Dabigatran Pharmacokinetics and Pharmacodynamics during Renal Replacement Therapy

Introduction: Dabigatran is an oral direct thrombin inhibitor approved for use in prevention and treatment of thromboembolism. There is currently no reliable strategy for reversing its anticoagulant effects. The use of activated prothrombin complex concentrates has been reported, however, the relationship between dabigatran concentration and anticoagulation parameters in this setting have not been formally assessed or documented. There are also few reports on the pharmacokinetics and pharmacodynamics of dabigatran in the context of renal replacement therapy. This report describes a case of dabigatran overdose and management with factor eight bypassing activity (FEIBA), and hemodialysis.

Case Presentation: A 62-year-old man taking dabigatran 110 mg twice daily presented with hematemesis, shock, acute kidney injury, INR > 8 and PTT > 150 s, hemoglobin 104 g/L and creatinine 1675 µmol/L. Last dose of dabigatran was ingested within 10 hours of presentation. Additional complications included hematuria, pulmonary hemorrhage, gastrointestinal bleeding and cardiac arrest. The patient required multiple blood transfusions at presentation. In an attempt to reverse the anticoagulant effects of dabigatran, the patient received 42 units/kg of FEIBA. A dialysis catheter was placed approximately 2 hours later without complication. Conventional hemodialysis (CHD) was initiated for high clearances with blood flows of 200 mL/min over 4 hours, followed by continuous venovenous hemodialysis (CVVHD). No further blood transfusions were required following administration of dialysis. He had resolution of all hemorrhagic symptoms by day 5 and achieved partial recovery of kidney function. Dialysis was discontinued on day 3 and the patient was discharged to a rehabilitation facility on day 34.

Results: Bloodwork drawn every 2 hours was analyzed for INR, PTT and dabigatran levels using HEMOCLOT® assay and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two hours following FEIBA administration, INR and PTT decreased from 7.4 to 3.6 and 114 s to 100 s, respectively despite no significant change in dabigatran levels (1.26 µg/mL - 1.30 µg/mL). Plasma dabigatran half-lives were 5.4 hours during CHD, 28 hours with CVVHD and 65 hours post-dialysis. Dialytic clearance values for dabigatran were estimated with a pharmacometric model. Plasma dialysis clearance for CHD was 66 mL/min (plasma perfusion rate of 128 mL/min) while the plasma dialysis clearance for CVVHD was 20 mL/min (plasma perfusion rate of 101 mL/min).

Conclusions: Information regarding management of dabigatran overdose is scarce. To the best of our knowledge, this is the first study to document the use of FEIBA in the acute management of dabigatran overdose with pharmacokinetic and pharmacodynamic testing. By use of HEMOCLOT® assay, we were able to demonstrate a rapid reversal of INR and PTT despite no significant change in dabigatran levels. This report supports the use of FEIBA for reversal of the anticoagulant effects of dabigatran for urgent procedures. This report also adds to literature demonstrating that dabigatran overdose should be initially treated with CHD rather than CVVHD. CHD with high flows and a high flux dialyzer is best, as it has greater efficiency of dabigatran clearance than CVVHD.