Apixaban

Apixaban is an oral direct factor Xa inhibitor. It prevents stroke in non valvular atrial fibrillation, treats and prevents venous thromboembolism, and prevents clots after hip or knee replacement. It has a predictable effect, no routine laboratory monitoring, few interactions, and lower rates of major bleeding than warfarin. It must not be used with mechanical heart valves, moderate to severe rheumatic mitral stenosis, or triple positive antiphospholipid syndrome. It is available in East Africa but costs more than warfarin.

Classification. Direct oral anticoagulant; factor Xa inhibitor.

Mechanism. Binds reversibly to the active site of free and clot bound factor Xa, blocking conversion of prothrombin to thrombin, and indirectly reducing platelet aggregation.

Pharmacodynamics. Peak effect 3 to 4 hours after the oral dose; anticoagulant effect lasts 12 to 24 hours. Prolongs PT and anti Xa assays (calibrated anti Xa assay is the best test).

Pharmacokinetics. Oral bioavailability about 50%; food has no effect. Half life 12 hours. About 27% cleared by the kidneys; the rest by CYP3A4 metabolism and biliary and intestinal excretion. A substrate of P-glycoprotein.

Stroke prevention in non valvular atrial fibrillation, adult.

• 5 mg twice daily.

• Reduce to 2.5 mg twice daily if two or more of the following: age 80 years or over, body weight 60 kg or less, serum creatinine 133 micromol/L (1.5 mg/dL) or more.

• Creatinine clearance 15 to 29 mL/min: 2.5 mg twice daily (caution); under 15 mL/min or dialysis: avoid or use a specialist label.

Treatment of deep vein thrombosis and pulmonary embolism, adult. 10 mg twice daily for 7 days, then 5 mg twice daily; 6 months minimum. Extended prevention after 6 months: 2.5 mg twice daily.

Prevention of venous thromboembolism after hip or knee replacement, adult. 2.5 mg twice daily starting 12 to 24 hours after surgery; 32 to 38 days after hip replacement and 10 to 14 days after knee replacement.

Cancer associated thrombosis, adult. 10 mg twice daily for 7 days, then 5 mg twice daily.

Children (where licensed). Weight based dosing for venous thromboembolism (specialist).

Contraindications. Active clinically significant bleeding; hepatic disease with coagulopathy and clinically relevant bleeding risk; mechanical heart valves; moderate to severe rheumatic mitral stenosis; triple positive antiphospholipid syndrome; concurrent strong dual inhibitors of CYP3A4 and P-glycoprotein (ketoconazole, itraconazole, ritonavir) in some labels; pregnancy; hypersensitivity.

Warnings. Bleeding; premature discontinuation raises stroke risk (cover with another anticoagulant if stopped); spinal or epidural haematoma (delay needle removal until 5 hours after the last dose); accumulation in kidney impairment; low body weight; avoid in significant liver disease.

Adverse effects. Bleeding (nose, gut, urinary), bruising, anaemia, nausea, raised liver enzymes, rash.

Interactions. Strong dual CYP3A4 and P-glycoprotein inhibitors (ketoconazole, itraconazole, ritonavir): avoid or halve the dose. Strong inducers (rifampicin, carbamazepine, phenytoin, St John's wort): avoid (reduced effect). Antiplatelet drugs, non steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, other anticoagulants: bleeding. Antiretrovirals (ritonavir boosted regimens): raised levels. Diltiazem and amiodarone: modest rise.

Reversal. Andexanet alfa where available; otherwise prothrombin complex concentrate 25 to 50 units/kg; activated charcoal if the dose was within 2 to 6 hours. Haemodialysis does not remove it.

Special groups.

• Pregnancy: contraindicated; use low molecular weight heparin.

• Breastfeeding: avoid; no data.

• Patients of African ancestry: no dose change; check for rheumatic mitral stenosis before using it.

• Older adults: reduce to 2.5 mg twice daily if two of the age, weight and creatinine criteria apply.

• Kidney impairment: creatinine clearance 25 to 29 mL/min: use caution; under 15 mL/min: avoid.

• Liver impairment: mild: no change; moderate: caution; severe: avoid.

Formulations. Tablets 2.5 and 5 mg; oral solution in some markets.

Administration. Oral twice daily about 12 hours apart, with or without food. Tablets may be crushed and given in water, apple sauce or through a nasogastric tube.

Baseline. Haemoglobin, platelet count, creatinine clearance (Cockcroft Gault), liver function, weight, drug history, pregnancy status, echocardiogram in rheumatic disease.

Monitoring. Creatinine clearance and haemoglobin at least yearly (every 6 months when over 75 years or creatinine clearance under 60 mL/min, and when unwell); liver function yearly; adherence at each visit; bleeding signs.

Stopping. Stop 24 hours before low bleeding risk surgery and 48 hours before high risk surgery (longer when creatinine clearance is under 50 mL/min); no bridging. Restart 24 to 72 hours after surgery when bleeding is controlled.

Common prescribing errors. Using it with a mechanical valve or rheumatic mitral stenosis; wrong dose reduction (needs two of three criteria); missing doses; combining with rifampicin; continuing 10 mg twice daily beyond 7 days; stopping without cover.