Comparison of calibrated dilute thrombin time and aPTT tests with LC-MS/MS for the therapeutic monitoring of patients treated with dabigatran etexilate
07 March 2013
Accepted after minor revision: 27 May 2013
22 November 2017 (online)
Ways to monitor dabigatran etexilate (DE) therapy would be useful in certain situations. Functional assays such as aPTT or Hemoclot® Thrombin Inhibitor (HTI) have been proposed to evaluate dabigatran concentrations, but previous findings are based on in vitro studies and results must be confirmed in clinical samples. The aim of this study was to compare aPTT and HTI measurements with liquid chromatography- tandem mass spectrometry (LC-MS/MS) measurements of dabigatran in plasma samples from DE treated patients. Seventy-one plasma samples were included. aPTT was performed using STA-CKPrest® and SynthASil®. HTI was performed according to instructions from the manufacturer. The LC-MS/MS method utilised dabigatran- d3 as internal standard. The plasma concentration range was 0 to 645 ng/ml as measured by LC-MS/MS. Overall, the HTI and LC-MS/ MS analyses correlated well (r2=0.97). The Bland-Altman analysis showed a mean difference of 9 ng/ml (SD: 20 ng/ml). However, the HTI performed poorly at concentrations <50 ng/ml. LC-MS/MS was sensitive (limit of quantification 1.1 ng/ml) and specific for dabigatran. The aPTT methods did not correlate well with plasma concentrations measured by LC-MS/MS (r2 = 0.59 with SynthASil® and 0.50 with STACKPrest ®). In conclusion, the poor sensitivity, the important inter-individual variability, and the poor correlation with LC-MS/MS preclude the use of aPTT to estimate dabigatran concentrations. Due to its small inter-individual variability and good agreement with LC-MS/MS measurements, we recommend the use of HTI assays to rather accurately estimate concentrations of dabigatran <50 ng/ml. Quantification of lower dabigatran levels in DE-treated patients requires the “reference” LC-MS/MS method.
- 1 E.M.A. EU - Summary of Product Characteristic: Pradaxa. 07/02/2013 [cited 2013 12th February]; Available from http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf
- 2 F.D.A. SUMMARY REVIEW for PRADAXA. 2010 Available from http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512Orig1s000SumR.pdf Accessed February 11, 2012
- 3 Dentali F, Riva N, Crowther M. et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012; 126: 2381-2391.
- 4 Camm AJ, Lip GY, De Caterina R. et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation--developed with the special contribution of the European Heart Rhythm Association. Europace 2012; 14: 1385-1413.
- 5 Stangier J, Clemens A. Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost 2009; 15 (Suppl. 01) 9S-16S.
- 6 Liesenfeld KH, Lehr T, Dansirikul C. et al. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 09: 2168-2175.
- 7 Ten Cate H. Monitoring new oral anticoagulants, managing thrombosis, or both?. Thromb Haemost 2012; 107: 803-805.
- 8 Rodriguez RA, Carrier M, Wells PS. Non-adherence to new oral anticoagulants: a reason for concern during long-term anticoagulation?. J Thromb Haemost 2013; 11: 390-394.
- 9 Douxfils J, Mullier F, Robert S. et al. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 2012; 107: 985-997.
- 10 Douxfils J, Mullier F, Loosen C. et al. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thromb Res 2012; 130: 956-966.
- 11 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103: 1116-1127.
- 12 Stangier J, Rathgen K, Stahle H. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 2007; 64: 292-303.
- 13 Baglin T, Hillarp A, Tripodi A. et al. Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: A recommendation from the Subcommittee on Control of Anticoagulation of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2013. Epub ahead of print
- 14 Curvers J, van de Kerkhof D, Stroobants AK. et al. Measuring direct thrombin inhibitors with routine and dedicated coagulation assays: which assay is helpful?. Am J Clin Pathol 2012; 138: 551-558.
- 15 Freyburger G, Macouillard G, Labrouche S. et al. Coagulation parameters in patients receiving dabigatran etexilate or rivaroxaban: two observational studies in patients undergoing total hip or total knee replacement. Thromb Res 2011; 127: 457-465.
- 16 Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23: 138-143.
- 17 Lindahl TL, Baghaei F, Blixter IF. et al. Effects of the oral, direct thrombin inhibitor dabigatran on five common coagulation assays. Thromb Haemost 2011; 105: 371-378.
- 18 Garcia D, Barrett YC, Ramacciotti E. et al. Laboratory assessment of the anticoagulant effects of the next generation of oral anticoagulants. J Thromb Haemost 2013; 11: 245-252.