Genetic polymorphisms and dosing of vitamin K antagonist in Indian patients after heart valve surgery

Vitamin K antagonists (VKAs), such as warfarin and acenocoumarol, exert their anti-coagulant effect by inhibiting the subunit 1 of vitamin K epoxide reductase complex (VKORC1). CYP2C9 is a hepatic drug-metabolizing enzyme in the CYP450 superfamily and is the primary metabolizing enzyme of warfarin. Three single nucleotide polymorphisms, two in the CYP2C9 gene, namely CYP2C9*2 and CYP2C9*3, and one in the VKORC1 gene (c.− 1639G > A, rs9923231), have been identified to reduce VKA metabolism and enhance their anti-coagulation effect. The purpose of this study is to evaluate the prevalence of CYP2C9 and VKORC1 polymorphism in Indians receiving VKA-based anti-coagulation after valve surgery and to evaluate the usefulness of genetic information in managing VKA-based anti-coagulation.

In the current prospective observational study, 150 patients who underwent heart valve surgery and had stable INR were genotyped for VKORC1 (− 1639 G > A), CYP2C9*2, and CYP2C9*3. The VKA dosage was estimated from published algorithms and compared to the clinically stabilized dosage.

Out of 150 patients, 101 (67.33%) were on warfarin and 49 (32.66%) were on acenocoumarol. Majority of the patients, the 83 in warfarin group and the 40 in acenocoumarol group, had a wild CYP2C9 diplotype. The rest had a mutant (CYP2C9*2 or CYP2C9*3) diplotype. Similarly, 67 patients in the warfarin group and 35 patients in the acenocoumarol group had wild type (G/G) of VKORC1 genotype. The rest had a mutant (G/A or A/A) VKORC1 genotype. In the warfarin group, based on the genotype, 51.5% of the patients were extensive or normal metabolizers, and 47.4% of the patients were intermediate metabolizers of VKAs. In the acenocoumarol group, 61.2% of the patients were extensive or normal metabolizers, and 38.8% of the patients were intermediate metabolizers. Individually, alleles of VKORC1 (− 1639 G > A), CYP2C9*2, and CYP2C9*3 had mean dosage reduction effect on VKA dosage, which co-related to the clinically stabilized dosages (P < 0.0001). Among the VKORC1 (− 1639 G > A) cohort, the reduction in warfarin mean weekly dosage was 13.48 mg as compared to the wild-type category (P < 0.0001) and similarly, the reduction in the mean weekly acenocoumarol dose was 6.07 mg (P < 0.03) as compared to the wild type after adjusting for age, gender, and body mass index.

Single nucleotide polymorphism in the CYP2C9 gene and in the VKORC1 gene is present in nearly 40% of Indian patients. VKORC1 (− 1639 G > A), CYP2C9*2, and CYP2C9*3 genotypes have significant dosage-lowering effects on VKA-based anti-coagulation therapy. The trend in estimated dosages of VKAs co-related to that of observed the clinically stabilized dosage in the cohort. The pharmacogenomic calculators used in this study tend to overestimate the VKA dosages as compared to clinical dosage due to the limitations in the algorithms and in our study. A new algorithm based on a larger dataset capturing the vast genetic variability across the Indian population and relevant clinical factors could provide better results.