Effects on routine coagulation screens and assessment of anticoagulant intensity in patients taking oral dabigatran or rivaroxaban: Guidance from the British Committee for Standards in Haematology

Abstract

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. Urgent assessment of the degree of anticoagulation may be required