Gene polymorphism: effectiveness and safety of anticoagulant therapy

Anticoagulant drugs play an important role in reducing the risk of complications and mortality that are associated with thrombotic events. Vitamin K antagonists have been used for prolonged oral therapy until recently, but their use has a number of limitations. These are a high percentage of hemorrhagic events, a high threat of interaction with other drugs and food, as well as the need for continuous monitoring of laboratory parameters of patients. That is why, due to the great limitations of these drugs, new direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban and edoxaban are now an integral part of practical healthcare. Because of their widespread use in cardiology, surgery, dermatology, neurology and many other branches of medicine for the prevention of thrombosis, as well as their differences in pharmacokinetics, it is crucial to study the genetic determinants for the possibility of effective and safe prescribing of these drugs. This will help in predicting the dosage of the drugs and using them as monotherapy or in combination with other drugs. They have several advantages over traditional drugs: they have a lower likelihood of drug-drug interactions and no need for continuous monitoring. However, polymorphisms of genes (CYP2C9, ABCB1, CES1) responsible for the metabolism of anticoagulants can affect the pharmacokinetics and pharmacodynamics, which significantly affects the efficacy and safety of drugs. In this regard, it is necessary to adjust dosing to achieve the necessary effect and reduce the risk of undesirable effects. The aim of this work is to review the current data on the influence of genetic polymorphism on the efficacy and safety of anticoagulant therapy, as well as to consider the prospects of personalized approach in the treatment of patients. Materials and methods: articles were searched in Google Scholar, PubMed and Medline databases by key terms and their combinations in titles, abstracts and keywords: pharmacogenetics of anticoagulants, gene polymorphisms, pharmacogenetic studies of NPOAC, dabigatran, apixaban, warfarin, pharmacogenetics of anticoagulants, gene polymorphisms, adverse effects of anticoagulants, DOAC. The literature search and selection of literature sources was performed from September 2024 to December 2024.

1. Petrov V. I., Gerasimenko A. S., Kulakova I.S., Shatalova O. V. V., Amosov A. A., Gorbatenko V. S. Mechanisms of development of COVID-19 associated coagulopathy. Diagnosis. Treatment. Lekarstvennyi vestnik = Medicinal Bulletin. 2021; 15 (2): 21–27 (In Russ.).

2. Jenner W. J., Gorog D. A. Incidence of thrombotic complications in COVID-19: On behalf of ICODE: The International COVID-19 Thrombosis Biomarkers Colloquium. Journal of Thrombosis and Thrombolysis. 2021; 52 (4): 999–1006. doi: 10.1007/s11239-021-02475-7. PMID: 34047938. PMCID: PMC8161345.

3. Kantemirova B. I., Vasilkova V. V. Gene polymorphism in patients with a new coronavirus infection COVID-19. Infektsionnyye bolezni: Novosti. Mneniya. Obucheniye = Infectious Diseases: News. Opinions. Education. 2022; 3 (42): 130–137 (In Russ.).

4. Eichelbaum M., Ingelman-Sundberg M., Evans W. E. Pharmacogenomics and individualized drug therapy. Annual Review of Medicine. 2006; 57: 119–137. doi: 10.1146/annurev.med.56.082103.104724. PMID: 16409140.

5. Kazakov R. E., Sychev D. A. Role of pharmacogenetic testing in clinical trials of new drugs. Meditsinskaya genetika = Medical Genetics. 2015; 14, 9 (159): 18–23. EDN UOHQLV (In Russ.).

6. Quiñones L., Roco Á., Cayún J. P., Escalante P., Miranda C., Varela N., Meneses F., Gallegos B., ZarumaTorres F., Lares-Asseff I. Clinical applications of pharmacogenomics. Revista Medica de Chile. 2017; 145 (4): 483– 500. doi: 10.4067/s0034-98872017000400009. PMID: 28748996.

7. Whirl-Carrillo M., Huddart R., Gong L., Sangkuhl K., Thorn C. F., R. Whaley and T. E. Klein. An evidencebased framework for evaluating pharmacogenomics knowledge for personalized medicine. Clinical Pharmacology & Therapeutics. 2021; 110 (3): 563–572. doi: 10.1002/cpt.2350.

8. Whirl-Carrillo M., McDonagh E. M., Hebert J. M., Gong L., Sangkuhl K., Thorn C. F., Altman R. B., Klein T. E. Pharmacogenomics knowledge for personalized medicine. Clinical Pharmacology & Therapeutics. 2012; 92 (4): 414–417.

9. Sychev I. N., Fedina L. V., Gabrielyan D. A., Rastvorova T.D., Strigunkova E. V., Mirzaev K. B., Sychev D. A. Anticoagulant therapy with direct oral anticoagulants in conditions of polypragmasia: a course for safety. Meditsinskiy sovet = Medical Council. 2022; 16 (17): 52–64 (In Russ.).

10. Ingelman-Sundberg M., Pirmohamed M. Precision medicine in cardiovascular therapeutics: Evaluating the role of pharmacogenetic analysis prior to drug treatment. Journal of Internal Medicine. 2024; 295 (5): 583–598. doi: 10.1111/joim.13772. PMID: 38343077.

11. Fedina L. V., Sychev I. N. N., Rastvorova T. D., Mirzaev K. B., Sychev D. A. Clinical-pharmacological approaches to personalization of personal anticoagulants: clinical cases // Meditsinskiy sovet = Medical Council. 2023; 17 (13): 8–14 (In Russ.).

12. Cross B., Turner R. M., Zhang J. E., Pirmohamed M. Being precise with anticoagulation to reduce adverse drug reactions: are we there yet? Pharmacogenomics Journal. 2024; 24 (2): 7. doi: 10.1038/s41397-024-00329-y. PMID: 38443337. PMCID: PMC10914631.

13. Turner R. M., Park B. K., Pirmohamed M. Parsing interindividual drug variability: an emerging role for systems pharmacology. Wiley Interdisciplinary Reviews: Systems Biology and Medicine. 2015; 7 (4): 221–241. doi: 10.1002/wsbm.1302. PMID: 25950758. PMCID: PMC4696409.

14. Al Ammari M., AlBalwi M., Sultana K., Alabdulkareem I. B., Almuzzaini B., Almakhlafi N. S., Aldrees M., Alghamdi J. The effect of the VKORC1 promoter variant on warfarin responsiveness in the Saudi WArfarin Pharmacogenetic (SWAP) cohort. Scientific Reports. 2020; 10 (1): 11613. doi: 10.1038/s41598-020-68519-9. PMID: 32669629. PMCID: PMC7363835.

15. Izmozherova N. V., Shambatov M. A., Popov A. A., Zhuk D. E., Solodchenko V. A. Farmakogenetika varfarina: obzor literatury = Pharmacogenetics of warfarin: a review of the literature. URL: https://omnidoctor.ru/upload/iblock/4eb/86m773ycy9tt2i3s0hvnzz1djmtd7kxj.pdf (In Russ.).

16. Liu J., Guan H., Zhou L., Cui Y., Cao W., Wang L. Impact of gene polymorphism on the initiation and maintenance phases of warfarin therapy in Chinese patients undergoing heart valve replacement. American Journal of Translational Research. 2019; 11 (4): 2507–2515. PMID: 31105858. PMCID: PMC6511795.

17. Shi K., Deng J. Comparative performance of pharmacogenetics-based warfarin dosing algorithms in Chinese population: use of a pharmacokinetic/pharmacodynamic model to explore dosing regimen through clinical trial simulation. Pharmacogenetics and Genomics. 2024; 34 (9): 275–284. doi: 10.1097/FPC.0000000000000545. PMID: 39356590. PMCID: PMC11424055.

18. Sychev D. A., Chernyaeva M. S., Ostroumova O. D. Genetic risk factors for the development of adverse drug reactions. Bezopasnost i risk farmakoterapii = Safety and risk of pharmacotherapy. 2022; 10 (1); 48–64 (In Russ.).

19. Filimonova A. S. Drug of choice in patients with left ventricular thrombosis: warfarin or POAC. Aktualnyye nauchnyye issledovaniya v sovremennom mire = Actual scientific research in the modern world. 2021; 8–2: 29–32 (In Russ.).

20. Holail J., Mobarak R., Al-Ghamdi B., Aljada A., Fakhoury H. Association of VKORC1 and CYP2C9 singlenucleotide polymorphisms with warfarin dose adjustment in Saudi patients. Drug Metabolism and Personalized Therapy. 2022; 37 (4): 353–359. doi: 10.1515/dmpt-2022-0108. PMID: 36476275.

21. de Oliveira Magalhães Mourão A., Braga Gomes K., Afonso Reis E., Pedra de Souza R., de Freitas Campos E. I., Dias Ribeiro D., da Costa Rocha M. O., & Parreiras Martins M. A. Algorithm for predicting low maintenance doses of warfarin using age and polymorphisms in genes CYP2C9 and VKORC1 in Brazilian subjects. Pharmacogenomics Journal. 2020. 20 (1): 104–113. doi: 10.1038/s41397-019-0091-3. PMID: 31395958.

22. Ragia G., Karantza I. M., Kelli-Kota E., Kolovou V., Kolovou G., Konstantinides S., Maltezos E., Tavridou A., Tziakas D., Maitland-van der Zee A. H., Manolopoulos V. G. Role of CYP4F2, CYP2C19, and CYP1A2 polymorphisms on acenocoumarol pharmacogenomic algorithm accuracy improvement in the Greek population: need for sub-phenotype analysis. Drug Metabolism and Personalized Therapy. 2017; 32 (4): 183–190. doi: 10.1515/dmpt2017-0034. PMID: 29252193.

23. Fahmi A. M., Bardissy A. E., Saad M. O., Fares A., Sadek A., Elshafei M. N., Eltahir A., Mohamed A., Elewa H. Accuracy of an internationally validated genetic-guided warfarin dosing algorithm compared to a clinical algorithm in an Arab population. Current Problems in Cardiology. 2024; 49 (12): 102865. doi: 10.1016/j.cpcardiol.2024.102865. PMID: 39317306.

24. Soh S. P. Y., See Toh W. Y., Ten W. Q., Leong K. P., Goh L. L. Validating two international warfarin pharmacogenetic dosing algorithms for estimating the maintenance dose for patients in Singapore. Annals, Academy of Medicine, Singapore. 2024; 53 (3): 208–210. doi: 10.47102/annals-acadmedsg.2023186. PMID: 38920246.

25. Deng J., Wang Y., An X. Comparison of Maintenance Dose Predictions by Warfarin Dosing Algorithms Based on Chinese and Western Patients. Journal of Clinical Pharmacology. 2023; 63 (5): 569–582. doi: 10.1002/jcph.2197. PMID: 36546564.

26. Shaw K., Amstutz U., Hildebrand C., Rassekh S. R., Hosking M., Neville K., Leeder J. S., Hayden M. R., Ross C. J., Carleton B. C. VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. Pediatric Blood & Cancer. 2014; 61 (6): 1055–1062. doi: 10.1002/pbc.24932. PMID: 24474498.

27. Misasi S., Martini G., Paoletti O., Calza S., Scovoli G., Marengoni A., Testa S., Caimi L., Marchina E. VKORC1 and CYP2C9 polymorphisms related to adverse events in case-control cohort of anticoagulated patients. Medicine (Baltimore). 2016; 95 (52): e5451. doi: 10.1097/MD.0000000000005451. PMID: 28033245. PMCID: PMC5207541.

28. International Warfarin Pharmacogenetics Consortium; Klein T. E., Altman R. B., Eriksson N., Gage B. F., Kimmel S. E., Lee M. T., Limdi N. A., Page D., Roden D. M., Wagner M. J., Caldwell M. D., Johnson J. A., Estim Al Ammari M., AlBalwi M., Sultana K., Alabdulkareem I. B., Almuzzaini B., Almakhlafi N. S., Aldrees M., Alghamdi J. The effect of the VKORC1 promoter variant on warfarin responsiveness in the Saudi WArfarin Pharmacogenetic (SWAP) cohort. Scientific Reports. 2020; 10 (1): 11613. doi: 10.1038/s41598-020-68519-9. PMID: 32669629. PMCID: PMC7363835.

29. Ferder N. S., Eby C. S., Deych E., Harris J. K., Ridker P. M., Milligan P. E., Goldhaber S. Z., King C. R., Giri T., McLeod H. L., Glynn R. J., Gage B. F. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. Journal of Thrombosis and Haemostasis. 2010; 8 (1): 95–100. doi: 10.1111/j.15387836.2009.03677.x. PMID: 19874474; PMCID: PMC3718044.

30. Lindh J. D., Holm L., Andersson M. L., Rane A. Influence of CYP2C9 genotype on warfarin dose requirements – a systematic review and meta-analysis. European Journal of Clinical Pharmacology. 2009; 65 (4): 365–375. doi: 10.1007/s00228-008-0584-5.

31. Jorgensen A. L., Fitz Gerald R. J., Oyee J., Pirmohamed M., Williamson P. R. Influence of CYP2C9 and VKORC1 on patient response to warfarin: a systematic review and meta-analysis. Plos One. 2012; 7 (8): e44064. doi: 10.1371/journal.pone.0044064.

32. Zhang J., Chen Z., Chen C. Impact of CYP2C9, VKORC1 and CYP4F2 genetic polymorphisms on maintenance warfarin dosage in Han-Chinese patients: A systematic review and meta-analysis. Meta Gene. 2016; 9: 197–209. doi: 10.1016/j.mgene.2016.07.002. PMID: 27617219. PMCID: PMC5006145

33. Limdi N. A., McGwin G., Goldstein J. A., Beasley T. M., Arnett D. K., Adler B. K., Baird M. F., Acton R. T. Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in AfricanAmerican and European-American patients on warfarin. Clinical Pharmacology & Therapeutics. 2008; 83 (2): 312–321. doi: 10.1038/sj.clpt.6100290. PMID: 17653141. PMCID: PMC2683398.

34. Xie H. G., Prasad H. C., Kim R. B., Stein C. M. CYP2C9 allelic variants: ethnic distribution and functional significance. Advanced Drug Delivery Reviews. 2002; 54 (10): 1257–1270. doi: 10.1016/s0169-409x(02)00076-5. PMID: 12406644.

35. Yang L., Ge W., Yu F., Zhu H. Impact of VKORC1 gene polymorphism on inter individual and interethnic warfarin dosage requirement--a systematic review and meta-analysis. Thrombosis Research. 2010; 125 (4): e159–e166. doi: 10.1016/j.thromres.2009.10.017. PMID: 19942260.

36. Yang J., Chen Y., Li X., Wei X., Chen X., Zhang L., Zhang Y., Xu Q., Wang H., Li Y., Lu C., Chen W., Zeng C., Yin T. Influence of CYP2C9 and VKORC1 genotypes on the risk of hemorrhagic complications in warfarintreated patients: a systematic review and meta-analysis. International Journal of Cardiology. 2013; 168: 4234–4243. doi: 10.1016/j.ijcard.2013.07.151.

37. Wanounou M., Shaul C., Abu Ghosh Z., Alamia S., Caraco Y. The Impact of CYP2C9*11 Allelic Variant on the Pharmacokinetics of Phenytoin and (S)-Warfarin. Clinical Pharmacology & Therapeutics. 2022; 112 (1): 156–163. doi: 10.1002/cpt.2613. PMID: 35426132. PMCID: PMC9322346.

38. Pharmacogenomics Knowledgebase (PharmGKB). Gene‐specific information tables for CYP2C9. URL: https://www.pharmgkb.org/page/cyp2c9RefMaterials.

39. Tidbury N., Preston J., & Lip G. Y. H. Lessons learned from the influence of CYP2C9 genotype on warfarin dosing. Expert Opinion on Drug Metabolism & Toxicology. 2023; 19 (4): 185–188. doi: 10.1080/17425255.2023.2220961.

40. Zubiaur P., Saiz-Rodríguez M., Ochoa D., Navares-Gómez M., Mejía G., Román M., Koller D., SoriaChacartegui P., Almenara S., Abad-Santos F. Effect of Sex, Use of Pantoprazole and Polymorphisms in SLC22A1, ABCB1, CES1, CYP3A5 and CYP2D6 on the Pharmacokinetics and Safety of Dabigatran. Advances in Therapy. 2020; 37 (8): 3537–3550. doi: 10.1007/s12325-020-01414-x. PMID: 32564268.

41. Cumitini L., Renda G., Giordano M., Rolla R., Shail T., Sacchetti S., Iezzi L., Giacomini L., Zanotti V., Auciello R., Angilletta I., Foglietta M., Zucchelli M., Antonucci I., Stuppia L., Gallina S., Dianzani U., Patti G. Role of CES1 and ABCB1 Genetic Polymorphisms on Functional Response to Dabigatran in Patients with Atrial Fibrillation. Journal of Clinical Medicine. 2024; 13 (9): 2545. doi: 10.3390/jcm13092545. PMID: 38731074. PMCID: PMC11084678.

42. Liu Y., Yang C., Qi W., Pei Z., Xue W., Zhu H., Dong M., Guo Y., Cong D., Wang F. The impact of ABCB1 and CES1 polymorphisms on dabigatran pharmacokinetics in healthy chinese subjects. Pharmgenom. Personalized Medicine. 2021; 14: 477–485. doi: 10.2147/PGPM.S291723.

43. Skripka A. I. Antikoagulyantnaya terapiya patsiyentov s fibrillyatsiyey predserdiy neklapannoy etiologii v sochetanii s khronicheskoy bolezn'yu pochek: farmakogeneticheskiy podkhod k prognozirovaniyu effektivnosti i bezopasnosti dabigatrana = Anticoagulant therapy of patients with atrial fibrillation of non-valvular etiology in combination with chronic kidney disease: pharmacogenetic approach to predicting the efficacy and safety of dabigatran. Moscow; 2020.

44. Yang Z., Tan W. R., Li Q., Wang Y., Liu S., Chen L., Zhou Y., Zeng C., Zeng Y., Xiong Y., Zhang Q., Li N., Du P., Liu L., Chen J., He Y. Population pharmacokinetic study of the effect of polymorphisms in the ABCB1 and CES1 genes on the pharmacokinetics of dabigatran. Frontiers in Pharmacology. 2024; 15: 1454612. doi: 10.3389/fphar.2024.1454612. PMID: 39619611. PMCID: PMC11605329.

45. Li H., Zhang Z., Weng H., Qiu Y., Zubiaur P., Zhang Y., Fan G., Yang P., Vuorinen A. L., Zuo X., Zhai Z., Wang C. Association between CES1 rs2244613 and the pharmacokinetics and safety of dabigatran: Meta-analysis and quantitative trait loci analysis. Frontiers in Cardiovascular Medicine. 2022; 9: 959916. doi: 10.3389/fcvm.2022.959916. PMID: 35990949. PMCID: PMC9386138.

46. Ji Q., Zhang C., Xu Q., Wang Z., Li X., Lv Q. The impact of ABCB1 and CES1 polymorphisms on dabigatran pharmacokinetics and pharmacodynamics in patients with atrial fibrillation. British Journal of Clinical Pharmacology. 2021; 87 (5): 2247–2255. doi: 10.1111/bcp.14646. PMID: 33179295.

47. Abdrakhmanov A., Zholdybayeva E., Shaimerdinova A., Kulmambetova G., Abildinova S., Albayev R., Tuyakova G., Rib E., Suleimen Z., Abdrakhmanova Z., Bekbossynova M. Genetic variants of ABCB1 and CES1 genes on dabigatran metabolism in the Kazakh population. Caspian Journal of Internal Medicine. 2024; 15 (3): 499–508. doi: 10.22088/cjim.15.3.499. PMID: 39011438. PMCID: PMC11246689.

48. Paré G., Eriksson N., Lehr T., Connolly S., Eikelboom J., Ezekowitz M. D., Axelsson T., Haertter S., Oldgren J., Reilly P., Siegbahn A., Syvanen A. C., Wadelius C., Wadelius M., Zimdahl-Gelling H., Yusuf S., Wallentin L. Genetic determinants of dabigatran plasma levels and their relation to bleeding. Circulation. 2013; 127 (13): 1404– 1412. doi: 10.1161/CIRCULATIONAHA.112.001233. PMID: 23467860.

49. Mescheryakov Y. V., Chertovskikh Y. V., Sychev D. A. Pharmacogenetics of a new oral anticoagulant dabigatran – the role of polymorphism rs2244613 ces1 in the development of adverse reactions. Farmakogenetika i farmakogenomika = Pharmacogenetics and pharmacogenomics. 2017; 2 (In Russ.).

50. Abdullaev Sh. P., Mirzaev K. B., Bochkov P. O., Sychev I. N., Sychev D. A. Implications of minor allely rs2244613 of the gene ces1 on the safety profile of dabigatran etexylate: meta-analysis. Regionalnaya farmakoterapiya v kardiologii = Regional pharmacotherapy in cardiology. 2020; 5: 699–705 (In Russ.).

51. Sychev D. A., Levanov A. N., Shelekhova T. V., Bochkov P. O., Denisenko N. P., Ryzhikova K. A., Mirzaev K. B., Grishina E. A., Gavrilov M. A. Influence of ABCB1 and CES1 gene polymorphisms on the levels of equilibrium concentrations of dabigatran in patients after knee joint endoprosthesis. Aterotromboz = Atherothrombosis. 2018; 1: 122–130 (In Russ.).

52. Skripka A. Pharmacogenetic testing as a tool for personalized approach to POAC prescribing. Sovremennaya kardiologiya = Modern Cardiology. 2019; 1 (11): 8–9 (In Russ.).

53. Olšerová A., Janský P., Magerová H., Šrámková T., Kešnerová P., Kmetonyová S., Šulc V., Halmová H., Šrámek M., Šarbochová I., Paulasová-Schwabová J., Benešová K., Macek J., Maťoška V., Tomek A. The Effect of ABCB1 and CES1 Polymorphisms on Plasma Levels of Dabigatran and Risk of Hemorrhagic Complications in Ischemic Stroke Patients. American Journal of Therapeutics 2024 doi: 10.1097/MJT.0000000000001710.