Measuring Dabigatran Levels: What Tests Are Available and What Still Needs to Be Done?

Dabigatran is an oral thrombin inhibitor that is licensed for stroke prevention in atrial fibrillation and for prevention and treatment of venous thromboembolism. Although dabigatran is administered in fixed doses without routine coagulation monitoring, quantification of the plasma levels of dabigatran is useful to detect accumulation in patients with acute kidney injury, for assessment of its potential contribution to serious bleeding, for determination of the optimal timing of urgent surgery and for identification of patients with acute ischemic stroke who can safely receive fibrinolytic therapy.1,2 With the introduction of idarucizumab, the availability of assays that can quantify plasma dabigatran concentrations is essential to identify appropriate candidates for reversal and to monitor them to ensure that reversal is achieved. This reflects the use of this reversal agent in serious bleeding or where patients on dabigatran require urgent surgery or interventional procedures.3,4 Routine coagulation assays such as the activated partial thromboplastin time (aPTT) and thrombin time are responsive to the anticoagulant effects of dabigatran. However, the aPTT lacks sensitivity and can be normal in the face of significant amounts of dabigatran, whereas the thrombin time is so sensitive that it is prolonged even by low concentrations of dabigatran. Therefore, there is an urgent need for widespread availability of rapid and accurate assays to quantify dabigatran levels. Both chromogenic and clot-based assays to quantify dabigatran levels are commercially available (►Table 1). The tests use thrombin (IIa) or ecarin to initiate clotting and they have been validated by comparing the results with dabigatran concentrations measured by liquid chromatography tandem mass spectroscopy (LC-MS/MS), the gold standard for dabigatran quantification. Both types of assays can be performed on commercially available coagulometers with rapid turnaround. In this issue of Thrombosis and Haemostasis, Poli et al used 288 stored samples from 48 dabigatran-treated patients to compare the diagnostic accuracy of the Biophen direct thrombin inhibitor (BDTI) assay, a new chromogenic anti-IIa assay, and the currently available clot-based Hemoclot thrombin inhibitor (HTI) assay, both of which are manufactured by Hyphen BioMed (Neuville-sur-Oise, France). The results with the two assayswere comparedwith dabigatran concentrations measured using LC-MS/MS. After establishing round-the-clock availability of the BDTI assay, its test performance in routine clinical practicewasthen furtherevaluated in150 freshcitrated blood samples collected from 25 dabigatran-treated patients. The BDTI assay has several potential advantages over the HTI assay. First, compared with LC-MS/MS, there is closer agreement with the BDTI assay than with the HTI assay. Second, with dabigatran concentrations below 60 ng/mL, the BDTI assay appears to be more accurate than the HTI assay because fewer samples aremisclassified. Thus, in several of the tested samples, dabigatran was detected with the HTI assay when none was detectable by LC-MS/MS. Although the BDTI assay did not suffer from this deficiency, it reported absence of dabigatran in a few samples where levels as high as 40 ng/mL were detected by LC-MS/MS. Therefore, neither test is perfect. Third, once reconstituted, reagents for the BDTI assay have longer stability at room temperature than those for the HTI assay (72 and 8 hours, respectively), which may be advantageous for busy clinical laboratories. Finally, the BDTI assay is less sensitive to heparin than the HTI assay, although neither assaydetectsheparinat levels below1 IU/mL,which covers the usual therapeutic range. Does the enhanced accuracy of the BDTI assay over the HTI assay really matter from a clinical perspective? Accuracy is important particularly with low levels of dabigatran. Thus, misclassificationofa level asbeing lowcould lead tobleeding if patients undergo major surgery or if thrombolysis is given for