Ukr.Biochem.J. 2020; Volume 92, Issue 3, May-Jun, pp. 77-85


Warfarin therapy in patients with coronary heart disease and atrial fibrillation: drug interactions and genetic sensitivity to warfarin

O. A. Panibratiuk, O. А. Yakovleva

National Pirogov Memorial Medical University, Vinnytsya, Ukraine;

Received: 26 February 2020; Accepted: 30 June 2020

In this research work we examined the effect of various factors on the efficacy and safety of warfarin pharmacotherapy. Particular emphasis was placed on drug interaction in the standardized treatment of patients with coronary heart disease and atrial fibrillation. Since the administration of such drugs as digoxin and statins with warfarin leads to an increase in the blood level of all three drugs (they interact at the level of P-glycoprotein) and warfarin has a narrow therapeutic window, the risk of hemorrhagic complications is increased. For the first time in patients of the Podillya region of Ukraine, the genetic polymorphism of cytochrome CYP2C9 was determined, which is associated with the slow withdrawal of anticoagulant from the bloodstream and the possible risk of bleeding. For safe pharmacotherapy, patients were given significantly different doses of warfarin in all comparison groups, according to the International Normalized Ratiо (INR). For example, in the group with a CYP2C9 mutation present, the dose was 3.08 ± 0.25 mg versus 4.15 ± 0.22 mg in the non-mutation group (P = 0.008). In addition, in patients with genetic polymorphism of detoxification enzymes, significantly more bleeding events (light or clinically significant; critical organ bleeding) were observed, but among these patients bleeding occurred at an INR of 2.6 (despite the recommendations of the European Society of Cardiology, that the INR can be maintained within 2.0-3.0). Therefore, patients with CYP2C9 mutations require a personalized approach and control of the INR in a safer range (2.0 to 2.5) and consideration of drug interactions.

Keywords: , , , ,


  1. Galli F, Borghi L, Carugo S, Cavicchioli M, Faioni EM, Negroni MS, Vegni E. Atrial fibrillation and psychological factors: a systematic review. PeerJ. 2017;5:e3537. PubMed, PubMedCentral, CrossRef
  2. Sychov OS, Romanova OM. Atrial fibrillation: the state of problems in Ukraine and abroad. Ukr J Cardiol. 2007;(5):63-66. (In Ukrainian).
  3. Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC, Heidbuchel H, Hendriks J, Hindricks G, AS Manolis, Oldgren J, Popescu BA, Schotten U, Van Putte B,  Vardas P, ESC Scientific Document Group. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J. 2016;37(38):2893-2962.  PubMed, CrossRef
  4. Ma Z, Cheng G, Wang P, Khalighi B, Khalighi K. Clinical Model for Predicting Warfarin Sensitivity. Sci Rep. 2019;9(1):12856. PubMed, PubMedCentral, CrossRef
  5. Jenner KM, Simmons BJ, Delate T, Clark NP, Kurz D, Witt DM. An Education Program for Patient Self-Management of Warfarin. Perm J. 2015;19(4):33-8. PubMed, PubMedCentral, CrossRef
  6. Christensen TD. Self-management of oral anticoagulation therapy–methodological and clinical aspects. Dan Med Bull. 2011;58(5):B4284. PubMed
  7. Karpov YA. Approaches to the therapy of patients with hypertension and atrial fibrillation. Cardiology News. 2013;(4):2-9. (In Russian).
  8. Shulkin AV, Yakusheva EN, Popova NM. The role of P-glycoprotein in rational pharmacotherapy in cardiology. Ration Pharmacother Cardiol. 2013;9(6):701-707. (In Russian). CrossRef
  9.  Vorobyeva NM, Panchenko EP, Dobrovolsky AB, Titaeva EV, Khasaeva ZB, Konovalova NV, Postnov AYu, Kirienko AI. Polymorphisms of genes CYP2C9 and VKORC1 in patients with venous thromboembolic complications in Moscow population: effects on stability of anticoagulant therapy and frequency of hemorrhage. Ter Arkh. 2011;83(6):59-65. (In Russian). PubMed
  10. Maliarchuk IV,  Horovenko NG. The role of intergenic interactions of genes encoding biotransformation enzymes of indirect anticoagulants and genes of the hemostatic system in the selection of a dose of warfarin. J Nat Acad Med Sci Ukraine. 2014;20(2):246-251. (In Russian).
  11. Sychov DA, Ramenskaya GV, Ignatiev IV, Kukes BG. Eds. Kukes VG, Bochkov NP. Clinical pharmacogenetics. M.: GEOTAR-Media, 2007. 245 p. (In Russian).
  12.  Zotova IV, Nikitin AG, Fattakhova EN, Brovkin AN, Khodyrev DS, Lavrikova EY, Isaeva MY, Kosukhina AS, Nosikov VV, Zateyshchikov DA. The affect of influence of genes’ polymorphisms CYP2C9 and VKORC1ON of the safety of the therapy by warfarin. J Clin Pract. 2013;4(4):3-10.  CrossRef
  13. Guidelines for cardiology/Ed. V.M. Kovalenko.  K.: MORION, 2009. 1257 p. (In Ukrainian).
  14. Rebrova OY. Statistical analysis of medical data. Application software package Statistica. M: Medisfera, 2006. 312 p.  (In Russian).
  15. Sivolob, AV, Rushkovsky SR, Kiryachenko SS. Genetics: a textbook. K .: Publishing and Printing Center “Kyiv University”, 2008. 320 p. (In Ukrainian).
  16. Zhang F, Finkelstein J. Inconsistency in race and ethnic classification in pharmacogenetics studies and its potential clinical implications. Pharmgenomics Pers Med. 2019;12:107-123.  PubMed, PubMedCentral, CrossRef
  17. Ma Q, Lu AYH. Pharmacogenetics, pharmacogenomics, and individualized medicine. Pharmacol Rev. 2011;63(2):437-59. PubMed, CrossRef
  18. Sánchez-Diz P, Estany-Gestal A, Aguirre C, Blanco, Carracedo A, Ibáñez L, Passiu M, Provezza L, Ramos-Ruiz R, Ruiz B, Salado-Valdivieso I, Velasco EA, Figueiras A. Prevalence of CYP2C9 polymorphisms in the south of Europe. Pharmacogenomics J. 2009;9(5):306-10. PubMed, CrossRef
  19. Xie HG, Prasad HC, Kim RB, Stein CM. CYP2C9 allelic variants: ethnic distribution and functional significance. Adv Drug Deliv Rev. 2002;54(10):1257-70.PubMed, CrossRef
  20. Dorado P, Sosa-Macias MG, Peñas-Lledó EM, Alanis-Bañuelos RE, Wong ML, Licinio J, Lares-Asseff I, Llerena A. CYP2C9 allele frequency differences between populations of Mexican-Mestizo, Mexican-Tepehuano, and Spaniards. Pharmacogenomics J. 2011;11(2):108-12. PubMed, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.