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.
BACKGROUND: The prevalence of knee osteoarthritis (OA)/degenerative joint disease (DJD) is increasing in the USA. Systematic reviews of treatment efficacy and adverse events (AEs) of hyaluronic acid (HA) injections report conflicting evidence about the balance of benefits and harms. We review evidence on efficacy and AEs of intraarticular viscosupplementation with HA in older individuals with knee osteoarthritis and account for differences in these conclusions from another systematic review.
METHODS: We searched PubMed and eight other databases and gray literature sources from 1990 to December 12, 2014. Double-blind placebo-controlled randomized controlled trials (RCTs) reporting functional outcomes or quality-of-life; RCTs and observational studies on delay/avoidance of arthroplasty; RCTs, case reports, and large cohort studies and case series assessing safety; and systematic reviews reporting on knee pain were considered for inclusion. A standardized, pre-defined protocol was applied by two independent reviewers to screen titles and abstracts, review full text, and extract details on study design, interventions, outcomes, and quality. We compared our results with those of a prior systematic review and found them to be discrepant; our analysis of why this discrepancy occurred is the focus of this manuscript.
RESULTS: Eighteen RCTs reported functional outcomes: pooled analysis of ten placebo-controlled, blinded trials showed a standardized mean difference of -0.23 (95 % confidence interval (CI) -0.45 to -0.01) favoring HA at 6 months. Studies reported few serious adverse events (SAEs) and no significant differences in non-serious adverse events (NSAEs) (relative risk (RR) [95 % CI] 1.03 [0.93-1.15] or SAEs (RR [95 % CI] 1.39 [0.78-2.47]). A recent prior systematic review reported similar functional outcomes, but significant SAE risk. Differences in SAE inclusion and synthesis accounted for the disparate conclusions.
CONCLUSIONS: Trials show a small but significant effect of HA on function on which recent systematic reviews agree, but lack of AE synthesis standardization leads to opposite conclusions about the balance of benefits and harms. A limitation of the re-analysis of the prior systematic review is that it required imputation of missing data.
Knee arthroscopy has historically been a common treatment for knee osteoarthritis. A Cochrane review of the literature up to 2006 has resulted in guidance that arthroscopy is not effective in knee osteoarthritis. It cited that deficiencies in the evidence base prevented widespread acceptance of the recommendations. The aim of this review is to update the evidence base for the efficacy of arthroscopy in knee osteoarthritis. The authors searched CINHAL, EMBASE, MEDLINE, and CENTRAL for randomised controlled trials that compared arthroscopic surgery in knee osteoarthritis with a control group (e.g. lavage, best medical care). The primary outcome measure was patient reported functional outcome. The study methodology was registered on Prospero, a systematic review register: Registration number CRD42012002891. Five randomised controlled trials included 516 patients, almost double the 271 episodes contained in previous reviews. Two high quality studies, according to the Jadad classification, published since the Cochrane review, addressed many of the methodological flaws criticised in previous reviews. However, certain subgroup analyses (e.g. patients with meniscal tears and mechanical symptoms) are still underpowered.
BACKGROUND: Although accepted as a conservative treatment option for knee osteoarthritis, the debate about the effectiveness of intra-articular treatment with hyaluronic acid (HA) is still ongoing because of contrasting outcomes in different clinical studies. Several well designed clinical studies showed a significant improvement in pain at follow-up compared with baseline but no significant improvement comparing the efficacy of HA with placebo (saline) or with other conservative treatment options. Notwithstanding the effectiveness of different types of intra-articular HA products, the question of whether one HA product is better than another is still unanswered. In this systematic review we compare the effects of intra-articularly administered HA with intra-articularly administered placebo in general and, more specifically, the effects of individual HA products with placebo. We also compare the efficacy of different HA products.
METHODS: A systematic review of randomized controlled trials (RCTs) was conducted using databases including MEDLINE, Cochrane Database of Systematic Reviews, Cochrane Clinical Trial Register and EMBASE.
RESULTS: Seventy-four RCTs were included in this systematic review. HA improves pain by approximately 40-50% compared with baseline levels. However, when compared with saline the difference in efficacy is not that large. Due to a large 'placebo effect' of saline (approximately 30% pain reduction, persisting for at least 3 months) we determined a weighted mean difference between the efficacy of HA and saline of just 10.20 using the visual analog scale for pain. It is debatable whether this difference reaches the minimum clinically important difference. Comparing the different HA products, which vary in the molecular weight, concentration, and volume of HA, we were not able to conclude that one brand has a better efficacy than another due to the heterogeneity of the studies and outcomes.
DISCUSSION: In the future it will be important to determine the exact mechanism of action of placebo as this may give us an idea of how to treat osteoarthritis more efficiently. Due to the limitations of this review (follow-up of just 3 months and large heterogeneity of the included studies), it is also important to compare the different HA products to determine which product(s), or which molecular weight range, concentration, or volume of HA is the best option to treat osteoarthritis. Our recommendation is to start large (multicenter) RCTs to give us more evidence about the efficacy of the different HA products.
Background: Osteoarthritis (OA) is the most prevalent chronic joint disorder worldwide and is associated with significant pain and disability. Objectives: To assess the effects of viscosupplementation in the treatment of OA of the knee. The products were hyaluronan and hylan derivatives (Adant, Arthrum H, Artz (Artzal, Supartz), BioHy (Arthrease, Euflexxa, Nuflexxa), Durolane, Fermathron, Go-On, Hyalgan, Hylan G-F 20 (Synvisc Hylan G-F 20), Hyruan, NRD-101 (Suvenyl), Orthovisc, Ostenil, Replasyn, SLM-10, Suplasyn, Synject and Zeel compositum). Search methods: MEDLINE (up to January (week 1) 2006 for update), EMBASE, PREMEDLINE, Current Contents up to July 2003, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched. Specialised journals and reference lists of identified randomised controlled trials (RCTs) and pertinent review articles up to December 2005 were handsearched. Selection criteria: RCTs of viscosupplementation for the treatment of people with a diagnosis of OA of the knee were eligible. Single and double-blinded studies, placebo-based and comparative studies were eligible. At least one of the four OMERACT III core set outcome measures had to be reported (Bellamy 1997). Data collection and analysis: Each trial was assessed independently by two reviewers for its methodological quality using a validated tool. All data were extracted by one reviewer and verified by a second reviewer. Continuous outcome measures were analysed as weighted mean differences (WMD) with 95% confidence intervals (CI). However, where different scales were used to measure the same outcome, standardized mean differences (SMD) were used. Dichotomous outcomes were analyzed by relative risk (RR). Main results: Seventy-six trials with a median quality score of 3 (range 1 to 5) were identified. Follow-up periods varied between day of last injection and eighteen months. Forty trials included comparisons of hyaluronan/hylan and placebo (saline or arthrocentesis), ten trials included comparisons of intra-articular (IA) corticosteroids, six trials included comparisons of nonsteroidal anti-inflammatory drugs (NSAIDs), three trials included comparisons of physical therapy, two trials included comparisons of exercise, two trials included comparisons of arthroscopy, two trials included comparisons of conventional treatment, and fifteen trials included comparisons of other hyaluronans/hylan. The pooled analyses of the effects of viscosupplements against 'placebo' controls generally supported the efficacy of this class of intervention. In these same analyses, differential efficacy effects were observed for different products on different variables and at different timepoints. Of note is the 5 to 13 week post injection period which showed a percent improvement from baseline of 28 to 54% for pain and 9 to 32% for function. In general, comparable efficacy was noted against NSAIDs and longer-term benefits were noted in comparisons against IA corticosteroids. In general, few adverse events were reported in the hyaluronan/hylan trials included in these analyses. Authors' conclusions: Based on the aforementioned analyses, viscosupplementation is an effective treatment for OA of the knee with beneficial effects: on pain, function and patient global assessment; and at different post injection periods but especially at the 5 to 13 week post injection period. It is of note that the magnitude of the clinical effect, as expressed by the WMD and standardised mean difference (SMD) from the RevMan 4.2 output, is different for different products, comparisons, timepoints, variables and trial designs. However, there are few randomised head-to-head comparisons of different viscosupplements and readers should be cautious, therefore, in drawing conclusions regarding the relative value of different products. The clinical effect for some products, against placebo, on some variables at some timepoints is in the moderate to large effect-size range. Readers should refer to relevant tables to review specific detail given the heterogeneity in effects across the product class and some discrepancies observed between the RevMan 4.2 analyses and the original publications. Overall, the analyses performed are positive for the HA class and particularly positive for some products with respect to certain variables and timepoints, such as pain on weight bearing at 5 to 13 weeks postinjection. In general, sample-size restrictions preclude any definitive comment on the safety of the HA class of products; however, within the constraints of the trial designs employed no major safety issues were detected. In some analyses viscosupplements were comparable in efficacy to systemic forms of active intervention, with more local reactions but fewer systemic adverse events. In other analyses HA products had more prolonged effects than IA corticosteroids. Overall, the aforementioned analyses support the use of the HA class of products in the treatment of knee OA.
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.
