Abstract 2870: Influence Of The Vkorc1 And Cyp2c9 Genotypes On The Frequency Of Bleeding And Maintenance Warfarin Dose In Russian Population
Purpose: Warfarin (W) is a highly effective drug for prevention and treatment of arterial and venous thromboembolic disorders. Bleeding is the most important complication of the oral anticoagulation. We investigated the genetic predictors of the bleeding complications in patients on long-term adjusted-dose W therapy.
Methods: The study included 86 pts (46 male), age 62,8±10,6(SD) years receiving long-term W therapy (international normalized ratio (INR) 2-3). The observation duration was from 1 month to 1 year. CYP2C9 (CYP2C9*2 and CYP2C9*3), VKORC1 G3673A genotypes were identified by the polymerize chain reaction. The indications for W therapy were: atrial fibrillation-83,7% (CHADS2 2±1,3);deep venous thrombosis-7%; LV thrombus-4,65%; prosthetic heart valve-4,65%. Arterial hypertension had 62% of pts, coronary artery disease (CAD)- 26%, congestive heart failure (NYHA II-IV)- 30%, previous ischemic stroke-12% and diabetes- 8%.
Results: The frequency of VKORC1 GG, VKORC1 GA and VKORC1 AA were 31%, 55% and 14 %, respectively. The frequency of CYP2C9*1, CYP2C9*2 and CYP2C9*3 were 67,8%, 15,5% and 14,3%. 2 pts (2,4%) had CYP2C9*2/*3 genotype. The mean W daily dose was the highest in wild-type pts (CYP2C9*1/*1 and VKORC1 GG genotypes together): 7±2,18 mg/day as compared with pts with only one: 5,1±1,85 mg/day (p=0,006) or combination of a VKORC1 and a CYP2C9 polymorphism: 3,4±1,37 mg/day (p=0,03). The carriers of the combination of VKORC1 and CYP2C9 polymorphism demonstrated higher frequency of the INR fluctuation (INR>3) as compared with wild-type pts: 81% vs 38% (p=0,03). Only the carriers of the combination of GA/AA and CYP2C9*3 genotypes had higher frequency of bleedings as compared with wild-type pts: 67% vs 12,5% (p=0,03), respectively. The possession of the VKORC1 AA and/or CYP2C9*3 genotypes, mean INR>2,5 during observation period, female gender and CAD were predictors of bleeding events according to the multivariate discriminant analysis (p<0,00001).
Conclusions: The carriers of the combination of VKORC1 and CYP2C9 polymorphism required lower maintenance W dose and demonstrated more INR fluctuations. Only the carriers of the combination of VKORC1 GA/AA and CYP2C9*3 genotypes demonstrated more bleedings. The possession of VKORC1 AA and/or CYP2C9*3 genotypes was one of the predictors of bleeding events on W therapy.
- © 2012 by American Heart Association, Inc.