Impact of age, CYP2C9 genotype and concomitant medication on the rate of rise for prothrombin time during the first 30 days of warfarin therapy.

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). Since this drug interaction may occur at the level of CYP2C9, we also assessed the impact of CYP2C9 genotype in our model. The impact of CYP2C9 genotype was marginally significant (p = 0.119, non-pooled dataset; p = 0.053, data pooled for CYP2C9 *2/*2, *2/*3 and *3/*3). CONCLUSIONS: Age and concomitant sulfonylurea therapy alter the rate of anticoagulation during the first 30 days of warfarin therapy.

A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data.

BACKGROUND: Rapid genetic screening for cytochrome P450 (CYP) 2C9 variants may play a role in improving the efficacy and safety of warfarin in individuals with CYP2C9 variants. The feasibility of prospective CYP2C9 model-based warfarin dosing has not yet been assessed. OBJECTIVES: To evaluate the feasibility of applying a CYP2C9 gene-based warfarin dosing model in clinical practice. DESIGN: Prospective, randomized, single-blinded clinical pilot trial. SETTING: Large multispecialty group practice. PATIENTS: Candidates were recruited from a list of clinic patients eligible for warfarin initiation. This included patients with newly diagnosed thromboembolic disease or atrial arrhythmia, as well as patients anticipating elective valvuloplasty or arthroplasty. Patients who previously received warfarin were excluded. INTERVENTIONS: Subjects were randomized to receive either 1) a standard initiation dose of 5 mg warfarin/day, or 2) rapid CYP2C9 genotyping and an initiation dose determined using parameters estimated from a previously published multivariate model [including age, body size, co-morbidity (e.g., diabetes), clinical indication (e.g., valvuloplasty) and CYP2C9 genotype]. MEASUREMENTS: Primary outcome measurements were patient willingness to participate, physician willingness to refer, sample processing time, ability to administer calculated dosage and adequacy of follow-up. LIMITATIONS: This pilot trial was designed to assess the feasibility of model-based warfarin dosing. Power was insufficient for statistical comparison of adverse event rates. RESULTS: Forty-three of 117 patients had no prior warfarin treatment and were eligible. Five declined to participate. Twenty patients were randomized to a standard initiation dose of 5 mg daily. Eighteen patients were randomized to model-based dosing. All but one participant received the assigned initiation dose. Blood draw to dosage calculation time (including genotyping) required approximately 4 hours. Six adverse events occurred within the standard dosing group, and two adverse events occurred within the model-based dosing group. CONCLUSIONS: Prospective application of a multivariate CYP2C9 gene-based warfarin dosing model is feasible.

Relative impact of covariates in prescribing warfarin according to CYP2C9 genotype.

Patients on warfarin anticoagulant therapy demonstrate wide variation in maintenance dose. Patients possessing variants (*2 and *3) of the cytochrome P450 2C9 gene require reduced maintenance doses compared to those having wild-type alleles (*1). Many other clinical factors have been shown to affect warfarin dose as well. To determine the relative impact of CYP2C9 genotype, age, gender, body surface area, concomitant medication, treatment indication and comorbidity, we conducted a retrospective cohort study in 453 patients managed by the anticoagulation service of a large, horizontally integrated, multispecialty group practice. In this largely Caucasian patient population, the CYP2C9 gene frequencies for *1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 were 65.1%, 19.0%, 12.1%, 1.6%, 1.8% and 0.4%, respectively, approximating Hardy-Weinberg equilibrium. Mean maintenance doses for these genotypes were 36.5, 29.1, 23.5, 28.0, 18.1 and 5.5 mg/week, respectively. In univariate analyses, genotype alone accounted for 19.8% of the variability in maintenance dose. Age, body surface area and male gender accounted for 14.6%, 7.5% and 4.7%, respectively, while cardiac valve replacement as the indication for warfarin accounted for 5.4% of the variability. Collectively, these factors accounted for 33.7% of all dosing variability according to multiple regression. These results will help strengthen the mathematical models that are currently being developed for prospective gene-based warfarin dosing.