Direct Thrombin Inhibitors

1. Mechanism of action: Thrombin inhibitors block the catalytic site or the substrate recognition site in the thrombin molecule. Oral dabigatran is used for the prevention and treatment of venous thromboembolism (VTE) and for stroke prevention in atrial fibrillation (AF). Agents used for other indications include recombinant hirudin (lepirudin, IV desirudin) and synthetic analogues of hirudin (bivalirudin, IV argatroban).

2. Monitoring of the anticoagulant effect is not necessary in patients treated with dabigatran. Within 1 to 3 hours of the administration of dabigatran, corresponding to the peak anticoagulant effect, a slightly prolonged prothrombin time and a prolonged activated partial thromboplastin time (aPTT) (up to 50-65 sec) can be seen in the majority of patients; the thrombin time is markedly prolonged, frequently beyond the limit of quantification and is considered an excessively sensitive test to measure the anticoagulant effect of dabigatran. In patients planned for urgent invasive procedures, an aPTT >40 seconds suggest a sustained residual anticoagulant effect; however, a normal aPTT does not exclude a residual anticoagulant effect. More reliable and precise methods of measuring the anticoagulant effect of dabigatran include the dilute thrombin time (using the Hemoclot assay that is approved for use in the European Union) and ecarin clotting time. The anticoagulant effects of bivalirudin can be monitored using the activated clotting time (this is used in patients with an acute coronary syndrome) or aPTT.

3. Contraindications are the same as in the case of heparins (except for heparin-induced thrombocytopenia) and additionally include pregnancy and breastfeeding. Dabigatran is contraindicated in patients with a glomerular filtration rate (GFR) <30 mL/min, patients with severe liver failure, as well as in patients treated with dronedarone, azole antifungal agents (ketoconazole, itraconazole, voriconazole, posaconazole), rifampin (INN rifampicin), phenobarbital, carbamazepine, phenytoin, and hypericum (St John’s wort). In patients with VTE or AF, the dose of dabigatran should be reduced from 150 mg bid to 110 mg bid in those >80 years, individuals with renal failure and a GFR 30 to 50 mL/min, and in those treated with amiodarone or verapamil. The concomitant use of dabigatran and other anticoagulants (except for unfractionated heparin at doses used to maintain the patency of a central venous or arterial catheter), antiplatelet agents, thrombolytic agents, or dextran may be associated with an increased risk of bleeding.

4. Discontinuation of treatment before surgical procedures: see Periprocedural Direct Oral Anticoagulant (DOAC) Management.

5. Complications: Mainly bleeding, dyspepsia (in the case of dabigatran). Idarucizumab is an antidote that neutralizes the anticoagulant effect of dabigatran; it should be considered in selected patients who have serious or life-threatening bleeding or who require an emergency (ie, within 6 h) or urgent (ie, within 24 h) surgery or procedure. Administer 5 g IV in two 2.5 g doses over 15 minutes. The anticoagulant effect of dabigatran may be neutralized by a prothrombin complex concentrate (PCC) 30 IU/kg or activated PCC 50 IU/kg (max, 200 IU/kg/d). Bivalirudin, argatroban, and dabigatran can be eliminated from blood by hemodialysis (without an anticoagulant) or hemoperfusion.