Using Pharmacogenetics in Real Time to Guide Warfarin Initiation

Abstract

A 75-year-old white woman is initiated on warfarin for atrial fibrillation. Empirical dosing generally would begin with 5 mg/d.1 If age, weight (132 kg), and height (63 in) are taken into account, the maintenance dose is estimated at 3.5 to 4 mg/d. In this case, a pharmacogenetic approach is chosen to guide initial dose selection. To augment clinical information, a rapid-turnaround assay (<4 hours) is used. Genotyping for CYP2C9 identifies the *2 CC (wild-type) and *3 AC (reduced-function heterozygote) alleles; genotyping for VKORC1 identifies an AA variant (reduced-function homozygote). With the use of a freely available Web-based algorithm (www.warfarindosing.org), a daily maintenance dose of 1.8 mg is calculated, with an optional miniloading dose of 2.7 mg/d on day 1. These calculated doses are rounded to doses of 2.5 mg on day 1 and 2.0 mg on days 2 and 3. A prothrombin time international normalized ratio (INR) measurement is planned on day 4 to guide dose adjustment if needed. Empirical dosing or dosing using only clinical characteristics would likely result in excessive anticoagulation with an increased risk of early out-of-range INRs and bleeding. Since its introduction as the mainstay of oral anticoagulation therapy, warfarin has achieved an unfavorable reputation among physicians and patients alike. This relates to the difficulty in achieving and maintaining the narrow therapeutic range of the drug (commonly INR of 2–3), a process that requires frequent INR testing and dose adjustment. Even dedicated anticoagulation clinics achieve a time in therapeutic range of only ≈60%. A major cause of this challenge is highly variable interindividual dosing requirements. Subtherapeutic anticoagulation may lead to thromboembolic events, whereas excessive anticoagulation increases the risk of bleeding. Not surprisingly, some of the most commonly reported drug-associated adverse events are warfarin related.2 An important part of interindividual dose variability arises from variation …