We conducted a NMA of the efficacy of intra-articular injection of HA versus IAS and IAP injections in OA of the knee. To our knowledge, this is the first study to use a NMA to assess the effectiveness of HA injection for knee OA through comparison of OMERACT-OARSI responder rates. Our results demonstrate evidence of small but statistically significant improvement for the group of subjects treated with HA injections compared with those treated with IAS or IAP injections with regard to pain and function as assessed by the relevant WOMAC subscales. Furthermore, on an individual level, our results indicate that HA instillation led to a 15% and 11% greater chance of achieving OARSI responder status than did IAS and IAP, respectively, each statistically significant. The OMERACT-OARSI criteria were developed in 2003 to standardize the assessment of individuals in clinical trials for knee OA who demonstrate a significant clinical response as a consequence of one or more treatment interventions (Pham et al, 2003). As such, by its very definition, statistically significant changes in OMERACT-OARSI responder rates represent clinically significant differences. Thus, the statistically significant results that we have identified for HA versus IAS and IAP also represent a clinically relevant difference.
We found no statistical or clinical benefit for IAS injection versus IAP injection, despite using the time point of maximal IAS benefit for comparison with IAP. Similarly, we were unable to identify significant differences in treatment response when comparing the efficacy of low versus high molecular weight HA products compared with IAP injection, a finding that was influenced by the limitation in power imposed by the paucity of studies of adequate quality to compare the effects of products of different molecular weights.
Our results of statistically significant benefit of HA injections over IAP injections are consistent with several of the previous meta-analyses of HA injections for knee OA.28–31 When analyzed in terms of mean rather than individual responses, the small effect size in our study (0.2) was also consistent with the majority of previous studies29 except for 1 study with smaller effect size.32 By way of context, the effect size identified by our study, although small, is similar to that found in a meta-analysis of nonsteroidal anti-inflammatory drugs (NSAIDs) for knee OA.32 The interpretation of the clinical relevance of the small statistical benefit has varied among reviews and has been considered controversial.33 Accordingly, our interpretation of the data, specifically our OMERACT-OARSI results reflecting superiority of HA injection over IAS and IAP, concurs with certain previous reviews28,31 by demonstrating a meaningful clinical correlate to the statistical benefit from HA injections, although not with other studies29,32 that have interpreted the data as reflecting no clinical benefit. The divergent conclusions from previous studies have been attributed to the varied methodology used in study selection, the assessment of effect size, and the interpretation of the clinical relevance of the statistical results.33 Furthermore, the relatively large and persistent placebo effects found in trials of knee OA in general, but particularly seen among trials using intra-articular saline controls, have been recognized as substantial barriers to OA therapeutics34 including viscosupplements.35 In fact, given that arthrocentesis with or without saline injection has been recognized as an effective intervention in knee OA patients presenting with a significant knee effusion,36 some researchers have suggested that intra-articular saline “placebo” injections might better be categorized as active controls rather than as “placebos.”33 As a consequence of the uncertainty generated by these issues, when the results of previous systematic reviews and meta-analyses have been used to generate evidence-based guidelines for the treatment of knee OA, recommendations regarding the use of HA injections have typically been measured. Thus, in their latest iterations, the American College of Rheumatology37 makes no official recommendation for the use of HA injections and the OARSI guidelines rate the benefit from HA as uncertain.38 A notable exception to this trend was the recent guideline published by the AAOS10 that changed their previous recommendation regarding the use of HA injections for knee OA from “inconclusive” to “strongly recommending against” its use. Of note, the latest AAOS review demonstrated the statistically significant benefit for HA injection on the WOMAC pain, stiffness, and function subscales that have been noted in most other reviews, including the previous AAOS review. The AAOS panel strongly recommended against the use of HA injections based on a re-evaluation of the existing literature according to a change in the analytic method by which clinical relevance was assessed.
The guideline relied on a relatively new outcome measure, the minimum clinical important improvement (MCII). The MCII and a closely-related concept that relates either improvement or worsening, the minimal clinically important difference,39 represent an effort by investigators to incorporate subjects' expectations for improvement from a given intervention into the assessment of its efficacy.39,40 Although these outcome measures are recognized as an important innovation for use in assessing the clinical relevance of statistical results in OA research trials, the methodology applied in certain guidelines has been criticized on several accounts.41 It should be noted that the MCII has not been adequately validated for use in isolation to guide clinical decision making.2 Furthermore, the application of the MCII in some guidelines does not seem to account for the variance in MCII by baseline symptom severity,39 treatment type,42 age, and trial assessment intervals.43 Thus, when the AAOS investigators used studies of NSAIDs and rehabilitation to generate a single cut-off value to assess MCII responses to HA injection with placebo controlled between group comparisons, the cut-off values to assess the MCII as a determinant of HA efficacy may have been higher than the appropriate level, thus biasing the results toward fewer studies achieving clinically relevant results.41 We used an alternative approach to capture the experience of individual subjects undergoing treatment in OA studies, the OMERACT-OARSI responder criteria,44 which seeks to identify the proportion of subjects who meet preset criteria for response as individuals. Using the OARSI responders, we are looking at the benefit to the individual patient rather than the benefit averaged across the group. Our NMA found that subjects undergoing HA injections had 15%, and 11%, greater likelihood of achieving an OARSI response versus IAS and IAP, respectively. This finding contradicts other's assertion, inferred from MCII results, that there is “a low likelihood that an appreciable number of (individual) patients achieved clinically important benefits in the outcomes.” Furthermore, the AAOS document seems to lack internal consistency with regard to its recommendations for IAS and HA injections. Unlike the AAOS study, our study design allowed a direct comparison of these treatments through the use of a NMA and has reached different conclusions.
A strong recommendation against the use of an HA injection is not without consequence, because individual patients find benefit from HA injections, as we demonstrate in this article. An incorrect recommendation against the use of HA may encourage third party payers to limit or eliminate reimbursement for HA as a cost-saving measure (commentary in Washington State Health Care Authority, Health Technology Assessment. “Hyaluronic Acid/Viscosupplementation Draft Evidence Report: Public Comment & Response.” Accessed online February 15, 2015, http://hca.wa.gov/hta/Documents/ha-visco_final_report_101113.pdf). Furthermore, given the limited armamentarium of nonoperative interventions available to treat symptomatic knee OA and that HA injections are typically reserved for those patients who are unresponsive to first-line lifestyle interventions, including exercise, weight loss, and oral medications, it is possible that an increase in the number of surgical procedures may result, in the absence of HA injections, although a recent meta-analysis of this question was inconclusive (Newberry et al, 2014). Two recent studies (Bannaru et al, 2015; Newberry et al, 2014) supported with funding from the Agency for Healthcare Research and Quality (ARHQ) have investigated questions related to the efficacy of HA on knee OA that differ from the focus of our research. Bannuru et al (Bannuru et al, 2015) performed the only other NMA of HA in knee OA use of which we are aware as part of a more global investigation of nonoperative treatment options. Although OMERACT-OARSI responder rates were not investigated, the results obtained with regard to HA injections are consistent with those we report. Specifically, HA injections demonstrated statistically significant benefit when prespecified criteria were met for clinical significance, which with regard to pain demonstrated the largest effect size (0.63, CI, 0.39-0.88) of any treatment tested. These investigators also noted greater improvement in response to intra-articular injections, including HA injections, than from oral treatments, and statistically significant improvements from HA injections in function when compared with IAS and IAP and stiffness when compared with IAP. Contrarily, another recent ARHQ-funded review (Newberry et al, 2014) that specifically targeted the population of severe OA of the knee found no functional benefit from HA injections and insufficient evidence to assess delay or avoidance of total knee replacement as a benefit of HA injections. Of note, the methodology of this latter ARHQ-funded study differs from ours in the impact of HA injection on pain, the most frequently assessed outcome parameter in the HA studies included in their analysis (Newberry et al, 2014) was not assessed. The differences reported between these 2 previous studies and our results likely reflect methodological differences.
Substantial heterogeneity in an individual's response to HA injections is suggested by the limited magnitude of the mean changes seen across groups in contrast to the more substantial changes we have demonstrated in individual responsiveness by OARSI responder criteria. It would seem that certain individuals respond more robustly than others to HA injection. Such variation in individual response has also been recognized for IAS injections.45 Numerous clinical parameters, including subject age,30 the presence46 or absence47 of effusion, higher baseline function,47 synovial fluid HA concentration,49 and certain structural measures (eg, the severity30 or location of joint damage46) have been suggested to improve an individual's responsiveness to injection. However, efforts to prospectively identify a set of clinical parameters that predict a favorable response to HA injection have been unsuccessful to date (Koolaee et al, 2014). Furthermore, when assessing the value of HA injections for knee OA, the magnitude of symptomatic benefit may not be the only criterion on which recommendations should be made. For instance, even among those without significant symptomatic improvement, HA injections may have structural benefit to cartilage, a long-held theory50 which has been supported by a recent study that links a decrease in synovial fluid hyaluronan molecular weight distribution with an increased risk of progressive cartilage loss in OA (Band et al, 2015). Similarly, the benefit of HA injection on symptoms and/or osteoarthritic cartilage may or may not allow delay in total knee replacement surgery.51 Putative mechanisms through which HA may reduce OA progression include improved cartilage/synovial fluid rheology, increased synthesis of extracellular matrix constituents including better “quality” HA, suppression of inflammatory mediators (eg, cytokines, prostaglandins, nitric oxide), reduction in fibronectin fragment-induced damage, and alteration in immune cell activity.52 Hyaluronic acid–mediated chondroprotection has been demonstrated in animal, in vitro, and clinical studies,52 including a recent article53 that found a decreased rate of medial and lateral tibial articular cartilage degeneration after HA injections through the use of a state-of-the art magnetic resonance imaging–based assessment of cartilage integrity. Other studies of the structural impact of HA injections of similar design have, however, failed to demonstrate structural benefit to cartilage from one series of injections.54 Thus, for patients with knee OA, HA injections may offer benefits that extend beyond the issues of the statistical significance and clinical relevance of the symptomatic results that they eventuate.
We chose to analyze the data regarding HA injections for knee OA according to a novel temporal scheme. We compared the results for each treatment at the time of the maximal treatment efficacy across studies rather than selecting a consistent single time from injection. Thus, the time at which data were assessed varied between some studies. When comparing HA with IAS, we used the time of optimal HA benefit for analysis of studies of HA versus IAS injections as our intent was to investigate whether HA injections had significant clinical efficacy at any time point. Our results suggest that maximal benefit occurs at different times after injection with HA and IAS. These results are consistent with previous systematic reviews28,55,56 that found superiority of IAS injection over HA injection from 0 to 4 weeks after administration but that HA injection was superior to IAS from 4 to 26 weeks. In this regard, each injectable medication may have a different role in treating those with knee OA. Specifically, IAS may have utility to rapidly abort a flare of knee OA,57 where rapid onset is required as a bridge to additional treatment including physical therapy which might, otherwise, prove too painful. Hyaluronic acid injections, contrarily, may be used to yield longer-term control of baseline symptoms but may not be appropriate for the treatment of acute exacerbations given the longer time to onset of relief.
Our study has several limitations. We did not include unpublished trials, although we searched for these items, a factor which may be biased toward the positive direction because of publication bias. However, the Egger value indicates that it is unlikely that publication bias exists. Furthermore, the outcome measures, assessment times, and study designs used in the included HA studies varied widely. Furthermore, as OARSI responder rates were not collected in all trials, we compared only trials that collected this data in this portion of our analysis. We had access to study level data only, not individual patient data, and were, thus, unable to impute OARSI responses from other trials. Additionally, a wide variety of HA products of different structure and molecular weight are available but we were unable to identify significant changes in efficacy related to these differences. Finally, our study is unable to distinguish whether the accuracy of HA injection affects its efficacy, for example, whether the use of ultrasound-guidance would improve the efficacy of HA injections in knee OA. A recent review by the AMSSM finds that ultrasound-guided (USG) injection in the knee is more accurate and that USG IAS injection is more efficacious than landmark-guided (LMG) injection.58 The significance of this difference for IAS injection is unknown for HA injections, as we are unaware of any published trials comparing USG versus LMG injections of HA for knee OA. Our data may better approximate the results of those using LMG injections in clinical practice if indeed a difference in efficacy and accuracy with USG exists for HA injection.
In light of the aforementioned results of our NMA, the AMSSM recommends the use of HA for the appropriate patients with knee OA. Using The Grades of Recommendation, Assessment, Development and Evaluation Working Group system,15 there are multiple RCTs indicating HIGH-QUALITY evidence.
“We RECOMMEND viscosupplementation injections for K-L grade II-III knee osteoarthritis in those patients above the age of 60 years based on HIGH quality evidence demonstrating benefit using OMERACT-OARSI Responder Rating.”
But the evidence should be downgraded because of indirectness for those younger than 60 years.
“We SUGGEST viscosupplementation injections for knee osteoarthritis for those under the age of 60 years based on MODERATE quality evidence due to response of treatment in those over 60 years of age.”
We also recommend that clinicians and researchers collect OMERACT-OARSI responder data to track individual response to the viscosupplementation. Furthermore, high-quality studies are needed to address the residual uncertainties regarding the clinical benefit achieved from HA injection, especially in the active 40- to 60-year age group. Prediction rules are needed to identify patient characteristics that prospectively identify members of the subgroup of OA patients that will demonstrate more robust response to HA injection as opposed to those who are unlikely to benefit.
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