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      Relative efficacy and safety of topical non-steroidal anti-inflammatory drugs for osteoarthritis: a systematic review and network meta-analysis of randomised controlled trials and observational studies

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          To compare the efficacy and safety of topical non-steroidal anti-inflammatory drugs (NSAIDs), including salicylate, for the treatment of osteoarthritis (OA).


          PubMed, Embase, Cochrane Library and Web of Science were searched from 1966 to January 2017. Randomised controlled trials (RCTs) comparing topical NSAIDs with placebo or each other in patients with OA and observational studies comparing topical NSAIDs with no treatment or each other irrespective of disease were included. Two investigators identified studies and independently extracted data. Bayesian network and conventional meta-analyses were conducted. The primary outcomes were pain relief for RCTs and risk of adverse effects (AEs) for observational studies.


          43 studies, comprising 36 RCTs (7 900 patients with OA) and seven observational studies (218 074 participants), were included. Overall, topical NSAIDs were superior to placebo for relieving pain (standardised mean difference (SMD)=−0.30, 95% CI −0.40 to –0.20) and improving function (SMD=−0.35, 95% CI −0.45 to –0.24) in OA. Of all topical NSAIDs, diclofenac patches were most effective for OA pain (SMD=−0.81, 95% CI −1.12 to –0.52) and piroxicam was most effective for functional improvement (SMD=−1.04, 95% CI −1.60 to –0.48) compared with placebo. Although salicylate gel was associated with higher withdrawal rates due to AEs, the remaining topical NSAIDs were not associated with any increased local or systemic AEs.


          Topical NSAIDs were effective and safe for OA. Diclofenac patches may be the most effective topical NSAID for pain relief. No serious gastrointestinal and renal AEs were observed in trials or the general population. However, confirmation of the cardiovascular safety of topical NSAIDs still warrants further observational study.

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          Most cited references 51

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          The results of direct and indirect treatment comparisons in meta-analysis of randomized controlled trials.

          When little or no data directly comparing two treatments are available, investigators often rely on indirect comparisons from studies testing the treatments against a control or placebo. One approach to indirect comparison is to pool findings from the active treatment arms of the original controlled trials. This approach offers no advantage over a comparison of observational study data and is prone to bias. We present an alternative model that evaluates the differences between treatment and placebo in two sets of clinical trials, and preserves the randomization of the originally assigned patient groups. We apply the method to data on sulphamethoxazole-trimethoprim or dapsone/pyrimethamine as prophylaxis against Pneumocystis carinii in HIV infected patients. The indirect comparison showed substantial increased benefit from the former (odds ratio 0.37, 95% CI 0.21 to 0.65), while direct comparisons from randomized trials suggests a much smaller difference (risk ratio 0.64, 95% CI 0.45 to 0.90; p-value for difference of effect = 0.11). Direct comparisons of treatments should be sought. When direct comparisons are unavailable, indirect comparison meta-analysis should evaluate the magnitude of treatment effects across studies, recognizing the limited strength of inference.
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            Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis

            Objective To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs. Design Network meta-analysis. Data sources Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data. Study selection All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility. Data extraction The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data. Data synthesis 31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death. Conclusions Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.
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              EULAR evidence based recommendations for the management of hand osteoarthritis: report of a Task Force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT).

              To develop evidence based recommendations for the management of hand osteoarthritis (OA). The multidisciplinary guideline development group comprised 16 rheumatologists, one physiatrist, one orthopaedic surgeon, two allied health professionals, and one evidence based medicine expert, representing 15 different European countries. Each participant contributed up to 10 propositions describing key clinical points for management of hand OA. Final recommendations were agreed using a Delphi consensus approach. A systematic search of Medline, Embase, CINAHL, Science Citation Index, AMED, Cochrane Library, HTA, and NICE reports was used to identify the best available research evidence to support each proposition. Where possible, the effect size and number needed to treat were calculated for efficacy. Relative risk or odds ratio was estimated for safety, and incremental cost effectiveness ratio was used for cost effectiveness. The strength of recommendation was provided according to research evidence, clinical expertise, and perceived patient preference. Eleven key propositions involving 17 treatment modalities were generated through three Delphi rounds. Treatment topics included general considerations (for example, clinical features, risk factors, comorbidities), non-pharmacological (for example, education plus exercise, local heat, and splint), pharmacological (for example, paracetamol, NSAIDs, NSAIDs plus gastroprotective agents, COX-2 inhibitors, systemic slow acting disease modifying drugs, intra-articular corticosteroids), and surgery. Of 17 treatment modalities, only six were supported by research evidence (education plus exercise, NSAIDs, COX-2 inhibitors, topical NSAIDs, topical capsaicin, and chondroitin sulphate). Others were supported either by evidence extrapolated from studies of OA affecting other joint sites or by expert opinion. Strength of recommendation varied according to level of evidence, benefits and harms/costs of the treatment, and clinical expertise. Eleven key recommendations for treatment of hand OA were developed using a combination of research based evidence and expert consensus. The evidence was evaluated and the strength of recommendation was provided.

                Author and article information

                Br J Sports Med
                Br J Sports Med
                British Journal of Sports Medicine
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                May 2018
                7 February 2018
                : 52
                : 10
                : 642-650
                [1 ] departmentDepartment of Orthopaedics , Xiangya Hospital, Central South University , Changsha, Hunan, China
                [2 ] departmentDivision of Rheumatology, Allergy and Immunology, Department of Medicine , Massachusetts General Hospital, Harvard Medical School , Boston, Massachusetts, USA
                [3 ] departmentHealth Management Center , Xiangya Hospital, Central South University , Changsha, China
                [4 ] departmentAcademic Rheumatology , Clinical Sciences Building, University of Nottingham, City Hospital , Nottingham, UK
                [5 ] Arthritis Research UK Pain Centre , Nottingham, UK
                [6 ] Hunan Key Laboratory of Joint Degeneration and Injury , Changsha, Hunan, China
                [7 ] departmentNational Clinical Research Center of Geriatric Disorders , Xiangya Hospital, Central South University , Changsha, Hunan, China
                [8 ] Center for Clinical Technology and Research of Joint Surgery , Hunan, China
                Author notes
                [Correspondence to ] Dr Guanghua Lei, Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, Hunan, China; lei_guanghua@ 123456csu.edu.cn and Professor Weiya Zhang, Academic Rheumatology, Clinical Sciences Building, University of Nottingham, City Hospital, Nottingham, UK; weiya.zhang@ 123456nottingham.ac.uk
                © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                Funded by: Fundamental Research Funds for the Central Universities of Central South University;
                Funded by: Xiangya Clinical Big Data System Construction Project of Central South University;
                Funded by: Scientific Research Project of Science and Technology Office of Hunan Province;
                Funded by: Postdoctoral Science Foundation of Central South University;
                Funded by: Key Research and Development Program of Hunan Province;
                Funded by: Clinical Scientific Research Foundation of Xiangya Hospital, Central South University;
                Funded by: Young Investigator Grant of Xiangya Hospital, Central South University;
                Funded by: Natural Science Foundation of Hunan Province;
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Funded by: Scientific Research Project of the Development and Reform Commission of Hunan Province;
                Custom metadata

                Sports medicine

                osteoarthritis, meta-analysis


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