Intra-Articular Hyaluronan Injections for Osteoarthritis
This policy has been revised. To view the updated version click here.
When criteria are met, a single course of therapy for the knee can be approved.
A second course of treatment for the knee may be approved after 6 months when there is objective documentation that the initial course resulted in improvement in pain and functional capacity. Objective documentation can be shown using a number of validated clinical instruments, such as Knee Injury and Osteoarthritis Outcome Score (KOOS), International Knee Documentation Committee (IKDC), Oxford Knee Score (OKS), and Lysholm Knee Scoring Scale
Intra-articular hyaluronan injections are considered investigational for all other joints.
Knee osteoarthritis (OA) is common, costly, and a cause of substantial disability. Among U.S. adults, the
most common causes of disability are arthritis and rheumatic disorders. Currently, no curative therapy is
available for OA, and thus the overall goals of management are to reduce pain, disability, and the need
for knee replacement surgery. Intra-articular injection of hyaluronan (HA) into osteoarthritic joints is
thought to replace endogenous HA, restore the viscoelastic properties of the synovial fluid, and improve
pain and function.
Most studies to date have assessed HA injections for knee OA, and this is the U.S. Food and Drug
Administration (FDA) approved indication. Other joints, such as the hip and shoulder, are currently being
investigated for intra-articular HA treatment of OA.
The largest amount of evidence is on treatment of OA of the knee. Individual trials show inconsistent
results in pain and functional outcomes for intra-articular injection of hyaluronan (IAHA) compared with
placebo or active control. Meta-analyses of randomized controlled trials (RCTs) show improvements in
pain and function that are statistically significant, but have not been demonstrated to be clinically
significant in an appreciable number of patients.
IAHA continues to be investigated for off-label uses in other joints. Current evidence on these off-label
uses is limited, consisting of small RCTs and case series. Some RCTs on IAHA injections for OA of the
ankle, foot, hand and shoulder have shown treatment benefits; however, these studies are not consistent
in reporting improvements that are significantly greater than placebo and/or control treatments. RCTs on
IAHA injections for OA of the hip have also been inconsistent, with some RCTs reporting improvements in
outcomes with IAHA hip injections and others reporting no improvement. Currently, given the limited and
inconsistent available data, and the low likelihood that IAHA for joints other than the knee are more
effective than IAHA for the knee, these uses are also considered not medically necessary.
IAHA has been proposed as a means of restoring the normal viscoelasticity of the synovial fluid in patients with OA and improving pain and function. This treatment may also be called viscosupplementation. HA is a naturally occurring macromolecule that is a major component of synovial fluid and is thought to contribute to its viscoelastic properties. Chemical crosslinking of hyaluronan increases its molecular weight; cross-linked hyaluronans are referred to as hylans. In OA, the overall length of HA chains present in cartilage and the HA concentration in the synovial fluid are decreased.
Seven preparations of intra-articular (IA) hyaluronan have been approved by FDA as an alternative to nonsteroidal anti-inflammatory drug therapy in the treatment of OA of the knee (Synvisc® and Synvisc-One®, Genzyme; Gel-One®, Zimmer; Hyalgan®, Fidia; Supartz®, Smith and Nephew; OrthoVisc®, Anika; and Euflexxa®, previously named Nuflexxa, Savient). All products are manufactured from rooster combs except for Euflexxa and Orthovisc, which are produced from bacterial fermentation. Also, Synvisc undergoes additional chemical crosslinking to create hylans with increased molecular weight (6000 kDa) compared with Hyalgan (500-730 kDa) and Supartz (620-1170 kDa). The differing molecular weights of the products lead to different half-lives; the half-life of Hyalgan or Supartz is estimated at 24 hours, while the half-life of Synvisc may range up to several days.
IAHA is “indicated for the treatment of pain in osteoarthritis of the knee in patients who have failed to respond adequately to conservative nonpharmacologic therapy, and to simple analgesics, e.g., acetaminophen.” The product inserts further indicate that Synvisc® and Euflexxa® should be injected intra-articularly into the knee joint once per week for a total of 3 injections over a 2- to 3-week period. In contrast, 5 weekly injections are recommended for the Hyalgan® and Supartz® products, and 3 to 4 weekly injections are recommended for OrthoVisc®. In February 2009, FDA approved the use of single-dose hylan G-F 20 (Synvisc-One™) for the treatment of OA of the knee. In 2011, FDA approved the use of the single-dose cross-linked hyaluronate Gel-One® (also known as Gel-200) for the treatment of OA of the knee.
In 2000, FDA approved removal of a precautionary statement from the package inserts for Hyalgan and Synvisc that stated that the safety and efficacy of repeat courses have not been established.
FDA has not approved intra-articular hyaluronan for joints other than the knee.
FDA product code: MOZ
Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage.
Assessment of efficacy for a therapeutic intervention involves a determination of whether the technology improves health outcomes. The optimal study design for this purpose is a randomized controlled trial (RCT) that includes clinically relevant measures of health outcomes. Intermediate outcome measures, also known as surrogate outcome measures, may also be adequate if there is an established link between the intermediate outcome and true health outcomes. Nonrandomized comparative studies and uncontrolled studies can sometimes provide useful information on health outcomes, but are prone to biases such as noncomparability of treatment groups, the placebo effect, and variable natural history of the condition. As there are a number of RCTs on intra-articular hyaluronan (IAHA) for osteoarthritis (OA), this evidence review will focus on RCTs and systematic reviews.
This policy was originally based on a 1998 TEC Assessment on IAHA for OA,(1) and in 2004, TEC published a Special Report on IAHA for OA of the knee.(2) Overall, the 2004 review found that the evidence was still consistent with that presented in the 1998 TEC Assessment, showing a statistically significant effect in almost all studies, although the magnitude and clinical significance of the effect may be small. Similar results were obtained in Cochrane reviews in 2005 and 2006.(3,4) In 2007, the TEC Evidence-based Practice Center published a technology assessment for the Agency for Healthcare Research and Quality on the treatment of primary and secondary OA of the knee.(5) The report concluded that results from 42 trials (n=5843) generally show positive effects of viscosupplementation on pain and function scores compared with placebo for patients with primary OA of the knee. However, the evidence on viscosupplementation was 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 (Synvisc, 6000 kDa), the highest molecular weight cross-linked product, generally reported better results than other trials. Similar concerns were noted in a 2012 meta-analysis of 89 trials (12,667 patients) on viscosupplementation for OA of the knee (6) and a 2013 systematic review from the American Academy of Orthopaedic Surgeons (AAOS) on treatments for OA of the knee.(7)
In 2014, TEC published a systematic review of recent meta-analyses on the treatment of knee OA with IAHA. (8) Included in the assessment were 5 meta-analyses published in 2011 or later. (6,7,9-11) Two meta-analyses concluded that IAHA provides a clinically meaningful benefit; 3 concluded that the evidence did not demonstrate a clinically meaningful benefit. It was not possible from the data to determine the proportions of patients achieving clinically meaningful improvement, although the AAOS analysis determined that is was unlikely that an appreciable number of patients would benefit compared with placebo. It is also possible that these results were biased in favor of IAHA, due to unpublished trial data. When results from unpublished trials were obtained, the magnitude of effect was notably lower compared with published results. Substantial heterogeneity between trials was also evident, increasing uncertainty. The Assessment concluded that the 5 meta-analyses, sampling from a similar collection of published trials and 2 unpublished ones, highlights biases and difficulty ascertaining clinically meaningful patient-level improvement compared with placebo. Although accumulating evidence would be expected to increase certainty about whether a clinically important treatment benefit exists, the current study results do not provide convincing evidence that net health outcomes are improved with IAHA over placebo.
Joints Except the Knee
Colen et al. conducted a 2012 systematic review of prospective trials of IAHA for joints other than the knee.(12) In addition to nonrandomized prospective studies, the search identified 5 RCTs for the hip, 1 for the shoulder, 4 for the ankle, 5 for the carpometacarpal-1 joint, 1 for the lumbar facet joint, and 1 for the first metatarsophalangeal joint. Examination of the literature for each joint found evidence for a positive effect of IAHA when compared with baseline, with limited evidence that IAHA is superior to placebo, and no evidence that IAHA is better than corticosteroids or other conservative therapies. Following is a summary of systematic reviews and primary evidence by joint.
Migliore et al conducted a review of 7 studies on IAHA for ankle OA, identified from the period of 2006 to 2009, that included 3 small RCTs with a total of 75 patients, and 4 case series.(13) For 2 of the RCTs, IAHA was compared with saline injection, and the results showed benefit on some outcome measures but not others. The third RCT compared IAHA with exercise therapy and reported no differences in outcomes. The authors were unable to do a meta-analysis due to the limited number of studies and study heterogeneity.
In 2012, DeGroot et al reported on an RCT of 64 patients with ankle OA that compared a single IAHA with a single intra-articular (IA) saline injection. (14) At 6 weeks and 12 weeks, there were no significant differences in improvement between treatment groups on the American Orthopaedic Foot & Ankle Society clinical rating score, the Ankle Osteoarthritis Scale score, and the patient-reported visual analog pain scale (VAS).
There is a very limited amount of evidence on IAHA injections in the foot. Munteanu et al reported on an RCT of a single IAHA injection in 151 patients with first metatarsophalangeal joint OA. (15) At 1-, 3-, and 6-month follow-up, there were no significant differences between the IAHA and placebo groups on the Foot Health Status Questionnaire.
Two small RCTs that enrolled a total of 100 patients evaluated HA injections compared with steroid injections for arthritis of the thumb.(16,17) Fuchs et al (17) reported that steroid injections were superior at 2 to 3 weeks posttreatment but that IAHA was superior at 6-month follow-up. Stahl et al (16) reported essentially equivalent outcomes between steroid injections and IAHA, although IAHA was superior to steroids for some aspects of fine motor function. The results of these trials are not sufficient to determine the efficacy of IAHA for thumb arthritis and are not sufficient for determining comparative efficacy with steroids.
A 2008 systematic review of 2 RCTs and 9 cohort studies 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.”(18) In their 2012 systematic review, Colen et al identified 3 RCTs that compared IAHA with placebo, 1 that compared IAHA with IA anesthetic, and 1 that compared hyaluronans of different molecular weights. (12) These 3 trials showed a statistical effect favoring IAHA treatment. However, the effect size was small compared with saline injections, and there were not significant differences between IAHA and other conservative treatments such as steroid injections.
The largest RCT randomized 101 patients to receive either HA injections or saline.(19) There was a small reduction in pain with walking in patients treated with HA injections over the 3-month evaluation period. An industry-sponsored RCT compared a single 2.5 mL IAHA (Adant, 900 kDa, unavailable in the U.S.) with saline injection for treatment of hip OA in 85 patients. (20) At 3 months, there were no significant differences between groups in any outcome measure. The number of patients who experienced mild to moderate treatment-related adverse events (injection-site pain, pain flare, hematoma, pruritus) did not differ between groups. Atchia et al reported on an RCT of 77 patients with hip OA who were potential candidates for total hip replacement. (21) In this study, patients were randomized to receive standard care or an injection of saline, HA or methylprednisolone and followed for 8 weeks. Significant improvement was only seen in the steroid group in the numerical rating scale for worst pain, and the Western Ontario and McMaster Osteoarthritis Index for pain and function. No improvements were reported in the IAHA group.
In an industry-sponsored, single-center, randomized, double-blind, active-controlled trial, published in 2009, 42 patients with OA of the hip were randomly assigned to receive 2 monthly injections of high-molecular weight IAHA (Hyalubrix® - unavailable in the U.S.) or IA mepivacaine, a local anesthetic. (22) At 3 and 6 months, there was a significant decrease in the Lequesne algofunctional index in the IAHA group compared with the mepivacaine group (5.15 vs 6.53 at 3 months; 3.94 vs 6.41 at 6 months, both respectively). The only reported adverse event was injection-site pain occurring in 1 patient in each group.
A 2010 meta-analysis of 19 blinded RCTs examined the use of viscosupplementation for chronic painful shoulder in a total of 2120 patients. (23) A variety of shoulder disorders were included, e.g., adhesive capsulitis, rotator cuff tear, shoulder impingement syndrome, frozen shoulder. Sample size ranged from 20 to 660 patients, mean trial duration was 3.5 weeks, and mean Jadad score was 3.5±1.5. Ten trials (1435 patients) reported pain outcomes. The combined effect size (standardized mean difference) for categorical and continuous pain ratings favored IAHA (0.39). There was no heterogeneity and no evidence of publication bias. Because the studies included in the meta-analysis were of short duration and included a variety of shoulder diseases, they do not provide conclusive evidence of the effectiveness of IAHA in OA of the shoulder.
The largest trial is an industry-sponsored RCT of 660 patients with persistent shoulder pain due to glenohumeral joint OA, rotator cuff tear, and/or adhesive capsulitis compared 3 weekly injections versus 5 weekly injections of sodium hyaluronate (Hyalgan) versus 5 weekly injections of saline. (24) Approximately 60% of patients had OA, although most 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 statistically significant decrease of 7.5 and 7.8 mm (on a 100-mm VAS scale) in reported pain in both treatment groups at 26 weeks compared with 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, and the difference may not be clinically important.
In 2013, Kwon et al reported a multicenter randomized double-blind placebo-controlled trial of IAHA in 300 patients with glenohumeral OA. (25) Intention-to-treat analysis found similar improvement in VAS for pain (19.88 mm for IAHA, 16.29 mm for placebo) and in the Outcome Measures in Rheumatoid Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) high responder rate (40.8% for IAHA, 34.9% for sham). In a subset of patients, there was a statistically significant difference in VAS of 4.0 mm on a 100-mm scale and 8.37% on the OMERACT-OARSI. However, the clinical significance of these differences is uncertain.
Data from small pilot studies, and case series have been reported using HA for arthritis of the spine and for lateral condylitis of the elbow (tennis elbow).
The evidence on the efficacy of IAHA for joints other than the knee is less robust. While some studies show benefit, others do not, and systematic reviews have not concluded that there is a clinically significant benefit.
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov in September 2014 identified a number of open trials with IAHA. These include phase 3 and phase 4 trials evaluating IAHA for OA of the knee (NCT01372475, NCT01543737, NCT01557868, and NCT01335321), and a pivotal multicenter trial of Hylan G-F 20 for OA of the hip (NCT01618708).
Clinical Input Received from Physician Specialty Societies and Academic Medical Centers
While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
In response to requests, input was received from 3 physician specialty societies and 5 academic medical centers (6 reviewers) while this policy was under review in 2011. Most reviewers agreed that IAHA of the knee was medically necessary. In addition, those providing input supported an interval of 6 months for repeat injections. In response to a question about total number of treatment courses, there was no consensus.
Summary of Evidence
Intra-articular injection of hyaluronan into osteoarthritic joints is thought to replace hyaluronan, restore the viscoelastic properties of the synovial fluid, and improve pain and function. The largest amount of evidence is on treatment of osteoarthritis (OA) of the knee. Individual trials show inconsistent results in pain and functional outcomes for intra-articular injection of hyaluronan (IAHA) compared with placebo or active control. Meta-analyses of randomized controlled trials (RCTs) show improvements in pain and function that are statistically significant, but have not been demonstrated to be clinically significant in an appreciable number of patients. IAHA continues to be investigated for off-label uses in other joints. Current evidence on these off-label uses is limited, consisting of small RCTs and case series. Some RCTs on IAHA injections for OA of the ankle, foot, hand and shoulder have shown treatment benefits; however, these studies are not consistent in reporting improvements that are significantly greater than placebo and/or control treatments. RCTs on IAHA injections for OA of the hip have also been inconsistent, with some RCTs reporting improvements in outcomes with IAHA hip injections and others reporting no improvement. Currently, given the limited and inconsistent available data, and the low likelihood that IAHA for joints other than the knee are more effective than IAHA for the knee, these uses are also considered not medically necessary.
Practice Guidelines and Position Statements
The American Academy of Orthopaedic Surgeons’ (AAOS) 2013 guideline on treatment of OA of the knee states that they cannot recommend using HA for patients with symptomatic knee OA. (7) This is a strong recommendation, meaning that the quality of the supporting evidence is high. This recommendation was based on a meta-analysis of 3 high-strength and 11 moderate-strength studies that showed that the overall effect was less than 0.5 minimally important different units, indicating a low likelihood that an appreciable number of patients achieved clinically important benefits. AAOS states that practitioners should follow a strong recommendation unless a clear and compelling rationale for an alternative approach is present. This replaces a 2008 guideline in which a recommendation could not be made for IAHA due to inconclusive evidence.
The 2009 AAOS Clinical Practice Guideline on glenohumeral joint osteoarthritis (26) includes a weak grade C recommendation that “the use of injectable viscosupplementation is an option when treating patients with glenohumeral [shoulder] osteoarthritis.” Grade C recommendations are based on poor-quality evidence. In this instance, the recommendation is based on a single case series of 30 patients with OA of the glenohumeral joint who received 3 weekly IA injections of Synvisc. (27) At 1, 3, and 6 months, clinically significant improvements were seen in pain, function, and quality-of life-measures.
The American College of Rheumatology (ACR) published updated guidelines in 2012 that addressed OA of the hand, hip, and knee. (28) A conditional recommendation was given for IAHA to treat OA of the knee. ACR recommends not using IAHA for OA of the hand. For OA of the hip, ACR explicitly makes no recommendation regarding treatment with IAHA.
The 2014 Osteoarthritis Research Society International (OARSI) guidelines, developed by consensus after review of existing guidelines and systematic reviews, gave an “uncertain” recommendation for the use of intra-articular injection of HA for knee OA and a recommendation of “not appropriate” for multiple-joint OA. (29)
2014 Guidelines published by the National Institute for Health and Clinical Excellence (30) state intra-articular corticosteroid injections should be considered, however intra-articular hyaluronan injections for osteoarthritis should not be offered.
U.S. Preventive Services Task Force Recommendations
Use of hyaluronan injections is not a preventive service.
Medicare National Coverage
There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers.
Hyaluronan or derivative, Hyalgan or Supartz, for intra-articular injection, per dose
Hyaluronan or derivative, Euflexxa, for intra-articular injection, per dose
Hyaluronan or derivative, Orthovisc, for intra-articular injection, per dose
Hyaluronan or derivative, Synvisc or Synvisc-One, for intra-articular injection, 1 mg
Hyaluronan or derivative, Gel-One, for intra-articular injection, per dose
Hyaluronan or derivative, Monovisc, for intra-articular injection, per dose
Type of Service
Place of Service
New policy, add to Medicine section. This policy replaces 5.01.506. Added the table listing FDA approved hyaluranon products and recommended course(s) of treatment per MPC request. The 3rd sentence of the 4th paragraph regarding The product inserts further indicates…was moved from the description to the policy guidelines section for ease of policy administration. Policy approved with 90-day hold for provider notification. The policy effective date is November 7, 2012.
Correct Error on Related Policy number. Changed from 7.01.118 to 7.01.117.
Update Coding Section – ICD-10 codes are now effective 10/01/2014.
Policy effective after hold for provider notification. 5.01.506 is deleted.
Policy updated. Rationale and references revised. “in the knee when the above criteria are not met, and” was added to the investigational statement.
Update Related Policies. Add 7.01.549, and remove 7.01.188 as it was archived.
Replace Policy. Policy updated with literature review through July 31, 2013; reference 7 added; policy changed to not medically necessary based on new guidelines from the American Academy of Orthopaedic Surgeons. Policy change aligns with UM initiative and recent change in coverage from BCBSA. Policy held for provider notification; the effective date is April 1, 2014.
Minor update: When this policy was approved last month a sentence was left out. A second policy statement is now included: “Intra-articular hyaluronan injections are considered not medically necessary to treat osteoarthritis of any joint other than the knee.”
Policy implementation delayed; the effective date of the policy is moved to June 1, 2014.
Policy implementation delayed; the effective date of the policy is moved to July 1, 2014.
Revised implementation date September 1, 2014. Delayed due to Plan internal system updates.
Update Related Policies. Change title to 7.01.549.
Policy implementation delayed until December 1, 2014.
Interim review. Policy updated with literature review; the policy statement is unchanged. Intra-articular hyaluronan for osteoarthritis is considered not medically necessary. Effective 03/1/15.
Coding update. New HCPCS code J7327 added to the policy.
Policy update implementation extended to May 1, 2015; this policy to remain effective until that date.
Policy update implementation extended to June 1, 2015; this policy to remain effective until that date.
Update Related Policies. Remove 1.01.27 as it was deleted. Change title to 7.01.549
Annual review. Policy updated with literature review and rewritten; renumbered from 2.01.31 to 2.01.534. Coverage to be effective from now until July 1, at which time the coverage will revert to policy 2.01.31 (link included within header of this policy.) Intra-articular hyaluronan injections of the knee may be considered medically necessary when all of the criteria are documented. CPT and ICD-9 codes removed; HCPCS codes listed for policy adjudication.
Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA).