Idarucizumab for dabigatran overdose in a child

We report the first use of idarucizumab in the management of a massive dabigatran overdose in a child. Anticoagulation overdose is a challenging clinical scenario. Dabigatran, an oral direct thrombin inhibitor, is licensed for treatment and secondary prevention of venous thromboembolism and for stroke prevention in atrial fibrillation. Idarucizumab is a humanised monoclonal high affinity antibody fragment that specifically binds to, and neutralises dabigatran. It has recently been approved by the European Medicines Agency and the US Food and Drug Administration. A 15-year-old girl presented to the emergency department following the ingestion of between thirty and fifty 150-mg dabigatran tablets 4 h previously (dabigatran prescribed for her father). She had a history of self-harm with multiple emergency department attendances and had been recently expelled from school. She had no other significant medical history, no regular medications and no known drug allergies. She had minor gum bleeding and was haemodynamically stable (weight 67 kg). Initial blood tests showed normal full blood count, renal and liver function (creatinine 46 μmol/l). The coagulation profile was abnormal with an international normalised ratio (INR) of 9·1 and an activated partial thromboplastin ratio (APTR) of 4·8. No alcohol, paracetamol or salicylate was detected. Repeat coagulation tests locally confirmed prolongation of INR and APTR, fibrinogen 2·6 g/l and thrombin time (TT) reported as 53 s. Thrombin time is the most sensitive standard coagulation test to dabigatran and is sensitive to minimum levels of dabigatran. The activated partial thromboplastin time (APTT) is sensitive to dabigratran within the normal therapeutic range, but the increase in APTT starts to plateau beyond about 200 ng/ml dabigatran. The INR is, in general, less sensitive to dabigatran than the APTT and its degree of prolongation is reagent dependent (Stangier et al, 2007; van Ryn et al, 2010). In this case, the PT and APTR were consistent with the history of dabigatran overdose but the TT was not. However the patient and her family confirmed that she had taken dabigatran, and that there were no other anticoagulants in the house. She had a normal coagulation screen from a previous emergency department attendance. As she had no significant active bleeding, and the coagulation results did not match the reported history, the decision was made to administer 10 mg/kg tranexamic acid and 10 mg vitamin K intravenously. Prothrombin complex concentrate (PCC) was to be used if the patient developed significant bleeding and idarucizumab requested (not initially on site) to be available in case of need. Blood samples were couriered to the tertiary centre. These coagulation screen results were consistent with massive dabigatran overdose, with an unclottable TT (Table 1). This was confirmed by a dabigatran assay (dilute thrombin time, Hemoclot® assay) (Table 1, Fig 1). Under standard conditions, this assay determines dabigatran levels between 30 and 500 ng/ml, however manual dilutions estimated initial dabigatran levels to be 1507–2040 ng/ml. The therapeutic peak dabigatran levels for patients taking 150 mg twice a day in the RE-LY trial was median 184 ng/ml (range 74·3–383 ng/ml, 10–90th percentile) (Reilly et al, 2014), and the half-life of dabigatran in patients with normal renal function is 10–13 h. Our 15-year-old patient had 5–10 times supranormal levels and it was therefore estimated that it would take approximately 48 h for dabigatran to be cleared to acceptable levels. Given this, the decision was made to reverse dabigatran with standard dose idarucizumab (5 g). The patient did not experience any immediate adverse reaction to idarucizumab and blood tests demonstrated complete dabigatran reversal at 30 min post-idarucizumab with normalisation of the APTT and TT (Table 1, Fig 1). There was a slight rebound of the TT at 15 h post-idarucizumab, but the dabigatran level remained below the standard limit of detection. Seventy-two h post-idarucizumab there was mild prolongation of TT and manual dilution gave a level of 8 ng/ml dabigatran. She had no further bleeding concerns and had no further haemostatic medical treatment. It was recently reported that 5 g idarucizumab resulted in complete reversal of dabigatran after overdose in an adult (dabigatran concentration measured by dilute TT was 735 ng/ml) (Peetermans et al, 2016). Prior to the development of idarucizumab, the guidelines for reversal of dabigatran in case of bleeding or overdose were generic and based on in vitro and animal studies and case reports. Guidelines advised considering gastric lavage and oral activated charcoal within 2 h of overdose to reduce the absorption; and administration of PCC or activated PCC in case of significant bleeding to counteract the anticoagulant effect of the dabigatran (though with concern for subsequently increased risk of thromboembolic events). As dabigatran is significantly protein-bound, haemodialysis could also be considered to accelerate renal clearance (50% reduction in dabigatran concentration after dialysis). The recent International Society on Thrombosis and Haemostasis guidelines (Levy et al, 2016) advise that idarucizumab should not generally be used for ‘high drug levels or excessive anticoagulation without associated bleeding.’ However, given the extremely high dabigatran levels in this instance and the potential risk of bleeding, it was felt that idarucizumab should be given. Idarucizimab binds free and thrombin-bound dabigatran and neutralises its activity. Both free dabigatran and these idaruzicumab-dabigatran complexes are renally cleared. Idaruzicumab is mostly present in the intravascular compartment and its half-life is about 45 min (Glund et al, 2015). Dabigatran has a larger volume of distribution and is in equilibrium between the intravascular compartment and the tissues (Blech et al, 2008). Although the 5 g licensed dose of idarucizumab was calculated to reverse the dabigatran load that corresponded to the 99th percentile of steady state peak dabigatran levels in the RE-LY study, this case shows that 5 g idarucizumab completely and immediately reversed dabigatran at an estimated level >1000 ng/ml in a 15-year-old child. There was a small partial rebound effect, which was detectable at 15 and 72 h post-idarucizumab based on prolongation of the TT. This rebound effect seems likely to be due to the redistribution of dabigtran from the extravascular to the intravascular compartment, and the short half-life of idarucizumab. Our case report demonstrates the use of idaruzizumab to reverse excess dabigtran, at levels estimated at >1000 ng/ml, and its safety and efficacy in a child. All authors contributed to the management of the patient and reviewed and approved the manuscript. SS wrote the paper. SS has received travel grants from Boeringher Inghelheim. DK had received fees for lectures and advisory boards from Boeringher Inghelheim.