Features of warfarin dosage in the condition of polypharmacotherapy in patients after the prosthetic heart valve implantation

Authors: E.Z. Golukhova, S.M. Arslanbekova, D.A. Sychev, E.V. Kuznetsova

Company: 1 A.N. Bakoulev Scientific Center for Cardiovascular Surgery of Russian Academy of Medical Sciences;
2 Center for clinical pharmacology “Scientific Center for expertise of remedies for medical application” of Ministry
of Health of the Russian Federation

For citation: Golukhova EZ, Arslanbekova SM, Sychev DA, et al. Features of warfarin dosage in the condition of polypharmacotherapy in patients after the prosthetic heart valve implantation. Kreativnaya kardiologiya. 2013; 1: 58-65 (in Russian)

Keywords: prosthetic heart valve warfarin polymorphism of cytochrome P450 2C9 gene antibacterial medication amiodarone рrednisolone

Full text:  



Objective. To study the impact of drug-drug interaction on the maintenance dose of warfarin in the early postoperative period in the condition of polypharmacotherapy.

Material and methods. The whole of 76 patients were included in the study, mean age 45±13 years. All patients underwent heart valve replacement. 2–4 days after surgery warfarin was administered for all patients according to the standard scheme 5mg/day under the control of the International normalized ratio (INR). In conjunction with warfarin patients received medication needed for prophylaxis and treatment of postoperative complications. CYP2C9 genotype bearing was determined with the technique of polymerase chain reaction with the restriction fragment length polymorphism (PCR–RFLP) assay after preliminary isolation of DNA from the whole blood.

Results. In the early postoperative period the chosen Warfarin doses were much lower from statistical standpoint than those in late postoperative period (4.4±1.8 mg vs. 5.6±2.1 mg, р=0.001). As a result of genotyping the statistically significant low therapeutic Warfarin doses were determined in patients with CYP2C9*1/*1 genotype who took amiodarone (4.4±1.8 mg vs. 5.5±2.1 mg, р=0.003) and prednisolone (3.6±1.5 mg vs. 5.1±1.9 mg, р=0.020). But patients with non-CYP2C9*1/*1 genotype did not show a statistically significant difference between the doses of warfarin.

Conclusion. Lower warfarin doses were associated only in patients with CYP2C9*1/*1 genotype, but not in patients bearing CYP2C9*2 and CYP2C9*3 genotypes (non-CYP2C9*1/*1 genotypes), who initially have had the genetically determined low CYP2C9 isoenzyme activity, which is already apparently not able for reduction under the influence of these inhibitors.


  1. Вавилова Т.В. Система гемостаза у больных с механическими искусственными клапанами сердца: дис. … д-ра мед. наук. СПб.; 2005.
  2. Сироткина О.В., Улитина А.С., Тараскина А.Е. и др. Аллельные варианты CYP2C9*2 и CYP2C*3 гена цитохрома CYP2C9 в популяции Санкт-Петербурга и их клиническое значение при антикоагулянтной терапии варфарином. Российский кардиологический журнал. 2004; 6: 47–50.
  3. Сычев Д.А. Значение фармакогенетических исследований системы биотрансформации и транспортеров для оптимизации фармакотерапии сердечно-сосудистыми лекарственными средствами: дис. … д-ра мед. наук. М.; 2006.
  4. Шевела А.И., Лифшиц Г.И., Новикова Я.В., Севостьянова К.С. Фармакогенетические основы применения варфарина. Флебология. 2008; 2 (3): 35–7.
  5. Herman D., Locatelli I., Grabnar I., Peternel P., Stegner 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 (3): 193–202.
  6. Lee S.J., Jang Y.J., Cha E.Y., Kim H.S., Lee S.S., Shin J.G. A haplotype of CYP2C9 associated with warfarin sensitivity in mechanical heart valve replacement patients. Br. J. Clin. Pharmacol. 2010. 70 (2): 213–21.
  7. Yin T., Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 – rationale and perspectives. Thromb. Res. 2007; 120 (1): 1–10.
  8. Herman D., Locatelli I., Grabnar I. et al. The influence of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose. Eur. J. Clin. Pharmacol. 2006; 62 (4): 291–6.
  9. Huang S.M., Rowland M. The role of physiologically based pharmacokinetic modeling in regulatory review. Clin. Pharmacol. Ther. 2012; 91 (3): 542–9. doi: 10.1038/clpt.2011.320.
  10. Mattias W., Anders S., Viveka F., Ma°rten R., Niclas E., Peter J. Svensson. Anticoagulation control in sweden: reports of time in therapeutic range, major bleeding, and thrombo-embolic complications from the national quality registry auricular. Eur. Heart J. 2011; 32: 2282–9.
  11. Snaith A., Pugh L., Simpson C.R. et al. The potential for interaction between warfarin and coprescribed medication. Am. J. Cardiovasc. Drugs. 2008; 8 (3): 207–12.
  12. Verhovsek M., Motlagh B., Crowther M.A. et al. Quality of anticoagulation and use of warfarin-interacting medications in long-term care: a chart review. BMC Geriatrics. 2008; 8: 13.
  13. Седов А.Н. Длительная профилактика тромбоэмболических осложнений варфарином в комплексной терапии фибрилляций предсер- дий: дис. … канд. мед. наук. М.; 2009.
  14. Holbrook A.M., Pereira J.A., Labiriset R. et al. Systematic overview of warfarin and its drug and food interactions. Arch. Intern. Med. 2005; 165: 1095–106.
  15. Lu Y., Won K.A., Nelson B.J., Qi D., Rausch D.J., Asinger R.W. Characteristics of the amiodarone-warfarin interaction during long-term followup. Am. J. Health. Syst. Pharm. 2008; 15; 65 (10): 947–52.

Chief Editor

Leo A. Bockeria, MD, PhD, DSc, Professor, Academician of Russian Academy of Sciences, President of Bakoulev National Medical Research Center for Cardiovascular Surgery