Intra-articular Hyaluronic Acid in Treating Knee Osteoarthritis: a PRISMA-Compliant Systematic Review of Overlapping Meta-analysis

Scientific Reports, Sep 2016

Numerous meta-analyses have been conducted aiming to compare hyaluronic acid (HA) and placebo in treating knee osteoarthritis (OA). Nevertheless, the conclusions of these meta-analyses are not in consistency. The purpose of the present study was to perform a systematic review of overlapping meta-analyses investigating the efficacy and safety of HA for Knee OA and to provide treatment recommendations through the best evidence. A systematic review was conducted based on the PRISMA guidelines. The meta-analyses and/or systematic reviews that compared HA and placebo for knee OA were identified. AMSTAR instrument was used to evaluate the methodological quality of individual study. The information of heterogeneity within each variable was fetched for the individual studies. Which meta-analyses can provide best evidence was determined according to Jadad algorithm. Twelve meta-analyses met the eligibility requirements. The Jadad decision making tool suggests that the highest quality review should be selected. As a result, a high-quality Cochrane review was included. The present systematic review of overlapping meta-analyses demonstrates that HA is an effective intervention in treating knee OA without increased risk of adverse events. Therefore, the present conclusions may help decision makers interpret and choose among discordant meta-analyses.

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Intra-articular Hyaluronic Acid in Treating Knee Osteoarthritis: a PRISMA-Compliant Systematic Review of Overlapping Meta-analysis

Intra-articular Hyaluronic Acid in Treating Knee Osteoarthritis: a PRISMA-Compliant Systematic Review of Overlapping Meta- analysis Dan Xing 0 Bin Wang 0 Qiang Liu 0 Yan Ke 0 Yuankun Xu 0 Zhichang Li 0 Jianhao Lin 0 0 Arthritis Clinic & Research Center, Peking University People's Hospital, Peking University , Beijing , China OPEN Numerous meta-analyses have been conducted aiming to compare hyaluronic acid (HA) and placebo in treating knee osteoarthritis (OA). Nevertheless, the conclusions of these meta-analyses are not in consistency. The purpose of the present study was to perform a systematic review of overlapping meta-analyses investigating the efficacy and safety of HA for Knee OA and to provide treatment recommendations through the best evidence. A systematic review was conducted based on the PRISMA guidelines. The meta-analyses and/or systematic reviews that compared HA and placebo for knee OA were identified. AMSTAR instrument was used to evaluate the methodological quality of individual study. The information of heterogeneity within each variable was fetched for the individual studies. Which meta-analyses can provide best evidence was determined according to Jadad algorithm. Twelve meta-analyses met the eligibility requirements. The Jadad decision making tool suggests that the highest quality review should be selected. As a result, a high-quality Cochrane review was included. The present systematic review of overlapping meta-analyses demonstrates that HA is an effective intervention in treating knee OA without increased risk of adverse events. Therefore, the present conclusions may help decision makers interpret and choose among discordant meta-analyses. - reported that HA is not recommended in the treatment of Knee OA13. However, Altman et al.14 investigated ten guidelines regarding the use of HA for the treatment of knee OA and reported that the recommendations were highly inconsistent as a result of the variability in guideline methodology. Thus, the inconsistent recommendations make it difficult for clinical professionals to determine its appropriateness when treating knee OA. The purpose of the present study is to perform a systematic review of overlapping meta-analyses determining the clinical effects of HA in treating Knee OA, to evaluate the mythological quality of included individual meta-analyses, and to take best evidence through the currently inconsistent evidence. Materials and Methods Search strategy. The present systematic review was conducted following the guideline of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis) statement15. PRISMA statement was used to guarantee high-quality reporting of systematic reviews or meta-analyses16. Electronic databases including MEDLINE, EMBASE and Cochrane library were searched for all meta-analysis or systematic review published through Nov 2015. The following MeSH items or free words were taken: osteoarthritis, knee, meta-analysis, systematic review, and hyaluronic acid. The references of searched studies were also reviewed to explore other meta-analyses or systematic reviews. No restrictions were made on the publication language. Inclusive and exclusive criteria. criteria: Studies were considered eligible for inclusion if they met the following (1) Meta-analyses or systematic reviews only including randomized controlled trial (RCT); (2) Meta-analyses or systematic reviews comparing HA with placebo in treating knee OA; (3) Meta-analyses or systematic reviews reported at least one variable (such as pain, function, and safety). Exclusion criteria included the following items: (1) Meta-analyses or systematic reviews including non-RCT; (2) Systematic reviews did not conducting meta-analysis or pooling data; (3) Abstract, commentary, methodological study, narrative review. Meta-analyses/systematic reviews selection. Firstly, two reviewers assessed the titles and abstracts of researched studies for the eligibility criteria independently. The two reviewers were not blinded to the journals, organizations, financial assistance, conflict of interest and researchers’ information. Subsequently, the full text of the studies that potentially met the inclusion criteria was read to determine the final inclusion. Any disagreement was resolved by reaching a consensus through discussion. Date extraction. Two reviewers independently extracted the data from each included literature by the use of a standard data extraction form. The following items were extracted: title, authors, original study design, database, total number of studies, level of evidence, the pooled results and methodological variables. Assessment of methodological quality. The quality assessment was independently conducted by two authors. Disagreements were resolved by discussion or a third reviewer was involved. The Assessment of Multiple Systematic Reviews (AMSTAR) method was used to evaluate the methodological quality of included studies17. The AMSTAR was a measurement scale containing eleven items, and it was applied extensively in assessing methodological quality of published meta-analysis or systematic review18. Heterogeneity within included studies. Heterogeneity of each outcome (primary and secondary outcomes) was reported for the each included meta-analyses. The following two questions were also evaluated: whether sensitivity analysis was performed in meta-analysis and whether the included meta-analyses evaluated potential sources of heterogeneity across primary studies. Upon the Cochrane Handbook, Heterogeneity of each outcome between 0% and 40% is regarded as not important; between 30% and 60% is moderate; between 50% and 90% is substantial, and between 75% and 100% is considerable. Therefore, I2 less than 60% are accepted in the present study. Choice of best evidence. Treatment recommendations were made according to the Jadad decision algorithm19. The methodological instrument confirmed the source of inconsistence between meta-analyses, including differences in clinical problem, inclusion and exclusion standard, extracted data, methodological quality assessment, data combining, and statistical analysis methods19. The application of algorithm was performed by two independent reviewers. Our evaluation group came to conformity as to which of included meta-analyses can provide best evidence based on the current information. Results Literature search. Thirty-three titles and abstracts were preliminarily identified with the first search strategy, of which 12 of the published meta-analyses6,9–12,20–26 ultimately met the eligibility criteria (Fig. 1). Two studies27,28 were excluded because they conducted network meta-analysis among each kinds of HA. Three meta-analyses29–31 were excluded because they were performed to compare the efficacy and safety of HA with corticosteroids. Three studies, including primary studies in ankle/hip joints, were also excluded32–34. Strand et al.6 − + − + − − − − − − − − − − + + + − − − + − − − − − − − − + − + + − − + − − − − − − − − − − + − − − + − − − − Strand et al.6 + + − + + − − − − + − − − + + − − − − − − − + + − − − − − − − − − − − − − − − + − − − − + − − − − + − − + Heterogeneity Assessment. Table 6 presented the data of heterogeneity of each variable in each meta-analysis. The I2 value was adopted to calculate the heterogeneity among original studies as a measurement aiming to ascertain the inter-studies variability in all included meta-analyses. Authors Results of Jadad Decision Algorithm. All outcomes reported in primary meta-analyses were reported in Fig. 2. According to the following three respects (the meta-analyses addressed the same clinical question, did not include the same original studies, and not have similar inclusion/exclusion criteria), the Jadad algorithm proposed that the eligible meta-analyses can be elected on account of the methodological quality and publication statue (Fig. 3). As a result, a Cochrane meta-analysis25 with highest quality was selected. Bellamy et al. supported the use of the HA in the treatment of knee OA with beneficial effects on pain, function and patient global assessment. Discussion According to the above mentioned methodology, the meta-analysis conducted by Bellamy et al.25 is with highest quality compared with others. The best available evidence hints that HA is an effective intervention in treating knee OA without increased risk of adverse events. Therefore, the current evidence supports the use of the HA in the treating knee OA. Meta-analyses or systematic reviews are commonly regarded as the highest level of clinical evidence35. Clinicians can make meaningful clinical decisions with the help of meta-analyses or systematic reviews. However, a larger number of meta-analyses involving in the same clinical question have been published with conflicting results. This phenomenon was also occurred in the evidence-based study in HA injections for knee OA. Although numerous meta-analyses or systematic reviews have been written in treating knee OA via HA, there was still in controversy. Such discrepancy results in some difficulties for decision makers (including clinicians, policymakers and patients, depending on the context) who rely on this synthesized evidence to help them make decisions among pharmacological interventions when the results of trials are not unanimous. Jadad et al.19 concluded the following potential sources of inconsistency among meta-analyses, including the clinical topic, eligible criteria, data extraction, quality assessment, assessment of the ability to combine studies, and statistical methods for data synthesis. Furthermore, Jadad et al.19 provided a decision methodological tool which summarizes the process for identifying and resolving causes of discordance. The ultimate purpose was to Sensitivity analysis Subgroup analysis GARDE evidence profiles YES NO YES YES NO YES YES YES NO YES NO YES 1 1 1 1 0 1 1 1 1 1 1 10 0 1 1 1 0 0 0 0 1 0 1 5 -NO YES NO NO NO NO YES YES NO NO NO YES 0 0 0 0 0 1 1 0 1 0 1 4 1 1 1 1 0 1 0 0 1 1 1 8 NO NO NO NO NO NO NO NO NO NO NO NO 0 0 1 1 0 1 1 0 1 1 1 7 Outcomes Overall pooled effect size Lequesne index score (early) Lequesne index score (late) Knee function (early) Knee function (late) Knee stiffness Physical function Pain with activities (early) Pain with activities (early) Pain during or immediately after exercise (early) Pain during or immediately after exercise (late) Patient global assessment (early) Patient global assessment (late) Pain at rest (early) Pain at rest (late) Knee pain outcomes (early) Knee pain outcomes (late) WOMAC pain WOMAC phsical function Overall adverse events Flare-ups Injection-site reaction Injection-site pain Arthralgia Arthropathy/arthrosis/arthritis Back pain Headache Knee effusion Discontinued due to adverse event Overall study withdrawal Mortality posttreatment standardized mean difference. The statistic results represented very large treatment effects for HA. Thus, it reported that US-approved HA is safe and efficacious through 26weeks in treating knee OA. The primary limitations of this meta-analysis include the following: (1) English language studies were included in the present overlapping meta-analyses. Although numerous meta-analyses were included in the present study, it is possible that we have omitted non-English language reviews. (2) Several factors of primary trials, such as study design, publication bias and clinical heterogeneity, may influence interpretation. (3) The selected meta-analysis was published in 2006, which will influence the stability of the results. Newest published high-quality meta-analyses are needed to confirm the present evidence. To sum up, the present systematic review of overlapping meta-analyses investigated efficacy and safety of HA in treating Knee OA. Currently, the best evidence suggested that HA is an effective intervention in treating knee OA without increased risk of adverse events. Therefore, the evidence supports the use of the HA in the treating knee OA. Further studies with effect size statistic are still required to qualify the clinical efficacy. 1 0 Author Contributions D.X. and Y.X. conducted literature search and determined studies for exclusion and inclusion. D.X., Q.L., Z.L. and Y.K. extracted data from the included studies, performed quality assessment, and drafted the manuscript. J.L., D.X. and B.W. conceived the idea of the study, designed the study, and critically revised the manuscript for important intellectual content. All authors reviewed the paper and approved the final manuscript. Additional Information Competing financial interests: The authors declare no competing financial interests. How to cite this article: Xing, D. et al. Intra-articular Hyaluronic Acid in Treating Knee Osteoarthritis: a PRISMA-Compliant Systematic Review of Overlapping Meta-analysis. Sci. Rep. 6, 32790; doi: 10.1038/ srep32790 (2016). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ This work was supported by funding from National Natural Science Foundation of China (no. 81501919 and no . 81357989 ).


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Dan Xing, Bin Wang, Qiang Liu, Yan Ke, Yuankun Xu, Zhichang Li, Jianhao Lin. Intra-articular Hyaluronic Acid in Treating Knee Osteoarthritis: a PRISMA-Compliant Systematic Review of Overlapping Meta-analysis, Scientific Reports, 2016, DOI: 10.1038/srep32790