Gage Brian F, Bass Anne R, Lin Hannah, Woller Scott C, Stevens Scott M, Al-Hammadi Noor, Li Juan, Rodríguez Tomás, Miller J Philip, McMillin Gwendolyn A, Pendleton Robert C, Jaffer Amir K, King Cristi R, Whipple Brandi DeVore, Porche-Sorbet Rhonda, Napoli Lynnae, Merritt Kerri, Thompson Anna M, Hyun Gina, Anderson Jeffrey L, Hollomon Wesley, Barrack Robert L, Nunley Ryan M, Moskowitz Gerard, Dávila-Román Victor, Eby Charles S
Washington University in St Louis, St Louis, Missouri.
Hospital for Special Surgery, New York, New York.
JAMA. 2017 Sep 26;318(12):1115-1124. doi: 10.1001/jama.2017.11469.
Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown.
To determine whether genotype-guided dosing improves the safety of warfarin initiation.
DESIGN, SETTING, AND PATIENTS: The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016.
Patients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C92, CYP2C93, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment.
The primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty.
Among 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths.
Among patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing.
clinicaltrials.gov Identifier: NCT01006733.
在老年患者中，华法林导致的与用药相关的急诊科就诊次数比其他任何药物都多。基于基因型指导的华法林给药是否能预防这些不良事件尚不清楚。
确定基于基因型指导的给药是否能提高华法林起始治疗的安全性。
设计、地点和患者：预防深静脉血栓形成的华法林随机临床基因信息试验（GIFT）纳入了年龄在65岁及以上、因择期髋关节或膝关节置换术开始使用华法林的患者，该试验在美国的6个医疗中心进行。招募于2011年4月开始，随访于2016年10月结束。
对患者进行以下多态性的基因分型：VKORC1 - 1639G>A、CYP2C92、CYP2C93和CYP4F2 V433M。采用2×2析因设计，患者在治疗的第1至11天被随机分配到基于基因型指导（n = 831）或临床指导（n = 819）的华法林给药组，并将目标国际标准化比值（INR）设定为1.8或2.5。华法林的推荐剂量为开放标签，但患者和临床医生对研究组分配情况不知情。
主要终点是大出血、INR为4或更高、静脉血栓栓塞或死亡的复合情况。患者在关节置换术后约1个月接受一次筛查下肢双功超声检查。
在1650例随机分组的患者中（平均年龄72.1岁[标准差5.4岁]；63.6%为女性；91.0%为白人），1597例（96.8%）接受了至少1剂华法林治疗并完成试验（基因型指导组808例，临床指导组789例）。基因型指导组共有87例患者（10.8%），临床指导华法林给药组有116例患者（14.7%）达到至少1个终点（绝对差异3.9%[95%CI，0.7% - 7.2%]，P = 0.02；相对率[RR]，0.73[95%CI，0.56 - 0.95]）。基因型指导组与临床指导组的个体事件数量分别为：大出血2例对8例（RR，0.24；95%CI，0.05 - 1.15），INR为4或更高56例对77例（RR，0.71；95%CI，0.51 - 0.99），静脉血栓栓塞33例对38例（RR，0.85；95%CI，0.54 - 1.34），且无死亡病例。
在接受择期髋关节或膝关节置换术并接受围手术期华法林治疗的患者中，与临床指导给药相比，基于基因型指导的华法林给药降低了大出血、INR为4或更高、静脉血栓栓塞或死亡的综合风险。需要进一步研究以确定个性化华法林给药的成本效益。
clinicaltrials.gov标识符：NCT01006733。
