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Thromb Haemost 2014; 111(02): 240-248
DOI: 10.1160/TH13-06-0470
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays

A multicentre French GEHT study
Isabelle Gouin-Thibault
1   Université Paris Descartes, Sorbonne Paris Cité, INSERM UMR-S765, Paris, France
2   Assistance Publique Hôpitaux de Paris, GH Cochin-Hôtel-Dieu, Service d’Hématologie biologique Paris, France
,
Claire Flaujac
2   Assistance Publique Hôpitaux de Paris, GH Cochin-Hôtel-Dieu, Service d’Hématologie biologique Paris, France
,
Xavier Delavenne
3   Laboratoire de Pharmacologie-Toxicologie, Université Jean Monnet, EA3065, CHU Saint-Etienne, France
,
Sara Quenet
3   Laboratoire de Pharmacologie-Toxicologie, Université Jean Monnet, EA3065, CHU Saint-Etienne, France
,
Marie-Hélenè Horellou
2   Assistance Publique Hôpitaux de Paris, GH Cochin-Hôtel-Dieu, Service d’Hématologie biologique Paris, France
,
Silvy Laporte
3   Laboratoire de Pharmacologie-Toxicologie, Université Jean Monnet, EA3065, CHU Saint-Etienne, France
,
Virginie Siguret
4   Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d’Hématologie biologique, Paris, France
,
Thomas Lecompte
5   Hopitaux Universitaires de Genève, Hematology, Genève, Switzerland
› Author Affiliations Financial support:This study was supported by Bristol-Myers Squibb/Pfizer.
Further Information

Publication History

Received: 11 June 2013

Accepted after major revision: 19 September 2013

Publication Date:
27 November 2017 (online)

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Summary

While laboratory monitoring is not required in patients treated with apixaban, a direct factor-Xa inhibitor, assessment of its concentration is useful in some critical situations. However, few data are available on its effect on coagulation tests and on the suitability of anti-Xa assays for its quantification. It was the objective of this study to identify laboratory tests suitable for apixaban concentration assessment. Coagulation tests – PT and aPTT- and anti-Xa assays were performed in apixaban-spiked plasma samples. To evaluate the sensitivity of PT and aPTT to apixaban, we conducted a first monocenter part, with a wide range of concentrations (50–1,000 ng/ml), a large panel of reagents (20 reagents), and two coagulometers (STAR®, Stago and ACL TOP®, IL), and a second multicenter part involving 13 laboratories using either a common PT reagent (RecombiPlastin2G®) or the local PT and aPTT reagents. In the multicentre part, five blinded apixaban-spiked plasma samples (0/100/200/400/800 ng/ml – checked by HPLC-MS/MS) were used; apixaban concentrations were measured with three anti-Xa assays, apixaban calibrators and controls (Stago). PT and aPTT tests using a large panel of reagents displayed a low sensitivity to a wide range of apixaban concentrations. The concentrations to double PT ranged from 400 to >1,000 ng/ml with the 10 reagents. With the three anti-Xa assays, interlaboratory precision and accuracy were below 11% and 12%, respectively. In conclusion, whereas PT and aPTT tests were not sensitive enough to detect apixaban, the three anti-Xa assays tested using lyophilised apixaban calibrators and controls allowed to reliably quantify a wide range of apixaban concentrations.

Keywords

Apixaban - blood coagulation tests - anti-Xa - anticoagulant agents - multicenter study
 

  • References

  • 1 Alves C, Batel-Marques F, Macedo AF. Apixaban and rivaroxaban safety after hip and knee arthroplasty: a meta-analysis. J Cardiovasc Pharmacol Ther 2012; 17: 266-276.
    CrossrefPubMedSearch in Google Scholar
  • 2 Connolly SJ, Eikelboom J, Joyner C. et al. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364: 806-817.
    CrossrefPubMedSearch in Google Scholar
  • 3 Granger CB, Alexander JH, McMurray JJV. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
    CrossrefPubMedSearch in Google Scholar
  • 4 Agnelli G, Buller HR, Cohen A. et al. Apixaban for Extended Treatment of Venous Thromboembolism. N Engl J Med 2013; 368: 699-708.
    CrossrefPubMedSearch in Google Scholar
  • 5 Agnelli G, Buller HR, Cohen A. et al. Oral Apixaban for the Treatment of Acute Venous Thromboembolism. N Engl J Med 2013 Epub ahead of print.
    PubMedSearch in Google Scholar
  • 6 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.
    PubMedSearch in Google Scholar
  • 7 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.
    CrossrefPubMedSearch in Google Scholar
  • 8 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Douxfils J, Chatelain C, Chatelain B. et al. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013; 110: 283-294.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 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 2013; 75: 476-487.
    CrossrefPubMedSearch in Google Scholar
  • 12 Frost C, Nepal S, Wang J. et al. Safety, pharmacokinetics and pharmacody-namics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013 Epub ahead of print.
    PubMedSearch in Google Scholar
  • 13 Ageno W, Gallus AS, Wittkowsky A. et al. Oral anticoagulant therapy: Anti-thrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e44S-88S.
    CrossrefPubMedSearch in Google Scholar
  • 14 Sié 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 Haemo-stasis and the French Study Group on Thrombosis and Haemostasis. Arch Car-diovasc Dis 2011; 104: 669-676.
    CrossrefPubMedSearch in Google Scholar
  • 15 Samama MM, Contant G, Spiro TE. et al. Evaluation of the anti-factor Xa chro-mogenic assay for the measurement of rivaroxaban plasma concentrations using calibrators and controls. Thromb Haemost 2012; 107: 379-387.
    Thieme ConnectPubMedSearch in Google Scholar
  • 16 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.
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Stangier J, Feuring M. Using the HEMOCLOT direct thrombin inhibitor assay to determine plasma concentrations of dabigatran. Blood Coagul Fibrinolysis 2012; 23: 138-143.
    CrossrefPubMedSearch in Google Scholar
  • 18 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 2013; 75: 476-487.
    CrossrefPubMedSearch in Google Scholar
  • 19 Barrett YC, Wang J, Song Y. et al. A randomised assessment of the pharmacoki-netic, pharmacodynamic and safety interaction between apixaban and enoxapa-rin in healthy subjects. Thromb Haemost 2012; 107: 916-924.
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Samama MM, Martinoli J-L, LeFlem L. et al. Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103: 815-825.
    Thieme ConnectPubMedSearch in Google Scholar
  • 21 Douxfils J, Mullier F, Loosen C. et al. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of riva-roxaban and review of the literature. Thromb Res 2012; 130: 956-966.
    CrossrefPubMedSearch in Google Scholar
  • 22 Mani H, Hesse C, Stratmann G. et al. Rivaroxaban differentially influences ex vivo global coagulation assays based on the administration time. Thromb Hae-most 2011; 106: 156-164.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Hillarp A, Baghaei F, Fagerberg Blixter I. et al. Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays. J Thromb Haemost 2011; 9: 133-139.
    CrossrefPubMedSearch in Google Scholar
  • 24 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.
    CrossrefPubMedSearch in Google Scholar
  • 25 Harenberg J, Krämer 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.
    CrossrefPubMedSearch in Google Scholar
  • 26 Harenberg J, Marx S, Weiss C. et al. Report of the Subcommittee of Control of Anticoagulation on the determination of the anticoagulant effects of riva-roxaban. J Thromb Haemost 2012; 10: 1433-1436.
    CrossrefPubMedSearch in Google Scholar