To assess the effectiveness and cost-effectiveness of hylan G-F 20 as a substitute for existing treatments for pain due to osteoarthritis (OA) of the knee, other viscosupplementation devices, and/or as an adjunct to conventional therapy.
Hylan G-F 20 (brand name Synvisc, which is manufactured by Genzyme) is a high molecular weight derivative of hyaluronan, a component of joint synovial fluid. It acts as a lubricant and shock absorber. It is administered by injection into the joint space to treat pain associated with OA of the knee. Although the injection procedure is an insured service in Ontario, the device, hylan G-F 20, is not.
Osteoarthritis is prevalent in 10% to 12% of Ontario adults, and exceeds 40% in Ontario residents aged 65 years and older. About one-half of these people have mild, moderate, or severe OA of the knee. Conventional treatment involves a combination of nonpharmacological management (e.g., weight loss, exercise, social support, and patient education), drugs, (e.g., acetaminophen, COX-2 inhibitors, nonsteroidal anti-inflammatory drugs with/without misoprostol, intra-articular glucocorticoids, opioids, and topical analgesics) and surgical interventions, such as debridement and total knee replacement, when pharmacological management fails.
The growing burden of OA of the knee in the aging Ontario population combined with recent safety concerns about COX-2 inhibitors and long wait times for total joint replacement is placing pressure on the demand for new, effective technologies to manage the pain of OA.
Hylan G-F 20 is derived from rooster comb hyaluronan (HA). At the time of writing, eight viscosupplement hyaluronic products are licensed in Canada. Hylan G-F 20 is distinguished from the other products by its chemical structure (i.e., cross-linked hyaluronan, hence hylan) and relatively higher molecular weight, which may bestow greater therapeutic viscoelastic properties. A complete treatment cycle of hylan G-F 20 involves an intra-articular injection of 2 ml of hylan G-F 20 once a week for 3 weeks. It is licensed for use for patients in all stages of joint pathology, but should not be used in infected or severely inflamed joints, in joints with large effusion, in patients that have skin diseases or infections in the area of the injection site, or in patients with venous stasis. It is also contraindicated in patients with hypersensitivities to avian proteins.
The Medical Advisory Secretariat used its standard search protocol to review the literature for evidence on the effectiveness of intra-articular hylan G-F 20 compared with placebo, as a substitute for alternate active treatments, or as an adjunct to conventional care for treatment of the pain of OA of the knee. All English-language journal articles and reviews with clearly described designs and methods (i.e., those sufficient to assign a Jadad score to) published or released between 1966 and February 2005 were included. Two more recently published meta-analyses were also included. The databases searched were Ovid MEDLINE, EMBASE, the Cochrane database and leading international organizations for health technology assessments, including the International Network of Agencies for Health Technology Assessments. The search terms were as follows: hyaluronan, hyaluronate adj sodium, hylan, hylan G-F 20 (Synvisc), Synvisc, Hyalgan, Orthovisc, Supartz, Artz, Artzal, BioHY, NASHA, NRD101, viscosupplementation, osteoarthritis, knee, knee joint. The primary outcome of interest was a clinically significant difference, defined as greater than 10 mm on 100 mm visual analogue scale, or a change from baseline of more than 20% in the mean magnitude of pain relief experienced among patients treated with hylan G-F 20 compared with those treated with the control intervention.
One clinical epidemiologist reviewed the full-text reports and extracted data using an extraction form. Key variables included, but were not limited to, the characteristics of the patients, method of randomization, type of control intervention, outcome measures for effectiveness and safety, and length of follow-up. The quality of the studies and level of the evidence was initially scored by one clinical epidemiologist using the Jadad scale and GRADE approach. Level of quality depends on the amount of certainty about the magnitude of effect and is based on study designs, extent of methodological limitations, consistency of results and applicability (i.e. directness) to the Ontario clinical context. The GRADE approach also permits comment on the strength of recommendations resulting from the evidence, based on estimates of the magnitude of effect relative to the magnitude of risk and burden and the level of certainty around these estimates. The quality assessments were subsequently peer-reviewed.
Summary of Findings
The literature search revealed 2 previous health technology assessments, 3 meta-analyses of placebo-controlled trials, 1 Cochrane review and meta-analysis encompassing 18 randomized controlled trials (RCTs) that compared hylan G-F 20 to either placebo or active treatments, 11 RCTs of hylan G-F 20 (all included in the Cochrane review), and 10 observational studies. Given the preponderance of evidence, the Medical Advisory Secretariat’s analysis focused on studies with Level 1 evidence of effectiveness (i.e., the meta-analyses of RCTs and the RCTs). Only safety data from the observational studies were included.
The authors of the 2 health technology assessments concluded 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 NSAIDs and intra-articular steroids. Hylan G-F 20 appeared to carry a risk of a local adverse reaction of in the range of 3% to 18% per 100 injections, but there was 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 one study concluding that intra-articular hyaluronans were efficacious, whereas the 2 other analyses 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 100 injections. Major adverse events were rare.
The authors of the Cochrane review concluded that a pooled analysis supported the efficacy of hyaluronans, including hylan G-F 20. The 5- to 13-week post-injection period showed 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 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, the following was noted:
There was inconsistent evidence that hylan G-F 20 was clinically superior to placebo at 5 to 26 weeks after treatment.
There was consistent evidence that, in terms of delivering pain relief, hylan G-F 20 was no better or worse than NSAIDs or intra-articular steroids at 5 to 26 weeks after treatment.
There was consistent evidence that hylan G-F 20 was not clinically superior to other hyaluronic products.
There was consistent evidence that hylan G-F 20 delivered a small magnitude of clinical benefit at 12 to 52 weeks post-injection when administered as an adjunct to conventional care.
There were limitations to the methods in many of the RCTs involving hylan G-F 20. When only the results from the 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 level 2 evidence that hylan G-F 20 was superior to placebo as an adjunct to conventional care 4 to 26 weeks after treatment.
With respect to safety, 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-severe post-injection inflammatory joint reactions have been reported, but the likelihood appears to be low (0.15% of patients).
Case-costing estimates suggest that the annual cost of 2 treatment cycles of hylan G-F 20 (plus analgesics for breakthrough pain) is almost equivalent to the annual cost of taking a NSAID (with a gastroprotective agent) and is more expensive that taking intra-articular corticosteroids (plus analgesics for breakthrough pain). The estimated cost of funding hylan G-F 20 as an adjunct to conventional therapy (i.e., any of analgesics, NSAIDs, intra-articular steroids, physiotherapy, and surgery) is $700 per patient per year. Given the huge burden of mild to moderate OA among adults who seek medical care for it in Ontario (about 300,000), funding hylan G-F 20 as an adjunct to existing treatment could be expensive, depending on its diffusion and uptake. If only 10% to 30% of patients choose this option, then the estimated budget impact would be $21 million to $63 million (Cdn) per year.
When the benefits relative to the risks and costs are considered, NSAIDs and hylan G-F 20 appear comparable, as the table shows. Consequently, there’s little evidence on which to recommend hylan G-F 20 over NSAIDs, except perhaps for patients who cannot tolerate NSAIDs, although this evidence is indirect, since no studies looked specifically at this population.
CC indicates conventional care; IA, intra-articular; NSAID, nonsteroidal anti-inflammatory drug.
Intra-articular steroids appear to deliver the same risks and clinical benefits as hylan G-F 20 at a lower cost; therefore, there’s evidence that intra-articular steroids are the preferred option. Hylan G-F 20 as an adjunct to conventional care appears to deliver some clinical benefit, although funding hylan G-F 20 as an adjunct would have considerable budget impact, so the benefits of this option do not clearly outweigh the costs. There’s some uncertainty about the effect of hylan G-F 20 relative to other hyaluronans, mostly because some of the trials of this comparison were not published.
Many of the studies of hylan G-F 20 have considerable methodological limitations that result in uncertainty about the magnitude of effect. An upcoming review of the evidence by the Osteoarthritis Advisory Panel of clinical experts will likely help to reduce some of this uncertainty.
There is moderate evidence that hylan G-F 20 is no more clinically effective than NSAIDs. The evidence that hylan G-F 20 might be an appropriate option for a person with OA of the knee who cannot tolerate NSAIDs is indirect. The possible benefit of fewer cases of NSAID-induced gastropathy in this population must be weighed against the uncertainty of a severe inflammatory adverse reaction to hylan G-F 20.
Similarly, there is moderate evidence that hylan G-F 20 is no more clinically effective than intra-articular corticosteroids. The lower cost of intra-articular corticosteroids makes them the preferred option.
There is moderate evidence that hylan G-F 20 is effective as an adjunct to conventional care, delivering a small magnitude of temporary relief at 4 to 26 weeks after treatment. The estimated additional cost to the system of providing hylan G-F 20 as an adjunct to conventional care is about $700 (Cdn) per patient annually. The magnitude and duration of clinical benefit of hylan G-F 20 must be weighed against the uncertainty and potential magnitude of the budget impact (about $35 million to $105 million (Cdn) per year) of funding this device given the high burden of OA in Ontario adults.
There is level 2 evidence that hylan G-F 20 is not effective in people with advanced OA for whom total knee replacement is indicated.