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...

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Warfarin anticoagulation is complicated by the highly variable inter-individual response. Approximately 50% of the dose variability arises from clinical factors and variants in two genes, CYP2C9 (*2 and *3 variants) and VKORC1 -1173 C > T. We tested variants in five additional genes (EPHX1, PROC, APOE, CYP4F2, CALU and a new variant in VKORC1 in an attempt to further reduce the variability in predicted stable warfarin dose. Consecutive consenting outpatients requiring anticoagulation on stable warfarin dose (target INR 2-3) were genotyped; the association of SNP genotypes with stable warfarin dose was evaluated using the test of linear contrasts in analysis of variance (ANOVA). Study participants were 71 ± 13 years, 53% female, 85 ± 23 kg, body mass index 29 ± 7 kg/m(2). Genotypes were in Hardy-Weinberg equilibrium with the exception of VKORC1 -1639. Weekly stable dosages were 31.7 ± 13.9 mg/week; median: 30 mg/week, range: 11-70 mg/week. Significant associations with dose were seen for VKORC1 -1639 (P < 0.001), CYP2C9*2 (P = 0.005) and *3 (P = 0.003), the CYP4F2 SNP (P-trend = 0.00037), and VKORC1 3730 (p-trend = 0.042). In linear regression, age, sex, weight, and CYP2C9 *2 and *3 and VKORC1-1639 genotype explained 42% of variance. The addition of CYP4F2 genotype to the regression model increased the degree of variance explained to 47%. Addition of VKORC1 SNP -1639 to a model eliminated the association of VKORC1 3730 with warfarin dose (P-trend = 0.74), but -1639 remained highly significant. No impact on dose was observed for the other tested genetic variants.

HBO2 therapy reduces cognitive sequelae after CO poisoning in the absence of the epsilon4 allele. Because apolipoprotein genotype is unknown at the time of poisoning, we recommend that patients with acute CO poisoning receive HBO2.