Monitoring DOACs with a Novel Dielectric Microsensor: A Clinical StudyFunding This work was supported by an American Heart Association Grant-in-Aid award (17GRNT33661005 to M.A.S., P.M., and E.X.S.), by XaTek, Inc. and the Oscar D. Ratnoff Endowed Professorship (to E.X.S.). The contents do not represent the views of the US Department of Veterans Affairs or the United States Government.
Background There are acute settings where assessing the anticoagulant effect of direct oral anticoagulants (DOACs) can be useful. Due to variability among routine coagulation tests, there is an unmet need for an assay that detects DOAC effects within minutes in the laboratory or at the point of care.
Methods We developed a novel dielectric microsensor, termed ClotChip, and previously showed that the time to reach peak permittivity (T peak) is a sensitive parameter of coagulation function. We conducted a prospective, single-center, pilot study to determine its clinical utility at detecting DOAC anticoagulant effects in whole blood.
Results We accrued 154 individuals: 50 healthy volunteers, 49 rivaroxaban patients, 47 apixaban, and 8 dabigatran patients. Blood samples underwent ClotChip measurements and plasma coagulation tests. Control mean T peak was 428 seconds (95% confidence interval [CI]: 401–455 seconds). For rivaroxaban, mean T peak was 592 seconds (95% CI: 550–634 seconds). A receiver operating characteristic curve showed that the area under the curve (AUC) predicting rivaroxaban using T peak was 0.83 (95% CI: 0.75–0.91, p < 0.01). For apixaban, mean T peak was 594 seconds (95% CI: 548–639 seconds); AUC was 0.82 (95% CI: 0.73–0.91, p < 0.01). For dabigatran, mean T peak was 894 seconds (95% CI: 701–1,086 seconds); AUC was 1 (p < 0.01). Specificity for all DOACs was 88%; sensitivity ranged from 72 to 100%.
Conclusion This diagnostic study using samples from “real-world” DOAC patients supports that ClotChip exhibits high sensitivity at detecting DOAC anticoagulant effects in a disposable portable platform, using a miniscule amount of whole blood (<10 µL).
Keywordsanticoagulation - monitoring - direct oral anticoagulants - point of care - coagulation tests
D.M., M.A.S., A.O., P.M., and E.X.S. conceptualized and designed the research; A.O. and E.X.S. designed the clinical study. D.M., M.A.S., K.L.B., and E.X.S. performed the research. D.M., A.O., M.A.S., K.L.B., B.M.W., P.M., and E.X.S. analyzed the data. B.M.W. provided analytical tools. D.M., A.O., M.A.S., P.M., and E.X.S. prepared the figures. A.O. and E.X.S. wrote the manuscript. All authors reviewed the manuscript before submission.
* Drs. Maji and Opneja contributed equally to this article.
Eingereicht: 03. März 2020
Angenommen: 03. Juli 2020
02. September 2020 (online)
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
- 1 Cuker A, Siegal DM, Crowther MA, Garcia DA. Laboratory measurement of the anticoagulant activity of the non-vitamin K oral anticoagulants. J Am Coll Cardiol 2014; 64 (11) 1128-1139
- 2 Maji D, Suster MA, Kucukal E. et al. ClotChip: a microfluidic dielectric sensor for point-of-care assessment of hemostasis. IEEE Trans Biomed Circuits Syst 2017; 11 (06) 1459-1469
- 3 Maji D, De La Fuente M, Kucukal E. et al. Assessment of whole blood coagulation with a microfluidic dielectric sensor. J Thromb Haemost 2018; 16 (10) 2050-2056
- 4 Rodeghiero F, Tosetto A, Abshire T. et al; ISTH/SSC joint VWF and Perinatal/Pediatric Hemostasis Subcommittees Working Group. ISTH/SSC bleeding assessment tool: a standardized questionnaire and a proposal for a new bleeding score for inherited bleeding disorders. J Thromb Haemost 2010; 8 (09) 2063-2065
- 5 Nagler M, Kathriner S, Bachmann LM, Wuillemin WA. Impact of changes in haematocrit level and platelet count on thromboelastometry parameters. Thromb Res 2013; 131 (03) 249-253
- 6 Nagler M, Bachmann LM, Alberio L. et al. Variability between laboratories performing coagulation tests with identical platforms: a nationwide evaluation study. Thromb J 2013; 11 (01) 6
- 7 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 2005; 61 (12) 873-880
- 8 Ezekowitz MD, Reilly PA, Nehmiz G. et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am J Cardiol 2007; 100 (09) 1419-1426
- 9 van Ryn J, Stangier J, Haertter S. et al. Dabigatran etexilate--a novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity. Thromb Haemost 2010; 103 (06) 1116-1127
- 10 Frost C, Nepal S, Wang J. et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol 2013; 76 (05) 776-786
- 11 Suster MA, Vitale NH, Maji D, Mohseni P. A circuit model of human whole blood in a microfluidic dielectric sensor. IEEE Trans Circuits Syst, II Express Briefs 2016; 63 (12) 1156-1160
- 12 Wolf M, Gulich R, Lunkenheimer P, Loidl A. Broadband dielectric spectroscopy on human blood. Biochim Biophys Acta 2011; 1810 (08) 727-740
- 13 Maji D, Pourang S, Sekhon UDS, Gupta AS, Suster MA, Mohseni P. Toward diagnosis of platelet loss in trauma injury using a microfluidic dielectric sensor. Paper presented at: 2019 IEEE SENSORS; October 27–30, 2019; Montreal, Canada:
- 14 Maji D, Suster MA, Mohseni P. Monitoring red blood cell aggregation dynamics in stasis and under flow using a microfluidic dielectric sensor. Paper presented at: 2018 IEEE Biomedical Circuits and Systems Conference (BioCAS); October 17–19, 2018; Cleveland, Ohio, United States:
- 15 Synek V. Evaluation of the standard deviation from duplicate results. Accredit Qual Assur 2008; 13 (06) 335-337
- 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 (01) 191-198
- 17 Douxfils J, Tamigniau A, Chatelain B. 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 2013; 110 (04) 723-731
- 18 Asmis LM, Alberio L, Angelillo-Scherrer A. et al. Rivaroxaban: quantification by anti-FXa assay and influence on coagulation tests: a study in 9 Swiss laboratories. Thromb Res 2012; 129 (04) 492-498
- 19 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 2014; 124 (15) 2450-2458
- 20 Wilson D, Charidimou A, Shakeshaft C. et al; CROMIS-2 collaborators. Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type. Neurology 2016; 86 (04) 360-366
- 21 Raccah BH, Perlman A, Danenberg HD, Pollak A, Muszkat M, Matok I. Major bleeding and hemorrhagic stroke with direct oral anticoagulants in patients with renal failure: systematic review and meta-analysis of randomized trials. Chest 2016; 149 (06) 1516-1524
- 22 Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015; 13 (11) 2012-2020
- 23 Graham DJ, Reichman ME, Wernecke M. et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation 2015; 131 (02) 157-164
- 24 Loo SY, Dell'Aniello S, Huiart L, Renoux C. Trends in the prescription of novel oral anticoagulants in UK primary care. Br J Clin Pharmacol 2017; 83 (09) 2096-2106
- 25 Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med 2015; 128 (12) 1300-1305
- 26 Halvorsen S, Ghanima W, Fride Tvete I. et al. A nationwide registry study to compare bleeding rates in patients with atrial fibrillation being prescribed oral anticoagulants. Eur Heart J Cardiovasc Pharmacother 2017; 3 (01) 28-36
- 27 Shehab N, Lovegrove MC, Geller AI, Rose KO, Weidle NJ, Budnitz DS. US emergency department visits for outpatient adverse drug events, 2013-2014. JAMA 2016; 316 (20) 2115-2125
- 28 Chan NC, Hirsh J, Ginsberg JS, Eikelboom JW. Real-world variability in dabigatran levels in patients with atrial fibrillation: reply. J Thromb Haemost 2015; 13 (06) 1168-1169
- 29 Reilly PA, Lehr T, Haertter S. et al; RE-LY Investigators. 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 2014; 63 (04) 321-328
- 30 Seiffge DJ, Traenka C, Polymeris A. et al. Feasibility of rapid measurement of Rivaroxaban plasma levels in patients with acute stroke. J Thromb Thrombolysis 2017; 43 (01) 112-116
- 31 Helin TA, Pakkanen A, Lassila R, Joutsi-Korhonen L. Laboratory assessment of novel oral anticoagulants: method suitability and variability between coagulation laboratories. Clin Chem 2013; 59 (05) 807-814
- 32 Samama MM, Martinoli JL, LeFlem L. et al. Assessment of laboratory assays to measure rivaroxaban--an oral, direct factor Xa inhibitor. Thromb Haemost 2010; 103 (04) 815-825
- 33 Barrett YC, Wang Z, Frost C, Shenker A. Clinical laboratory measurement of direct factor Xa inhibitors: anti-Xa assay is preferable to prothrombin time assay. Thromb Haemost 2010; 104 (06) 1263-1271
- 34 Barrett YC, Wang Z, Knabb RM. A novel prothrombin time assay for assessing the anticoagulant activity of oral factor Xa inhibitors. Clin Appl Thromb Hemost 2013; 19 (05) 522-528
- 35 Gouin-Thibault I, Flaujac C, Delavenne X. et al. Assessment of apixaban plasma levels by laboratory tests: suitability of three anti-Xa assays. A multicentre French GEHT study. Thromb Haemost 2014; 111 (02) 240-248
- 36 Douxfils J, Mullier F, Robert S, Chatelain C, Chatelain B, Dogné JM. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 2012; 107 (05) 985-997
- 37 Hapgood G, Butler J, Malan E, Chunilal S, Tran H. The effect of dabigatran on the activated partial thromboplastin time and thrombin time as determined by the Hemoclot thrombin inhibitor assay in patient plasma samples. Thromb Haemost 2013; 110 (02) 308-315
- 38 Henskens YMC, Gulpen AJW, van Oerle R. et al. Detecting clinically relevant rivaroxaban or dabigatran levels by routine coagulation tests or thromboelastography in a cohort of patients with atrial fibrillation. Thromb J 2018; 16: 3
- 39 Francart SJ, Hawes EM, Deal AM. 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 2014; 111 (06) 1133-1140
- 40 Samama MM, Contant G, Spiro TE. et al; Rivaroxaban Prothrombin Time Field Trial Laboratories. Evaluation of the prothrombin time for measuring rivaroxaban plasma concentrations using calibrators and controls: results of a multicenter field trial. Clin Appl Thromb Hemost 2012; 18 (02) 150-158
- 41 Harenberg J, Giese C, Marx S, Krämer R. Determination of dabigatran in human plasma samples. Semin Thromb Hemost 2012; 38 (01) 16-22
- 42 Pollack Jr CV, Reilly PA, van Ryn J. et al. Idarucizumab for dabigatran reversal - full cohort analysis. N Engl J Med 2017; 377 (05) 431-441
- 43 Connolly SJ, Gibson CM, Crowther M. Andexanet alfa for factor Xa inhibitor reversal. N Engl J Med 2016; 375 (25) 2499-2500
- 44 Testa S, Tripodi A, Legnani C. et al; START-Laboratory Register. Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: results observed in four anticoagulation clinics. Thromb Res 2016; 137: 178-183
- 45 Harenberg J, Du S, Wehling M. 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 2016; 54 (02) 275-283
- 46 Harenberg J, Beyer-Westendorf J, Crowther M. et al. Working Group Members. Accuracy of a rapid diagnostic test for the presence of direct oral factor Xa or thrombin inhibitors in urine—a multicenter trial. Thromb Haemost 2020; 120 (01) 132-140
- 47 Moll J, Meyer dos Santos S, Hils B. et al. Micro-optical prototyping of a surface acoustic wave-based point-of-care coagulation assay and first application in anticoagulated patients. Int J Clin Pharmacol Ther 2016; 54 (03) 177-184
- 48 Harder S, Santos SMD, Krozer V, Moll J. Surface acoustic wave-based microfluidic coagulation device for monitoring anticoagulant therapy. Semin Thromb Hemost 2019; 45 (03) 253-258
- 49 Ho P, Lim HY, Ng C, Smith CL, Donnan G, Nandurkar H. Global coagulation assays in the normal population: female gender, older age and East Asian ethnicity associated with prothrombotic parameters. Blood 2015; 126 (23) 4678