Results: 63 trials with a median Jadad score of 3 were identified. Thirty-seven trials compared hyaluronan or hylan G-F 20 with placebo, 9 trials compared a viscosupplement with intra-articular corticosteroids, and 5 trials compared a hyaluronic product with NSAIDs. The authors concluded that the pooled analyses supported the efficacy of this class of hyaluronic products. In the 5-to-13 week postinjection period, there was an improvement from baseline of 11% to 54% for pain and 9% to 15% for function. In general, comparable efficacy was noted against NSAIDs, and longer-term benefits were noted compared with corticosteroids. Few adverse events were reported. Differential efficacy effects were observed for different products on different variables at different time points.
Seventeen of the studies, comprising 23 separate comparisons included in the Cochrane Review, involved hylan G-F 20. The Medical Advisory Secretariat undertook a subanalysis of these 17 studies.
Medical Advisory Secretariat Subanalysis
The objective of the Medical Advisory Secretariat subanalysis was to do impose more rigorous criteria on the interpretation of the results of these 17 studies by:
- Distinguishing clinically significant results from statistically significant results by identifying studies that report a difference in outcome pain scores among subjects treated with hylan G-F 20 compared with patients in the control group that clearly exceed the minimal clinically significant thresholds outlined in , and
- Distinguishing high-quality studies from low-quality studies and drawing conclusions and basing recommendations primarily on the results of high-quality studies.
The 17 studies that involved hylan G-F 20 are described in Appendix 5
. Some of these were unpublished or were not English-language studies; therefore, the Medical Advisory Secretariat could not interpret or appraise them, particularly with respect to their quality. Consequently, the bulk of this subanalysis is based on the published studies that the Medical Advisory Secretariat could access (i.e., those that were English-language studies). Overall, the 17 studies had a mean Jadad score of 2.9. They varied in their length of follow-up periods; in their length to outcome; type of outcome measure and instrument used; and extent of concomitant therapy permitted. Comparators were placebos, intra-articular steroids, NSAIDs, other intra-articular hyaluronans, and appropriate care without hylan G-F 20.
Evidence of clinical effectiveness of Hylan G-F 20 (Medical Advisory Secretariat’s Subanalysis)
Trials of Hylan G-F 20 Versus Placebo
Of the 9 trials that compared hylan G-F 20 with placebos, 6 reported a difference in the VAS score for pain with weight bearing at 1 to 4 weeks after treatment. The 3 trials that did not report an outcome at this endpoint were Ardic, (45
) Groppa, (46
) and Dickson (34
). The 6 remaining studies that reported the outcome were sufficiently homogenous (I2
, -64.8%) to be combined, producing a weighted mean estimate (and 95% CI) of-12.54 (-20.4 to -4.7) that failed to exceed with confidence the MCID threshold of 10 mm imposed by the Medical Advisory Secretariat. Five trials reported this outcome at 5 to 13 weeks after treatment. The level of heterogeneity among the studies (I2
, 82.9% was deemed excessive according to Medical Advisory Secretariat criteria. Three of the 5 studies reported outcome pain levels that clearly exceeded the MCID. Two of these (scale a and scale b) were 2 arms of a very small trial. At 14 to 26 weeks, 4 studies reported outcomes at this level. Two reported a treatment effect that clearly exceeded the MCID threshold; 2 did not. Overall evidence of a clinically significant difference in pain reduction between the treatment and control groups was inconsistent.
Trials of Hylan G-F 20 Versus Intra-Articular Corticosteroids
Trials Comparing Hylan G-F 20 With Intra-Articular Corticosteroids
The trial by Leopold et al. (48
) found a modest improvement in pain in both the hylan G-F 20 and intra-articular steroid arms, but the differences between the arms were not significant. The Caborn (49
) trial reported outcomes using a 0 to 4 Likert scale rather than 100 mm VAS scores. The Caborn trial reported a statistically significant difference in favor of hylan G-F 20 compared with triamcinolone hexacetonide for WOMAC pain walking on a flat surface (scored 0 to 4) at 5 to 13 weeks post-injection (WMD, -0.40; 95% CI -0.65 to -0.15) and at 14 to 26 weeks (WMD, -0.40; 95% CI-.0.68 to -0.12) post-injection. However according to Medical Advisory Secretariat criteria, the CI failed to exceed clearly the MCID threshold of 0.4 (). The authors reported that hylan G-F 20 was 17% more effective than triamcinolone hexacetonide. Again, according to Medical Advisory Secretariat criteria, the size of the effect did not reach the MCID threshold of 20%.
Trials of Hylan G-F 20 Versus Nonsteroidal Anti-Inflammatory Drugs
Trials Comparing Hylan G-F 20 With Nonsteroidal Anti-Inflammatory Drugs
) found no statistically significant differences in any of the efficacy outcome measures. There was a statistically significant difference in favour of hylan G-F 20 compared with NSAIDs in the WOMAC subscale (0 to 100 mm VAS) (WMD, -12.00; 95% CI, -23.09 to -0.91) at 5 to 13 weeks post-injection in the Dickson (34
) study; however, according to Medical Advisory Secretariat criteria, the 95% CI surrounding this estimate failed to exceed clearly the MCID threshold. In terms of safety, there was a statistically significant difference in favour of hylan G-F 20 compared with NSAIDs for the number of patients with possible or probable related systemic adverse events at 5 to 13 weeks post-injection (RR, 0.46; 95% CI, 0.25–0.83; P
= .01). The number need to treat was 4.
Trials of Hylan G-F 20 Versus Other Hyaluronans
Trials Comparing Hylan G-F 20 With Other Hyaluronans
According to Figure 201 in the review by Bellamy, (1
) there was sufficient homogeneity among the 3 higher-quality studies to generate a summary estimate of the WMD in outcome pain scores at 1 to 4 (-2.06; 95% CI, -7.45 to 3.32) and 5 to 13 weeks (-6.59; 95% CI, -12.46 to -0.73) after injection. However, the WMD failed to exceed clearly the MCID threshold of -10 defined by the Medical Advisory Secretariat at these end points. Only 1 study (44
) presented outcomes at 14 to 26 weeks after injection. The mean difference (-5.00; 95% CI, -14.98 to 4.98) was not clinically significant according to Medical Advisory Secretariat criteria.
Trials of Hylan G-F 20 Versus Appropriate Care
Trials Comparing Hylan G-F 20 With Appropriate Care
The Raynauld (32
) and Kahan (53
) studies were open-label studies that compared hylan G-F 20 plus conventional care, defined as any appropriate nonpharmacological, pharmacological, complementary, or surgical intervention, with only conventional care The studies measured the primary outcome (pain with movement) with different scales. Raynauld found a statistically significant between-group difference that favoured hylan G-F 20 plus appropriate care at 45 to 52 weeks after injection as measured by the WOMAC pain subscale (0–20 Likert) (WMD, -3.16; 95% CI, -4.17 to -2.15). Assuming that the validity of this Likert scale can be maintained by dividing it by a factor of 5 to place it on the more conventional 4-point scale, the lower bound of the CI (-2.14/5 = - 0.43) exceeds the MCID according to Medical Advisory Secretariat criteria (). Similarly, Kahan found a statistically significant between-group difference in favour of hylan G-F 20 and appropriate care as measured by the WOMAC OA Index pain subscale (0–100 mm VAS) (WMD, -12.7; 95% CI, -16.4 to -8.9). Patients that received hylan G-F 20 plus appropriate care experienced a 21.5% to 25% reduction in pain compared with baseline, which just exceeds the MCID threshold (). In terms of safety, there was no statistically significant difference in the number of patients reporting side effects from baseline (RR, 0.94; 95% CI, 0.44–2.02). Significantly more patients in the appropriate care only group reported adverse effects compared with those in the combination group (68% vs. 52%).
A summary of the Medical Advisory Secretariat subanalysis of the clinical significance of the results reported in the 18 RCTs of hylan G-F 20 compared with placebo and active treatment is shown in . According to the Medical Advisory Secretariat’s analysis, there is some evidence that hylan G-F 20 is clinically better than placebo at 5 to 13 weeks after treatment; however, the evidence that hylan G-F 20 is clinically better than placebo at 14 to 26 weeks is inconsistent. There is also evidence that adding hylan G-F 20 to conventional care is clinically better than conventional care only at 36 to 52 weeks after injection, and that hylan G-F 20, is equivalent, but not clinically superior, to NSAIDs, intra-articular corticosteroids, and other hyaluronans on magnitude of pain relief at 1 to 26 weeks after treatment.
Summary of Medical Advisory Subanalysis of Clinical Significance of Results
Quality of Studies of Hylan G-F 20 (Medical Advisory Secretariat Subanalysis of Cochrane Review)
The Cochrane review by Bellamy et al. (24
) on viscosupplementation for OA of the knee was released just as the Medical Advisory Secretariat finished its literature search and data extraction for its review. Consequently, the Secretariat’s familiarity with most of the studies in the Cochrane review permitted it to evaluate the quality of the individual studies. According to a recent meta-analysis, (54
) many systematic reviews, including Cochrane reviews, fail to take into account the quality of the studies when they interpret the results.
To assess the quality of the evidence, the Medical Advisory Secretariat adopted the GRADE approach, (29
) which considers the study’s design and quality, and the consistency of estimates of effect and applicability (i.e., directness) of people, interventions, and outcome measures. (See Appendix 4
.) This exercise enabled the Secretariat to identify the high-quality studies, assess the overall quality of the evidence available through the Cochrane review, and modulate recommendations on the clinical utility of hylan G- F 20.
GRADE criteria: Study design
Initially, this literature review () identified and considered including 10 observational studies, 2 of which assessed the safety and effectiveness of repeat treatments of hylan G-F 20, and 8 that looked at its safety and effectiveness. In the end, however, only the safety outcomes from these studies were included, because there were RCTs to measure effectiveness, and because of the compromised quality of these observational studies (summarized in Appendix 6
The limitations of the methods that were identified in some of the RCTs on hylan G-F 20 are described in . The impact of a limitation on study quality is a matter of judgment. For this review, the following criteria were used to identify significant limitations: The Jadad score indicates that appropriate randomization, blinding, and accounting for drop-outs are key quality measures of RCTs. Consequently, any RCT with a Jadad score lower than 3 was deemed to have significant limitations. In addition, failure to blind, despite a Jadad score of 3, was considered a significant limitation because of the potential for detection bias. Offering the incentive of free treatment of hylan G-F 20 upon completion of the trial was also considered a serious limitation, because it implies that treatment with hylan G-F 20 is superior.
Concerns With the Quality of the Evidence of the Randomized Controlled Trials of Hylan G-F 20*
Other limitations pertained to treatments that were not equivalent between arms (in particular, whether arthrocentesis was performed on both intervention and control groups), subtherapeutic dosing in control groups, and significant differences in influential baseline characteristics between treatment and control groups, which implies a problem with randomization.
The consistency of the estimate of effect depends in part on the magnitude of effect deemed significant. When a magnitude of effect is deemed significant (i.e., if the mean difference in outcome pain scores between the treatment and control group exceeds zero), then, based on the Cochrane review by Bellamy, there’s evidence that hylan G-F 20 is superior to placebo at 4 to 26 weeks after injection, to intra-articular corticosteroids at 4 weeks after injection, to other hyaluronans, to conventional treatment without it, and that it is equivalent to NSAIDs.
However, when a threshold difference of at least 10 mm on a 100 mm VAS scale is deemed the MCID, then, as the Medical Advisory Secretariat’s analysis suggests, there is evidence that hylan G-F 20 is equivalent to NSAIDs, intra-articular steroids, other hyaluronans, and placebo at 4 weeks after injection. There is also evidence that hylan G-F 20 is better than conventional care without hylan at 36 to 52 weeks after treatment, and, finally, the evidence that hylan G-F 20 is superior to placebo between 4 and 26 weeks after treatment is inconsistent.
Directness refers to the extent to which the people, interventions, and outcome measures are similar to those of interest. To some extent, the directness of the outcome measures has been discussed in the point on consistency, because one’s interpretation depends on the magnitude of effect of interest. From the perspective of the Medical Advisory Secretariat, a clinically significant difference in pain is more relevant than a statistically significant difference. In terms of the characteristics of the participants, in nearly every RCT on hylan G-F 20, the inclusion criteria included individuals with OA of the knee with persistent moderate-to-severe pain (i.e., baseline VAS > 40 mm), despite conventional care. No study looked at individuals for whom NSAIDs were contraindicated, and only one looked at the clinical utility of hylan G-F 20 in patients with advanced disease (defined on the basis of pain, disability, radiographic grade, and duration of disease), for whom total knee replacement may be imminently indicated.
However, the greatest area of uncertainty when assessing the directness of the evidence on hylan G-F 20 has to do with the appropriateness of its placement among the options for managing pain due to arthritis, particularly among the placebo-controlled trials. There was a great deal of heterogeneity in the definitions of the studies’ intervention treatments. Few isolated hylan G-F 20 as the only intervention. Some permitted break-through analgesics (any of Tylenol, NSAIDs, opiates, to varying degrees and doses), some conducted arthrocentesis, some conducted saline lavage, and some administered hylan G-F 20 as an adjunct to conventional care, which may have included physiotherapy, acupuncture, arthroscopic debridement, and total knee replacement. Consequently, it is difficult to draw conclusions about the clinical indications for which hylan G-F 20 is most appropriate as a substitute versus an adjunct.
Summary of GRADE Quality of Evidence of Trials Comparing the Effectiveness of Hylan G-F 20 to Other Treatments for Pain Due to Osteoarthritis of the Knee
Using the GRADE approach, one might conclude that there is moderate evidence that hylan G-F 20 plus conventional care is more effective than conventional care without hylan G-F 20, and that hylan G-F 20 is equivalent to NSAIDs and intra-articular steroids. There is low-quality evidence and, hence, uncertainty about the effectiveness of hylan G-F 20 compared to placebo or other hyaluronan products.
However, in using the GRADE approach, several limitations were identified in the evidence that limit the strength of the conclusions that can be drawn when all RCTs on hylan G-F 20 are considered. Consequently, the Medical Advisory Secretariat undertook to identify the high-quality studies, which meant excluding studies with serious limitations (). As a result, only 4 high-quality studies (, ) involving 6 comparisons were identified. These are reviewed in some detail.
Trials Excluded From the Medical Advisory Secretariat’s Review
Figure 4: Number of and Reasons for Excluded Comparisons* Karlsson (44)
Design: This was a double-blinded, multicentre RCT of 246 patients who were allocated to one of 3 arms (hylan G-F 20, Artzal, or placebo). According to the authors’ power calculations, 50 patients were needed in the placebo group, 75 in each of the 2 active treatment groups, to enable detection of a difference of 15 mm in the decrease in weight-bearing pain from baseline between the placebo and active treatment groups. Per-protocol (hylan G-F 20 (N = 77), Artzal (N = 76), placebo (N = 57) and intention-to-treat (hylan G-F 20) (N = 86), Artzal (N = 90), placebo (N = 66)) analyses were conducted. There was a 2-week washout period before measuring baseline scores. Breakthrough acetaminophen up to 4 grams a day was permitted, but not within 12 hours of outcome assessments. The study ran for 1 year. The primary outcome was weight-bearing pain between 0 and 26 weeks after treatment and duration of clinical benefit over 0 to 52 weeks. Clinical failure was defined as the use of concurrent treatment for the study knee.
Patients: Swedish study. Inclusion criteria were age over 59 years, advanced disease (Lequesne score of at least 10), weight-bearing pain of at least 40/100 mm VAS, radiological confirmed OA grade I or II by Ahlback criteria, and a normal physical exam. The exclusion criterion was any intra-articular procedure in the study knee within the previous 6 months. The mean age of the subjects was 71 years. Baseline values were nearly equivalent among the 3 arms: 100 mm VAS weight-bearing pain, 63 to 65; total WOMAC score, 48.7 to 48.9; total Lequesne score, 13.4 to 13.9.
Results: Patients in all 3 arms improved significantly from baseline. However, the magnitude of difference between the hylan G-F 20 and placebo arms at 5 to 13 weeks after treatment (WMD, -5.0; 95% CI, -18.6–8.65), and at 14 to 26 weeks after treatment (WMD, -1.0, 95% CI; -14.5–12.6), was not clinically significant. Nor was it clinically significant between the hylan G-F 20 and Artz arms at 5 to 13 weeks (WMD, -1.0; 95% CI, -9.8–7.8) or at 14 to 26 weeks (WMD, -5.0; 95% CI, -15.9–4.9) after treatment. Compared with placebo, neither of the hyaluronic acid treatments had a significantly longer duration of clinical benefit. By week 26, 20% to 30% of participants had dropped out. By week 52, this had risen to 60% to 70%.
Wobig 1998 (43)
Design: This was a double-blinded, multicentre RCT of 110 patients randomized to receive either hylan G-F 20 (N = 52) or placebo (N = 54). The authors did an intention-to treat analysis. There was a 2-week washout period prior baseline measures were taken Concurrent therapy was permitted throughout the trial, which included steroids, NSAIDs, analgesics, physiotherapy, and surgery. One of the primary outcomes was pain with weight bearing. The study lasted 12 weeks, and there was a follow-up phone call at 26 weeks.
Patients: German study. Although anyone older than 18 was permitted to enter, the mean age was 62 years. Inclusion criteria were radiological evidence and persistent pain despite use of NSAIDs or analgesics. The mean duration of disease was 6 years. The baseline 100 mm VAS scores for pain with weight bearing were virtually the same between the treatment and control groups (71 mm and 75 mm, respectively). There was some imbalance between the treatment and control groups: significantly more patients in the hylan G-F 20 group had had the disease for less than 1 year, and their disease was less advanced according to radiographic (Larsen) grades. However, an analysis of variance, breaking the study sample down by population and Larsen grade, showed no significant treatment-by-grade interactions.
Results: More patients in the hylan G-F 20 group reported clinically significant improvements in outcome VAS pain scores compared with the placebo group at 5 to 13 weeks after treatment (WMD, -37.0; 95% CI, -45.3 to -28.7) and at 14 to 26 weeks after treatment (WMD, -21.0; 95% CI, -32.1 to -9.9). Rescue therapy was required by only 11% of patients in the hylan G-F 20 group, compared with 53% of the saline-treated group.
Wobig 1999 (47)
Design: This was double-blinded, multicentre RCT of 70 patients randomized to receive either intra-articular hylan G-F 20 (n = 38) or Artz, another intra-articular hyaluronan (n = 32). There was a 2-week washout of NSAIDs and analgesics. Concurrent therapy was permitted throughout the trial. Primary outcome was weight-bearing pain at 12 weeks.
Patients: German-based study. Although anyone older than 18 could participate, the mean age was 60 years. Inclusion criteria were radiological and laboratory evidence of OA and persistent pain despite use of NSAIDs or analgesics. The mean duration of disease was 4.6 years. The baseline 100 mm VAS scores for pain with weight bearing were virtually the same between the treatment and control groups (70mm and 72mm). Patients with effusions were excluded.
Results: Hylan G-F 20 was significantly more effective at relieving OA knee pain; however, the magnitude of effect on pain with weight bearing at 12 weeks after injection did not exceed the MCID of – 10 mm with confidence (WMD, -16.0; 95% CI, -27.1 to -5.0).
Design: This was a 12-week, double-blinded, multicentre RCT conducted in 18 general practices in the United Kingdom. It involved 165 patients randomized to one of 3 arms: hylan G-F 20 and placebo pills, arthrocentesis and diclofenac retard 100 mg daily, or arthrocentesis and placebo pills). Up to 3000 mg of break-through paracetamol was permitted.
Patients: British study. Subjects were required to have radiologically confirmed OA and baseline pain exceeding 40 mm on a 100 mm VAS. The baseline WOMAC pain score ranged from 59 to 61, and the baseline Lequesne score ranged from 13.9 to 14.4, indicating the disease was advanced.
Results: The magnitude of effect of hylan G-F 20 compared with diclofenac failed to exceed the MCID of-10 mm with confidence (WMD, -12.0; 95% CI, -23.1 to -0.9). (The per-protocol analysis was underpowered.)
Five of the 6 systematic reviews considered safety. Their conclusions are shown in .
Safety of Hylan G-F 20 According to Level 1a Evidence
The rates of local adverse events reported in the RCTs and observational studies reviewed by the Medical Advisory Secretariat are shown in .
Reported Rates of Local Adverse Reactions With Hylan G-F 20
The 8 Level 4 studies (33
), in addition to the RCTs, were reviewed for safety. Twelve of the 17 studies reviewed reported local adverse event rates of less than 5% of either injections or patients. One apparent outlier, Kahan, (53
) reported an adverse event rate of 44% among patients in the hylan G-F 20 arm, compared with a 32% rate among the control group. Most (37%) of the hylan-related reactions in this study were due to pain or swelling at the injection site. The results of a retrospective chart review (64
) suggested that the risk of a local reaction increased with repeat treatments of hylan G-F 20; however, a recent prospective analysis (65
) identified no statistically significant differences in the rates of adverse events between the first and repeat treatment cycles.
The rate of severe adverse reactions to hylan G-F 20 in this review was low, with 5 (4%) moderate to severe events reported in one study, (Clarke (62
)) resulting in pain and swelling requiring joint aspiration. There was also one episode of severe arthrosis in another study (Waddell (66
)) (1.4%), and 3 (1%) episodes in another (Wobig 1999 (33
In 2002, 6 cases of granulomatous inflammation of the synovium after hylan G-F 20 injections were reported. (67
) Recently, the Canadian Adverse Reaction Newsletter (68
) reported that Health Canada had received 31 reports of suspected incidents associated with hylan G-F 20 between 1996 and 2005; 23 were received in 2003 to 2004. In 9 cases, synovial fluid was not removed before each injection. Six of the 23 recent reports described patients who had pain, walking disability, and knee swelling, with or without effusion, after the third injection of the first course.
An estimated 5,000 people in Ontario receive hylan G-F 20 treatments a years, which is about 0.04% of the Ontario population. By presuming that a similar proportion of people across Canada receive hylan G-F 20, then an estimated 15,000 people a year are treated with hylan G-F 20. This means that injection with hylan G-F 20 may carry a risk of a moderate-to-severe inflammatory joint reaction; however, the likelihood of this complication appears to be low, at about 23/15,000 (0.15%).
The 2 health technology assessments found that the data were sparse and poor quality. There was some evidence that hylan G-F 20 delivered a small clinical benefit at 3 to 6 months after treatment on a magnitude comparable to that of NSAIDs and intra-articular steroids. Hylan G-F 20 appeared to carry a risk of a local adverse reaction of 3% to 18% per injection, but no apparent risk of a severe adverse event, although the data were limited.
Each of the 3 meta-analyses of placebo-controlled trials of intra-articular hyaluronans had only 3 trials involving hylan G-F 20. There results were inconsistent, with 1 analysis concluding that intra-articular hyaluronans were efficacious, whereas the 2 others concluded the effect size was small (0.32) and probably not clinically significant. The risk of a minor adverse event ranged from 8% to 19% per injection. Major adverse events were rare.
The Cochrane review concluded that pooled analysis supported the efficacy of hylauronans, including hylan G-F 20. At 5 to 13 weeks after the injection, there was an improvement from baseline of 11% to 54% for pain and 9% to 15% for function. Comparable efficacy was noted against NSAIDs, and longer-term benefits were noted in comparison against steroids. Few adverse events were noted.
When the Medical Advisory Secretariat applied the criterion of clinical significance to the magnitude of pain relief reported in the RCTs on hylan G-F 20 it found the following:
- inconsistent evidence that hylan G-F 20 was clinically superior to placebo at 5 to 26 weeks after treatment,
- consistent evidence that for pain relief, hylan G-F 20 was no better or worse than NSAIDs or intra-articular steroids at 5 to 26 weeks after treatment,
- consistent evidence that hylan G-F 20 was not clinically superior to other hyaluronic products, and
- consistent evidence that hylan G-F 20 delivered a small magnitude of clinical benefit at 12 to 52 weeks after injection when administered as an adjunct to conventional care.
There were substantial limitations to the methods of many of the RCTs involving hylan G-F 20. When only the results from higher-quality studies were considered, there was level 2 evidence that hylan G-F 20 was not clinically superior to placebo (or another hyaluronan) at 1 to 26 weeks after treatment in older patients with advanced disease for whom total knee replacement was indicated. There was level 2 evidence that hylan G-F 2- was comparable to NSAIDs at 4 to 13 weeks after treatment and that it was superior to placebo when delivered as an adjunct to conventional care 4 to 26 weeks after treatment.
Overall, hylan G-F 20 carries a risk of a minor, local adverse event rate of about 8 to 19 per 100 injections. Incidents of moderate-to-sever post-injection inflammatory joint reactions have been reported, but the likelihood appears to be low (0.15% per patient).