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.