| Coverage Policy Manual | |
| Policy #: | 1998119 |
| Category: | Pharmacy |
| Initiated: | February 1998 |
| Last Review: | April 2024 |
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| Viscosupplementation for the Treatment of Osteoarthritis of the Hip, Knee, and All Other Joints | |
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| 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 individuals 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.
See CPT/HCPCS Code section below.
Viscosupplementation for the treatment of osteoarthritis of the hip is handled in policy #2004006 (Archived April, 2016).
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Policy/ Coverage: |
Effective April 2016
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
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:
A repeat course of hyaluronan injections could be covered if the following 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.
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:
For contracts without primary coverage criteria, the following, are considered investigational and are not covered.
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:
A repeat course of hyaluronan injections could be covered at 8-12 months if the following 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.
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:
For contracts without primary coverage criteria, the following, are considered investigational and are not covered.
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 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:
are not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For contracts without primary coverage criteria;
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
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| 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.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2023. No new literature was identified that would prompt a change in the coverage statement.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through April 2024. No new literature was identified that would prompt a change in the coverage statement.
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