POTENTIAL OF PHARMACOGENETICS IN THE CORRECTION OF ANTICOAGULANT THERAPY AMONG PATIENT WITH PROSTHETIC HEART VALVES

Aim. To compare the effectiveness of various pharmacogenetics algorithms of warfarin dosage and to identify the strengths and limitations of standard genetic tests for the warfarin dose correction during the late postoperative period among 134 warfarin-treated patients with prosthetic heart valves.

Material and methods. All patients underwent genotyping for the CYP2C9 gene polymorphisms (CYP2C9*2 (С430Т) and CYP2C9*3 (А1075C) and for the vitamin K epoxide reductase complex subunit 1 VKORC1 (G-1639A). To compare the empirical and calculated warfarin doses, formulas by Gadge BF et al., Sconce EA et al., Anderson JL et al., and Takahashi H et al. were used.

Results. In 54 (40%) patients with adequate levels of international normalised ratio (INR; 2,0–3,0), empirical warfarin doses were the closest to the doses calculated using the formula by Gadge BF et al. In 49 (37%) patients with 2>INR>3, there was a mismatch between empirical and calculated warfarin doses, while in 31 (23%) patients, the pharmacogenetics algorithm of choice was inadequate.

Conclusion. The algorithm by Gadge BF et al. should be the first option in the process of choosing and/or correcting the dosage of warfarin. Additional pharmacogenetics algorithms require further improvement.

pharmacogenetics, indirect anticoagulants, warfarin, dosage

1. Antonov IM. Efficacy and safety of indirect anticoagulant warfarin when dosing, based on the results of pharmacogenetic testing. PhD Thesis. Candidate. Moscow 2009; 22 р. Russian (Антонов И. М. Эффективность и безопасность применения непря- мого антикоагулянта варфарина при его дозировании, основан- ном на результатах фармакогенетического тестирования. Автореф дисс канд мед наук. Москва 2009; 22 с).

2. Kozlova TV. Monitoring of treatment with oral anticoagulants. Pharmatec 2003; 3: 87–92. Russian (Козлова Т. В. Контроль за лечением оральны- ми антикоагулянтами. Фарматека 2003; 3: 87–92).

3. Kropacheva ES, Panchenko EP. Anticoagulants of indirect action in a therapeutic clinic overview. Russian Medical Journal: an independent publication for doctors in 2009; 17 (8): 507–13. Russian (Кропачева Е. С., Панченко Е. П.. Антикоагулянты непрямого действия в терапевтиче- ской клинике: Обзор. Русский медицинский журнал: независимое издание для практикующих врачей 2009; 17 (8): 507–13).

4. Sychev DA, Kropacheva ES, Ignat’ev IV, et al. Pharmacogenetics indirect anticoagulants: the importance of genotype in enhancing the effectiveness and safety of treatment. Cardiology 2006; 7: 72–8. Russian (Сычев Д. А., Кропачева Е. С., Игнатьев И. В. и др. Фармакогенетика непрямых антикоагулянтов: значение генотипа в повышении эффективности и безопасности терапии. Кардиология 2006; 7: 72–8).

5. Sychev DA, Antonov IM, Zagrebin SV, et al. Warfarin dosing algorithms, based on the results of pharmacogenetic testing: a real opportunity to optimize pharmacotherapy. Rational Pharmacotherapy in Cardiology 2007; 2: 59–66. Russian (Сычев Д. А., Антонов И. М., Загребин С. В. и др. Алгоритмы дозирования варфарина, основанные на результатах фар- макогенетического тестирования: реальная возможность оптимиза- ции фармакотерапии. Рациональная Фармакотерапия в Кардиологии 2007; 2: 59–66).

6. Sychev DA, Antonov IM, Kropacheva ES, et al. Which of warfarin dosing algorithms based on the results of pharmacogenetic testing, suitable Russian patients? Cardiology 2010, 4: 35–7. Russian (Сычев Д. А., Антонов И. М., Кропачева Е. С. и др. Какой из алгоритмов дозирова- ния варфарина, основанных на результатах фармакогенетического тестирования, подходит российским пациентам? Кардиология 2010; 4: 35–7).

7. ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease). JACC 2006; 48 (3): 148 р.

8. Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007; 116: 2563–70.

9. Bayliss A, Faber P, Dunning J, Ronald A. What is the optimal level of anticoagulation in adult patients receiving warfarin following the implantation of a mechanical prosthetic mitral valve? Interact Cardio Vasc Thorac Surg 2007; 6: 390–6.

10. Gage BF, Eby CS. Pharmacogenetis and Anticoagulant Therapy. J Thromb Thrombolysis 2003; 16 (1–2): 73–8.

11. Guidelines on the management of valvular heart disease. The task force on the management of valvular heart disease of the European Society of Cardiology. European Heart J 2007; 2: 230–68.

12. Sconce EA, Khan TI, Wynne HA, 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: 2329–33.

13. Takahashi H, Wilkinson GR, Nutescu EA, et al. Different contributions of polymorphisms in VKORC1 and CYP2C9 to intra- and inter-population differences in maintenance dose of warfarin in Japanese, Caucasians and African-Americans. Pharmacogenet Genomics 2006; 16 (2): 101–10.