1. Aetna considers viscosupplementation (e.g., Hyalgan (sodium hyaluronate), Supartz (sodium hyaluronate), Synvisc (Hylan G-F 20), Synvisc One (Hylan G-F 20), Euflexxa (1 % sodium hyaluronate), or Orthovisc (high molecular weight form of hyaluronic acid)) medically necessary for members with osteoarthritis of the knee who meet all of the following selection criteria:

   1. Conservative therapy (including physical therapy, pharmacotherapy (e.g., non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen (up to 1 g four times per day) and/or topical capsaicin cream)) has been attempted in each joint to be treated with viscosupplements and has not resulted in functional improvement after at least 3 months or the member is unable to tolerate conservative therapy because of adverse side effects; and
   2. The member has documented symptomatic osteoarthritis of the knee; and
   3. The member has failed to adequately respond to aspiration and injection of intra-articular steroids; and
   4. The member reports pain which interferes with functional activities (e.g., ambulation, prolonged standing); and
   5. The pain cannot be attributed to other forms of joint disease; and

   6. There are no contraindications to the injections (e.g., active joint infection, bleeding disorder).

   Additional series of injections for members who have responded to previous series are considered medically necessary under the following circumstances:

   1. At least three months has elapsed since the prior series of injections; and 
   2. The medical record demonstrates a reduction in the dose of NSAIDS (or other analgesics or anti-inflammatory medication) during the 3-month period following the previous series of injections; and

   3. The medical record objectively documents significant improvement in pain and functional capacity as the result of the previous injections.

2. Aetna considers viscosupplementation experimental and investigational for all other indications such as chondromalacia patellae, facet joint arthropathy, osteochondritis dissecans, or patellofemoral syndrome (patellar knee pain), or for use in joints other than the knee (e.g., ankle, carpo-metacarpal joint, elbow, hip, metatarso-phalangeal joint, shoulder, and temporomandibular joint) because the effectiveness of viscosupplementation for these indications has not been established.

Osteoarthritis of the knee is a disease in which the elastoviscous properties of the synovial fluid in the knee joint becomes diminished, resulting in less protection and shock absorption. In May 1997, the FDA approved sodium hyaluronate (Hyalgan), an injectable form of hyaluronic acid, for the treatment of pain associated with knee osteoarthritis. In November 1996, the Orthopedics and Rehabilitation Devices Panel of the FDA recommended Synvisc for approval in the United States, with the condition that a post-market study be performed. Hylan G-F 20 (Synvisc and Synvisc One), a cross-linked preparation of hyaluronan, is a viscosupplementation drug injected into knee joints to increase the elastoviscous properties of arthritic joint (synovial) fluid, while at the same time slowing its egress from the joint. Trials have indicated that both compounds appear to result in a small but statistically significant improvement in reducing pain and increasing levels of mobility in the majority of individuals treated, as compared with placebo, and may even slow down deterioration of joints.

Hyalgan is usually given as weekly intra-articular injections administered for up to 5 weeks. Noticeable improvements usually occur beginning at week 5 after treatment initiation, and symptom relief may last for six months. Hyalgan should not be used to treat joint dysfunction.

Two formulations of Hylan GF-20 are currently available. Synvisc is administered once per week for a total of three intra-articular injections. Synvisc One is administered in a single intraarticular injection. 

Supartz (sodium hyaluronate) was approved by the FDA on January 24, 2001.  It is indicated for the treatment of pain in osteoarthritis of the knee in patients who have failed to respond adequately to conservative non-pharmacologic therapy (e.g., physical therapy) and simple analgesics (e.g., acetaminophen).  Supartz is administered by an injection once a week for a total of five injections.

In 2000, the American College of Rheumatology updated its guidelines for the treatment of OA of the knee. In mild symptomatic OA, treatment may be limited to patient education, physical and occupational therapy and other non-pharmacologic modalities, and pharmacologic therapy including non-opioid oral and topical analgesics. In patients who are unresponsive to this regimen, the use of non-steroidal anti-inflammatory drugs (NSAIDs) is appropriate.

According to ACR guidelines, intra-articular injections of corticosteroids or hyaluronan may be used for patients who fail to respond to management that is more conservative. Patients with severe symptomatic OA of the knee may require surgical intervention, e.g. osteotomy or total joint arthroplasty. The guidelines on knee pain from the American College of Orthopedic Surgeons (1999) and the National Institute for Health and Clinical Excellence (2007) also recommend use of intra-articular steroids in patients with osteoarthritis of the knee that fail to respond to more conservative measures (e.g., NSAIDS or acetaminophen, physical therapy, decreased activity).  According to the literature, patients with joint effusions and local tenderness may have greater benefit from intra-articular steroid injections. Neither patient function, radiographic features, intra-articular crystals nor a raised synovial fluid cell count predict a good response (Creamer, 1997). At the basic science level, there are a number of mechanisms by which the improvement is thought to occur - mRNA synthesis, B and T cell function, cytokine levels, metalloproteases and synovial permeability (Creamer 1997, Genovese 1998).  The benefits of corticosteroids may also be due to relief of effusions from aspiration and disruption of adhesions within the joint.  Although there are only a limited number of studies that have directly compared the viscosupplementation with corticosteroid injections, these studies indicate that corticosteroid injections are as effective as viscosupplementation in the treatment of osteoarthritis of the knee (Johnston, 2003).  The most serious complication is septic arthritis, with an incidence of 1/17,000 to 1/50,000 (SCHIN, 2002). There is a risk of local tissue atrophy and depigmentation, particularly when small joints are injected with potent corticosteroids. Concern about progressive joint damage following repeated corticosteroid injections is controversial; despite the large number of people treated with intra-articular corticosteroids, case reports that suggest this may result in joint damage are rare (SCHIN, 2002).  According to available literature, it is inadvisable to treat patients with a complete collapse of joint space or bone loss with intra-articular hyaluronic acid or corticosteroids, given their poor clinical response (Evanich, et al., 2001).

Viscosupplementation is a therapeutic modality for the treatment of osteoarthritis based on the physiologic importance of hyaluronan in synovial joints (Bellamy, 2002).  Its therapeutic goal is to restore the visco-elasticity of synovial hyaluronan, thereby decreasing pain, improving mobility and restoring the natural protective functions of hyaluronan in the joint. The short-term mode of action of viscosupplementation is believed to be based on the pain relieving effect of the elastoviscous fluid in the affected joint. In the long term, the restoration of the joint mobility due to relief of pain triggers a sequence of events, which restores the trans-synovial flow and subsequently the metabolic and rheological homeostasis of the joint.

According to a review of the literature in the journal Clinical Evidence (Scott & Kowalczyk, 2006), compared with placebo, intra-articular hyaluronan and hyaluronan derivatives may improve pain and function compared with placebo at up to 13 weeks after injection, but may have no longer-term benefits. The review stated that this conclusion is based upon low-quality evidence. The assessment also found that, compared with intra-articular corticosteroids, hyaluronan may be more effective than intra-articular corticosteroids at reducing pain at 5–13 weeks, although they may be as effective as each other in the shorter term. According to the review, this conclusion is based upon very low-quality evidence. The assessment also noted that there is no evidence on the effectiveness of subsequent courses of hyaluronan, and if diminishing returns exist.

Kirwan (1997) reviewed 10 clinical trials of hyaluronan of the knee joint. The review found slightly greater benefit from the injections versus placebo at 1 to 6 months after treatment. Of four subsequently published randomized controlled trials, three (Lohmander, 1996; Corrado, et al, 1995; Formiguera, 1995) found no significant difference versus placebo at 2 to 5 months after treatment, but both active and placebo groups improved compared with baseline. One of the trials (240 people) included a subgroup analysis of people aged over 60 years with moderate to severe symptoms; these benefited more with active treatment than placebo (Lohmander, 1996). The fourth subsequent randomized controlled trial, involving 100 people, found significant benefit on a standardized pain assessment tool (the Lequense index) with hyaluronan versus placebo, both at 5 weeks and four months (Huskisson, 1999). Another randomized controlled clinical trial also found a trend toward greater pain relief and functional recovery in patients treated with intra-articular hyaluronan versus placebo injection, but the differences between the two groups were not statistically significant (Tamir, 2001).

Bellamy (2002) viewed the evidence comparing viscosupplementation to steroid injections. One randomized controlled clinical trial reviewed by Bellamy (2002) found a benefit of hyaluronan at 5 and 8 weeks against steroids, but no difference in effect between steroid and hyaluronan injections was found in two other randomized controlled clinical trials.

The Galacian Agency for Health Technology Assessment (Fernandez Lopez & Ruano-Ravina, 2005) systematically reviewed the evidence for the use of viscosupplementation in hip osteoarthritis. The authors of the systematic review identified seven clinical trials that met the inclusion criteria and one systematic review. The number of patients in the trials ranged from 22 to 104. Five trials had no control group, one compared two viscosupplements of different molecular weight, and the remainder compared viscosupplements with administration of intraarticular glucocorticoids and with a group that received placebo. Relief of pain was estimated to be around 40% to 50% by most studies, though the duration of this effect post-treatment was not known. The authors reported that the randomized clinical trial with three arms reported no differences between the treatments at the end of the follow-up period. Moreover, this study displayed the highest quality of all those included. The authors concluded that the absence of a control group in most of the clinical trials means that there is no way of ascertaining the effectiveness of viscosupplements in hip osteoarthritis. Accordingly, viscosupplements "should not be used outside the ambit of experimental studies until better-quality evidence is available."

In a review on viscosupplementation in the treatment for patients with hip osteoarthritis (OA), Conrozier and Vignon (2005) concluded that to date, in the absence of placebo-controlled studies, the effectiveness of intra-articular injections of hyaluronic acid or its derivatives in the symptomatic treatment of hip OA cannot be determined conclusively.  Nevertheless the published data suggest that viscosupplementation may be effective.  These researchers stated that double-blind, controlled studies are needed to confirm these data, before viscosupplementation should be included into the treatment paradigm for patients with hip OA.

Migliore, et al. (2006) reported the effects of hylan G-F 20 administered through ultrasound (US)-guided intra-articular (IA) injections in patients with symptomatic hip OA.  They treated 30 patients with symptomatic hip OA.  Under US guidance, 7 patients received one injection, 21 patients had two injections, and 2 patients received three injections, each with 2 ml of hylan G-F 20.  Lequesne index, visual analog scale (VAS) scale of hip pain, and NSAID consumption were evaluated at baseline as well as 2 and 6 months after the beginning of the treatment.  No systemic adverse events were observed.  Lequesne index, VAS pain score, and NSAID consumption showed a reduction that was statistically significant to the baseline.  The present observation suggested the potentiality for the safety and effectiveness of hylan G-F 20 injected under US guidance in patients with symptomatic hip OA.  The authors stated that further controlled studies are needed.

The Canadian Agency for Drugs and Technologies in Health's report on IA hyaluronic acid for hip OA (Dagenais, 2007) stated that the best available evidence suggests that hyaluronic acid may offer symptomatic relief in patients with mild to moderate hip OA for whom other conservative therapies are contraindicated or have failed.  Currently, there is insufficient good quality evidence to determine this conclusively.

van den Bekerom, et al. (2008) evaluated the effectiveness of viscosupplementation in the treatment of hip OA.  A total of 16 articles concerning the effectiveness of a total of 509 patients undergoing viscosupplementation for hip OA were included -- 12 European studies, 3 Turkish studies and 1 American study with levels of evidence ranging from I to IV evaluated the following products: Hylan G-F 20, Hyalgan, Ostenil, Durolane, Fermatron and Orthovisc.  Heterogeneity of included studies did not allow pooled analysis of data.  The authors noted that despite the relatively low level of evidence of the included studies, viscosupplementation performed under fluoroscopic or ultrasound guidance seems an effective treatment and may be an alternative treatment of hip OA.  Intra-articular injection of (derivatives of) HA into the hip joint appears to be safe and well-tolerated.  However, the authors stated that viscosupplementation can not be recommended as standard therapy in hip OA for wider populations, and therefore the indications remain a highly individualized matter.

In a pilot study, Salk, et al. (2005) examined the safety and effectiveness of viscosupplementation with sodium hyaluronate versus phosphate-buffered saline control for pain associated with OA of the ankle.  Results of this study suggested that 5 weekly intra-articular injections of sodium hyaluronate in patients who have OA of the ankle are well tolerated, can provide sustained relief of pain, and improve ankle function.  These findings are consistent with previously published studies using intra-articular injections of sodium hyaluronate in other articular joints but require confirmation in a large, randomized, saline-controlled study.  These investigators concluded that if confirmed, these findings would provide a valuable non-operative treatment option for patients who have OA of the ankle.

Carpenter and Motley (2008) noted that although anecdotal data exist, no long-term studies regarding the use of viscosupplementation in the ankle have been published to date.  These researchers compared pain reduction following ankle arthroscopy versus that following ankle arthroscopy combined with weekly intra-articular instillation of hylan G-F 20 during the first 3 post-operative weeks.  They found that both treatment groups experienced statistically significantly decreased pain following the intervention (p = 0.002 and p = 0.0009 for the arthroscopy alone and arthroscopy plus hylan groups, respectively), and that those who received 3 intra-articular injections of hylan G-F 20 following ankle arthroscopy improved statistically significantly (p = 0.0014) more than did those who underwent arthroscopy as a sole therapy.  These preliminary results suggested that viscosupplementation combined with arthroscopy may be more beneficial than arthroscopy alone, and provide further insight into the role of viscosupplementation in the treatment of ankle OA.

van Brakel and Eygendaal (2006) assessed the safety and effectiveness of IA injection of hyaluronic acid in 19 consecutive elbows with post-traumatic OA.  In 18 patients (10 male and 8 female patients; mean age, 45.6 years [SD, 15.0 years]), 3 injections of sodium hyaluronate were given within 4 weeks at regular intervals.  Evaluation took place just before the first injection, as well as after 3 and 6 months, and consisted of the Elbow Function Assessment Score, the Functional Rating Index of Broberg and Morrey, and the Modified Andrews Elbow Scoring System.  Pain was also assessed by means of VAS.  Viscosupplementation resulted in slight, short-term pain relief and a very limited decrease in activity impairment at evaluation after 3 months.  After 6 months, no beneficial effects were noticed in any of the 19 injected elbows.  Other parameters were not influenced by treatment with viscosupplementation at any time.  Systemic or local adverse effects did not occur.  The authors concluded that because the use of viscosupplementation for the treatment of post-traumatic OA of the elbow provides only slight, short-term pain relief and a very limited decrease in activity impairment and the other parameters were not modified, viscosupplementation is not suitable for this indication.

An assessment of viscosupplementation for knee osteoarthritis by the Canadian Agency for Drugs and Technologies in Health (CADTH) (Dagenais, 2006) found that evidence suggests modest short-term reductions in pain and improvements in function, and no superiority among viscosupplement products. Adverse events are rare, benign, temporary, and likely associated with the intraarticular injection. The assessment reported that clinical practice guidelines and evidence suggest that this approach is most suitable for patients with mild to moderate knee osteoarthritis, and in those for whom other approaches are contraindicated, or have failed.

Guidance from the National Institute for Health and Clinical Excellence (2008) found that the research evidence on the efficacy of viscosupplementation is often difficult to interpret because of confounders including different molecular weights of hyaluronans, different injection schedules (ranging from once weekly to a series of 5 injections), poor trial design despite large numbers of studies (for example lack of intention-to-treat analyses, limitations in blinding). The guidance concludes that the evidence seems to suggest a benefit for reducing pain up to 3 months after a series of 3-5 injections, although the effect size is generally small. "Given this, and the cost of the therapies together with increased clinician visits required for injections, there appears to be a poor rationale for routine clinical use." The guidance noted that clinical trials do not suggest subgroups of osteoarthritis patients who may have greater benefit from viscosupplementation.

An assessment by AETMIS (2007) reached similar conclusions to the NICE guidance. The AETMIS assessment concluded that viscosupplementation offers clinically modest relief from the symptoms of knee osteoarthritis over a period that could last up to several weeks. The assessment found viscosupplementation to be a safe short-term treatment. The assessment noted, however, that these conclusion are based on secondary analyses of a multitude of small primary studies of poor methodological quality.  AETMIS reported that available data did not help distinguish differences in the effectiveness of any one product over the others. They were also unable to identify patient subgroups more likely to benefit from this treatment compared with other available therapeutic modalities. AETMIS concluded that, given the modest effectiveness of viscosupplementation compared with its relatively high cost and the additional professional resources required to administer it, it is not currently justified to contemplate funding viscosupplementation for all patients with osteoarthritis of the knee. The assessment noted, however, that it is possible that viscosupplementation could be offered as a last-resort treatment to patients who do not achieve pain relief from conventional therapies or for whom these are contraindicated.

A systematic evidence review prepared by the BlueCross BlueShield Association Technology Evaluation Center Evidence-based Practice Center for the Agency for Healthcare Research and Quality (Samson, et al., 2007) concluded: "Viscosupplementation trials generally report positive effects on pain and function scores compared to placebo, but the evidence on clinical benefit is uncertain, due to variable trial quality, potential publication bias, and unclear clinical significance of the changes reported."

The American Academy of Orthopaedic Surgeons' clinical guideline on the treatment of OA of the knee (2008) can not recommend for or against use of intra-articular HA injections.

There is limited evidence of the effectiveness of repeat viscosupplement treatments. Available evidence is limited to uncontrolled case series, so that improvements following repeat treatment may be due to the natural history of the condition and placebo effects. Evidence submitted to the FDA regarding repeat treatment consisted of two studies. One study, by Scali, et al. (1995) was an uncontrolled study of 5 weekly injections of viscosupplementation repeated every 6 months for 30 months, for a total of 25 injections. A second study by Kotz and Kolarz (1999) examined the effectiveness of viscosupplementation in 108 patients, 14 of whom received repeat injections within 4 to 8 months due to pain recurrence, 6 of whom completed 12 month followup. Guidance from the National Institute for Health and Clinical Excellence (NICE, 2007) found that the evidence seems to suggest a benefit for reducing pain up to 3 months after a series of 3-5 injections, although the effect size is generally small.

In a randomized controlled trial, Jüni, et al. (2007) compared the safety and effectiveness of intra-articular hylan and two hyaluronic acids (HAs) in OA of the knee (n = 660). Patients were randomly assigned to receive 1 cycle of 3 intra-articular injections per knee of 1 of 3 preparations: (i) a high molecular weight cross-linked hylan, (ii) a non-cross-linked medium molecular weight HA of avian origin, or (iii) a non-cross-linked low molecular weight HA of bacterial origin. The primary outcome measure was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 6 months. Secondary outcome measures included local adverse events (effusions or flares) in injected knees. During months 7 to 12, patients were offered a second cycle of viscosupplementation. Pain relief was similar in all 3 groups. The difference in changes between baseline and 6 months between hylan and the combined HAs was 0.1 on the WOMAC pain score (95% confidence interval [95% CI] -0.2, 0.3). No relevant differences were observed in any of the secondary efficacy outcomes, and stratified analyses provided no evidence for differences in effects across different patient groups. There was a trend toward more local adverse events in the hylan group than in the HA groups during the first cycle (difference 2.2% [95% CI -2.4, 6.7]), and this trend became more pronounced during the second cycle (difference 6.4% [95% CI 0.6, 12.2]). The authors concluded that there was no evidence for a difference in effectiveness between hylan and HAs. In view of its higher costs and potential for more local adverse events, these investigators see no rationale for the continued use of hylan in patients with knee OA.

In a pilot study, Cleary and colleagues (2008) examined the potential effectiveness of HA injection therapy in the treatment of lumbar facet joint arthritis. A total of13 patients with symptomatic lumbar facet joint arthritis who met the inclusion criteria were prospectively recruited. Pre-treatment evaluation of patients was by questionnaire, including the VAS and Oswestry Disability Questionnaire. A single injection of HA into affected facet joints was then performed, with correct placement confirmed on fluoroscopy. Patients were similarly evaluated 6 weeks after treatment. A total of 18 facets were injected with HA. At 6-week follow-up, there was no significant improvement in pain when measured on the VAS. There was also no significant improvement in the Oswestry Disability Questionnaire. The authors concluded that preliminary results from this pilot study did not demonstrate any benefit of viscosupplementation in the management of symptomatic lumbar facet joint arthropathy.

Grogan and colleagues (2009) noted that in the recent past, non-surgical treatment of OA was limited to rest, immobilization, physical therapy, activity modifications, NSAIDs, analgesics, weight loss, assistive devices for walking, and corticosteroid injections. Viscosupplementation is a welcome addition to the non-surgical armamentarium available to physicians. It is used to introduce hyaluronic acid into the joint to provide initial lubrication and shock absorption, and to change the long-term disease process. These investigators discussed the pathology of OA; the characteristics, physiology, and administration of commercial viscosupplements; and reviewed the research on hyaluronic acid (HA) use in the foot and ankle. They concluded that additional studies are& needed to test the safety and effectiveness of this treatment in other parts of the foot. Furthermore, in a review on the use of HA as a treatment for ankle OA, Sun, et al. (2009) stated that there is only limited published literature relating to the use of HA in the ankle.

Salini, et al. (2009) evaluated the effectiveness of a single ultrasound-guided injection of HA in patients suffering from carpo-metacarpal OA (CMC-OA). A total of 18 patients with CMC-OA, grade 2-3 Kellgren and Lawrence score were enrolled. They underwent clinical evaluation at baseline and after 1 month follow-up, evaluating: grading of pain (VAS at rest and during activities), function (Dreiser Index), grip and pinch strengths Jamar dynamometer), as well as NSAIDs consumption. Each patient received a single ultrasound-guided injection of HA into the articular CMC joint. The results were that pain at rest and during activities decreased from 1.8 +/- 1.07 to 0.5 +/- 0.68 (p < 0.001) and from 8.05 +/- 0.94 to 4.15 +/- 1.42 (p < 0.001), respectively. Dreiser Functional Index showed a significant improvement (+11.59%; p < 0.004), as well as pulp pinch strength (24.07%; p < 0.001). The consumption of NSAIDs was also clearly reduced, from 16 to 7 patients (-45%) and from 2.45 +/- 1.98 to 1.15 +/- 1.30 tablets per week (p < 0.02). Mild local side effects, lasting less than 3 hours, were observed only in 2 cases. The authors concluded that a single ultrasound-guided injection of HA is a safe and effective procedure in CMC-OA, with a significant improvement in terms of pain and function. However, they stated that studies with larger samples and longer term follow-up are needed.

Conrozier, et al. (2009) assessed the effectiveness and tolerability of a single intra-articular injection of non-animal-stabilized HA (NASHA) in patients treated for symptomatic hip OA (HOA). A total of 40 patients suffering from HOA were treated by a single intra-articular injection of NASHA in the painful hip under fluoroscopy. Patient global assessment (PGA) and walking pain (WP) on a 100-mm VAS, WOMAC index, and Lequesne index were assessed at each visit. Treatment effectiveness was assessed using OMERACT-OARSI response criteria, minimal clinically important improvement (MCII), patient acceptable symptom state (PASS) obtained from PGA, WOMAC and WP. Predictive factors of effectiveness were also studied. A total of 34 patients were assessable (mean follow-up of 159 days). All clinical variables (WP, PGA, WOMAC, Lequesne index) decreased significantly between baseline and last evaluation. Twenty-two patients (71%) were classified OMERACT-OARSI responders, 25 subjects (75.8%) were classified PASS+, and 19 (61.3%) fulfilled criteria for MCII. Out of clinical and radiological variables only Lequesne index (p = 0.04) and WOMAC (p = 0.04) at baseline were found to be predictive of treatment effectiveness; the treatment was well-tolerated. There were no severe adverse events related to the treatment or to the procedure. However 15 of the 28 assessable patients experienced transient increase of pain in the target hip during the first week following injection. The authors concluded that viscosupplementation of the hip with NASHA is easily feasible in daily clinical practice, safe and well-tolerated despite a frequent increase of pain the days following injection. Moreover, they stated that prospective, controlled trials are needed to confirm these data and to evaluate both safety and effectiveness of a second course of treatment.

Appendix

Table: Viscosupplementation Dosing

Sources: Euflexxa prescribing information; Hyalgan prescribing information; Orthovisc prescribing information; Supartz prescribing information; Synvisc One prescribing information; Synvisc prescribing information.