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Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Research Article

Urine Metabolites as a Predictor of Warfarin Response Based on INR in Atrial Fibrillation

Author(s): Abdulkader Ahmad Bawadikji, Chin-Hoe Teh, Muhamad Ali Bin Sheikh Abdul Kader, Syed Azhar Syed Sulaiman and Baharudin Ibrahim*

Volume 23, Issue 5, 2022

Published on: 31 May, 2022

Page: [415 - 422] Pages: 8

DOI: 10.2174/1389200223666220413112649

Price: $65

Abstract

Background: Warfarin is an anticoagulant with wide inter-individual variations in drug responses monitored based on the International Normalized Ratio (INR). It is commonly prescribed for Atrial Fibrillation (AF) and stroke. Oral anticoagulants (e.g., warfarin) reduce the risk of getting a stroke but increase the risk of hemorrhage. The proton Nuclear Magnetic Resonance (1H-NMR) pharmacometabonomics technique is useful for determining drug responses. Furthermore, pharmacometabonomics analysis can help identify novel biomarkers of warfarin outcome/ INR stability in urine.

Objectives: The focus of this research was to determine if urine metabolites could predict the warfarin response based on INR in patients who were already taking warfarin (identification; phase I) and to determine if urine metabolites could distinguish between unstable and stable INR in patients who had just started taking warfarin (validation; phase II).

Methods: A cross-sectional study was conducted. Ninety urine samples were collected for phase 1, with 49 having unstable INR and 41 having stable INR. In phase II, 21 urine samples were obtained, with 13 having an unstable INR and eight having a stable INR. The metabolites associated with unstable INR and stable INR could be determined using univariate and multivariate logistic regression analysis.

Results: Multivariate Logistic Regression (MVLR) analysis showed that unstable INR was linked with seven regions.

Discussion: The urine pharmacometabonomics technique utilized could differentiate between the urine metabolite profiles of the patients on warfarin for INR stability.

Conclusion: 1H-NMR-based pharmacometabonomics can help lead to a more individualized, controlled side effect for warfarin, thus minimizing undesirable effects in the future.

Keywords: Warfarin, atrial fibrillation, pharmacometabonomics, proton nuclear magnetic resonance, international normalized ratio, multivariate logistic regression, biomarkers.

Graphical Abstract

[1]
Freestone, B.; Rajaratnam, R.; Hussain, N.; Lip, G.Y. Admissions with atrial fibrillation in a multiracial population in Kuala Lumpur, Malay-sia. Int. J. Cardiol., 2003, 91(2-3), 233-238.
[http://dx.doi.org/10.1016/S0167-5273(03)00031-7] [PMID: 14559136]
[2]
Kirchhof, P.; Camm, A.J.; Goette, A.; Brandes, A.; Eckardt, L.; Elvan, A.; Fetsch, T.; van Gelder, I.C.; Haase, D.; Haegeli, L.M.; Hamann, F.; Heidbüchel, H.; Hindricks, G.; Kautzner, J.; Kuck, K.H.; Mont, L.; Ng, G.A.; Rekosz, J.; Schoen, N.; Schotten, U.; Suling, A.; Taggeselle, J.; Themistoclakis, S.; Vettorazzi, E.; Vardas, P.; Wegscheider, K.; Willems, S.; Crijns, H.J.G.M.; Breithardt, G. Early rhythm-control therapy in patients with atrial fibrillation. N. Engl. J. Med., 2020, 383(14), 1305-1316.
[http://dx.doi.org/10.1056/NEJMoa2019422] [PMID: 32865375]
[3]
Camm, A.J.; Kirchhof, P.; Lip, G.Y.; Schotten, U.; Savelieva, I.; Ernst, S.; Van Gelder, I.C.; Al-Attar, N.; Hindricks, G.; Prendergast, B.; Heidbuchel, H.; Alfieri, O.; Angelini, A.; Atar, D.; Colonna, P.; De Caterina, R.; De Sutter, J.; Goette, A.; Gorenek, B.; Heldal, M.; Hohloser, S.H.; Kolh, P.; Le Heuzey, J.Y.; Ponikowski, P.; Rutten, F.H.; Vahanian, A.; Auricchio, A.; Bax, J.; Ceconi, C.; Dean, V.; Filippatos, G.; Funck-Brentano, C.; Hobbs, R.; Kearney, P.; McDonagh, T.; Popescu, B.A.; Reiner, Z.; Sechtem, U.; Sirnes, P.A.; Tendera, M.; Vardas, P.E.; Widimsky, P.; Vardas, P.E.; Agladze, V.; Aliot, E.; Balabanski, T.; Blomstrom-Lundqvist, C.; Capucci, A.; Crijns, H.; Dahlof, B.; Folliguet, T.; Glikson, M.; Goethals, M.; Gulba, D.C.; Ho, S.Y.; Klautz, R.J.M.; Kose, S.; McMurray, J.; Perrone Filardi, P.; Raatikainen, P.; Salvador, M.J.; Schalij, M.J.; Shpektor, A.; Sousa, J.; Stepinska, J.; Uuetoa, H.; Zamorano, J.L.; Zupan, I. Guidelines for the management of atrial fibril-lation: The task force for the management of atrial fibrillation of the European society of cardiology (ESC). Eur. Heart J., 2010, 31(19), 2369-2429.
[http://dx.doi.org/10.1093/eurheartj/ehq278] [PMID: 20802247]
[4]
Katsanos, A.H.; Kamel, H.; Healey, J.S.; Hart, R.G. Stroke prevention in atrial fibrillation: Looking forward. Circulation, 2020, 142(24), 2371-2388.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.049768] [PMID: 33315494]
[5]
Pisters, R.; Lane, D.A.; Nieuwlaat, R.; de Vos, C.B.; Crijns, H.J.; Lip, G.Y. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro heart survey. Chest, 2010, 138(5), 1093-1100.
[http://dx.doi.org/10.1378/chest.10-0134] [PMID: 20299623]
[6]
Fox, K.A.; Velentgas, P.; Camm, A.J.; Bassand, J-P.; Fitzmaurice, D.A.; Gersh, B.J.; Goldhaber, S.Z.; Goto, S.; Haas, S.; Misselwitz, F.; Pie-per, K.S.; Turpie, A.; Verheugt, F.; Dabrowski, E.; Luo, K.; Gibbs, L.; Kakkar, A.K. GARFIELD-AF Investigators. Outcomes associated with oral anticoagulants plus antiplatelets in patients with newly diagnosed atrial fibrillation. JAMA Netw. Open, 2020, 3(2), e200107.
[http://dx.doi.org/10.1001/jamanetworkopen.2020.0107] [PMID: 32101311]
[7]
Warfarin sensitivity genotyping: A review of the literature and summary of patient experience. In: Moyer, T.P.; O’Kane, D.J.; Baudhuin, L.M.; Wiley, C.L.; Fortini, A.; Fisher, P.K.; Dupras, D.M.; Chaudhry, R.; Thapa, P.; Zinsmeister, A.R.; Heit, J.A., Eds.; Mayo Clin. Proc., 2009, 84(12), 1079-1094.
[PMID: 19955245]
[8]
Shi, C.; Yan, W.; Wang, G.; Wang, F.; Li, Q.; Lin, N. Pharmacogenetics-based versus conventional dosing of warfarin: A meta-analysis of randomized controlled trials. PLoS One, 2015, 10(12), e0144511.
[http://dx.doi.org/10.1371/journal.pone.0144511] [PMID: 26672604]
[9]
Ansell, J.; Hirsh, J.; Hylek, E.; Jacobson, A.; Crowther, M.; Palareti, G. Pharmacology and management of the vitamin K antagonists: Ameri-can college of chest physicians evidence-based clinical practice guidelines. Chest, 2008, 133(6 Suppl.), 160S-198S.
[http://dx.doi.org/10.1378/chest.08-0670] [PMID: 18574265]
[10]
Cannegieter, S.C.; Rosendaal, F.R.; Wintzen, A.R.; van der Meer, F.J.; Vandenbroucke, J.P.; Briët, E. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N. Engl. J. Med., 1995, 333(1), 11-17.
[http://dx.doi.org/10.1056/NEJM199507063330103] [PMID: 7776988]
[11]
van den Besselaar, A.M.; Poller, L.; Tripodi, A. Definition of the international normalized ratio (INR) and its consequences for the calibration procedure of thromboplastin preparations: A rebuttal. J. Thromb. Haemost., 2004, 2(8), 1490-1491.
[http://dx.doi.org/10.1111/j.1538-7836.2004.00793.x] [PMID: 15304071]
[12]
Bawadikji, A.A.; Teh, C-H.; Kader, M.A.B.S.A.; Sulaiman, S.A.S.; Ibrahim, B. Pharmacometabonomics technique to identify warfarin re-sponse using nuclear magnetic resonance spectroscopy. Curr. Pharm. Biotechnol., 2017, 18(9), 740-747.
[http://dx.doi.org/10.2174/1389201018666171103141828] [PMID: 29110602]
[13]
Vinogradova, Y.; Coupland, C.; Hill, T.; Hippisley-Cox, J. Risks and benefits of direct oral anticoagulants versus warfarin in a real world setting: Cohort study in primary care. BMJ, 2018, 362, k2505.
[PMID: 29973392]
[14]
Elango, K.; Javaid, A.; Khetarpal, B.K.; Ramalingam, S.; Kolandaivel, K.P.; Gunasekaran, K.; Ahsan, C. The effects of warfarin and direct oral anticoagulants on systemic vascular calcification: A review. Cells, 2021, 10(4), 773.
[http://dx.doi.org/10.3390/cells10040773] [PMID: 33807457]
[15]
Ayisi, J.G.; van’t Hoog, A.H.; Agaya, J.A.; Mchembere, W.; Nyamthimba, P.O.; Muhenje, O.; Marston, B.J. Care seeking and attitudes to-wards treatment compliance by newly enrolled tuberculosis patients in the district treatment programme in rural western Kenya: A qualitative study. BMC Public Health, 2011, 11(1), 515.
[http://dx.doi.org/10.1186/1471-2458-11-515] [PMID: 21714895]
[16]
Ageno, W.; Gallus, A.S.; Wittkowsky, A.; Crowther, M.; Hylek, E.M.; Palareti, G. Oral anticoagulant therapy: Antithrombotic therapy and prevention of thrombosis: American college of chest physicians evidence-based clinical practice guidelines. Chest, 2012, 141(2 Suppl.), e44S-e88S.
[http://dx.doi.org/10.1378/chest.11-2292] [PMID: 22315269]
[17]
Caboni, P.; Liori, B.; Kumar, A.; Santoru, M.L.; Asthana, S.; Pieroni, E.; Fais, A.; Era, B.; Cacace, E.; Ruggiero, V.; Atzori, L. Metabolomics analysis and modeling suggest a lysophosphocholines-PAF receptor interaction in fibromyalgia. PLoS One, 2014, 9(9), e107626.
[http://dx.doi.org/10.1371/journal.pone.0107626] [PMID: 25238064]
[18]
Ventola, C.L. Role of pharmacogenomic biomarkers in predicting and improving drug response: Part 1: The clinical significance of phar-macogenetic variants. P&T, 2013, 38(9), 545-560.
[PMID: 24273401]
[19]
van der Wouden, C.H.; Böhringer, S.; Cecchin, E.; Cheung, K-C.; Dávila-Fajardo, C.L.; Deneer, V.H.M.; Dolžan, V.; Ingelman-Sundberg, M.; Jönsson, S.; Karlsson, M.O.; Kriek, M.; Mitropoulou, C.; Patrinos, G.P.; Pirmohamed, M.; Rial-Sebbag, E.; Samwald, M.; Schwab, M.; Stein-berger, D.; Stingl, J.; Sunder-Plassmann, G.; Toffoli, G.; Turner, R.M.; van Rhenen, M.H.; van Zwet, E.; Swen, J.J.; Guchelaar, H.J. Generat-ing evidence for precision medicine: Considerations made by the ubiquitous pharmacogenomics consortium when designing and operational-izing the PREPARE study. Pharmacogenet. Genomics, 2020, 30(6), 131-144.
[http://dx.doi.org/10.1097/FPC.0000000000000405] [PMID: 32317559]
[20]
Sauer, U.; Heinemann, M.; Zamboni, N. Genetics. Getting closer to the whole picture. Science, 2007, 316(5824), 550-551.
[http://dx.doi.org/10.1126/science.1142502] [PMID: 17463274]
[21]
Bawadikji, A.A.; Teh, C.H.; Kader, M.A.B.S.A.; Wahab, M.J.B.A.; Sulaiman, S.A.S.; Ibrahim, B. Plasma metabolites as predictors of warfarin outcome in atrial fibrillation. Am. J. Cardiovasc. Drugs, 2020, 20(2), 169-177.
[PMID: 31435902]
[22]
Jacob, M.; Lopata, A.L.; Dasouki, M.; Abdel Rahman, A.M. Metabolomics toward personalized medicine. Mass Spectrom. Rev., 2019, 38(3), 221-238.
[http://dx.doi.org/10.1002/mas.21548] [PMID: 29073341]
[23]
Fiehn, O. Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks. Comp. Funct. Genomics, 2001, 2(3), 155-168.
[http://dx.doi.org/10.1002/cfg.82] [PMID: 18628911]
[24]
Clayton, T.A.; Lindon, J.C.; Cloarec, O.; Antti, H.; Charuel, C.; Hanton, G.; Provost, J.P.; Le Net, J.L.; Baker, D.; Walley, R.J.; Everett, J.R.; Nicholson, J.K. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature, 2006, 440(7087), 1073-1077.
[http://dx.doi.org/10.1038/nature04648] [PMID: 16625200]
[25]
Schnackenberg, L.K.; Beger, R.D. Metabolomic biomarkers: Their role in the critical path. Drug Discov. Today. Technol., 2007, 4(1), 13-16.
[http://dx.doi.org/10.1016/j.ddtec.2007.10.012] [PMID: 24980715]
[26]
Li, H.; Ni, Y.; Su, M.; Qiu, Y.; Zhou, M.; Qiu, M.; Zhao, A.; Zhao, L.; Jia, W. Pharmacometabonomic phenotyping reveals different respons-es to xenobiotic intervention in rats. J. Proteome Res., 2007, 6(4), 1364-1370.
[http://dx.doi.org/10.1021/pr060513q] [PMID: 17311441]
[27]
Clayton, T.A.; Baker, D.; Lindon, J.C.; Everett, J.R.; Nicholson, J.K. Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc. Natl. Acad. Sci. USA, 2009, 106(34), 14728-14733.
[http://dx.doi.org/10.1073/pnas.0904489106] [PMID: 19667173]
[28]
Guţiu, I.A.; Andrieş, A.; Mircioiu, C.; Rădulescu, F.; Georgescu, AM.; Cioacă, D. Pharmacometabonomics, pharmacogenomics and person-alized medicine. Rom. J. Intern. Med., 2010, 48(2), 187-191.
[PMID: 21428184]
[29]
Everett, J.R. NMR-based pharmacometabonomics: A new paradigm for personalised or precision medicine. Prog. Nucl. Magn. Reson. Spectrosc., 2017, 102-103, 1-14.
[http://dx.doi.org/10.1016/j.pnmrs.2017.04.003] [PMID: 29157489]
[30]
Yang, Z.; Marotta, F. Pharmacometabolomics in drug discovery & development: Applications and challenges. Metabolomics, 2012, 2(5), e122.
[31]
Witt, D.M.; Delate, T.; Clark, N.P.; Martell, C.; Tran, T.; Crowther, M.A.; Garcia, D.A.; Ageno, W.; Hylek, E.M. Outcomes and predictors of very stable INR control during chronic anticoagulation therapy. Blood, 2009, 114(5), 952-956.
[http://dx.doi.org/10.1182/blood-2009-02-207928] [PMID: 19439733]
[32]
Manoni, F.; Valverde, S.; Caleffi, A.; Alessio, M.; Silvestri, M.; De Rosa, R. Stability of common analytes and urine particles stored at room temperature before automated analysis. RIMeL-IJLaM., 2008, 4, 192-198.
[33]
Steinhauser, M.L.; Olenchock, B.A.; O’Keefe, J.; Lun, M.; Pierce, K.A.; Lee, H.; Pantano, L.; Klibanski, A.; Shulman, G.I.; Clish, C.B.; Fazeli, P.K. The circulating metabolome of human starvation. JCI Insight, 2018, 3(16), 121434.
[http://dx.doi.org/10.1172/jci.insight.121434] [PMID: 30135314]
[34]
Rubio-Aliaga, I.; de Roos, B.; Duthie, S.J.; Crosley, L.K.; Mayer, C.; Horgan, G.; Colquhoun, I.J.; Le Gall, G.; Huber, F.; Kremer, W.; Rych-lik, M.; Wopereis, S.; van Ommen, B.; Schmidt, G.; Heim, C.; Bouwman, F.G.; Mariman, E.C.; Mulholland, F.; Johnson, I.T.; Polley, A.C.; Elliott, R.M.; Daniel, H. Metabolomics of prolonged fasting in humans reveals new catabolic markers. Metabolomics, 2011, 7(3), 375-387.
[http://dx.doi.org/10.1007/s11306-010-0255-2]
[35]
Rådjursöga, M.; Lindqvist, H.M.; Pedersen, A.; Karlsson, B.G.; Malmodin, D.; Ellegård, L.; Winkvist, A. Nutritional metabolomics: Post-prandial response of meals relating to vegan, lacto-ovo vegetarian, and omnivore diets. Nutrients, 2018, 10(8), 1063.
[http://dx.doi.org/10.3390/nu10081063] [PMID: 30103400]
[36]
Beckonert, O.; Keun, H.C.; Ebbels, T.M.; Bundy, J.; Holmes, E.; Lindon, J.C.; Nicholson, J.K. Metabolic profiling, metabolomic and metabo-nomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts. Nat. Protoc., 2007, 2(11), 2692-2703.
[http://dx.doi.org/10.1038/nprot.2007.376] [PMID: 18007604]
[37]
Gronwald, W.; Klein, M.S.; Kaspar, H.; Fagerer, S.R.; Nürnberger, N.; Dettmer, K.; Bertsch, T.; Oefner, P.J. Urinary metabolite quantification employing 2D NMR spectroscopy. Anal. Chem., 2008, 80(23), 9288-9297.
[http://dx.doi.org/10.1021/ac801627c] [PMID: 19551947]
[38]
Craig, A.; Cloarec, O.; Holmes, E.; Nicholson, J.K.; Lindon, J.C. Scaling and normalization effects in NMR spectroscopic metabonomic data sets. Anal. Chem., 2006, 78(7), 2262-2267.
[http://dx.doi.org/10.1021/ac0519312] [PMID: 16579606]
[39]
Pennazza, G.; Santonico, M.; Martinelli, E.; D'Amico, A.; Di Natale, C. Interpretation of exhaled volatile organic compounds. 2010.
[http://dx.doi.org/10.1183/1025448x.00018609]
[40]
Blasco, H. Błaszczyński, J.; Billaut, J.-C.; Nadal-Desbarats, L.; Pradat, P.-F.; Devos, D.; Moreau, C.; Andres, C.R.; Emond, P.; Corcia, P.; Słowiński, R. Comparative analysis of targeted metabolomics: Dominance-based rough set approach versus orthogonal partial least square-discriminant analysis. J. Biomed. Inform., 2015, 53, 291-299.
[http://dx.doi.org/10.1016/j.jbi.2014.12.001] [PMID: 25499899]
[41]
Izquierdo-García, J.L.; Villa, P.; Kyriazis, A.; del Puerto-Nevado, L.; Pérez-Rial, S.; Rodriguez, I.; Hernandez, N.; Ruiz-Cabello, J. Descriptive review of current NMR-based metabolomic data analysis packages. Prog. Nucl. Magn. Reson. Spectrosc., 2011, 59(3), 263-270.
[http://dx.doi.org/10.1016/j.pnmrs.2011.02.001] [PMID: 21920221]
[42]
Broadhurst, D.I.; Kell, D.B. Statistical strategies for avoiding false discoveries in metabolomics and related experiments. Metabolomics, 2006, 2(4), 171-196.
[http://dx.doi.org/10.1007/s11306-006-0037-z]
[43]
Witten, I.H.; Frank, E.; Hall, M.A.; Pal, C., Eds.; Data Mining: Practical Machine Learning Tools and Techniques, 4th ed.; , 2005.
[44]
Eriksson, L.; Trygg, J.; Wold, S. CV-ANOVA for significance testing of PLS and OPLS models. J. Chemometr., 2008, 22(11-12), 594-600.
[http://dx.doi.org/10.1002/cem.1187]
[45]
Ibrahim, B.; Basanta, M.; Cadden, P.; Singh, D.; Douce, D.; Woodcock, A.; Fowler, S.J. Non-invasive phenotyping using exhaled volatile organic compounds in asthma. Thorax, 2011, 66(9), 804-809.
[http://dx.doi.org/10.1136/thx.2010.156695] [PMID: 21749985]
[46]
Basanta, M.; Ibrahim, B.; Dockry, R.; Douce, D.; Morris, M.; Singh, D.; Woodcock, A.; Fowler, S.J. Exhaled volatile organic compounds for phenotyping chronic obstructive pulmonary disease: A cross-sectional study. Respir. Res., 2012, 13(1), 72.
[http://dx.doi.org/10.1186/1465-9921-13-72] [PMID: 22916684]
[47]
Dunn, W.B.; Broadhurst, D.I.; Deepak, S.M.; Buch, M.H.; McDowell, G.; Spasic, I.; Ellis, D.I.; Brooks, N.; Kell, D.B.; Neyses, L. Serum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2-oxoglutarate. Metabolomics, 2007, 3(4), 413-426.
[http://dx.doi.org/10.1007/s11306-007-0063-5]
[48]
Altmaier, E.; Fobo, G.; Heier, M.; Thorand, B.; Meisinger, C.; Römisch-Margl, W.; Waldenberger, M.; Gieger, C.; Illig, T.; Adamski, J.; Suhre, K.; Kastenmüller, G. Metabolomics approach reveals effects of antihypertensives and lipid-lowering drugs on the human metabolism. Eur. J. Epidemiol., 2014, 29(5), 325-336.
[http://dx.doi.org/10.1007/s10654-014-9910-7] [PMID: 24816436]
[49]
Sekula, P.; Goek, O-N.; Quaye, L.; Barrios, C.; Levey, A.S.; Römisch-Margl, W.; Menni, C.; Yet, I.; Gieger, C.; Inker, L.A.; Adamski, J.; Gronwald, W.; Illig, T.; Dettmer, K.; Krumsiek, J.; Oefner, P.J.; Valdes, A.M.; Meisinger, C.; Coresh, J.; Spector, T.D.; Mohney, R.P.; Suhre, K.; Kastenmüller, G.; Köttgen, A. A metabolome-wide association study of kidney function and disease in the general population. J. Am. Soc. Nephrol., 2016, 27(4), 1175-1188.
[http://dx.doi.org/10.1681/ASN.2014111099] [PMID: 26449609]
[50]
Zou, C.; Zhang, Z.; Zhao, W.; Li, G.; Ma, G.; Yang, X.; Zhang, J.; Zhang, L. Predictive value of pre-procedural autoantibodies against M 2-muscarinic acetylcholine receptor for recurrence of atrial fibrillation one year after radiofrequency catheter ablation. J. Transl. Med., 2013, 11(1), 1-8.
[http://dx.doi.org/10.1186/1479-5876-11-7]
[51]
Lee, X-P.; Kumazawa, T.; Sato, K. A simple analysis of 5 thinner components in human body fluids by headspace solid-phase microextrac-tion (SPME). Int. J. Legal Med., 1995, 107(6), 310-313.
[http://dx.doi.org/10.1007/BF01246879] [PMID: 7577695]
[52]
Piao, R-L.; Zhang, H-Y. Anti-coagulation and Anti-thrombosis Effects of n-butanol extract from Oenanthe aquatic. Shipin Kexue, 2010, 7.

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