Université Paris Descartes, Paris, France.
Clin Pharmacol Ther. 2010 Jan;87(1):57-64. doi: 10.1038/clpt.2009.178. Epub 2009 Sep 30.
Determining the optimal dose of warfarin for frail elderly patients is a challenging task because of the low dose requirements in such patients, the wide interindividual variability of response, and the associated risk of bleeding. The objective of this study was to address the influence of 13 common variations in eight genes on the maintenance dose of warfarin in a cohort of frail elderly inpatients. For our study, we enrolled 300 Caucasian subjects who were hospital inpatients, with a mean age of 86.7 +/- 6 years. In addition to age, genetic variants of VKORC1, CYP2C9, CYP4F2, and EPHX1 were found to be significant predictor variables for the maintenance dose of warfarin, explaining 26.6% of dose variability. Among 132 patients in whom warfarin therapy was initiated with the same low-dose regimen, we studied the relative influences of genetic and nongenetic factors. The time to first international normalized ratio (INR) > or =2 was influenced by VKORC1 and CYP2C9 genotypes (P = 0.0003 and P = 0.0016, respectively); individuals with multiple variant alleles were at highest risk for overanticoagulation (INR >4) (odds ratio, 12.8; 95% confidence interval, 2.73-60.0). In this special population of frail elderly patients with multiple comorbidities and polypharmacy, we demonstrated the main impact of genetic factors on warfarin response.
确定体弱老年患者华法林的最佳剂量是一项具有挑战性的任务，因为此类患者的剂量要求较低，个体间反应的差异较大，且出血风险较高。本研究的目的是探讨 8 个基因中的 13 个常见变异对华法林维持剂量在体弱老年住院患者中的影响。本研究纳入了 300 名高加索裔住院体弱老年患者，平均年龄为 86.7 +/- 6 岁。除年龄外，VKORC1、CYP2C9、CYP4F2 和 EPHX1 的基因变异也被发现是华法林维持剂量的显著预测变量，可解释 26.6%的剂量变异性。在 132 名接受相同低剂量方案起始华法林治疗的患者中，我们研究了遗传和非遗传因素的相对影响。首次 INR > 2 的时间受 VKORC1 和 CYP2C9 基因型的影响（P = 0.0003 和 P = 0.0016）；具有多个变异等位基因的个体发生过度抗凝（INR > 4）的风险最高（比值比，12.8；95%置信区间，2.73-60.0）。在患有多种合并症和多种药物治疗的体弱老年特殊人群中，我们证实了遗传因素对华法林反应的主要影响。
