Original article
Nonsteroidal Anti-Inflammatory Drugs and Hepatic Toxicity: A Systematic Review of Randomized Controlled Trials in Arthritis Patients

https://doi.org/10.1016/S1542-3565(04)00777-3Get rights and content

Background & Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) might cause hepatic side effects, but the frequency of these laboratory and clinical side effects is uncertain. Methods: Searches of bibliographic databases MEDLINE and EMBASE and of public archives of the Food and Drug Administration were conducted to identify randomized controlled trials of diclofenac, naproxen, ibuprofen, celecoxib, rofecoxib, valdecoxib, or meloxicam in adults with osteoarthritis or rheumatoid arthritis that provided information on aminotransferase elevations >3× upper limit of normal, liver-related discontinuations, hepatic serious adverse events, liver-related hospitalizations, or liver-related deaths. The proportion of patients with each of the hepatic toxicity outcomes was calculated separately by using sample size weighted pooling for each NSAID. Results: Sixty-seven articles from the bibliographic database and 65 studies from the Food and Drug Administration archives met inclusion criteria. Diclofenac (3.55%; 95% confidence interval [CI], 3.12%–4.03%) and rofecoxib (1.80%; 95% CI, 1.52%–2.13%) had higher rates of aminotransferase >3× upper limit of normal than placebo (0.29; 95% CI, 0.17–0.51) and the other NSAIDs (all ≤ 0.43%). The 95% CIs for liver-related discontinuations of all NSAIDs except diclofenac (2.17%; 95% CI, 1.78%–2.64%) overlapped with placebo. Only 1 liver-related hospitalization (among 37,671 patients) and 1 liver-related death (among 51,942 patients) occurred, with naproxen. Conclusions: Diclofenac and rofecoxib had higher rates of aminotransferase elevations than placebo and other NSAIDs studied. No NSAID studied had increased rates of liver-related serious adverse events, hospitalizations, or deaths.

Section snippets

Literature search

Separate literature searches were conducted in MEDLINE, EMBASE, and the Cochrane library (from date of inception to January 30, 2004) in accordance with published recommendations.3, 4 The obtained citations from each search were combined and uploaded into a web-based database system for collaborative citation screening and quality assessment (SRS Systematic Review System; TrialStat Corporation, Ottawa, Ontario, Canada). Duplicates and non-English language citations5 were removed.

The public

Included studies

The search strategy (Appendix 1) identified 1984 citations of studies relating to the NSAIDs of interest. A first level screen to identify randomized controlled trials of at least 4 weeks’ duration, with each study arm having at least 40 patients, resulted in 335 potentially relevant studies. The most common reasons for screen failure were small, short-term studies and review articles. The 335 potentially relevant studies were retrieved in full and assessed formally for inclusion. Articles that

Discussion

Our systematic review indicates that the commonly used NSAIDs ibuprofen, naproxen, meloxicam, celecoxib, and valdecoxib have very low rates of “significant” aminotransferase elevations, defined as ALT or AST greater than 3 times ULN. These levels of aminotransferases developed in less than 0.5% of patients with these NSAIDs, the 95% CIs overlapped the placebo 95% CI, and the upper bound of the 95% CIs was under 0.75%. Our data represent a compilation of different studies rather than direct

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    Copyright © 2005 American Gastroenterological Association. Published by Elsevier Ltd. All rights reserved.