Argatroban

Argatroban is an intravenous direct thrombin inhibitor used to treat heparin induced thrombocytopenia and to anticoagulate patients with that condition during percutaneous coronary intervention. It is cleared by the liver, so the dose is cut sharply in liver disease and in critical illness, and it is safe in kidney failure. It raises the INR, which makes the changeover to warfarin tricky. It is rarely available in East Africa.

Classification. Parenteral direct thrombin inhibitor; synthetic arginine derivative.

Mechanism. Binds reversibly to the active site of free and clot bound thrombin, blocking fibrin formation, activation of factors V, VIII and XIII, and platelet aggregation.

Pharmacodynamics. Onset immediate; steady state aPTT within 1 to 3 hours. Prolongs aPTT, activated clotting time, thrombin time and the INR.

Pharmacokinetics. Half life 40 to 50 minutes (about 3 hours in liver impairment). Metabolised by the liver (CYP3A4/5 contributes little) and excreted mainly in bile. Protein binding about 54%.

Heparin induced thrombocytopenia, adult.

• Start 2 micrograms/kg/minute IV by continuous infusion, with no bolus.

• Check aPTT 2 hours after starting and after each change; aim for 1.5 to 3 times the baseline value, and not above 100 seconds.

• Adjust in steps of 0.5 micrograms/kg/minute to a maximum of 10 micrograms/kg/minute.

• Continue until the platelet count recovers to 150 x 10^9/L or more and warfarin is therapeutic.

Reduced starting dose. Liver impairment, heart failure, multiple organ failure, severe anasarca or after cardiac surgery: 0.5 micrograms/kg/minute (up to 1.2 micrograms/kg/minute in critically ill patients).

Percutaneous coronary intervention in heparin induced thrombocytopenia, adult. Bolus 350 micrograms/kg over 3 to 5 minutes, then infusion 25 micrograms/kg/minute; check activated clotting time after 5 to 10 minutes and aim for 300 to 450 seconds. Adjust the infusion and give a further bolus 150 micrograms/kg if the value is too low.

Changeover to warfarin. Start warfarin at the usual dose (no loading). Argatroban raises the INR, so when the INR on combined therapy is above 4, halve the argatroban dose, or stop the infusion and repeat the INR 4 to 6 hours later; continue until the INR on warfarin alone is in range.

Children. Initial 0.75 micrograms/kg/minute (0.2 micrograms/kg/minute in liver impairment); specialist use only.

Contraindications. Active major bleeding; hypersensitivity.

Warnings. Bleeding; no antidote; unreliable aPTT in baseline liver disease or lupus anticoagulant; unreliable INR during the changeover; severe liver disease (cut the dose); hypotension in sick patients.

Adverse effects. Bleeding, hypotension, dyspnoea, fever, nausea, diarrhoea, haematuria, sepsis in critically ill patients.

Interactions. Heparin, warfarin, antiplatelet drugs, thrombolytics: bleeding. Stop heparin and wait for the aPTT to normalise before starting.

Special groups.

• Pregnancy: avoid unless essential; limited data.

• Breastfeeding: no data; avoid.

• Patients of African ancestry: no dose change.

• Older adults: monitor aPTT more closely.

• Kidney impairment: no adjustment.

• Liver impairment: reduce the starting rate to 0.5 micrograms/kg/minute.

Formulations. Concentrate 250 mg/2.5 mL (100 mg/mL) and ready diluted 50 mg/50 mL (1 mg/mL).

Administration. Dilute the concentrate 100 fold to 1 mg/mL in 0.9% sodium chloride or 5% glucose by mixing 250 mg in 250 mL; use the infusion pump. Mix the diluted bag for 1 minute. Protect from light.

Baseline. Platelet count, aPTT, INR, haemoglobin, liver function, creatinine, weight.

Monitoring. aPTT 2 hours after starting and after each change, then daily. Platelet count daily. Haemoglobin daily. INR during the changeover. Liver function.

Stopping. Stop after the platelet count recovers and warfarin is therapeutic for at least 5 days with an adequate INR.

Common prescribing errors. Using the full dose in liver impairment; not allowing for the raised INR during the changeover; giving a loading dose of warfarin; stopping too early; mixing up micrograms/kg/minute with mg/kg/hour.