Systematic reviews including this primary study

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Systematic review

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The Impact of Excluding Patients with End-Stage Knee Disease in Intra-Articular Hyaluronic Acid Trials: A Systematic Review and Meta-Analysis.

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Journal Advances in Therapy
Year 2019
Links Pubmed DOI PubMed Central

This article includes 20 Primary studies 20 Primary studies (20 references)

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INTRODUCTION: The Kellgren-Lawrence (K-L) grade is the most commonly used measure of radiographic disease severity in knee osteoarthritis (OA). Studies suggest that intra-articular hyaluronic acid (IA-HA) should only be considered in cases of early stage knee OA. The purpose of this review was to determine if trials administering IA-HA in early-moderate knee OA patients demonstrated greater pain relief than studies that also included patients with end-stage disease.METHODS: We conducted a systematic search of the literature to identify randomized controlled trials (RCT) comparing IA-HA with saline injections and that diagnosed disease severity using the K-L grade criteria. The primary outcome was mean change in pain from baseline at 4-13 weeks and 22-27 weeks. Safety was evaluated on the total number of participants experiencing a treatment-related adverse event (AE).RESULTS: Twenty RCTs were included. In the early-moderate OA subgroup, the mean change in pain scores was statistically significant favoring IA-HA from baseline to 4-13 weeks [SMD = - 0.30, 95% CI - 0.44 to - 0.15, p < 0.0001] and within 22-27 weeks [SMD = - 0.27, 95% CI - 0.39 to - 0.16, p < 0.00001]. No significant differences were observed in the late OA subgroup. IA-HA was associated with a significantly greater risk of treatment-related AEs relative to saline in the late OA subgroup [RR = 1.76, 95% CI 1.16-2.67, p = 0.008].CONCLUSION: IA-HA provides significant pain relief compared to saline for patients with early-moderate knee OA, compared to cohorts including patients with end-stage OA (KL grade 4), with no increase in the risk of treatment-related AEs, up to 6 months. Patients with end-stage disease had lower levels of pain relief and may be diluting study results if included in the treatment cohort.Funding: Ferring Pharmaceuticals.

Systematic review

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Mixed Treatment Comparisons for Nonsurgical Treatment of Knee Osteoarthritis: A Network Meta-analysis.

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Journal The Journal of the American Academy of Orthopaedic Surgeons
Year 2018
Links Pubmed DOI

This article includes 52 Primary studies 54 Primary studies (52 references)

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INTRODUCTION: Knee osteoarthritis (KOA) is a significant health problem with lifetime risk of development estimated to be 45%. Effective nonsurgical treatments are needed for the management of symptoms. METHODS: We designed a network meta-analysis to determine clinically relevant effectiveness of nonsteroidal anti-inflammatory drugs, acetaminophen, intra-articular (IA) corticosteroids, IA platelet-rich plasma, and IA hyaluronic acid compared with each other as well as with oral and IA placebos. We used PubMed, EMBASE, and Cochrane Central Register of Controlled Trials to perform a systematic search of KOA treatments with no date limits and last search on October 7, 2015. Article inclusion criteria considered the following: target population, randomized controlled study design, English language, human subjects, treatments and outcomes of interest, ≥30 patients per group, and consistent follow-up. Using the best available evidence, two abstractors independently extracted pain and function data at or near the most common follow-up time. RESULTS: For pain, all active treatments showed significance over oral placebo, with IA corticosteroids having the largest magnitude of effect and significant difference only over IA placebo. For function, no IA treatments showed significance compared with either placebo, and naproxen was the only treatment showing clinical significance compared with oral placebo. Cumulative probabilities showed naproxen to be the most effective individual treatment, and when combined with IA corticosteroids, it is the most probable to improve pain and function. DISCUSSION: Naproxen ranked most effective among conservative treatments of KOA and should be considered when treating pain and function because of its relative safety and low cost. The best available evidence was analyzed, but there were instances of inconsistency in the design and duration among articles, potentially affecting uniform data inclusion.

Systematic review

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The efficacy of multiple versus single hyaluronic acid injections: a systematic review and meta-analysis.

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Journal BMC musculoskeletal disorders
Year 2017
Links Pubmed DOI PubMed Central

This article includes 30 Primary studies 30 Primary studies (30 references)

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BACKGROUND: Intra-articular hyaluronic acid (IA-HA) is a common therapy used to treat knee pain and suppress knee inflammation in knee osteoarthritis (OA), typically prescribed in regimens ranging from a single injection to 5 weekly injections given once weekly. We conducted a systematic review to determine the efficacy of IA-HA, with subgroup analyses to explore the differences in knee pain and adverse events (AEs) across different dosing regimens. METHODS: We conducted a systematic search of the literature to identify studies evaluating IA-HA for the management of knee OA compared to IA-saline. Primary outcome measure was the mean knee pain score at 13 Weeks (3 months) or 26 weeks (6 months). Secondary outcome was the number of treatment-related AEs and treatment-related serious adverse events (SAEs). We evaluated differences in levels of pain and AEs/SAEs between dosing regimens compared to IA-Saline. RESULTS: Thirty articles were included. Overall, IA-HA injections were associated with less knee pain compared to IA-Saline injections for all dosing regimens. 2-4 injections of IA-HA vs. IA-Saline produced the largest effect size at both 3-months and 6-months (Standard mean difference [SMD] = -0.76; -0.98 to -0.53, 95% CI, P < 0.00001, and SMD = -0.36; -0.63 to -0.09 95% CI, P = 0.008, respectively). Additionally, single injection studies yielded a non-significant treatment effect at 3 and 6 months, while ≥5 5 injections demonstrated a significant improvement in pain only at 6 months. Five or more injections of IA-HA were associated with a higher risk of treatment-related AEs compared to IA-Saline (Risk ratio [RR] = 1.67; 1.09 to 2.56 95% CI, p = 0.02), which was a result not seen within the 1 and 2-4 injection subgroups. CONCLUSION: Overall, 2-4 and ≥5 injection regimens provided pain relief over IA-Saline, while single injection did not. Intra-articular injections of HA used in a 2-4 injection treatment regimen provided the greatest benefit when compared to IA-Saline with respect to pain improvement in patients with knee OA, and was generally deemed safe with few to no treatment-related AEs reported across studies. Future research is needed to directly compare these treatment regimens.

Systematic review

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The Therapeutic Effect of Intra-articular Normal Saline Injections for Knee Osteoarthritis: A Meta-analysis of Evidence Level 1 Studies.

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Journal American Journal of Sports Medicine
Year 2017
Links Pubmed DOI

This article includes 13 Primary studies 13 Primary studies (13 references)

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BACKGROUND: Intra-articular normal saline (IA-NS) injections have been utilized as a placebo in a number of randomized controlled trials pertaining to the management of knee osteoarthritis (OA); however, it is believed that these “placebo” injections may have a therapeutic effect that has not been quantified in the literature. PURPOSE: To (1) quantify the effect of IA-NS injections on patient-reported outcomes (PROs) and (2) compare postinjection PROs to established minimal clinically important difference (MCID) criteria to demonstrate a potential therapeutic effect. STUDY DESIGN: Meta-analysis. METHODS: A review was conducted to identify all randomized, placebo-controlled trials on injection therapy for knee OA between 2006 and 2016. Patient demographics and PROs before the injection and at 3 and 6 months after the injection were collected for patients in the IA-NS injection group in each study. A random-effects model was used to compare preinjection scores and scores at each postinjection time point in a pairwise fashion. RESULTS: In total, there were 14 placebo cohorts in 13 studies that were analyzed after meeting inclusion criteria for this meta-analysis. This included 1076 patients (Kellgren-Lawrence grade 1-4), with a weighted mean age of 62.53 years and mean body mass index of 28.67 kg/m2. There was only sufficient information to perform analyses of visual analog scale (VAS) pain and Western Ontario and McMaster Universities Arthritis Index (WOMAC) total scores. At 3 months after the IA-NS placebo injection, there was a significant improvement in VAS pain scores (mean difference [MD], 12.10 [95% CI, 3.27 to 20.93]; P = .007), whereas improvement in the WOMAC total scores approached but did not reach statistical significance (MD, 19.75 [95% CI, –0.50 to 40.09]; P = .06). At 6 months, both VAS pain scores (MD, 16.62 [95% CI, 12.13-21.10]; P < .00001) and WOMAC total scores (MD, 11.34 [95% CI, 7.03-15.65]; P < .00001) were significantly improved in comparison to preinjection values. Furthermore, improvements in both the VAS pain and WOMAC total scores at 6 months were clinically significant (MCID, 1.37 and 9, respectively). CONCLUSION: The administration of an IA-NS placebo injection yields a statistically and clinically meaningful improvement in PROs up to 6 months after the injection in patients with knee OA. This observation supports the notion that the so-called placebo effect for IA-NS injections achieves a clinically meaningful response in patients with OA when provided during comparison studies to an active treatment group (ie, hyaluronic acid).

Systematic review

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AMSSM Scientific Statement Concerning Viscosupplementation Injections for Knee Osteoarthritis: Importance for Individual Patient Outcomes.

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Journal Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine
Year 2016
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This article includes 11 Primary studies 11 Primary studies (11 references)

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OBJECTIVE: Osteoarthritis (OA) is a disabling disease that produces severe morbidity reducing physical activity. Our position statement on treatment of knee OA with viscosupplementation injection [hyaluronic acid (HA)] versus steroid [intra-articular corticosteroid (IAS)] and placebo [intra-articular placebo (IAP)] is based on the evaluation of treatment effect by examining the number of subjects within a treatment arm that met the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria, which is different and more relevant than methods used in other reviews which examined if the average change across the treatment groups was clinically different. DATA SOURCES: We performed a systematic literature search for all relevant articles from 1960 to August 2014 in the MEDLINE, EMBASE, and Cochrane CENTRAL. We performed a network meta-analysis (NMA) of the relevant literature to determine if there is a benefit from HA as compared with IAS and IAP. MAIN RESULTS: Eleven articles met the inclusion criteria from the search strategy. On NMA, those subjects receiving HA were 15% and 11% more likely to respond to treatment by the OMERACT-OARSI criteria than those receiving IAS or IAP, respectively (P < 0.05 for both). CONCLUSIONS: In light of the aforementioned results of our NMA, the American Medical Society for Sport Medicine recommends the use of HA for the appropriate patients with knee OA.

Systematic review

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Clinical benefit of intra-articular saline as a comparator in clinical trials of knee osteoarthritis treatments: A systematic review and meta-analysis of randomized trials.

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Journal Seminars in arthritis and rheumatism
Year 2016
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This article includes 40 Primary studies 40 Primary studies (40 references)

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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."

Systematic review

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Product Differences in Intra-articular Hyaluronic Acids for Osteoarthritis of the Knee.

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Journal The American journal of sports medicine
Year 2016
Links Pubmed DOI

This article includes 68 Primary studies 68 Primary studies (68 references)

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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.

Systematic review

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AMSSM scientific statement concerning viscosupplementation injections for knee osteoarthritis: importance for individual patient outcomes.

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Journal British journal of sports medicine
Year 2016
Links Pubmed DOI

This article includes 11 Primary studies 11 Primary studies (11 references)

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Osteoarthritis (OA) is a disabling disease that produces severe morbidity reducing physical activity. Our position statement on treatment of knee OA with viscosupplementation injection (hyaluronic acid, HA) versus steroid (intra-articular corticosteroids, IAS) and placebo (intra-articular placebo, IAP) is based on the evaluation of treatment effect by examining the number of participants within a treatment arm who met the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria, which is different and more relevant than methods used in other reviews which examined if the average change across the treatment groups were clinically different. We performed a systematic literature search for all relevant articles from 1960 to August 2014 in the MEDLINE, EMBASE and Cochrane CENTRAL. We performed a network meta-analysis (NMA) of the relevant literature to determine if there is a benefit from HA as compared with IAS and IAP. 11 papers met the inclusion criteria from the search strategy. On NMA, those participants receiving HA were 15% and 11% more likely to respond to treatment by OMERACT-OARSI criteria than those receiving IAS or IAP, respectively (p<0.05 for both). In the light of the aforementioned results of our NMA, the American Medical Society for Sport Medicine recommends the use of HA for the appropriate patients with knee OA.

Systematic review

Unclassified

Comparative safety profile of hyaluronic acid products for knee osteoarthritis: a systematic review and network meta-analysis.

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Journal Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society
Year 2016
Links Pubmed DOI www.epistemonikos.org

This article includes 73 Primary studies 73 Primary studies (73 references)

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PURPOSE: Intra-articular (IA) hyaluronic acid (HA) is considered a safer alternative to oral NSAIDs and opioids for knee osteoarthritis. A recent review raised potential safety concerns about HA, warranting further review of safety outcomes. We examined the risks of HA compared with IA placebo and investigated whether the risks vary among individual HA preparations. METHODS: We searched all relevant databases from inception to October 2015 and sought unpublished data. We included all knee osteoarthritis trials which compared any of the 18 HA products and reported on adverse events and withdrawals. We calculated Odds Ratios for safety data reported at the longest follow-up. Network meta-analysis was performed using a Bayesian hierarchical random effects model for mixed multiple treatment comparisons. RESULTS: We identified 74 studies involving 13,032 participants aged between 45-75 years. The proportion of women ranged from 28% -100%. The overall incidence of local reactions reported across all products was 8.5%. Commonly reported adverse events were transient local reactions, such as pain, swelling and arthralgia, which subsided rapidly. None of the HA products were statistically significantly different from IA placebo or from each other with regard to incidence of adverse events. Three treatment-related serious adverse events were reported among 9,214 participants. CONCLUSIONS: Given the very low incidence of any particular adverse events, we conclude that HA products are relatively well tolerated. These products have a similar safety profile compared to each other. This information along with the comparative effectiveness profile and relative cost would be helpful for clinicians in delivering individualized patient care.

Systematic review

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Hyaluronic acid injection therapy for osteoarthritis of the knee: concordant efficacy and conflicting serious adverse events in two systematic reviews.

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Journal Systematic reviews
Year 2016
Links Pubmed DOI PubMed Central

This article includes 56 Primary studies 56 Primary studies (56 references)

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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.