Direct Thrombin Inhibitors

Chapter: Direct Thrombin Inhibitors
McMaster Section Editor(s): James Douketis
Section Editor(s) in Interna Szczeklika: Krystyna Zawilska†, Anetta Undas, Wiktoria Leśniak
McMaster Author(s): James Douketis
Author(s) in Interna Szczeklika: Anetta Undas, Krystyna Zawilska†
† Deceased.
Additional Information

1. Mechanism of action: Thrombin inhibitors block the catalytic site or the substrate recognition site in the thrombin molecule. Oral dabigatran is used for prevention of venous thromboembolism. 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 usually not necessary in patients treated with dabigatran. Within 2 to 4 hours of the administration of dabigatran, a slightly prolonged prothrombin time and a prolonged activated partial thromboplastin time (aPTT) (up to 50-65 seconds) can be seen in the majority of patients; the thrombin time is markedly prolonged, frequently beyond the limit of quantification. In patients planned for urgent invasive procedures, determine the aPTT; values >40 seconds suggest a sustained anticoagulant effect. Specific but rarely available methods of monitoring the anticoagulant effect of dabigatran include a modified thrombin time (with baseline 16-fold dilution of the serum sample using the Hemoclot set 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 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). The dose of dabigatran should be reduced in patients >80 years, patients with renal failure and a GFR 30 to 50 mL/min, and in patients 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 (Table ): Dabigatran can be managed relatively easily in patients requiring an elective surgical or other invasive procedure because of its short half-life (10-12 hours) and the resultant rapid offset and onset of action. In general, patients having a minor surgery (associated with a low risk of bleeding) can receive the last drug dose two days before the surgery or procedure (none on the day of surgery) and can resume the drug the day afterwards. Patients having a major surgery and/or spinal anesthesia (associated with a high risk of bleeding) can receive the last drug dose three days before the surgery or procedure (none on the day of surgery) and can resume the drug the 1 to 2 days afterwards when hemostasis is secured. If patients taking dabigatran have impaired renal function (creatinine clearance, <50 mL/min), the preprocedure interruption period should be extended by an additional 1 to 2 days due to the greater dependence of dabigatran on renal clearance than rivaroxaban and apixaban. In patients having major surgery, the time interval between the last dose of dabigatran and surgery is at least 5 drug half-lives (ie, ~60 hours). Research is ongoing to inform best practices regarding the perioperative management of dabigatran.

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 surgery or procedure. Administer 5 g IV in two 2.5 g doses over 15 minutes. The anticoagulant effect of dabigatran can be partially neutralized by a prothrombin complex concentrate (PCC) 25 U/kg (the dose may be repeated twice) or activated PCC 50 U/kg (maximum, 200 U/kg/d). Bivalirudin, argatroban, and dabigatran can be eliminated from blood by hemodialysis (without an anticoagulant) or hemoperfusion.

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