华法林基因指导剂量的随机试验。
A randomized trial of genotype-guided dosing of warfarin.
机构信息
From the University of Liverpool (M.P., G.B., A.L.J., C.H.T., J.E.Z., P.R.W.) and Royal Liverpool and Broadgreen University Hospital National Health Service (NHS) Trust (M.P., C.H.T.), Liverpool, Whiston Hospital, Prescot (T.N.), and Newcastle upon Tyne NHS Trust (P.K.) and Newcastle University (J.B.L., A.K.D., P.A., F.K.), Newcastle upon Tyne - all in the United Kingdom; Uppsala University, Department of Medical Sciences (N.E., C.C., H.K., M.W.), Uppsala Clinical Research Center (N.E.) and Uppsala University Hospital (C.C., B.W., M.W.), Uppsala, and Enköping Hospital, Enköping (C.S.) - all in Sweden; and Utrecht University, Utrecht, the Netherlands (A.H.M.Z.).
出版信息
N Engl J Med. 2013 Dec 12;369(24):2294-303. doi: 10.1056/NEJMoa1311386. Epub 2013 Nov 19.
BACKGROUND
The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.
METHODS
We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C92, CYP2C93, and VKORC1 (-1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.
RESULTS
A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).
CONCLUSIONS
Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy. (Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.).
背景
在开始使用华法林治疗时，很难预测固定剂量方案的抗凝效果。我们前瞻性比较了基因指导剂量与标准剂量对开始华法林治疗的患者抗凝控制的影响。
方法
我们进行了一项多中心、随机、对照试验，纳入了心房颤动或静脉血栓栓塞患者。使用即时检测法进行 CYP2C92、CYP2C93 和 VKORC1（-1639G→A）的基因分型。对于分配到基因指导组的患者，在前 5 天根据基于药物遗传学的算法开具华法林剂量。对照组（标准剂量）患者接受 3 天的负荷剂量方案。启动期后，所有患者的治疗均根据常规临床实践进行管理。主要结局指标是华法林启动后 12 周内国际标准化比值（INR）在治疗范围内（2.0 至 3.0）的时间百分比。
结果
共招募了 455 名患者，其中 227 名随机分配到基因指导组，228 名分配到对照组。基因指导组 INR 治疗范围内的时间百分比为 67.4%，而对照组为 60.3%（调整差异为 7.0 个百分点；95%置信区间为 3.3 至 10.6；P<0.001）。基因指导组过度抗凝（INR≥4.0）的发生率明显较低。基因指导组达到治疗 INR 的中位时间为 21 天，而对照组为 29 天（P<0.001）。
结论
与标准剂量相比，基因指导剂量与华法林治疗启动时 INR 治疗范围内的时间百分比更高。（由欧盟第七框架计划和其他机构资助；ClinicalTrials.gov 编号，NCT01119300。）
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