Dabigatran

Dabigatran is an oral direct thrombin inhibitor given as the prodrug dabigatran etexilate. It prevents stroke in non valvular atrial fibrillation, treats and prevents venous thromboembolism, and prevents clots after hip or knee replacement. It is the direct oral anticoagulant with the highest kidney clearance, so it accumulates quickly in kidney impairment. It has a specific antidote, idarucizumab. It must not be used with mechanical heart valves. Availability in East Africa is limited and cost is high.

Classification. Direct oral anticoagulant; direct thrombin inhibitor.

Mechanism. The active form binds the active site of free and clot bound thrombin, blocking conversion of fibrinogen to fibrin and thrombin induced platelet activation.

Pharmacodynamics. Peak effect 1 to 3 hours after the oral dose. Prolongs aPTT, thrombin time and ecarin clotting time; a normal thrombin time excludes a clinically relevant level.

Pharmacokinetics. Oral bioavailability only 3 to 7%, needing an acidic capsule environment. Half life 12 to 14 hours (up to 28 hours in severe kidney impairment). About 80% cleared unchanged by the kidneys. A substrate of P-glycoprotein. Protein binding about 35%.

Stroke prevention in non valvular atrial fibrillation, adult.

• 150 mg twice daily.

• 110 mg twice daily in patients aged 80 years or over, and in those taking verapamil.

• Consider 110 mg twice daily in patients aged 75 to 79 years, with creatinine clearance 30 to 50 mL/min, gastritis or reflux, or high bleeding risk.

Treatment of deep vein thrombosis and pulmonary embolism, adult. After 5 to 10 days of a parenteral anticoagulant, 150 mg twice daily for at least 3 months. Extended prevention uses the same dose. Use 110 mg twice daily at age 80 years or over or with verapamil.

Prevention of venous thromboembolism after hip or knee replacement, adult.

• 110 mg taken 1 to 4 hours after surgery, then 220 mg once daily.

• Duration 28 to 35 days after hip replacement and 10 days after knee replacement.

• Age 75 years or over, creatinine clearance 30 to 50 mL/min, or with verapamil, amiodarone or quinidine: 75 mg first dose, then 150 mg once daily.

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

Contraindications. Active clinically significant bleeding; creatinine clearance under 30 mL/min; mechanical heart valves; hepatic disease with coagulopathy; concurrent strong P-glycoprotein inhibitors (ketoconazole, itraconazole, dronedarone, ciclosporin); pregnancy; hypersensitivity.

Warnings. Bleeding; dyspepsia and gastro-oesophageal reflux (the capsule contains tartaric acid); premature discontinuation raises stroke risk; spinal or epidural haematoma; accumulation in kidney impairment and with dehydration; slightly more myocardial infarction signals than with warfarin in some studies; use with caution at age 75 years or over; triple positive antiphospholipid syndrome (avoid).

Adverse effects. Dyspepsia, abdominal pain, gastrointestinal bleeding, nose bleeding, bruising, anaemia, raised liver enzymes, rash.

Interactions.

• Strong P-glycoprotein inhibitors (ketoconazole, itraconazole, dronedarone, ciclosporin): avoid.
• Verapamil, amiodarone, quinidine, clarithromycin: raised levels, so give 110 mg twice daily for atrial fibrillation (or 150 mg once daily after joint replacement).
• Strong inducers (rifampicin, carbamazepine, phenytoin, St John's wort): avoid, as effect is lost.
• Antiplatelet drugs, non steroidal anti-inflammatory drugs, selective serotonin reuptake inhibitors, other anticoagulants: bleeding.
• Proton pump inhibitors: small fall in exposure, not significant.

Reversal. Idarucizumab 5 g IV (two 2.5 g doses given no more than 15 minutes apart) where available; otherwise prothrombin complex concentrate 25 to 50 units/kg and activated charcoal if taken within 2 hours. Haemodialysis removes about 60% over 2 to 3 hours.

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 and use warfarin if it is moderate to severe.

• Older adults: from age 75 years, consider 110 mg twice daily for atrial fibrillation; check creatinine clearance.

• Kidney impairment: creatinine clearance 30 to 50 mL/min: 110 mg twice daily should be considered; under 30 mL/min: contraindicated.

• Liver impairment: avoid if liver enzymes exceed twice the upper limit of normal.

Formulations. Capsules 75, 110, 150 mg.

Administration. Oral with a full glass of water, with or without food. Swallow whole; never open the capsule (bioavailability rises by 75% and bleeding risk follows). Keep in the original bottle or blister to protect from moisture, and discard 4 months after opening a bottle.

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 at age 75 years or over or when creatinine clearance is under 60 mL/min; more often when dehydrated or unwell. Liver function yearly. Adherence at each visit.

Stopping. Stop 24 hours before low bleeding risk surgery and 2 to 4 days before high bleeding risk surgery; stop longer (up to 5 days) when creatinine clearance is 30 to 50 mL/min. No bridging. Restart 24 to 72 hours after surgery when bleeding is controlled.

Common prescribing errors. Prescribing when creatinine clearance is under 30 mL/min; opening or crushing capsules; decanting into pill boxes; using it with a mechanical valve; combining with a strong P-glycoprotein inhibitor; not reducing the dose with verapamil; not rechecking kidney function during dehydration.