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Comparative Efficacy of Non-Steroidal Anti-Inflammatory Drugs In Downloaded from http://ard.bmj.com/ on August 9, 2015 - Published by group.bmj.com ARD Online First, published on August 6, 2015 as 10.1136/annrheumdis-2015-207677 Clinical and epidemiological research EXTENDED REPORT Comparative efficacy of non-steroidal anti-inflammatory drugs in ankylosing spondylitis: a Bayesian network meta-analysis of clinical trials Runsheng Wang, Abhijit Dasgupta, Michael M Ward Handling editor Tore K Kvien ABSTRACT such as celecoxib and etoricoxib, have shown ▸ Additional material is Objective To compare the efficacy of 20 non-steroidal similar efficacy in AS with non-selective NSAIDs, published online only. To view anti-inflammatory drugs (NSAIDs) in the short-term including naproxen,56diclofenac7 and ketopro- please visit the journal online treatment of ankylosing spondylitis (AS). fen,8 with lower risk of gastrointestinal (GI) tox- (http://dx.doi.org/10.1136/ annrheumdis-2015-207677). Methods We performed a systematic literature review icity. Head-to-head RCTs comparing two or more of randomised controlled trials of NSAIDs in patients NSAIDs have been performed in AS, but a compre- Intramural Research Program, with active AS. We included trials that reported efficacy hensive comparison among the most commonly National Institute of Arthritis – fi and Musculoskeletal and Skin at 2 12 weeks. Ef cacy outcomes were the change in used NSAIDs is not available. For example, indo- Diseases, National Institutes of pain score and change in the duration of morning methacin and piroxicam have not been compared Health, Bethesda, Maryland, stiffness. We also examined the number of adverse with COX-2 inhibitors in any trials. Information on USA events. We used Bayesian network meta-analysis to the relative efficacy and safety of different NSAIDs Correspondence to compare effects directly and indirectly between drugs. would aid clinical decision-making. In the absence Dr Michael M Ward, NIAMS/ Results We included 26 trials (66 treatment arms) of of direct comparisons, indirect comparisons of two NIH, Building 10 CRC, Room 20 NSAIDs with 3410 participants in the network meta- or more drugs can be made through a common 4-1339, 10 Center Drive, analysis. Fifty-eight per cent of trials had fewer than 50 comparator using Bayesian network meta-analysis.9 Bethesda, MD 20892, USA; participants. All 20 NSAIDs reduced pain more than We conducted a systematic literature review and [email protected] placebo (standardised mean difference ranging from meta-analysis of RCTs to assess the relative efficacy Received 27 March 2015 −0.65 to −2.2), with 15 NSAIDs significantly better and safety of 20 NSAIDs in the short-term treat- Revised 2 June 2015 than placebo. Etoricoxib was superior to celecoxib, ment of AS. Accepted 13 July 2015 ketoprofen and tenoxicam in pain reduction, but no other interdrug comparisons were significant. There were no significant differences among NSAIDs in decreases in METHODS the duration of morning stiffness or the likelihood of Literature search adverse events. Adverse events were uncommon in these The study protocol was registered at PROSPERO short-term studies. In 16 trials that used NSAIDs at full (registration number CRD42014014329). With the doses, etoricoxib was superior to all but two other help of a medical informationist, we searched NSAIDs in pain reduction. PubMed, EMBASE, Scopus and the Cochrane Conclusions Etoricoxib was more effective in reducing Database for published RCTs of NSAIDs in AS pain in AS than some other NSAIDs, but there was from 1 January 1960 to 31 December 2014 in all otherwise insufficient evidence to conclude that any languages. Search terms are provided in online sup- particular NSAID was more effective in the treatment of plementary table S1. We also performed manual AS. Comparisons were limited by small studies. searches of reference lists of reviews and searched ClincalTrials.gov and clinicaltrialsregister.eu for RCTs. Two authors (RWand MMW) independently reviewed the search results for eligible studies. fl Non-steroidal anti-in ammatory drugs (NSAIDs) Disagreements were resolved by discussion. form the cornerstone of pharmacological treatment of ankylosing spondylitis (AS). Currently, 11 NSAIDs are approved for the treatment of AS in Selection criteria Europe and 5 are approved in USA; additional Studies were eligible if they were RCTs evaluating NSAIDs are approved for other indications and are the efficacy and safety of an NSAID compared with available for use.1 A question that naturally arises placebo or a different NSAID in adults with active when there are many treatment options is whether AS and reported outcomes at 2–12 weeks. AS was any particular NSAID is more effective and safer defined by the modified New York criteria; for for the typical patient. In the past, phenylbutazone trials conducted before 1984, we included trials was considered the NSAID of choice for the treat- that required radiographic sacroiliitis to establish a ment of AS, but it was supplanted by NSAIDs diagnosis of AS. To enhance homogeneity, we without similar risk of bone marrow suppression.2 excluded trials of axial spondyloarthritis, unless a To cite: Wang R, Indomethacin has also been favoured as a particu- subgroup analysis of patients with AS was reported. Dasgupta A, Ward MM. Ann Rheum Dis Published Online larly effective NSAID in patients with AS, despite We also excluded trials with concomitant use of First: [please include Day the lack of randomised controlled trials (RCTs) other anti-inflammatory drugs, such as corticoster- Month Year] doi:10.1136/ demonstrating superior efficacy.34More recently, oids, aspirin, immunosuppressants or biologics. annrheumdis-2015-207677 cyclooxygenase-2 (COX-2) selective inhibitors, Finally, we excluded trials that did not report Wang R, et al. Ann Rheum Dis 2015;0:1–9. doi:10.1136/annrheumdis-2015-207677 1 Copyright Article author (or their employer) 2015. Produced by BMJ Publishing Group Ltd (& EULAR) under licence. Downloaded from http://ard.bmj.com/ on August 9, 2015 - Published by group.bmj.com Clinical and epidemiological research relevant efficacy outcomes or measures of variance for the size. The analyses of pain and morning stiffness were performed outcomes. under the model assumption of a normal (Gaussian) likelihood and conjugate priors, which were used to compute the posterior Data extraction and assessment of bias distribution of the effect of each NSAID compared with placebo Data extraction was done independently by two authors (RW (or another NSAID).12 We presented these results as relative effect and MMW). We extracted aspects of the study design, partici- sizes of the two interventions with 95% credible intervals. We ana- pant characteristics and relevant outcomes. For cross-over trials, lysed safety outcomes using a Poisson model, where the rate of if a washout period was present before the cross-over and events (the hazard) was modelled accounting for study sample results of the two phases were reported separately, the results of sizes. Results were presented as relative risks of the two interven- the second phase were recorded as a separate study. tions in comparison, in the form of log (HR). We assumed that the We analysed the change in total pain score and change in dur- hazard did not depend on the duration of each study. All computa- ation of morning stiffness as the efficacy outcomes. When the tions were done using R (V.3.1.2) package gemtc (V.0.6),13 14 total pain score was not reported, we used the results for spinal along with the Markov Chain Monte Carlo engine JAGS pain, night pain, pain at rest and day pain, in this order of prior- (V.3.4.0).15 ity. We either abstracted the mean change score and its SD, or We performed three subgroup analyses to address trial hetero- estimated the change from baseline and final scores. When only geneity: first excluding cross-over trials without an intervening medians and ranges were reported, we imputed the means by washout period; second excluding trials without intention-to- standard methods.10 Pain scores were assessed using 10 cm treat analysis; and third, stratifying by trial duration. visual analogue scales, 5-point Likert scales or other numerical Some trials tested less than full daily doses of NSAIDs. rating scales. To create a uniform scale for analysis, we con- Therefore, for the pain outcome, we also performed a subgroup verted mean differences to standardised mean differences, analysis of trials that used full doses, including trials of celecoxib which are defined as the effect divided by the baseline variabil- 400 mg daily, diclofenac 150 mg daily, etoricoxib 90 mg daily ity.11 Data on duration of morning stiffness were collected simi- or more, indomethacin 100 mg daily or more, ketoprofen larly. Because these data were always reported as minutes, we 200 mg daily or more, meloxicam 15 mg daily or more, analysed mean differences for morning stiffness. naproxen 1000 mg daily and phenylbutazone 400 mg daily or For safety outcomes, we examined the numbers of patients more. For NSAIDs evaluated in a single dosage (eg, piroxicam), with any adverse event (total AE), GI adverse events and GI we included trials of the single dosage. Except for indometh- bleeding. We defined GI adverse events as any GI complaints, acin, the full-dose analysis included trials with doses equal to or including nausea, vomiting, diarrhoea and epigastric or abdom- higher than ‘100’ in the Assessment of Spondyloarthritis inal pain, but excluding haematemesis and haematochezia. In International Society (ASAS)-NSAIDs equivalent score.16 trials that reported the number of events, we used this to impute the number of affected patients. RESULTS We used the Cochrane Collaboration’s tool for assessment of Literature review risk of bias to assess study quality.10 We scored each study on six Of the 63 trials identified by literature review, we excluded 37, domains (sequence generation, allocation concealment, blinding, primarily because no relevant efficacy outcomes or measures of incomplete outcome data, selective reporting, other sources of variation were reported (see online supplementary figure S1).
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