Impact of Age, CYP2C9 Genotype and Concomitant Medication on the Rate of Rise for Prothrombin Time During the First 30 Days of Warfarin Therapy

Abstract

Objectives:To characterize the impact of several important clinical variables on the rate of anticoagulation during warfarin initiation (i.e., the first 30 days).Design: Retrospective study.Setting: An anticoagulation service of a large horizontally integrated, multispecialty group practice in central and northern Wisconsin. Participants:Patients with sufficient laboratory data obtained during the initiation phase of warfarin treatment. Methods:Patients were consented and genotyped for cytochrome P450 (CYP) 2C9 polymorphisms. Anticoagulation laboratory data were then electronically abstracted and fitted to a logistic growth model. Rate of anticoagulation was compared between groups.Results: During warfarin initiation, the mean slope for rise in International Normalized Ratio (INR) of prothrombin time was significantly associated with age (p=0.03, n=166). Because a relationship between diabetes and warfarin dosing has been suggested previously, we assessed the impact of this comorbidity in our model as well. Diabetes showed relatively little impact, but concomitant treatment with an anti-diabetic sulfonylurea medication was associated with an increase in slope (3-fold, p<0.05).

Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy

“…Variants in these 2 genes affect warfarin dose requirements at steady state substantially [6][7][8][9][10][11][12][13][14][15][16][17]20,21 ; moreover, at the start of warfarin therapy, VKORC1 and, to a lesser extent, CYP2C9 genotypes also affect early INR responses. 22,23 The clinically useful contribution of genotype to individualizing warfarin dose will probably be greatest in the initiation phase of therapy, before a person's dose requirement has been determined empirically by titration according to INR response. However, the genetic contribution to warfarin dose requirements has most often been studied using steady-state dose requirements in patients already receiving stable doses of warfarin, without considering the information provided by the early INR responses during initiation of warfarin therapy.…”

Pharmacogenetics: potential role in the treatment of diabetes and obesity

“…A retrospective study of 68 cases and 69 controls suggested that variation in a candidate gene for drug metabolism (CYP3A5) may alter the degree of creatine kinase (a marker of muscle damage) in atorvastatin-induced myositis [80]. Other genes have been implicated in statin-induced myositis including COQ2, which is involved in the ubiquitylation pathway [81].…”

Evaluation of the VKORC 1 and CYP2C9 Gene Polymorphisms and Their Effects on the Emergency Complications in the Patients Using Warfarin

“…VKORC1 is a gene and its polymorphism belonging to vitamin K epoxide reductase enzyme enabling vitamin K to be formed from reduced vitamin K epoxide. It has recently been reported that there are a lack of a resistance to warfarin (2), whereas the most common mutations that affect the dosage regulation of warfarin in VKORC 1 genotypes are 1173, 3730, and -1639 single nucleotide polymorphisms (5)(6)(7)(8). Another important genetic factor is CYP2C9, a liver enzyme that plays a role in the oxidative metabolism of many other drugs as well as warfarin, and a series of gene polymorphisms were identified in the CYP2C9 gene area (3,4).…”