The myths behind DOAC measurement: Analyses of prescribing information from different regulatory bodies and a call for harmonization

Abstract

For more than a decade, US laboratories have failed to implement solutions to help their clinicians in managing complex situations or patients on direct oral anticoagulants (DOACs). The problem may find different origins, among which is the position of the Food and Drug Administration, which categorized these drugs as monitoring‐ and measurement‐free, whereas other regulatory bodies like the European Medicines Agency or the Therapeutic Goods Administration in Australia were more conservative on the principle that the absence of proof (of monitoring/measurement benefits) is not proof of an absence (of monitoring/measurement needs). Pivotal clinical studies that led to the approval of DOACs were presented as devoid of such testing, although some companies considered monitoring as a solution to improve their benefit/risk ratio. In this JTH In Clinics issue, we report more than a decade of development that has permitted the activation of smart laboratory solutions to qualify or quantify DOACs and discuss myths and misconceptions around technical and regulatory requirements that support the current reluctance of implementing these technologies in most US laboratories. Use of DOACs is ever expanding, with DOAC prescriptions now exceeding those of other anticoagulants, including vitamin K antagonists, in some geographies. As this use increases, the likely need to measure DOAC exposure will also increase. Measurement of DOACs does not represent any technical difficulty. That these laboratory tests are not available in some locations suggests disparities in patient care, and we suggest it is time to address such inequalities.

Algorithm for Rapid Exclusion of Clinically Relevant Plasma Levels of Direct Oral Anticoagulants in Patients Using the DOAC Dipstick: An Expert Consensus Paper

“…thromboplastin time ( 4 , 5 ). Instead, the levels must be determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) or with specialized assays, such as calibrated chromogenic assays.…”

Performance of direct oral anticoagulant (DOAC) testing by hemostasis laboratories: The Australasian/Asia‐Pacific experience

“…1,2,11 Given the convenience and efficacy of DOACs, these agents have replaced the classical anticoagulants for many (but not all) indications. [11][12][13] Although there is no need to monitor the DOACs during anticoagulation therapy, there are several situations where measurement of plasma levels may be beneficial, for example prior to elective or emergency surgery to ensure absence of DOACs to prevent bleeding. [1][2][3][4]11 To measure DOACs, several laboratory methods have been developed.…”

“…[11][12][13] Although there is no need to monitor the DOACs during anticoagulation therapy, there are several situations where measurement of plasma levels may be beneficial, for example prior to elective or emergency surgery to ensure absence of DOACs to prevent bleeding. [1][2][3][4]11 To measure DOACs, several laboratory methods have been developed. [1][2][3][4]11 Although liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/ MS) is sometimes touted as a gold standard, the complexity of the test, and the need for specialised instruments, prevents this method being used for urgent measurement of DOACs.…”

“…[1][2][3][4]11 To measure DOACs, several laboratory methods have been developed. [1][2][3][4]11 Although liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/ MS) is sometimes touted as a gold standard, the complexity of the test, and the need for specialised instruments, prevents this method being used for urgent measurement of DOACs. Instead, modifications of standard laboratory hemostasis tests have become popular, with anti-Xa assays utilised for measuring anti-Xa DOAC agents, and the dilute thrombin time (dTT) or other direct thrombin inhibitor (DTI) assays used to measure dabigatran.…”

“…Instead, modifications of standard laboratory hemostasis tests have become popular, with anti-Xa assays utilised for measuring anti-Xa DOAC agents, and the dilute thrombin time (dTT) or other direct thrombin inhibitor (DTI) assays used to measure dabigatran. [1][2][3][4]11 Most of these tests can be completed within 10 minutes on automated analyser platforms. 11 Published reports of laboratory surveys of practice for these methods are scarce.…”