Background

Safe administration of warfarin presents challenges due to a narrow therapeutic INR range and significant variability in inter-individual dose response. Bleeding secondary to warfarin use is a leading cause of hospitalization.

Methods

Five warfarin dosing algorithms were assessed for accuracy of predicted compared to the INR target dose for patients with a HAS-BLED score ≥3 participating in the ENGAGE-AF TIMI 48 trial. Three warfarin metabolism subgroups (normal, sensitive, and highly sensitive responders) were established based on genotype. Mean differences between calculated and prescribed dose were determined for each algorithm across groups.

Results

A total of 7036 patients were analyzed and 1846 participants with HAS-BLED ≥3 were genotyped. The mean absolute error of predicted versus INR target dose for warfarin ranged from 8.1 mg/week on the pharmacogenetic-guided International Warfarin Pharmacogenetics Consortium (IWPC) and Gage algorithms to 11.3 mg/week on fixed dose. Overestimation of INR target dose occurred in 98% of highly sensitive responders by 21 mg/week for subjects on fixed dose. Pharmacogenetic-guided IWPC saw 89% overestimation with mean difference of 8.3 mg/week for highly sensitive responders. Major or clinically relevant non-major bleeding in the first 90 days of beginning warfarin was 3.27 times more likely for highly sensitive than normal responders.

Conclusions

Initial doses were higher than INR target doses in high-risk bleeding subpopulations as defined by the modified HAS-BLED and genotype sensitivity analysis when compared to established algorithms. Clinical and pharmacogenetic-guided algorithms improved dosing in highly sensitive responders with HAS-BLED ≥3 compared to fixed dosing.

中文翻译：

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药物遗传学指导的和临床的华法令剂量算法评估，出血结果由遗传和协变量亚组风险分层。

背景

由于狭窄的治疗性INR范围和个体间剂量反应的显着差异，安全管理华法林带来了挑战。华法林使用继发的出血是住院的主要原因。

方法

对于参与ENGAGE-AF TIMI 48试验的HAS-BLED得分≥3的患者，评估了五种华法林给药算法与INR目标剂量相比的预测准确性。根据基因型建立了三个华法林代谢亚组（正常，敏感和高度敏感的应答者）。确定各组算法在计算剂量和处方剂量之间的平均差异。

结果

分析了7036名患者，并对1846名HAS-BLED≥3的参与者进行了基因分型。华法林的预测目标剂量与INR目标剂量的平均绝对误差范围为：在药物遗传学指导的国际华法林药物遗传学联合会（IWPC）和Gage算法上为8.1 mg /周，在固定剂量下为11.3 mg /周。对于固定剂量的受试者，每周21 mg /周的高敏感性应答者中有98％的人对INR目标剂量进行了高估。药物遗传学指导的IWPC对高敏感反应者的估计值高估了89％，平均差为8.3 mg /周。在开始使用华法林的前90天内，发生重大或临床相关的非重大出血的高敏患者发生率比正常应答者高3.27倍。

结论

与已建立的算法相比，经改良的HAS-BLED和基因型敏感性分析确定的高风险出血亚群中的初始剂量高于INR目标剂量。与固定剂量相比，HAS-BLED≥3的高度敏感反应者的临床和药物遗传学指导算法改善了剂量。