Background - Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. Methods - We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were 18 years or older, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range (%TTR) of the international normalized ratio (INR) during the first 12 weeks after starting warfarin therapy. Results - A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher %TTR than the control group (58.8% vs. 53.2%, 95% confidence interval of group difference (95%CI): 1.1-10.2; P=0.01). The genotype-guided dosing group also achieved the target INR sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher %TTR during the first 12 weeks compared to the control group (60.8% vs. 48.9%; 95% CI: 1.1-24.4). The incidence of adverse events was low in both groups. Conclusions - The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China.

Abstract.Warfarin is an oral anticoagulant with significant interpatient variability in dosage. A large number of studies have confirmed that the individual warfarin dose is mainly affected by the cytochrome P450 complex subunit 2C9 and vitamin K epoxide reductase complex subunit 1. However, the association between cytochrome P450 4F2 (CYP4F2) gene polymorphisms and warfarin dosage in the Asian population remains controversial. To investigate the impact of the CYP4F2 polymorphism rs2108622 (p.V433M) on warfarin dose requirement, a systematic review and meta-analysis were conducted. According to the strict inclusion and exclusion criteria set, a comprehensive literature search was performed, and the studies published before August 5, 2015 were searched for in PubMed, EMBASE and the China National Knowledge Infrastructure databases. The references were checked by two independent reviewers. The association between the warfarin maintenance dose and CYP4F2 polymorphism was analyzed. Twenty-two studies were included in the meta-analysis. Compared with the CYP4F2 genotype CC, carriers of the CT and TT genotypes required a 9 [95% confidence interval (CI): 6.0-13.0] and 20% (95% CI, 13.0-27.0) higher warfarin dose, respectively. In the combined analysis, T carriers (CT+TT) required an 11% (95% CI, 8.0-14.0) higher warfarin dose compared to the CC genotype. In addition, there was a 10% (95% CI, 5.0-15.0) higher warfarin dose in TT carriers compared to the CT genotype (all P<0.05). The results of the meta-analysis suggest that the effects of the CYP4F2 polymorphism on individual warfarin dose have a statistically significant difference, and the effect degree is variable in the subgroups. Further studies are expected to explore whether the pharmacogenetics model including the CYP4F2 polymorphism can strengthen the prediction of warfarin dose. IntroductionWarfarin is a commonly oral anticoagulant, mainly used clinically in the treatment of thromboembolic diseases, such as atrial fibrillation (AF) and deep venous thrombosis (DVT); however, the existence of high interpatient variability in drug dosage may increase the risk of bleeding or thrombosis. Studies indicated that individual warfarin dose was influenced by a host of factors, including genetic and environmental factors. Genetic factors are one of the main reasons for the individual difference in warfarin maintenance dosage. Previous studies have also suggested that cytochrome P450 complex subunit 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) polymorphisms, age, weight and body surface area can explain ~50% of the influence on warfarin dose requirement (1-6). Therefore, there remains a 50% uncertainty of the other factors to be further explored.The cytochrome P450 4F2 (CYP4F2) gene, consisting of 13 exons and 12 introns and encoding 520 amino acid residues, is located on chromosome 19p13.12 in humans. Studies have shown that there are numerous single-nucleotide polymorphisms (SNPs) in the CYP4F2 gene open reading frame, such as rs2108622, rs2074...

This is the first meta-analysis of the association between APOE genotypes and warfarin dose. APOE E2/E2 might be one of the factors affecting warfarin dose requirements. The effect of APOE may vary between ethnicities.

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