View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Hindawi International Journal of Hepatology Volume 2018, Article ID 5253623, 13 pages https://doi.org/10.1155/2018/5253623 Review Article Hepatotoxicity of Nonsteroidal Anti-Inflammatory Drugs: A Systematic Review of Randomized Controlled Trials Pajaree Sriuttha , Buntitabhon Sirichanchuen, and Unchalee Permsuwan Faculty of Pharmacy, Chiang Mai University, Chiang Mai, Tailand Correspondence should be addressed to Pajaree Sriuttha; [email protected] Received 24 July 2017; Revised 25 September 2017; Accepted 17 October 2017; Published 15 January 2018 Academic Editor: Maria Buti Copyright © 2018 Pajaree Sriuttha et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background. Nonsteroidal anti-infammatory drugs (NSAIDs) are the most widely used medication in several countries, including Tailand. NSAIDs have been associated with hepatic side efects; however, the frequency of these side efects is uncertain. Aim of the Review. To systematically review published literature on randomized, controlled trials that assessed the risk of clinically signifcant hepatotoxicity associated with NSAIDs. Methods. Searches of bibliographic databases EMBASE, PubMed, and the Cochrane Library were conducted up to July 30, 2016, to identify randomized controlled trials of ibuprofen, naproxen, diclofenac, piroxicam, meloxicam, mefenamic acid, indomethacin, celecoxib, and etoricoxib in adults with any disease that provide information on hepatotoxicity outcomes. Results. Among the 698 studies, 18 studies met the selection criteria. However, only 8 studies regarding three NSAIDs (celecoxib, etoricoxib, and diclofenac) demonstrated clinically signifcant hepatotoxic evidence based on hepatotoxicity justifcation criteria. Of all the hepatotoxicity events found from the above-mentioned three NSAIDs, diclofenac had −2 −2 the highest proportion, which ranged from 0.015 to 4.3 (×10 ), followed by celecoxib, which ranged from 0.13 to 0.38 (×10 ), and −2 etoricoxib, which ranged from 0.005 to 0.930 (×10 ). Conclusion. Diclofenac had higher rates of hepatotoxic evidence compared to other NSAIDs. Hepatotoxic evidence is mostly demonstrated as aminotransferase elevation, while liver-related hospitalization or discontinuation was very low. 1. Introduction hepatic side efects ranging from asymptomatic elevations in serum aminotransferase levels and hepatitis with jaundice to Nonsteroidal anti-infammatory drugs (NSAIDs) are the fulminant liver failure and death [5]. In 2008, lumiracoxib most widely used medication in several countries, including was withdrawn from the market in several countries, mostly Tailand, for treatment of symptoms of pain and infamma- duetoitspotentialtocauseseverehepaticfailure[6],which tion, such as osteoarthritis (OA) and rheumatoid arthritis is classifed as one type of hepatotoxicity. (RA) [1, 2]. It has been reported that 12.1% of the US Drug-induced hepatotoxicity leads to abnormalities in population took NSAIDs at least three times per week for liver tests or liver dysfunction. An elevation of ALT, ALP or more than 3 months [3]. In Tailand, NSAIDs are both widely conjugatedbilirubinwasconfrmedas“> 2 × ULN” according prescribed by physicians and available for purchase over-the- to CIOMS criteria [7, 8]. At present, the thresholds and counter without a physician’s prescription in drug stores. the cutofs for ALT have been modifed; the 5 × ULN has BasedonthedataofTaiFoodandDrugAdministration been suggested in a recent state-of-the art paper written by (Tai FDA) during 1984–2016, medications used for muscu- international experts [9]. loskeletal system disorders were the second-most common Hepatotoxicity is more frequently discovered during cause of adverse drug events (ADE), resulting in 14% of all postmarketing studies or, even, much later. Tis is due to reported ADEs. Ibuprofen and diclofenac were listed among the slightly low incidence rate of NSAIDs associated with the top 15 drugs to cause ADE [4]. While the major adverse hepatotoxicity[5,10,11].Tesamplesizeofthepremarketing efects of NSAIDs such as gastrointestinal mucosa injury studies designed to assess the efcacy or safety of NSAIDs arewellknown,NSAIDshavealsobeenassociatedwith might not be sufcient to provide the true incidence rate 2 International Journal of Hepatology of hepatotoxicity. Although clinically apparent liver injury were elevation of transaminases (alanine aminotransferase from NSAIDs is rare (∼1–10 cases per 100,000 prescriptions) or aspartate aminotransferase) to >3 × ULN or ALP to >2 [5], NSAIDs are consumed in massive amounts worldwide; × ULN threshold as a signifcant elevation because it is the hence, despite the overall low incidence rate of NSAID- most commonly used initial screen for hepatic injury [35]. induced hepatotoxicity, their widespread use makes them an Terefore, randomized controlled trials of adults (age ≥18 important cause of drug-induced liver injury. years) with any diseases were included for data extraction if In2005,Rostometal.[12]conductedasystematicre- (1) the studies described at least one of the following NSAIDs: view of randomized controlled trials (RCT) of diclofenac, ibuprofen, naproxen, diclofenac, piroxicam, meloxicam, naproxen, ibuprofen, celecoxib, rofecoxib, valdecoxib, and mefenamic acid, indomethacin, celecoxib, and etoricoxib and meloxicam in arthritis patients. Te authors defned hepatic (2) hepatotoxicity outcomes were reported as the number toxicity as aminotransferase elevations > 3 × ULN, liver- of events related to at least one of the following outcomes: related drug discontinuation, serious hepatic adverse events, elevation of aspartate aminotransferase (AST) > 3 × ULN, liver-related hospitalizations, and liver-related deaths. Tey elevation of ALT > 3 × ULN, elevation of ALT, AST or both > concluded that diclofenac and rofecoxib had higher rates of 3 × ULN, elevation of ALP > 2 × ULN, Hy’s case (ALT > 3 × aminotransferases, three times greater than ULN when com- ULN and total bilirubin > 1.5 × ULN), liver-related treatment pared with either placebo or other NSAIDs. However, none discontinuations, and liver-related hospitalization. of these studies found high rates of serious hepatic adverse Eligibility assessment was performed independently in events,hospitalization,ordeath.Teseresultsareinconcor- an unblinded standardized manner by two reviewers (PS dance with the fndings reported by Rubenstein and Laine [11] and BS) to identify potential relevant articles. Disagreement who evaluated the incidence and risk of serious liver-related between reviewers was resolved by consensus. All duplicated NSAID toxicity using published literature for population- studies and nonrelevant articles were excluded. Data extrac- based observational studies (case-control, controlled cohort, tion and quality assessment were then performed for all andsinglecohortpopulation-basedstudies).Teyfoundthat included studies (Figure 1). the incidence rate of hepatotoxicity associated with hospital admission was in the range of 3.1–23.4/100000 patient-years. 2.3. Data Extraction and Quality Assessment. Te included Te incidence rate of hepatotoxicity associated with NSAIDs, full text articles were reviewed, and data related to study also obtained from a retrospective study, was found to be in characteristics and safety outcome were extracted. Ten, all the range of 1.4–9/100000 patient-years [13–15]. the extracted data were entered into a standardized prepared Terefore, randomized, controlled trials that assessed table. the risk of clinically signifcant hepatotoxicity associated Te data were extracted from each of the included studies with NSAIDs that are commonly used in Tailand were according to the following criteria: (1) characteristics of systematically reviewed. Tose NSAIDs included ibupro- the trial participants (including gender, age, comorbidity, fen, naproxen, diclofenac, piroxicam, meloxicam, mefenamic alcohol use, and indication of NSAIDs); (2) type of inter- acid, indomethacin, celecoxib, and etoricoxib. vention (including type, dose, duration, and frequency of the NSAID); versus placebo, or versus another NSAID; and 2. Methods (3)typeofsafetyoutcomesthatweremeasured,suchas elevation of AST or ALT < 3 × ULN, elevation of AST 2.1. Search Methods for Identifcation of Studies. Te relevant or ALT > 3 × ULN, elevated total bilirubin > 2 × ULN, articles were identifed by searching the following databases elevation of ALP > 2 × ULN, serum ALT elevation > 3 × ULN for data up to July 30, 2016: the Cochrane Library, EMBASE, accompanied by a serum bilirubin elevation > 2 × ULN (Hy’s and PubMed. A comprehensive search was systematically case), liver-related treatment discontinuation, hospitalization performed, and the search was limited to the English duetohepaticcauseandacuteliverfailure,transplant,or language. Te electronic search terms are summarized in death. supplement 1. Manual searching for relevant publications To ascertain the validity of the eligible RCTs, the method- from extracted articles was also performed. ological quality of the included studies was assessed inde- pendently by two reviewers (Pajaree Sriuttha and Buntitab- 2.2. Study Selection. Atotalof9NSAIDsthatarecom- honSirichanchuen)usingtheJadadscore[36].TeJadad monly used in Tailand were chosen. Tere were ibupro- score