Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

Description

Policy

Intra-articular hyaluronan injections may be considered medically necessary for treatment of painful osteoarthritis of the knee in patients who have insufficient pain relief from conservative nonpharmacologic therapy and simple analgesics.

Repeated courses of intra-articular hyaluronan injections of the knee may be considered medically necessary under the following conditions:

• Significant pain relief achieved with the prior course of injections; and
• At least 6 months have passed since completion of the prior course.
  

The use of intra-articular hyaluronan injections in joints other than the knee is considered investigational.

Policy Guidelines

Benefit Application

BlueCard/National Account Issues

The coverage for hyaluronan injections is typically based on coverage benefits for injectable drugs, in addition to the office visit.

State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational and must be considered on the basis of medical necessity.

Rationale

This policy is based in part on a 1998 TEC Assessment on intra-articular hyaluronan for osteoarthritis of the knee (1) that offered the following conclusions:

• There are 13 randomized controlled trials comparing intra-articular hyaluronan (IA-HA) to placebo. These trials include 1,350 patients. Although the quality of this evidence is somewhat limited by a variety of methodological flaws, the preponderance of evidence is consistent in suggesting that a small incremental benefit is associated with IA-HA treatment over the benefit achieved with placebo-control treatments.
• The 2 available studies comparing IA-HA treatment to pharmacologic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) suggest that IA-HA has comparable effectiveness to NSAIDs.
• There are inadequate data to determine the net effect of multiple courses of IA-HA on health outcomes.
  

Originally, the policy suggested that multiple courses of therapy would be considered investigational; the policy was revised to delete that statement, in part due to an FDA labeling change for Hyalgan. The original labeling for both Hyalgan and Synvisc, at the time of their 1997 FDA approval, included the following statement in the Patient Information section.

“The safety and effectiveness of repeat treatment cycles [of Hyalgan and Synvisc] have not been established.”

In 2000, the FDA approved revised labeling for Hyalgan by deleting the above statement regarding repeat treatment cycles. Therefore, the current labeling for Hyalgan is silent on the issue of multiple courses of therapy, while the labeling of Synvisc is unchanged. In support of the labeling change to Hyalgan, the manufacturers cited 2 studies, although no study has specifically focused on the multiple courses of therapy. Scali conducted an uncontrolled study of 75 patients with osteoarthritis of the knee who received 5 weekly intra-articular injections of 2 mL Hyalgan repeated every 6 months, for a total of 25 intra-articular injections over 2 years. (2) Over the course of the study, progressive reduction was noted in various symptoms, including pain, stiffness, and analgesic intake. There were no serious systemic side effects. Kotz and Kolarz conducted an open-label, multicenter study of 108 patients who received 5 weekly injections of Hyalgan, 14 of whom began a new treatment cycle after 4 to 8 months due to pain recurrence. (3) Six of these patients completed the second cycle follow-up of 12 months. Patients who received a second treatment cycle showed further improvement. There were no significant systemic side effects. In other international studies of both Synvisc and Hyalgan, multiple treatment courses have been reported, but the studies do not permit separate assessment of the effectiveness of multiple courses of therapy. (4,5) In 2000, the policy was revised such that no statement was made regarding multiple courses of therapy. In 2003, an explicit statement was added, identifying multiple courses of therapy as investigational. This revision was made based on the panel consensus that controlled trials are required to determine the effectiveness of multiple courses of therapy, particularly given the unclear method of action of hyaluronan.

In 2004, a TEC Special Report on intra-articular hyaluronan for osteoarthritis of the knee (6) offered the following conclusions:

• The evidence base regarding the comparison between hyaluronan and alternative treatments has not been advanced significantly since the 1998 TEC Assessment, with only 1 study confirming the prior conclusion that hyaluronan is about as roughly effective as NSAIDs. However, this literature base remains small, and the quality of the evidence is not very good.
• There is no rigorous controlled evidence regarding the effectiveness of repeated treatments of hyaluronan. Case series showing improvement of symptoms after repeated treatments could be due to either placebo effects or selection bias.
• Overall, the review shows that the evidence is still consistent with that presented in the 1998 TEC Assessment. The evidence shows a statistically significant effect in almost all studies, although the magnitude and clinical significance of the effect may be small.
• There are inadequate data to determine the clinical efficacy of hyaluronan injections in joints other than the knee.

In 2005, a Cochrane review of viscosupplementation for osteoarthritis of the knee was published that evaluated a total of 63 clinical trials identified from a literature review conducted up to April 2004. (8) Overall, the review concluded hyaluronan is safe and effective in improving pain, function, and global patient function in the treatment of osteoarthritis of the knee. Included in the 63 trials evaluated for the review were 37 trials comparing hyaluronan/hylan products to placebo. The pooled analyses for these 37 trials demonstrated that hyaluronan treatment was more effective than placebo, most notably in the 5 to 13 weeks after treatment. Five trials were evaluated that compared hyaluronan to nonsteroidal anti-inflammatory drugs (NSAIDs). In the analysis of this comparison, hyaluronan was found to be comparable in efficacy to NSAIDs. In 9 trials comparing hyaluronan to corticosteroid injections, analysis demonstrated longer term benefits with hyaluronan than with corticosteroid injections. The authors noted that the clinical effects of the hyaluronan products have considerable heterogeneity and therapeutic variability. However, conclusions about the clinical effectiveness of products could not be drawn given the limited data comparing products head-to-head.

Another 2005 systematic review and meta-analysis by Arrich and colleagues evaluated 22 randomized controlled trials through April 2004 on hyaluronic acid injections for osteoarthritis of the knee. (9) The authors’ analysis found pain relief from osteoarthritis of the knee related to movement was only slightly better with hyaluronic acid injections than placebo but was of borderline clinical significance. Also, pain at rest and joint function were not improved with hyaluronic acid injections. The authors emphasized the poor methodologic quality of the trials, and thereby concluded that there was no proof that hyaluronic acid injections provide clinically relevant benefits, and they may even increase the incidence of adverse events.

The conclusions of the Cochrane review are consistent with the 2004 TEC Special Report. While hyaluronan has some beneficial effect, the magnitude and clinical significance of the effect may be small. As noted in the Cochrane review, further research would be useful, such as head-to-head comparisons of the various hyaluronan products, longer term trials (up to 1 year), and trials examining repeated courses of treatment with hyaluronan. The Arrich review also found some improvement in pain with hyaluronic acid injections but emphasized that the benefits were borderline in clinical significance. However, the Arrich reviewers concluded that the evidence was not sufficient to demonstrate the clinical effectiveness of hyaluronic acid injections. Therefore, the authors recommended hyaluronic acid injections not be used for the treatment of pain in osteoarthritis of the knee until large clinical trials determine the clinical benefits on defined clinical endpoints versus the risk of adverse events.

2006 Update

A literature review for the period of May 2005 through July 2006 did not identify any clinical trials that would alter the conclusions reached above. Therefore, the policy statements are unchanged. An April 2006 update of the Cochrane review of viscosupplementation for osteoarthritis of the knee evaluated a total of 76 clinical trials identified from a literature review conducted up through the 1st week of January 2006. (10) The Cochrane review came to the same conclusions it had made previously, as noted above, including that hyaluronan treatment was more effective than placebo, most notably in the 5 to 13 weeks after treatment. In a meta-analysis of literature reviewed in a search conducted through October 2004, Pagnano and Westrich concluded that repeat courses of hyaluronan for osteoarthritis of the knee were as safe and effective as a single course of hyaluronan injections. (11) However, as noted in the 2004 TEC Special Report, there is no rigorous controlled evidence regarding the effectiveness of repeated treatments with hyaluronan.

The data to determine the clinical efficacy of hyaluronan injections in joints other than the knee also continue to be inadequate. In a randomized, controlled trial (RCT) of 101 patients receiving hyaluronan injections for osteoarthritis of the hip versus corticosteroid or saline, Qvistgaard and colleagues reported only a small reduction in pain with walk-in patients treated with hyaluronan injections over the 3-month evaluation period, whereas patients injected with corticosteroid had significant pain reductions with walking. (12) Recent RCTs that enrolled a total of 100 patients on hyaluronan injections for arthritis of the thumb have shown some benefit with hyaluronan. (13,14) However, benefits have been similar to treatment with corticosteroids and further studies are needed. In addition, data from only small pilot studies have also been reported using hyaluronan for arthritis of the ankle and shoulder.

2007 Update

The TEC Evidence-based Practice Center published a technology assessment for the Agency for Healthcare Research and Quality (AHRQ) on the treatment of primary and secondary osteoarthritis of the knee. (15)

The report concluded that:

• Results from 42 trials (n=5,843) generally show positive effects of viscosupplementation on pain and function scores compared to placebo for patients with primary osteoarthritis of the knee. However, the evidence on viscosupplementation is accompanied by considerable uncertainty due to variable trial quality, potential publication bias, and unclear clinical significance of the changes reported.
• Trials of hylan G-F 20, the highest molecular weight cross-linked product, generally reported better results than other trials.
• There was no evidence for differential effects according to subgroups defined by age, sex, primary/disease, BMI/weight, or disease severity.
• Minor adverse events accompanying intra-articular injections are common, but the relative risk accompanying hyaluronan injections over placebo appears to be small. The risk of local adverse events appears to increase with prior courses of treatment. Pseudoseptic reactions associated with hyaluronans appear relatively uncommon but can be severe.

A literature review of safety and efficacy for multiple courses of viscosupplementation indicates no loss in efficacy for repeat courses. (16) Pseudoseptic reactions were more frequently reported with hylan G-F 20 than with sodium hyaluronate.

For osteoarthritis of the hip, a search of the MEDLINE database for the period of August 2006 through September 2007 retrieved 2 systematic reviews. (17, 18) These evidence reviews identified only 1 controlled study, which did not show significant benefit of viscosupplementation over placebo (reference 12, reviewed above), and 1 RCT comparing hyaluronans of different molecular weights. Although the case series reviewed in these papers suggested that hyaluronan “might have a beneficial effect in relieving pain” in patients with hip osteoarthritis, in the absence of comparative studies, efficacy could not be evaluated.

The literature search identified a number of case series on the use of viscosupplementation for arthritis of the temporomandibular joint, thumb, shoulder, and elbow. Controlled studies are lacking, and evidence remains insufficient to evaluate the efficacy of hyaluronan for joints other than the knee.

2008–2009 Update

The policy was updated with a literature search using MEDLINE in June 2009. Two guidelines for the treatment of osteoarthritis (OA) published in 2008 evaluate the existing evidence for intra-articular hyaluronan (IAHA) in the treatment of osteoarthritis.

The Osteoarthritis Research Society International (OARSI) guidelines (19), developed by consensus after review of existing guidelines and systematic reviews, recommend:

Injections of IA [intra-articular] hyaluronate may be useful in patients with knee or hip OA [osteoarthritis]. They are characterised by delayed onset, but prolonged duration, of symptomatic benefit when compared to IA injections of corticosteroids.

The recommendation is made with a strength of 64%, confidence interval 43–85%.

Guidelines published by the National Institute for Health and Clinical Excellence (NICE) (20) do not recommend IAHA injections for the treatment of OA because “the cost-effectiveness estimate is outside the realms of affordability” to the National Health Service. However, guideline developers state, “Overall, the evidence suggests that hyaluronans and hylan derivatives seem to be superior to placebo in terms of efficacy and quality of life outcomes in patients with OA in the knee at different post-injection periods but especially at the 5- to 13-week post-injection period.” Toxicity of IAHA was noted to be small.

In 2009, the FDA approved the use of single-dose hylan G-F 20 (Synvisc-One™) for the treatment of knee OA. This approval was based on a double-blind, randomized clinical trial that compared a single 6 ml IA injection of either hylan G-F 20 or saline in 253 osteoarthritic knees. (21) At 26 weeks, there was a significant reduction in pain (>20%) in both groups as measured by the Western Ontario and McMaster University (WOMAC) A (pain) subscale. The improvement at 26 weeks in the treatment group was greater than in the control group (-0.84 vs. -0.69, p=0.047), and the magnitude of the improvement is similar to that noted in trials with three to five injections of hylan G-F 20 vs. placebo when the scores are adjusted for the overall scale. The difference between groups, while statistically significant at 26 weeks, had not shown statistical significance at 12 weeks. Thus, this formulation appears to provide improvements similar to those noted for existing agents.

Two studies from Switzerland compared IAHA with high molecular weight hylan (Synvisc). A RCT (22) compared three injections of either high molecular weight HA (Synvisc), medium molecular weight HA (Orthovisc) or low molecular weight HA (Ostenil, unavailable in the U.S.) in 660 patients. At six months, there was no difference between groups in any outcome measure. This RCT was one of 13 trials included in the second Swiss study, a meta-analysis (23) that found no superior effectiveness of hylan over hyaluronic acids. No new clinical trials describing outcomes with repeated course of IAHA for OA of the knee were identified.

In contrast, several studies investigated IA viscosupplementation for OA of the hip. A systematic review of two RCTs and nine cohort studies (24) concluded that viscosupplementation therapy with HA appears to be “a safe and effective method in the treatment of hip OA resistant to conventional treatment modalities.” However, the authors recommend future studies with a large number of patients to confirm results and to answer questions about doses, intervals between doses, and the number of injections needed to achieve a therapeutic and safe effect. One industry-sponsored RCT published since that review (25) compared a single 2.5 mL IA injection of HA (Adant, 900 kDa, unavailable in the U.S.) to saline injection for treatment of hip OA in 85 patients. At three months, there were no significant differences between groups in any outcome measure. The number of patients that experienced mild to moderate treatment-related adverse events (injection-site pain, pain flare, hematoma, pruritus) did not differ between groups.

Several small RCTs and observational studies have investigated the use of IA viscosupplementation for osteoarthritis of the foot, ankle, spine, thumb, shoulder, and temporomandibular joint. An industry-sponsored RCT (26) of 660 patients with persistent shoulder pain due to glenohumoral joint OA, rotator cuff tear, and/or adhesive capsulitis compared 3 weekly injections vs. 5 weekly injections of sodium hyaluronate (Hyalgan) vs. 5 weekly injections of saline. About 60% of patients had OA, although the majority of those with OA also had rotator cuff disorders or capsulitis. Sixty-nine percent (n=456) of the patients had a follow-up visit at 26 weeks. There was no significant difference among groups in the primary outcome measure, shoulder pain with movement at 13 weeks. Analysis of predefined, stratified subgroups revealed no significant differences in reported pain at 13 weeks, but a significant decrease in reported pain in both treatment groups at 26 weeks compared to placebo among patients with OA. In those without OA, there was no significant improvement with either regimen. Of note, this appears to be an as-treated analysis of the OA subgroup data. Differences in range of motion among groups were judged to be not clinically important. In September 2009, results from the first of two RCTs listed on clinicaltrials.gov that examine IAHA in OA of the shoulder are expected. Presently, the evidence is insufficient to determine the efficacy of hyaluronan in joints other than the knee.

References:

1. 1998 TEC Assessment; Tab 17.
2. Scali JJ. Intra-articular hyaluronic acid in the treatment of osteoarthritis of the knee: a long term study. Eur J Rheumatol Inflam 1995;15(1):57-62.
3. Kotz R, Kolarz G. Intra-articular hyaluronic acid: duration of effect and results of repeated treatment cycles. Am J Orthop 1999: 28(11 suppl):5-7.
4. Carrabba M, Paresce E, Angeline M et al. The safety and efficacy of different dose schedules of hyaluronic acid in the treatment of painful osteoarthritis of the knee with joint effusions. Eur J Rheumatol Inflam 1995; 15(1):25-31.
5. Lussier A, Cividino AA, McFarlane CA et al. Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheumatol 1996; 23(9):1579-85.
6. TEC Special Report 2004.
7. Lo GH, LaValley M, McAlindon T et al. Intra-articular hyaluronic acid in the treatment of knee osteoarthritis: a meta-analysis. JAMA 2003; 290(23):3115-21.
8. Bellamy N, Campbell J, Robinson V et al. Viscosupplementation for the treatment of osteoarthritis of the knee. The Cochrane Database of Systematic Review 2005. Issue 2. Art. No.: CD005321.
9. Arrich J, Piribauer F, Mad P, et al. Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. Can Med Assoc J 2005; 172(8):1039 - 1043.
10. Bellamy N, Campbell J, Robinson V et al. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006; (2):CD005321.
11. Pagnano M, Westrich G. Successful nonoperative management of chronic osteoarthritis pain of the knee: safety and efficacy of retreatment with intra-articular hyaluronans. Osteoarthritis Cartilage 2005; 13(9):751-61.
12. Qvistgaard E, Christensen R, Torp-Pedersen S et al. Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. Osteoarthritis Cartilage 2006; 14(2):163-70.
13. Stahl S, Karsh-Zafrir I, Ratzon N et al. Comparison of intraarticular injection of depot corticosteroid and hyaluronic acid for treatment of degenerative trapeziometacarpal joints. J Clin Rheumatol 2005; 11(6):299-302.
14. Fuchs S, Monikes R, Wohlmeiner A et al. Intra-articular hyaluronic acid compared with corticoid injections for the treatment of rhizarthrosis. Osteoarthritis Cartilage 2006; 14(1):82-8.
15. Samson DS, Grant MD, Ratko TA et al. Treatment of primary and secondary osteoarthritis of the knee. AHRQ Publication No. 07-E012 September 2007; available at: http://www.ahrq.gov/downloads/pub/evidence/pdf/oaknee/oaknee.pdf
16. Pagnano M, Westrich G. Successful nonoperative management of chronic osteoarthritis pain of the knee: safety and efficacy of retreatment with intra-articular hyaluronans. Osteoarthritis Cartilage 2005; 13(9):751-61.
17. Fernandez Lopez JC, Ruano-Ravina A. Efficacy and safety of intraarticular hyaluronic acid in the treatment of hip osteoarthritis: a systematic review. Osteoarthritis Cartilage 2006; 14(12):1306-11.
18. van den Bekerom MP, Lamme B, Sermon A et al. What is the evidence for viscosupplementation in the treatment of patients with hip osteoarthritis? Systematic review of the literature. Arch Orthop Trauma Surg 2007 Sep 15; [Epub ahead of print] 
19. Zhang W, Moskowitz R, Nuki G et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008; 16(2):137-62.
20. National Institute for Health and Clinical Excellence. Osteoarthritis: national clinical guideline for care and management in adults. Available at: www.nice.org.uk/nicemedia/pdf/CG059FullGuideline.pdf. Last viewed June 2009.
21. Chevalier X, Jerosch J, Goupille P et al. Single, intra-articular treatment with 6 mL of Hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomized, multi-centre, double-blind, placebo-controlled trial. Ann Rheum Dis 2009 March 19 [Epub ahead of print].
22. Juni P, Reichenbach S, Trelle S et al. Efficacy and safety of intraarticular hylan or hyaluronic acid for osteoarthritis of the knee: a randomized controlled trial. Arthritis Rheum 2007; 56(11):3610-9.
23. Reichenbach S, Blank S, Rutjes A et al. Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis. Arthritis Rheum 2007; 57(8):1410-8.
24. Abate M, Pelotti P, De Amicis D et al. Viscosupplementation with hyaluronic acid in hip osteoarthritis (a review). Ups J Med Sci 2008; 113(3):261-77.
25. Richette P, Ravaud P, Conrozier T et al. Effect of hyaluronic acid in symptomatic hip osteoarthritis: a multicenter, randomized, placebo-controlled trial. Arthritis Rheum 2009; 60(3):824-30.
26. Blaine T, Moskowitz R, Udell J et al. Treatment of persistent shoulder pain with sodium hyaluronate: a randomized, controlled trial. A multicenter study. J Bone Joint Surg Am 2008; 90:970-9.

Index

Policy History