CMS Hyaluronic Acid Injections for Knee Osteoarthritis Form

Summary Of Evidence

Kolasinski, et al. (2020) developed guidelines and recommendations for clinicians and patients in making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision-making that accounts for patients’ values, preferences, and comorbidities. Many providers want the option of using HA injections when glucocorticoid injections or other interventions fail to adequately control local joint symptoms. The conditional recommendation is consistent with the use of HA injections, in the context of shared decision-making that recognizes the limited evidence of benefit of this treatment, when other alternatives have been exhausted or failed to provide satisfactory benefit.²

Maheu, et al. (2019) conducted a literature review to determine the strength of evidence in support of the efficacy and safety of intra-articular HA, from randomized controlled trials (RCTs) and meta-analyses. The results of their analysis showed that intra-articular HA provides a moderate symptomatic benefit to knee OA patients and without major safety concerns. In fact, intra-articular HA may offer 1 of the best benefit/risk ratios among pharmacologic options, as measured by improvements in knee OA health outcomes, overall gain in quality adjusted life years and substantial delays in time to total knee replacement (TKR). They concluded by advocating for the consideration of recommending intra-articular HA injection as a treatment option in the management of knee OA, tailored by disease stage and patient phenotype. Further research efforts should focus on identification of OA patient subgroups that demonstrate a more robust response to intra-articular HA, determination of long term effects of repeat intra-articular HA injections on patient reported outcomes and TKR-sparing effect, further elucidation of disease-modifying effects, and the potential for combination therapy with other pharmacologic and non-pharmacologic therapies to optimize the management of knee OA.³

Newberry, et al. (2015) conducted a review of the evidence that intra-articular injections of HA in individuals with degenerative joint disease (OA) of the knee improve function and quality of life (QoL) and that they delay or prevent the need for TKR, specifically for individuals age 65 and over. They concluded that RCTs enrolling older participants showed a small, statistically significant effect of HA on function and relatively few serious adverse events; however, no studies limited participation to those 65 years or older. No conclusions can be drawn from the available literature on delay or avoidance of TKR through the use of HA. Studies that can compare large numbers of treated and untreated individuals, preferably with a randomized design, are needed to answer this question.¹

The American Academy of Orthopaedic Surgeons (AAOS) Management of Osteoarthritis of the Knee (Non-Arthroplasty) Evidence-Based Clinical Practice Guideline adopted August 31, 2021 is based on a systemic review of the available scientific and clinical information and accepted approaches to treatment and/or diagnosis. Twenty-eight studies (17 high-strength and 11 moderate-strength) assessed intra-articular HA injections when compared to controls. When we differentiated high-versus low-molecular weight viscosupplementation our analyses demonstrated no significant differences among different viscosupplementation formulations. Some studies demonstrated a statistical benefit with the use of HA but could not reach the significance for a minimally clinical meaningful difference, leading to the conclusion that viscosupplementation can represent a viable option for some patients that failed other treatments when appropriately indicated. The number needed to treat to see a tangible benefit from HA was 17 patients. Furthermore, this difference was most evident at 6 weeks and 3 months. This 2021 version of this guideline found that statistically significant improvements were associated with high-molecular cross-linked HA but when compared to mid-range molecular weight, statistical significance was not maintained. This newer analysis did not demonstrate clinically relevant differences when compared to controls. However, as previous research reported benefits in their use, the group felt that a specific subset of patients might benefit from its use. The HA recommendation was downgraded to Moderate Strength of recommendation due to lack of generalized results. HA intra-articular injection(s) is not recommended for routine use in the treatment of symptomatic OA of the knee. Currently intra-articular treatments are a commonly utilized approach in treating symptomatic knee OA, hence there should be no issues implementing this recommendation as it does not influence a major change in clinical practice, and it provides further evidence to support and guide these practices. Future research in this area should embrace detailed OA characterization including sub-group analyses and OA severity stratification.⁴

Bannuru, et al. (2016) conducted a systemic review on RCTs and meta-analyses to examine the risks of HA compared with intra-articular placebo and investigated whether the risks vary among individual HA preparations. They identified 74 studies involving 13,032 participants aged between 45 and 75 years. The overall incidence of local reactions reported across all products was 8.5%. Commonly reported adverse events (AEs) were transient local reactions, such as pain, swelling and arthralgia, which subsided rapidly. They concluded that given the very low incidence of any particular AEs, that HA products are relatively well tolerated. These products have a similar safety profile compared to each other.⁵

Bannuru, et al. (2015) examined the efficacy of treatments of primary knee OA using a network meta-analysis design, which estimates relative effects of all treatments against each other. For pain, all interventions significantly outperformed oral placebo, with effect sizes from 0.63 for the most efficacious treatment (HA) to 0.18 for the least efficacious treatment (acetaminophen). For function, all interventions except intra-articular corticosteroids were significantly superior to oral placebo. For stiffness, most of the treatments did not significantly differ from one another.⁶

Campbell, et al. (2015) conducted a systematic literature review of meta-analyses comparing treatment of knee OA with intra-articular viscosupplementation (intra-articular HA) versus oral NSAIDs, intra-articular corticosteroids, intra-articular platelet-rich plasma, or intra-articular placebo to determine which meta-analyses provide the best current evidence and identify potential causes of discordance. The available evidence shows that intra-articular HA provides small but clinically relevant improvements in knee pain and function when compared with intra-articular placebo. Although there were no major clinical differences in the efficacy of intra-articular HA versus oral NSAIDs in relieving knee pain and restoring function, the fact that intra-articular HA has a more favorable side-effect profile than oral NSAIDs makes intra-articular HA a good option for patients unable to tolerate oral NSAIDs. Both intra-articular HA and intra-articular corticosteroids were effective in controlling pain, with steroids providing better short-term relief and HA providing more long-term relief starting in the 5 to 13-week post injection period and lasting for up to 26 weeks. Regarding intra-articular HA versus intra-articular platelet-rich plasma, intra-articular HA improved knee function at 2 and 6 months after injection but the effects were less robust than those of intra-articular platelet-rich plasma. Intra-articular HA in terms of pain and function may be a better treatment option as more high quality randomized, double-blinded studies are needed to compare the effects of platelet-rich plasma versus other treatments before it can be fully endorsed as a viable universal option for patients with knee OA. They concluded the current highest level of evidence suggests that intra-articular HA is a viable option for patients with knee OA. Its use results in improvements in knee pain and function that can persist for up to 26 weeks in comparison with other treatment modalities. Intra-articular HA has been shown to have a good safety profile, and its use should be considered in patients with early knee OA.⁸

Berkoff, et al. (2012) conducted a peer-reviewed literature search to compare the accuracy of intra-articular large joint injections with imaging guidance versus conventional anatomical guidance. Numerous imaging modalities may be used to aid the clinician in identifying the correct trajectory for intra-articular injections including ultrasound, fluoroscopy, CT, and MRI. The results of the current analysis demonstrate that use of imaging guidance improves the accuracy of intra-articular injection in large joints including the knee. Furthermore, the use of ultrasound guidance specifically at the knee greatly increases the likelihood of correct needle placement. Ultrasound guidance of knee injections resulted in better accuracy than anatomical guidance (95.8% versus 77.8%, P < 0.001), yielding an odds ratio of 6.4 (95% confidence interval 2.9-14).⁹

Ong, et al. (2016) conducted a retrospective observational study design based on the 5% sample of Part B Medicare data (carrier/physician claims) from 2005 to 2012. The 5% Part B Medicare data (2005-2012) were used to identify knee OA patients who underwent knee arthroplasty (KA).The time from diagnosis of OA to KA was compared between patients with HA injections and without (no HA) intra-articular HA use. The “HA” cohort was associated with a longer time to KA of 8.7 months (95% confidence interval: 8.3 – 9.1 months; P < 0.001) compared with the “no HA” cohort. Their analysis of a large, elderly, knee OA population showed a significantly longer time from diagnosis of OA to KA for those who were treated with intra-articular HA. It is unclear if the extended time may lead to less KA utilization or whether the delay could provide additional time for patients to better address or control preexisting conditions before KA, which could aid in reducing postoperative morbidity.¹²

Newberry, et al. (2015) conducted a systematic review of the effectiveness of HA in the treatment of severe degenerative joint disease of the knee. The Coverage and Analysis Group at the Centers for Medicare and Medicaid Services (CMS) requested from The Technology Assessment Program (TAP) at the Agency for Healthcare Research and Quality (AHRQ), a review of the evidence that intra-articular injections of HA in individuals with degenerative joint disease (OA [HA]) of the knee improve function and QoL and that they delay or prevent the need for TKR, specifically for individuals age 65 and over. The results of the study noted only 1 RCT reported on delay or avoidance of TKR as a pre-specified outcome of interest and found a non-statistically significantly longer delay of TKR compared with placebo; 2 RCTs reported TKR only as a secondary outcome; and 13 published observational studies reported on TKR as an outcome in HA-treated participants.

Eighteen RCTs that enrolled participants of average age 65 or older reported on functional outcomes of intra-articular HA injection: pooled analysis of 10 sham-injection placebo-controlled, assessor-blinded trials showed a standardized mean difference of -0.23 (95% CI -0.34, -0.02) significantly favoring HA at 6 month follow-up. Durability of effect could not be assessed because of the short duration of most studies. Too few head-to-head trials were available to assess superiority of 1 product over another. Three RCTs that compared changes in QoL/Health-Related QoL between HA- and placebo-treated participants reported no differences between active treatment and placebo. Two recent large, good quality systematic reviews that conducted meta-analysis of the effects of HA on pain and function (pooling 71 and 52 RCTs for the outcome of pain, respectively) showed a significant and clinically important effect of HA on both outcomes among adults of all ages, but a subgroup analysis that included only the largest double-blind placebo-controlled studies reduced the average effect of HA to less than the prespecified minimum clinically important difference. Studies of intra-articular HA reported few serious adverse events, with no statistically significant difference in the rates of serious or non-serious adverse events between HA- and placebo-treated groups.

They concluded that trials enrolling older participants show a small, statistically significant effect of HA on function and relatively few serious adverse events; however, no studies limited participation to those 65 years or older. No conclusions can be drawn from the available literature on delay or avoidance of TKR through the use of HA. Studies that can compare large numbers of treated and untreated individuals, preferably with a randomized design, are needed to answer this question.¹

Kolasinski, et al. (2020) developed an evidence-based guideline for the comprehensive management of OA as a collaboration between the American College of Rheumatology (ACR) and the Arthritis Foundation, updating the 2012 ACR recommendations for the management of hand, hip, and knee OA. Based on the available evidence, either strong or conditional recommendations were made for or against the approaches evaluated. This guideline provides direction for clinicians and patients making treatment decisions for the management of OA. Clinicians and patients should engage in shared decision-making that accounts for patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies. In OA generally, intra-articular glucocorticoid injection is conditionally recommended over other forms of intra-articular injection, including HA preparations. Head-to-head comparisons are few, but the evidence for efficacy of glucocorticoid injections is of considerably higher quality than that for other agents.

Many providers want the option of using HA injections when glucocorticoid injections or other interventions fail to adequately control local joint symptoms. In clinical practice, the choice to use HA injections in the knee OA patient who has had an inadequate response to nonpharmacologic therapies, topical and oral NSAIDs, and intra-articular steroids may be viewed more favorably than offering no intervention, particularly given the impact of the contextual effects of intra-articular HA injections. The conditional recommendation against is consistent with the use of HA injections, in the context of shared decision-making that recognizes the limited evidence of benefit of this treatment, when other alternatives have been exhausted or failed to provide satisfactory benefit.²

Trojian, et al. (2016) performed a network meta-analysis of the relevant literature to determine if there is a benefit from HA as compared with intra-articular corticosteroid and intra-articular placebo based on the evaluation of treatment effect by examining the number of subjects within a treatment arm that met the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria, which is different and more relevant than methods used in other reviews which examined if the average change across the treatment groups was clinically different. Our results demonstrate evidence of small but statistically significant improvement for the group of subjects treated with HA injections compared with those treated with intra-articular corticosteroid or intra-articular placebo injections with regard to pain and function as assessed by the relevant Western Ontario and McMaster University Arthritis Index (WOMAC) subscales. The statistically significant results that we have identified for HA versus intra-articular corticosteroid and intra-articular placebo also represent a clinically relevant difference.

The American Medical Society for Sport Medicine (AMSSM) recommends the use of HA for the appropriate patients with knee OA. “We RECOMMEND viscosupplementation injections for K-L grade ll-lll knee OA in those patients above the age of 60 years based on HIGH quality evidence demonstrating benefit using OMERACT-OARSI Responder Rating.” But the evidence should be downgraded because of indirectness for those younger than 60 years. “We SUGGEST viscosupplementation injections for knee OA for those under the age of 60 years based on MODERATE quality evidence due to response of treatment in those over 60 years of age.”¹⁴

Strand, et al. (2015) performed a meta-analysis for randomized, sham controlled trials of intra-articular HA injection for treatment of knee OA. All sham-controlled trials used saline injections as a control. Viscosupplementation resulted in very large treatment effects between 4 and 26 weeks for knee pain and function compared to preinjection values, with standardized mean difference values ranging from 1.07 to 1.37 (all P < 0.001). Compared to controls, standardized mean difference with viscosupplementation ranged from 0.38 to 0.43 for knee pain and 0.32 to 0.34 for knee function (all P < 0.001). There were no statistically significant differences between viscosupplementation and controls for any safety outcome. They concluded that intra-articular injection of U.S.-approved viscosupplements is safe and efficacious through 26 weeks in patients with symptomatic knee OA. Limitations of this meta-analysis were significant heterogeneity in efficacy outcomes among included studies and smaller treatment effects in higher quality trials.¹⁵

Altman, et al. (2018) stated the evidence suggests HA has significant short-term efficacy (less than or equal to 6 months) for treating knee OA pain. While a single series of intra-articular HA has been well studied, the efficacy and safety of repeated courses of intra-articular HA injection therapy in knee OA patients have not been evaluated as frequently. They conducted a literature search using MEDLINE, EMBASE and PubMed databases. A total of 17 articles (RCTs and 10 cohort studies) met the pre-defined inclusion criteria. The inclusion criteria were (1) RCTs, (2) cohort studies with intra-articular HA as the primary treatment, (3) studies that provide at least 1 repeat course of intra-articular HA, (4) studies that measured knee pain as an outcome and (5) articles published in English. Studies ranged from investigating a single reinjection cycle to 4 repeat injection cycles. All studies reported pain reduction from baseline in the intra-articular HA treatment group throughout the initial treatment cycle, and either sustained or further reduced pain throughout the repeated courses of treatment. The study with the longest follow-up repeated intra-articular HA injection every 6 months for 25 months. Pain decreased after the first course and continued to decrease until the end of the study, with an approximate 55% reduction in pain compared to baseline. The authors concluded that repeated courses of intra-articular HA injections are an effective and safe treatment for knee OA. Repeat courses were demonstrated to maintain or further improve pain reduction while introducing no increased safety risk.¹⁶

The 2020 Department of Veteran Affairs/Department of Defense (VA/DoD) OA Clinical Practice Guidelines (CPG) Work Group decided upon a “Weak for” recommendation and suggest offering intra-articular viscosupplementation injection(s) for patients with persistent pain due to OA of the knee inadequately relieved by other interventions. Recent evidence comparing viscosupplementation injections to corticosteroid injections found that corticosteroid injections improved the short-term (1 month) visual analog scale (VAS) pain scores better than viscosupplementation injections, but that they are equivalent at 3 months, and viscosupplementation injections provided statistically significant improvement in VAS pain scores compared to corticosteroid injections at 6, 9, and 12 months. Further, they shared similar functional improvements in range of motion at 3 and 6 months and similar risk profiles.¹⁸

Analysis of Evidence

The analysis of evidence reviewed for the use of HA injections for knee OA included a literature review from RCTs and meta-analyses, retrospective observational study design, and evidence based clinical practice guidelines from the AAOS and the ACR and the Arthritis Foundation and the VA/DoD OA CPG Work Group. The results of an analysis of literature reviewed to determine the strength of evidence in support of the efficacy and safety of intra-articular HA showed that intra-articular HA provides a moderate symptomatic benefit in knee OA patients and without safety concerns.³

The Evidence-Based Clinical Practice Guidelines from the AAOS concluded that viscosupplementation can represent a viable option for some patients that failed other treatments when appropriately indicated. HA intra-articular injection(s) is not recommended for routine use in the treatment of symptomatic OA of the knee.⁴ The HA recommendation was downgraded to Moderate Strength of recommendation due to lack of generalized results.⁴

Literature evaluating pain control and function concluded that intra-articular HA results in improvements in knee pain and function that can persist for up to 26 weeks in comparison with other treatment modalities.^6,8

The systematic review by the TAP concluded that trials enrolling older participants showed a small, statistically significant effect of HA on function and relatively few serious adverse events.¹

The Evidence Based Guideline from the ACR and the Arthritis Foundation stated "a conditional recommendation against is consistent with the use of HA injections, in the context of shared decision making that recognizes the limited evidence of benefit of this treatment, when other alternatives have been exhausted or failed to provide satisfactory benefit."²

Literature evaluating the efficacy and safety of repeated courses of intra-articular HA injection therapy in knee OA patients concluded that repeated courses of intra-articular HA injections are an effective and safe treatment for knee OA.¹⁶

The AMSSM recommends the use of HA for the appropriate patients with knee OA. “We RECOMMEND viscosupplementation injections for K-L grade ll-lll knee OA in those patients above the age of 60 years based on HIGH quality evidence demonstrating benefit using OMERACT-OARSI Responder Rating.” But the evidence should be downgraded because of indirectness for those younger than 60 years. “We SUGGEST viscosupplementation injections for knee OA for those under the age of 60 years based on MODERATE quality evidence due to response of treatment in those over 60 years of age.”¹⁴

The VA/DoD OA CPG Work Group decided upon a “Weak for” recommendation and suggest offering intra-articular viscosupplementation injection(s) for patients with persistent pain due to OA of the knee inadequately relieved by other interventions.¹⁸

In the United States (U.S.), osteoarthritis (OA) is the most common type of arthritis and joint disorder, with the knee being the most frequently involved symptomatic joint.⁷

Degenerative joint disease (usually termed OA) of the knee is a condition characterized by the progressive destruction of the articular cartilage that lines the knee joints, the subchondral bone surfaces, and synovium, accompanied by pain, immobility, and reduction in function and the ability to complete activities of daily living (ADL).¹ Knee OA is a chronic debilitating condition - predominantly occurring among the elderly - that affects a large share of the population worldwide. It is the predominant form of arthritis and the leading cause of disability in the U.S.⁵

Hyaluronic acid (HA) is a component of synovial fluid, which lubricates the joint and absorbs shock. HA is a glycosaminoglycan molecule within the knee joint where it provides viscoelastic properties to synovial fluid.³ HA is a glycosaminoglycan that occurs naturally within the synovial fluid of the knee, providing lubrication of the joint and protecting the cartilage from mechanical degradation. HA has been shown to provide anti-inflammatory and chondroprotective effects, increase proteoglycan and HA synthesis, and reduce nerve impulses and nerve sensitivity associated with OA pain.¹⁶ HA production is generally reduced and may be of poorer quality with OA, which may exacerbate inflammation. Intra-articular HA aims to replace depleted or poor-quality HA in the joint. HA is available commercially prepared and ready for injection. HA products differ by molecular weight and cross-linkage.

HA injections reduce cartilage breakdown that results from a loss of cartilage oligomeric matrix protein and also reduces inflammatory cytokines such as interleukin-1.⁷

HA is also known as Hyaluronan or Hyaluronate. Intra-articular injection of HA is also known as viscosupplementation. Viscosupplementation is the injection of an intra-articular compound made of high molecular weight fluid containing hylan products (derivative of hyaluronan) that essentially functions as a viscoelastic glycosaminoglycan.⁸

Patients with OA of the knee who are not responsive to conservative treatments, may be candidates for intra-articular HA for treatment of knee OA. There are several viscosupplementation products (such as Euflexxa^®, Durolane^®, Gel-One^®, GenVisc^® 850, Gelsyn-3^®, Hyalgan^®, Hymovis^®, Monovisc^®, Orthovisc^®, Supartz FX^®, Synvisc^®, Synvisc-One^®, SynoJoynt™, Visco-3™, TriVisc^®, and Triluron^®) that have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of pain associated with OA of the knee who have failed to respond adequately to conservative non-pharmacologic therapy and simple analgesics (e.g., acetaminophen).

Covered Indications

Various Hyaluronan preparations (viscosupplementation) for intra-articular injections of the knee are considered reasonable and necessary when ALL of the following criteria documented in the medical record are met:

1. Symptomatic OA of the knee. Pain that interferes with functional activities (such as, ambulation and prolonged standing).

2. The diagnosis is supported by radiographic evidence of OA of the knee, for example, joint space narrowing, subchondral sclerosis, osteophytes, and subchondral cysts.

3. Trial and failure or contraindication of at least 3 months of conservative therapy:

• Non-pharmacologic therapy (e.g., physical therapy, exercise, weight management, self-management programs, knee brace, cane)
• Pharmacologic therapy (e.g., acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) (oral, topical), topical capsaicin)

4. Failure of or contraindication to intra-articular glucocorticoid injections.

For patients who have responded to a prior series, a REPEAT* series of viscosupplement therapy is considered reasonable and necessary when ALL of the following are met:

• Patient continues to meet initial criteria
• Symptoms have recurred
• Patient has experienced improvement in pain and functional capacity following the previous series of injections
• At least 6 months have elapsed since the prior series of injections

* A series is defined as a set of injections for each joint and each treatment as per the FDA prescribing information

Limitations

Services that are not reasonable and necessary and cannot be covered by Medicare are the following:

1. The dose and frequency of administration should be consistent with the FDA approved labeling. Doses and frequencies that exceed the FDA recommended dosage/frequency as per the prescribing information, are considered not reasonable and necessary and not covered by Medicare.

2. Initiation of a repeat series of treatment when at least 6 months have not elapsed since the prior series of injections is considered not reasonable and necessary and not covered.

3. It is considered not reasonable and necessary as the initial treatment of OA of the knee.

4. It is contraindicated with infections or skin disease in the area of the injection site or joint and considered not reasonable and necessary and not covered by Medicare.

5. It is contraindicated to administer these products if you are allergic to hyaluronate products.

6. A diagnosis other than OA is considered not reasonable and necessary and not covered by Medicare.

7. When there was no improvement in knee pain and functional improvement from a previous series of injections, a repeat series of injections will be considered not reasonable and necessary and will not be covered.

8. Imaging procedures for the purpose of needle guidance that may be considered reasonable and necessary are ultrasound or fluoroscopy. The documentation must support why imaging is needed for needle guidance and insertion. Other imaging modalities (e.g., computed tomography (CT) scan, magnetic resonance imaging (MRI), arthrography) for the purpose of needle guidance and insertion will be considered not reasonable and necessary and not covered by Medicare.