How Common Is Diclofenac-Associated Liver Injury? Analysis of 17,289 Arthritis Patients in a Long-Term Prospective Clinical Trial
How Common Is Diclofenac-Associated Liver Injury? Analysis of 17,289 Arthritis Patients in a Long-Term Prospective Clinical Trial
复制标题
DOI：
10.1038/ajg.2008.149
复制
发表时间：
2009-02-01
影响因子：
9.8
通讯作者：
Cannon, Christoper P.
中科院分区：
文献类型：
--
作者：
Laine, Loren;Goldkind, Lawrence;Cannon, Christoper P.
目的：从前瞻性试验中获得的数据很少，无法确定双氯芬酸的肝毒性，双氯芬酸是世界上最广泛使用的非甾体抗炎药（NSAID）。我们确定了一个大型双盲试验中的实验室和临床不良肝脏反应率双氯芬酸.METHODS：患者>= 50岁类风湿性关节炎或骨关节炎被随机分配到双氯芬酸（150毫克，每天）或依托考昔（60或90毫克，每天）。肝病患者或报告每周饮酒≥ 14次的患者被排除在外。患者每4个月进行一次访视（进行肝脏检查），并在访视之间和停药后每6个月通过电话联系，直至研究结束。对肝脏相关的住院治疗、Hy's病例（AST或ALT > 3 ×正常上限（ULN）和胆红素> 2 × ULN的严重不良事件）和肝功能衰竭/移植/死亡进行因果关系评估。双氯芬酸的肝脏终点为ALT/AST>3xULN：527例（3.1%）; ALT/AST> 10 xULN：86例（0.5%）;肝脏相关住院：4例（0.023%）; Hy病例：2例（0.012%）;肝衰竭/死亡/移植：0例。转氨酶升高主要发生在治疗的前4-6个月内，而肝脏相关的住院治疗发生在9天和21个月之间。结论：双氯芬酸通常与转氨酶升高相关，通常发生在治疗的前4-6个月。需要住院治疗的临床肝脏事件相对罕见（23/100，000例患者），但可能在治疗早期或晚期发生。双氯芬酸组转氨酶升高率的显著增加可能不会被临床肝脏事件的成比例显著增加所抵消，尽管在临床试验环境中定期监测也可能减少临床事件。
OBJECTIVES: Few data are available from prospective trials to define the hepatotoxicity of diclofenac, the most widely prescribed non-steroidal anti-inflammatory drug (NSAID) in the world. We determined the rate of laboratory and clinical adverse hepatic effects in a large double-blind trial of diclofenac.METHODS: Patients >= 50 years with rheumatoid arthritis or osteoarthritis were randomly assigned to diclofenac (150 mg daily) or etoricoxib (60 or 90 mg daily). Patients with hepatic disease or who reported >= 14 alcoholic drinks weekly were excluded. Patients had visits (with liver tests) every 4 months and were contacted by phone between visits and every 6 months after discontinuation until the end of the study. Causality assessment was performed for liver-related hospitalizations, Hy's cases (serious adverse events with AST or ALT >3x upper limit of normal (ULN) and bilirubin >2xULN), and liver failure/transplant/death.RESULTS: A total of 17,289 patients received diclofenac for a mean of 18 months. Liver end points with diclofenac were ALT/AST>3xULN: 527(3.1%); ALT/AST>10xULN: 86(0.5%); liver-related hospitalizations: 4(0.023%); Hy's cases: 2(0.012%); liver failure/death/transplant: 0. Aminotransferase elevations occurred primarily within the first 4-6 months of therapy, whereas liver-related hospitalizations occurred between 9 days and 21 months.CONCLUSIONS: Diclofenac is commonly associated with aminotransferase elevations, generally in the first 4-6 months of therapy. Clinical liver events requiring hospitalization are relatively rare (23/100,000 patients), but may develop early or late in therapy. The markedly increased rate of aminotransferase elevation with diclofenac may not be paralleled by a proportional marked increase in clinical liver events, although clinical events potentially also may be decreased with regular monitoring in a clinical trial setting.