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Meta-Analysis
. 2022 Jul 6:378:e069722.
doi: 10.1136/bmj-2022-069722.

Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis

Tiago V Pereira  1   2 , Peter Jüni  1   3   4 , Pakeezah Saadat  1   3 , Dan Xing  5 , Liang Yao  6 , Pavlos Bobos  1   7 , Arnav Agarwal  3   6 , Cesar A Hincapié  8   9 , Bruno R da Costa  10   3   11
Affiliations
Meta-Analysis

Viscosupplementation for knee osteoarthritis: systematic review and meta-analysis

Tiago V Pereira et al. BMJ. .

Abstract

Objective: To evaluate the effectiveness and safety of viscosupplementation for pain and function in patients with knee osteoarthritis.

Design: Systematic review and meta-analysis of randomised trials.

Data sources: Searches were conducted of Medline, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to 11 September 2021. Unpublished trials were identified from the grey literature and trial registries.

Eligibility criteria for study selection: Randomised trials comparing viscosupplementation with placebo or no intervention for knee osteoarthritis treatment.

Main outcome measures: The prespecified primary outcome was pain intensity. Secondary outcomes were function and serious adverse events. Pain and function were analysed as standardised mean differences (SMDs). The prespecified minimal clinically important between group difference was -0.37 SMD. Serious adverse events were analysed as relative risks.

Methods: Two reviewers independently extracted relevant data and assessed the risk of bias of trials using the Cochrane risk of bias tool. The predefined main analysis was based only on large, placebo controlled trials with ≥100 participants per group. Summary results were obtained through a random effects meta-analysis model. Cumulative meta-analysis and trial sequential analysis under a random effects model were also performed.

Results: 169 trials provided data on 21 163 randomised participants. Evidence of small study effects and publication biases was observed for pain and function (Egger's tests with P<0.001 and asymmetric funnel plots). Twenty four large, placebo controlled trials (8997 randomised participants) included in the main analysis of pain indicated that viscosupplementation was associated with a small reduction in pain intensity compared with placebo (SMD -0.08, 95% confidence interval -0.15 to -0.02), with the lower bound of the 95% confidence interval excluding the minimal clinically important between group difference. This effect corresponds to a difference in pain scores of -2.0 mm (95% confidence interval -3.8 to -0.5 mm) on a 100 mm visual analogue scale. Trial sequential analysis for pain indicated that since 2009 there has been conclusive evidence of clinical equivalence between viscosupplementation and placebo. Similar conclusions were obtained for function. Based on 15 large, placebo controlled trials on 6462 randomised participants, viscosupplementation was associated with a statistically significant higher risk of serious adverse events than placebo (relative risk 1.49, 95% confidence interval 1.12 to 1.98).

Conclusion: Strong conclusive evidence indicates that viscosupplementation leads to a small reduction in knee osteoarthritis pain compared with placebo, but the difference is less than the minimal clinically important between group difference. Strong conclusive evidence indicates that viscosupplementation is also associated with an increased risk of serious adverse events compared with placebo. The findings do not support broad use of viscosupplementation for the treatment of knee osteoarthritis.

Systematic review registration: PROSPERO CRD42021236894.

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Conflict of interest statement

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Arthritis Society, Canada Research Chairs Programme, National Institute for Health Research, Chevening Scholarship Program for the submitted work. PJ serves as unpaid member of the steering group of trials funded by Appili Therapeutics, Abbot Vascular, and Terumo; he has received research grants to the institution from Appili Therapeutics, and honorariums to the institution for participation in advisory boards or consulting from Amgen, Ava and Fresenius, but has not received personal payments by any pharmaceutical company or device manufacturer. All other authors report no financial relationships with any organisations that might have an interest in the submitted work in the previous three years. All authors report no other relationships or activities that could appear to have influenced the submitted work.

Figures

Fig 1
Fig 1
Flowchart showing steps in the selection of relevant trials. RCT=randomised controlled trial
Fig 2
Fig 2
Main and subgroup analyses for pain. Results are based on 24 large, placebo controlled trials, including 8997 randomised participants. The shaded areas represent the areas of clinical equivalence (darker areas represent the minimal clinically important difference of 0.37, lighter areas represent the more stringent 0.2 margin of equivalence). P denotes two tailed P values for interaction (two subgroups only) or trend tests for interaction (three or more subgroups). For the molecular weight categories, the P value was based on a simple interaction test because one trial examined a preparation made of high and low molecular weight hyaluronic acids. Cycles: patients are usually given a single injection or a course of two to six injections; one cycle refers to one such course of treatment. Number of participants analysed (shown for each subgroup) might be smaller than number of randomised participants. A τ2 of up to 0.04 was prespecified to represent low heterogeneity, 0.09 to represent moderate, and 0.16 to represent high statistical heterogeneity among trial estimates. visco=viscosupplementation
Fig 3
Fig 3
Cumulative pooled analysis for knee pain based on large, placebo controlled trials (n=24 trials, 8997 patients randomised). The shaded areas represent the areas of clinical equivalence (darker areas represent the minimal clinically important difference of 0.37, lighter areas represent the more stringent 0.2 margin of equivalence). Results are for random effects model. Over the years, between trial variance estimates (τ2) varied between 0 and 0.02, suggesting low heterogeneity. P values for equivalence are based on two one sided tests. The number of participants analysed might be smaller than the number of randomised participants
Fig 4
Fig 4
Main and subgroup analyses for function. Results are based on 19 large, placebo controlled trials, including 6307 randomised participants. The shaded areas represent the areas of clinical equivalence (darker areas represent the minimal clinically important difference of 0.37, lighter areas represent the more stringent 0.2 margin of equivalence). P denotes two tailed P values for interaction (two subgroups only) or trend tests for interaction (three or more subgroups). For the molecular weight categories, the P value was based on a simple interaction test because one trial examined a preparation made of high and low molecular weight hyaluronic acids. Cycles: patients are usually given a single injection or a course of two to six injections; one cycle refers to one such course of treatment. Number of participants analysed (shown for each subgroup) might be smaller than number of randomised participants. A τ2 of up to 0.04 was prespecified to represent low heterogeneity, 0.09 to represent moderate, and 0.16 to represent high statistical heterogeneity among trial estimates. visco=viscosupplementation
Fig 5
Fig 5
Trial sequential analysis for pain. Results are based on 24 large, placebo controlled trials (8997 randomised participants). Cumulative z scores were calculated under a random effects model. RIS (required information size; vertical lines) detects a minimal clinically important difference of −0.37 with 90% of power at α level of 0.005. O'Brien-Fleming monitoring boundaries are represented by dashed orange lines. The inner wedges (futility boundaries) are shown in pink and represent limits to the equivalence region considering the 0.2 equivalence margin. Circles denote cumulative z score for each additional trial added to the analysis. Between trial variation was accounted for using diversity (D2) index adjusted sample sizes. A D2 of 50% was assumed. Number of participants analysed (shown by year) might be smaller than number of randomised participants
Fig 6
Fig 6
Trial sequential analysis of 15 large placebo controlled trials for serious adverse events. The analysis was based on 6462 randomised participants. Given the weak association between viscosupplementation and pain reduction in knee osteoarthritis, any increase in risk of serious adverse events caused by viscosupplementation compared with placebo can be considered a clinically important increase. Cumulative z scores are calculated under a random effects model. RIS (required information size) was calculated as the sample size that gives a trial 80% power to detect a 50% relative risk (RR) increase of serious adverse events, assuming a control event rate of 2.5% and a two sided α=0.05. O’Brien-Fleming monitoring boundaries are represented by dashed orange lines. Circles denote the z score for each additional trial. A D2 of 25% was assumed. Non-peer reviewed reports had their disclosure year defined as the earliest year in which the document was first officially created (when available within the file), year of online publication (eg, results first posted date on ClinicalTrials.gov), or the date on which the material was made available for review. Number of participants analysed (shown by year) might be smaller than number of randomised participants
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