Chest
Volume 151, Issue 1, January 2017, Pages 127-138
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Original Research: Antithrombotic Therapy
Laboratory Assessment of the Anticoagulant Activity of Direct Oral Anticoagulants: A Systematic Review

https://doi.org/10.1016/j.chest.2016.08.1462Get rights and content

Background

Direct oral anticoagulants (DOACs) are the treatment of choice for most patients with atrial fibrillation and/or noncancer-associated venous thromboembolic disease. Although routine monitoring of these agents is not required, assessment of anticoagulant effect may be desirable in special situations. The objective of this review was to summarize systematically evidence regarding laboratory assessment of the anticoagulant effects of dabigatran, rivaroxaban, apixaban, and edoxaban.

Methods

PubMed, Embase, and Web of Science were searched for studies reporting relationships between drug levels and coagulation assay results.

Results

We identified 109 eligible studies: 35 for dabigatran, 50 for rivaroxaban, 11 for apixaban, and 13 for edoxaban. The performance of standard anticoagulation tests varied across DOACs and reagents; most assays, showed insufficient correlation to provide a reliable assessment of DOAC effects. Dilute thrombin time (TT) assays demonstrated linear correlation (r2 = 0.67-0.99) across a range of expected concentrations of dabigatran, as did ecarin-based assays. Calibrated anti-Xa assays demonstrated linear correlation (r2 = 0.78-1.00) across a wide range of concentrations for rivaroxaban, apixaban, and edoxaban.

Conclusions

An ideal test, offering both accuracy and precision for measurement of any DOAC is not widely available. We recommend a dilute TT or ecarin-based assay for assessment of the anticoagulant effect of dabigatran and anti-Xa assays with drug-specific calibrators for direct Xa inhibitors. In the absence of these tests, TT or APTT is recommended over PT/INR for assessment of dabigatran, and PT/INR is recommended over APTT for detection of factor Xa inhibitors. Time since last dose, the presence or absence of drug interactions, and renal and hepatic function should impact clinical estimates of anticoagulant effect in a patient for whom laboratory test results are not available.

Section snippets

Literature Search

We performed a systematic review of the literature to examine use of coagulation assays for assessment of the anticoagulant activity of DOACs. A search of PubMed, Web of Science, and Embase from inception through July 1, 2015, was undertaken for dabigatran, rivaroxaban, apixaban, and edoxaban using the key words “name of drug” AND (monitoring OR measurement OR laboratory OR prothrombin time OR partial thromboplastin time OR activated partial thromboplastin time OR PT OR APTT). For anti-Xa

Dabigatran

Dabigatran etexilate is taken orally as an inactive nonpeptide prodrug and is rapidly converted by nonspecific esterases to a potent, direct inhibitor of free- and fibrin-bound thrombin. Absorption is rapid, but bioavailability is only 6.5%. The half-life is 12 to 14 hours, and elimination is 80% renal.13 The expected steady-state concentrations of dabigatran as measured by LC-MS/MS are shown in Table 1.

Discussion

Although there are no established therapeutic ranges for any of these drugs or evidence to support routine monitoring with or without titration of dose, there are a variety of circumstances in which assessing anticoagulant effect may be useful. A number of professional societies, including the ISTH and CHEST, have published recommendations for urgent or routine assessment of the anticoagulant effects of direct thrombin inhibitors and anti-Xa agents. In this systematic review, we have examined

Acknowledgments

Author contributions: B. T. S., had full access to all the data in the study and takes full responsibility for the integrity of the data and the accuracy of the data analysis. A. C., D. M. S., M. C., and D. A. G. contributed substantially to the study design, data analysis and interpretation, and writing of the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: A. C. has served as a consultant for Amgen, Bracco, and Genzyme and has received research

References (121)

  • J. van Ryn et al.

    Interpretation of point-of-care INR results in patients treated with dabigatran

    Am J Med

    (2012)
  • J. Douxfils et al.

    Does the Russell viper venom time test provide a rapid estimation of the intensity of oral anticoagulation? A cohort study

    Thromb Res

    (2015)
  • J. Dinkelaar et al.

    In vitro assessment, using thrombin generation, of the applicability of prothrombin complex concentrate as an antidote for rivaroxaban

    J Thromb Haemost

    (2013)
  • E. Perzborn et al.

    In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939: an oral, direct factor Xa inhibitor

    J Thromb Haemost

    (2005)
  • D. Adelmann et al.

    Measuring the activity of apixaban and rivaroxaban with rotational thrombelastometry

    Thromb Res

    (2014)
  • D.R. Arachchillage et al.

    Interactions between rivaroxaban and antiphospholipid antibodies in thrombotic antiphospholipid syndrome

    J Thromb Haemost

    (2015)
  • L.M. Asmis et al.

    Rivaroxaban: quantification by anti-FXa assay and influence on coagulation tests—a study in 9 Swiss laboratories

    Thromb Res

    (2012)
  • C. Attard et al.

    The in vitro anticoagulant effect of rivaroxaban in children

    Thromb Res

    (2012)
  • B.J. Dale et al.

    Comparison of the effects of apixaban and rivaroxaban on prothrombin and activated partial thromboplastin times using various reagents

    J Thromb Haemost

    (2014)
  • J. Douxfils 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)
  • G.T. Gerotziafas et al.

    Optimisation of the assays for the measurement of clotting factor activity in the presence of rivaroxaban

    Thromb Res

    (2012)
  • G.T. Gerotziafas et al.

    In vitro inhibition of thrombin generation, after tissue factor pathway activation, by the oral, direct factor Xa inhibitor rivaroxaban

    J Thromb Haemost

    (2007)
  • S. Harder et al.

    Monitoring direct FXa-inhibitors and fondaparinux by Prothrombinase-induced Clotting Time (PiCT): relation to FXa-activity and influence of assay modifications

    Thromb Res

    (2008)
  • A. Hillarp et al.

    Effects of the oral, direct factor Xa inhibitor rivaroxaban on commonly used coagulation assays

    J Thromb Haemost

    (2011)
  • S. Rathbun et al.

    Comparison of methods to determine rivaroxaban anti-factor Xa activity

    Thromb Res

    (2015)
  • A. Tripodi 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)
  • M. Wolzt et al.

    Open-label, randomized study of the effect of rivaroxaban with or without acetylsalicylic acid on thrombus formation in a perfusion chamber

    Thromb Res

    (2013)
  • M. Skeppholm et al.

    Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation

    Thromb Res

    (2015)
  • A.C. Martin et al.

    Multimodal assessment of non-specific hemostatic agents for apixaban reversal

    J Thromb Haemost

    (2015)
  • C. Kearon et al.

    Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed—American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

    Chest

    (2012)
  • J.E. Ansell

    Management of venous thromboembolism: clinical guidance from the Anticoagulation Forum

    J Thromb Thrombolysis

    (2016)
  • C.T. January et al.

    2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society

    Circulation

    (2014)
  • S.J. Connolly et al.

    Dabigatran versus warfarin in patients with atrial fibrillation

    N Engl J Med

    (2009)
  • C.B. Granger et al.

    Apixaban versus warfarin in patients with atrial fibrillation

    N Engl J Med

    (2011)
  • M.R. Patel et al.

    Rivaroxaban versus warfarin in nonvalvular atrial fibrillation

    N Engl J Med

    (2011)
  • R.P. Giugliano et al.

    Edoxaban versus warfarin in patients with atrial fibrillation

    N Engl J Med

    (2013)
  • Baglin T, Hillarp A, Tripodi A, et al. Measuring Oral Direct Inhibitors (ODIs) of thrombin and factor Xa: A...
  • A. Cuker et al.

    Laboratory measurement of the anticoagulant activity of edoxaban: a systematic review

    J Thromb Thrombolysis

    (2015)
  • J. Stangier et al.

    Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor

    Clin Appl Thromb Hemost

    (2009)
  • J.P. Antovic et al.

    Evaluation of coagulation assays versus LC-MS/MS for determinations of dabigatran concentrations in plasma

    Eur J Clin Pharmacol

    (2013)
  • S.T. Avecilla et al.

    Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy

    Am J Clin Pathol

    (2012)
  • P.K. Chin et al.

    Coagulation assays and plasma fibrinogen concentrations in real-world patients with atrial fibrillation treated with dabigatran

    Br J Clin Pharmacol

    (2014)
  • W.E. Dager et al.

    Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study

    Ann Pharmacother

    (2012)
  • J.D. Dias et al.

    Use of thromboelastography (TEG) for detection of new oral anticoagulants

    Arch Pathol Lab Med

    (2015)
  • J. Douxfils et al.

    Comparison of calibrated dilute thrombin time and aPTT tests with LC-MS/MS for the therapeutic monitoring of patients treated with dabigatran etexilate

    Thromb Haemost

    (2013)
  • J. Douxfils 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)
  • R.C. Gosselin et al.

    Evaluating the use of commercial drug-specific calibrators for determining PT and APTT reagent sensitivity to dabigatran and rivaroxaban

    Thromb Haemost

    (2015)
  • R.C. Gosselin et al.

    Measuring dabigatran concentrations using a chromogenic ecarin clotting time assay

    Ann Pharmacother

    (2013)
  • W.M. Halbmayer et al.

    Interference of the new oral anticoagulant dabigatran with frequently used coagulation tests

    Clin Chem Lab Med

    (2012)
  • J. Harenberg et al.

    Determination of dabigatran in human plasma samples

    Semin Thromb Hemost

    (2012)
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    FUNDING/SUPPORT: This research was supported in part by the National Heart, Lung, and Blood Institute [T32HL007093].

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