Nonsteroidal Anti-Inflammatory Drugs and Hepatic Toxicity: A Systematic Review of Randomized Controlled Trials in Arthritis Patients
2005; Elsevier BV; Volume: 3; Issue: 5 Linguagem: Inglês
10.1016/s1542-3565(04)00777-3
ISSN1542-7714
AutoresAlaa Rostom, Lawrence Goldkind, Loren Laine,
Tópico(s)Drug-Induced Hepatotoxicity and Protection
ResumoBackground & 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. 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. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used medications in the United States. The main concern limiting their use is the development of serious gastrointestinal complications such as bleeding ulcers. However, NSAIDs have also been associated with hepatic side effects, ranging from elevations in aminotransferase levels to serious hepatic injury with acute liver failure. For example, diclofenac is known to cause elevated aminotransferase levels, and its product information carries a precaution recommending periodic monitoring of aminotransferase levels.1Physicians' desk reference. 58th ed. Thomson PDR, Montvale, NJ2004Google Scholar In addition, the NSAIDs benoxaprofen and bromfenac were each withdrawn from the market after approval in the US as a result of serious episodes of hepatotoxicity.2Bromfenac withdrawal.WHO Drug Information. 1998; 12: 146Google ScholarNevertheless, hepatic side effects with NSAIDs are uncommon, with cases of clinically serious adverse events, such as hospitalization, occurring rarely. Thus, individual studies designed to assess the efficacy or safety of NSAIDs are unlikely to provide reliable estimates of the risk of hepatic side effects. For this reason we undertook a systematic review of randomized controlled trials of commonly used NSAIDs in patients with osteoarthritis or rheumatoid arthritis. Our goal was to determine how frequently patients taking NSAIDs, including cyclooxygenase-2 (COX-2) specific inhibitors, developed both laboratory and clinical hepatic side effects. We evaluated the most commonly used nonselective NSAIDs, ibuprofen, naproxen, and diclofenac, as well as the newer COX-2 selective/specific inhibitors.MethodsLiterature searchSeparate literature searches were conducted in MEDLINE, EMBASE, and the Cochrane library (from date of inception to January 30, 2004) in accordance with published recommendations.3Haynes R. Wilczynski N. McKibbon K. et al.Developing optimal search strategies for detecting clinically sound studies in MEDLINE.J Am Med Inform Assoc. 1994; 1: 447-458Crossref PubMed Scopus (565) Google Scholar, 4Hunt D. McKibbon K. Locating and appraising systematic reviews.Ann Intern Med. 1997; 126: 532-538Crossref PubMed Scopus (144) Google Scholar 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 citations5Moher D. Pham B. Lawson M.L. Klassen T.P. The inclusion of reports of randomised trials published in languages other than English in systematic reviews.Health Technol Assess. 2003; 7: 1-90PubMed Google Scholar were removed.The public archives of the US Food and Drug Administration (FDA)6Food and Drug Administration (FDA) web site. Available at: www.fda.gov. Accessed September 23, 2004.Google Scholar were also searched for clinical trial data that were submitted to the FDA by companies as part of new or supplemental drug applications. These archives are available on the FDA web site.Inclusion and exclusion criteriaStudy types, patient population, and exposureRandomized controlled trials of adults (age > 18 years) with osteoarthritis or rheumatoid arthritis were considered for inclusion if (1) the study duration was 4 weeks or greater; (2) data were reported on at least one of the following NSAIDs: celecoxib, rofecoxib, valdecoxib, meloxicam, diclofenac, naproxen, or ibuprofen; (3) the study arms of the NSAIDs of interest included more than 40 patients.Nonrandomized extensions of controlled trials were not included.Reported study outcomes required for study inclusionFor inclusion in the review a study was required to explicitly report the number of events relating to at least one of the following outcomes: (1) death due to hepatic cause; (2) liver transplantation; (3) hospitalization as a result of acute liver disease; (4) serious adverse event (SAE) related to a hepatic cause (eg, considered life-threatening, requires hospitalization or prolongs hospitalization, causes significant disability or incapacity, requires treatment to prevent these outcomes); (5) discontinuation from the study as a result of elevated liver test results or clinical hepatic events; (6) patients with ALT/AST >3× the upper limit of normal (ULN).The ALT/AST >3× ULN threshold was chosen as a "significant" elevation. This is a commonly used cutoff for defining potentially significant hepatic injury.7Temple R. Drug induced liver injury: a national and global problem, FDA-PhaRMA-AALSD Conference: drug-induced liver injury: a national and global problem. Available at: www.fda.gov/cder/livertox/Presentations/im1389/tsld001.htm. 2001.Google Scholar, 8PhRMA/FDA/AASLD drug induced hepatotoxicity white paper postmarketing considerations. Available at: www.fda.gov/cder/livertox/postmarket.pdf. 2000.Google Scholar In addition, we planned on evaluating the rate of concomitant elevations in aminotransferases and bilirubin. This is based on the suggestion by Zimmerman9Zimmerman H. The adverse effects of drugs and other chemicals on the liver. 2nd ed. Lippincott Williams & Wilkins, Philadelphia1999Google Scholar that drug-induced hepatocellular jaundice predicts approximately a 10% chance of liver failure and/or death. Although this "Hy's rule" has not been systematically validated, FDA documents also suggest this might be an important metric to explore when assessing potential hepatotoxicity of new medications. Levels of bilirubin as low as 1.5 or 2 times ULN in concert with the aminotransferase elevation have been proposed.7Temple R. Drug induced liver injury: a national and global problem, FDA-PhaRMA-AALSD Conference: drug-induced liver injury: a national and global problem. Available at: www.fda.gov/cder/livertox/Presentations/im1389/tsld001.htm. 2001.Google Scholar, 8PhRMA/FDA/AASLD drug induced hepatotoxicity white paper postmarketing considerations. Available at: www.fda.gov/cder/livertox/postmarket.pdf. 2000.Google Scholar However, Zimmerman suggested the use of jaundice, rather than merely hyperbilirubinemia, so a bilirubin level associated with clinical jaundice (eg, >3 mg/dL) might be a more appropriate threshold.9Zimmerman H. The adverse effects of drugs and other chemicals on the liver. 2nd ed. Lippincott Williams & Wilkins, Philadelphia1999Google Scholar In any event, information on concomitant bilirubin elevations in association with ALT or AST >3× ULN were virtually never provided in the studies in this review, so we were unable to systematically assess Hy's rule.Studies that reported events not meeting the above criteria or that reported mean pre-post changes rather than the number of patients with increased liver test results were not included in the review.Studies were included if they explicitly reported the absence of hepatic toxicity outcomes or if all causes of the outcome of interest were detailed as described below: studies described all causes of deaths or explicitly stated that death did not occur; studies described all causes of hospitalizations or explicitly stated that hospitalization did not occur; studies described all causes of SAEs (not just those thought to be related to the study drug) or explicitly stated that SAEs did not occur; studies described all causes of discontinuations or explicitly stated that discontinuations did not occur.Study selection and abstractionStudy selection from the bibliographic databases occurred in 2 phases and was performed in duplicate independently by 2 investigators (L.L., A.R.). Selection conflicts were automatically tracked by the SRS system and were resolved by consensus.During the first broad phase of study selection all potentially relevant articles of the NSAIDs of interest were selected on the basis of a review of the title, abstract, and keywords. Review articles were excluded but were kept for reference. Articles that clearly failed inclusion on the basis of a review of the citation data were also excluded.All studies passing the level one screen were retrieved in full and further assessed for inclusion/exclusion by 2 independent reviewers (L.L., A.R.), with conflicts resolved by consensus.Articles meeting the inclusion criteria were abstracted by both investigators (L.L., A.R.), and any conflicts were discussed and resolved by consensus. For each study, basic demographic data such as study type, publication year, patient type (osteoarthritis or rheumatoid arthritis), group size, and study duration were recorded. The outcomes available from a particular study were abstracted, and note was made of which outcomes were not reported. Data abstraction was conducted by using an electronic computer-based form to allow ease of review and for export for statistical analysis.The FDA web site was searched independently by 2 investigators (L.G., L.L.) for all studies meeting the criteria outlined above for the bibliographic database search. Studies selected by either author were reviewed together by both authors, and any conflicts regarding inclusion were resolved by consensus. Data were then abstracted independently by both authors, and any conflicts were discussed and resolved by consensus.Quality assessmentThe methodologic quality of included studies was assessed independently by 2 investigators (L.L., A.R.) by using the primary items of Jadad et al10Jadad A.R. Moore R.A. Carroll D. et al.Assessing the quality of reports of randomized clinical trials is blinding necessary?.Control Clin Trials. 1996; 17: 1-12Abstract Full Text PDF PubMed Scopus (13357) Google Scholar (randomization, blinding, full accounting of all patients randomized). Conflicts were resolved by consensus.Subgroups and statistical analysisAttempts were made to minimize statistical and clinical heterogeneity by dividing pooled analyses into logical subgroups based on clinical parameters. Studies of osteoarthritis and rheumatoid arthritis were analyzed separately as were data from each NSAID type. Because of potential differences in hepatic toxicity among different NSAIDs (even among the newer COX-2 inhibitors), pooling of all NSAIDs or standard NSAIDs versus COX-2 selective inhibitors was not performed.The proportion of patients with each of the hepatic toxicity outcomes was calculated separately by using sample size weighted pooling for each subgroup. The 95% confidence intervals (95% CIs) were calculated for each pooled estimate. Subgroup analyses were conducted by study duration and dose of NSAID. Data analysis was conducted by using SPSS version 11 (SPSS Inc, Chicago, IL).Role of funding sourceThe funding source had no role in the design, performance, analysis, or reporting of this systematic review.ResultsIncluded studiesThe 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 did not explicitly comment on the study outcomes of interest were excluded. 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