Summary of Recent Articles of Interest

Abstract

Received April 21, 2009; accepted April 21, 2009. 1. International Warfarin Pharmacogenetics Consortium; Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009;360:753–764. PMID: 19228618. ### Study Hypothesis Interindividual variation in the response to warfarin therapy is in part determined by genetic factors. Specifically, variation in 2 genes, CYP2C9 (encoding cytochrome P450, family 2, subfamily C, and polypeptide 9) and VKORC1 (encodes vitamin K epoxide reductase complex subunit-1), are known to affect warfarin dose requirements. It is conceivable that an algorithm including genetic predictors in addition to clinical information improves warfarin dose estimation incrementally over algorithms based on clinical data alone. ### How Was the Hypothesis Tested? Within the International Warfarin Pharmacogenetics Consortium, 5052 participants with a target international normalized ratio of 2 to 3 were selected for analyses. Of the eligible patients, 80% (n=4043) were randomly selected as the “derivation cohort,” the remaining 20% (n=1009) constituted the “validation cohort.” After evaluating different statistical models, a least-squares linear regression model (with the square root of warfarin dose as the dependent variable) best fit the data and was used for further analyses. Three models were compared in their ability to predict the therapeutic warfarin dose (defined as the steady-state dose leading to stable anticoagulation levels): a clinical model (including information about age, height, weight, race, enzyme inducer status, and Amiodarone use status), a fixed-dose model (5 mg per day), and a pharmacogenetic model that included CYP2C9 and VKORC1 genotypic information in addition to the above-described clinical covariates. Furthermore, the performance of the 3 algorithms was evaluated in 3 subgroups based on the weekly warfarin dose: ≤21, >21 and <49, and ≥49 mg per week. To evaluate the models’ predictive accuracy, the …