One-year efficacy and safety of single or one to three weekly injections of hylan G-F 20 for knee osteoarthritis: a systematic literature review and meta-analysis

The aim of this study was to evaluate the long-term efficacy and safety of single or 1–3 weekly injections of hylan G-F 20 at 1 year following the first injection for knee osteoarthritis (OA). Searches were conducted in PubMed/MEDLINE, Embase, and CENTRAL and included relevant conference proceedings (January 1, 1995–August 17, 2020). Randomized controlled trials (RCTs), non-randomized trials, and observational studies investigating 1-year efficacy and safety of 1–3 weekly injections or single hylan G-F 20 injection for knee OA were included. Primary outcomes were WOMAC pain, physical function, and stiffness. Meta-analyses of RCTs and non-randomized studies were conducted separately. Our search identified 24 eligible studies. Hylan G-F 20, in the meta-analyses of RCTs, showed statistically significant improvement in WOMAC pain (SMCC − 0.98, 95% CI − 1.50, − 0.46), physical function (SMCC − 1.05, 95% CI − 1.28, − 0.83), and stiffness (SMCC − 1.07, 95% CI −1.28, −0.86). Improvement was also seen for VAS pain, SF-36 MCS (mental component summary), and SF-36 PCS (physical component summary). Analyses of non-randomized studies showed similar efficacy estimates. There were no significant differences in efficacy based on injection schedule, nor between RCT and non-randomized studies. Rates of adverse events (AEs) were low for most types of AEs. Hylan G-F 20 (either as single or 1–3 weekly injections) showed improvement in 1-year efficacy outcomes in comparison to baseline and was generally well tolerated. While further research will inform the medical field regarding viscosupplementation treatment options for knee OA, these findings show that hylan G-F 20 at both frequencies/dosages are efficacious and generally well tolerated for long-term use. Supplementary Information The online version contains supplementary material available at 10.1007/s10067-020-05477-7.


Supplemental Material
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Hylan        Describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.
Selection bias (biased allocation to interventions) due to inadequate generation of a randomized sequence.
Allocation concealment. Describe the method used to conceal the allocation sequence in sufficient detail to determine whether intervention allocations could have been foreseen in advance of, or during, enrolment.
Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment.

Blinding of participants and personnel
Assessments should be made for each main outcome (or class of outcomes).
Describe all measures used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.
Performance bias due to knowledge of the allocated interventions by participants and personnel during the study.

Detection bias
Blinding of outcome assessment Assessments should be made for each main outcome (or class of outcomes).
Describe all measures used, if any, to blind outcome assessors from knowledge of which intervention a participant received. Provide any information relating to whether the intended blinding was effective.
Detection bias due to knowledge of the allocated interventions by outcome assessors.

Attrition bias
Incomplete outcome data Assessments should be made for each main outcome (or class of outcomes).
Describe the completeness of outcome data for each main outcome, including attrition and exclusions from the analysis. State whether attrition and exclusions were reported, the numbers in each intervention group (compared with total randomized participants), reasons for attrition/exclusions where reported, and any re-inclusions in analyses performed by the review authors.
Attrition bias due to amount, nature or handling of incomplete outcome data.

Reporting bias
Selective reporting State how the possibility of selective outcome reporting was examined by the review authors, and what was found.
Reporting bias due to selective outcome reporting.

Other bias
Other sources of bias State any important concerns about bias not addressed in the other domains in the tool. If particular questions/entries were pre-specified in the review's protocol, responses should be provided for each question/entry.
Bias due to problems not covered elsewhere in the table.  The Newcastle-Ottawa Scale is an instrument that is used to evaluate three domains of bias: selection of study groups, comparability of the groups, and assessment of outcome/exposure (Table S9). 25 Each highquality item was allocated with a star. A maximum of one star can be designated for each item within the "Selection" and "Outcome/Exposure" and a maximum of two stars for "Comparability." The sum of stars for each study can range from 0 to 9 stars. Studies are rated as low (0-3 stars), moderate (4-6 stars), or high (7-9 stars) quality.
The quality of 10 non-RCT studies were assessed with the Newcastle-Ottawa Scale (Table S10).
Boutefnouchet et al. 2017 5 is a case series and was not assessed using the Newcastle-Ottawa Scale as the scale is designed for cohort and case control studies. Overall, studies were mainly rated as moderate quality.