Provides guidance on the effects of dabigatran and rivaroxaban on routine coagulation screens to prevent clinical misinterpretation, such as falsely diagnosing DIC.
Oral direct inhibitors of thrombin and activated factor X (factor Xa) are now approved as anticoagulant drugs. The first two drugs to complete phase III clinical trials are dabigatran etexilate and rivaroxaban, which are given at fixed dose and do not require monitoring. In most circumstances both have predictable bioavailability, pharmacokinetic and pharmacodynamic effects, however, there will be clinical circumstances when urgent assessment of the anticoagulant effect of these drugs will be required. The effects of dabigatran and rivaroxaban on laboratory tests have been determined in vitro by spiking normal samples with a known concentration of active compound or ex vivo using plasma samples from volunteers and patients. To date there are few data on the sensitivity of different reagents and so only general guidance as to the effect and interpretation of a test result can be given at present. Laboratories should be aware of the sensitivity of their own assays to each drug, which can be achieved using commercially available dabigatran and rivaroxaban calibrants. Dabigatran etexilate is an oral prodrug that is hydrolysed in the liver to the direct thrombin inhibitor dabigatran. Doses recommended for clinical use are 150 mg od, 220 mg od, 110 mg bd and 150 mg bd. Peak plasma levels are reached 2 to 3 h after ingestion. Dabigatran is 80% renally excreted with a half-life of approximately 13 h with a glomerular filtration rate (GFR) of >80 ml/min, and 18 h with a GFR of 30–50 ml/min. There is a dose-dependent effect of dabigatran on laboratory clotting tests (Wienen et al, 2007; van Ryn et al, 2010; Freyburger et al, 2011; Lindahl et al, 2011). Rivaroxaban is an oral direct inhibitor of factor Xa. Doses recommended for clinical use are 10 mg od and 20 mg od (15 mg bd for first 3 weeks of treatment of DVT). Peak plasma levels are reached 2 to 3 h after ingestion. Rivaroxaban is 33% renally excreted and has a half-life of 9 h in patients with normal renal function. There is a dose-dependent effect of rivaroxaban on laboratory clotting tests (Samama et al, 2010; Freyburger et al, 2011; Hillarp et al, 2011). For both drugs, peak plasma concentrations are in the range of 100 to 400 ng/ml. Trough concentrations are in the range of 20 to 150 ng/ml. Clinicians require knowledge as to how routine coagulation tests are affected because many patients having a 'coagulation screen' will be taking these drugs. They also need to know if and how the degree of anticoagulation can be assessed using routine coagulation tests. In this situation a test must be readily available, easily performed and provide a result within 30 to 60 min. The result of the test can indicate whether anticoagulation is supratherapeutic, therapeutic or subtherapeutic, but cannot be used to determine the plasma concentration of the drug. The test results are dependent on when the last dose of drug was taken and therefore require interpretation with reference to the dose, anticipated half-life and factors that influence pharmacokinetics. The thrombin time (TT) shows a linear concentration response to dabigatran (van Ryn et al, 2010; Lindahl et al, 2011) but results are highly dependent on the reagents and coagulometer used and most TT assays will be too sensitive. Their only use may be as a sensitive method for determining if any dabigatran is present, which will be excluded by a normal TT. Rivaroxaban has no effect on the TT. Drug levels can be measured directly by non-coagulation tests, such as high-performance liquid chromatography-tandem mass spectrometry. The Hemoclot® thrombin inhibitor assay is a sensitive dabigatran-calibrated thrombin clotting time which can be used to determine the drug concentration (Stangier Asmis et al, 2012). By using rivaroxaban calibrators and controls, the anti-factor Xa chromogenic method is suitable for measuring a wide range of rivaroxaban plasma concentrations (20–660 ng/ml), which covers the expected rivaroxaban plasma levels after therapeutic doses (Samama et al, 2010, 2012). It is likely that coagulation tests will be performed on patients who are taking anticoagulants as part of a routine clinical assessment, e.g. admission to Accident and Emergency. It is important that clinical staff appreciate that tests results (PT, APTT, TT and fibrinogen) can be affected so that they are not misinterpreted. Measurement of fibrinogen in patients taking dabigatran can give falsely low results but, with marked variation with different reagents (Lindahl et al, 2011), some substantially underestimate the fibrinogen concentration whilst others (using higher thrombin concentrations and/or higher dilutions of test plasma) are little affected. D-dimer levels are suppressed by all anticoagulant drugs but these agents do not interfere with the D-dimer assay. For example, patients taking dabigatran or rivaroxaban could have a prolonged APTT and/or PT and those on dabigatran a falsely low fibrinogen and the results might wrongly be interpreted as suggesting disseminated intravascular coagulation (DIC). However, dabigatran and rivaroxaban do not cause thrombocytopenia and the D-dimer level is likely to be low. While the advice and information in these guidelines is believed to be true and accurate at the time of going to press, neither the authors, the British Society for Haematology nor the publishers accept any legal responsibility for the content of these guidelines.
Baglin et al. (Thu,) studied this question.