Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation

Article

关键词: REDUCTASE COMPLEX SUBUNIT-1;    MOLECULAR-WEIGHT HEPARIN;    VENOUS THROMBOEMBOLISM;    DOSE REQUIREMENTS;    HUMAN GENOME;    CYP2C9;    THERAPY;    PHARMACOGENETICS;    VKORC1;    CYTOCHROME-P450;   

DOI  :  10.1161/CIRCULATIONAHA.107.737312

来源: SCIE

【 摘 要 】

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 (n=206) being initiated on warfarin were randomized to pharmacogenetic-guided 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. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses ( P<0.001), resulting in smaller ( P=0.002) and fewer (P=0.03) dosing changes and INRs (P=0.06). However, percent out-of-range INRs (pharmacogenetic=30.7%, standard=33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P=0.001) and multiple variant carriers (who required smaller doses; P<0.001) in exploratory analyses, results (pharmacogenetic=29%, standard=39%) achieved nominal significance (P=0.03). Multiple variant allele carriers were at increased risk of an INR of >= 4 (P=0.03). Conclusions-An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.

【 授权许可】

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