Background-Pharmacogenetic-guided dosing of warfarin is a promising application of "personalized medicine" but has not been adequately tested in randomized trials. Methods and Results-Consenting patients (nϭ206) being initiated on warfarin were randomized to pharmacogeneticguided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1 C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight.

Background-Warfarin is characterized by marked variations in individual dose requirements and a narrow therapeutic window. Pharmacogenetics (PG) could improve dosing efficiency and safety, but clinical trials evidence is meager. Methods and Results-A Randomized and Clinical Effectiveness Trial Comparing Two Pharmacogenetic Algorithms andStandard Care for Individualizing Warfarin Dosing (CoumaGen-II) comprised 2 comparisons: (1) a blinded, randomized comparison of a modified 1-step (PG-1) with a 3-step algorithm (PG-2) (Nϭ504), and (2) a clinical effectiveness comparison of PG guidance with use of either algorithm with standard dosing in a parallel control group (Nϭ1866). A rapid method provided same-day CYP2C9 and VKORC1 genotyping. Primary outcomes were percentage of out-of-range international normalized ratios at 1 and 3 months and percentage of time in therapeutic range. Primary analysis was modified intention to treat. In the randomized comparison, PG-2 was noninferior but not superior to PG-1 for percentage of out-of-range international normalized ratios at 1 month and 3 months and for percentage of time in therapeutic range at 3 months. However, the combined PG cohort was superior to the parallel controls (percentage of out-of-range international normalized ratios 31% versus 42% at 1 month; 30% versus 42% at 3 months; percentage of time in therapeutic range 69% versus 58%, 71% versus 59%, respectively, all PϽ0.001). Differences persisted after adjustment for age, sex, and clinical indication. There were fewer percentage international normalized ratios Ն4 and Յ1.5 and serious adverse events at 3 months (4.5% versus 9.4% of patients, PϽ0.001) with PG guidance. Conclusions-These findings suggest that PG dosing should be considered for broader clinical application, a proposal that is being tested further in 3 major randomized trials. The simpler 1-step PG algorithm provided equivalent results and may be preferable for clinical application. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00927862. Key Words: anticoagulants Ⅲ clinical trial Ⅲ genetics Ⅲ pharmacogenetics Ⅲ warfarin P harmacogenomics, the study of interactions of genetics with pharmacotherapy, is a promising area for applying genetics to personalized or precision medicine. [1][2][3] Warfarin is prescribed to over 2 million patients in the United States for prevention of thromboembolic events associated with atrial fibrillation, venous and arterial thrombosis, orthopedic surgery, and prosthetic heart valves. Unfortunately, clinical management is difficult because of a narrow therapeutic index and marked interpatient variability in drug pharmacokinetics and pharmacodynamics, which lead to unpredictable and variable (up to 10-fold or greater) dosing requirements. 4 Anticoagulation trials for nonrheumatic atrial fibrillation have determined the optimal prothrombin time international normalized ratio (INR) range to be 2 to 3 with ratios Ͻ2 increasing thrombotic events and those Ͼ4 increasing hemorrhagic events. 5...