Direct Thrombin Inhibitors

Direct thrombin inhibitors bind the active site of thrombin without needing antithrombin, inhibiting free and clot-bound thrombin and preventing fibrin formation and thrombin-mediated platelet activation. They are used to treat heparin-induced thrombocytopenia, as an alternative to heparin in percutaneous coronary intervention, and (dabigatran) as an oral anticoagulant.

Members. Intravenous: argatroban (small molecule, bivalent binding at the active site only), bivalirudin (peptide, binds active site and exosite 1). Subcutaneous: desirudin. Oral: dabigatran etexilate. Lepirudin is withdrawn.

Mechanism. The drugs form reversible (bivalirudin is cleaved by thrombin itself) or direct complexes with thrombin, preventing cleavage of fibrinogen, activation of factors V, VIII, XI and XIII, and platelet protease-activated receptor activation.

Pharmacokinetics. Argatroban is hepatically metabolised, with a half-life of 40 to 50 minutes and onset in minutes. Bivalirudin has a half-life of 25 minutes, with 20% renal clearance and proteolytic breakdown. Dabigatran is renally cleared, about 80%.

• Argatroban: hepatic clearance, suited to renal failure; raises INR and so complicates warfarin transition.
• Bivalirudin: short acting; percutaneous coronary intervention; renal dose adjustment.
• Desirudin: subcutaneous prophylaxis after hip replacement.
• Dabigatran: oral; the only oral member.

• Heparin-induced thrombocytopenia: argatroban 2 micrograms/kg/minute (0.5 to 1.2 micrograms/kg/minute in hepatic impairment, heart failure, multiorgan failure or after cardiac surgery), adjusted to aPTT 1.5 to 3 times baseline (not over 100 seconds). Transition to warfarin or a direct oral anticoagulant after platelets exceed 150 x 10^9/L.
• Bivalirudin in percutaneous coronary intervention: 0.75 mg/kg bolus then 1.75 mg/kg/hour during the procedure, with activated clotting time over 225 seconds, optionally continued for up to 4 hours. Reduce the infusion to 1 mg/kg/hour in creatinine clearance under 30 mL/min.
• Bivalirudin in heparin-induced thrombocytopenia with cardiac surgery: specialist dosing.
• Selection: use where heparin must be avoided. Bivalirudin offers less bleeding than heparin with a glycoprotein IIb/IIIa inhibitor in some patients, with a small stent thrombosis risk early.

Contraindications. Active major bleeding and hypersensitivity. Argatroban is used with great caution in hepatic failure.

Adverse effects. Bleeding, hypotension, nausea, and raised INR (argatroban). Antibodies to desirudin and lepirudin cause anaphylaxis after re-exposure.

Interactions. Anticoagulants, antiplatelet drugs and thrombolytics raise bleeding. Argatroban interferes with INR measurement.

Reversal. There is no specific antidote for argatroban or bivalirudin, and their short half-lives allow recovery within hours after stopping. Idarucizumab reverses dabigatran.

Monitoring. aPTT every 2 hours until stable for argatroban, activated clotting time for bivalirudin, platelets, liver function and renal function.

Referral and escalation. Heparin-induced thrombocytopenia with thrombosis needs haematology input and ideally critical care.

Special groups. Hepatic impairment: reduce argatroban. Renal impairment: reduce bivalirudin. Pregnancy: limited data. Children: argatroban used under specialist dosing.