Plasma Warfarin Level and International Normalized Ratio do not Correlate with Bleeding Events in Indonesian Patients of Minangkabau Ethnicity with Atrial Fibrillation

  • Rahmatini Rahmatini Department of Pharmacology and Therapeutics, Faculty of Medicine, Andalas University, Padang, West Sumatera, Indonesia
  • Gestina Aliska Department of Pharmacology and Therapeutics, Faculty of Medicine, Andalas University, Padang, West Sumatera, Indonesia
  • Elly Usman Department of Pharmacology and Therapeutics, Faculty of Medicine, Andalas University, Padang, West Sumatera, Indonesia
  • Mefri Yanni Department of Cardiology and Vascular Medicine, Faculty of Medicine, Andalas University, Padang, West Sumatera, Indonesia
  • Cimi Ilmiawati Department of Pharmacology and Therapeutics, Faculty of Medicine, Andalas University, Padang, West Sumatera, Indonesia
Keywords: Atrial fibrillation, Indonesian, International normalized ratio, Thromboembolism, Warfarin

Abstract

BACKGROUND: Warfarin is the mainstay of anticoagulant therapy to prevent thromboembolism in atrial fibrillation (AF). It has a narrow therapeutic window, rendering monitoring prothrombin time necessary using the international normalized ratio (INR). However, INR value is not always correlated with the clinical risk of bleeding.

AIM: We aimed to monitor plasma warfarin concentration and to analyze its correlation with bleeding events in Indonesian patients of Minangkabau ethnicity with AF.

METHODS: We consecutively recruited outpatients with AF from January to November 2017 at a tertiary hospital in West Sumatera, Indonesia. At the time of the study, patients had received at least 5 weeks of warfarin. Their characteristics were obtained from medical records, and INR data were collected. Warfarin plasma concentration was analyzed using high-performance liquid chromatography.

RESULTS: There were a total of 45 patients (25 males and 20 females; mean age 54.6 years). The number of patients with INR value lower than, within, and higher than target value (2.0–3.0) was 25, 12, and 8, respectively. Half of the patients (n = 23; 51.1%) had subtherapeutic plasma warfarin levels and nearly half (n = 20; 44.4%) of the patients had therapeutic plasma warfarin levels. INR value was not significantly correlated with plasma warfarin level (r = 0.273; p = 0.07). Bleeding events occurred in 14 patients. INR value was not significantly different (p = 0.12), while the plasma warfarin level was marginally significantly different (p = 0.05) between those with bleeding and no bleeding events.

CONCLUSION: Neither warfarin plasma concentration nor INR was correlated with bleeding events in Indonesian patients of Minangkabau ethnicity with AF.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

References

Chug SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: A global burden of disease 2010 study. Circulation. 2014;129(8):837-47. https://doi.org/10.1161/ circulationaha.113.005119 PMid:24345399

Zoni-Berisso M, Lercari, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol. 2014;6:213-20. https://doi.org/10.2147/clep.s47385 PMid:24966695

PERKI. 2014. Pedoman tata Laksana Fibrilasi Atrium (Atrial Fibrillation Management Guideline). Perhimpunan Dokter Spesialis Kardiovaskular Indonesia (Indonesian Heart Association). Centra Communications. 1st ed. Jakarta, Indonesia: Indonesian Heart Association. p. 11-35. Available from: http://www.inaheart.org/upload/file/FA_Final_Launch.pdf. [Last accessed on 2018 Mar 20].

Zehnder JL. Drugs used in disorders of coagulation. In: Katzung BG, SB Masters, Trevor AJ, editors. Basic and Clinical Pharmacology. 11th ed. Singapore: McGraw-Hill; 2009. p. 598-99.

Boroumand M, Goodarzynejad H. Monitoring of anticoagulant therapy in heart disease: Considerations for the current assays. J Tehran Heart Center 2010;5(2):57-68. PMid:23074569

Setiabudi E, Alwi I, Setiati S. Oral anticoagulant treatment in management of elderly patients with atrial fibrillation: Is it beneficial or detrimental? Acta Med Indones. 2008;40(1):40-7. PMid:18326899

Morgan CL, McEwan P, Tukiendorf A, Robinson PA, Clemens A, Plumb JM. Warfarin treatment in patients with atrial fibrillation: Observing outcomes associated with varying concentrations of INR control. Thromb Res. 2009;124(1):37-41. https://doi. org/10.1016/j.thromres.2008.09.016 PMid:19062079

Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: Proposal for a new dosing regimen. Blood. 2005;106(7):2329- 33. https://doi.org/10.1182/blood-2005-03-1108 PMid:15947090

Suriapranata IM, Tjong WY, Wang T, Utama A, Raharjo SB, Yuniadi Y, et al. Genetic factors associated with patient-specific warfarin dose in ethnic Indonesians. BMC Med Genet. 2011;12:80. https://doi.org/10.1186/1471-2350-12-80 PMid:21639946

Yong C, Azarbal F, Abnousi F, Heidenreich P, Schmitt S, Fan J, et al. Racial differences in quality of anticoagulation therapy for atrial fibrillation (from the TREAT-AF study). Am J Cardiol. 2016;117:61-8. https://doi.org/10.1016/j.amjcard.2015.09.047 PMid:26552504

Fung E, Patsopoulos NA, Belknap SM, O’Rourke DJ, Robb JF, Anderson JL, et al. Effect of genetic variants, especially CYP2C9 and VKORC1, on the pharmacology of warfarin. Semin Thromb Hemost. 2012;38:893-904. https://doi. org/10.1055/s-0032-1328891 PMid:23041981

January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr., et al. AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: Executive summary: A report of the American College of cardiology/ American heart association task force on practice guidelines and the heart rhythm society. Circulation. 2014;130:2071-104. https://doi.org/10.1161/cir.0000000000000040 PMid:24682348

Mehran R, Rao SV, Bhatt DL, Gibson M, Caixeta A, Eikelboom J. Standardized bleeding definitions for cardiovascular clinical trials. Circulation. 2011;123(23):2736-2747. https://doi. org/10.1161/circulationaha.110.009449 PMid:21670242

Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation. Chest. 2010;138(5):1093-1100. https://doi.org/10.1378/chest.10-0134 PMid:20299623

European Medicines Agency. Guidelines on Bioanalytical Method Validation; 2012. Available from: http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_guideline/2011/08/ WC500109686.pdf. [Last accessed on 2018 Mar 20].

Sornsuvit C, Niamhun N, Luengpiansamut N, Sangsrijan S, Niwatananum W, Kaewvichit S, et al. Pharmacokinetics and bioequivalence studies of warfarin sodium 5 milligrams tablet in healthy Thai subjects. Int J Pharm Pharm Sci. 2015;7:219-22.

Chua YA, Abdullah WZ, Gan SH. Development of a high-performance liquid chromatography method for warfarin detection in human plasma. Turk J Med Sci. 2012;42:930-41.

Sun S, Wang M, Su L, Li J, Li H, Gu D. Study on warfarin plasma concentration and its correlation with international normalized ratio. J Pharm Biomed Anal. 2006;18;42:218-22. PMid:16860509

Kwon MJ, Kim HJ, Kim JW, Lee KH, Sohn KH, Cho HJ, et al. Determination of plasma warfarin concentrations in Korean patients and its potential for clinical application. Korean J Lab Med. 2009;29:515-23. https://doi.org/10.3343/ kjlm.2009.29.6.515 PMid:20046082

McDonald MG, Rieder MJ, Nakano M, Hsia CH, Rettie AE. Cyp4f2 is a Vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433m variant. Mol Pharmacol. 2009;75(6):1337-46. https://doi.org/10.1124/mol.109.054833 PMid:19297519

Cain D, Hutson SM, Wallin R. Assembly of the warfarin-sensitive Vitamin K 2,3-epoxide reductase enzyme complex in the endoplasmic reticulum membrane. J Biol Chem. 1997;272:29068-75. https://doi.org/10.1074/jbc.272.46.29068 PMid:9360981

Kamali F, Khan TI, King BP, Frearson R, Kesteven P, Wood P, et al. Contribution of age, body size, and CYP2C9 genotype to anticoagulant response to warfarin. Clin Pharmacol Ther. 2004;75(3):204-12. https://doi.org/10.1016/j.clpt.2003.10.001 PMid:15001972

Xue L, Holford N, Ding X, Shen Z, Huang C, Zhang H, et al. Theory-based pharmacokinetics and pharmacodynamics of S- and R-warfarin and effects on international normalized ratio: Influence of body size, composition and genotype in cardiac surgery patients. Br J Clin Pharmacol. 2017;83(4):823-35. https://doi.org/10.1111/bcp.13157 PMid:27763679

Herman D, Locatelli I, Grabnar I, Peternel P, Stegnar M, Mrhar A, et al. Influence of CYP2C9 polymorphisms, demographic factors and concomitant drug therapy on warfarin metabolism and maintenance dose. Pharmacogenomics J. 2005;5:193-202. https://doi.org/10.1038/sj.tpj.6500308 PMid:15824753

Gage BF, Eby C, Milligan PE, Banet GA, Duncan JR, McLeod HL. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost. 2004;91(1):87-94. https://doi.org/10.1160/th03-06-0379 PMid:14691573

Gong IY, Schwarz UI, Crown N, Dresser GK, Lazo-Langner A, Zou GY, et al. Clinical and genetic determinants of warfarin pharmacokinetics and pharmacodynamics during treatment initiation. PLoS One. 2011;6(11):e27808. https://doi. org/10.1371/journal.pone.0027808 PMid:22114699

Lombardi R, Chantarangkul V, Cattaneo M, Tripodi A. Measurement of warfarin in plasma by high performance liquid chromatography (HPLC) and its correlation with the international normalized ratio. Thromb Res. 2003;111(4-5):281-4. https://doi. org/10.1016/j.thromres.2003.09.006 PMid:14693176

Rusdiana T, Araki T, Nakamura T, Subarnas A, Yamamoto K. Responsiveness to low-dose warfarin associated with genetic variants of VKROC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population. Eur J Clin Pharmacol. 2013;69(3):395- 405. https://doi.org/10.1007/s00228-012-1356-9 PMid:22855348

Mansur AP, Takada JY, Avakian SD, Strunz CM. Warfarin doses for anticoagulation therapy in elderly patients with chronic atrial fibrillation. Clinics. 2012;67:543-6. https://doi.org/10.6061/ clinics/2012(06)01 PMid:22760890

Gallagher AM, Setakis E, Plumb JM, Clemens A, van Staa TP. Risks of stroke and mortality associated with suboptimal anticoagulation in atrial fibrillation patients. Thromb Haemost. 2011;106(5):968-77. https://doi.org/10.1160/th11-05-0353 PMid:21901239

Kearon C, Ginsberg JS, Kovacs MJ, Anderson DR, Wells P, Julian JA, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349(7):631-9. https://doi.org/10.1016/j. accreview.2003.09.054 PMid:12917299

Published
2020-04-27
How to Cite
1.
Rahmatini R, Aliska G, Usman E, Yanni M, Ilmiawati C. Plasma Warfarin Level and International Normalized Ratio do not Correlate with Bleeding Events in Indonesian Patients of Minangkabau Ethnicity with Atrial Fibrillation. Open Access Maced J Med Sci [Internet]. 2020Apr.27 [cited 2020Oct.31];8(B):192-7. Available from: https://www.id-press.eu/mjms/article/view/3436