Objective To investigate whether the number of hyaluronic acid (HA) injections in a sodium hyaluronate (Hyalgan) course of therapy alters effectiveness in reducing knee osteoarthritis (OA) pain. Data Sources Electronic databases, including PubMed and Embase, were searched from January 1980 until November 2015. Study Selection We included clinical studies that evaluated the effectiveness of a course of 3 or 5 weekly intra-articular injections of Hyalgan to treat knee OA pain. We also included clinical studies evaluating the effectiveness of a 3-week course of other Food and Drug Administration–approved HA treatments of knee OA pain. Twenty-four studies were identified, comprising 2168 study participants in 30 treated cohorts. Data Extraction We determined effect sizes for selected studies by extracting knee OA pain scores before and after HA or control treatments. Meta-regressions were implemented to determine whether the number of weekly injections in a course of Hyalgan therapy modified outcomes. Data Synthesis The pooled estimate for relief from baseline pain was −31.4 (SE, 5.46; 95% confidence interval [CI], −45.5 to −17.4) with a 3-week course of Hyalgan and −32.2 (SE, 5.25; 95% CI, −45.6 to −18.7) with a 5-week course of Hyalgan. Findings from the meta-analysis indicate relief of knee OA pain with a 3-week course of Hyalgan is similar to that with a 5-week course of Hyalgan ( P =.916). The pooled estimate for relief from baseline pain with a 3-week course of other HA products was −29.4 (SE, 4.98; 95% CI, −42.2 to −16.6), also indicating pain relief with a 3-week course of Hyalgan is similar to that with a 3-week course of other HA products ( P =.696). Conclusions There was no statistical difference between reduction in knee OA pain with a 3-week course of Hyalgan compared with reduction in knee OA pain with a 5-week course of Hyalgan or a 3-week course of other HA products. These findings demonstrate that comparable knee OA pain relief is achieved with a 3-week course of Hyalgan and the 2 control groups.
OBJECTIVE: To investigate whether the number of hyaluronic acid (HA) injections in a Hyalgan(®) course of therapy alters effectiveness in reducing knee osteoarthritis (OA) pain.
DATA SOURCES: Electronic databases, including PubMed and EMBase, were searched from January 1980 until November 2015.
STUDY SELECTION: We included clinical studies that evaluated the effectiveness of a course of three or five weekly intra-articular injections of Hyalgan to treat knee OA pain. We also included clinical studies evaluating the effectiveness of a three-week course of other FDA-approved HA treatments of knee OA pain. Twenty-four studies were identified, comprising 2,168 study participants in 30 treated cohorts.
DATA EXTRACTION: We determined effect sizes for selected studies by extracting knee OA pain scores before and after HA or control treatments. Meta-regressions were implemented to determine whether the number of weekly injections in a course of Hyalgan therapy modified outcomes.
DATA SYNTHESIS: The pooled estimate for relief from baseline pain was -31.4 (5.46 SE; 95% confidence interval [CI], -45.5, -17.4) with a three-week course of Hyalgan and -32.2 (5.25; CI, -45.6, -18.7) with a five-week course of Hyalgan. Findings from the meta-analysis indicate relief of knee OA pain with a three-week course of Hyalgan is similar to that with a five-week course of Hyalgan (P = .916). The pooled estimate for relief from baseline pain with a three-week course of other HA products was -29.4 (4.98; CI, -42.2, -16.6), also indicating pain relief with a three-week course of Hyalgan is similar to that with a three-week course of other HA products (P = .696).
CONCLUSIONS: There was no statistical difference between reduction in knee OA pain with a three-week course of Hyalgan compared to reduction in knee OA pain with a five-week course of Hyalgan or a three-week course of other HA products. These findings demonstrate that comparable knee OA pain relief is achieved with a three-week course of Hyalgan and the two control groups.
OBJECTIVES: Hyaluronic acid and corticosteroids are common intra-articular (IA) therapies widely used for the management of mild to moderate knee osteoarthritis (OA). Many trials evaluating the efficacy of IA administered therapies commonly use IA saline injections as a placebo comparator arm. Using a systematic review and meta-analysis, our objective was to assess the clinical benefit associated with use of IA saline in trials of IA therapies in the treatment of patients with painful knee OA.
METHODS: MEDLINE and Embase databases were searched for articles published up to and including August 14th, 2014. Two reviewers assessed the eligibility of potential reports and the risk of bias of included trials. We analyzed short (≤3 months) and long-term (6-12 months) pain reduction of the saline arm of included trials using standardized mean differences (SMDs; estimated assuming a null effect in a comparator group) that were combined and weighted using a random effects model. Treatment-related adverse events (AEs) were tabulated and presented using descriptive statistics.
RESULTS: From 40 randomized controlled trials (RCTs) eligible for inclusion only 38 provided sufficient data to be included in the meta-analysis. Based on data with moderate inconsistency IA saline was found to significantly improve short-term knee pain in 32 studies involving 1705 patients (SMD = -0.68; 95% CI: -0.78 to -0.57; P < 0.001; I(2) = 50%). Long-term knee pain was significantly decreased following IA injection with saline in 19 studies involving 1445 patients (SMD = -0.61; 95% CI: -0.76 to -0.45; P < 0.001) with a substantial degree of inconsistency (I(2) = 74%). Overall, 29 of the included trials reported on adverse events, none of which found any serious treatment-related AEs following IA injection with saline.
CONCLUSIONS: Pain relief observed with IA saline should prompt health care providers to consider the additional effectiveness of current IA treatments that use saline comparators in clinical studies, and challenges of identifying IA saline injection as a "placebo."
BACKGROUND: Knee osteoarthritis (OA) is a common and often disabling joint disorder among adults that may result in impaired activity and daily function. A variety of treatment options are currently available and prescribed for knee OA depending on the severity of the disorder and physician preference. Intra-articular hyaluronic acid (IA-HA) injection is a treatment for knee OA that reportedly provides numerous biochemical and biological benefits, including shock absorption, chondroprotection, and anti-inflammatory effects within the knee. Clarity is needed as to whether the available IA-HA products should be considered for therapy as a group or whether there are significant differences in the products that need to be considered in treatment of OA of the knee.
PURPOSE: To determine whether there are differences in efficacy and safety with respect to intrinsic properties of available IA-HA injections for knee OA.
STUDY DESIGN: Meta-analysis.
METHODS: A comprehensive literature search of the Medline, EMBASE, and PubMed databases was conducted for all existing randomized trials of IA-HA. The primary outcome measure analyzed was the mean pain score at the reported follow-up nearest to 26 weeks after injection. Pooled efficacy and safety results were recorded for subgroupings of HA product characteristics.
RESULTS: A total of 68 studies were included for analysis. Products with an average molecular weight ≥3000 kDa provided favorable efficacy results when compared with products of an average molecular weight <3000 kDa. Products with a molecular weight ≥3000 kDa demonstrated significantly fewer discontinuations due to treatment-related adverse events than did ≤1500 kDa counterparts, while trial discontinuation rates were similar between biological fermentation-derived HA products and avian-derived HA. The results did not demonstrate a significant difference in the occurrence of effusion across molecular weight subgroups. Additionally, biological fermentation-derived HA had a significantly smaller incidence of effusion than did avian-derived HA. Biological fermentation-derived HA demonstrated fewer acute flare-ups at the injection site than did avian-derived HA products, while high-molecular-weight products demonstrated the highest rate of injection site flare-up.
CONCLUSION: Despite similarities, IA-HA products should not be treated as a group, as there are differences in IA-HA products that influence both efficacy and safety. In the available literature, IA-HA products with a molecular weight ≥3000 kDa and those derived from biological fermentation relate to superior efficacy and safety-factors that may influence selection an IA-HA product for OA of the knee.
BACKGROUND: Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis vary in efficacy, systematic differences would substantially affect interpretation of the results of placebo-controlled trials.
OBJECTIVE: To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis.
DATA SOURCES: MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data.
STUDY SELECTION: 149 randomized trials of adults with knee osteoarthritis that reported pain outcomes and compared widely used pharmaceuticals against oral, intra-articular, topical, and oral plus topical placebos.
DATA EXTRACTION: Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool.
DATA SYNTHESIS: Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior.
LIMITATIONS: Few studies compared different placebos directly. The study could not decisively conclude whether disease severity and co-interventions systematically differed between trials evaluating different placebos.
CONCLUSION: All placebos are not equal, and some can trigger clinically relevant responses. Differential placebo effects can substantially alter estimates of the relative efficacies of active treatments, an important consideration for the design of clinical trials and interpretation of their results.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.
Background: Intra-articular injection of hyaluronic acid is a common, yet controversial, therapeutic option for patients with knee osteoarthritis (OA). The purpose of this research was to determine the safety and efficacy of US-approved viscosupplements for symptomatic knee OA. Methods: We searched MedLine and EMBase for randomized, sham-controlled trials evaluating safety and/or clinical efficacy of US-approved viscosupplements in patients with symptomatic knee OA. Knee pain severity and knee joint function were assessed at 4 to 13 weeks and 14 to 26 weeks. Safety outcomes included serious adverse events, treatment-related serious adverse events, patient withdrawal, and adverse event-related patient withdrawal occurring at any time during follow-up. Results: A total of 29 studies representing 4,866 unique patients (active: 2,673, control: 2,193) were included. All sham-controlled trials used saline injections as a control. Viscosupplementation resulted in very large treatment effects between 4 and 26 weeks for knee pain and function compared to preinjection values, with standardized mean difference values ranging from 1.07 to 1.37 (allP<0.001). Compared to controls, standardized mean difference with viscosupplementation ranged from 0.38 to 0.43 for knee pain and 0.32 to 0.34 for knee function (all P<0.001). There were no statistically significant differences between viscosupplementation and controls for any safety outcome, with absolute risk differences of 0.7% (95% confidence interval [CI]: –0.2 to 1.5%) for serious adverse events, 0% (95% CI: –0.4 to 0.4%) for treatment-related serious adverse events, 0% (95% CI: –1.6 to 1.6%) for patient withdrawal, and 0.2% (95% CI: –0.4 to 0.8%) for adverse event-related patient withdrawal. Conclusion: Intra-articular injection of US-approved viscosupplements is safe and efficacious through 26 weeks in patients with symptomatic knee OA.
OBJECTIVE: To assess the relative efficacy of intra-articular hyaluronic acid (IAHA) in comparison with non-steroidal anti-inflammatory drugs (NSAIDs) for knee osteoarthritis (OA). METHODS: We searched Medline, EMBASE, Google Scholar, ISI Web of Science, and Cochrane Database from inception until February 2013. Randomized controlled trials comparing HA with NSAIDs for knee OA were included if they reported at least one pain outcome. Two reviewers abstracted data and determined quality. Outcomes included pain, function, and stiffness. Random-effects meta-analyses were performed. RESULTS: Five trials (712 participants) contributed to the pain analysis. Both groups showed improvement from baseline. The analysis found an effect size (ES) of −0.07 (95% CI: −0.24 to 0.10) at trial end, favoring neither treatment. There were no statistically significant differences between the groups at 4 and 12 weeks in function [ES = −0.08 (95% CI: −0.39 to 0.23)] or stiffness [ES = 0.03 (95% CI: −0.27 to 0.34)] analyses based on two trials. Injection site pain was the most common adverse event reported in the HA group, and gastrointestinal adverse events were more common in the NSAIDs group. CONCLUSION: This meta-analysis suggests that IAHA is not significantly different from continuous oral NSAIDs at 4 and 12 weeks. Our study detected no safety concerns; however, the included trials had only a short follow-up duration. Given the favorable safety profile of IAHA over NSAIDs, this result suggests that IAHA might be a viable alternative to NSAIDs for knee OA, especially for older patients at greater risk for systemic adverse events.
