Accuracy of a Rapid Diagnostic Test for the Presence of Direct Oral Factor Xa or Thrombin Inhibitors in Urine—A Multicenter Trial

Abstract

The rapid determination of the presence of direct oral anticoagulants (DOACs) in a patient remains a major challenge in emergency medicine and for rapid medical treatment decisions. All DOACs are excreted into urine. A sensitive and specific point-of-care test has been developed to determine whether they are present in patient urine samples. This prospective multicenter study aimed to demonstrate at least 95% correct positive and negative predictive results for factor Xa and thrombin inhibitors in urine samples using DOAC Dipstick pads compared with liquid chromatography-tandem mass spectrometry (LC-MS/MS) (NCT03182829). Nine hundred and fourteen subjects were included and 880 were evaluated per protocol (factor Xa inhibitors apixaban, edoxaban, and rivaroxaban: n = 451, thrombin inhibitor dabigatran: n = 429) at 18 centers. The sensitivity, specificity, accuracy, and predictive values and agreement between methods for determination of factor Xa inhibitors were at least noninferior to 95% with a 0.5% margin and of thrombin inhibitor superior to 97.5%. These results were compared with LC-MS/MS results in the intention-to-analyze cohort (all p < 0.05). The receiver operating curve showed c-values of 0.989 (factor Xa inhibitors) and 0.995 (thrombin inhibitor). Visual evaluation of the factor Xa and thrombin inhibitor pads was not different between centers. Qualitative determination of both types of DOACs was accurate using the DOAC Dipstick compared with using LC-MS/MS. The high predictive values may impact laboratory and clinical decision-making processes.

Keywords

direct oral anticoagulants - point-of-care test - apixaban - edoxaban - rivaroxaban - dabigatran

Participating Centers (alphabetical order per town, number of included patients in brackets)

Bad Krozingen, Universitätsherzzentrum, Klinik für Kardiologie und Angiologie II, Prof. Dr. Dietmar Trenk, Prof. Dr. Julia Hromek, Dr. Stefan Leggewie (n = 232); Bad Oeynhausen, Herz - und Diabeteszentrum NRW, Klinik für Kardiologie, Prof. Dr. Cornelia Piper, Dr. Isgandarova Potratz (n = 79); Berlin, Vivantes Klinikum Neukölln, Kardiologie, Prof. Dr. Harald Darius, Dr. Lorenz Reill (n = 36); Berlin, Vivantes Klinikum im Friedrichshain, Zentrum für Gefäßmedizin - Sprechstunde für Gerinnungsstörung und Hämophiliezentrum, Priv. Doz Dr. Robert Klamroth, Dr. Cornelia Kubicek-Hofmann, Dr. Ana Marija Orlovic (n = 27); Berlin, Gerinnungszentrum Berlin, Priv.-Doz. Dr . Christoph Sucker (n = 46); Coburg, II. Medizinische Klinik – Innere Medizin – Kardiologie, Dr. Steffen Schnupp, Dr. Issameddine Ajimi, Dr. Christian Mahnkopf, Dr. Thomas Mischke (n = 70); Darmstadt, Klinik für Gefäßmedizin - Angiologie, Prof. Dr Rupert Bauersachs, Priv. Doz. Dr. Jörg Herold (n = 18); Dessau-Roßlau, Praxis für Innere Medizin, Kardiologie, Angiologie, Dr. Frank Menzel, Frank (n = 41); Dresden, Studienambulanz Klinische Thromboseforschung, Priv. Doz. Dr. Jan Beyer-Westendorf, Dr. Sandra Marten, Dr. Christiane Naue (n = 3); Dresden, Studienambulanz der GWT – TUD GmbH, Prof. Dr. Sebastian Schellong, Dr. Carsten Müller (n = 12); Frankfurt, CCB Studienzentrum GmbH, Prof. Dr. Edelgard Lindhoff-Last, Dr. Barbara Zydek (n = 89); Freiburg, Klinik für Kardiologie und Angiologie I, Prof. Dr Daniel Dürschmied, Dr. Roland Giesen, Dr. Christoph Olivier (n = 12); Hamburg, Onkologisches Zentrum, II. Medizinische Klinik und Poliklinik, Gerinnungsambulanz, Prof. Dr. Florian Langer, Dr. Minna Voigtländer, (n = 16); Heidenheim, Facharztpraxis für Innere Medizin, Schwerpunkt Hämatologie, Onkologie und Hämostaseologie, Priv. Doz. Dr. Martin Grünewald (n = 14); Köln, Klinik für Kardiologie und internistische Intensivmedizin, Prof. Dr. Ingo Ahrens, Ingo, Dr. Timo Bömicke (n = 2); Leipzig, Zentrum für Blutgerinnungsstörungen, Dr. Ute Scholz, Dr. Michael Krause (n = 18); Stahnsdorf, Parkkardiologie, Dr. Ulrich Wolf (n = 129); Siegen, Zentrum für Prävention und Rehabilitation, Dr. Ulrich Overhoff, Dr. Fabian Krämer (n = 68).

• References

• 1 Steffel J, Verhamme P, Potpara TS. , et al; ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018; 39 (16) 1330-1393
• 2 Schünemann HJ, Cushman M, Burnett AE. , et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018; 2 (22) 3198-3225
• 3 Spyropoulos AC, Al-Badri A, Sherwood MW, Douketis JD. To measure or not to measure direct oral anticoagulants before surgery or invasive procedures: comment. J Thromb Haemost 2016; 14 (12) 2556-2559
• 4 Tripodi A. To measure or not to measure direct oral anticoagulants before surgery or invasive procedures. J Thromb Haemost 2016; 14 (07) 1325-1327
• 5 Ebner M, Birschmann I, Peter A. , et al. Limitations of specific coagulation tests for direct oral anticoagulants: a critical analysis. J Am Heart Assoc 2018; 7 (19) e009807
• 6 Bluecher A, Meyer Dos Santos S, Ferreirós N. , et al. Microfluidic coagulation assay for monitoring anticoagulant therapy in acute stroke patients. Thromb Haemost 2017; 117 (03) 519-528
• 7 Harenberg J, Schreiner R, Hetjens S, Weiss C. Detecting anti-IIa and anti-Xa direct oral anticoagulant (DOAC) agents in urine using a DOAC Dipstick. Semin Thromb Hemost 2019; 45 (03) 275-284
• 8 Kim PY, Di Giuseppantonio LR, Wu C, Douketis JD, Gross PL. An assay to measure levels of factor Xa inhibitors in blood and plasma. J Thromb Haemost 2019; 17 (07) 1153-1159
• 9 Ten Cate H, Henskens YM, Lancé MD. Practical guidance on the use of laboratory testing in the management of bleeding in patients receiving direct oral anticoagulants. Vasc Health Risk Manag 2017; 13: 457-467
• 10 Douxfils J, Gosselin RC. Laboratory assessment of direct oral anticoagulants. Semin Thromb Hemost 2017; 43 (03) 277-290
• 11 Harenberg J, Krämer S, Du S, Weiss C, Krämer R. Concept of a point of care test to detect new oral anticoagulants in urine samples. Thromb J 2013; 11 (01) 15
• 12 Harenberg J, Du S, Krämer S, Weiss C, Krämer R, Wehling M. Patients' serum and urine as easily accessible samples for the measurement of non-vitamin K antagonist oral anticoagulants. Semin Thromb Hemost 2015; 41 (02) 228-236
• 13 Schreiner R, Hetjens S, Giese C. , et al. Determination of rivaroxaban, apixaban, edoxaban and dabigatran by liquid chromatography-tandem massspectrometry and chromogenic assays from urine samples of patients. Res Pract Thromb Haemost 2017; 1: 491
• 14 Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI. ; Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (03) 623-627
• 15 Albaladejo P, Pernod G, Godier A. , et al; members of the French Working Group on Perioperative Haemostasis. Management of bleeding and emergency invasive procedures in patients on dabigatran: updated guidelines from the French Working Group on Perioperative Haemostasis (GIHP) - September 2016. Anaesth Crit Care Pain Med 2018; 37 (04) 391-399
• 16 Wiegele M, Schöchl H, Haushofer A. , et al. Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement. Crit Care 2019; 23 (01) 62
• 17 Landis JR, Miller ME, Davis CS, Koch GG. Some general methods for the analysis of categorical data in longitudinal studies. Stat Med 1988; 7 (1-2): 109-137
• 18 Ebner M, Birschmann I, Peter A. , et al. Limitations of specific coagulation tests for direct oral anticoagulants: a critical analysis. J Am Heart Assoc 2018; 7 (19) e009807
• 19 Gosselin RC, Adcock DM, Bates SM. , et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 2018; 118 (03) 437-450
• 20 Cuker A, Burnett A, Triller D. , et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol 2019; 94 (06) 697-709
• 21 Merrelaar A, Buchtele N, Schörgenhofer C. , et al. Dark-colored urine affects test results of the novel DOAC Dipstick point-of-care strip test. Res Pract Thromb Haemost 2019; PB 181
• 22 Tafur A, Harenberg J, Walenga J. , et al. Accuracy of DOASENSE Dipstick for assessing patients treated peri-operatively with DOACs – pilot study. Res Pract Thromb Haemost 2019; PB 179
• 23 Gulmez MD, Yildirim O, Soyhan M. , et al. Purple urine: an astonishing symptom in an elderly patient with acute kidney injury. Intern Med J 2019; 49 (05) 677-679
• 24 Dicko A, Roh ME, Diawara H. , et al. Efficacy and safety of primaquine and methylene blue for prevention of Plasmodium falciparum transmission in Mali: a phase 2, single-blind, randomised controlled trial. Lancet Infect Dis 2018; 18 (06) 627-639