Abstract
Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the therapeutic dose. Complications from inappropriate warfarin dosing are one of the most common reasons for emergency room visits. Approximately one third of warfarin dose variability results from common genetic variants. Therefore, it is very necessary to recognize warfarin sensitivity in individuals caused by genetic variants. Based on combined polymorphisms in CYP2C9 and VKORC1, we established a clinical classification for warfarin sensitivity. In the International Warfarin Pharmacogenetic Consortium (IWPC) with 5542 patients, we found that 95.1% of the Black in the IWPC cohort were normal warfarin responders, while 74.8% of the Asian were warfarin sensitive (P < 0.001). Moreover, we created a clinical algorithm to predict warfarin sensitivity in individual patients using logistic regression. Compared to a fixed-dose approach, the clinical algorithm provided significantly better performance. In addition, we validated the derived clinical algorithm using the external Easton cohort with 106 chronic warfarin users. The AUC was 0.836 vs. 0.867 for the Easton cohort and the IWPC cohort, respectively. With the use of this algorithm, it is very likely to facilitate patient care regarding warfarin therapy, thereby improving clinical outcomes.
Highlights
Warfarin is the most widely used oral anticoagulant worldwide
We developed a clinical algorithm to predict the warfarin sensitivity in patients without laboratory tests for CYP2C9 and VKORC1 polymorphisms using a large and diverse data set with patients around the world
Due to a narrow therapeutic index and interpatient variability, it is of great importance to recognize the warfarin response individually
Summary
Warfarin is the most widely used oral anticoagulant worldwide. There were more than 25 million prescriptions for warfarin in 20101 and about 7 to 8 million warfarin treatment visits annually between 2009 and 2014 in the United States[2]. Warfarin has a narrow therapeutic window and large interpatient variability with a 10- to 20-fold differences in the therapeutic dose required to achieve target International Normalized Ratio (INR) Because of these challenges associated with warfarin use, it is one of the leading causes in emergency department visits and the most often cited cause of drug-related mortality[3]. We developed a clinical algorithm to predict the warfarin sensitivity in patients without laboratory tests for CYP2C9 and VKORC1 polymorphisms using a large and diverse data set with patients around the world. We compared it with a fixed-dose strategy to determine whether the performance of the algorithm was significantly better. We validated the algorithm externally with an independent cohort to test how generalizable the algorithm is
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