Coverage Policy Manual
Policy #: 1998119
Category: Pharmacy
Initiated: February 1998
Last Review: April 2022
  Viscosupplementation for the Treatment of Osteoarthritis of the Hip, Knee, and All Other Joints

Description:
Hyaluronan (HA), also known as hyaluronate or hyaluronic acid, 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; crosslinked hyaluronans are referred to as hylans. In osteoarthritis, the overall length of HA chains present in cartilage and the HA concentration in the synovial fluid are decreased. Intra-articular injection of HA (IA-HA) has been proposed as a means of restoring the normal viscoelasticity of the synovial fluid in patients with osteoarthritis. This treatment has been called viscosupplementation.
 
Currently, no curative therapy is available for osteoarthritis, and thus the overall goals of management are to reduce pain and prevent disability. In 1995, the American College of Rheumatology published guidelines for the treatment of osteoarthritis of the knee, which recommended acetaminophen as first-line therapy, followed by low-dose ibuprofen and then full-dose non-steroidal anti-inflammatory drugs (NSAIDs), if necessary.  Several preparations of intra-articular hyaluronan (IAHA) have been approved by the U.S. Food and Drug Administration (FDA) as an alternative to nonsteroidal anti-inflammatory drug therapy in the treatment of OA of the knee: e.g., Synvisc® and Synvisc-One® (Genzyme); Gel-One® (Zimmer); Hyalgan® (Fidia); Supartz FX™ (Bioventus); Orthovisc® (Anika); Euflexxa®, previously named Nuflexxa (Savient); Monovisc® (Anika Therapeutics); and Gel-Syn™ (Institut Biochimique SA). All products are manufactured from rooster combs except for Euflexxa®, Orthovisc®, Monovisc®, Gel-Syn™ and GenVisc® 850, 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). Monovisc® is also cross-linked with a proprietary cross-linker. 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 (e.g., 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 2014, Monovisc® was also approved as a single-dose treatment while Gel-Syn™ was approved as a course of 3 weekly injections. In 2015, GenVisc® 850 was approved as a course of 3 weekly injections.
 
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.
 
Coding
 
The injection of the knee should be billed using CPT 20610 when done without ultrasound guidance. If ultrasound guidance is used, CPT code 20611 should be used.  Appropriate RT or LT modifiers must be coded. There are specific HCPCS codes for the injections.
 
J7318 Hyaluronan or derivative, durolane, for intra-articular injection, 1 mg
 
J7329 Hyaluronan or derivative, trivisc, for intra-articular injection, 1 mg
 
J7331-Hyaluronan or derivative, synojoynt, for intra-articular injection, 1 mg
 
J7332-Hyaluronan or derivative, triluron, for intra-articular injection, 1 mg
 
J7333-Hyaluronan or derivative, visco 3, for intra articular injection, per dose.
 
Related Policies
Viscosupplementation for the treatment of osteoarthritis of the hip is handled in policy #2004006 (Archived April, 2016).
 

Policy/
Coverage:
Effective April 2016
 
Viscosupplementation for treatment of osteoarthritis of the hip, knee or any other joint does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria,  viscosupplementation for treatment of osteoarthritis of the hip, knee or any other joint is considered investigational. Investigational services are specific contract exclusions in most member certificates of coverage.
 
Effective October 2014
 
Viscosupplementation for treatment of osteoarthritis of the knee or any other indication does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For contracts without primary coverage criteria, viscosupplementation for treatment of osteoarthritis of the knee or any other indication is considered investigational. Investigational services are specific contract exclusions in most member certificates of coverage.
 
Effective June 2011
 
A single course of 3 weekly injections of hyaluronan polymers or 5 weekly injections of hylan polymers meets primary coverage criteria for effectiveness and is covered when the following criteria are met:
    • The patient must not have end-stage degenerative joint disease.  The preliminary studies and the manufacturer's data reveal no criteria to identify patients who are likely to respond, other than the observation that patients with less severe disease respond better;
    • The patient must have documented symptomatic osteoarthritis of the knee, and interference with functional activity because of the knee involvement;
    • Medical records should reflect failure of conservative treatment as defined as physical therapy and acetaminophen and/or NSAIDs.
  
A repeat course of hyaluronan injections could be covered if the following criteria are met:
    • Significant pain relief achieved with the prior course of injections; and
    • At least 6 months have passed since completion of the prior course; and
    • The criteria required for the initial injection are still met.
  
The coverage for Orthovisc is the same as the other three covered materials.  Three injections are allowed.  If a 4th injection is given as part of the initial  series, the cost of the 4th injection is considered a component of the other 3 injections and would be denied as a fragmentation of the previous injections.
  
Synvisc-One is a single 6 mL injection treatment regimen. The single injection formulation should not be followed with subsequent doses of the multiple-injection formulations.
  
The following do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
    • The use of intraarticular hyaluronan injections into joints other than the knee; OR
    • Viscosupplementation for patients with end-stage osteoarthritis of the knee, defined by radiographic criteria for Ahlback Grade II or greater, or Kellgren and Lawrence Grade IV (definition below);
  
For contracts without primary coverage criteria, the following, are considered investigational and are not covered.  
    • The use of intraarticular hyaluronan injections into joints other than the knee, or
    • Viscosupplementation for patients with end-stage osteoarthritis, defined by radiographic criteria for Ahlback Grade II or greater, or Kellgren and Lawrence Grade IV (definition below);
 
Investigational services are an exclusion in the member benefit contract.  
  
DEFINITIONS
  Ahlback Definition       
    Grade 1   joint space narrowing (<3 mm)
    Grade II  joint space obliteration                      
    Grade III minor bone attrition (0-5 mm)
    Grade IV moderate bone attrition (5-10 mm)
    Grade V  severe bone attrition (>10 mm)
  
Kellgren & Lawrence Definition
    Grade 1  "doubtful" minute osteophyte, doubtful significance     
    Grade II  "Minimal"  definite osteophyte, unimpaired joint space
    Grade III "Moderate"  moderate diminution of joint space
    Grade IV "Severe" joint space greatly impaired with sclerosis of subchondral bone
 
 
Effective, January 2010
 
A single course of 3 weekly injections of hyaluronan polymers or 5 weekly injections of hylan polymers meets primary coverage criteria for effectiveness and is covered when the following criteria are met:
    • The patient must not have end-stage degenerative joint disease.  The preliminary studies and the manufacturer's data reveal no criteria to identify patients who are likely to respond, other than the observation that patients with less severe disease respond better;
    • The patient must have documented symptomatic osteoarthritis of the knee, and interference with functional activity because of the knee involvement;
    • Medical records should reflect failure of conservative treatment as defined as physical therapy and acetaminophen and/or NSAIDs.
 
A repeat course of hyaluronan injections could be covered at 8-12 months if the following criteria are met:
    • Significant pain relief achieved with the prior course of injections; and
    • At least 6 months have passed since completion of the prior course; and
    • The criteria required for the initial injection are still met.
 
 
The coverage for Orthovisc is the same as the other three covered materials.  Three injections are allowed.  If a 4th injection is given as part of the initial series, the cost of the 4th injection is considered a component of the other 3 injections and would be denied as a fragmentation of the previous injections.
 
Synvisc-One is a single 6 mL injection treatment regimen. The single injection formulation should not be followed with subsequent doses of the multiple-injection formulations.
 
The following do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
    • the use of intraarticular hyaluronan injections into joints other than the knee; or
    • Viscosupplementation for patients with end-stage osteoarthritis of the knee, defined by radiographic criteria for Ahlback Grade II or greater, or Kellgren and Lawrence Grade IV (definition below);
 
 
For contracts without primary coverage criteria, the following, are considered investigational and are not covered.  
    • the use of intraarticular hyaluronan injections into joints other than the knee, or
    • Viscosupplementation for patients with end-stage osteoarthritis, defined by radiographic criteria for Ahlback Grade II or greater, or Kellgren and Lawrence Grade IV (definition below);
Investigational services are an exclusion in the member benefit contract.  
 
DEFINITIONS
  Ahlback Definition       
    Grade 1   joint space narrowing (<3 mm)
    Grade II  joint space obliteration                      
    Grade III minor bone attrition (0-5 mm)
    Grade IV moderate bone attrition (5-10 mm)
    Grade V  severe bone attrition (>10 mm)
 
  Kellgren & Lawrence Definition
    Grade 1  "doubtful" minute osteophyte, doubtful significance     
    Grade II  "Minimal"  definite osteophyte, unimpaired joint space
    Grade III "Moderate"  moderate diminution of joint space
    Grade IV "Severe" joint space greatly impaired with sclerosis of subchondral bone
 
Effective, February 1998 to December 2009
 
A single course of 3 weekly injections of hyaluronan polymers or 5 weekly injections of hylan polymers meets primary coverage criteria for effectiveness and is covered when the following criteria are met:
    • The patient must not have end-stage degenerative joint disease.  The preliminary studies and the manufacturer's data reveal no criteria to identify patients who are likely to respond, other than the observation that patients with less severe disease respond better;
    • The patient must have documented symptomatic osteoarthritis of the knee, and interference with functional activity because of the knee involvement;
    • Medical records should reflect failure of conservative treatment as defined as physical therapy and acetaminophen and/or NSAIDs.
  
The injection of the knee should be billed using CPT 20610.  Appropriate RT and LT modifiers must be coded.
  
A repeat course of hyaluronan injections could be covered at 8-12 months if other coverage criteria are met.
  
The coverage for Orthovisc is the same as the other three covered materials. Three injections are allowed.  If a 4th injection is given as part of the initial series, the cost of the 4th injection is considered a component of the other 3 injections and would be denied as a fragmentation of the previous injections.
  
The following:
    • the use of intraarticular hyaluronan injections into joints other than the knee; or
    • Viscosupplementation for patients with end-stage osteoarthritis of the knee, defined by radiographic criteria for Ahlback Grade II or greater, or Kellgren and Lawrence Grade IV (definition below) (added May 2003);
are not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
  
For contracts without primary coverage criteria;
    • the use of intraarticular hyaluronan injections into joints other than the knee, or
    • Viscosupplementation for patients with end-stage osteoarthritis, defined by radiographic criteria for Ahlback Grade II or greater, or Kellgren and Lawrence Grade IV (definition below);
is considered investigational and is not covered.  Investigational services are an  exclusion in the member benefit contract.  
  
DEFINITIONS (added May 2003)
 
Ahlback Definition       
Grade 1   joint space narrowing (<3 mm)
Grade II  joint space obliteration                      
Grade III minor bone attrition (0-5 mm)
Grade IV moderate bone attrition (5-10 mm)
Grade V  severe bone attrition (>10 mm)
  
Kellgren & Lawrence Definition
Grade 1  "doubtful" minute osteophyte, doubtful significance     
Grade II  "Minimal"  definite osteophyte, unimpaired joint space
Grade III "Moderate"  moderate diminution of joint space
Grade IV "Severe" joint space greatly impaired with sclerosis of subchondral bone
 
 

Rationale:
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 two 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 current policy has been 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.  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.  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.
 
Hyaluronic acid products are somewhat unusual in that they are regulated as a device, due to their presumed mechanical action in restoring synovial fluid viscoelasticity. However, the effectiveness (i.e., pain reduction) of these products outlasts their estimated half-lives by several months, suggesting that the products have biologic effects in addition to mechanical effects. Observations in animal models suggest that viscosupplementation is associated with the following beneficial effects: increased synthesis of native hyaluronic acid, a decrease in degradation of proteoglycans, or inhibition of prostaglandin E-2 synthetase.   In this sense, these products are more akin to drugs than devices. While the data regarding retreatment with either Hyalgan or Synvisc are minimal, if the issue is considered from the perspective of a drug, repeat treatment would appear reasonable in patients who had responded to the initial course of therapy.
 
There are inadequate data to determine the clinical efficacy of hyaluronan injections in joints other than the knee.
 
2003 Update
A literature search was conducted in February 2003 for studies assessing the effectiveness of hyaluronan. There appears to be no evidence that would substantially change the conclusions of the policy. In 2002, Felson and Anderson published an editorial critiquing a study by Petrella et. al.  and also reviewed 3 large studies of hyaluronan claiming that these studies, if properly analyzed using intent-to-treat analysis, show no benefit of hyaluronan over placebo. The appropriate interpretation of these 3 trials remains somewhat controversial.   However, these differing interpretations are not based on any new information; thus, there are no sufficient grounds to change the policy.
 
2008 Update
In 2006 David Felson his belief that too little attention was paid to nonpharmcologic treatments for oseoarthritis of the knee.  He also commented on the inconsistent data about the efficacy of hyaluronic acid injections.  Results in large studies and unpublished data showing no efficacy suggest the benefit of these injections may be overestimated.  
 
The 2007 AHRQ reviewed three treatments for osteoarthritis of the knee: intra-articular injections of viscosupplements; oral glucosamine or chondroitin or a combination; and arthroscopic lavage and debridement.  Results from 42 trials (N=5,843) generally showed positive effects of viscosupplementation on pain and function scores compared to placebo.  The pooled effects from poor quality trials were as much as twice those obtained from the highest quality trials.   This finding was stated to be consistent with the selective publication of underpowered positive trials.  Studies that include 25% of total patients have not been published as full articles.
 
2010 Update
This policy is updated with a literature search using MEDLINE through December 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 (Zhang, 2008), 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 British National Institute for Health and Clinical Excellence (NICE)  do not recommend IAHA injections for the treatment of OA because “the cost-effectiveness estimate is outside the realms of affordability” to the British 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 (Chevalier, 2009).  At 26 weeks, there was a significant reduction in pain 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 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 Randomized controlled trial (Juni, 2007) 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 trial was one of 13 trials included in the second Swiss study, a meta-analysis that found no superior effectiveness of hylan over hyaluronic acids (Reichenbach, 2007). No new clinical trials describing outcomes with repeated course of IAHA for OA of the knee were identified.
 
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.  However, presently, the evidence is insufficient to determine the efficacy of hyaluronan in joints other than the knee.
 
2012 Update
A search of the MEDLINE database did not reveal any new information that would prompt a change in the coverage statement. The following is a summary of the identified studies assessing the use of viscosupplementation for the treatment of OA for the knee and other joints with the exception of the hip.
 
Bannuru et al. published another meta-analysis of IAHA for knee OA in 2011 (Bannuru, 2011). This meta-analysis evaluated 54 randomized clinical trials published between 1983 and 2009, 49 of which compared the effects over time of IAHA to placebo for pain relief in a total of 6,962 patients. Trial quality and conduct varied. By week 4, the effect size favored IAHA (0.31; 95% CI 0.17, 0.45), peaked at 8 weeks (0.46; 95% CI 0.28, 0.65), and decreased by week 24 to a lesser residual effect (0.21; 95% CI 0.10, 0.31). The authors noted the therapeutic effect was also consistent on multivariate analysis of the subset of high quality trials (2,570 participants) adjusting for correlation between time points.
 
Results from an RCT on the effects of repeat IAHA for knee OA (the AMELIA project) were published in 2011 (Navarro-Sarabia, 2011). In this trial of 306 patients, 5 injections of IAHA or placebo were given weekly for 4 treatment cycles. Patients were followed a total of 40 months, including a 6-month follow-up after the first and second cycles and a 1-year follow-up after the third and fourth cycles. Patients were not permitted to use non-steroidal anti-inflammatory medications 1 week before follow-up evaluations, nor were they permitted to receive corticosteroid injections in the treatment knee during the entire study period. After each treatment cycle, more patients in the IAHA group progressively responded (from 71.1% to 80.5%) compared to the placebo group (from 67.8% to 65.8%) according to Osteoarthritis Research Society International (OARSI) 2004 criteria. At the end of follow-up, 120 patients responded to IAHA or 22% more than the 100 patients that responded to placebo (relative risk [RR] 1.22, 95% CI 1.07 to 1.41; p=0.004). Adverse events included local bleeding, mild pain, or allergic reaction and occurred at a rate of 0.029 per cycle in both groups. Serious adverse events did not occur. The authors noted repeated injections of IAHA progressively increased the number of patients responding and demonstrated a positive carry-over effect for up to 1 year but whether this suggests remission or alteration of the course of OA could not be determined.
 
In 2 randomized controlled, non-inferiority trials, published in 2011, different hyaluronans were also compared and found to have similar outcomes. In one trial of 381 patients, highly purified hyaluronic acid (Sinovial®) was found to be equivalent to 0.8% hylan G-F20 (Synvisc®) (Pavelka, 2011). In the other trial of 276 patients, a medium' molecular weight hyaluronan product (F60027, Structovial) was also found to be equivalent to hylan G-F 20 (Synvisc®).
 
Other Joints
The evidence on IAHA injections in the ankle consists of a few small RCTs and case series. DeGroot et al. reported on an RCT of 64 patients with ankle OA that compared a single IAHA to a single IA saline injection (Degroot, 2012). 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).
 
Migliore and colleagues conducted a review of 7 studies on IAHA for ankle OA, identified from the period of 2006-2009, that included 3 small RCTs with a total of 75 patients, and 4 case series. For 2 of the RCTs, IAHA was compared to saline injection, and the results showed benefit on some outcome measures but not others. The third RCT compared IAHA to exercise therapy and reported no differences in outcomes (Migliore, 2011). The authors were unable to do a meta-analysis due to the limited number of studies and study heterogeneity.
 
There is a very limited amount of evidence on IAHA injections in the foot. Munteanu and colleagues reported on an RCT of a single IAHA injection in 151 patients with first metatarsophalangeal joint OA (Munteanu, 2011).  At 1, 3, and 6 months’ 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 to steroid injections for arthritis of the thumb (Stahl, 2005) (Fuchs, 2006). Fuchs et al. reported that steroid injections were superior at 2-3 weeks post-treatment but that IAHA was superior at 6 months’ follow-up (Fuchs, 2006). Stahl et al. reported essentially equivalent outcomes between steroid injections and IAHA, although IAHA was superior to steroids for some aspects of fine motor function (Stahl, 2005). 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 to steroids.
 
2013 Update
A search of the MEDLINE database through March 2013 did not reveal any new literature that would support a change in the coverage statement. The following is a summary of the key identified literature.
 
Rutjes et al. published a 2012 meta-analysis of 89 trials (12,667 patients) on viscosupplementation for OA of the knee (Rutjes, 2012). The main results showed that viscosupplementation moderately reduced pain (effect size, -0.37). However, several limitations of this body of literature were noted. Trial quality was low, there was considerable between-trial heterogeneity, and an asymmetrical funnel plot suggested publication bias. Five unpublished trials showed an insignificant effect size of -0.03, while analysis of 18 large trials with blinded outcome assessment showed an effect size of -0.11, which is of uncertain clinical significance. Viscosupplementation was also associated with an increased risk for serious adverse events.
 
In 2011, the FDA approved the use of a single dose of Gel-One®, a cross-linked formulation of hyaluronic acid. Approval was based on a multicenter randomized double-blind placebo controlled trial in 377 patients (Strand, 2012). The percentage of patients reporting a 30% or greater improvement in the WOMAC pain subscore was 56.8% at week 3 compared to 47.2% for placebo. The percentage of patients reporting a 50% or greater improvement in the WOMAC pain subscore was 42.8% at week 3 compared to 28.0% for placebo. Significant differences between the groups in mean scores persisted throughout the 13 week follow-up period.
  
2014 Update
This policy is being updated as a result of the findings of systematic review published by the American Academy of Orthopaedic Surgeons (AAOS) in 2013 (AAOS, 2013). Included in the review was a meta-analysis of 3 high-strength and 11 moderate-strength studies of IAHA for OA of the knee. Pain outcomes were significantly lower in the treatment group compared to placebo, but the difference was found to be not clinically important, since the lower bound of the confidence interval was higher than the minimal clinically important difference. This indicated a low likelihood that an appreciable number of patients achieved clinically important benefits. Similar results were obtained for functional outcomes. This meta-analysis found evidence that high molecular-weight preparations were more effective than those with low weights, indicating a possible clinically important difference for the higher molecular-weight preparations.
 
This guideline on treatment of OA of the knee states that they cannot recommend using hyaluronic acid for patients with symptomatic knee OA (AAOS, 2013).  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.
 
In summary, there are a large number of RCTs completed on treatment of OA of the knee with hyaluronan (HA) and numerous systematic reviews of these trials. The majority of systematic reviews concluded that there is a modest beneficial effect of treatment, but that the clinical significance of the magnitude of difference is uncertain. The 2013 meta-analysis by the AAOS that included 14 moderate- to high-strength studies concluded that the improvements in health outcomes with IAHA were statistically but not clinically significant.
 
The policy statement has been changed in response to the findings of the 2013 meta-analysis by the AAOS.
 
There are four ongoing clinical trials evaluating IAHA for OA of the knee listed on the ClinicalTrials.gov website. These include phase 3 and phase 4 trials (NCT01372475, NCT01543737, NCT01557868, NCT01335321).
 
2016 Update
This update includes literature that focus’ on treatment of OA of the hip, as well as the new information for all indications. A literature search conducted through February 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
A systematic review of two RCTs and nine cohort studies (Abate, 2008) 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.
 
In 2009, one industry-sponsored RCT (Richette, 2009) 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.
 
Colen and colleagues conducted a 2012 systematic review of prospective trials of IAHA for joints other than the knee. In their review, 3 RCTs were identified that compared IAHA with placebo, 1 that compared IAHA with IA anesthetic, and 1 that compared hyaluronans of different molecular weights (Colen, 2012). These three trials showed a statistical effect favoring IAHA treatment. However, the effect size was small compared to saline injections, and there were not significant differences between IAHA and other conservative treatments such as steroid injections.
 
Atchia and colleagues reported on a randomized, controlled trial (RCT) of 77 patients with hip OA who were potential candidates for total hip replacement (Atchia, 2011). In this study, patients were randomized to receive standard care or an injection of saline, hyaluronan 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 (Hyalubrix29® - unavailable in the U.S. or IA mepivacaine, a local anesthetic (Migliore, 2009). At 3 and 6 months, there was a significant decrease in the LFI in the IAHA group compared to 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.
 
The 2016 literature review did not identify any additional RCTs evaluating IAHA for treating knee OA. However, a number of systematic reviews and meta-analyses were published (Jevsevar, 2015; Richette, 2015; Trojian, 2016; Ammar, 2015; Strand, 2015; Wang, 2015; Newberry, 2015; Bannuru, 2016). Four of these reported pooled analyses synthesizing results of RCTs comparing IAHA with placebo, and reported pain as an outcome (Jevsevar, 2015; Richette, 2015; Trojian, 2016; Strand, 2015). Three of the 4 new meta-analyses concluded that IAHA provided a clinically meaningful reduction in pain compared with placebo for knee OA (Richette, 2015; Trojian, 2016; Strand, 2015). The fourth meta-analysis (Jevsevar et al) concluded that evidence from trials at low risk of bias (e.g. double-blind, sham-controlled) did not demonstrate a clinically meaningful benefit of IAHA (Jevsevar, 2015). (Two of the meta-analyses concluding benefit of IAHA also limited analysis to trials at low risk of bias.) Only the Jevsevar and colleagues trial reported minimally clinically important difference (-0.29). As noted in the 2014 Assessment, “...for a standardized mean difference, a minimally important difference of -0.37 is sometimes cited”.
 
In addition to the meta-analyses of trials directly comparing IAHA and placebo, a network meta-analysis by Bannuru and colleagues addressed this comparison indirectly (Bannuru, 2015). The investigators included 137 studies examining 8 treatments for knee OA IAHA, IA steroids, acetaminophen, diclofenac, ibuprofen, naproxen, and celecoxib. Although none of the included trials compared IAHA with oral placebo, the authors concluded that, if IAHA were to be compared with oral placebo, it would be the most effective of the agents considered in the review. For example, compared with oral placebo, the standardized mean difference for pain relief reported at (or nearest) 3 months for IAHA was 0.63 (95% credible interval [CrI], 0.39 to 0.88)a and for ibuprofen was 0.44 (95 CrI, 0.25 to 0.63). The estimated pain relief effect for IAHA acid compared with oral placebo was almost double that for IAHA compared with a sham procedure.
 
However, conclusions that can be drawn from the new meta-analyses are limited by potential biases with included trials. The presence of publication bias has been documented in the IAHA literature (Rutjes, 2012). Likewise, a small-trial bias has been noted with effect estimates from smaller trials (<100 participants) almost 3-fold that of large trials. These observations are consistent with positive results from a small trial having a higher probability of being reported than a small negative one (or possibly a small negative trial even completed). In summary, the results from the 2015-2016 meta-analyses, which do not include any new RCTs, do not alter conclusions of the 2014 TEC Assessment on the impact of IAHA on health outcomes in patients with knee OA.
 
Joints Other Than the Knee
Ankle Osteoarthritis
RCTs and systematic reviews have been published. A 2015 Cochrane review by Witteveen and colleagues addressed IAHA and other conservative treatments for ankle OA (Witteveen, 2015). The investigators identified 6 RCTs, 3 of which were double-blind and compared IAHA with placebo. The other trials were single-blind. Two of them compared IAHA to another treatment (exercise in 1 study and botulinum toxin in the other study) and the sixth study compared different doses of HA. Five of the 6 studies included patients with unilateral ankle pain. Sample sizes at the time of randomization ranged from 17 to 75 and length of follow-up ranged from 3 to 12 months. The authors pooled findings only for the 3 studies comparing IAHA and placebo. Meta-analyses of efficacy outcomes (pain and function) did not find statistically significant benefit of IAHA over placebo with the exception of the outcome Ankle Osteoarthritis Scale score total score at 6 months. For the latter outcome, the pooled effect size was -12.53 (95% confidence interval [CI], -23.84 to -1.22) and the evidence for this analysis was rated as very low due to “serious imprecision of results” and unclear risk of bias. No serious adverse events were reported and no patient withdrew from the study due to an adverse event.
 
Thumb Oteoarthritis
Two systematic reviews evaluated IAHA, as well as corticosteroid injections, for treating thumb OA. The 2016 review by Kroon and colleagues identified 3 studies comparing HA and placebo and 6 comparing HA and corticosteroids (Koon, 2016).  Findings of the HA studies were not pooled. Unlike the Kroon and colleagues review, the 2015 systematic review by Trellu and colleagues included only RCTs and pooled study data (Trellu, 2015). Six trials (total N=428 patients) were included in the meta-analyses; 169 patients were treated with HA, 147 with corticosteroids and 74 with placebo. In pooled analyses of studies comparing HA and placebo (74 patients in each arm), there was no significant between-group difference in pain at week 12 (standardized response mean [SRM], -0.95; 95% CI, -3.87 to 1.97). Functional capacity at week 12 was significantly better after HA than after corticosteroid injection (SRM = -1.14; 95% CI, -1.69 to -0.60). When HA and corticosteroids were compared, there was no significant difference in pain, functional capacity, or pulp pinch force at 12 weeks. At 24 weeks, findings were mixed. There was not a significant between-group difference in functional capacity, HA was superior on pulp pinch force status (SRM=1.44; 95% CI, 0.14 to 2.74) and corticosteroids were superior on pain (SRM=1.44; 95% CI, 0.14 to 2.74).
 
Hip Osteoarthritis
A 2015 systematic review by Lieberman and colleagues included RCTs and observational studies with a minimum of 10 patients evaluating IAHA for treatment of pain associated with hip OA (Lieberman, 2015).  A total of 23 studies were identified, 6 of which were RCTs. The studies evaluated 11 different formulations of HA. Duration of follow-up varied; 19 studies followed patients for 6 months or less, 3 had between 6 months and a year of follow-up and only 1 study followed patients for more than a year. The primary efficacy outcome was change from baseline in pain measured by a visual analogue scale (VAS). The authors did not report the number of points on the VAS scale but presumably this differed across studies and the authors appeared to standardize results on a 10-point VAS scale. A pooled analysis of data from all studies found a statistically significantly lower pain score at follow-up compared to baseline. Mean change was -1.97 points on a VAS (95% CI, -2.83 to -1.12). In a pooled analysis of the 6 RCTs, there was a significantly greater decrease in pain with IAHA compared with a control intervention (-0.27 points on a VAS; 95% CI, -0.43 to -0.11). Although statistically significant, a between-group difference of 0.27 points on a VAS may not be clinically meaningful.
 
Shoulder Osteoarthritis
A 2014 systematic review by Colen and colleagues identified RCTs, controlled observational studies and case series evaluating IAHA for treatment of glenohumeral OA in adult patients (Colen, 2014). Eight studies met the eligibility criteria; 2 were RCTs, 5 were prospective case series and 1 was a retrospective case control study. Due to heterogeneity among studies and the small number of controlled studies, authors did not pool study findings on the efficacy of IAHA for treating shoulder OA compared with placebo or an alternative intervention. The RCTs are described next.
 
American Medical Society for Sport Medicine
In a 2016 scientific statement from the American Medical Society for Sport Medicine (AMSSM), AMSSM recommended IAHA for “appropriate” patients with knee OA based on high-quality evidence (Trojian, 2016). Patient selection criteria include individuals age 60 and older with Kellgren-Lawrence grade II-III OA. The society also “suggests” IAHA for patients under age 60 with knee OA based on moderate quality indirect evidence.
 
National Institute for Health and Clinical Excellence
The 2014 guidelines by the National Institute for Health and Clinical Excellence  state: “Do not offer intraarticular hyaluronan injections for the management of osteoarthritis.”
 
2017 Update
A literature search conducted through March 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
Two additional meta-analyses concluded that there was a small, statistically significant benefit and clinical significance depends on the threshold used.  
 
The O’Hanlon (2016) meta-analysis of placebo-controlled, blinded trials found an SMD of -0.23 (O’Hanlon, 2016). In contrast, the Johansen and colleagues meta-analysis of placebo-controlled trials found an SMD of -0.39 (Johansen, 2016). However, when trials were stratified by risk of bias, the effect size of low-risk-of-bias trials was 0.0 and the effect sizes of the unclear and high-risk-of-bias trials were -0.81 and -0.35, respectively.11 Moreover, a stratified analysis by trial size found an SMD of -0.72, whereas trials with at least 100 patients showed an SMD of -0.21.
 
2 RCTs published in 2016 compared IA hyaluronan to corticosteroid injection. Neither found a clinically meaningful benefit of IA hyaluronan compared with corticosteroids. Limitations of both studies included lack of a placebo control group, so conclusions cannot be drawn about the efficacy of IA hyaluronan to corticosteroids versus placebo.
 
Tammachote and colleagues reported on a double-blind study in 110 patients with knee osteoarthritis (Tammachote, 2016). Patients received 1 injection of IA hyaluronan or corticosteroid and were followed for 6 months. The primary outcome, pain at 6 months (measured by a 100-point visual analog scale [VAS]) did not differ significantly between groups. Mean VAS score at 6 months was 24 in the IA hyaluronan group and 21 in the corticosteroid group (p>0.05). At 1 week post-injection, reported pain levels were significantly lower in the corticosteroid group (mean VAS score, 14) than in the IA hyaluronan group (mean VAS score, 23; p=0.018).
 
The other RCT comparing IA hyaluronan to corticosteroid injection in patients with knee OA was published by Askari and colleagues (Askari, 2016).  Like the Tammachote (2016) study, it, too, was double-blind and involved a single injection. Patients were followed for 3 months, and pain was assessed using a 0- to 10-cm VAS. At follow-up, there were no significant differences in pain scores between the groups. Mean VAS score at 3 months was 6.70 in the IA hyaluronan group and 6.26 in the corticosteroid group (p=0.720). After 1 month, mean pain score was significantly lower in the corticosteroid group (mean VAS score, 5.59) than the IA hyaluronan group (mean VAS score, 6.63; p=0.018).
 
Piccirilli and colleagues published a systematic review of RCTs of IA hyaluronan for any type of hip disorder (Piccirilli, 2016). They identified 25 RCTs; the trials addressed hip OA, hip rheumatoid arthritis, and femoroacetabular impingement. Reviewers provided a table of individual studies and noted that studies used different modalities and protocols; no attempt was made to synthesize findings quantitatively or qualitatively.
 
2019 Update
A literature search was conducted through March 2019.  There was no new information identified that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
Wu et al published a meta-analysis of RCTs investigating the therapeutic effects of hyaluronan injections in patients with hip OA (Wu, 2017). Six studies were selected. To measure the effects of hyaluronan injection, a series of pain and functionality assessments were conducted using a VAS, the Lequesne Index, and the Western Ontario and McMaster Universities Osteoarthritis Index. All 6 trials consisted of 2 treatment groups (hyaluronan vs control). Follow-up ranged from 52 to 180 days. When comparing hyaluronan with control, the pooled effect size of improvement in pain scores was 0.03 (95% CI, -0.20 to 0.26; p<0.05). The SMD for improvement in Lequesne Index scores and the Western Ontario and McMaster Universities Osteoarthritis Index scores were -0.24 (95% CI, -0.50 to 0.02; p>0.05) and -0.13 (95% CI, -0.64 to 0.37;p>0.05), respectively. Reviewers noted there were likely no significant differences between hyaluronan injections and saline or other treatments. Limitations included the small sizes of selected studies, selection bias, and expectation bias.
 
2020 Update
A literature search was conducted through March 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
A study aimed to compare the efficacy of four treatments in the management of knee osteoarthritis. A randomized clinical trial with four study arms in an outpatient Department of Physical Medicine and Rehabilitation at a University Hospital was carried out. In total, 120 patients with knee osteoarthritis ≥50 years of age were randomly allocated to four groups. The primary outcome was knee pain in visual analog scale and the secondary outcome was the Knee Injury and Osteoarthritis Outcome Score. The exercise was prescribed daily for all participants throughout the study. For physical therapy (group 1), participants received superficial heat, transcutaneous electrical nerve stimulation and pulsed ultrasound. A single intra-articular injection of botulinum neurotoxin type A (group 2) and three injections of hyaluronic acid (group 3) or 20% dextrose (group 4) was administered to patients in the corresponding groups. Mixed analysis of variance showed that there was statistically significant difference between the groups in pain (P < 0.001), and Knee Injury and Osteoarthritis Outcome Score (P < 0.001). Pairwise between- and within-group comparisons showed that botulinum neurotoxin and dextrose prolotherapy were the most, and hyaluronic acid was the least efficient treatments for controlling pain and recovering function in patients. An intra-articular injection of botulinum toxin type A or dextrose prolotherapy is effective first-line treatments. In the next place stands physical therapy particularly if the patient is not willing to continue regular exercise programs. The study was not very supportive of intra-articular injection of hyaluronic acid as an effective treatment of knee osteoarthritis. (Rezasoltani Z, Azizi S, Najafi S, et. al., 2020)
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2022. No new literature was identified that would prompt a change in the coverage statement.

CPT/HCPCS:
20610Arthrocentesis, aspiration and/or injection, major joint or bursa (eg, shoulder, hip, knee, subacromial bursa); without ultrasound guidance
20611Arthrocentesis, aspiration and/or injection, major joint or bursa (eg, shoulder, hip, knee, subacromial bursa); with ultrasound guidance, with permanent recording and reporting
C9465Hyaluronan or derivative, Durolane, for intra articular injection, per dose (See J7318)
J7318Hyaluronan or derivative, durolane, for intra articular injection, 1 mg
J7320Hyaluronan or derivitive, genvisc 850, for intra articular injection, 1 mg
J7321Hyaluronan or derivative, hyalgan or supartz, for intra articular injection, per dose
J7322Hyaluronan or derivative, hymovis, for intra articular injection, 1 mg
J7323Hyaluronan or derivative, euflexxa, for intra articular injection, per dose
J7324Hyaluronan or derivative, orthovisc, for intra articular injection, per dose
J7325Hyaluronan or derivative, synvisc or synvisc one, for intra articular injection, 1 mg
J7326Hyaluronan or derivative, gel one, for intra articular injection, per dose
J7327Hyaluronan or derivative, monovisc, for intra articular injection, per dose
J7328Hyaluronan or derivative, gelsyn 3, for intra articular injection, 0.1 mg
J7329Hyaluronan or derivative, trivisc, for intra articular injection, 1 mg
J7331Hyaluronan or derivative, synojoynt, for intra articular injection, 1 mg
J7332Hyaluronan or derivative, triluron, for intra articular injection, 1 mg
J7333Hyaluronan or derivative, visco 3, for intra articular injection, per dose

References: . O'Hanlon CE, Newberry SJ, Booth M, et al.(2016) Hyaluronic acid injection therapy for osteoarthritis of the knee: concordant efficacy and conflicting serious adverse events in two systematic reviews. Syst Rev. Nov 04 2016;5(1):186. PMID 27814744

Abate M, Pelotti P, De Amicis D et al.(2008) Viscosupplementation with hyaluronic acid in hip osteoarthritis (a review) Ups J Med Sci 2008; 113(3):261-77

Adams ME, Lussier AJ, Peyron JG.(2000) A risk benefit assessment of injections of hyaluronan and its derivatives in the treatment of osteoarthritis of the knee. Drug Saf 2000; 23:115-30.

Adams ME, Martin AH, Lussier AJ, et al.(1995) The role of viscosupplementation with hylan G-F 20 (Synvisc®) in the treatment of osteoarthritis of the knee: a Canadian multicenter trial comparing hylan G-F 20 alone, hylan G-F 20 with non-steroidal anti-inflammatory drugs (NSAIDs) and NSAIDs alone. Osteoarthritis Cartilage 1995; 3:213-25.

Agency for Healthcare Research and Quality(2016) Evidence-based Practice Center Systematic Review Protocol: Treatment of Osteoarthritis of the Knee: An Update. 2016 July; https://effectivehealthcare.ahrq.gov/ehc/products/633/2247/osteoarthritis-knee-update=protocol-160615.pdf.

Altman R, Brandt K, Hochberg M, et al.(1996) Special Report: Design and conduct of clinical trials in patients with osteoarthritis - Recommendations from a task force of the Osteoarthritis Research Society. Osteoarthritis Cartilage 1996; 4:217-43.

Altman RD, Moskowitz R.(1998) Intraarticular sodium hyaluronate (Hyalgan R) in the treatment of patients with osteoarthritis of the knee: a randomized clinical trial. J Rheum 1998; 25:2203-2212.

American Academy of Orthopaedic Surgeons.(2013) Treatment of osteoarthritis of the knee. Available online at: http://www.aaos.org/research/guidelines/TreatmentofOsteoarthritisoftheKneeGuideline.pdf. Last accessed July, 2013.

Ammar TY, Pereira TA, Mistura SL, et al.(2015) Viscosupplementation for treating knee osteoarthrosis: review of the literature. Rev Bras Ortop. Sep-Oct 2015;50(5):489-494. PMID 26535192

Arrich J, Piribauer F, et al.(2005) Intra-articular hyaluronic acid for the treatment of osteoarthritis of the knee: systematic review and meta-analysis. www.cmaj.ca/cgi/content; 2005.

Askari A, Gholami T, NaghiZadeh MM, et al.(2016) Hyaluronic acid compared with corticosteroid injections for the treatment of osteoarthritis of the knee: a randomized control trail. Springerplus. 2016;5:442. PMID 27104130

Atchia I, Kane D, Reed MR et al.(2011) Efficacy of a single ultrasound-guided injection for the treatment of hip osteoarthritis. Ann Rheum Dis 2011; 70(1):110-6.

Aviad AD, Houpt JB.(1994) The molecular weight of therapeutic hyaluronan (sodium hyaluronate): how significant is it? J Rheum 1994; 21:297-301.

Bannuru RR, Natov NS, Dasi UR et al.(2011) Therapeutic trajectory following intra-articular hyaluronic acid injection in knee osteoarthritis--meta-analysis. Osteoarthritis Cartilage 2011; 19(6):611-9.

Bannuru RR, Schmid CH, Kent DM, et al.(2015) Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. Jan 6 2015;162(1):46-54. PMID 25560713

Bellamy N, Campbell J, et al.(2006) Viscosupplementation for the treatment of osteoarthritis of the knee. The Cochrane Database of Systemic Reviews, 2006, issue 2. Art #:CD005321.pub2.

Bertolami CN, Gay T, Clark GT, et al.(1993) Use of sodium hyaluronate in treating temporomandibular joint disorders: a randomized, double-blind, placebo-controlled clinical trial. J Oral Maxillofac Surg 1993; 51:232-42.

Brandt KD, Block JA, Michalski JP, et al.(2001) Efficacy and safety of intraarticular sodium hyaluronate in knee osteoarthritis. Clin Orthop 2001; 385:130-43.

Campbell WJ, Patterson CC.(1998) Quantifying meaningful changes in pain. Anes 1998; 53:121-5.

Carrabba M, Paresc E, Angelini M, et al.(1995) The safety and efficacy of different dose schedules of hyaluronic acid in the treatment of painful osteoarthritis of the knee with joint effusion. Eur J Rheum Infamm 1995; 15:25-31.

Chevalier X, Jerosch J, Goupille P et al.(2009) 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].

Colen S, Geervliet P, Haverkamp D, et al.(2014) Intra-articular infiltration therapy for patients w ith glenohumeral osteoarthritis: A systematic review of the literature. Int J Shoulder Surg. Oct 2014;8(4):114-121. PMID 25538430

Colen S, Haverkamp D, Mulier M et al.(2012) Hyaluronic acid for the treatment of osteoarthritis in all joints except the knee: what is the current evidence? BioDrugs 2012; 26(2):101-12.

Corrado EM, Peluso GF, Gigliotti S, et al.(1995) The effects of intraarticular administration of hyaluronic acid on osteoarthritis of the knee: a clinical study with immunological and biochemical evaluations. Eur J Rheumatol Infamm 1995; 15:205-13.

Creamer P, Sharif M, George E, et al.(1994) Intraarticular hyaluronic acid in osteoarthritis of the knee: an investigation into mechanisms of action. Osteoarthritis Cartilage 1994; 2:133-40.

Dahlberg L, Lohmander LS, Ryd L.(1994) Intraarticular injections of hyaluronan in patients with cartilage abnormalities and knee pain. Arthrit Rheum 1994; 37:521-8.

Davis MA, Ettinger WH, Neuhaus JM, et al.(1992) Correlates of knee pain among US adults with and without radiographic knee osteoarthritis. J Rheum 1992; 19:1943-9.

Degroot H, Uzunishvili S, Weir R et al.(2012) Intra-articular injection of hyaluronic Acid is not superior to saline solution injection for ankle arthritis: a randomized, double-blind, placebo-controlled study. J Bone Joint Surg 2012; 94(1):2-8.

Dickson DJ, Hosie G.(1998) Double-blind, double control comparison of viscosupplementation with Synvisc® against diclofenac and control in knee osteoarthritis. Brit Med Society Rheum; April 24 1998.

Dougados M, Nguyen M, Listrat V, et al.(1993) High molecular weight sodium hyaluronate (Hyalectin) in osteoarthritis of the knee: a 1 year placebo-controlled trial. Osteoarthritis Cartilage 1993; 1:97-103.

Edwards JL.(1994) Sodium hyaluronate for temporomandibular joint disorders. Ann R Aust Col Dent Surg 1994; 12:217-22.

Evanich JD, Evanich CJ, Wright MB, et al.(2001) Efficacy of intraarticular hyaluronic acid injections in knee osteoarthritis. Clin Orthop 2001; 390: 173-81.

Fajardo M, DiCesare PE.(2005) Disease-modifying therapies for osteoarthritis. Drugs Aging 2005; 22:141-161.

FDA.(1983) Conditions of approval of for Synvisc® Hylan G-F 20. Premarket approval #P940015. Summary of Safety and Effectiveness Data. Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH). http://208.206.43.181/cdrh/ pmaaug97.html/P940015.pdf. Accessed April 16.

Felson DT and Anderson JJ.(2002) Hyaluronate sodium injections for osteoarthritis: hope, hype, and hard truths. Arch Intern Med 2002; 162:245-247.

Felson, David.(2006) Osteoarthritis of the knee. NEJM; 2006; 354:841-8.

Fernandez Lopez JC, Ruano-Ravina A.(2006) Efficacy and safety of intraarticular hyaluronic acid in the treatment of hip osteoarthritis: a systematic review. Osteoarthritis Cartilage 2006; 14(12):1306-11.

Ghosh P.(1994) The role of hyaluronic acid (hyaluronan) in health and disease: interactions with cells, cartilage and components of synovial fluid. Clin Exp Rheum 1994; 12:75-82.

Goldberg SH, Von Feldt JM, Lonner JH.(2002) Pharmacologic therapy for osteoarthritis. A J Orthoped 2002; 31:673-80.

Graf J, Neusel E, Schneider E, et al.(1993) Intraarticular treatment with hyaluronic acid in osteoarthritis of the knee joint: a controlled clinical trial versus mucopolysaccharide polysulfuric acid ester. Clin Exp Rheum 1993; 11:367-72.

Grecomero G, Piccione F, Letizia G.(1992) Therapeutic synergism between hyaluronic acid and dexamethasone in the intra-articular treatment of osteoarthritis of the knee: a preliminary open study. Curr Med Res Opin 1992; 13:49-55.

Henderson EB, Smith EC, Pegley F, et al.(1994) Intraarticular injections of 750 kD hyaluronan in the treatment of osteoarthritis: a randomized single centre double-blind placebo-controlled trial of 91 patients demonstrating lack of efficacy. Ann Rheum Dis 1994; 53:529-34.

Hochberg MC, Altman RD, Brandt KD, et al.(1995) Guidelines for the medical management of osteoarthritis. Part 1, Osteoarthritis of the hip. Arthrit Rheum 1995; 38:1535-40.

Hochberg MC, Altman RD, Brandt KD, et al.(1995) Guidelines for the medical management of osteoarthritis. Part 1, Osteoarthritis of the knee. Arthrit Rheum 1995; 38:1541-6.

Jevsevar D, Donnelly P, Brow n GA, et al.(2015) Viscosupplementation for osteoarthritis of the knee: a systematic review of the evidence. J Bone Joint Surg Am. Dec 16 2015;97(24):2047-2060. PMID 26677239

Johansen M, Bahrt H, Altman RD, et al.(2016) Exploring reasons for the observed inconsistent trial reports on intra-articular injections with hyaluronic acid in the treatment of osteoarthritis: Meta-regression analyses of randomized trials. Semin Arthritis Rheum. Aug 2016;46(1):34-48. PMID 27139169

Jones AC, Pattrick M, Doherty S, et al.(1995) Intraarticular hyaluronic acid compared to intra-articular triamcinolone hexacetonide in inflammatory knee osteoarthritis. Osteoarthritis Cartilage 1995; 3:269-73.

Juni P, Reichenbach S, Trelle S et al.(2007) 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.

Kirwan JR, Rankin E.(1997) Intraarticular therapy in osteoarthritis. Bailliere’s Clin Rheum 1997; 11:769-94.

Kolarz G, Kotz R, Broll H, et al.(1995) Hyaluronic acid in the treatment of osteoarthritis of the knee joint: interim results of a comparative clinical study. Eur J Rheumatol Infam 1995; 15:39-45.

Kotz R, Kolarz G.(1999) Intra-Articular hyaluronic acid: duration of effect and results of repeated treatment cycles. Am J Ortho 1999; 28(11sup):5-7.

Kraus VB.(1997) Pathogenesis and treatment of osteoarthritis. Med Clin N Am 1997; 81:85-112.

Kroon FP, Rubio R, Schoones JW, et al.(2016) Intra-Articular Therapies in the Treatment of Hand Osteoarthritis: A Systematic Literature Review . Drugs Aging. Feb 2016;33(2):119-133. PMID 26650235

Leopold SS, Redd BB, Warme WJ, et al.(2003) Corticosteroid compared with hyaluronic acid injections for the treatment of osteoarthritis of the knee. J Bone Jt Surg 2003; 85-A; 1197-1203.

Lieberman JR, Engstrom SM, Solovyova O, et al.(2015) Is intra-articular hyaluronic acid effective in treating osteoarthritis of the hip joint? J Arthroplasty. Mar 2015;30(3):507-511. PMID 25542833

Listrat V, Ayral X, Patarnello F, et al.(1997) Arthroscopic evaluation of potential structure modifying activity of hyaluronan (Hyalgan®) in osteoarthritis of the knee. Osteoarthritis Cartilage 1997; 5:153-60.

Lohmander LS, Dalen N, Englund G, et al.(1996) Intraarticular hyaluronan injections in the treatment of osteoarthritis of the knee: a randomized, double blind, placebo controlled multicenter trial. Ann Rheum Dis 1996; 55:424-31.

Lozada CJ, Altman RD.(1997) Chondroprotection in osteoarthritis. Bull Rheum Dis 1997; 46:5-7.

Lussier A, Cividino AA, McFarlane CA, et al.(1996) Viscosupplementation with hylan for the treatment of osteoarthritis: findings from clinical practice in Canada. J Rheum 1996; 23:1579-85.

Maheu E, Zaim M, Appelboom T et al.(2011) Comparative efficacy and safety of two different molecular weight (MW) hyaluronans F60027 and Hylan G-F20 in symptomatic osteoarthritis of the knee (KOA). Results of a non inferiority, prospective, randomized, controlled trial. Clin Exp Rheumatol 2011; 29(3):527-35.

Marshall KW.(1997) The current status of Hylan therapy for the treatment of osteoarthritis. Today’s Therapeutic Trends 1997; 15:99-108.

Massucam SA, Brandt KD.(1999) Plain radiography as an outcome measure in clinical trials involving patients with knee osteoarthritis. Rheumatic Diseases Clinics N Am 1999; 25:467-80.

Migliore A, Giovannangeli F, Bizzi E et al.(2011) Viscosupplementation in the management of ankle osteoarthritis: a review. Arch Orthop Trauma Surg 2011; 131(1):139-47.

Migliore A, Massafra U, Bizzi E et al.(2009) Comparative, double-blind, controlled study of intraarticular hyaluronic acid (Hyalubrix) injections versus local anesthetic in osteoarthritis of the hip. Arthritis Res Ther 2009; 11(6):R183.

Munteanu SE, Zammit GV, Menz HB et al.(2011) Effectiveness of intra-articular hyaluronan (Synvisc, hylan G-F 20) for the treatment of first metatarsophalangeal joint osteoarthritis: a randomised placebo-controlled trial. Ann Rheum Dis 2011; 70(10):1838-41.

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.

Navarro-Sarabia F, Coronel P, Collantes E et al.(2011) A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis 2011; 70(11):1957-62.

New berry SJ, Fitzgerald JD, Maglione MA, et al.(2015) Systematic Review for Effectiveness of Hyaluronic Acid in the Treatment of Severe Degenerative Joint Disease (DJD) of the Knee. Agency for Healthcare Research and Quality; Rockville MD2015.

Osteoarthritis - Clinical issues in drug management. Am Medical Association Health Management Bulletin (July) 1997.

Osteoarthritis of the knee and hip. Am Medical Association Health Management Bulletin (March) 1997.

Petersson IF, Boegard, T, Saxne T, et al.(1997) Radiographic osteoarthritis of the knee classified by the Ahlback and Kellgren & Lawrence systems for the tibiofemoral joint in people aged 35-54 years with chronic knee pain. Ann Rheum Dis 1997; 56:493-6.

Petrella RJ, DiSilvestro MD, Hildebrand C.(2002) Effects of hyaluronate sodium on pain and physical functioning in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled clinical trial. Arch Intern Med 2002; 162:292-298.

Pharmacological management of osteoarthritis. Am Medical Association Health Management Bulletin (May) 1997.

Piccirilli E, Oliva F, Mure MA, et al.(2016) Viscosupplementation with intra-articular hyaluronic acid for hip disorders. A systematic review and meta-analysis. Muscles Ligaments Tendons J. Jul-Sep 2016;6(3):293-299. PMID 28066733

Pinals RS.(1996) Mechanisms of joint destruction, pain and disability in osteoarthritis. Drugs 1996; 52(sup 3):14-20.

Poiraudeau S, Dougados M, Ait-Hadad Hpion-Graff J, et al.(1993) Evaluation of the French version of a quality of life scale (AIMS2) in rheumatology patients. Rev Rhum Engl Ed 1993; 60:466-72.

Puhl W, Bernau A, Greiling H, et al.(1993) Intraarticular sodium hyaluronate in osteoarthritis of the knee: a multicenter, double-blind study. Osteoarthritis Cartilage 1993; 1:233-241.

Puttick MPE, Wade JP, Chalmers A, et al.(1995) Acute local reactions after intraarticular hylan for osteoarthritis of the knee. J Rheum 1995; 22:1311-4.

Qvistgaard E, Christensen R, Torp-Pedersen S et al.(2006) Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. Osteoarthritis Cartilage 2006; 14(2):163-70.

Reichenbach S, Blank S, Rutjes A et al.(2007) Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis. Arthritis Rheum 2007; 57(8):1410-8.

Rezasoltani Z, Azizi S, Najafi S, Sanati E, Dadarkhah A, Abdorrazaghi F.(2020) Physical therapy, intra-articular dextrose prolotherapy, botulinum neurotoxin, and hyaluronic acid for knee osteoarthritis: randomized clinical trial. Int J Rehabil Res. 2020 Sep;43(3):219-227. doi: 10.1097/MRR.0000000000000411. PMID: 32776763.

Richette P, Chevalier X, Ea HK, et al.(2015) Hyaluronan for knee osteoarthritis: an updated meta-analysis of trials with low risk of bias. RMD Open. 2015;1(1):e000071. PMID 26509069

Richette P, Ravaud P, Conrozier T et al.(2009) Effect of hyaluronic acid in symptomatic hip osteoarthritis: a multicenter, randomized, placebo-controlled trial. Arthritis Rheum 2009; 60(3):824- 30.

Rutjes AW, Juni P, da Costa BR et al.(2012) Viscosupplementation for osteoarthritis of the knee: a systematic review and meta-analysis. Ann Intern Med 2012; 157(3):180-91.

Sala SF, de Miguel RE.(1995) Intraarticular hyaluronic acid in the treatment of osteoarthritis of the knee: a short term study. Eur J Rheumatol Infam 1995; 15:33-38.

Samson DJ, Grant MD, et al.(2007) Treatment of primary and secondary osteroarthritis of the knee. Evidence Report/Technology Assessment #157. AHRQ publication No. 07-E012, Sep 2007:http://www.ahrq.gov/.

Scale D, Wobig M, Wolpert W.(1994) Viscosupplementation of osteoarthritic knees with hylan: a treatment schedule study. Curr Ther Res 1994; 55:219-32.

Scali JJ.(1995) Intraarticular hyaluronic acid in the treatment of osteoarthritis of the knee: a long term study. Eur J Rheum Infamm 1995; 15:57-61.

Simo LS.(1999) Viscosupplementation therapy with intraarticular hyaluronic acid. Fact or Fantasy. Rheum Dis Clin North Am 1999; 25:345-357.

Special report: intra-articular hyaluronan for osteoarthritis of the knee. 2004 Blue Cross Blue Shield Association Technology Evaluation Center Assessment; Vol 19; Tab 17.

Stahl S, Karsh-Zafrir I, Ratzon N et al.(2005) Comparison of intraarticular injection of depot corticosteroid and hyaluronic acid for treatment of degenerative trapeziometacarpal joints. J Clin Rheumatol 2005; 11(6):299-302.

Strand V, Baraf HS, Lavin PT et al.(2012) A multicenter, randomized controlled trial comparing a single intra-articular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee. Osteoarthritis Cartilage 2012; 20(5):350-6.

Strand V, McIntyre LF, Beach WR, et al.(2015) Safety and efficacy of US-approved viscosupplements for knee osteoarthritis: a systematic review and meta-analysis of randomized, saline-controlled trials. J Pain Res. 2015;8:217-228. PMID 26005358

Tamir E, Robinson D, Koren R, et al.(2001) Intra-articular hyaluronan injection for the treatment of osteoarthritis of the knee: a randomized, double-blind, placebo controlled study. Clin Exp Rheum 2001; 19:265-70.

Tammachote N, Kanitnate S, Yakumpor T, et al.(2016) Intra-articular, single-shot Hylan G-F 20 hyaluronic acid injection compared with corticosteroid in knee osteoarthritis: a double-blind, randomized controlled trial. J Bone Joint Surg Am. Jun 01 2016;98(11):885-892. PMID 27252432

Tehranzadeh J, Booya F, Root J.(2005) Cartilage metabolism in osteoarthritis and the influence of viscosupplementation and steroid: a review. Acta Rad 2005; (3):288-96.

Tho EM, Prasad PS, Teanby D.(2002) Correlating the efficacy of knee viscosupplementation with osteoarthritic changes on roentgenological examination. Knee 2002; 9: 321-30.

Toh EM, Prasad PS, Teanby D.(2002) Correlating the efficacy of knee viscosupplementation with osteoarthritic changes on roentgenological examination. Knee 2002; 9:321-330.

Tomford WW.(1998) Review of hyaluronic acid, glucosamine, chondroitin sulfate therapies for OA pain. AAOS Bulletin 1998; February:56-7.

Towheed TE, Hochberg MC.(1997) A systematic review of randomized controlled trials of pharmacological therapy in osteoarthritis of the knee, with an emphasis on trial methodology. Semin Arthritis Rheum 1997; 26:755-70.

Trellu S, Dadoun S, Berenbaum F, et al.(2015) Intra-articular injections in thumb osteoarthritis: A systematic review and meta-analysis of randomized controlled trials. Joint Bone Spine. Oct 2015;82(5):315-319. PMID 25776442

Trojian TH, Concoff AL, Joy SM, et al.(2016) AMSSM scientific statement concerning viscosupplementation injections for knee osteoarthritis: importance for individual patient outcomes. Br J Sports Med. Jan 2016;50(2):84-92. PMID 26729890

van den Bekerom MP, Lamme B, Sermon A et al.(2008) What is the evidence for viscosupplementation in the treatment of patients with hip osteoarthritis? Systematic review of the literature. Arch Orthop Trauma Surg. 2008 Aug;128(8):815-23.

Wang F, He X.(2015) Intra-articular hyaluronic acid and corticosteroids in the treatment of knee osteoarthritis: A meta-analysis. Exp Ther Med. Feb 2015;9(2):493-500. PMID 25574222

Watterson JR, Esdaile JM.(2000) Viscosupplementation: therapeutic mechanisms and clinical potential in osteoarthritis of the knee. J Am Acad Orthop Surg 2000; 8:277-84.

Weiss C, Band P.(1995) Musculoskeletal applications of hyaluronan and hylan – potential uses in the foot and ankle. Clin Podiatr Med Surg 1995; 12:497-517.

Witteveen AG, Hofstad CJ, Kerkhoffs GM.(2015) Hyaluronic acid and other conservative treatment options for osteoarthritis of the ankle. Cochrane Database Syst Rev. 2015;10:CD010643. PMID 26475434

Wobig M, Dickhut A, Maier R, et al.(1998) Viscosupplementation with Hylan G-F 20: A 26-week controlled trial of efficacy and safety in the osteoarthritic knee. Clin Ther; 20:410-23.

Wright KE, Maurer SG, DiCeasre PE.(2000) Viscosupplementation for osteoarthritis. Am J Ortho 2000; 29: 88-9.

Wu B, Li YM, Liu YC.(2017) Efficacy of intra-articular hyaluronic acid injections in hip osteoarthritis: a meta-analysis of randomized controlled trials. Oncotarget. Oct 17 2017;8(49):86865-86876. PMID 29156841

Wu JJ, Shih LY, Hsu HC, et al.(1997) The double blind test of sodium hyaluronate (ARTZ) on osteoarthritis knee. Chin Med J (Taipei) 1997; 59:99-106.

Zhang W, Moskowitz R, Nuki G et al.(2008) 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.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
CPT Codes Copyright © 2022 American Medical Association.