The effect of VKORC1 (-1639 G>A) gene polymorphism and its related clotting factor IIa and Xa on warfarin therapy in patients with atrial fibrillation: a multi-ethnic Sarawak population study

Warfarin, the most frequently prescribed oral anticoagulant therapy management is challenging due to its narrow therapeutic index. It is associated with an increased risk of bleeding when overdose, while an insufficient dose may lead to thromboembolism or stroke. Due to the wide variation of response among patients, frequent monitoring of the efficacy of this drug through INR is essential. Recently emerged Novel Oral Anticoagulants (NOACs) have demonstrated to be non-inferior to warfarin therapy while abolishing the need for frequent blood INR testing. However, these are not commonly prescribed due to their current commercial pricing strategy with relatively limited indications compared to warfarin therapy, scenarios typically encountered in developing countries. Hence, there is a need to delineate a predictive model to determine the appropriate use of anticoagulant therapies in our country. This study aims to investigate the influences of coagulation factors (thrombin and Factor Xa) on poor TTR control patients while taking into account the impact of previously identified VKORC1 (-1639G>A) gene polymorphism. The VKORC1 AA genotype predominates in the multi-ethnic Sarawak population at a 71.5% majority. There was a significant difference in average daily warfarin dose (ADWD) between ethnic groups. Plasma thrombin levels were found to be significantly correlated with the TTR, ADWD, and BMI and were also found to be significantly higher in female patients but not plasma FXa levels. Majority of the patients with poor TTR<60% were on alternate dosing regimen with subtherapeutic INR readings. Multivariate analysis showed that alternate dosing regimen and plasma thrombin levels were independently associated with TTR while the VKORC1 (-1639G>A) gene polymorphism, diabetes mellitus, age and BMI are independent predictors or ADWD. Hence, it is demonstrated that the VKORC1 (-1639G>A) gene polymorphism together with other atrial fibrillation risk factors may be a strong predictive variable for ADWD, while the plasma thrombin levels may be a potential candidate marker in reflecting the quality of anticoagulation control based on TTR. Together, both models may be adopted to delineate a new strategy to determine who may potentially benefit from switching warfarin to the new NOACs.