren in diabetes or kidney impairment; hypersensitivity.

Warnings. Symptomatic hypotension, especially in volume depletion and in those starting low; hyperkalaemia; kidney function decline; angioedema, more often in patients of African ancestry (stop permanently if it occurs). Sick day rule: hold during dehydrating illness. Bilateral renal artery stenosis.

Adverse effects. Hypotension, hyperkalaemia, creatinine rise, cough, dizziness, angioedema, kidney impairment.

Interactions. Angiotensin converting enzyme inhibitors: contraindicated (angioedema). Potassium supplements, potassium sparing diuretics, trimethoprim: hyperkalaemia. Non steroidal anti-inflammatory drugs: kidney injury. Lithium: toxicity. Sildenafil and other vasodilators: hypotension. Statins (atorvastatin): raised exposure through transporter inhibition. Metformin: small rise in levels.

Special groups.

• Pregnancy: contraindicated; stop when pregnancy is confirmed.

• Breastfeeding: avoid; no data.

• Patients of African ancestry: higher angioedema risk; start with low dose and close observation.

• Older adults: start at 24/26 mg twice daily.

• Kidney impairment: eGFR under 30 mL/min: start 24/26 mg twice daily; titrate with monitoring.

• Liver impairment: moderate (Child-Pugh B): start 24/26 mg twice daily; severe: avoid.

Formulations. Tablets 24/26, 49/51, 97/103 mg (sacubitril/valsartan).

Administration. Oral twice daily, with or without food, about 12 hours apart. Do not combine with a separate valsartan or angiotensin receptor blocker tablet.

Baseline. Blood pressure, creatinine and eGFR, potassium, NT-proBNP, pregnancy status, 36 hour washout if previously on an angiotensin converting enzyme inhibitor.

Monitoring. Blood pressure, creatinine and potassium 1 to 2 weeks after starting and after each dose increase, then every 3 to 6 months. Accept a creatinine rise up to 30%; reduce or stop if over 30% or potassium is over 6.0 mmol/L; review contributors if potassium is over 5.5 mmol/L. Use NT-proBNP for follow up, not BNP.

Stopping. Stop for pregnancy, angioedema, or creatinine rise over 30% or potassium over 6.0 mmol/L. If switching back to an angiotensin converting enzyme inhibitor, wait 36 hours.

Common prescribing errors. Starting within 36 hours of an angiotensin converting enzyme inhibitor; giving with a separate angiotensin receptor blocker; using BNP to monitor; starting at the full dose in low risk patients with low blood pressure; use in pregnancy.