期刊
BMC MEDICINE
卷 16, 期 -, 页码 -出版社
BMC
DOI: 10.1186/s12916-018-1093-8
关键词
Pharmacogenetics; Pharmacogenomics; Precision medicine; CYP2C9; Cytochrome P450; VKORC1; Warfarin; Anticoagulants; Anticoagulation; Polymorphism
资金
- Singapore Ministry of Health's National Medical Research Council [NMRC/CSA/021/2010, NMRC/CSA/0048/2013]
- Biomedical Research Council of the Agency for Science, Technology and Research (A*STAR) [SPF2014/001]
- National Research Foundation Singapore
- Singapore Ministry of Education under their Research Centres of Excellence Initiative
Background: Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved. Methods: An open-label, non-inferiority, 1: 1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy. Results: Among 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2. 93, difference - 1.16, 90% CI - 1.48 to - 0.84, P < 0.001 for both non-inferiority and superiority). The percentage of time within the therapeutic range over 3 months and median time to stable international normalized ratio (INR) did not differ between the genotype-guided and traditional dosing groups. The frequency of dose titrations (incidence rate ratio 0.76, 95% CI 0.67 to 0.86, P = 0.001), but not frequency of INR measurements, was lower at 1, 2, and 3 months in the genotype-guided group. The proportions of patients who experienced minor or major bleeding, recurrent venous thromboembolism, or out-of-range INR did not differ between both arms. For predicting maintenance doses, the pharmacogenetic algorithm achieved an R-2 = 42.4% (P < 0.001) and mean percentage error of - 7.4%. Conclusions: Among Asian adults commencing warfarin therapy, a pharmacogenetic algorithm meets criteria for both non-inferiority and superiority in reducing dose titrations compared with a traditional dosing approach, and performs well in prediction of actual maintenance doses. These findings imply that clinicians may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages in Asian patients.
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