The International Warfarin Pharmacogenetics Consortium comprises 21 research groups from 9 countries and 4 continents. The research groups contributed clinical and genetic data for a total of 5700 patients who were treated with warfarin. These data were curated (i.e., collected, formatted, and subjected to quality control) by staff at the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB, www.pharmgkb.org) and by members of the consortium. The cohort whose data were analyzed for this study included the subgroup of 5052 patients who had a target international normalized ratio (INR) of 2 to 3. The requirement for informed consent was waived because consent had been obtained previously by each participating center, and only de-identified data were used in the study.
We collected data on clinical factors that have previously been associated with warfarin therapy and that were available from the information received from all or most sites. These data included information on demographic characteristics, the primary indication for warfarin treatment, the stable therapeutic dose of warfarin, the treatment INR (the INR achieved with a stable warfarin dose), the target INR (the desired INR), the use of concomitant medications (grouped according to those that increase and those that decrease the INR), and the presence of genotype variants of CYP2C9 (*1, *2 and *3) and VKORC1 (at least one of seven single nucleotide polymorphisms [SNPs] in linkage disequilibrium11 (link)), as detailed in Section 1 in Supplementary Appendix 1, available with the full text of this article at NEJM.org. Information on race or ethnic group was reported by the patient or determined by the local investigator. Several potentially important variables (e.g., vitamin K intake and smoking status) were not consistently available and thus were not included. Data on adverse events such as thromboembolic events or bleeding or the need for repeated measurements of the INR before a stable dose was achieved were not available for this study. The outcome variable was the stable therapeutic dose of warfarin, defined as the steady-state dose that led to stable anticoagulation levels. Although the centers used different definitions for steady-state dose, most centers required stable levels of anticoagulation (i.e., INR) over a period during which the dose of warfarin was stable (Section 2 in Supplementary Appendix 1).