Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide

Summary

Apixaban does not require monitoring nor frequent dose adjustment. However, searching for the optimal dose for the individual patient may be useful in some situations. Moreover, there is a need for clinicians to know whether coagulation assays are influenced by apixaban use. The aim of this study was to determine which coagulation assay could be used to assess the impact of apixaban on haemostasis and provide good laboratory recommendations for the accurate interpretation of haemostasis assays. Apixaban is spiked at concentrations ranging from 5 to 500 ng/ml in platelet-poor plasma. Routinely used or more specific coagulation assays are tested. Results show a concentration dependent prolongation of aPTT, PT and dilute PT. The sensitivity mainly depends on the reagent, but none of these tests is sensitive enough to ensure an accurate estimation of the pharmacodynamic effect of apixaban. FXa chromogenic assays show high sensitivity and a linear correlation depending on the reagent and/or the methodology. Immunological assays and assays acting below the FXa are not influenced by apixaban. In conclusion, PT and/or dilute PT cannot be used to assess apixaban pharmacodynamic properties. More specific and sensitive assays such as chromogenic FXa assays using specific calibrators are required. In case of thrombophilia or in the exploration of a haemorrhagic event, immunological assays should be recommended, when applicable. Standardisation of the time between the last intake of apixaban and the sampling is mandatory.

Keywords

Apixaban - monitoring - coagulation assays - assessment - laboratory recommendations

• References

• 1 E.M.A. EPAR Public Assessment Report for Eliquis. 2012 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002148/WC500107726.pdf Accessed November 29, 2012.
• 2 Squibb B-M. ELIQUIS®(apixaban) Approved in Europe for Prevention of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation. Available from: http://news.bms.com/press-release/financial-news/eliquisapixaban-approved-europe-prevention-stroke-and-systemic-embolism&t=634890181706594412 Accessed November 22, 2012.
• 3 F.D.A. FDA approves Eliquis to reduce the risk of stroke, blood clots in patients with non-valvular atrial fibrillation. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333634.htm Accessed Frebruary 28, 2013.
• 4 Alexander JH, Lopes RD, James S. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med 2011; 365: 699-708.
• 5 Buller H, Deitchman D, Prins M. et al. Efficacy and safety of the oral direct factor Xa inhibitor apixaban for symptomatic deep vein thrombosis. The Botticelli DVT dose-ranging study. J Thromb Haemost 2008; 06: 1313-1318.
• 6 Agnelli G, Buller HR, Cohen A. et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368: 699-708.
• 7 Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis 2011; 31: 326-343.
• 8 Ten Cate H. Monitoring new oral anticoagulants, managing thrombosis, or both?. Thromb Haemost 2012; 107: 803-805.
• 9 Sie P, Samama CM, Godier A. et al. Surgery and invasive procedures in patients on long-term treatment with direct oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the Working Group on Perioperative Haemostasis and the French Study Group on Thrombosis and Haemostasis. Arch Cardiovasc Dis 2011; 104: 669-676.
• 10 Turpie AG, Kreutz R, Llau J. et al. Management consensus guidance for the use of rivaroxaban-an oral, direct factor Xa inhibitor. Thromb Haemost 2012; 108: 876-886.
• 11 Camici GG, Steffel J, Akhmedov A. et al. Dimethyl sulfoxide inhibits tissue factor expression, thrombus formation, and vascular smooth muscle cell activation: a potential treatment strategy for drug-eluting stents. Circulation 2006; 114: 1512-1521.
• 12 Hemker HC, Giesen P, Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb 2003; 33: 4-15.
• 13 Robert S, Ghiotto J, Pirotte B. et al. Is thrombin generation the new rapid, reliable and relevant pharmacological tool for the development of anticoagulant drugs?. Pharmacol Res 2009; 59: 160-166.
• 14 Samama MM, Martinoli JL, LeFlem L. et al. Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103: 815-825.
• 15 Tripodi A, Chantarangkul V, Guinet C. et al. The International Normalized Ratio calibrated for rivaroxaban has the potential to normalize prothrombin time results for rivaroxaban-treated patients: results of an in vitro study. J Thromb Haemost 2011; 09: 226-228.
• 16 Wong PC, Crain EJ, Xin B. et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihaemostatic studies. J Thromb Haemost 2008; 06: 820-829.
• 17 Barrett YC, Wang Z, Frost C. et al. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104: 1263-1271.
• 18 Barrett YC, Wang Z, Knabb RM. A Novel Prothrombin Time Assay for Assessing the Anticoagulant Activity of Oral Factor Xa Inhibitors. Clin Appl Thromb Haemost. 2012 Epub ahead of print.
• 19 Becker RC, Yang H, Barrett Y. et al. Chromogenic laboratory assays to measure the factor Xa-inhibiting properties of apixaban--an oral, direct and selective factor Xa inhibitor. J Thromb Thrombolysis 2011; 32: 183-187.
• 20 Becker RC, Alexander JH, Newby LK. et al. Effect of apixaban, an oral and direct factor Xa inhibitor, on coagulation activity biomarkers following acute coronary syndrome. Thromb Haemost 2010; 104: 976-983.
• 21 Mani H, Rohde G, Stratmann G. et al. Accurate determination of rivaroxaban levels requires different calibrator sets but not addition of antithrombin. Thromb Haemost 2012; 108: 191-198.
• 22 Samama MM, Amiral J, Guinet C. et al. An optimised, rapid chromogenic assay, specific for measuring direct factor Xa inhibitors (rivaroxaban) in plasma. Thromb Haemost 2010; 104: 1078-1079.
• 23 Harenberg J, Kramer R, Giese C. et al. Determination of rivaroxaban by different factor Xa specific chromogenic substrate assays: reduction of interassay variability. J Thromb Thrombolysis 2011; 32: 267-271.
• 24 Frost C, Wang J, Nepal S. et al. Apixaban, an oral, direct factor Xa inhibitor: single-dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol. 2012 pub ahead of print.
• 25 Raghavan N, Frost CE, Yu Z. et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab Dispos 2009; 37: 74-81.
• 26 Barrett YC, Wang J, Song Y. et al. A randomised assessment of the pharmacokinetic, pharmacodynamic and safety interaction between apixaban and enoxaparin in healthy subjects. Thromb Haemost 2012; 107: 916-924.
• 27 Gerotziafas GT, Depasse F, Busson J. et al. Towards a standardisation of thrombin generation assessment: the influence of tissue factor, platelets and phospholipids concentration on the normal values of Thrombogram-Thrombinoscope assay. Thromb J 2005; 03: 16.
• 28 Mani H, Hesse C, Stratmann G. et al. Ex vivo effects of low-dose rivaroxaban on specific coagulation assays and coagulation factor activities in patients under real life conditions. Thromb Haemost 2012; 109: 127-136.
• 29 Gerotziafas GT, Baccouche H, Sassi M. et al. Optimisation of the assays for the measurement of clotting factor activity in the presence of rivaroxaban. Thromb Res 2012; 129: 101-103.
• 30 van Os GM, de Laat B, Kamphuisen PW. et al. Detection of lupus anticoagulant in the presence of rivaroxaban using Taipan snake venom time. J Thromb Haemost 2011; 09: 1657-1659.
• 31 Mani H, Hesse C, Stratmann G. et al. Rivaroxaban differentially influences ex vivo global coagulation assays based on the administration time. Thromb Haemost 2011; 106: 156-164.
• 32 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.