Monitoring of low dabigatran concentrations: diagnostic performance at clinically relevant decision thresholds
- 15 Downloads
The direct oral anticoagulant dabigatran does not require therapeutic drug monitoring, however emergency measurements are gaining importance. Current assays feature good performance at intermediate and high dabigatran concentrations but show limited accuracy at low concentrations. This area requires more attention as clinical decision threshold values currently lie at 30 and 50 ng/ml. The objective of the study was to evaluate and compare diagnostic performance of dabigatran assays at these thresholds. Dabigatran concentrations of 293 plasma samples taken from 50 patients were measured with the INNOVANCE direct thrombin inhibitor assay (DTI) from Siemens, the Biophen direct thrombin inhibitor assay (BDTI), the BDTI using a low range calibrator (BDTI-low), the Hemoclot direct thrombin inhibitor assay (HTI) and an ecarin clotting time assay (ECT). Assay results were compared to ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS), and test characteristics were calculated for thresholds of 30 and 50 ng/ml. DTI, BDTI-low and ECT showed very strong correlation and high agreement with UPLC-MS/MS and an improved determination of low dabigatran concentrations. ROC curve analyses revealed very high accuracy at the 30/50 ng/ml thresholds for DTI (AUC = 0.989/0.995), BDTI-low (AUC = 0.980/0.991) and ECT (AUC = 0.990/0.996) measurements. Sensitivity and specificity in detecting were calculated for DTI (98/92%), BDTI-low (87/95%), ECT (97/96%), BDTI (99/82%) and HTI (86/89%) measurements. Compared to the previously available HTI and BDTI, both novel assays, DTI and BDTI-low, reliably determine low dabigatran plasma concentrations around the clinical decision thresholds with very high sensitivity and specificity.
KeywordsDabigatran Direct thrombin inhibitor assays Monitoring Emergency situations Thresholds
We thank S. Faix and I. Riedlinger from the University Hospital Tübingen for excellent technical assistance and all the participants that contributed in this study.
SP, ME and FH designed the study. IB, JK, AP and SH conducted all laboratory-based tests and UPLC-MS/MS. FH, SP, AP and SH analyzed and interpreted the data and wrote the manuscript. UZ, RL and HUH reviewed the data and supervised the preparation of the manuscript. All authors have reviewed and approved the final version of the manuscript.
Compliance with ethical standards
Conflict of interest
SP received speaker’s honoraria and consulting honoraria from Bayer, Boehringer-Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo and Werfen, reimbursement for congress traveling and accommodation from Bayer and Boehringer-Ingelheim, and research support from Bristol-Myers Squibb/Pfizer (significant), Boehringer-Ingelheim, Daiichi Sankyo (significant) and Helena Laboratories (all other contributions: modest). ME and FH received reimbursement for congress traveling and accommodation from Bayer (contributions: modest). IB received speaker’s honoraria from Aspen Germany GmbH, Bristol-Myers Squibb/Pfizer, Siemens Healthcare and CSL Behring and reimbursement for congress traveling and accommodation from Aspen and Bristol-Myers Squibb and performed contract research for Siemens Healthcare. IB is a member of the advisory board of LFB biomedicaments. UZ received personal fees from Biogen Idec GmbH, Bayer Vital GmbH, Bristol-Myers Squibb/Pfizer, CorTec GmbH, Medtronic GmbH, and grants from Biogen Idec GmbH, Servier, and Janssen Pharmaceuticals NV, outside of the submitted work (all contributions: modest). AP received speaker’s honoraria unrelated to the topic of this manuscript from Siemens Healthineers (modest) and research support unrelated to the topic of this manuscript from Siemens Healthineers (modest) and Boehringer-Ingelheim (significant). The remaining authors have disclosed that they do not have any conflicts of interest.
Institutional review board approval was obtained from the ethics committee at the University Hospital Tübingen (Protocol Number 259/2013BO1 and 270/2015B01). All studies were performed in accordance with the ethical standards of the Declaration of Helsinki.
Written informed consent was obtained from all participants at the beginning of the study.
- 1.Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L, RE-LY Steering Committee and Investigators (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151. https://doi.org/10.1056/NEJMoa0905561 CrossRefPubMedGoogle Scholar
- 2.Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ, RE-COVER Study Group (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361(24):2342–2352. https://doi.org/10.1056/NEJMoa0906598 CrossRefPubMedGoogle Scholar
- 3.Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ, Investigators R-MT, Investigators R-ST (2013) Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 368(8):709–718. https://doi.org/10.1056/NEJMoa1113697 CrossRefPubMedGoogle Scholar
- 4.Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383(9921):955–962. https://doi.org/10.1016/S0140-6736(13)62343-0 CrossRefPubMedGoogle Scholar
- 5.Fitzmaurice DA, Accetta G, Haas S, Kayani G, Lucas Luciardi H, Misselwitz F, Pieper K, Ten Cate H, Turpie AG, Kakkar AK, GARFIELD-AF Investigators (2016) Comparison of international normalized ratio audit parameters in patients enrolled in GARFIELD-AF and treated with vitamin K antagonists. Br J Haematol 174(4):610–623. https://doi.org/10.1111/bjh.14084 CrossRefPubMedGoogle Scholar
- 6.Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GY, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K (2016) 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 37(38):2893–2962. https://doi.org/10.1093/eurheartj/ehw210 CrossRefGoogle Scholar
- 7.Heidbuchel H, Verhamme P, Alings M, Antz M, Diener HC, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, ESC Scientific Document Group (2017) Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J 38(27):2137–2149. https://doi.org/10.1093/eurheartj/ehw058 CrossRefPubMedGoogle Scholar
- 9.Kitchen S, Gray E, Mackie I, Baglin T, Makris M, committee B (2014) Measurement of non-coumarin anticoagulants and their effects on tests of Haemostasis: guidance from the British Committee for Standards in Haematology. Br J Haematol 166(6):830–841. https://doi.org/10.1111/bjh.12975 CrossRefPubMedGoogle Scholar
- 16.Ebner M, Peter A, Spencer C, Hartig F, Birschmann I, Kuhn J, Wolf M, Winter N, Russo F, Zuern CS, Blumenstock G, Ziemann U, Poli S (2015) Point-of-care testing of coagulation in patients treated with non-vitamin K antagonist oral anticoagulants. Stroke 46(10):2741–2747. https://doi.org/10.1161/STROKEAHA.115.010148 CrossRefPubMedGoogle Scholar
- 17.Ebner M, Birschmann I, Peter A, Hartig F, Spencer C, Kuhn J, Blumenstock G, Zuern CS, Ziemann U, Poli S (2017) Emergency coagulation assessment during treatment with direct oral anticoagulants: limitations and solutions. Stroke 48(9):2457–2463. https://doi.org/10.1161/STROKEAHA.117.017981 CrossRefPubMedGoogle Scholar
- 18.Douxfils J, Lessire S, Dincq AS, Hjemdahl P, Ronquist-Nii Y, Pohanka A, Gourdin M, Chatelain B, Dogne JM, Mullier F (2015) Estimation of dabigatran plasma concentrations in the perioperative setting. An ex vivo study using dedicated coagulation assays. Thromb Haemost 113(4):862–869. https://doi.org/10.1160/TH14-09-0808 CrossRefPubMedGoogle Scholar
- 19.Gosselin RC, Adcock DM, Bates SM, Douxfils J, Favaloro EJ, Gouin-Thibault I, Guillermo C, Kawai Y, Lindhoff-Last E, Kitchen S (2018) International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 118(3):437–450. https://doi.org/10.1055/s-0038-1627480 CrossRefPubMedGoogle Scholar
- 20.van Ryn J, Stangier J, Haertter S, Liesenfeld KH, Wienen W, Feuring M, Clemens A (2010) Dabigatran etexilate: a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 103(6):1116–1127. https://doi.org/10.1160/TH09-11-0758 CrossRefPubMedGoogle Scholar
- 21.Schmitz EM, Boonen K, van den Heuvel DJ, van Dongen JL, Schellings MW, Emmen JM, van der Graaf F, Brunsveld L, van de Kerkhof D (2014) Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. J Thromb Haemost 12(10):1636–1646. https://doi.org/10.1111/jth.12702 CrossRefPubMedGoogle Scholar
- 22.Douxfils J, Mullier F, Robert S, Chatelain C, Chatelain B, Dogne JM (2012) Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 107(5):985–997. https://doi.org/10.1160/TH11-11-0804 CrossRefPubMedGoogle Scholar
- 23.Poli S, Hartig F, Spencer C, Ebner M, Birschmann I, Kuhn J, Faix S, Ziemann U, Haring HU, Lehmann R, Peter A, Horber S (2017) Diagnostic accuracy of a novel chromogenic direct thrombin inhibitor assay: clinical experiences for dabigatran monitoring. Thromb Haemost 117(12):2369–2375. https://doi.org/10.1160/TH17-04-0280 CrossRefPubMedGoogle Scholar
- 24.Kuhn J, Gripp T, Flieder T, Dittrich M, Hendig D, Busse J, Knabbe C, Birschmann I (2015) UPLC-MRM mass spectrometry method for measurement of the coagulation inhibitors dabigatran and rivaroxaban in human plasma and its comparison with functional assays. PLoS ONE 10(12):e0145478. https://doi.org/10.1371/journal.pone.0145478 CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Cini M, Legnani C, Cosmi B, Testa S, Dellanoce C, Paoletti O, Marcucci R, Poli D, Paniccia R, Pengo V, Tripodi A, Palareti G, Register ST-L (2018) Comparison of five specific assays for determination of dabigatran plasma concentrations in patients enrolled in the START-Laboratory Register. Int J Lab Hematol 40(2):229–236. https://doi.org/10.1111/ijlh.12772 CrossRefPubMedGoogle Scholar
- 31.Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Y, Blais N, Fontana P, Cohen A, Llau JV, Rosencher N, Schved JF, de Maistre E, Samama MM, Mismetti P, Sie P, Working Group on Perioperative H (2013) Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP)-March 2013. Arch Cardiovasc Dis 106(6–7):382–393. https://doi.org/10.1016/j.acvd.2013.04.009 CrossRefPubMedGoogle Scholar
- 32.Godier A, Martin AC, Leblanc I, Mazoyer E, Horellou MH, Ibrahim F, Flaujac C, Golmard JL, Rosencher N, Gouin-Thibault I (2015) Peri-procedural management of dabigatran and rivaroxaban: duration of anticoagulant discontinuation and drug concentrations. Thromb Res 136(4):763–768. https://doi.org/10.1016/j.thromres.2015.08.006 CrossRefPubMedGoogle Scholar
- 33.Steiner T, Bohm M, Dichgans M, Diener HC, Ell C, Endres M, Epple C, Grond M, Laufs U, Nickenig G, Riess H, Rother J, Schellinger PD, Spannagl M, Veltkamp R (2013) Recommendations for the emergency management of complications associated with the new direct oral anticoagulants (DOACs), apixaban, dabigatran and rivaroxaban. Clin Res Cardiol 102(6):399–412. https://doi.org/10.1007/s00392-013-0560-7 CrossRefPubMedGoogle Scholar
- 35.Chan N, Sager PT, Lawrence J, Ortel T, Reilly P, Berkowitz S, Kubitza D, Eikelboom J, Florian J, Stockbridge N, Rose M, Temple R, Seltzer JH (2018) Is there a role for pharmacokinetic/pharmacodynamic-guided dosing for novel oral anticoagulants? Am Heart J 199:59–67. https://doi.org/10.1016/j.ahj.2017.10.002 CrossRefPubMedGoogle Scholar
- 36.Reiffel JA, Weitz JI, Reilly P, Kaminskas E, Sarich T, Sager P, Seltzer J, Cardiac Safety Research Consortium presenters and participants (2016) NOAC monitoring, reversal agents, and post-approval safety and effectiveness evaluation: a cardiac safety research consortium think tank. Am Heart J 177:74–86. https://doi.org/10.1016/j.ahj.2016.04.010 CrossRefPubMedGoogle Scholar
- 38.Pollack CV Jr, Reilly PA, Eikelboom J, Glund S, Verhamme P, Bernstein RA, Dubiel R, Huisman MV, Hylek EM, Kamphuisen PW, Kreuzer J, Levy JH, Sellke FW, Stangier J, Steiner T, Wang B, Kam CW, Weitz JI (2015) Idarucizumab for dabigatran reversal. N Engl J Med 373(6):511–520. https://doi.org/10.1056/NEJMoa1502000 CrossRefPubMedGoogle Scholar
- 40.Stangier J, Rathgen K, Stahle H, Gansser D, Roth W (2007) The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. Br J Clin Pharmacol 64(3):292–303. https://doi.org/10.1111/j.1365-2125.2007.02899.x CrossRefPubMedPubMedCentralGoogle Scholar
- 41.Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, Ezekowitz MD, Nehmiz G, Wang S, Wallentin L, Investigators R-L (2014) 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(4):321–328. https://doi.org/10.1016/j.jacc.2013.07.104 CrossRefPubMedGoogle Scholar