The influence of clinical and genetic factors on the stability of warfarin’s anticoagulant effect in patients with atrial fibrillation

Authors

DOI:

https://doi.org/10.14739/2310-1237.2022.1.252662

Keywords:

atrial fibrillation, warfarin, CYP2C9, CYP4F2, VKORC1, polymorphism, genes, SAMe-TT2R2, anticoagulation stability

Abstract

The aim. To investigate the influence of clinical and genetic factors on the stability of warfarin’s anticoagulant effect in patients with atrial fibrillation (AF) during the year.

Materials and methods. The study involved 60 patients with AF, age 70.50 (64.25; 76.25) years (32 men and 28 women). Coagulogram indexes with International Normalized Ratio (INR) were determined using Coag Chrome 3003 monthly; the CHA2DS2-VASC, HAS-BLED, SAMe-TT2R2 scales scores were evaluated; the calculation of TTR was performed using the Rosendaal method. CYP2C9, CYP4F2, VKORC1 genes polymorphisms were determined using multiplex real time polymerase chain reaction in CFX-96 thermocycler (BioRad).

Results. Median TTR in groups of patients with SAMe-TT2R2 score <2 (n = 33) and ≥2 (n = 27) did not differ significantly (74 % versus 68 % respectively, P > 0.05). There were significantly more patients with TTR <70 % in the group with predicted labile INR (59.36 % versus 30.30 %; χ2 = 5.07, P < 0.05). SAMe-TT2R2 score ≥2 increased the risk of poor INR control by 1.96 times (CI 1.05–3.63). No association of TTR with CYP2C9, CYP4F2 and VKORC1 gene polymorphisms was found.

Episodes of excessive hypocoagulation (INR >4) were detected in 21 (40 %) patients during the year. Excessive hypocoagulation was significantly more common in patients carrying the allele A of the VKORC1 gene in comparison with non-carriers (51.43 % versus 24.00 %; χ2 = 4.57, P < 0.05). The presence of mutant allele A was associated with 2.14-fold higher risk of excessive hypocoagulation (RR = 2.14; CI 1.06–4.69).

Taking amiodarone (χ2 = 3.13; P < 0.05) had a significant effect on the development of excessive hypocoagulation with a relative risk RR = 1.83 (CI 1.01–3.35).

Conclusions. SAMe-TT2R2 score can be useful to predict poor INR control, while VKORC1 genotype estimating – to predict excessive hypocoagulation episodes. An integrated approach using clinical and genetic methods is needed to determine the potential efficacy and safety of warfarin therapy.

Author Biography

Ya. M. Mykhailovskyi, Zaporizhzhia State Medical University, Ukraine

PhD-student of the Department of Family Medicine, Therapy, Cardiology and Neurology of Faculty of Postgraduate Education

References

Hindricks, G., Potpara, T., Dagres, N., Arbelo, E., Bax, J. J., Blomström-Lundqvist, C., Boriani, G., Castella, M., Dan, G. A., Dilaveris, P. E., Fauchier, L., Filippatos, G., Kalman, J. M., La Meir, M., Lane, D. A., Lebeau, J. P., Lettino, M., Lip, G., Pinto, F. J., Thomas, G. N., … ESC Scientific Document Group (2021). 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. European heart journal, 42(5), 373-498. https://doi.org/10.1093/eurheartj/ehaa612

Asiimwe, I. G., Zhang, E. J., Osanlou, R., Jorgensen, A. L., & Pirmohamed, M. (2021). Warfarin dosing algorithms: A systematic review. British journal of clinical pharmacology, 87(4), 1717-1729. https://doi.org/10.1111/bcp.14608

Holm, J., Lindh, J. D., Andersson, M. L., & Mannheimer, B. (2017). The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. Journal of thrombosis and haemostasis: JTH, 15(3), 446-453. https://doi.org/10.1111/jth.13614

Ramasamy, T., Pillai, N. K., Yap, C. G. & Jahan, N. K. (2020). Non-Clinical Factors Associated with International Normalized Ratio Control in Patients on Warfarin Therapy: A Review Paper. Open Access Library Journal, 7, 1-21. https://doi.org/10.4236/oalib.1106947

Al-Eitan, L. N., Almasri, A. Y., & Khasawneh, R. H. (2019). Effects of CYP2C9 and VKORC1 polymorphisms on warfarin sensitivity and responsiveness during the stabilization phase of therapy. Saudi pharmaceutical journal : SPJ, 27(4), 484-490. https://doi.org/10.1016/j.jsps.2019.01.011

Johnson, J. A., Caudle, K. E., Gong, L., Whirl-Carrillo, M., Stein, C. M., Scott, S. A., Lee, M. T., Gage, B. F., Kimmel, S. E., Perera, M. A., Anderson, J. L., Pirmohamed, M., Klein, T. E., Limdi, N. A., Cavallari, L. H., & Wadelius, M. (2017). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clinical pharmacology and therapeutics, 102(3), 397-404. https://doi.org/10.1002/cpt.668

Sun, X., Yu, W. Y., Ma, W. L., Huang, L. H., & Yang, G. P. (2016). Impact of the CYP4F2 gene polymorphisms on the warfarin maintenance dose: A systematic review and meta-analysis. Biomedical reports, 4(4), 498-506. https://doi.org/10.3892/br.2016.599

Ageno, W., Gallus, A. S., Wittkowsky, A., Crowther, M., Hylek, E. M., & Palareti, G. (2012). Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 141(2 Suppl), e44S-e88S. https://doi.org/10.1378/chest.11-2292

January, C. T., Wann, L. S., Calkins, H., Chen, L. Y., Cigarroa, J. E., Cleveland, J. C., Jr, Ellinor, P. T., Ezekowitz, M. D., Field, M. E., Furie, K. L., Heidenreich, P. A., Murray, K. T., Shea, J. B., Tracy, C. M., & Yancy, C. W. (2019). 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology, 74(1), 104-132. https://doi.org/10.1016/j.jacc.2019.01.011

Själander, S., Sjögren, V., Renlund, H., Norrving, B., & Själander, A. (2018). Dabigatran, rivaroxaban and apixaban vs. high TTR warfarin in atrial fibrillation. Thrombosis research, 167, 113-118. https://doi.org/10.1016/j.thromres.2018.05.022

Haas, S., Ten Cate, H., Accetta, G., Angchaisuksiri, P., Bassand, J. P., Camm, A. J., Corbalan, R., Darius, H., Fitzmaurice, D. A., Goldhaber, S. Z., Goto, S., Jacobson, B., Kayani, G., Mantovani, L. G., Misselwitz, F., Pieper, K., Schellong, S. M., Stepinska, J., Turpie, A. G., van Eickels, M., … GARFIELD-AF Investigators (2016). Quality of Vitamin K Antagonist Control and 1-Year Outcomes in Patients with Atrial Fibrillation: A Global Perspective from the GARFIELD-AF Registry. PloS one, 11(10), e0164076. https://doi.org/10.1371/journal.pone.0164076

Amin, A., Deitelzweig, S., Jing, Y., Makenbaeva, D., Wiederkehr, D., Lin, J., & Graham, J. (2014). Estimation of the impact of warfarin's time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials. Journal of thrombosis and thrombolysis, 38(2), 150–159. https://doi.org/10.1007/s11239-013-1048-z

Fihn, S. D., McDonell, M., Martin, D., Henikoff, J., Vermes, D., Kent, D., & White, R. H. (1993). Risk factors for complications of chronic anticoagulation. A multicenter study. Warfarin Optimized Outpatient Follow-up Study Group. Annals of internal medicine, 118(7), 511-520. https://doi.org/10.7326/0003-4819-118-7-199304010-00005

Apostolakis, S., Sullivan, R. M., Olshansky, B., & Lip, G. (2013). Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT2R2 score. Chest, 144(5), 1555-1563. https://doi.org/10.1378/chest.13-0054

Zulkifly, H., Lip, G., & Lane, D. A. (2018). Use of the SAMe-TT2R2 score to predict anticoagulation control in atrial fibrillation and venous thromboembolism patients receiving vitamin K antagonists: A review. Heart rhythm, 15(4), 615-623. https://doi.org/10.1016/j.hrthm.2017.11.026

Pivatto Junior, F., Scheffel, R. S., Ries, L., Wolkind, R. R., Marobin, R., Barkan, S. S., Amon, L. C., & Biolo, A. (2017). SAMe-TT2R2 Score in the Outpatient Anticoagulation Clinic to Predict Time in Therapeutic Range and Adverse Events. Arquivos brasileiros de cardiologia, 108(4), 290-296. https://doi.org/10.5935/abc.20170052

Poli, D., Antonucci, E., Testa, S., & Lip, G. Y. (2014). A prospective validation of the SAME-TT2R 2 score: how to identify atrial fibrillation patients who will have good anticoagulation control on warfarin. Internal and emergency medicine, 9(4), 443-447. https://doi.org/10.1007/s11739-014-1065-8

Rosendaal, F. R., Cannegieter, S. C., van der Meer, F. J., & Briët, E. (1993). A method to determine the optimal intensity of oral anticoagulant therapy. Thrombosis and haemostasis, 69(3), 236-239.

Kolesnyk, M. Y., & Mykhailovskyi, Y. M. (2021). Frequencies of polymorphisms in genes affecting the pharmacokinetics of warfarin in the Zaporizhzhia region. Zaporozhye Medical Journal, 23(4), 476-479. https://doi.org/10.14739/2310-1210.2021.4.227002

Proietti, M., Lane, D. A., & Lip, G. Y. (2016). Relation of the SAMe-TT2R2 score to quality of anticoagulation control and thromboembolic events in atrial fibrillation patients: Observations from the SPORTIF trials. International journal of cardiology, 216, 168-172. https://doi.org/10.1016/j.ijcard.2016.04.131

Lin, K. J., Singer, D. E., Glynn, R. J., Blackley, S., Zhou, L., Liu, J., Dube, G., Oertel, L. B., & Schneeweiss, S. (2017). Prediction Score for Anticoagulation Control Quality Among Older Adults. Journal of the American Heart Association, 6(10), e006814. https://doi.org/10.1161/JAHA.117.006814

Del-Toro-Cervera, J., Demelo-Rodriguez, P., Galeano-Valle, F., Fidalgo, Á., Sampériz, Á., Muñoz-Torrero, J., Lima, J., Sigüenza, P., Tufano, A., Monreal, M., & RIETE Investigators (2020). Evaluation of the SAMe-TT2R2 score to predict the quality of anticoagulation control in patients with venous thromboembolism treated with vitamin K antagonists: Findings from the RIETE registry. Thrombosis research, 194, 178-182. https://doi.org/10.1016/j.thromres.2020.06.022

Van Miert, J., Bos, S., Veeger, N., & Meijer, K. (2018). Clinical usefulness of the SAMe-TT2R2 score: A systematic review and simulation meta-analysis. PloS one, 13(3), e0194208. https://doi.org/10.1371/journal.pone.0194208

Park, Y. K., Lee, M. J., Kim, J. H., Kim, S. J., Kim, J. S., Lee, S. Y., & Bang, O. Y. (2015). Lack of Association of Clinical Factors (SAMe-TT2R2) with CYP2C9/VKORC1 Genotype and Anticoagulation Control Quality. Journal of stroke, 17(2), 192-198. https://doi.org/10.5853/jos.2015.17.2.192

Da Silveira, M., Melo, L. A., Gomes, F., Andrade, L., Serur, I. P., Piscoya, I., Gueiros, R. M., Palmeira do Ó, K., de Lima, R. E., Brasileiro, V., Vasconcelos, L., & Sobral Filho, D. C. (2019). Polymorphisms of CYP2C9*2, CYP2C9*3 and VKORC1 genes related to time in therapeutic range in patients with atrial fibrillation using warfarin. The application of clinical genetics, 12, 151-159. https://doi.org/10.2147/TACG.S197316

Skov, J., Bladbjerg, E. M., Leppin, A., & Jespersen, J. (2013). The influence of VKORC1 and CYP2C9 gene sequence variants on the stability of maintenance phase warfarin treatment. Thrombosis research, 131(2), 125-129. https://doi.org/10.1016/j.thromres.2012.11.004

Elewa, H., Qurishi, I., Abouelhassan, R., Abou Safrah, S., Alhamoud, E., & Bader, L. (2020). Effect of SAMe-TT2R2 score and genetic polymorphism on the quality of anticoagulation control in Qatari patients treated with warfarin. Journal of thrombosis and thrombolysis, 49(4), 659-666. https://doi.org/10.1007/s11239-020-02102-x

Li, Y., Yu, J., Kuang, Y., Wu, C., Yang, L., Fang, Q., Pei, Q., & Yang, G. (2020). Quality of oral anticoagulation control in Chinese patients with non-valvular atrial fibrillation: a prospective controlled study. Current medical research and opinion, 36(9), 1433-1439. https://doi.org/10.1080/03007995.2020.1796611

Gorter J. W. (1999). Major bleeding during anticoagulation after cerebral ischemia: patterns and risk factors. Stroke Prevention In Reversible Ischemia Trial (SPIRIT). European Atrial Fibrillation Trial (EAFT) study groups. Neurology, 53(6), 1319-1327. https://doi.org/10.1212/wnl.53.6.1319

Kolesnyk, M. Y., & Mykhailovskyi, Y. M. (2021). The interrelation of CYP2C9, CYP4F2, VKORC1 genes polymorphisms with warfarin dose and hemorrhagic complications risk rise in patients with atrial fibrillation: a retrospective study. East European science journal, 1(1), 37-43.

Published

2022-04-15

How to Cite

1.
Mykhailovskyi YM. The influence of clinical and genetic factors on the stability of warfarin’s anticoagulant effect in patients with atrial fibrillation. Pathologia [Internet]. 2022Apr.15 [cited 2024Apr.16];19(1):12-7. Available from: http://pat.zsmu.edu.ua/article/view/252662

Issue

Section

Original research