Systematic Review for Effectiveness of Hyaluronic Acid in the Treatment of Severe Degenerative Joint Disease (DJD) of the Knee

Purpose The Coverage and Analysis Group at the Centers for Medicare and Medicaid Services (CMS) requested from The Technology Assessment Program (TAP) at the Agency for Healthcare Research and Quality (AHRQ), a review of the evidence that intraarticular injections of hyaluronic acid (HA) in individuals with degenerative joint disease (osteoarthritis [HA]) of the knee improve function and quality of life (QoL) and that they delay or prevent the need for total knee replacement (TKR), specifically for individuals age 65 and over. AHRQ assigned this report to the following Evidence-based Practice Center: RAND Southern California Evidence –based Practice Center (Contract Number: HHSA290201200006I). Data Sources Searches of Medline, Cochrane Library, Web of Science, Clinicaltrials.gov , the FDA Premarket Approval database, and unpublished documents identified in grey literature searches or provided by manufacturers. Review Methods Randomized controlled trials (RCTs) or observational studies that reported on HA administration and delay or avoidance of TKR; double-blind placebo-controlled RCTs that reported on functional outcomes or QoL; RCTs, case reports, and large cohort studies and case series that assessed the safety of HA; and unpublished data identified through grey literature searches or provided by manufacturers for efficacy or safety outcomes, in human subjects of mean age 65 or older, were considered for inclusion, as were recent comprehensive systematic reviews that reported on the effects of HA injections on knee pain as an outcome. A standardized protocol with predefined criteria was used to extract details on study design, interventions, outcomes, and study quality and to analyze the data. Results Only one RCT reported on delay or avoidance of TKR as a pre-specified outcome of interest and found a non-statistically significantly longer delay of TKR compared with placebo; two RCTs reported TKR only as a secondary outcome; and 13 published observational studies reported on TKR as an outcome in HA-treated participants. Eighteen RCTs that enrolled participants of average age 65 or older reported on functional outcomes of intra-articular HA injection: pooled analysis of ten sham-injection placebo-controlled, assessor-blinded trials showed a standardized mean difference of −0.23 (95% CI −0.34, −0.02) significantly favoring HA at 6 months’ follow-up. Durability of effect could not be assessed because of the short duration of most studies. Too few head-to-head trials were available to assess superiority of one product over another. Three RCTs that compared changes in QoL/HRQoL between HA- and placebo-treated participants reported no differences between active treatment and placebo. Two recent large, good quality systematic reviews that conducted meta-analysis of the effects of HA on pain and function (pooling 71 and 52 RCTs for the outcome of pain, respectively) showed a significant and clinically important effect of HA on both outcomes among adults of all ages, but a subgroup analysis that included only the largest double-blind placebo-controlled studies reduced the average effect of HA to less than the prespecified minimum clinically important difference. Studies of intra-articular HA reported few serious adverse events, with no statistically significant difference in the rates of serious or non-serious adverse events between HA- and placebo-treated groups. Conclusions Trials enrolling older participants show a small, statistically significant effect of HA on function and relatively few serious adverse events; however no studies limited participation to those 65 years or older. No conclusions can be drawn from the available literature on delay or avoidance of TKR through the use of HA. Studies that can compare large numbers of treated and untreated individuals, preferably with a randomized design, are needed to answer this question.