Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) Application of this Data Organization Approach to Phase III Clinical Trials of Rivaroxaban after Total Hip or Knee Replacement Surgery
Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) Application of this Data Organization Approach to Phase III Clinical Trials of Rivaroxaban after Total Hip or Knee Replacement Surgery
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DOI：
10.2165/11586600-000000000-00000
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发表时间：
2011-01-01
期刊：
影响因子：
4.2
通讯作者：
Maddrey, Willis
中科院分区：
文献类型：
--
作者：
Watkins, Paul B.;Desai, Mehul;Maddrey, Willis
背景资料：临床试验数据库中药物性肝损伤信号的最特异性指标被认为是发生药物相关血清ALT和血清总胆红素（TB）升高而血清碱性磷酸酶（ALP）无显著升高的受试者。eDISH（药物诱导的严重肝毒性的评价）是最近描述的工具，其通过图形显示每个受试者的血清ALT和TB峰值水平来组织肝脏实验室数据，并且还可以提供与每个受试者的相关临床和实验室数据的直接链接。目的：通过使用III期临床试验数据说明eDISH方法在显示肝脏安全性数据方面的有用性，方法：在全世界范围内对进行选择性髋关节或膝关节置换手术的受试者进行四项随机、活性对照研究，以比较抗凝剂利伐沙班（一种口服、直接Xa因子抑制剂）与低分子量肝素依诺肝素的功效和安全性。研究期间经常进行肝脏实验室评估，包括ALT、AST、TB和ALP。数据被纳入eDISH和选定的受试者的关联数据进行了analysed.Results：在汇总分析的四项研究中，共有12 262例受试者（6131利伐沙班，6131依诺肝素）接受至少一个剂量的研究药物，并在研究期间至少有一个中心和/或当地实验室评估。共有143例（2.33%）利伐沙班受试者和223例（3.64%）依诺肝素受试者出现ALT峰值>3 x正常上限（ULN），但未出现TB升高>2 x ULN;这些受试者显示在eDISH图的右下象限，称为“Temple推论象限”。存在t&I利伐沙班和10名依诺肝素受试者，其峰值ALT >3 x ULN和峰值TB >2 x ULN;这些受试者显示在eDISH图的右上象限中，称为“海氏法则象限”。eDISH可以有效检查每个受试者的相关数据。结论：eDISH方法是组织和检查随机对照临床试验大型肝脏安全数据库的高效且有效的方法。它极大地促进了对相关肝脏安全性实验室数据的系统和透明检查。我们认为eDISH应该成为临床试验中评估和研究肝脏安全性问题的标准方法。
Background: The most specific indicator of a drug-induced liver injury signal in a clinical trial database is believed to be the occurrence of subjects experiencing drug-associated elevations in both serum ALT and serum total bilirubin (TB) without a significant elevation in serum alkaline phosphatase (ALP). eDISH (evaluation of Drug-Induced Serious Hepatotoxicity) is a recently described tool that organizes liver laboratory data by graphically displaying peak serum ALT and TB levels for each subject, and can also provide direct links to the pertinent clinical and laboratory data for each subject.Objective: To illustrate the usefulness of the eDISH approach in the presentation of liver safety data by using phase III clinical trial data for rivaroxaban.Methods: Four randomized, active-controlled studies were conducted worldwide in subjects undergoing elective hip or knee replacement surgery to compare the efficacy and safety of the anticoagulant rivaroxaban, an oral, direct Factor Xa inhibitor, with the low-molecular-weight heparin, enoxaparin. Liver laboratory assessments, including ALT, AST, TB and ALP, were performed frequently during the studies. Data were incorporated into eDISH and linked data for selected subjects were analysed.Results: In the pooled analysis of the four studies, a total of 12 262 subjects (6131 rivaroxaban, 6131 enoxaparin) received at least one dose of study drug and had at least one central and/or local laboratory assessment during the study. A total of 143 (2.33%) rivaroxaban subjects and 223 (3.64%) enoxaparin subjects experienced a peak ALT >3 x upper limit of normal (ULN) but did not experience an elevation of TB >2 x ULN; these subjects are displayed in the right lower quadrant of the eDISH plot, termed the 'Temple's Corollary quadrant'. There were t&I rivaroxaban and ten enoxaparin subjects with a peak ALT >3 x ULN and a peak TB >2 x ULN; these subjects were displayed in the right upper quadrant of the eDISH plot, termed the 'Hy's Law quadrant'. eDISH allowed efficient examination of the relevant data for each of these subjects.Conclusions: The eDISH approach is an efficient and effective way to organize and examine large liver safety databases for randomized controlled clinical trials. It greatly facilitates a systematic and transparent examination of the relevant liver safety laboratory data. We believe eDISH should become a standard approach for assessing and studying liver safety issues in clinical trials.