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.
Table 1
Commercially available assays for quantifying dabigatran concentrations
|
Method
|
Principle
|
Specific assays
|
|
Chromogenic
|
Thrombin-based
|
Hyphen Biomed Biophen DTI
|
|
Ecarin-based
|
Stago ECA-II
|
|
Clot-based
|
Thrombin-based
|
Hyphen Biomed HTI
|
|
HemosIL DTI
|
|
Technoclot DTI
|
|
Roche Dilute Thrombin Time
|
|
Siemens INNOVANCE DTI
|
Abbreviations: DTI, Direct thrombin inhibitor; ECA, ecarin chromogenic assay; HTI,
Hemoclot thrombin inhibitor.
Source: Adapted from European Medicines Agency.[8]
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 assays were
compared with dabigatran concentrations measured using LC-MS/MS. After establishing
round-the-clock availability of the BDTI assay, its test performance in routine clinical
practice was then further evaluated in 150 fresh citrated 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 are misclassified. 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 assay detects heparin at levels below 1 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, misclassification of a level as being low could lead to bleeding if patients
undergo major surgery or if thrombolysis is given for treatment of acute ischemic
stroke. In reality, however, with the widespread availability of idarucizumab, clinicians
often reverse dabigatran before waiting for the results of coagulation assays in life-threatening
or emergency circumstances.[5]
[6] Therefore, despite the advantages of the BDTI assay over the HTI assay, the more
important factor is ensuring widespread availability of at least one of these tests.
Access to quantitative assays for dabigatran remains problematic. Despite the availability
of numerous assays ([Table 1]), none are approved in the United States. In Ontario, the most populous province
in Canada, only 4% of clinical laboratories offer these assays. Likewise, based on
data from the Royal College of Pathologists of Australasia Quality Assurance Program
and a survey by the United Kingdom National External Quality Assessment Service, approximately
26% of laboratories in Australasia and 12% of those in the United Kingdom offer quantitative
assays for dabigatran.[7]
[8] Barriers to the uptake and implementation of quantitative assays include the cost
of implementing new assays in an environment of shrinking hospital budgets and the
current lack of regulatory body–approved reagents, calibrators and methods in some
jurisdictions. Therefore, much work still needs to be done.
In conclusion, the BDTI assay represents another step forward in the development of
quantitative assays for dabigatran. We now have the means to rapidly and accurately
measure dabigatran levels. However, implementation of these assays at the bedside
requires cooperation among regulators, standardization committees and hospitals. Such
cooperation is urgently needed.
