Non-VKA Oral Anticoagulants: Accurate Measurement of Plasma Drug Concentrations

Abstract

Non-VKA oral anticoagulants (NOACs) have now widely reached the lucrative market of anticoagulation. While the marketing authorization holders claimed that no routine monitoring is required and that these compounds can be given at fixed doses, several evidences arisen from the literature tend to demonstrate the opposite. New data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of at least dabigatran. Information regarding the association of rivaroxaban and apixaban exposure and the bleeding risk is available in the drug approval package on the FDA website. These reviews suggest that accumulation of these compounds increases the risk of experiencing a bleeding complication. Therefore, in certain patient populations such as patients with acute or chronic renal impairment or with multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This paper aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.

Management of major bleeding and outcomes in patients treated with direct oral anticoagulants: results from the START-Event registry

“…Laboratory tests included: blood cell count, liver enzymes (AST, ALT), renal function (creatinine clearance calculated using the Cockcroft-Gault formula), coagulation screening tests (PT and aPTT), and specific DOAC measurements. DOACs levels, expressed as drug concentration equivalent (ng/ml), were measured with diluted thrombin time (dTT) or ecarin chromogenic assay (ECA) calibrated for dabigatran and specific anti-factor X activated (FXa) assays calibrated for apixaban, edoxaban, and rivaroxaban [12,21,22]. All tests were performed locally, and each investigator made decision on whether to perform laboratory or not.…”

Non-vitamin-K oral anticoagulants and laboratory testing: now and in the future

“…The classical coagulation tests can be misleading for determining NOAC activity 11 , 12 . Product information for all these medicines warns against use of INR.…”

“…In contrast, specific assays (dTT—diluted thrombin time, or ecarin-based assays such as ecarin chromogenic assay (ECA) for dabigatran, chromogenic factor Xa assays for the factor Xa inhibitors, see Table 2 ) correlate well with plasma concentrations 11 , 12 although they may be less reliable at very low concentrations and require product-specific calibration. …”

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“…Edoxaban was non inferior to warfarin regarding prevention of systemic embolism or stroke and had a significant reduction of bleeding and death from cardiovascular causes. Betrixaban is a new direct factor Xa inhibitor and was studied in phase II studies in atrial fibrillation 14 .…”