Measurement and reversal of the direct oral anticoagulants

Blood Reviews

Volumn 31, Issue 1, 2017, Pages 77-84

  Samuelson, Bethany T ^a   Cuker, Adam ^b  

^a UNIVERSITY OF WASHINGTON   (United States)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Apixaban; Dabigatran; DOACs; Edoxaban; Measurement; Reversal; Rivaroxaban

Indexed keywords

ANDEXANET ALFA; ANTICOAGULANT AGENT; APIXABAN; BLOOD CLOTTING FACTOR 10A ANTIBODY; CIRAPARANTAG; DABIGATRAN; ECARIN; EDOXABAN; IDARUCIZUMAB; PLACEBO; PROTEIN ANTIBODY; RIVAROXABAN; UNCLASSIFIED DRUG; ANTITHROMBIN; BLOOD CLOTTING FACTOR 10A INHIBITOR;

ANTICOAGULANT THERAPY; ANTICOAGULATION; ANTICOAGULATION REVERSAL; ATRIAL FIBRILLATION; BINDING AFFINITY; BLOOD CLOTTING PARAMETERS; CALIBRATION; CEREBROVASCULAR ACCIDENT; CLINICAL TRIAL (TOPIC); DRUG APPROVAL; DRUG BINDING; DRUG BLOOD LEVEL; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG INDICATION; DRUG MECHANISM; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; EMBOLISM; HEMODIALYSIS; HEMOSTASIS; HUMAN; INFUSION RELATED REACTION; LIQUID CHROMATOGRAPHY-MASS SPECTROMETRY; MULTICENTER STUDY (TOPIC); NONHUMAN; OUTCOME ASSESSMENT; PARTIAL THROMBOPLASTIN TIME; PHARMACEUTICAL CARE; PROTHROMBIN TIME; RECOMMENDED DRUG DOSE; REVIEW; RISK BENEFIT ANALYSIS; THROMBIN TIME; THROMBOSIS; URTICARIA; VENOUS THROMBOEMBOLISM; BLOOD CLOTTING; BLOOD CLOTTING TEST; DRUG EFFECTS; INTERNATIONAL NORMALIZED RATIO; ORAL DRUG ADMINISTRATION;

ADMINISTRATION, ORAL; ANTICOAGULANTS; ANTITHROMBINS; BLOOD COAGULATION; BLOOD COAGULATION TESTS; DABIGATRAN; FACTOR XA INHIBITORS; HUMANS; INTERNATIONAL NORMALIZED RATIO; RIVAROXABAN;

EID: 84995493960     PISSN: 0268960X     EISSN: 15321681     Source Type: Journal    
DOI: 10.1016/j.blre.2016.08.006     Document Type: Review

References (78)

1. [1] Chai-Adisaksopha, C., Crowther, M., Isayama, T., Lim, W., The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 124 (2014), 2450–2458.
2. [2] Kearon, C., Akl, E.A., Ornelas, J., Blaivas, A., Jimenez, D., Bounameaux, H., et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 149 (2016), 315–352.
3. [3] Burnett, A.E., Mahan, C.E., Vazquez, S.R., Oertel, L.B., Garcia, D.A., Ansell, J., Guidance for the practical management of the direct oral anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis 41 (2016), 206–232.
4. [4] Eby, C., Novel anticoagulants and laboratory testing. Int J Lab Hematol 35 (2013), 262–268.
5. [5] Ezekowitz, M.D., Reilly, P.A., Nehmiz, G., Simmers, T.A., Nagarakanti, R., Parcham-Azad, K., et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO study). Am J Cardiol 100 (2007), 1419–1426.
6. [6] Kowalsk, K., Nielsen, J., Roy, A., Thanneer, N., Byon, W., Boyd, R., et al. Apixaban exposure and anti-Xa activity in nonvalvular atrial fibrillation patients: an application of population PK/PD analysis [abstract]. J Pharmacokinet Pharmacodyn, 41(Suppl. 1), 2014 [Abstract M-027].
7. [7] Mueck, W., Stampfuss, J., Kubitza, D., Becka, M., Clinical pharmacokinetic and pharmacodynamic profile of rivaroxaban. Clin Pharmacokinet 53 (2014), 1–16.
8. [8] Weitz, J.I., Connolly, S.J., Patel, I., Salazar, D., Rohatagi, S., Mendell, J., et al. Randomised, parallel-group, multicentre, multinational phase 2 study comparing edoxaban, an oral factor Xa inhibitor, with warfarin for stroke prevention in patients with atrial fibrillation. Thromb Haemost 104 (2010), 633–641.
9. [9] Reilly, P.A., Lehr, T., Haertter, S., Connolly, S.J., Yusuf, S., Eikelboom, J.W., et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY trial (randomized evaluation of long-term anticoagulation therapy). J Am Coll Cardiol 63 (2014), 321–328.
10. [10] Ruff, C.T., Giugliano, R.P., Braunwald, E., Morrow, D.A., Murphy, S.A., Kuder, J.F., et al. Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 385 (2015), 2288–2295.
11. [11] Cuker, A., Siegal, D., Monitoring and reversal of direct oral anticoagulants. Hematology Am Soc Hematol Educ Program 2015 (2015), 117–124.
12. [12] Cuker, A., Laboratory measurement of the non-vitamin K antagonist oral anticoagulants: selecting the optimal assay based on drug, assay availability, and clinical indication. J Thromb Thrombolysis 41 (2016), 241–247.
13. [13] Cuker, A., Siegal, D.M., Crowther, M.A., Garcia, D.A., Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 64 (2014), 1128–1139.
14. [14] Bouchard, J., Ghannoum, M., Bernier-Jean, A., Williamson, D., Kershaw, G., Weatherburn, C., et al. Comparison of intermittent and continuous extracorporeal treatments for the enhanced elimination of dabigatran. Clin Toxicol (Phila) 53 (2015), 156–163.
15. [15] Siegal, D.M., Cuker, A., Reversal of target-specific oral anticoagulants. Drug Discov Today 19 (2014), 1465–1470.
16. [16] Pradaxa prescribing information. 2010.
17. [17] van Ryn, J., Stangier, J., Haertter, S., Liesenfeld, K.H., Wienen, W., Feuring, M., et al. Dabigatran etexilate—a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103 (2010), 1116–1127.
18. [18] Avecilla, S.T., Ferrell, C., Chandler, W.L., Reyes, M., Plasma-diluted thrombin time to measure dabigatran concentrations during dabigatran etexilate therapy. Am J Clin Pathol 137 (2012), 572–574.
19. [19] Chin, P.K., Patterson, D.M., Zhang, M., Jensen, B.P., Wright, D.F., Barclay, M.L., et al. Coagulation assays and plasma fibrinogen concentrations in real-world patients with atrial fibrillation treated with dabigatran. Br J Clin Pharmacol 78 (2014), 630–638.
20. [20] Dager, W.E., Gosselin, R.C., Kitchen, S., Dwyre, D., Dabigatran effects on the international normalized ratio, activated partial thromboplastin time, thrombin time, and fibrinogen: a multicenter, in vitro study. Ann Pharmacother 46 (2012), 1627–1636.
21. [21] Dietrich, K., Stang, L., van Ryn, J., Mitchell, L.G., Assessing the anticoagulant effect of dabigatran in children: an in vitro study. Thromb Res 135 (2015), 630–635.
22. [22] Antovic, J.P., Skeppholm, M., Eintrei, J., Boija, E.E., Soderblom, L., Norberg, E.-M., et al. Evaluation of coagulation assays versus LC–MS/MS for determinations of dabigatran concentrations in plasma. Eur J Clin Pharmacol 69 (2013), 1875–1881.
23. [23] Gosselin, R.C., Adcock, D., Hawes, E.M., Francart, S.J., Grant, R.P., Moll, S., Evaluating the use of commercial drug-specific calibrators for determining PT and APTT reagent sensitivity to dabigatran and rivaroxaban. Thromb Haemost 113 (2015), 77–84.
24. [24] Jones, S.D., Eaddy, N.S., Chan, G.T., Dabigatran: laboratory monitoring. Pathology 44 (2012), 578–580.
25. [25] Schmohl, M., Gansser, D., Moschetti, V., Stangier, J., Measurement of dabigatran plasma concentrations by calibrated thrombin clotting time in comparison to LC–MS/MS in human volunteers on dialysis. Thromb Res 135 (2015), 532–536.
26. [26] Favaloro, E.J., Bonar, R., Butler, J., Marsden, K., Laboratory testing for the new oral anticoagulants: a review of current practice. Pathology 45 (2013), 435–437.
27. [27] Gosselin, R.C., Dwyre, D.M., Dager, W.E., Measuring dabigatran concentrations using a chromogenic ecarin clotting time assay. Ann Pharmacother 47 (2013), 1635–1640.
28. [28] Potzsch, B., Hund, S., Madlener, K., Unkrig, C., Muller-Berghaus, G., Monitoring of recombinant hirudin: assessment of a plasma-based ecarin clotting time assay. Thromb Res 86 (1997), 373–383.
29. [29] Hawes, E.M., Deal, A.M., Funk-Adcock, D., Gosselin, R., Jeanneret, C., Cook, A.M., et al. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 11 (2013), 1493–1502.
30. [30] Douxfils, J., Mullier, F., Robert, S., Chatelain, C., Chatelain, B., Dogne, J.M., Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 107 (2012), 985–997.
31. [31] Douxfils, J., Dogne, J.-M., Mullier, F., Chatelain, B., Ronquist-Nii, Y., Malmstrom, R.E., 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 110 (2013), 543–549.
32. [32] Helin, T.A., Pakkanen, A., Lassila, R., Joutsi-Korhonen, L., Laboratory assessment of novel oral anticoagulants: method suitability and variability between coagulation laboratories. Clin Chem 59 (2013), 807–814.
33. [33] Baglin, T., Hillarp, A., Tripodi, A., Elalamy, I., Buller, H., Ageno, W., 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.
34. [34] Bonar, R., Favaloro, E.J., Mohammed, S., Pasalic, L., Sioufi, J., Marsden, K., The effect of dabigatran on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 47 (2015), 355–364.
35. [35] Skeppholm, M., Al-Aieshy, F., Berndtsson, M., Al-Khalili, F., Ronquist-Nii, Y., Soderblom, L., et al. Clinical evaluation of laboratory methods to monitor apixaban treatment in patients with atrial fibrillation. Thromb Res 136 (2015), 148–153.
36. [36] Wilson, J.A., Goralski, K.B., Soroka, S.D., Morrison, M., Mossop, P., Sleno, L., et al. An evaluation of oral dabigatran etexilate pharmacokinetics and pharmacodynamics in hemodialysis. J Clin Pharmacol 54 (2014), 901–909.
37. [37] Dias, J.D., Norem, K., Doorneweerd, D.D., Thurer, R.L., Popovsky, M.A., Omert, L.A., Use of thromboelastography (TEG) for detection of new oral anticoagulants. Arch Pathol Lab Med 139 (2015), 665–673.
38. [38] Douxfils, J., Chatelain, B., Hjemdahl, P., Devalet, B., Sennesael, A.-L., Wallemacq, P., et al. Does the Russell viper venomtime test provide a rapid estimation of the intensity of oral anticoagulation? A cohort study. Thromb Res 135 (2015), 852–860.
39. [39] Du, S., Weiss, C., Christina, G., Kramer, S., Wehling, M., Kramer, R., et al. Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods. Clin Chem Lab Med 53 (2015), 1237–1247.
40. [40] Brunetti, L., Sanchez-Catanese, B., Kagan, L., Wen, X., Liu, M., Buckley, B., et al. Evaluation of the chromogenic anti-factor IIa assay to assess dabigatran exposure in geriatric patients with atrial fibrillation in an outpatient setting. Thromb J, 14, 2016, 10.
41. [41] Glund, S., Moschetti, V., Norris, S., Stangier, J., Schmohl, M., van Ryn, J., et al. A randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatran. Thromb Haemost 113 (2015), 943–951.
42. [42] Pollack, C.V. Jr., Reilly, P.A., Eikelboom, J., Glund, S., Verhamme, P., Bernstein, R.A., et al. Idarucizumab for dabigatran reversal. N Engl J Med 373 (2015), 511–520.
43. [43] Kubitza, D., Becka, M., Wensing, G., Voith, B., Zuehlsdorf, M., Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 61 (2005), 873–880.
44. [44] AG. BP. Xarelto Product Monograph, 2015.
45. [45] Frost, C., Nepal, S., Wang, J., Schuster, A., Byon, W., Boyd, R.A., et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 76 (2013), 776–786.
46. [46] Eliquis package insert. Available at: http://packageinserts.bms.com/pi/pi_eliquis.pdf.
47. [47] Edoxaban prescribing information. http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206316lbl.pdf.
48. [48] Asmis, L.M., Alberio, L., Angelillo-Scherrer, A., Korte, W., Mendez, A., Reber, G., et al. Rivaroxaban: quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res 129 (2012), 492–498.
49. [49] Douxfils, J., Tamigniau, A., Chatelain, B., Chatelain, C., Wallemacq, P., Dogne, J.M., et al. Comparison of calibrated chromogenic anti-Xa assay and PT tests with LC–MS/MS for the therapeutic monitoring of patients treated with rivaroxaban. Thromb Haemost 110 (2013), 723–731.
50. [50] Becker, R.C., Yang, H., Barrett, Y., Mohan, P., Wang, J., Wallentin, L., 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 32 (2011), 183–187.
51. [51] Mendell, J., Noveck, R.J., Shi, M., A randomized trial of the safety, pharmacokinetics and pharmacodynamics of edoxaban, an oral factor Xa inhibitor, following a switch from warfarin. Br J Clin Pharmacol 75 (2013), 966–978.
52. [52] Ogata, K., Mendell-Harary, J., Tachibana, M., Masumoto, H., Oguma, T., Kojima, M., et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J Clin Pharmacol 50 (2010), 743–753.
53. [53] Wolzt, M., Samama, M.M., Kapiotis, S., Ogata, K., Mendell, J., Kunitada, S., Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux. Thromb Haemost 105 (2011), 1080–1090.
54. [54] Pathologists CoA, Surveys participant summary for CGE, CGL, GCS, and ACM. 2013, College of American Pathologists, Northfield IL.
55. [55] Samama, M.M., Contant, G., Spiro, T.E., Perzborn, E., Flem, L.L., Guinet, C., et al. Evaluation of the prothrombin time for measuring rivaroxaban plasma concentrations using calibrators and controls: results of a multicenter field trial. Clin Appl Thromb Hemost 18 (2012), 150–158.
56. [56] Tripodi, A., Chantarangkul, V., Guinet, C., Samama, M.M., 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 9 (2011), 226–228.
57. [57] Francart, S.J., Hawes, E.M., Deal, A.M., Adcock, D.M., Gosselin, R., Jeanneret, C., et al. Performance of coagulation tests in patients on therapeutic doses of rivaroxaban. A cross-sectional pharmacodynamic study based on peak and trough plasma levels. Thromb Haemost 111 (2014), 1133–1140.
58. [58] Zafar, M.U., Vorchheimer, D.A., Gaztanaga, J., Velez, M., Yadegar, D., Moreno, P.R., et al. Antithrombotic effects of factor Xa inhibition with DU-176b: phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thromb Haemost 98 (2007), 883–888.
59. [59] Morishima, Y., Kamisato, C., Laboratory measurements of the oral direct factor Xa inhibitor edoxaban: comparison of prothrombin time, activated partial thromboplastin time, and thrombin generation assay. Am J Clin Pathol 143 (2015), 241–247.
60. [60] Douxfils, J., Chatelain, B., Chatelain, C., Dogne, J.M., Mullier, F., Edoxaban: impact on routine and specific coagulation assays. A practical laboratory guide. Thromb Haemost 115 (2016), 368–381.
61. [61] Tripodi, A., Padovan, L., Veena, C., Scalambrino, E., Testa, S., Peyvandi, F., How the direct oral anticoagulant apixaban affects thrombin generation parameters. Thromb Res 135 (2015), 1186–1190.
62. [62] Bonar, R., Favaloro, E.J., Mohammed, S., Ahuja, M., Pasalic, L., Sioufi, J., et al. The effect of the direct factor Xa inhibitors apixaban and rivaroxaban on haemostasis tests: a comprehensive assessment using in vitro and ex vivo samples. Pathology 48 (2016), 60–71.
63. [63] Dale, B.J., Ginsberg, J.S., Johnston, M., Hirsh, J., Weitz, J.I., Eikelboom, J.W., Comparison of the effects of apixaban and rivaroxaban on prothrombin and activated partial thromboplastin times using various reagents. J Thromb Haemost 12 (2014), 1810–1815.
64. [64] Eller, T., Busse, J., Dittrich, M., Flieder, T., Alban, S., Knabbe, C., et al. Dabigatran, rivaroxaban, apixaban, argatroban and fondaparinux and their effects on coagulation POC and platelet function tests. Clin Chem Lab Med 52 (2014), 835–844.
65. [65] Harenberg, J., Du, S., Wehling, M., Zolfaghari, S., Weiss, C., Kramer, R., et al. Measurement of dabigatran, rivaroxaban and apixaban in samples of plasma, serum and urine, under real life conditions. An international study. Clin Chem Lab Med 54 (2016), 275–283.
66. [66] Lu, G., DeGuzman, F.R., Hollenbach, S.J., Karbarz, M.J., Abe, K., Lee, G., et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med 19 (2013), 446–451.
67. [67] Ansell, J.E., Bakhru, S.H., Laulicht, B.E., Steiner, S.S., Grosso, M., Brown, K., et al. Use of PER977 to reverse the anticoagulant effect of edoxaban. N Engl J Med 371 (2014), 2141–2142.
68. [68] Eerenberg, E.S., Kamphuisen, P.W., Sijpkens, M.K., Meijers, J.C., Buller, H.R., Levi, M., Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 124 (2011), 1573–1579.
69. [69] Nagakari, K., Emmi, M., Iba, T., Prothrombin time tests for the monitoring of direct oral anticoagulants and their evaluation as indicators of the reversal effect. Clin Appl Thromb Hemost, 2016, 10.1177/1076029616638506.
70. [70] Martin, A.C., Gouin-Thibault, I., Siguret, V., Mordohay, A., Samama, C.M., Gaussem, P., et al. Multimodal assessment of non-specific hemostatic agents for apixaban reversal. J Thromb Haemost 13 (2015), 426–436.
71. [71] Levi, M., van der Poll, T., A short contemporary history of disseminated intravascular coagulation. Semin Thromb Hemost 40 (2014), 874–880.
72. [72] Zahir, H., Brown, K.S., Vandell, A.G., Desai, M., Maa, J.F., Dishy, V., et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 131 (2015), 82–90.
73. [73] Majeed, A., Eelde, A., Agren, A., Schulman, S., Holmstrom, M., Thromboembolic safety and efficacy of prothrombin complex concentrates in the emergency reversal of warfarin coagulopathy. Thromb Res 129 (2012), 146–151.
74. [74] Siegal, D.M., Managing target-specific oral anticoagulant associated bleeding including an update on pharmacological reversal agents. J Thromb Thrombolysis 39 (2015), 395–402.
75. [75] Ehrlich, H.J., Henzl, M.J., Gomperts, E.D., Safety of factor VIII inhibitor bypass activity (FEIBA): 10-year compilation of thrombotic adverse events. Haemophilia 8 (2002), 83–90.
76. [76] Herrmann, R., Thom, J., Wood, A., Phillips, M., Muhammad, S., Baker, R., Thrombin generation using the calibrated automated thrombinoscope to assess reversibility of dabigatran and rivaroxaban. Thromb Haemost 111 (2014), 989–995.
77. [77] Marlu, R., Hodaj, E., Paris, A., Albaladejo, P., Cracowski, J.L., Pernod, G., Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 108 (2012), 217–224.
78. [78] Levi, M., Levy, J.H., Andersen, H.F., Truloff, D., Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med 363 (2010), 1791–1800.