Easton Cardiovascular Associates, Easton, PA, USA.
Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.
Sci Rep. 2019 Sep 6;9(1):12856. doi: 10.1038/s41598-019-49329-0.
Warfarin is a widely used anticoagulant with a narrow therapeutic index and large interpatient variability in the therapeutic dose. Complications from inappropriate warfarin dosing are one of the most common reasons for emergency room visits. Approximately one third of warfarin dose variability results from common genetic variants. Therefore, it is very necessary to recognize warfarin sensitivity in individuals caused by genetic variants. Based on combined polymorphisms in CYP2C9 and VKORC1, we established a clinical classification for warfarin sensitivity. In the International Warfarin Pharmacogenetic Consortium (IWPC) with 5542 patients, we found that 95.1% of the Black in the IWPC cohort were normal warfarin responders, while 74.8% of the Asian were warfarin sensitive (P < 0.001). Moreover, we created a clinical algorithm to predict warfarin sensitivity in individual patients using logistic regression. Compared to a fixed-dose approach, the clinical algorithm provided significantly better performance. In addition, we validated the derived clinical algorithm using the external Easton cohort with 106 chronic warfarin users. The AUC was 0.836 vs. 0.867 for the Easton cohort and the IWPC cohort, respectively. With the use of this algorithm, it is very likely to facilitate patient care regarding warfarin therapy, thereby improving clinical outcomes.
华法林是一种广泛应用的抗凝药物，治疗指数较窄，治疗剂量的个体间差异较大。华法林剂量不当导致的并发症是急诊科就诊最常见的原因之一。大约三分之一的华法林剂量差异是由常见的遗传变异引起的。因此，识别由遗传变异引起的个体对华法林的敏感性是非常必要的。基于 CYP2C9 和 VKORC1 的联合多态性，我们建立了一种用于评估华法林敏感性的临床分类。在包含 5542 名患者的国际华法林药物基因组学联合会（IWPC）中，我们发现 IWPC 队列中的黑人中有 95.1%是正常华法林反应者，而亚洲人中有 74.8%对华法林敏感（P<0.001）。此外，我们使用逻辑回归创建了一种用于预测个体患者对华法林敏感性的临床算法。与固定剂量方法相比，该临床算法提供了更好的性能。此外，我们使用包含 106 名慢性华法林使用者的外部伊斯顿队列验证了推导的临床算法。AUC 分别为 0.836 和 0.867，用于伊斯顿队列和 IWPC 队列。使用该算法，很可能有助于华法林治疗患者的护理，从而改善临床结局。
