Background Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring
Background Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Results The 420 C>T substitution of CYP2C9*2, the 1075 A>C substitution of CYP2C9*3 and the 1173 C>T substitution of VKORC1 had minor allele frequencies of, 11.3%, 5.7% and 36.6% respectively. Warfarin weekly dose varied between 17 mg and 74 mg among the patients. INR did not vary between genotypes. Warfarin dosage requirement was significantly associated with CYP2C9 and VKORC1 genotypes, treatment group and age. The VKORC1 genotype contributed 24.5% to the interindividual variation in warfarin dosage, whereas the combined CYP2C9 genotypes were only responsible for 7.2% of the dose variation. Conclusion CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have comparable impact on warfarin maintenance dose. Background Warfarin and aspirin (ASA) have a well established role in secondary prevention of atherothrombotic disease, reducing new thromboembolic events [1-4]. However, response to anticoagulant treatment varies between individuals, requiring careful monitoring in order to keep international normalized ratio (INR) within a narrow therapeutic range. In spite of adherence to dosage regimens, INR values have been observed to be outside the target range 50% of the time [5,6], and this could possibly lead to treatment failure or adverse events. An important issue is to improve anticoagulation treatment in order to avoid thrombosis and treatment-induced bleeding. Warfarin antagonizes the vitamin K-dependent activation of a range of coagulation factors (II, VII, IX, X) and anticoagulants (protein C, protein S), and INR is used as an indicator of coagulation status. Two gene products known to influence warfarin dose are the enzymes Cytochrom P 450 subtype 2C9 (CYP2C9) and the Vitamin K 874101-00-5 supplier Epoxide Reductase 1 (VKORC1), which are involved in drug metabolism and vitamin K activation, respectively. Common 874101-00-5 supplier gene polymorphisms exist for both enzymes, resulting in marked alteration of enzyme activity, and several studies have characterized the role of these polymorphisms in explaining a substantial part of the variation in warfarin dosage requirement [7-15]. In the study of Aithal et al. , carriers of CYP2C9 gene polymorphisms were affected by bleeding complicatins more often than non-carriers during warfarin treatment. In the WARIS-II study, warfarin alone or in combination with low dose ASA (75 mg daily) were superior to 160 mg ASA in prevention of new thrombotic events after acute myocardial infarction, but was also associated with higher risk of bleeding . Thus, 15.0 C 16.7% of the patients in the warfarin groups experienced the primary endpoint (new thrombotic events or fatal bleeding) and 11.3C13.1% experienced minor or major nonfatal bleeding during four years treatment. In comparison, ASA alone resulted in new thrombotic events in 20% of the patients and minor or major nonfatal bleeding in 4.0%. It is not known whether different frequencies of gene polymorphisms in the treatment groups contributed to the differences in bleeding risk. The primary aim of the present study was 874101-00-5 supplier to investigate the relation between genotypes of CYP2C9 and VKORC1 and warfarin maintenance dose in myocardial infarction patients (from the WARIS-II study). The secondary aim was to relate the genotypes to international normalized ratio (INR). Methods Patients This substudy was established from the Warfarin Aspirin Reinfarction Study (WARIS-II), a Norwegian multicenter study, comparing three different antithrombotic regimens on clinical end-points of mortality, reinfarction and cerebral stroke after acute myocardial infarction . All patients provided written informed consent before participation in the study. Three groups of patients were randomly assigned to treatment with either a daily dose of 160 mg ASA (Albyl E, Nycomed Pharma, Norway), warfarin (Marevan, Nycomed Pharma) with a target international normalized 874101-00-5 supplier ratio (INR) of 2.8 to 4.2, or 75 mg of ASA combined with warfarin (target INR 2.0 C 2.5) and followed for CDK4 4 years. Coagulation status of the warfarin patients was controlled by recording INR systematically. The present populace consisted of totally 212 patients from the Oslo subset of the study at Ullevaal University Hospital, from whom we acquired blood samples for genotyping..