Interlaboratory variability in the measurement of direct oral anticoagulants: results from the external quality assessment scheme

Abstract

Background Tests for direct oral anticoagulants (DOACs) are not widely available. The perception that they are difficult to perform and are subject to large between-laboratory variation makes their implementation difficult. Aims We carried out proficiency-testing surveys for DOACs within the activity of the external quality-assessment scheme of the Italian Federation of Thrombosis Centers. Design Participants were provided with coded freeze-dried plasmas without or with graded concentrations of the three main DOACs, and asked to measure prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time and DOAC concentrations with dedicated tests. The results were centralized for statistical analysis. Results and conclusions All participants (n = 235) reported results for PT and APTT, and approximately one-third reported results for DOAC concentration. PT and APTT showed variable responsiveness to DOACs: PT was more responsive to rivaroxaban than to dabigatran or apixaban. APTT was more responsive to dabigatran than to rivaroxaban or apixaban. The thrombin time ratio (test/normal) was close to unity for plasmas without dabigatran, and was high (i.e. 7.6-fold or 15.4-fold longer than the plasma free from the drug) for plasmas containing dabigatran at low (i.e. 42 ng mL ) or high (i.e. 182 ng mL ) concentration. Dedicated tests were responsive to the respective drugs, and their interlaboratory variability was relatively small (overall coefficients of variation of 8.7%, 8.4% or 10.3% for dabigatran, rivaroxaban and apixaban, respectively) and was comparable to that observed within the same survey for the International Normalized Ratio (i.e. 11.4%). In conclusion, tests for DOAC measurement performed reasonably well in a national quality-control scheme. Regulatory authorities should urgently issue recommendations on their use, and clinical laboratories should make them available.

What have we learned from coagulation laboratory participation in external quality programs?

“…The remainder of the laboratories reported only the results from their routine clotting times for specimens containing DOACS. Relatively minimal between‐laboratory variability was observed with overall CVs of 8.7% for dabigatran, 8.4% for rivaroxaban, and 10.3% for apixaban measurement . It is unclear why the CVs observed in this study indicate less assay variability than was seen in the ECAT/NASCOLA study.…”

“…Relatively minimal between-laboratory variability was observed with overall CVs of 8.7% for dabigatran, 8.4% for rivaroxaban, and 10.3% for apixaban measurement. 36 It is unclear why the CVs observed in this study indicate less assay variability than was seen in the ECAT/NASCOLA study. Results from RCPAQAP included 70 laboratories evaluating samples containing dabigatran and 44 laboratories evaluating samples that contained either rivaroxaban or apixaban.…”

“…Inter-laboratory variability in DOAC measurement has also recently been reported in EQA data from the Italian Federation of Thrombosis Centers and RCPAQAP. [36][37][38] In Italy, quantitative results from dedicated tests for DOACS were available from approximately one-third of the 235 participating laboratories, highlighting the limited availability of this testing. The remainder of the laboratories reported only the results from their routine clotting times for specimens containing DOACS.…”

Coordinating emergent procedures after andexanet alfa

“…As the PT and aPTT do not correlate consistently with therapeutic drug levels, they should not be used to interpret degree of anticoagulation with apixaban or rivaroxaban. [6][7][8][9][10] The anti-Xa assay (UFH/LMWH) is available at many institutions and can be used to rule out clinically significant anticoagulation to determine need for reversal. A normal result (less than 0.10 units/ml) provides reassurance that there is no clinically relevant FXai concentration, however long turnaround times may limit use in life-threatening bleeding.…”

“…Elevated values should be considered as a relative measure of activity and not interpreted in a linear fashion to represent drug concentration levels. [6][7][8][9][10] Importantly, standard clinical anti-Xa assays, such as Stago STA-Liquid Anti-FXa or HemosIL Liquid Anti-Xa, cannot be used to measure degree or efficacy of reversal during or after administration of andexanet alfa, as sample processing factors result in dissociation of andexanet alfa from FXai. 11…”