Conservative Management of Intentional Massive Dabigatran Overdose

Dabigatran etexilate mesylate (Pradaxa®)is an oral direct thrombin inhibitor converted to the active form through in vivo plasma and hepatic esterases. It is currently used for stroke prophylaxis in individuals with atrial fibrillation (AF), for the prevention of venous thromboembolism (VTE) after hip surgery, and for treatment of acute VTE.1 Dabigatran has a wide therapeutic window at fixed dosing regimens, with no requirement for routine laboratory monitoring in standard clinical conditions, although measurement of its anticoagulant activity may be desirable in special clinical settings such as a known or suspected overdose.2 Liquid chromatography–tandem mass spectrometry is the reference method for measurement of dabigatran plasma concentration.3 Dilute thrombin time (dTT), ecarin clotting time, and ecarin chromogenic assay show a high degree of linearity at drug levels greater than 50 ng/mL and are useful for quantification across the entire on-therapy range.4 However, these assays are still not routinely available in all clinical centers, and it is not clear what the risk of bleeding is in individuals who had short-term exposure to a high plasma concentration of dabigatran. According to recent guidelines, prothrombin complex concentrates (PCCs), activated PCCs, recombinant factor VIIa, and hemodialysis should be used in the case of life-threatening bleeding in individuals taking direct oral anticoagulants (DOACs),5 although hemodialysis in these individuals may cause bleeding complications, and the administration of high doses of coagulation factors may be associated with risk of thrombotic events.6 Thus, their use in asymptomatic individuals with drug overdose remains debatable. Clinical experience with dabigatran overdoses in humans is limited. The case of an individual who took an intentional dabigatran overdose who received conservative management is presented. An 81-year-old man with a history of permanent AF (CHA2DS2-VASc score 4; HAS-BLED score 2), hypertension, and blindness from age-related macular degeneration presented 150 minutes after an intentional ingestion of 1,650 mg of dabigatran (15 capsules of 110 mg) for a suicide attempt. Dabigatran 110 mg twice daily had been started 6 months before. At the time of first prescription of dabigatran and on a laboratory test 3 months later, he had moderate renal insufficiency with a creatinine clearance (CrCl) of 52 mL/min according to the Cockroft-Gault formula and normal platelet count. His current medications included also ramipril 10 mg daily. On admission, he was fully conscious, with blood pressure 127/80 mmHg, heart rate 108 beats per minute, and oxygen saturation 98% on room air. On physical examination, there was no evidence of acute bleeding. Laboratory analysis revealed normal hemoglobin, platelet, electrolyte, and liver enzyme levels. Serum creatinine was 1.33 mg/dL, confirming moderate renal failure (CrCl 44 mL/min). Screening clotting assays revealed an activated partial thromboplastin time (aPTT) of 79 seconds (normal 23–37 seconds) and an international normalized ratio (INR) of 3.3. Twelve-lead electrocardiogram confirmed AF, without any other significant alteration. An orogastric tube was immediately placed for particle lavage and gastric decontamination with activated charcoal therapy. A urinary catheter was placed, with clear yellow urine drained. Head computed tomography, chest X-ray, and abdominal ultrasound were unremarkable. Considering the absence of acute signs of bleeding, after consultation with a coagulation specialist, the treatment team decided against PCC administration. Because of the high risk of the procedure, the nephrologist did not recommend hemodialysis to decrease the blood dabigatran level. Fresh frozen plasma (900 mL) was administered. Balanced salt solution was administered intravenously (100–120 mL/h) in an attempt to increase the renal clearance of dabigatran, and diuresis was forced using loop diuretics (furosemide 80 mg/24 h). Hemoglobin and coagulation parameters remained unchanged on subsequent laboratory tests performed after 2 hours after his arrival in the emergency department. aPTT was serially measured throughout the hospital course as a surrogate marker for dabigatran level of anticoagulation (Figure 1). aPTT remained high until 15 hours after his arrival, after which it started to slowly decrease and was almost normalized 48 hours after arrival. His INR had a similar trend, reaching 1.3 at 48 hours after arrival. Hemoglobin and hematocrit levels showed no significant changes, and no blood loss or signs of hematoma were observed. Furthermore, 6 hours after his admission, prothrombin time, aPTT, thrombin time, and dabigatran anticoagulant level (dTT) were measured in a plasma sample. Prothrombin time, INR and aPTT results were unchanged, thrombin time was incoagulable, and dabigatran concentration was 4,170 ng/mL. After 4 days of inpatient monitoring, he was discharged without complications, after psychiatric consultation, under treatment with sertraline and alprazolam. Despite a massive dabigatran intake, he did not have any bleeding complications. Data on the risk of bleeding complications after transitory exposure to DOACs overdose are not compelling, and it is unclear whether the risks of thromboembolic complications outweigh the potential benefits of rapidly lowering anticoagulation DOACs in different settings. Only a few case reports have addressed this issue.7-9 In two cases with rivaroxaban overdose, PCCs have been used 7, 8 whereas in a case of ingestion of more than 11 g of dabigatran, a more-conservative approach was taken.9 In the current case, prompt management using gastric lavage and activated charcoal therapy may have prevented further dabigatran accumulation. As in many clinical scenarios, it was not possible to measure the dabigatran plasma level at the time of presentation because this test was not immediately available (high dabigatran plasma levels confirmed 6 hours after arrival), and only a serial evaluation of coagulation using aPTT as a surrogate marker of dabigatran level could be made. Thus, laboratory tests appeared useful to confirm the presence of the drug and monitor the progressive decrease of dabigatran anticoagulation levels. A specific antidote for dabigatran is not available but is under development;10 future studies should evaluate its role in asymptomatic individuals with drug overdose. In conclusion, this case report supports a conservative approach after prompt gastric lavage and activated charcoal therapy in individuals with dabigatran overdose without any symptoms or signs of bleeding. Screening coagulation laboratory tests, such as aPTT, may be useful to monitor drug levels in plasma indirectly. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: NM, MC, PP: caring for patient. NM, MC, MF, ST, FD: data collection, analysis, and interpretation. NM, ST, FD wrote the report. Written consent to publish was obtained. Sponsor's Role: None.