Facts and artefacts of coagulation assays for factor Xa inhibitors.

Direct factor Xa inhibitors are among the compounds at the forefront of clinical development for the prevention and treatment of thromboembolic disorders; of these, rivaroxaban, apixaban and edoxaban (DU-176b) are in the most advanced stages of development. Rivaroxaban is approved in several countries for the prevention of venous thromboembolism (VTE) after elective hip or knee arthroplasty, and trials are ongoing for other indications. Apixaban and edoxaban are undergoing clinical development for several indications. In phase II studies, various dosage regimens of rivaroxaban showed similar efficacy and safety to enoxaparin for the prevention of VTE after total hip and total knee arthroplasty (THA and TKA, respectively) (1–3) and for the treatment of deep-vein thrombosis when compared with overlapping treatment with enoxaparin and vitamin K antagonists (VKAs) (4, 5). Rivaroxaban inhibits factor Xa in a concentrationdependent manner and was found to have predictable pharmacokinetics and pharmacodynamics across a wide range of doses in healthy individuals (6, 7), as well as in patients undergoing THA (8, 9) or TKA (9). A fixed dosing regimen (10 mg once daily) has been shown to be suitable for the prevention of VTE after THA or TKA (10–13) and in VTE treatment in patients who have previously completed 6–12 months of anticoagulant therapy (20 mg once daily) (14). Unlike VKAs, direct factor Xa inhibitors have a single target and have been found to have a predictable mode of action; therefore, they do not require regular coagulation monitoring. Although rivaroxaban and other direct factor Xa inhibitors can be administered without the need for regular coagulation monitoring, the ability to measure their pharmacodynamic effects (monitorability) might be useful (15), for example, when assessing patient compliance or in emergency situations. However, there is no specific laboratory test, and clinicians could be misled by the results of conventional coagulation tests, which are not specifically affected by the new, oral, direct factor Xa inhibitors. This may also be the case for other single-target anticoagulants such as direct thrombin inhibitors. The study by Samama et al. (16) published in this issue of Thrombosis Haemo stasis aimed to find the most appropriate coagulation assays to measure rivaroxaban pharmacodynamics and explored how pharmacodynamics can be measured by use of specific tests for factor Xa measurement. The investigators found that although rivaroxaban prolonged the conventional tests for prothrombin time (PT; also known as thromboplastin time or Quick test), dilute PT and activated partial thromboplastin time (aPTT) in a concentrationdependent manner, the results were reported to vary depending on the assay reagent used (16).