Edoxaban

Edoxaban is an oral direct factor Xa inhibitor given once daily. It prevents stroke in non valvular atrial fibrillation and treats and prevents venous thromboembolism after at least 5 days of a parenteral anticoagulant.

Its effect is reduced when creatinine clearance is high in atrial fibrillation. Its dose is reduced for low body weight, moderate kidney impairment and some interacting drugs.

It must not be used with mechanical valves or moderate to severe rheumatic mitral stenosis. It is rarely available in East Africa.

Classification. Direct oral anticoagulant; factor Xa inhibitor.

Mechanism. Reversibly blocks the active site of free and clot bound factor Xa, reducing thrombin generation.

Pharmacodynamics. Peak effect 1 to 2 hours after the oral dose; anticoagulant effect about 24 hours. Prolongs PT and anti Xa assays.

Pharmacokinetics. Oral bioavailability about 62%; food has little effect. Half life 10 to 14 hours. About 50% cleared by the kidneys unchanged; the rest by metabolism and biliary excretion. A substrate of P-glycoprotein.

Stroke prevention in non valvular atrial fibrillation, adult. 60 mg once daily; 30 mg once daily if creatinine clearance is 15 to 50 mL/min, body weight is 60 kg or less, or with certain P-glycoprotein inhibitors (ciclosporin, dronedarone, erythromycin, ketoconazole). Not advised when creatinine clearance exceeds 95 mL/min (lower efficacy; use another agent).

Treatment of deep vein thrombosis and pulmonary embolism, adult. After at least 5 days of a parenteral anticoagulant, 60 mg once daily (30 mg once daily with the same dose reduction criteria); treat for at least 3 months.

Children. Not established.

Contraindications. Active clinically significant bleeding; hepatic disease with coagulopathy; creatinine clearance under 15 mL/min; uncontrolled severe hypertension; mechanical heart valves; moderate to severe rheumatic mitral stenosis; triple positive antiphospholipid syndrome; pregnancy and breastfeeding; hypersensitivity.

Warnings. Bleeding; reduced stroke protection in atrial fibrillation when creatinine clearance is above 95 mL/min; accumulation in kidney impairment; low body weight; spinal or epidural haematoma; premature discontinuation raises stroke risk.

Adverse effects. Bleeding (gastrointestinal, nose, urinary), anaemia, rash, raised liver enzymes, abnormal liver function.

Interactions. P-glycoprotein inhibitors (ciclosporin, dronedarone, erythromycin, ketoconazole): reduce the dose to 30 mg. Strong inducers (rifampicin, carbamazepine, phenytoin, St John's wort): avoid. Antiplatelet drugs, non steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, other anticoagulants: bleeding.

Reversal. Andexanet alfa where available; otherwise prothrombin complex concentrate 25 to 50 units/kg. Haemodialysis does not remove it.

Special groups.

• Pregnancy: contraindicated.

• Breastfeeding: contraindicated.

• Patients of African ancestry: no dose change; check for rheumatic mitral stenosis; use warfarin if present.

• Older adults: no dose change by age alone; adjust for weight and creatinine clearance.

• Kidney impairment: creatinine clearance 15 to 50 mL/min: 30 mg once daily; under 15 mL/min: avoid.

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

Formulations. Tablets 15, 30, 60 mg.

Administration. Oral once daily at the same time, with or without food. Tablets may be crushed and given in water or apple puree.

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 over 75 years or when creatinine clearance is under 60 mL/min); liver function yearly; adherence.

Stopping. Stop 24 hours before low bleeding risk surgery and 48 hours before high risk surgery; no bridging. Restart 24 to 72 hours after surgery when bleeding is controlled.

Common prescribing errors. Starting without the 5 day parenteral overlap in venous thromboembolism; full dose with weight 60 kg or less; using it when creatinine clearance is above 95 mL/min in atrial fibrillation; using it in mechanical valves or rheumatic mitral stenosis; combining with rifampicin.