Compliance with the provisions in this policy may be monitored and addressed
through post payment data analysis and subsequent medical review audits.

**History/Background and/or General Information**

**HYALUR** onic acid, also known as **HYALUR** onan or **HYALUR** onate, is a
naturally occurring substance found in the synovial fluid surrounding joints.
Osteoarthritic joints are found to have lower concentrations of **HYALUR**
onic acid.1 Intra-articular injection of **HYALUR** onic acid, also known as
viscosupplementation, has been proposed as a means of restoring the normal
viscoelasticity of the synovial fluid in individuals with osteoarthritis.

Viscosupplementation is most commonly used to treat symptoms of osteoarthritis
of the knee. Osteoarthritis (OA) results from articular cartilage failure due
to the complex interplay of genetic, metabolic, biochemical and biomechanical
factors with a secondary component of inflammation. In most patients the
initiating mechanism is damage to the articular cartilage either as a single
large injury or a series of repeated smaller injuries. The primary symptom of
osteoarthritis of the knee is pain, however, because cartilage is aneural,
significant radiographic findings are often noted in asymptomatic individuals
imaged for other reasons.

Typical candidates for viscosupplementation are those with knee osteoarthritis
who have failed to improve with other non-surgical treatments. Several
synthetic preparations of **HYALUR** onic acid-based polymers have been
approved by the U.S. Food and Drug Administration (FDA) and are indicated for
the treatment of pain in OA of the knee in patients who have failed to respond
adequately to conservative non-pharmacologic therapy and simple analgesics
(e.g., acetaminophen) or non-steroidal anti-inflammatory drugs (NSAIDS).2

By adding **HYALUR** onic acid to the existing joint fluid of an
osteoarthritic knee, the goal is to:

  * Facilitate better knee movement
  * Reduce pain
  * Perhaps slow osteoarthritis progression3

The most recent research, however, has not found viscosupplementation to be
effective at significantly reducing pain or improving function. Although some
patients report pain relief with the procedure, others are not helped by the
injections.1

**Covered Indications**

Viscosupplementation therapy for the knee via intra-articular injections of
**HYALUR** onic preparations will be considered medically reasonable and
necessary when **ALL** of the following conditions are met:

  1. The patient is symptomatic. Such symptoms may include pain which interferes with the activities of daily living such as ambulation and prolonged standing, or pain interrupting sleep, crepitus, and/or knee stiffness.
  2. The clinical diagnosis is supported by radiologic evidence of osteoarthritis of the knee such as joint space narrowing, subchondral sclerosis, osteophytes and sub-chondral cysts.
  3. If appropriate, other diagnoses have been excluded by appropriate evaluation and management services, laboratory and imaging studies (i.e., the pain and functional disability is not considered likely to be due to a diagnosis other than osteoarthritis of the knee).
  4. The patient has failed at least three months of conservative therapy. Conservative therapy is defined as: 
    * Nonpharmacologic therapy (such as but not limited to home exercise program, education, weight loss, physical therapy if indicated); and
    * If not contraindicated, pharmacologic therapy (e.g., acetaminophen, nonsteroidal inflammatory drugs (NSAIDS) (oral, topical), and topical capsaicin)
  5. The patient has failed to respond to aspiration of the knee when effusion is present and intra-articular corticosteroid injection therapy when inflammation is a significant component of the patient's symptoms and intra-articular corticosteroids are not contraindicated.

A **repeat series*** of **HYALUR** onan knee injection(s) for patients who
have responded to a prior series is considered to be reasonable and necessary
under the following circumstances:

  * Symptoms have recurred **AND** ,
  * At least six months have elapsed since the prior series of injections **AND** ,
  * There was significant improvement in pain and functional capacity achieved with the prior series of injections using a standardized assessment tool **AND**
  * Patient continues to meet initial criteria

***Note:** A series is defined as a set of injections for each joint and each
treatment as per FDA prescribing information (initial or repeat).

**Limitations**  
The following are considered not reasonable and necessary and therefore will
be denied:

  1. Drugs and biologicals and other products approved for marketing by the FDA are considered safe and effective when used for indications specified on the labeling. The labeling lists the safe and effective, i.e., medically reasonable and necessary dosage and frequency. Therefore, doses and frequencies that exceed the accepted standard of recommended dosage and/or frequency, as described in the package insert, are considered not reasonable and necessary and therefore, not subject to coverage.
  2. Intra-articular injections of other therapeutic agents, such as corticosteroids, should not be performed in the same knee during the course of viscosupplementation therapy unless there is documented medical necessity (e.g., for documented reactions requiring the use of the additional therapeutic agent).
  3. Viscosupplementation of joints other than the knee(s) are considered not reasonable and necessary and are not subject to coverage.
  4. Imaging procedures (e.g., arthrography, CT scan, MRI) for the purpose of visualization of the knee to provide guidance for needle placement are considered not medically reasonable and necessary and will not be covered. The only imaging procedures that may be considered reasonable and necessary for the purpose of needle guidance for viscosupplementation are fluoroscopy or ultrasound. If needle guidance is utilized, the documentation must support that the presentation of the patient's affected knee on the day of the procedure makes needle insertion problematic. Routine use of fluoroscopy or ultrasound guidance may result in a pre-payment medical review of records. No other imaging modality for the purpose of needle guidance and placement will be covered. The imaging modality used for the purpose of needle guidance must be reported appropriately and in conjunction with the appropriate intra-articular injection procedure code for the knee. For coding information on the use of imaging procedures with viscosupplementation of the knee, please refer to the companion Article A56157, Billing and Coding: Intraarticular Knee Injections of Hyaluronan.
  5. If the **HYALUR** onan preparation is denied, then any associated procedure code(s) (e.g., intra-articular injection, fluoroscopy, ultrasound) would be considered not medically reasonable and necessary.
  6. The course of treatment must consist of the use of one agent for the entire course of treatment. Therefore, initiating a course of treatment with one agent, then switching before completion to a different agent is considered not medically reasonable and necessary. Example: Treatment is initiated with Synvisc. After the application of two doses, the provider switches to Synvisc-One. The Synvisc-One would not be considered medically reasonable and necessary.
  7. Coverage of viscosupplementation therapy of the knee assumes that knee arthroplasty is not being considered as a current treatment option.
  8. Viscosupplementation is considered not medically reasonable and necessary following total or partial knee arthroplasty.
  9. Viscosupplementation is considered not medically reasonable and necessary at the end of a knee surgical procedure or during the postoperative period following a knee surgical procedure (e.g., anterior cruciate ligament [ACL] reconstruction or arthroscopic meniscectomy). It would be expected that use of viscosupplementation would not be initiated until after the patient has made a full recovery from the knee surgery (individualized for each patient); and the patient is symptomatic with a diagnosis of osteoarthritis; and clinical presentation meets the covered indications as stated.
  10. Viscosupplementation is considered not medically reasonable and necessary and will not be covered for the any of the following: 
    * When the diagnosis is anything other than osteoarthritis
    * As the initial treatment of osteoarthritis of the knee
    * When failure of/or contraindication to conservative therapy and/or corticosteroid injections are not documented in the medical record
    * When a repeat series of injections is initiated prior to six months after completion of the previous course of treatment
    * When a repeat series of injections is administered when there was no symptomatic/functional improvement evidenced from the previous series of injections
    * Topical application of hyaluronate preparations

**Provider Qualifications**

Services will be considered medically reasonable and necessary only if both of
the following criteria are met:

  * All aspects of the procedure and its related care are within the scope of practice of the provider's professional licensure; and
  * All procedures are performed by appropriately trained providers in the appropriate setting. Patient safety and quality of care mandate that healthcare professionals who perform intra-articular injections for treatment of osteoarthritis of the knee are appropriately trained and are competent to perform all aspects of these procedures safely and effectively. The core curriculum of any training program should include the performance and management of the procedures addressed in this policy with documentation of trainee competency assessment included by formal examination and case history document review.

*At a minimum, training must cover and develop an understanding of anatomy and drug pharmacodynamics and kinetics, proficiency in evaluation, diagnosis and management of diseases necessitating the procedures, technical performance of the procedure and performing and interpreting medically reasonable imaging modalities required for procedure performance (imaging technique, contrast material use, and image interpretation) as well as the evaluation, diagnosis and management of potential complications from the intervention.

Acceptable training or certification may be evidenced by any one of the
following means:

  1. Satisfactory completion of an Accreditation Council for Graduate Medical Education (ACGME) or American Osteopathic Association (AOA) accredited residency and/or fellowship program in a relevant specialty; or
  2. Board certification in a relevant specialty by an American Board of Medical Specialties (ABMS) member board or equivalent AOA board; or
  3. Satisfactory completion of an accredited non-physician practitioner educational program that provides substantially equal content and scope as those mentioned in bullets 1 or 2 above and includes the minimum requirements stated in the preceding paragraph (see * above), with trainee competency directly assessed by state licensure examination or certification examination by a nationally recognized accrediting agency and maintenance of a case log of procedures performed; or
  4. Demonstration of satisfactory performance of the specific services in this policy on a regular basis over the five years immediately preceding implementation of this policy. Medicare considers an average of ten services per month to meet this requirement, and may be substantiated by Medicare or other payer claim history supported by patient medical records of appropriate care, procedural performance and outcomes.

Reimbursement for procedures utilizing imaging may be made to providers who
meet training requirements for the procedures in this policy when permitted
under relevant state professional practice acts.

Documentation of training and licensures must be made available to Medicare
upon request.

Please refer to the Local Coverage Article: Billing and Coding: Intraarticular
Knee Injections of Hyaluronan , A56157, for coding guidelines and drug wastage
information.

**Notice:** Services performed for any given diagnosis must meet all the
indications and limitations stated in this policy, the general requirements
for medical necessity as stated in CMS payment policy manuals, any and all
existing CMS national coverage determinations, and all Medicare payment rules.

The redetermination process may be utilized for consideration of services
performed outside of the reasonable and necessary requirements in this LCD.

**Technology Assessment Systematic Review**

Newberry et al4 conducted a systematic review for effectiveness of **HYALUR**
onic acid in the treatment of severe degenerative joint disease (DJD) 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 intraarticular injections of **HYALUR** onic acid (HA) in individuals
with degenerative joint disease (osteoarthritis [OA]) of the knee improve
function and quality of life (QoL) and that they delay or prevent the need for
total knee replacement (TKR), specifically for individuals age 65 and over.
The results of the systematic review were as follows: Only one randomized
controlled trial (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; two 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 ten
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 months' 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 one product over another. Three RCTs
that compared changes in QoL/Health-Related (HR) 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.

The authors 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 using HA. Studies that can compare large numbers of treated
and untreated individuals, preferably with a randomized design, are needed to
answer this question.

**Evidence-Based Guidelines**

The Department of Veterans Affairs (VA) and The Department of Defense (DoD)
Evidence Based Clinical Practice Guideline for Non-surgical Management of the
Hip and Knee Osteoarthritis Guideline Summary5 states there is insufficient
evidence to recommend for or against the use of intra-articular **HYALUR**
onate/hylan injection in patients with osteoarthritis of the knee; however, it
may be considered for patients who have not responded adequately to
nonpharmacologic measures and who have an inadequate response, intolerable
adverse events, or contraindications to other pharmacologic therapies.

The National Institute for Health and Care Excellence (NICE) Clinical
Guideline Osteoarthritis: care and management6 recommendations include: do not
offer intra-articular **HYALUR** onan injections for the management of
osteoarthritis.

The American Academy of Orthopaedic Surgeons (AAOS) Treatment of
Osteoarthritis of the Knee: Evidence-Based Guideline, 2nd Edition7, is based
on a systematic review of the current scientific and clinical research. This
guideline contains 15 recommendations, replaces the 2008 AAOS clinical
practice guideline, and was reevaluated earlier than the 5-year recommendation
of the National Guideline Clearinghouse because of methodologic concerns
regarding the evidence used in the first guideline. The current guideline does
not support the use of viscosupplementation for the treatment of
osteoarthritis of the knee. In addition, the work group highlighted the need
for better research in the treatment of knee osteoarthritis.

Hochberg et al8 (American College of Rheumatology 2012 recommendations for the
use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the
hand, hip, and knee) conditionally recommended for the initial management of
patients with knee OA included acetaminophen, oral and topical NSAIDs,
tramadol, and intraarticular corticosteroid injections. Intraarticular
**HYALUR** onate injections, duloxetine, and opioids were conditionally
recommended in patients who had an inadequate response to initial therapy.

**Published Literature**

Filardo et al9 conducted a double-blind randomized controlled trial to
evaluate the effects, in terms of pain control and functional recovery,
provided by a single HA injection performed at the end of arthroscopic
meniscectomy. The results showed no major adverse events were reported using
HA postoperatively. A statistically significant increase in all the clinical
scores was reported in both treatment groups, but no significant intergroup
difference was documented at any follow-up evaluation. No difference was
observed also in the objective measurements. The mean time to return to full
sports activity was not different between groups, and a comparable
satisfaction rate was recorded in both treatment groups. The authors concluded
that early postoperative viscosupplementation did not provide significant
clinical benefits after arthroscopic meniscectomy. Despite the lack of major
adverse events, the administration of a single HA injection at the end of the
surgical procedure is not a successful strategy to provide either faster
functional recovery or symptomatic improvement after meniscectomy.

DiMartino et al10 conducted a double-blind, randomized controlled trial to
evaluate pain control and functional recovery provided by a single injection
of HA performed the day after anterior cruciate ligament (ACL) reconstruction.
The results showed no severe adverse events were documented after early
viscosupplementation. A significant improvement was documented in both
treatment groups. Significant differences were documented in the transpatellar
circumference at 60 days and in active range of motion (ROM) at 30 days
postoperatively; patients who received HA had better values compared with the
placebo group (P equal to .022 and .027, respectively). No statistically
relevant intergroup differences were found in the clinical scores. The authors
concluded that the study documented no adverse events and had some positive
findings in terms of active ROM recovery and transpatellar circumference
reduction. However, the early postoperative application of
viscosupplementation did not lead to significant improvement in clinical
scores after ACL reconstruction.

Berkoff et al11 conducted a review to determine the effect of ultrasound
guidance on the accuracy of needle placement, clinical outcomes, and cost-
effectiveness in comparison with anatomical landmark-guided intra-articular
large joint injections, with particular emphasis on the knee. A total of 13
relevant studies were identified; five studied the knee, seven studied the
shoulder, one used both the knee and shoulder, and none studied the hip.
Ultrasound was used in seven studies; the remaining studies utilized air
arthrography, fluoroscopy, magnetic resonance arthrography, or magnetic
resonance imaging. Across all studies (using all imaging modalities and all
joints), needle placement accuracy ranged from 63% to 100% with ultrasound and
from 39% to 100% with conventional anatomical guidance. Imaging guidance
improved the accuracy of intra-articular injections of the knee (96.7% versus
81.0%, P less than 0.001) and shoulder (97.3% versus 65.4%, P less than
0.001). In particular, ultrasound guidance of knee injections resulted in
better accuracy than anatomical guidance (95.8% versus 77.8%, P less than
0.001), yielding an odds ratio of 6.4 (95% confidence interval 2.9-14).
Ultrasound guidance notably improves injection accuracy in the target intra-
articular joint space of large joints including the knee. The enhanced
injection accuracy achieved with ultrasound needle guidance directly improves
patient-reported clinical outcomes and cost-effectiveness.

Various polymers of **HYALUR** onic acid have been approved and marketed as
implanted prosthetic devices. Clinical practice guidelines for the treatment
of knee osteoarthritis have conflicting recommendations for intra-articular
**HYALUR** onic acid treatment for knee osteoarthritis.12 The systematic
review by the technology assessment program4 reported a small, statistically
significant effect of HA on function. Clinical studies of sodium **HYALUR**
onate and hylan G-F 20 have demonstrated that injection of these agents into
the joint space of osteoarthritic knees is sometimes marginally more effective
than placebo procedures in reduction of pain and improvement in functional
capacity in some patients. These marginal beneficial results are more
pronounced with the larger molecular weight compound hylan G-F 20. There is no
data indicating that these agents reverse or retard the osteoarthritic process
in the injected joints. The long-term effects of repeated injections are
unknown.

Literature evaluating pain control and functional recovery of
viscosupplementation performed at the end of arthroscopic meniscectomy or in
the postoperative period after ACL reconstruction does not demonstrate
significant clinical benefits.9-10

Literature suggests that fluoroscopy or ultrasound guidance may improve
injection accuracy in the target intra-articular joint space of large joints
including the knee. The use of other imaging procedures for viscosupplement
injections has not been established as having an improvement on health
outcomes.