**VISCOSUPPLEMENTATION for Osteoarthritis of the Knee:**

**Intra-Articular Administration of Hyaluronan (Hyaluronic Acid) and
Hylan G-F 20 Products**

**VHA Pharmacy Benefits Management Services and the Medical Advisory
Panel**

**[Executive Summary]{.underline}**

In this review, the efficacy and safety of intra-articular
administration of hyaluronic acid (HA) or hylan (chemically cross-linked
hyaluronan chains) is explored as a treatment for osteoarthritis of the
knee. All five agents are FDA approved as "Biologic Devices" and are
indicated in patients with OA of the knee who have not responded
sufficiently to non-pharmacologic interventions (e.g. weight loss,
exercise, etc.) as well as simple analgesics (e.g. acetaminophen). In
appropriate candidates, a course of treatment will involve between 3 and
5 intra-articular injections depending upon the product used.

[Efficacy:]{.underline}

-   There are seven meta-analyses examining the treatment effect of
    intra-articular (IA) administration of hyaluronic (HA) or hylan. Six
    of the meta-analyses compared the effect of HA or hylan to placebo
    while the seventh compared pooled HA data to hylan. In four of the
    six analyses, a treatment benefit of HA or hylan versus placebo was
    observed but no significant effect was seen in two of the
    meta-analyses. At least two authors commented on the large observed
    IA placebo effect. Generally, all seven authors noted the quality of
    the evidence for this treatment to be of poor or unsatisfactory
    quality. The authors state that additional well designed clinical
    trials are needed to help identify those candidates that may most
    benefit from this treatment.

-   In the one meta-analysis comparing HA to hylan, there was no
    efficacy advantage of either group of agents. However, the relative
    risk for experiencing an adverse event, flare or joint effusion was
    increased in the hylan recipients.

-   The American Academy of Orthopaedic Surgeons (AAOS), American
    College of Rheumatology (ACR), American Pain Society and the
    European League Against Rheumatism (EULAR) recognize the use of IA
    HA or hylan in those patients having an inadequate response despite
    nonpharmacologic therapies, topical or simple analgesics or NSAIDs
    and/or those who are either unable to tolerate or unable to take
    NSAIDs/COX-2s. The National Center for Clinical Excellence (NICE)
    does not recognize this treatment for OA of the knee.

-   There is some evidence that patients with severe OA and/or those
    with significant joint space narrowing are less likely to experience
    a beneficial response.

-   There is some low level evidence for repeat treatment with Hyalgan
    or Synvisc in patients experiencing a prior beneficial response.
    There did not appear to be an increase in adverse events with repeat
    Hyalgan but there was an increase in adverse events in those having
    repeat treatments with Synvisc.

-   The evidence does not support routinely considering IA HA or hylan
    for joints other than the knee (e.g. hip, shoulder, ankle, etc.)
    since there a lack of data and many unanswered questions.

[Safety]{.underline}

-   IA HA or hylan is a very well tolerated treatment. The most common
    adverse effect is mild, short-lived pain and inflammation at the
    injection site. Two meta-analyses assessed the frequency of adverse
    events vs. placebo and noted only a slight increase in the risk of
    mild adverse events (RR 1.19, 95% CI 1.01-1.41 and RR 1.08, 95% CI
    1.01-1.15). In the meta-analysis by Wang, et al, major adverse
    events were noted in 3 of 1002 knees with HA (1-swelling,
    1-vasculitis, 1-hypersensitivity) and 1 of 139 knees with treated
    with cross-linked HA or hylan (painful acute local reaction).

-   There is no evidence to suggest a safety advantage of one HA product
    over the other. However, there is some lower level evidence to
    suggest a unique safety concern for rare localized inflammatory
    reactions, pseudosepsis, granulomatous inflammation and severe acute
    inflammatory reactions (SAIR) with the cross-linked hyaluronic acid
    (Hylan G-F 20 or Synvisc®). It is important to distinguish local
    pseudoseptic reactions from systemic anaphylactoid reactions that
    have been rarely reported after IA HA administration. Pseudosepsis
    or SAIR may occur with the second or third injection in a cycle or
    with subsequent courses of Hylan G-F 20 or Synvisc.

-   Although the mechanism for pseudosepsis is unknown, it has been
    hypothesized that the chemical cross-linking (using formaldehyde and
    vinylsulfone) used to increase the molecular weight of hylan may be
    responsible for its unique safety differences.

**[Introduction]{.underline}**

Osteoarthritis (OA) is the most common form of arthritis. It has been
estimated that approximately 21 million Americans have symptomatic
OA.^1-2^ Osteoarthritis is a chronic progressive condition characterized
by loss of cartilage, changes in synovial fluid within the affected
joint and increasing pain and disability. Available treatments are
limited to controlling associated pain and include exercise, weight
loss, bracing/orthotics, topical (e.g. NSAIDs or capsaicin) or simple
analgesics (e.g. acetaminophen) and nonsteroidal anti-inflammatory drugs
(NSAIDs/COX-2s). In those patients having an inadequate response or a
contraindication to these therapies and in whom surgery is not
appropriate or should be delayed, consideration may be given to the use
of intra-articular steroids or intra-articular hyaluronic acid or
hylans. The intra-articular administration of hyaluronic acid or hylan
(chemically cross-linked hyaluronan chains) is referred to as
viscosupplementation. Hyaluronic acid and hylan products for
intra-articular use are categorized as "Biologic Devices" by the FDA
with the first products gaining approval in 1997.

The purpose of this document is two-fold: 1) to review the efficacy and
safety of the available hyaluronans and hylans for the treatment of OA
of the knee; 2) to determine if there are substantive differences
between the available agents in terms of efficacy and safety. This
review will serve as a tool to determine whether contracting for one
agent is possible.

**^Table\ 1:\ Intra-Articular\ Hyaluronans\ (Hyaluronic\ Acid)\ and\ Hylan\ Products\ Available\ in\ the\ U.S.3-9^**

+--------------+----------+---------+---------+---------+------------+
| **Variable** | **Euf    | **Hya   | **Ortho | **Sup   | **         |
|              | lexxa®** | lgan®** | visc®** | artz®** | Synvisc®** |
+--------------+----------+---------+---------+---------+------------+
| *            | Ferring  | San     | Anika   | Se      | Genzyme    |
| *Manufacture | Pharmac  | ofi-Syn | Thera   | ikagaku |            |
| r/Licensee** | euticals | thelabo | peutics |         |            |
+--------------+----------+---------+---------+---------+------------+
| **D          | Sodium   | Sodium  | High    | Sodium  | Hylan G-F  |
| escription** | Hya      | Hyal    | mo      | Hyal    | 20         |
|              | luronate | uronate | lecular | uronate |            |
|              |          |         | weight  |         | (Hylan A   |
|              |          |         | hya     |         | fluid 80%  |
|              |          |         | luronan |         |            |
|              |          |         |         |         | Hylan B    |
|              |          |         |         |         | gel 20%)   |
+--------------+----------+---------+---------+---------+------------+
| **HA         | Biologic | Rooster | Rooster | Rooster | Cr         |
| Source+**    | ferme    | combs   | combs   | combs   | oss-linked |
|              | ntation/ |         |         |         | polymers   |
|              | b        |         |         |         | of         |
|              | acterial |         |         |         | hyaluronan |
|              | cells    |         |         |         | from       |
|              |          |         |         |         | rooster    |
|              |          |         |         |         | combs      |
+--------------+----------+---------+---------+---------+------------+
| **MW (x10^6^ | 2.4-3.6  | 0.5-0.7 | 1-2.9   | 0.6-1.2 | 6          |
| d)\***       |          |         |         |         |            |
+--------------+----------+---------+---------+---------+------------+
| **HA         | 10 mg/ml | 10      | 15      | 10      | 8 mg/ml    |
| Con          |          | mg/ml   | mg/ml   | mg/ml   |            |
| centration** |          |         |         |         |            |
+--------------+----------+---------+---------+---------+------------+
| **FDA        | December | May     | F       | January | August     |
| Approved**   | 2004     | 1997    | ebruary | 2001    | 1997       |
|              |          |         | 2004    |         |            |
+--------------+----------+---------+---------+---------+------------+

\* Molecular weight of human hyaluronic acid approximates 6 million
daltons; +HAs are naturally occurring (derived from rooster combs or
bacterial cells, purified and separated into non inflammatory form) or
synthetic, hylans.

HA=hyaluronic acid, MW=molecular weight

**[FDA Approved Indications and Off-Label Uses]{.underline}**

[FDA Approved:]{.underline}

a.  All of the available HA and hylan products are FDA approved for the
    treatment of pain associated with OA of the knee in patients who
    have not had an adequate response to non-pharmacologic conservative
    measures (e.g. weight loss, exercise, etc.) and simple analgesics
    (e.g. acetaminophen).

[Off-Label Use]{.underline}:

a.  There is some evidence for the use of viscosupplementation with HA
    products in the hip, ankle and shoulder joints.

b.  Retreatment with HA or hylan products in those patients having a
    favorable response to a previous cycle.

**[Current VA National Formulary Alternatives]{.underline}**

None of the HA or hylan products are currently on the VANF. Currently,
there are no alternative intra-articularly administered agents
considered to produce an equivalent, prolonged effect similar to the HAs
products. However, some may consider the use of intra-articular
corticosteroids to be an alternative since these agents are generally
attempted prior to HA products.

**[Methods]{.underline}**

1.  All of the available hyaluronic acid or hylan products approved by
    the FDA for intra-articular administration (viscosupplementation)
    are included in this review. The products are listed in alphabetical
    order as follows: Euflexxa®, Hyalgan®, Orthovisc®, Supartz®, and
    Synvisc®.

2.  A literature search was performed of MEDLINE (1966 through
    October 2007) using all of the names of the available products,
    osteoarthritis, arthritis, hip, knee, shoulder, ankle,
    viscosupplementation, hyaluronic acid, hyaluronans. Due to the large
    number of relatively small clinical trials, efficacy assessments are
    limited to use of meta-analyses or systematic reviews of
    viscosupplementation.

**[Pharmacology/Pharmacokinetics]{.underline}^9-12^**

[Pharmacology]{.underline}

Endogenous hyaluronic acid is produced by type B synoviocytes and
fibroblasts in the synovium and is released into the joint space.
Hyaluronic acid, within synovial fluid, has viscoelastic properties with
two distinct mechanical functions depending upon the shear force applied
during movement: 1) during slow movement, the fluid is more viscous and
acts as a joint lubricant; 2) during rapid movement, the fluid becomes
more elastic and acts as a shock absorber. In the normal knee, there is
approximately 2 milliliters of synovial fluid containing about 2.5-4
mg/ml of HA. The molecular weight of HA in the normal knee is about 6
million Daltons. In the osteoarthritic knee, the molecular weight and
concentration of HA is considerably reduced (as low as 2x10^5^d and 2-3
fold due to degradation and dilution, respectively). (The
elastoviscosity of HA is believed to be greater with higher molecular
weight hyaluronans.) The changes observed with osteoarthritis lead to a
marked impairment of the viscoelasticity of the joint resulting in
altered joint mechanics, reduced lubrication and further damage to the
diseased cartilage.

Aside from the viscoelastic properties of HA, observations from *in
vitro* studies suggest that there may be other possible mechanisms for
the efficacy of HA including inhibition of leukocyte chemotaxis,
inhibition of lymphocyte proliferation and inhibition of phagocytosis.
Additionally, enzymatic cartilage degradation, apoptosis, prostaglandin
E2 and certain arachidonic activities are inhibited in the presence of
HA. These biologic changes, induced by exogenous HA, can lead to
increased synthesis of endogenous HA, reduced degradation of cartilage
proteoglycans and collagen. The *in vitro* studies do demonstrate that
there are some differences between HAs of low to mid versus high
molecular weight in biologic activities that are affected. It has been
hypothesized that the high molecular weight HAs have a mechanical
advantage due to their higher viscoelasticity, but low to mid molecular
weight HAs may have an advantage in the receptor-mediated biologic
activities since they may be better able to penetrate and access
diseased tissues. However, clinical studies have not suggested an
advantage of one agent over the other.

Finally, data from *in vitro* and animal studies suggest that HA may be
disease modifying. However, there are no human studies to support this.

[Pharmacokinetics]{.underline}

In the process of movement, HA exits the joint capsule through the
lymphatic system; into the circulation; and then moves towards the liver
for conversion into water and carbon dioxide. This process is ongoing.
The duration of analgesia, achieved after a cycle of intra-articular
administration of HA or hylan, is about 3 to 6 months for most of the HA
or hylan products and even longer in some patients. However, because the
residence time of the HA or hylan within the joint is typically not more
than hours to days for most products and up to 30 days for hylan B gel,
it is believed that the benefit of HA or hylan is not purely mechanical,
as previously discussed. As a result, residence time within the joint
should not be used to determine superiority between products.

**Table 2: HA or Hylan Residence Time in Joint**

  -------------- --------------- -------------- ---------------- -------------- --------------
  **Variable**   **Euflexxa®**   **Hyalgan®**   **Orthovisc®**   **Supartz®**   **Synvisc®**

  **Residence    Hours to days   Hours to days  Hours to days    Hours to days  Hylan A-1
  Time in                                                                       week, Hylan
  Joint\***                                                                     B-30 days
  -------------- --------------- -------------- ---------------- -------------- --------------

\*Approximates

**[Dosage and Administration/Storage^3-8^]{.underline}**

All five products are indicated for intra-articular use. Strict, aseptic
technique must be used to reduce the risk of infection. If joint
effusion is present, it must be removed before administering HAs or
hylans. Each injection, within a cycle (3-5), is given at weekly
intervals until the cycle is complete. The effectiveness of
administering less than 3 injections per cycle (of any of the available
HA or hylan agents) is not known.

**Table 3**

+-------------+----------+----------+----------+----------+----------+
| *           | **Euf    | **Hy     | **Orth   | **Su     | **Sy     |
| *Variable** | lexxa®** | algan®** | ovisc®** | partz®** | nvisc®** |
+-------------+----------+----------+----------+----------+----------+
| **HA Dose   | 20 mg    | 20 mg    | 30 mg    | 25 mg    | 16 mg    |
| per         |          |          |          |          |          |
| Injection** |          |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+
| **Volume    | 2 ml     | 2 ml     | 2 ml     | 2.5 ml   | 2 ml     |
| Infused per |          |          |          |          |          |
| Injection** |          |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+
| **Number of | 3        | 3 or 5   | 3 or 4   | 3 or 5   | 3        |
| Injections  |          |          |          |          |          |
| per Course  |          |          |          |          |          |
| (Cycle)**   |          |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+
| **Duration  | 3 months | 3 Inj-   | 6 months | 3 inj-90 | 6 months |
| of Pain     |          | 60       |          | days\*\* |          |
| Relief**    |          | days\*\* |          |          |          |
|             |          |          |          | 6 months |          |
|             |          | 5 Inj:-6 |          |          |          |
|             |          | months   |          |          |          |
+-------------+----------+----------+----------+----------+----------+
| **Storage   | Store at | Store    | Store    | Store    | Store    |
| Requi       | 36-77ºF, | below    | below    | below    | below    |
| rements\*** | protect  | 77ºF,    | 77ºF at  | 77ºF     | 86ºF at  |
|             | from     | protect  | room     |          | room     |
|             | light    | from     | temp.    |          | temp.,   |
|             |          | light    |          |          | protect  |
|             |          |          |          |          | from     |
|             |          |          |          |          | light    |
+-------------+----------+----------+----------+----------+----------+
| **Pr        | If       | None     | None     | None     | None     |
| eparation** | refr     | stated   | stated   | stated   | stated   |
|             | igerated |          |          |          |          |
|             | remove   |          |          |          |          |
|             | from     |          |          |          |          |
|             | refr     |          |          |          |          |
|             | igerator |          |          |          |          |
|             | 20-30    |          |          |          |          |
|             | minutes  |          |          |          |          |
|             | prior to |          |          |          |          |
|             | use.     |          |          |          |          |
+-------------+----------+----------+----------+----------+----------+

**\***None of the products should be frozen and all should be stored in
their original packaging. \*\*Studies examining 3 vs. 5 injections
followed patients for 60 days (Hyalgan) and 90 days (Supartz).

**[Efficacy]{.underline}**

Due to the large number of clinical trials assessing the efficacy and
safety of IA HA or hylan, this section will be limited primarily to
inclusion of meta-analyses and systematic reviews of the efficacy and
safety of intra-articular HA or hylans for OA of the knee. Additionally,
evidence for the use of intra-articular HA or hylans in other joints
(e.g. hip, ankle, shoulder) and for repeat administration will be
included.

[Efficacy Measures]{.underline}^14^

The task force of the Osteoarthritis Research Society has recommended
the following pain measurement scales for assessment of OA of the knee.
They are listed in order of preference.

a.  Global knee pain score (visual analogue scale or Likert scale)

b.  Knee pain on walking (visual analogue scale or Likert scale)

c.  Western Ontario and McMaster Universities (WOMAC) Osteoarthritis
    Index: A self-administered, disease-specific measure of health
    status. The WOMAC queries for symptoms related to pain, stiffness
    and physical function in patients with OA of the hip and/or knee. It
    consists of 24 questions including five assessing for pain, two for
    stiffness, and seventeen for physical function. WOMAC is a valid and
    reliable measure of clinically significant changes in health status
    following surgical or pharmacologic interventions. Each question is
    assigned a score between 0 and 4. Scores from the 24 questions are
    summed. A higher score (highest possible score is 96) corresponds to
    less pain, stiffness and better function. A lower score (lowest
    possible score is 0) correlates with more pain, stiffness and lower
    function.

d.  Lequesne Index: An interview-style survey consisting of 10 questions
    administered to patients with OA of the knee. Five questions deal
    with pain or discomfort, one with furthest distance walked, and four
    dealing with activities of daily living. The questionnaire is scored
    from 0-24 with lower scores correlating with less impairment and
    higher scores with more functional impairment.

e.  Activity related knee pain (other than while walking).

Currently, there are seven published meta-analyses examining the
efficacy and safety of intra-articular (IA) administration of HA or
hylan for OA of the knee. In six of the seven meta-analyses^15-20^, the
effect of HA or hylan versus intra-articular placebo was explored and in
the seventh, the efficacy and safety of hylan was compared to pooled
HAs.^21^ Of the 6 trials comparing IA HA or hylan to placebo, at least a
modest benefit of IA HA was observed in 4 of the trials.^15-16,\ 18-19^
In the single meta-analysis directly comparing IA HA to IA hylan, the
authors did not find an efficacy advantage of hylan over HA but did
observe a safety advantage of HA vs. hylan.^21^

In general, each meta-analysis did identify heterogeneity among included
studies related to their treatment effect size (in the overall analysis
of all included trials). There are a number of factors that are believed
to be responsible for the differences in efficacy between included
studies as well as differences in the authors conclusions from each
meta-analysis, as follows: the decision to include published or both
published and unpublished data, allocation concealment, blinding of the
patient or treating provider, study size, varied population, overall
quality of the methodology of included studies and finally, variation in
the methodology used for each meta-analysis. Generally, the quality of
included clinical trials in the meta-analyses was considered to be poor
or unsatisfactory.

**Table 4: Meta-Analyses of Intra-Articular Administration of Hyaluronic
Acid or Hylan for OA of the Knee (detailed tables included in Appendix
A)^15-21,23^**

+---------+--------+----+-------------+-----------+-----------------+
| **M     | **C    | ** | **Results   | **Authors | **Comments**    |
| eta-Ana | ompara | \# | of the      | Overall   |                 |
| lysis** | tors** | In | Me          | Conc      |                 |
|         |        | cl | ta-Analysis | lusions** |                 |
|         |        | ud | (Primary    |           |                 |
|         |        | ed | Measure)**  |           |                 |
|         |        | S  |             |           |                 |
|         |        | tu |             |           |                 |
|         |        | di |             |           |                 |
|         |        | es |             |           |                 |
|         |        | ** |             |           |                 |
+---------+--------+----+-------------+-----------+-----------------+
| Lo, et  | IA HA  | 22 | Pooled      | Modest    | -Identified     |
| al^15^  | or     |    | effect size | benefit   | publication     |
|         | Hylan  |    | 0.32\* (95% | in OA of  | bias, effect    |
|         | vs. IA |    | CI          | the knee  | size may be     |
|         | p      |    | 0.17-0.27)  |           | overestimated.  |
|         | lacebo |    |             |           |                 |
|         |        |    |             |           | -Drop-out rate  |
|         |        |    |             |           | large in some   |
|         |        |    |             |           | trials          |
|         |        |    |             |           |                 |
|         |        |    |             |           | -Most trials no |
|         |        |    |             |           | intent to treat |
|         |        |    |             |           | stats           |
|         |        |    |             |           |                 |
|         |        |    |             |           | -Authors infer  |
|         |        |    |             |           | large placebo   |
|         |        |    |             |           | effect from     |
|         |        |    |             |           | knee aspiration |
|         |        |    |             |           |                 |
|         |        |    |             |           | -Unable to      |
|         |        |    |             |           | conclude        |
|         |        |    |             |           | advantage of HA |
|         |        |    |             |           | vs. Hylan       |
+---------+--------+----+-------------+-----------+-----------------+
| Wang,   | IA HA  | 20 | Pain with   | Efficacy  | -Those over 65  |
| et      | or     |    | activities  | and       | with near       |
| al^16^  | Hylan  |    | modified to | safety of | complete loss   |
|         | vs. IA |    | SPID 7.9%   | IA HAs    | of joint space, |
|         | p      |    | (95% CI     | are       | less likely to  |
|         | lacebo |    | 4.1-11.7%)  | b         | benefit         |
|         |        |    |             | eneficial |                 |
|         |        |    |             |           | -Indirect       |
|         |        |    |             |           | comparison of   |
|         |        |    |             |           | HAs to Hylan    |
|         |        |    |             |           | showed greater  |
|         |        |    |             |           | benefit with    |
|         |        |    |             |           | Hylan.          |
|         |        |    |             |           | Limitations: no |
|         |        |    |             |           | heterogeneity   |
|         |        |    |             |           | among HA        |
|         |        |    |             |           | trials, not     |
|         |        |    |             |           | tested for      |
|         |        |    |             |           | Hylan.          |
|         |        |    |             |           |                 |
|         |        |    |             |           | -One large      |
|         |        |    |             |           | hylan trial     |
|         |        |    |             |           | showing no      |
|         |        |    |             |           | benefit was not |
|         |        |    |             |           | included in     |
|         |        |    |             |           | meta-analysis   |
+---------+--------+----+-------------+-----------+-----------------+
| Arrich, | IA HA  | 22 | [Pain at    | Evidence  | -Low quality    |
| et      | or     |    | rest]{.     | does not  | studies         |
| al^17^  | Hylan  |    | underline}: | prove a   |                 |
|         | vs.    |    | 2-6 wks:    | clinical  | -Significant    |
|         | p      |    | sig.        | benefit   | heterogeneity   |
|         | lacebo |    | het         | but there | in effect sizes |
|         |        |    | erogeneity, | are more  | between studies |
|         |        |    | results not | minor     |                 |
|         |        |    | combined.   | ADEs.     |                 |
|         |        |    | No benefit  | Recommend |                 |
|         |        |    | at 10-14,   | a large   |                 |
|         |        |    | 22-30 or    | hig       |                 |
|         |        |    | 44-60 wks.  | h-quality |                 |
|         |        |    |             | trial be  |                 |
|         |        |    | [Pain       | c         |                 |
|         |        |    | during or   | onducted. |                 |
|         |        |    | after       |           |                 |
|         |        |    | exercise]{. | (No       |                 |
|         |        |    | underline}: | benefit   |                 |
|         |        |    | 2-6 wks:    | of IA HA  |                 |
|         |        |    | sig.        | or hylan  |                 |
|         |        |    | het         | for pain  |                 |
|         |        |    | erogeneity, | at rest   |                 |
|         |        |    | results not | or joint  |                 |
|         |        |    | combined.   | function. |                 |
|         |        |    | 10-14 and   | Small     |                 |
|         |        |    | 22-30 pain  | benefit   |                 |
|         |        |    | on VAS      | noted in  |                 |
|         |        |    | reduced 4.3 | pain with |                 |
|         |        |    | and 7.2 in  | movement) |                 |
|         |        |    | favor of    |           |                 |
|         |        |    | treatment,  |           |                 |
|         |        |    | re          |           |                 |
|         |        |    | spectively. |           |                 |
|         |        |    | No          |           |                 |
|         |        |    | difference  |           |                 |
|         |        |    | at 44-60    |           |                 |
|         |        |    | wks.        |           |                 |
|         |        |    |             |           |                 |
|         |        |    | [Joint      |           |                 |
|         |        |    | function:]{ |           |                 |
|         |        |    | .underline} |           |                 |
|         |        |    | No benefit  |           |                 |
|         |        |    | of          |           |                 |
|         |        |    | treatment.  |           |                 |
+---------+--------+----+-------------+-----------+-----------------+
| M       | IA HA  | 11 | Reduced     | IA HA     | -Effect size    |
| odawal, | or     |    | pain using  | benefits  | was reduced in  |
| et      | Hylan  |    | VAS: 1      | patients  | good quality    |
| al^18^  | vs. IA |    | wk=4.4, 5-7 | at 5-7    | studies         |
|         | p      |    | wks=17.6,   | and 8-12  |                 |
|         | lacebo |    | 8-12        | wks after | -Hylan produced |
|         | (10    |    | wks=18.1,   | the last  | greater effect  |
|         | st     |    | 15-22       | i         | size but both   |
|         | udies) |    | wks=4.4     | njection. | trials were of  |
|         |        |    |             | No        | poor quality    |
|         |        |    |             | benefit   | and so authors  |
|         |        |    |             | at 1 wk   | are unable to   |
|         |        |    |             | or 15-22  | conclude an     |
|         |        |    |             | wks.      | advantage of    |
|         |        |    |             |           | hylan over HAs. |
|         |        |    |             |           |                 |
|         |        |    |             |           | -Data           |
|         |        |    |             |           | insufficient to |
|         |        |    |             |           | determine if    |
|         |        |    |             |           | severity of OA  |
|         |        |    |             |           | or other        |
|         |        |    |             |           | patient factors |
|         |        |    |             |           | have an affect  |
|         |        |    |             |           | on outcomes.    |
+---------+--------+----+-------------+-----------+-----------------+
| B       | IA HA  | 37 | Multiple    | [Sup      | -Authors        |
| ellamy, | or     |    | analyses.   | artz:]{.u | acknowledge     |
| et      | Hylan  |    | See details | nderline} | complexity of   |
| al^19^  | vs.    |    | in Appendix | Data      | conducting a    |
|         | p      |    | A.          | generally | review of this  |
|         | lacebo |    |             | support   | class of agents |
|         | or     |    | Results     | efficacy  | because of the  |
|         | active |    | separated   |           | vast number of  |
|         | tre    |    | by agent.   | [Eufl     | variables (e.g. |
|         | atment |    |             | exxa]{.un | study design,   |
|         | (st    |    |             | derline}: | population,     |
|         | eroids |    |             | Placebo-c | outcome         |
|         | or     |    |             | ontrolled | measures,       |
|         | N      |    |             | data      | observation     |
|         | SAIDs) |    |             | ins       | time intervals, |
|         |        |    |             | ufficient | comparator, HA  |
|         |        |    |             | to        | or hylan        |
|         |        |    |             | determine | product         |
|         |        |    |             | efficacy. | differences).   |
|         |        |    |             | Some      |                 |
|         |        |    |             | support   | -Data showed    |
|         |        |    |             | for       | similar         |
|         |        |    |             | safety.   | efficacy of IA  |
|         |        |    |             |           | HA or hylan to  |
|         |        |    |             | [Hya      | NSAIDs and were |
|         |        |    |             | lgan:]{.u | longer lasting  |
|         |        |    |             | nderline} | than IA         |
|         |        |    |             | Analysis  | steroids.       |
|         |        |    |             | strongly  |                 |
|         |        |    |             | supports  |                 |
|         |        |    |             | efficacy  |                 |
|         |        |    |             | and       |                 |
|         |        |    |             | safety.   |                 |
|         |        |    |             | Equal or  |                 |
|         |        |    |             | superior  |                 |
|         |        |    |             | to IA     |                 |
|         |        |    |             | steroids. |                 |
|         |        |    |             |           |                 |
|         |        |    |             | [Hylan    |                 |
|         |        |    |             | GF-20     |                 |
|         |        |    |             | (Synv     |                 |
|         |        |    |             | isc):]{.u |                 |
|         |        |    |             | nderline} |                 |
|         |        |    |             | Analysis  |                 |
|         |        |    |             | strongly  |                 |
|         |        |    |             | supports  |                 |
|         |        |    |             | efficacy  |                 |
|         |        |    |             | and       |                 |
|         |        |    |             | safety.   |                 |
|         |        |    |             | Superior  |                 |
|         |        |    |             | to IA     |                 |
|         |        |    |             | steroids. |                 |
|         |        |    |             |           |                 |
|         |        |    |             | [Ortho    |                 |
|         |        |    |             | visc:]{.u |                 |
|         |        |    |             | nderline} |                 |
|         |        |    |             | Data      |                 |
|         |        |    |             | support   |                 |
|         |        |    |             | the       |                 |
|         |        |    |             | efficacy  |                 |
|         |        |    |             | and       |                 |
|         |        |    |             | safety    |                 |
+---------+--------+----+-------------+-----------+-----------------+
| Medina, | IA HA  | 7  | [WOMAC:]{   | No        | -Effect sizes   |
| et      | or     |    | .underline} | s         | were not        |
| al^20^  | Hylan  |    | Pain=NS,    | ufficient | different       |
|         | vs. IA |    | Dis         | reason    | between placebo |
|         | p      |    | ability=NS, | either to | and baseline    |
|         | lacebo |    | Stiffn      | recommend | groups on       |
|         |        |    | ess=benefit | or not to | change from     |
|         |        |    | of HA or    | recommend | baseline to     |
|         |        |    | hylan       | IA HA for | post-treatment  |
|         |        |    |             | OA. (HA   |                 |
|         |        |    | [Lequesne   | may       | -Narrow         |
|         |        |    | Index:]{    | improve   | inclusion of    |
|         |        |    | .underline} | s         | studies         |
|         |        |    | Up to 6     | hort-term |                 |
|         |        |    | months      | relief of | -Conversion of  |
|         |        |    | post        | pain and  | data into a     |
|         |        |    | -injection: | func      | percent of the  |
|         |        |    | benefit of  | tionality | total possible  |
|         |        |    | HA or hylan | using the | score for each  |
|         |        |    |             | Lequesne  | outcome measure |
|         |        |    | 6 months or | index.    | using a method  |
|         |        |    | longer: NS  | Pain and  | that may not be |
|         |        |    |             | d         | valid.          |
|         |        |    |             | isability |                 |
|         |        |    |             | were not  |                 |
|         |        |    |             | improved  |                 |
|         |        |    |             | as        |                 |
|         |        |    |             | assessed  |                 |
|         |        |    |             | using     |                 |
|         |        |    |             | WOMAC.    |                 |
|         |        |    |             | Stiffness |                 |
|         |        |    |             | was       |                 |
|         |        |    |             | improved) |                 |
+---------+--------+----+-------------+-----------+-----------------+
| Reich   | IA HA  | 13 | [Pooled     | Analysis  | -Smaller effect |
| enbach, | vs IA  |    | effect      | does not  | sizes in trials |
| e       | Hylan  |    | size]{.     | support   | with adequate   |
| tal^21^ | (head  |    | underline}: | an        | allocation      |
|         | to     |    | (-)0.27     | advantage | concealment,    |
|         | head   |    | (95% CI     | of hylan  | blinding of     |
|         | st     |    | -0.55 to    | over HAs. | patients and    |
|         | udies) |    | 0.01) NS    | However,  | trials using    |
|         |        |    |             | their     | intent to treat |
|         |        |    | (A negative | analysis  | analysis.       |
|         |        |    | effect size | of ADEs,  |                 |
|         |        |    | indicates a | flares    | \- No impact on |
|         |        |    | superiority | and joint | effect size of  |
|         |        |    | of hylan    | effusions | avian vs.       |
|         |        |    | over HA. A  | does      | bacterial       |
|         |        |    | pooled      | de        | origin of HA or |
|         |        |    | effect size | monstrate | molecular       |
|         |        |    | of (-) 0.30 | a         | weight of HA vs |
|         |        |    | was         | potential | hylan.          |
|         |        |    | considered  | dis       |                 |
|         |        |    | clinically  | advantage | -High-degree of |
|         |        |    | relevant)   | of hylan  | heterogeneity   |
|         |        |    |             | over HAs. | when pooling    |
|         |        |    | [Adverse    |           | all studies.    |
|         |        |    | events:]{   |           |                 |
|         |        |    | .underline} |           | -When trial     |
|         |        |    |             |           | size was        |
|         |        |    | Local: RR   |           | considered,     |
|         |        |    | 1.91 (95%   |           | data from       |
|         |        |    | CI          |           | larger trials   |
|         |        |    | 1.04-3.39)  |           | favored HAs     |
|         |        |    | of hylan vs |           | while smaller   |
|         |        |    | HA          |           | trial favored   |
|         |        |    |             |           | hylan.          |
|         |        |    | Flares: RR  |           |                 |
|         |        |    | 2.04 (95%   |           | -Quality of     |
|         |        |    | CI          |           | included trials |
|         |        |    | 1.18-3.53   |           | was generally   |
|         |        |    | of hylan vs |           | poor            |
|         |        |    | HA          |           |                 |
|         |        |    |             |           |                 |
|         |        |    | Joint       |           |                 |
|         |        |    | Effusion:   |           |                 |
|         |        |    | 2.40 (95%   |           |                 |
|         |        |    | CI          |           |                 |
|         |        |    | 1.21-4.76)  |           |                 |
|         |        |    | of hylan vs |           |                 |
|         |        |    | HA          |           |                 |
+---------+--------+----+-------------+-----------+-----------------+

ADEs=adverse events, HA=hyaluronic acid, IA=intra-articular, NS=non
significant difference, SPID=sum of pain intensity difference,
VAS=visual analogue scale

\*Effect size: small effect size 0.2-0.5 is roughly similar to the
effect of NSAIDs, large effect size 1-1.8 is similar to that observed
with a knee replacement.

In the meta-analysis by Lo, et al^15^, the authors assert that there is
a large placebo effect with intra-articular aspiration of the knee. In
one assessment, the authors infer that nearly 80% of the observed
response seen with intra-articular HA results from knee
aspiration/injection and is not likely related to the injection
contents. Similarly, in the analysis by Medina, et al^20^, the effect
size from baseline to post-treatment was not different between IA HA and
IA placebo (both showing similar improvement from baseline).

[Efficacy Summary: Intra-Articular HA or Hylan for OA of the
Knee]{.underline}^15-20^

Of the 6 meta-analyses comparing IA HA or hylan to placebo, at least a
modest benefit of IA HA was observed in 4 of the trials in patients with
OA of the knee.^15-16,\ 18-19^ The remaining two meta-analysis found
minimal to no efficacy benefit of the HA or hylan vs. placebo.^17,20^
Overall, the authors conclude that the quality of the available data is
poor or unsatisfactory and at least two of the authors commented on a
sizable IA placebo effect.^15,20^

[Efficacy Summary: Comparison of Low Molecular Weight HA vs.
High-Molecular Weight Hylan for OA of the Knee]{.underline} ^19,21^

In the meta-analysis directly comparing IA HA to IA hylan, the authors
did not find an efficacy advantage of either hylan or HA but did observe
a safety disadvantage of hylan vs. HA.^21^

[**Off-Label** **Use:** Intra-Articular Administration of HA or Hylan
for OA of the Hip, Ankle or Shoulder]{.underline}

Generally, the use of viscosupplementation with HA or hylans for joints
other than the knee cannot be routinely recommended due to the poor
quality of the available evidence as well as the lack of evidence. As a
result, the best candidates for treatment, volume and frequency of
injections, administration technique, and whether or not ultrasound or
fluoroscopic guidance for injection is needed, etc. are unknown. (Note:
Intra-articular administration of HA or hylan for OA of the hip is most
often guided by fluoroscopy or ultrasound because of the greater
difficulty with intra-articular administration of the hip in comparison
to the knee).

[Hip:]{.underline}

At this time, most of the published literature related to IA
administration of HA or hylan for OA of the hip is in the form of
case-series or open-label experiences in a small number of
patients.^24-25^ There are, however, two systematic reviews examining
the available evidence (see table 5).^26-27^ Additionally, there are two
publications in which the efficacy of different HA and hylan products
are compared.^28-29^ In the study by Tikiz, et al,^28^ a low molecular
weight hyaluronic acid (Ostenil®) was compared to a high molecular
weight hylan (Synvisc®) in 43 patients with OA of the hip. Both groups
noted a reduction in pain as assessed using visual analogue scale (VAS),
WOMAC or Lequesne Index. There were no efficacy differences noted
between groups. Local adverse events were noted in 3/32 hips (9%)
treated with Ostenil and in 3/24 (12.5%) hips treated with Synvisc. In
the study by van den Bekerom, et al,^29^ 120 patients were stated to
have been consecutively given Adant (n=91), Synocrom (n=20) (neither
available in the US) or Synvisc (n=19). A statistically significant
reduction in pain was noted in both the Adant and Synocrom groups but
not the Synvisc group. However, the number of patients exposed to
Synvisc was lower than the other two groups and the difference between
groups was not statistically significant.

**Table 5: Intra-Articular Administration of HA or Hylan for OA of the
Hip**

+------------+----------+----------+----------+----------+----------+
| **Pub      | **\#     | **Study  | **Fi     | *        | **Co     |
| lication** | Included | C        | ndings** | *Authors | mments** |
|            | S        | haracter |          | Overall  |          |
|            | tudies** | istics** |          | Concl    |          |
|            |          |          |          | usions** |          |
+------------+----------+----------+----------+----------+----------+
| Con        | 9        | 8-uncon  | Hylan:   | In the   | 8/9      |
| rozier^26^ | studies  | trolled, | 5-OL     | absence  | studies  |
|            | (n=287   | OL; 1-R, | studies  | of       | were     |
|            | p        | DB       | (n-141): | pl       | uncon    |
|            | atients) |          | 50%      | acebo-co | trolled. |
|            |          |          | success  | ntrolled |          |
|            |          |          |          | studies, |          |
|            |          |          | HA (3-5  | effec    |          |
|            |          |          | inj,     | tiveness |          |
|            |          |          | n=44)    | of HA or |          |
|            |          |          | 68% of   | hylan    |          |
|            |          |          | patients | for OA   |          |
|            |          |          | r        | of the   |          |
|            |          |          | esponded | hip      |          |
|            |          |          |          | cannot   |          |
|            |          |          | HA (103  | be       |          |
|            |          |          | inj,     | co       |          |
|            |          |          | n=28),   | nfirmed. |          |
|            |          |          | weak     | However, |          |
|            |          |          | benefit. | unco     |          |
|            |          |          |          | ntrolled |          |
|            |          |          | Hylan    | data     |          |
|            |          |          | vs.      | support  |          |
|            |          |          | Durolane | a        |          |
|            |          |          | (not     | benefit. |          |
|            |          |          | a        | R, DB    |          |
|            |          |          | vailable | studies  |          |
|            |          |          | in US):  | are      |          |
|            |          |          | No       | needed.  |          |
|            |          |          | di       |          |          |
|            |          |          | fference |          |          |
+------------+----------+----------+----------+----------+----------+
| Van den    | 16       | 2-R, DB, | Hylan-8  | Due to   | -14/16   |
| B          | studies  | 13-case  | studi    | low      | studies  |
| ekerom^27^ | (n=509   | series,  | es-noted | level of | were     |
|            | p        | 1 not    | benefit. | e        | rated    |
|            | atients) | m        |          | vidence, | level IV |
|            |          | entioned | HA       | only     | e        |
|            |          |          | (Hy      | pre      | vidence. |
|            |          |          | algan)-2 | liminary |          |
|            |          |          | studi    | con      | -ADE     |
|            |          |          | es-noted | clusions | ranged   |
|            |          |          | benefit. | and      | from     |
|            |          |          |          | sug      | 10-30%   |
|            |          |          | 2        | gestions |          |
|            |          |          | studies  | for      | -ADEs    |
|            |          |          | compared | future   | did not  |
|            |          |          | Hylan    | study    | appear   |
|            |          |          | with     | are      | to       |
|            |          |          | HA-No    | made.    | increase |
|            |          |          | di       |          | with     |
|            |          |          | fference | In       | su       |
|            |          |          |          | jections | bsequent |
|            |          |          |          | cannot   | inj.     |
|            |          |          |          | be       |          |
|            |          |          |          | rec      | -T       |
|            |          |          |          | ommended | ransient |
|            |          |          |          | as       | hip pain |
|            |          |          |          | standard | with     |
|            |          |          |          | therapy  | inj.     |
|            |          |          |          | for hip  |          |
|            |          |          |          | OA.      | -No      |
|            |          |          |          |          | dif      |
|            |          |          |          |          | ferences |
|            |          |          |          |          | between  |
|            |          |          |          |          | products |
|            |          |          |          |          |          |
|            |          |          |          |          | -        |
|            |          |          |          |          | Patients |
|            |          |          |          |          | with     |
|            |          |          |          |          | mild to  |
|            |          |          |          |          | mod      |
|            |          |          |          |          | disease  |
|            |          |          |          |          | and      |
|            |          |          |          |          | those    |
|            |          |          |          |          | r        |
|            |          |          |          |          | eceiving |
|            |          |          |          |          | 4 inj    |
|            |          |          |          |          | exp      |
|            |          |          |          |          | erienced |
|            |          |          |          |          | the most |
|            |          |          |          |          | imp      |
|            |          |          |          |          | rovement |
|            |          |          |          |          | in       |
|            |          |          |          |          | s        |
|            |          |          |          |          | ymptoms. |
+------------+----------+----------+----------+----------+----------+

ADE=adverse effects, DB=double-blind, OL=open-label, R=randomized

[Ankle or Shoulder:]{.underline}^30-31^

There is a lack of published data related to the use of
viscosupplementation for joints other than the knee (e.g. ankle,
shoulder, temporal mandibular joint, etc.) and so the use of this
treatment cannot be routinely recommended for other joints. In addition,
there are many unanswered questions for use of this procedure in other
joints including the volume and frequency of injections, injection
technique, need for ultrasound or fluoroscopic guidance, etc.

[Repeat or Chronic Treatment with Intra-Articular Administration of HA
or Hylan]{.underline} ^32-33^

The efficacy and safety of repeated courses of HA or hylan was explored
in a paper by Pagnano, et al.^32^ In their review, the authors summarize
the available evidence for each product (See table six). Generally,
repeat cycles may be considered in those patients having a beneficial
response with a previous cycle and a desire to delay surgery. From the
available data (low level of evidence), adverse events do not appear to
increase with repeat cycles of HA, however, may increase with repeat
hylan cycles. In one retrospective review in a large orthopedic
practice, the incidence of local adverse events occurred in 3.4% of
patients with the first course, 13.1% with the second course and 17.3%
with the third course. The majority of adverse events were local and
considered to be mild to moderate and persisted for less than 48 hours.
The authors of the Pagnano paper also examined studies in which the
efficacy and safety of repeat treatment with Hyalgan® and Hylan GF-20®
were compared. One study was a retrospective review of 166 patients
receiving 2800 injections (142 received HA, 24 received Hylan). Severe
acute inflammatory reaction (SAIR) was reported in 16.3% of hylan
recipients vs. none of the HA patients. The second was an open-label
study in 61 patients randomized to HA or hylan. Although there were no
differences in efficacy between groups, pseudoseptic reactions were
reported in 10.3% of hylan vs. none of the HA recipients

**Table 6: Retreatment with HA or Hylan**

  ----------------- --------------- ------------------ ---------------- --------------- --------------
  **Retreatment**   **Euflexxa®**   **Hyalgan®**       **Orthovisc®**   **Supartz®**    **Synvisc®**

  **Clinical        N/A             6 Studies (1-RCT,  N/A              N/A             8 studies
  Studies**                         1-OL, 3 case                                        (8-case
                                    series,                                             series)
                                    1-retrospective)                                    

  **Number of       \--             2-8                \--              \--             2-4
  courses (from                                                                         
  studies above)**                                                                      

  **Increase in     \--             No                 \--              \--             Yes^32-33^
  ADEs with repeat                                                                      
  cycles**                                                                              

  **Product         Potential for   Statement          The              The safety and  Statement
  Labeling**        immune          regarding repeat   effectiveness    effectiveness   regarding
                    response, not   treatment was      has not been     of repeat       repeat
                    assessed in     removed.^32^       established for  cycles have not treatment was
                    humans. Safety                     more than 1      been            removed.^32^
                    and Efficacy                       treatment.       established.    
                    not                                                                 
                    established.                                                        
  ----------------- --------------- ------------------ ---------------- --------------- --------------

ADE=adverse event, N/A=not available, OL=open-label, RCT=randomized
controlled trial

**[Treatment guidelines/Place in Therapy]{.underline}**

In general, intra-articular administration of hyaluronic acid or hylan
can be considered in those patients who have mild to moderate
osteoarthritis of the knee with continued pain despite nonpharmacologic
and pharmacologic (topical NSAIDs, capsaicin, acetaminophen,
NSAIDs/COX-2s) approaches and/or in whom pharmacologic treatments
(NSAIDs/COX-2s) are either not appropriate due to the risk for ADEs or
the patient has experienced a prior intolerance to these agents. In
those patients with more severe or advanced disease and with significant
joint space narrowing, IA HA has been shown to have less of an effect.
However, there is a need for additional randomized, controlled clinical
trials to help determine the best candidate knees for treatment.

**Table 7: Recommendations for the Intra-Articular Administration of HA
or Hylan for Knee OA**

  --------------------- ------------------ --------------- --------------- ---------------- --------------
  **Guideline/Group**   **ACR 2000^34^**   **AAOS^35^**    **Am Pain       **EULAR          **NICE^38^**
                                                           Society^36^**   2003^37^**       

  **Summary**           An alternative     Mild to         HA or hylan can There is         IA HA or hylan
                        approach to the    moderate OA     be used in      evidence to      not recognized
                        use of oral agents pain despite    patients with   support the      as treatment
                        in the palliation  traditional non OA knee pain    efficacy of HA   for OA of the
                        of joint pain.     pharmacologic   unresponsive to in knee OA for   knee
                                           and             APAP, NSAIDs/   both pain        
                                           pharmacologic   Cox-2s or in    reduction and    
                                           treatments      those who       functional       
                                           and/or who are  cannot take     improvement and  
                                           intolerant of   these           may modify joint 
                                           these           medications.    structure        
                                           treatments.                                      

  **Recommended Place   In patients not    More studies    May be          HA was discussed \--
  in Therapy**          responding to      needed to help  considered at   prior to         
                        nonpharmacologic   determine most  any time during discussion of    
                        therapies and      appropriate     the course of   joint            
                        simple analgesics  candidates.     illness.        replacement and  
                        or in whom         However,                        prior to         
                        NSAIDs/COX-2s are  appears those                   corticosteroid   
                        not sufficient or  with                            discussion.      
                        contraindicated    mild-moderate                                    
                                           disease with                                     
                                           less JPN                                         
                                           benefited.                                       
  --------------------- ------------------ --------------- --------------- ---------------- --------------

AAOS=American Academy of Orthopaedic Surgeons, ACR=American College of
Rheumatology, EULAR=European League Against Rheumatism, JPN=joint space
narrowing, NICE=National Institute for Clinical Excellence (UK)

**[Adverse Events]{.underline}**

Intra-articular administration of HA or hylan is a well tolerated
treatment. The most common adverse event is mild, short-lived pain and
inflammation at the injection site. Two meta-analyses assessed the
frequency of adverse events vs. placebo and noted only a slight increase
in the risk of mild adverse events (RR 1.19, 95% CI 1.01-1.41^16^ and RR
1.08, 95% CI 1.01-1.15^17^) with treatment vs. placebo. In the
meta-analysis by Wang, et al,^16^ major adverse events were noted in 3
of 1002 knees with HA (1-severe swelling, 1-vasculitis,
1-hypersensitivity) and 1 of 139 knees treated with cross-linked HA or
hylan (painful acute local reaction).

There is no evidence to suggest a safety advantage of one HA product
over the other. However, there is some lower level evidence to suggest a
unique safety concern for rare localized inflammatory reactions,
pseudosepsis, granulomatous inflammation^47^ and severe acute
inflammatory reactions (SAIR) with the cross-linked hyaluronic acid
(Hylan G-F 20 or Synvisc®). It is important to distinguish local
pseudoseptic reactions from systemic anaphylactoid reactions that have
been rarely reported after IA HA administration.

**Serious Adverse Events**

There is accumulating evidence of a unique safety concern for rare
localized inflammatory reactions such as pseudosepsis and severe acute
inflammatory reactions (SAIR) with the cross-linked hyaluronan or hylan
product.^10,\ 32,\ 39-43^ Pseudosepsis presents within 1-3 days of the
injection as a severe inflammatory process of the joint with a large
joint effusion and marked pain. Evaluation of the patient involves a
differential diagnosis including true sepsis or inflammatory arthritis
and requires synovial aspiration and assessment. In pseudosepsis, joint
aspirates generally show a moderate cell count consisting of
eosinophils, neutrophils and macrophages and an absence of organisms or
calcium pyrophosphate crystals. Treatment is symptomatic and includes
rest, application of cold compresses, analgesics or NSAIDs and once
infection is ruled out, intra-articular steroids may be considered.

Pseudosepsis has been reported to occur upon the second or third
injection in a cycle or upon repeat courses with hylan. In one
review,^32^ the use of more than one cycle of HA or hylan was evaluated.
In that paper, the authors examined reports (n=2) in which the efficacy
and safety of repeat treatment with Hyalgan® and Hylan GF-20® were
compared. One of those reports was a retrospective review of 166
patients receiving 2800 injections (142 received HA, 24 received Hylan).
Severe acute inflammatory reaction (SAIR) was reported in 16.3% of hylan
recipients vs. none of the HA patients. The second was an open-label
study in 61 patients randomized to HA or hylan. Although there were no
differences in efficacy between groups, pseudoseptic reactions were
reported in 10.3% of hylan vs. none of the HA recipients.

The mechanism for this unique adverse event is unclear but some conclude
an immunologic response. However, a small prospective study comparing
aspirates in those with SAIRs after hylan vs. controls have indicated
their findings were more consistent with a cell-mediated
hypersensitivity reaction.^44^ To date, the other available hyaluronic
acid products have not been associated with this type of reaction. That
being said, there are two case reports of acute pseudoseptic arthritis
in patients who received HA products not available in the US (Curavisc®
and Ostenil®).^45-46^ It has been hypothesized that the chemical
cross-linking (using formaldehyde and vinylsulfone) used to increase the
molecular weight of hylan may be responsible for its unique safety
differences.

**[Precautions/Contraindications]{.underline}**

**Table 8: Precautions/Warnings**

  ------------------- --------------- -------------- ----------------- -------------- --------------
  **PRECAUTIONS**     **Euflexxa®**   **Hyalgan®**   **Orthovisc®**    **Supartz®**   **Synvisc®**

  **Effect of \<3 inj **NS**          **Y**          **Y**             **Y**          **Y**
  unknown**                                                                           

  **Strict aseptic    **Y**           **Y**          **Y**             **Y**          **Y**
  technique**                                                                         

  **Remove joint      **Y**           **Y**          **Y**             **Y**          **Y**
  effusion**                                                                          

  **Use Caution in    **No**          **Y**          Contraindicated   **Y**          **Y**
  those with allergy                                                                  
  to avian proteins,                                                                  
  feathers or eggs**                                                                  

  **Efficacy/Safety   **NS**          **Y**          **Y**             **Y**          **Y**
  in other joints not                                                                 
  established**                                                                       

  **Efficacy/Safety   **Y**           **Y**          **NS**            **Y**          Label
  of other IA agents                                                                  recommends
  given concomitantly                                                                 avoiding
  not known**                                                                         injecting
                                                                                      anesthetic or
                                                                                      other med into
                                                                                      knee joint
                                                                                      during Synvisc
                                                                                      since these
                                                                                      may dilute the
                                                                                      Synvisc and
                                                                                      alter
                                                                                      response.

  **Efficacy/Safety   **Y**           **Y**          **Y**             **Y**          **Y**
  in pregnant women                                                                   
  not established**                                                                   

  **Repeated          **Y**           **NS**         **NS**            **NS**         **NS**
  exposures may have                                                                  
  the potential for                                                                   
  an immune                                                                           
  response-not                                                                        
  assessed in                                                                         
  humans**                                                                            
  ------------------- --------------- -------------- ----------------- -------------- --------------

NS=not stated, Y=yes, listed as precaution/warning; No=no, not listed as
precaution or warning

**Table 9: Contraindications**

  ----------------------- --------------- ----------------- ---------------- -------------- --------------
  **CONTRAINDICATIONS**   **Euflexxa®**   **Hyalgan®**      **Orthovisc®**   **Supartz®**   **Synvisc®**

  **Known allergy to      **No**          **No**            **Y**            **No**         **No**
  avian proteins,                                                                           
  feathers and eggs**                                                                       

  **Known                 **Y**           **Y**             **Y**            **Y**          **Y**
  hypersensitivity or                                                                       
  allergy to                                                                                
  hyaluronans**                                                                             

  **Known knee joint      **Y**           Contraindicated   **Y**            **Y**          **Y**
  infection, skin disease                 in those with                                     
  or infection in the                     past and present                                  
  area of the injection                   infections or                                     
  site**                                  skin disease of                                   
                                          the area to be                                    
                                          injected.                                         
  ----------------------- --------------- ----------------- ---------------- -------------- --------------

Y=yes, listed as a contraindication; No=no, not listed as a
contraindication

**[Drug-Interactions]{.underline}**

There are no known drug-drug interactions with IA HA or hylan. However,
most manufacturers state that the efficacy and safety of concomitant
administration of other IA products with IA HA or hylan is not known.

**[Acquisition Costs]{.underline}**

Table 10

+-----------+-----------+-----------+-----------+-----------+-----------+
|           | **Eu      | **H       | **Ort     | **S       | **S       |
|           | flexxa®** | yalgan®** | hovisc®** | upartz®** | ynvisc®** |
+-----------+-----------+-----------+-----------+-----------+-----------+
| **Cost/In | \$86.71   | \$65.00   | \$198.32  | \$68.28   | \$142.10  |
| jection** |           |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| **Co      | \$260.15  | \$195.00  | \$594.96  | \$204.84  | \$426.30  |
| st/Course |           | to        | to        | to        |           |
| (#        | \(3\)     | \$325.00  | \$793.28  | \$341.40  | \(3\)     |
| inj/      |           |           |           |           |           |
| course)** |           | (3 to 5)  | (3 to 4)  | (3 to 5)  |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| *         | 3         | 60 days\* | 6 months  | 90 days\* | 6 months  |
| *Duration | months\*  | to 6      |           | to 6      |           |
| of        |           | months    |           | months    |           |
| R         |           |           |           |           |           |
| esponse** |           |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| **Cost/6  | \$5       | \$585\*\* | \$594.96  | \$4       | \$426.30  |
| months**  | 20.30\*\* | to        | to        | 09.68\*\* |           |
|           |           | \$325.00  | \$793.28  | to        |           |
|           |           |           |           | \$341.40  |           |
+-----------+-----------+-----------+-----------+-----------+-----------+

\*Duration of study follow-up determined duration of response. \*\*In
general, it is not recommended that repeat courses be administered
earlier than 6 months after the last course was completed. (Prices from
VACO PBM as of 4-30-08)

**[Purchases in VHA FY2007]{.underline}** (Total dollars spent on all
products combined: \$6,230,801)

Table 11

+-----------+-----------+-----------+-----------+-----------+-----------+
|           | **Eu      | **H       | **Ort     | **S       | **S       |
|           | flexxa®** | yalgan®** | hovisc®** | upartz®** | ynvisc®** |
+-----------+-----------+-----------+-----------+-----------+-----------+
| **Units   | 1,720     | 577 -     | 45        | 6,445     | 5,881     |
| Pu        |           | vial      |           |           |           |
| rchased** |           |           |           |           |           |
|           |           | 32,938    |           |           |           |
|           |           | -syringe  |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+
| **Total   | \$437,733 | \$        | \$8,934   | \$539,884 | \$        |
| Expen     |           | 2,767,384 |           |           | 2,476,866 |
| ditures** |           |           |           |           |           |
+-----------+-----------+-----------+-----------+-----------+-----------+

**[Conclusions/Place in Therapy]{.underline}**

In this review, the efficacy and safety of viscosupplementation with
hyaluronans or hylan for osteoarthritis of the knee has been explored.
All five agents are FDA approved as "Biologic Devices" and are approved
in patients with OA of the knee who have not responded sufficiently to
nonpharmacologic interventions as well as simple analgesics. The
following questions/answers are posed for discussion:

**Does the evidence support use of IA HA or hylan for OA of the knee?**
Yes. There are seven meta-analyses assessing the treatment effect of HA
or hylan in patients with OA of the knee. Six of those analyses compared
HA or hylan to placebo and the seventh compared pooled HA to hylan. Four
out of the six meta-analyses comparing HA or hylan to placebo observed a
treatment effect vs. placebo, while the remaining two did not. Two
authors commented on a large observed IA placebo effect. Generally, all
seven authors noted the quality of the evidence for this treatment to be
of poor or unsatisfactory quality. The authors do call for additional
well conducted clinical trials to help determine candidates that may
most benefit from this treatment.

The American Academy of Orthopaedic Surgeons (AAOS), American College of
Rheumatology (ACR), American Pain Society and the European League
Against Rheumatism (EULAR) recognize the use of IA HA or hylan in those
patients not having an adequate response despite nonpharmacologic
therapies, topic or simple analgesics or NSAIDs or who are either
intolerant to or unable to take NSAIDs/COX-2s. The National Center for
Clinical Excellence (NICE) does not recognize this treatment for OA of
the knee.

The evidence does not support routinely considering IA HA or hylan for
joints other than the knee (e.g. hip, shoulder, ankle, etc.) since there
a lack of data and many unanswered questions.

**Does the evidence support an advantage of one product vs.**
**another?** No. There is one meta-analysis comparing HA to hylan. There
was no advantage of either type of agent (HA or hylan). However, the
risk for adverse events was observed to be higher with the hylan (local
ADEs, flares, and joint effusions) product. There may be some advantages
of one product over the other on a case-by-base basis:

-   Individuals with avian allergy may consider use of Euflexxa since
    the source of HA is from biologic fermentation while the remaining
    four products are from avian sources.

-   From the Cochrane meta-analysis, all agents were determined to have
    sufficient data for efficacy and safety for OA of the knee except
    Euflexxa (placebo-controlled data to be insufficient to determine
    efficacy. Some support for safety).

-   The number of injections per cycle is likely to be an advantage.
    However, the duration of response for Euflexxa, Hyalgan and Supartz
    are based upon the length of the study which proved a benefit with 3
    injections (Hyalgan and Supartz).

-   There is some low level evidence (open-label, case-series, and
    retrospective) for repeat treatment with Hyalgan and Synvisc ranging
    from 2-8 courses. There did not appear to be an increase in the
    number of adverse events with repeat Hyalgan but there were with
    Synvisc (See page 7).

**Are there differences in safety between products?** Potentially.
Although there does not appear to be safety different between the HA
products, there does appear to be some unique but rare safety concerns
related to use of Synvisc (case reports of pseudosepsis or severe acute
inflammatory reactions (SAIR) and at least a few reporting granulomatous
inflammation). The risk may increase with the second or third injection
in a course or with subsequent courses. (Refer to page 7 and 9).

**[References]{.underline}**

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2.  Arthritis Rheum 1998;41(5):778--799.

3.  Euflexxa \[Prescribing information\]. Ferring Pharmaceuticals,
    Suffern, NY; 2006

4.  Hyalgan \[Presccribing information\]. Sanofi-Synthelabo Inc, New
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5.  Orthovisc \[Prescribing information\]. Anika Therapeutics, Woburn,
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6.  Supartz \[Prescribing information\]. Seikagaku Corp, Tokyo, Japan;
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7.  Synvisc \[Prescribing information\]. Genzyme Corp, Ridgefield, NJ;
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9.  Adams ME, Lussier AJ, Peyron JG. A Risk-Benefit Assessment of
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10. Brockmeier SF, Shaffer BS. Viscosupplementation Therapy for
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11. Vitanzo PC, Sennett BJ. Hyaluronans: Is Clinical Effectiveness
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12. Moreland LW. Intra-Articular Hyaluronan (Hyaluronic Acid) and Hylans
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13. Carrabba M, Paresce E, Angelini M, et al. The Safety and Efficacy of
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14. Altman R, Brandt K, Hochberg, et al. Design and Conduct of Clinical
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15. Lo GH, LaValley M, McAlindon T, Felson DT. Intra-Articular
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16. Wang CT, Lin J, Change CJ, et al. Therapeutic Effects of Hyaluronic
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18. Modawal A, Ferrer MF, Choi HK, Castle JA. Hyaluronic Acid Injections
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19. Bellamy N, Campbell J, Robinson V, et al. Viscosupplementation for
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20. Medina JM, Thomas A, Denegar DR. Knee Osteoarthritis: Should Your
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23. Divine JG, Zazulak BT, Hewett TE. Viscosupplementation for Knee
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24. Migliore A, Tormenta S, Martin LSM, et al. The Symptomatic Effects
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    2006;25:389-393.

25. Van Den Bekerom MPJ, Mylle G, Rys B, Mulier M. Viscosupplementation
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26. Conrozier T, Vignon E. Is There Evidence to Support the Inclusion of
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27. Van Den Bekerom MPJ, Lamme B, Sermon A, Mulier M. What is the
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    Hip Osteoarthritis? Systematic Review of the Literature. Arch Orthop
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28. Tikiz C, Unlu Z, Sener A, et al. Comparison of the Efficacy of Lower
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29. van den Bekerom MPJ, Rys B, Mulier M. Viscosupplementation in the
    Hip: Evaluation of Hyaluronic Acid Formulations. Arch Orthop Trauma
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30. Pleimann JH, Davis WH, Cohen BE, Anderson RB. Viscosupplementation
    for the Arthritis Ankle. Foot Ankle Clin N Am 2002;7:489-494.

31. Valiveti M, Reginato AJ, Falasca GF. Viscosupplementation for
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32. Pagnano M, Westrich G. Successful Nonoperative Management of Chronic
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33. Waddell DD, Bricker DC. Hylan G-F 20 Tolerability with Repeat
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37. Jordan KM, Arden NK, Doherty M, et al. EULAR Recommendations 2003:
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39. Rees JD, Wojtulewski JA. Systemic Reaction to Viscosupplementation
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40. Martens PB. Bilateral Symmetric Inflammatory Reaction to Hylan G-F
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41. Leopold SS, Warme WJ, Pettis PD, Shott S. Increased Frequency of
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45. Roos J, Epaulard O, Juvin R, et al. Acute Pseudoseptic Arthritis
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46. Tahiri L, Benbouazza K, Amine B, Hajjaj-Hassouni N. Acute
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47. Chen AL, Desai P, Adler EM, Di Cesare PE. Granulomatous Inflammation
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**Appendix A.**

**Table 4: Summary of the Meta-Analyses of Intra-Articular
Administration of Hyaluronic Acid or Hylan for OA of the Knee**

+-----+----------+-------------+---------------------+----------------+
| **P | **M      | **Outcome   | **Results/Adverse   | *              |
| ubl | ethods** | Measures**  | Effects**           | *Conclusions** |
| ica |          |             |                     |                |
| tio |          |             |                     |                |
| n** |          |             |                     |                |
+-----+----------+-------------+---------------------+----------------+
| Lo, | [Sear    | a\. When a  | a\. 22 trials met   | a\. The        |
| et  | ch]{.und | study used  | inclusion, 19       | authors        |
| al^ | erline}: | more than 1 | published in full,  | concluded      |
| 15^ | MEDLINE  | pain scale, | 3 in abstract form. | based upon     |
|     | (        | the         | (n=2949 knees       | their          |
|     | 1966-Feb | preferred   | enrolled, n=2584    | meta-analysis  |
|     | 2003);   | scale       | knees analyzed.)    | that IA HA     |
|     | Cochrane | (based upon |                     | provides a     |
|     | CTR;     | hierarchy   | b\. Overall         | modest benefit |
|     | biblio   | located     | drop-out was 12.4%  | in OA of the   |
|     | graphies | above in    | but ranged from     | knee similar   |
|     | of       | efficacy    | 0-40%               | to what is     |
|     | included | measures    |                     | reported with  |
|     | studies; | section)    | c\. 17 studies      | NSAIDs.        |
|     | r        | was used.   | industry sponsored, | However, the   |
|     | heumatic |             | 5 not               | authors point  |
|     | disease  | b\. In      |                     | out that since |
|     | j        | order to    | d\. Trial size      | they did       |
|     | ournals, | compare     | ranged from 24-408  | identify       |
|     | a        | results     | patients.           | publication    |
|     | bstracts | between     |                     | bias, they     |
|     | from     | trials,     | e\. **Pooled effect | admit that     |
|     | sc       | s           | size of IA HA vs.   | their results  |
|     | ientific | tandardized | IA Pla was 0.32     | may be         |
|     | meetings | mean        | (95% CI 0.17-0.27,  | overestimated  |
|     | i        | difference  | p\<0.001). Once the |                |
|     | ncluding | was used as | Synvisc trials were | Furthermore,   |
|     | unp      | the measure | removed, the effect | the drop-out   |
|     | ublished | of effect   | size was 0.19 (95%  | rate in some   |
|     | data.    | size\* and  | CI 0.1-0.27,        | of the trials  |
|     |          | was         | p\<0.001)**         | was fairly     |
|     | [Includ  | calculated  |                     | large and the  |
|     | ed:]{.un | \[Pain      | f\. 3 trials        | majority of    |
|     | derline} | (HA)-Pain   | evaluated Synvisc.  | trials did not |
|     | English  | (           | 2 showed effect     | use            |
|     | and      | Pla)/pooled | sizes of 1.5        | i              |
|     | non-     | SD\] from   | (n=117, n=30) and   | ntent-to-treat |
|     | English, | change from | the third (n=105)   | analysis.      |
|     | human,   | baseline at | showed almost no    |                |
|     | RCTs     | 2-3 months  | effect.             | b\. The        |
|     | either   | after 1^st^ |                     | authors state  |
|     | single   | inj. If not | g\. Heterogeneity   | that they      |
|     | or       | available,  | was significant.    | believe there  |
|     | double   | change at   | Once the 3 Synvisc  | is a large     |
|     | blind    | 1-4 months  | studies were        | placebo effect |
|     | c        | was used.   | removed,            | with IA        |
|     | omparing |             | heterogeneity was   | aspiration of  |
|     | IA HA    | c\.         | no longer           | the knee. They |
|     | vs. IA   | Heterogenei | significant.        | determined the |
|     | placebo  | ty-Cochrane |                     | pooled change  |
|     | for OA   | Q test      | h\. Publication     | in baseline    |
|     | of the   |             | bias present p=0.07 | for IA HA and  |
|     | knee.    | d\.         |                     | for IA Pla     |
|     | Minimal  | Publication | i\. Only 7 trials   | (0.82 SD units |
|     | f        | bias-funnel | presented           | vs. 0.65 SD    |
|     | ollow-up | plot and    | intent-to-treat     | units,         |
|     | of 2     | Egger test. | data.               | respectively). |
|     | months   | Recommended |                     | They infer     |
|     | and      | level of    | j\. Adverse events  | that nearly    |
|     | \<50%    | s           | were not addressed  | 80% of the     |
|     | d        | ignificance | in this paper.      | response seen  |
|     | rop-out. | [\<]{.und   |                     | with IA HA is  |
|     |          | erline}0.10 |                     | as a result of |
|     | 2        |             |                     | IA knee        |
|     | r        |             |                     | aspiration/    |
|     | eviewers |             |                     | injection and  |
|     | ab       |             |                     | is unrelated   |
|     | stracted |             |                     | to the         |
|     | data and |             |                     | injection's    |
|     | dif      |             |                     | content.       |
|     | ferences |             |                     |                |
|     | were     |             |                     | c\. The        |
|     | resolved |             |                     | authors did    |
|     | by       |             |                     | not feel they  |
|     | co       |             |                     | could conclude |
|     | nsensus. |             |                     | an advantage   |
|     |          |             |                     | of the highest |
|     |          |             |                     | MW vs. lower   |
|     |          |             |                     | MW products    |
|     |          |             |                     | based upon the |
|     |          |             |                     | data.          |
+-----+----------+-------------+---------------------+----------------+
| Wa  | [Sear    | Efficacy    | 20 studies included | a\. The        |
| ng, | ch:]{.un | (pain and   | (Efficacy n=1647    | authors        |
| et  | derline} | function)   | knees, Safety       | concluded that |
| al^ | MEDLINE  | were        | n=2252 knees)       | the            |
| 16^ | and      | modified    |                     | therapeutic    |
|     | EMBASE   | to: SPID,   | [a. Pain with       | efficacy and   |
|     | (January | ASPID, Peak | activ               | safety of IA   |
|     | 1966-    | PID and     | ities]{.underline}: | administered   |
|     | December | SFID,       |                     | HAs are        |
|     | 2001);   | ASFID, Peak | SPID for HA: 7.9%   | beneficial in  |
|     | Cochrane | FID,        | (95% CI 4.1-11.7%)  | the treatment  |
|     | CTR;     | re          |                     | of OA of the   |
|     | biblio   | spectively. | ASPID for HA: 13.4% | knee.          |
|     | graphies | These       | (adjusted for       |                |
|     | from     | measures    | baseline pain       | b\. Multiple   |
|     | review   | take into   | intensity, 95% CI   | subgroup       |
|     | articles | account the | 5.5-21.3%)          | analyses were  |
|     | and      | change from |                     | done and       |
|     | included | baseline    | Peak PID for HA:    | showed         |
|     | a        | (pain or    | 9.9% (95% CI        | that: 1) lower |
|     | rticles; | function)   | 4.8-15%)            | quality trials |
|     | r        | for the     |                     | tend to report |
|     | heumatic | treatment   | (Overall changes in | higher         |
|     | disease  | and Pla     | function not        | efficacy       |
|     | journals | groups at a | provided)           | estimates; 2)  |
|     |          | point in    |                     | use of         |
|     | [Includ  | time. The   | \*The cross-linked  | acetaminophen  |
|     | ed:]{.un | sum of pain | HA (Synvisc-3       | as a rescue    |
|     | derline} | intensity   | studies) had        | medicine may   |
|     | English  | difference  | significantly       | reduce         |
|     | language | (SPID) is   | greater pooled mean | efficacy since |
|     | only,    | the average | differences in      | placebo        |
|     | single   | of two      | efficacy (both pain | recipients may |
|     | or       | consecutive | and function) vs.   | have           |
|     | doubl    | pain        | the non             | additional     |
|     | e-blind, | intensity   | cross-linked HA     | effects from   |
|     | RCTs     | differences | (all others). See   | it; 3)         |
|     | c        | multiplied  | b. for results:     | patients over  |
|     | omparing | by the time |                     | 65 years and   |
|     | IA HA to | interval    | [b. Pain with       | those with the |
|     | IA Pla   | between two | activities: (CL vs  | most advanced  |
|     | to treat | points (the | N                   | radiographic   |
|     | OA of    | area under  | on-CL)]{.underline} | stages of OA   |
|     | the      | the pain    |                     | (complete loss |
|     | knee.    | intensity   | SPID: 23.6% vs.     | of joint       |
|     | Unp      | difference  | 5.4%                | space) are     |
|     | ublished | vs. time    |                     | less likely to |
|     | reports  | curve).     | ASPID: 34.8% vs.    | benefit.       |
|     | were not | Peak PID    | 8.7%                |                |
|     | i        | represents  |                     | c\.            |
|     | ncluded. | the maximum | Peak PID: 27.1% vs. | Limitations of |
|     |          | efficacy    | 7.4%                | the trial      |
|     | 2        | during the  |                     | include        |
|     | r        | study. The  | [c.                 | that 1)        |
|     | eviewers | same is     | Fun                 | efficacy       |
|     | ab       | done for    | ction:]{.underline} | measures used  |
|     | stracted | function    |                     | in the trials  |
|     | data and | (SFID).     | SFID: 21.9% vs.     | may not easily |
|     | resolved |             | 5.3%                | fit into the   |
|     | dif      | a\. Pain    |                     | outcomes of    |
|     | ferences | with        | ASFID: 38.3 vs.     | this           |
|     | by       | activities  | 11.7%               | meta-analysis  |
|     | c        | (walking,   |                     | (pain with     |
|     | onsensus | climbing).  | Peak FID: 26.8% vs. | activities,    |
|     |          |             | 8.2%                | etc.) 2)       |
|     |          | b\. Pain    |                     | Unpublished    |
|     |          | without     | Major ADEs: 3/1002  | trials were    |
|     |          | activities  | knees treated with  | not included   |
|     |          | (during     | non-cross-linked    | which may      |
|     |          | rest)       | HAs (1-severe       | influence the  |
|     |          |             | swelling,           | results; 3)    |
|     |          | c\.         | 1-vasculitis,       | One larger     |
|     |          | Function    | 1-hypersensitivity) | trial with     |
|     |          |             | vs. 1/139 knees     | cross-linked   |
|     |          | d\. ADEs    | with cross-linked   | HA (Karlsson   |
|     |          | were        | HA (1-painful acute | n=105) showing |
|     |          | classified  | local reaction).    | almost no      |
|     |          | as minor or |                     | effect was not |
|     |          | major       | d\. Pooled relative | included.      |
|     |          |             | risk of minor ADEs  |                |
|     |          | e\.         | for all trials was  |                |
|     |          | Chi-Square  | 1.19 (95% CI        |                |
|     |          | for Q       | 1.01-1.41). No      |                |
|     |          | statistics  | heterogeneity       |                |
|     |          | was used to | between studies in  |                |
|     |          | test for    | ADEs.               |                |
|     |          | between     |                     |                |
|     |          | study       | e\. Between study   |                |
|     |          | het         | heterogeneity tests |                |
|     |          | erogeneity. | were performed on   |                |
|     |          |             | the                 |                |
|     |          | f\. Funnel  | non-cross-linked    |                |
|     |          | plots were  | HAs because of the  |                |
|     |          | used to     | differences in      |                |
|     |          | assess for  | efficacy results    |                |
|     |          | publication | between             |                |
|     |          | bias.       | cross-linked and    |                |
|     |          |             | non-cross-linked    |                |
|     |          |             | HAs. No             |                |
|     |          |             | heterogeneity was   |                |
|     |          |             | found in the        |                |
|     |          |             | non-cross-linked HA |                |
|     |          |             | studies. No such    |                |
|     |          |             | analysis was done   |                |
|     |          |             | on the studies      |                |
|     |          |             | involving the       |                |
|     |          |             | cross-linked HA.    |                |
|     |          |             |                     |                |
|     |          |             | f\. Funnel plots    |                |
|     |          |             | showed that         |                |
|     |          |             | publication bias    |                |
|     |          |             | was unlikely to     |                |
|     |          |             | influence results.  |                |
+-----+----------+-------------+---------------------+----------------+
| A   | [Sear    | a\.         | a/b. 22 trials were | The authors of |
| rri | ch:]{.un | Efficacy    | included.           | this           |
| ch, | derline} | m           |                     | meta-analysis  |
| et  | EMBASE,  | easures: 1) | [Pain at            | concluded that |
| al^ | MEDLINE  | pain at     | rest:]{.underline}  | the available  |
| 17^ | (19      | rest, 2)    | 8 trials reported a | data for       |
|     | 66-April | pain during | reduction in the    | viscos         |
|     | 2004),   | or          | treatment group     | upplementation |
|     | CINAHL,  | immediately | (n=231) vs. control | of OA is       |
|     | BIOSIS   | after       | (n=237) at 2-6      | comprised      |
|     | and      | movement,   | weeks. Significant  | mostly of low  |
|     | Cochrane | 3) joint    | heterogeneity       | quality        |
|     | CTR to   | function.   | existed             | studies in     |
|     | identify |             | (*I^2^*=94%) so     | which blinding |
|     | all      | b\.         | pooling of data is  | of allocation  |
|     | RCTs.    | Efficacy    | not recommended.    | and outcome    |
|     |          | measures    |                     | assessment is  |
|     | [        | were noted  | 2 high-quality      | questionable   |
|     | Included | at 2-6      | trials did not find | and            |
|     | articl   | weeks,      | an effect at 10-14  | i              |
|     | es:]{.un | 10-14       | or 22-30 weeks and  | ntent-to-treat |
|     | derline} | weeks,      | one other           | analysis are   |
|     | RCTs     | 22-30 weeks | high-quality trial  | limited. In    |
|     | r        | and 44-60   | did not find a      | their search   |
|     | eporting | weeks.      | benefit at 44-60    | of a number of |
|     | at least |             | weeks.              | databases,     |
|     | of the   | c\.         |                     | there          |
|     | efficacy | Allocation  | [Pain during or     | identified 22  |
|     | v        | c           | just after          | studies to     |
|     | ariables | oncealment, | exe                 | include in     |
|     | c        | degree of   | rcise:]{.underline} | their          |
|     | omparing | outcome     | 9 trials reported a | meta-analysis  |
|     | IA HA to | assessment  | reduction in pain   | but only 4 of  |
|     | a        | blinding    | in the treatment    | those were of  |
|     | control  | and         | group (n=559) vs.   | high-quality.  |
|     | in       | inte        | control (n=582) at  | They also note |
|     | patients | nt-to-treat | 2-6 weeks. The      | that when      |
|     | with OA  | analysis    | weighted mean       | allocation     |
|     | of the   | was         | difference in VAS   | concealment    |
|     | knee     | determined. | was -3.8 mm.        | was not clear, |
|     | were     |             | Heterogeneity was   | i              |
|     | i        | d\. Summary | *I^2^*=82%), again  | ntent-to-treat |
|     | ncluded. | risk ratios | pooling not         | analysis was   |
|     | No other | were used   | advisable. One      | not done or    |
|     | details  | to combine  | trial found a       | outcome        |
|     | p        | ADEs.       | better response in  | assessment was |
|     | rovided. |             | less severe OA but  | not blinded,   |
|     |          | e\.         | more pain in more   | the effect of  |
|     | 2        | Cochrane Q, | severe OA with HA.  | the treatment  |
|     | r        | with        | Once this trial was | was            |
|     | eviewers | resulting   | removed,            | overestimated. |
|     | ab       | degrees of  | heterogeneity was   | In those four  |
|     | stracted | freedom     | 20% so results      | high-quality   |
|     | data and | were used   | could be pooled;    | studies, an    |
|     | dif      | to test     | weighted mean VAS   | effect of      |
|     | ferences | unexplained | was similar at 4.2  | treatment on   |
|     | were     | het         | mm.                 | pain at rest,  |
|     | resolved | erogeneity. |                     | during         |
|     | by       | (low \<20%, | At 10-14 weeks, 5   | movement or    |
|     | c        | moderate    | comparisons were    | joint function |
|     | onsensus | 20-50%)     | made (n=435 HA vs.  | was not        |
|     | among 3  |             | n=442 control).     | observed.      |
|     | re       | f\.         | Weighted mean       | However, they  |
|     | viewers. | Regression  | difference VAS was  | do note that   |
|     |          | methods     | -4.3 mm in favor of | there were a   |
|     |          | were used   | treatment.          | limited number |
|     |          | to assess   | Heterogeneity=0%    | of studies     |
|     |          | publication |                     | reported the   |
|     |          | bias.       | At 22-30 weeks, 4   | chosen         |
|     |          |             | comparisons were    | outcomes at    |
|     |          | g\.         | made (n=227 HA vs.  | the chosen     |
|     |          | M           | n=236 control).     | time intervals |
|     |          | ultivariate | Weighted mean VAS   | which also may |
|     |          | meta        | was -7.2 mm in      | limit the      |
|     |          | -regression | favor of treatment. | effect size.   |
|     |          | analysis    | No heterogeneity.   |                |
|     |          | was used to |                     | They noted     |
|     |          | assess      | One trial at 44-60  | that they were |
|     |          | whether an  | weeks showing no    | unable to      |
|     |          | effect was  | effect.             | conclude a     |
|     |          | influenced  |                     | benefit for    |
|     |          | by          | \*Authors note that | pain during    |
|     |          | allocation  | trial quality had   | rest but did   |
|     |          | c           | no undue effect on  | observe a      |
|     |          | oncealment, | effect size in this | small benefit  |
|     |          | blinded     | analysis but only   | in pain with   |
|     |          | outcome     | one trial was of    | movement with  |
|     |          | assessment  | high quality.       | HA. No         |
|     |          | or          |                     | difference in  |
|     |          | inte        | [Joint              | joint function |
|     |          | nt-to-treat | Fun                 | was found.     |
|     |          | analysis.   | ction:]{.underline} |                |
|     |          |             | 9 trials assessed   | The authors    |
|     |          |             | function at 2-6     | conclude that  |
|     |          |             | weeks (n=489 HA vs. | the available  |
|     |          |             | 505 control).       | evidence does  |
|     |          |             | Standardized        | not prove a    |
|     |          |             | weighted mean       | clinical       |
|     |          |             | difference between  | benefit, but   |
|     |          |             | the groups was 0    | there are more |
|     |          |             | with significant    | minor ADEs.    |
|     |          |             | unexplained         | They recommend |
|     |          |             | heterogeneity       | a large,       |
|     |          |             | *I^2^*=66%.         | high-quality   |
|     |          |             | Assessment of joint | trial be       |
|     |          |             | function during     | conducted to   |
|     |          |             | other treatment     | determine the  |
|     |          |             | periods (e.g. 10-14 | true           |
|     |          |             | weeks, etc.) did    | benefit/risk   |
|     |          |             | not show a benefit  | ratio of this  |
|     |          |             | of treatment.       | intervention.  |
|     |          |             |                     |                |
|     |          |             | d\.                 |                |
|     |          |             | [ADEs]{.underline}: |                |
|     |          |             | 15 trials reported  |                |
|     |          |             | ADEs. ADEs          |                |
|     |          |             | occurring more      |                |
|     |          |             | frequently in the   |                |
|     |          |             | treatment group but |                |
|     |          |             | were mostly minor   |                |
|     |          |             | (e.g. pain at       |                |
|     |          |             | injection site).    |                |
|     |          |             |                     |                |
|     |          |             | f\. No publication  |                |
|     |          |             | bias was idenfied.  |                |
|     |          |             |                     |                |
|     |          |             | g\. Efficacy        |                |
|     |          |             | measures were       |                |
|     |          |             | repeated for those  |                |
|     |          |             | trials (n=4)        |                |
|     |          |             | reporting           |                |
|     |          |             | allocation          |                |
|     |          |             | concealment,        |                |
|     |          |             | blinding of outcome |                |
|     |          |             | assessment and      |                |
|     |          |             | intent-to-treat     |                |
|     |          |             | analysis; no effect |                |
|     |          |             | was found in favor  |                |
|     |          |             | of treatment.       |                |
|     |          |             |                     |                |
|     |          |             | h\. The             |                |
|     |          |             | meta-analysis did   |                |
|     |          |             | not prove an        |                |
|     |          |             | advantage based     |                |
|     |          |             | upon molecular      |                |
|     |          |             | weight.             |                |
+-----+----------+-------------+---------------------+----------------+
| Mo  | [Sear    | a\. Studies | 11 RCT were         | The authors    |
| daw | ch:]{.un | reporting   | included. There     | concluded from |
| al^ | derline} | change in   | were actually 9     | their analysis |
| 18^ | MEDLINE  | VAS for     | trials but in one   | that patients  |
|     | (196     | pain at     | trial, there were 2 | achieve        |
|     | 5-August | rest or     | subgroups of pain   | benefit with   |
|     | 2004);   | during      | severity and one    | IA HA or hylan |
|     | manual   | movement    | trial in which      | at 5-7 and     |
|     | search   | were        | there were 2        | 8-12 weeks vs. |
|     | of       | included    | treatment groups,   | placebo. No    |
|     | r        | (mean       | these were both     | difference was |
|     | eference | differences | considered as 2     | observed at 1  |
|     | lists of | of change   | separate trials.    | week or 15-22  |
|     | included | from        | Two studies         | weeks after    |
|     | articles | baseline    | evaluated Hylan     | the last       |
|     | and      | between     | GF-20 and the rest  | injection.     |
|     | review   | treatment   | hyaluronans. Only 3 | However, only  |
|     | a        | and         | trials had          | 3 studies      |
|     | rticles; | placebo).   | published outcome   | assessed pain  |
|     | Cochrane | Joint       | data at 15-22       | after 12       |
|     | Library  | function    | weeks.              | weeks.         |
|     | and      | was not     |                     |                |
|     | Agency   | used as an  | Five studies were   | When only the  |
|     | for      | outcome in  | classified as "good | good quality   |
|     | He       | the         | quality" while 4    | trials were    |
|     | althcare | met         | were "poor          | examined, the  |
|     | Research | a-analysis. | quality."           | effect size of |
|     | and      | Efficacy    |                     | treatment was  |
|     | Quality  | assessments | [a. The mean        | smaller.       |
|     | (AHRQ)   | were        | difference in pain  |                |
|     | website. | included at | scores (VAS)        | Although Hylan |
|     |          | 1 week, 5-7 | between treatment   | GF-20 had a    |
|     | [        | weeks, 8-12 | and                 | greater effect |
|     | Included | weeks,      | pl                  | size, both     |
|     | articl   | 15-22       | acebo:]{.underline} | trials were of |
|     | es:]{.un | weeks.      |                     | poor quality   |
|     | derline} |             |   --------          | so the authors |
|     | p        | b\.         | --------- --------- | did not feel   |
|     | ublished | He          |   Time              | they could     |
|     | doubl    | terogeneity |      All       Good | conclude an    |
|     | e-blind, | was tested  |   Period            | advantage of   |
|     | RCTs,    | using       |   studies   Quality | hylans vs.     |
|     | English  | Galbraith   |                     | HAs. Data were |
|     | language | plots. If   |   1                 | not sufficient |
|     | using    | he          | week   4.4       -1 | to determine   |
|     | VAS to   | terogeneity |                     | if severity of |
|     | measure  | was         |   5-7               | OA or other    |
|     | pain at  | present,    |       17.6      7.2 | patient        |
|     | rest or  | ra          |                     | factors may    |
|     | during   | ndom-effect | weeks               | affect         |
|     | m        | regression  |                     | outcomes.      |
|     | ovement. | models were |   8-1               |                |
|     |          | performed   | 2     18.1      7.1 | In 5 of the 9  |
|     | 2        | to explore  |                     | studies,       |
|     | r        | 3           | weeks               | patients were  |
|     | eviewers | po          |                     | allowed to     |
|     | ab       | ssibilities |   15-               | take           |
|     | stracted | of the      | 22    4.4       \-- | acetaminophen  |
|     | data,    | source of   |                     | or NSAIDs for  |
|     | dif      | he          | weeks               | pain which may |
|     | ferences | terogeneity |                     | alter their    |
|     | were     | (pain at    |                     | response.      |
|     | resolved | rest or     |                     | I              |
|     | between  | during      |   --------          | ntent-to-treat |
|     | by       | movement;   | --------- --------- | analysis was   |
|     | co       | type of HA; |                     | only used in 2 |
|     | nsensus. | and study   | b\. A high degree   | studies.       |
|     |          | quality).   | of heterogeneity    |                |
|     |          |             | was observed at all |                |
|     |          | c\.         | time periods except |                |
|     |          | Publication | at 1 week. 4/5      |                |
|     |          | bias was    | trials outside the  |                |
|     |          | assessed by | confidence          |                |
|     |          | the Eggar   | intervals were of   |                |
|     |          | regression  | poor quality.       |                |
|     |          | asymmetry   |                     |                |
|     |          | test.       | Random-effect       |                |
|     |          |             | regression model:   |                |
|     |          |             | Pain assessment     |                |
|     |          |             | during rest or      |                |
|     |          |             | movement did not    |                |
|     |          |             | influence effect    |                |
|     |          |             | size. Trials using  |                |
|     |          |             | Hylan GF-20 showed  |                |
|     |          |             | better results at   |                |
|     |          |             | weeks 5-7 and 8-12  |                |
|     |          |             | but both trials     |                |
|     |          |             | were of poor        |                |
|     |          |             | quality. Poor       |                |
|     |          |             | quality studies     |                |
|     |          |             | also showed a       |                |
|     |          |             | larger effect size  |                |
|     |          |             | but the difference  |                |
|     |          |             | was only            |                |
|     |          |             | significant at 1    |                |
|     |          |             | week.               |                |
|     |          |             |                     |                |
|     |          |             | c\. No publication  |                |
|     |          |             | bias was found.     |                |
+-----+----------+-------------+---------------------+----------------+
| Be  | [Sear    | a\. Outcome | Only data for those | In this        |
| lla | ch:]{.un | measures:   | products available  | analysis, 76   |
| my^ | derline} | Pain,       | in the U.S. will be | clinical       |
| 19^ | MEDLINE  | physical    | presented. (RevMan  | trials with a  |
|     | (        | function,   | Analysis): 37       | median quality |
|     | 1966-Jan | patient     | trials were         | of 3 (Jadad    |
|     | 2006),   | global      | included in the     | score range    |
|     | EMBASE,  | assessment, | meta-analysis       | 1-5). 45       |
|     | PRE      | joint       |                     | trials         |
|     | MEDLINE, | imaging.    | 1\. Artz (Artzal or | compared HAs   |
|     | Current  | Outcomes    | **Supartz**) vs.    | or hylans to   |
|     | Contents | were        | Placebo: 7 Trials,  | placebo, 10    |
|     | to July  | evaluated   | mean Jadad          | trials         |
|     | 2003,    | at the      | score=4.3           | included IA    |
|     | Cochrane | following   |                     | co             |
|     | CTR.     | time        | <table              | rticosteroids, |
|     | Spe      | periods:    | s                   | 6 trials       |
|     | cialized | 1-4 weeks,  | tyle="width:100%;"> | compared HAs   |
|     | journals | 5-13 weeks, | <colgroup>          | ot NSAIDs, 15  |
|     | and      | 14-26 weeks | <col                | trials         |
|     | r        | and 45-52   | st                  | compared       |
|     | eference | weeks       | yle="width: 21%" /> | various HA or  |
|     | lists of | post        | <col                | hylan products |
|     | included | -injection. | st                  | and the        |
|     | articles | Weighted    | yle="width: 19%" /> | remaining      |
|     | and      | mean        | <col                | compared HAs   |
|     | p        | difference  | st                  | or hylans to   |
|     | ertinent | (WMD) was   | yle="width: 19%" /> | other          |
|     | review   | reported    | <col                | interventions. |
|     | articles | for         | st                  |                |
|     | up to    | continuous  | yle="width: 19%" /> | The authors    |
|     | Dec 2005 | outcome     | <col                | acknowledge    |
|     | were     | data        | st                  | the complexity |
|     | searched | measured on | yle="width: 19%" /> | of conducting  |
|     | by hand. | the same    | </colgroup>         | a systematic   |
|     |          | scale. When | <tbody>             | review of this |
|     | [        | pain and    | <tr class="odd">    | class of       |
|     | Included | function    | <td>Weeks:</td>     | agents because |
|     | articl   | were        | <td>1-4</td>        | of the many    |
|     | es:]{.un | measured on | <td>5-13</td>       | variables      |
|     | derline} | difference  | <td>14-26</td>      | (study design, |
|     | Single   | scales, a   | <td>45-52</td>      | populations,   |
|     | or       | hierarchy   | </tr>               | outcome        |
|     | doub     | of pain and | <tr class="even">   | measures,      |
|     | le-blind | function    | <td>WOMAC           | observation    |
|     | studies  | measures    | Pain</td>           | time periods,  |
|     | in which | were        | <td>--</td>         | type of        |
|     | visc     | defined,    | <td>NS</td>         | comparator and |
|     | osupplem | then        | <td>--</td>         | variability in |
|     | entation | s           | <td>--</td>         | molecular      |
|     | is       | tandardized | </tr>               | weight,        |
|     | compared | mean        | <tr class="odd">    | vi             |
|     | to       | differences | <td>WOMAC           | scoelasticity, |
|     | placebo, | (SMD) were  | Function</td>       | concentration, |
|     | or       | used to     | <td>--</td>         | residence time |
|     | active   | pool RCTs.  | <td>NS</td>         | in joint, etc. |
|     | tr       |             | <td>--</td>         | for the        |
|     | eatments | \*All data  | <td>--</td>         | different      |
|     | (e.g.    | are         | </tr>               | hyaluronic     |
|     | s        | presented   | <tr class="even">   | acid or hylan  |
|     | teroids, | by HA or    | <td>Lequesne</td>   | products.      |
|     | NSAIDs)  | hylan       | <td>NS</td>         |                |
|     | in       | products    | <td>NS</td>         | -Overall, the  |
|     | patients | since there | <td>NS</td>         | authors' state |
|     | with OA  | are         | <td>NS</td>         | that the       |
|     | of the   | differences | </tr>               | pooled         |
|     | knee. At | in          | <tr class="odd">    | analysis of    |
|     | least    | molecular   | <td>Pt. Global      | results from   |
|     | one of   | weight,     | Assess</td>         | all agents     |
|     | the 4    | treatment   | <td>RR 1.17         | supports a     |
|     | OMERACT  | schedules,  | (1.04-1.32) NNT     | benefit of     |
|     | III core | etc.        | 5-11</td>           | vi             |
|     | set of   |             | <td>NS</td>         | scosupplements |
|     | outcome  | b\. ADEs    | <td>Better than     | with HA or     |
|     | measures | were        | Placebo</td>        | hylan products |
|     | needed   | analyzed.   | <td>--</td>         | against        |
|     | to be    |             | </tr>               | placebo.       |
|     | suff     | c\.         | <tr class="even">   |                |
|     | iciently | He          | <td>Pain VAS        | -When compared |
|     | reported | terogeneity | (100)</td>          | to NSAIDs, IA  |
|     | (pain,   | was tested  | <td>NS</td>         | HA showed      |
|     | physical | using Chi   | <td><p>-4.55</p>    | similar        |
|     | f        | Square.     | <p>(-               | efficacy.      |
|     | unction, | Fixed       | 9.09-0.00)</p></td> |                |
|     | patient  | effects     | <td>NS</td>         | -IA HA         |
|     | global   | model was   | <td>NS</td>         | demonstrated   |
|     | as       | used when   | </tr>               | longer lasting |
|     | sessment | he          | <tr class="odd">    | benefits       |
|     | or joint | terogeneity | <td>Range of        | compared in IA |
|     | imaging  | was not     | Motion</td>         | co             |
|     | (studies | present.    | <td>NS</td>         | rticosteroids. |
|     | of 1     | When        | <td>--</td>         |                |
|     | year or  | present,    | <td>--</td>         | Authors        |
|     | \>)      | random      | <td>--</td>         | conclusion by  |
|     |          | effects     | </tr>               | product:       |
|     | Data was | model was   | <tr class="even">   |                |
|     | ab       | used.       | <td>Clinical        | 1\. [Artz      |
|     | stracted |             | Failures</td>       | (Supartz)      |
|     | by one   |             | <td>--</td>         | :]{.underline} |
|     | reviewer |             | <td>--</td>         |                |
|     | and      |             | <td>11% Pla vs.     | Data generally |
|     | verified |             | 2% HA</td>          | support        |
|     | by a     |             | <td>NS</td>         | efficacy.      |
|     | second.  |             | </tr>               |                |
|     |          |             | <tr class="odd">    | Artz vs. Hylan |
|     |          |             | <td>Safety</td>     | GF-20-no       |
|     |          |             | <td>NS</td>         | difference     |
|     |          |             | <td>NS</td>         |                |
|     |          |             | <td>NS</td>         | 2\. [BioHy     |
|     |          |             | <td>NS</td>         | (Euflexxa,     |
|     |          |             | </tr>               | others)        |
|     |          |             | </tbody>            | ]{.underline}: |
|     |          |             | </table>            |                |
|     |          |             |                     | Plac           |
|     |          |             | \*1 trial of Artz   | ebo-controlled |
|     |          |             | vs. Hylan GF-20-No  | data           |
|     |          |             | difference in any   | insufficient   |
|     |          |             | outcome measure at  | to determine   |
|     |          |             | any time interval.  | efficacy.      |
|     |          |             |                     | However, some  |
|     |          |             | 2\. Biohy           | support for    |
|     |          |             | (Arthrease,         | safety of this |
|     |          |             | **Euflexxa**,       | product.       |
|     |          |             | Nuflexxa): 1 Trials |                |
|     |          |             | vs. placebo and 1   | BioHy vs.      |
|     |          |             | vs. Hylan GF-20     | Hylan GF-20:   |
|     |          |             |                     | no difference  |
|     |          |             | Trial vs. placebo:  |                |
|     |          |             | pain and stiffness  | 3\.            |
|     |          |             | were reported to be | [Hyalgan       |
|     |          |             | improved from       | ]{.underline}: |
|     |          |             | baseline but no     |                |
|     |          |             | values given.       | Overall,       |
|     |          |             |                     | analysis       |
|     |          |             | Euflexxa vs. Hylan  | strongly       |
|     |          |             | GF-20: Some         | support        |
|     |          |             | differences noted   | efficacy vs.   |
|     |          |             | but publication     | placebo.       |
|     |          |             | analysis vs. RevMan |                |
|     |          |             | analysis differed.  | Safety of      |
|     |          |             | A higher number of  | Hyalgan also   |
|     |          |             | Hylan vs. Euflexxa  | supported vs.  |
|     |          |             | patients had a      | placebo.       |
|     |          |             | joint effusion (8%  |                |
|     |          |             | vs. 0.6%,           | Overall,       |
|     |          |             | respectively)       | Hyalgan is     |
|     |          |             |                     | equal or       |
|     |          |             | **Hyalgan:** 29     | superior to IA |
|     |          |             | studies (14 vs.     | steroids.      |
|     |          |             | placebo, 3 against  | However,       |
|     |          |             | other HAs, 5        | steroids may   |
|     |          |             | against steroids    | have faster    |
|     |          |             | and others varied)  | onset but HAs  |
|     |          |             | Mean Jadad score    | have a longer  |
|     |          |             | 2.81                | duration.      |
|     |          |             |                     |                |
|     |          |             | Hyalgan vs.         | 4\. [Hylan     |
|     |          |             | Placebo:            | GF-20          |
|     |          |             |                     | :]{.underline} |
|     |          |             | <table>             |                |
|     |          |             | <colgroup>          | Overall,       |
|     |          |             | <col                | analysis       |
|     |          |             | st                  | strongly       |
|     |          |             | yle="width: 19%" /> | supports       |
|     |          |             | <col                | efficacy vs.   |
|     |          |             | st                  | placebo.       |
|     |          |             | yle="width: 23%" /> |                |
|     |          |             | <col                | Safety of      |
|     |          |             | st                  | hylan GF-20    |
|     |          |             | yle="width: 23%" /> | also           |
|     |          |             | <col                | supported.     |
|     |          |             | st                  |                |
|     |          |             | yle="width: 19%" /> | Overall, hylan |
|     |          |             | <col                | GF-20 is       |
|     |          |             | st                  | superior to IA |
|     |          |             | yle="width: 14%" /> | steroids but   |
|     |          |             | </colgroup>         | steroids have  |
|     |          |             | <tbody>             | a faster onset |
|     |          |             | <tr class="odd">    | but hylan has  |
|     |          |             | <td>Weeks</td>      | a longer       |
|     |          |             | <td>1-4</td>        | duration.      |
|     |          |             | <td>5-13</td>       |                |
|     |          |             | <td>14-26</td>      | 5\.            |
|     |          |             | <td>45-52</td>      | [Orthovisc     |
|     |          |             | </tr>               | :]{.underline} |
|     |          |             | <tr class="even">   |                |
|     |          |             | <td>Pain-wb VAS     | Data support   |
|     |          |             | (WMD)</td>          | the efficacy   |
|     |          |             | <td>-6.20,          | of Orthovisc   |
|     |          |             | p=0.009</td>        | vs. placebo as |
|     |          |             | <td>-9.04,          | well as        |
|     |          |             | p=0.0005*</td>      | safety.        |
|     |          |             | <td>-4.12,          |                |
|     |          |             | p=0.005</td>        | Orthovisc is   |
|     |          |             | <td>NS</td>         | comparable to  |
|     |          |             | </tr>               | IA steroids at |
|     |          |             | <tr class="odd">    | 1-4 weeks but  |
|     |          |             | <td>% More          | superior at    |
|     |          |             | effective vs.       | 5-13 weeks.    |
|     |          |             | Plac</td>           |                |
|     |          |             | <td>2-31%</td>      | Orthovisc vs.  |
|     |          |             | <td>18-44%</td>     | hylan GF-20:   |
|     |          |             | <td>3-26%</td>      | no difference  |
|     |          |             | <td>--</td>         | noted.         |
|     |          |             | </tr>               |                |
|     |          |             | <tr class="even">   |                |
|     |          |             | <td><p>Pain</p>     |                |
|     |          |             | <p>VAS              |                |
|     |          |             | (WMD)</p></td>      |                |
|     |          |             | <td>-23.88,         |                |
|     |          |             | p=0.00001</td>      |                |
|     |          |             | <td>-22.28,         |                |
|     |          |             | p=0.009*</td>       |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | </tr>               |                |
|     |          |             | <tr class="odd">    |                |
|     |          |             | <td>% more          |                |
|     |          |             | effective vs.       |                |
|     |          |             | Plac</td>           |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | <td>38-68%</td>     |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | </tr>               |                |
|     |          |             | <tr class="even">   |                |
|     |          |             | <td>Pain-rest VAS   |                |
|     |          |             | (WMD)</td>          |                |
|     |          |             | <td>-6.37,          |                |
|     |          |             | p=0.02*</td>        |                |
|     |          |             | <td>-9.65,          |                |
|     |          |             | p=0.0003</td>       |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | <td>NS</td>         |                |
|     |          |             | </tr>               |                |
|     |          |             | <tr class="odd">    |                |
|     |          |             | <td>% more          |                |
|     |          |             | effective vs.       |                |
|     |          |             | Plac</td>           |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | <td>13-116%</td>    |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | </tr>               |                |
|     |          |             | </tbody>            |                |
|     |          |             | </table>            |                |
|     |          |             |                     |                |
|     |          |             | wb=weight bearing   |                |
|     |          |             | \*Heterogeneity     |                |
|     |          |             | noted               |                |
|     |          |             |                     |                |
|     |          |             | -Response was       |                |
|     |          |             | measured in a       |                |
|     |          |             | number of other     |                |
|     |          |             | methods with some   |                |
|     |          |             | showing benefit of  |                |
|     |          |             | treatment vs.       |                |
|     |          |             | placebo most often  |                |
|     |          |             | at 1-4 and/or 5-13  |                |
|     |          |             | weeks.              |                |
|     |          |             |                     |                |
|     |          |             | -No difference in   |                |
|     |          |             | the rate of         |                |
|     |          |             | withdrawal between  |                |
|     |          |             | groups.             |                |
|     |          |             |                     |                |
|     |          |             | -Hyalgan was more   |                |
|     |          |             | effective than      |                |
|     |          |             | steroids at 5-13    |                |
|     |          |             | weeks but not 1-4   |                |
|     |          |             | weeks.              |                |
|     |          |             |                     |                |
|     |          |             | -One trial compared |                |
|     |          |             | 3 doses to 5 doses  |                |
|     |          |             | of Hyalgan. No      |                |
|     |          |             | difference was      |                |
|     |          |             | noted in response   |                |
|     |          |             | rates (79% vs. 67%, |                |
|     |          |             | respectively)       |                |
|     |          |             |                     |                |
|     |          |             | -One trial compared |                |
|     |          |             | Hyalgan to Hylan    |                |
|     |          |             | GF-20. It was       |                |
|     |          |             | stopped because of  |                |
|     |          |             | acute inflammatory  |                |
|     |          |             | reactions with      |                |
|     |          |             | Hylan (21%) vs.     |                |
|     |          |             | Hyalgan (0%).       |                |
|     |          |             |                     |                |
|     |          |             | **Hylan GF-20**: 24 |                |
|     |          |             | trials (9 vs.       |                |
|     |          |             | placebo, 9 vs.      |                |
|     |          |             | another hyaluronan, |                |
|     |          |             | 2 vs. steroids,     |                |
|     |          |             | others various      |                |
|     |          |             | comparisons) Mean   |                |
|     |          |             | Jadad score 3       |                |
|     |          |             |                     |                |
|     |          |             | Hyalgan vs.         |                |
|     |          |             | Placebo:            |                |
|     |          |             |                     |                |
|     |          |             | <table>             |                |
|     |          |             | <colgroup>          |                |
|     |          |             | <col                |                |
|     |          |             | st                  |                |
|     |          |             | yle="width: 19%" /> |                |
|     |          |             | <col                |                |
|     |          |             | st                  |                |
|     |          |             | yle="width: 21%" /> |                |
|     |          |             | <col                |                |
|     |          |             | st                  |                |
|     |          |             | yle="width: 23%" /> |                |
|     |          |             | <col                |                |
|     |          |             | st                  |                |
|     |          |             | yle="width: 23%" /> |                |
|     |          |             | <col                |                |
|     |          |             | st                  |                |
|     |          |             | yle="width: 12%" /> |                |
|     |          |             | </colgroup>         |                |
|     |          |             | <tbody>             |                |
|     |          |             | <tr class="odd">    |                |
|     |          |             | <td>Weeks</td>      |                |
|     |          |             | <td>1-4</td>        |                |
|     |          |             | <td>5-13</td>       |                |
|     |          |             | <td>14-26</td>      |                |
|     |          |             | <td>45-52</td>      |                |
|     |          |             | </tr>               |                |
|     |          |             | <tr class="even">   |                |
|     |          |             | <td>Pain-wb VAS     |                |
|     |          |             | (WMD)</td>          |                |
|     |          |             | <td>-12.54,         |                |
|     |          |             | p=0.002*</td>       |                |
|     |          |             | <td>-22.4,          |                |
|     |          |             | p=0.0006*</td>      |                |
|     |          |             | <td>-20.70,         |                |
|     |          |             | p=0.006*</td>       |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | </tr>               |                |
|     |          |             | <tr class="odd">    |                |
|     |          |             | <td>% More          |                |
|     |          |             | effective vs.       |                |
|     |          |             | Plac</td>           |                |
|     |          |             | <td>4-24%</td>      |                |
|     |          |             | <td>1-43%</td>      |                |
|     |          |             | <td>1-49%</td>      |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | </tr>               |                |
|     |          |             | <tr class="even">   |                |
|     |          |             | <t                  |                |
|     |          |             | d><p>Pain-night</p> |                |
|     |          |             | <p>VAS              |                |
|     |          |             | (WMD)</p></td>      |                |
|     |          |             | <td>-8.03,          |                |
|     |          |             | p&lt;0.0001</td>    |                |
|     |          |             | <td>-13.08,         |                |
|     |          |             | p=0.0004*</td>      |                |
|     |          |             | <td>-17.12,         |                |
|     |          |             | p&lt;0.00001</td>   |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | </tr>               |                |
|     |          |             | <tr class="odd">    |                |
|     |          |             | <td>% more          |                |
|     |          |             | effective vs.       |                |
|     |          |             | Plac</td>           |                |
|     |          |             | <td>13-31%</td>     |                |
|     |          |             | <td>28-50%</td>     |                |
|     |          |             | <td>28-96%</td>     |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | </tr>               |                |
|     |          |             | <tr class="even">   |                |
|     |          |             | <td>Pain-rest VAS   |                |
|     |          |             | (WMD)</td>          |                |
|     |          |             | <td>-9.44,          |                |
|     |          |             | p&lt;0.0001</td>    |                |
|     |          |             | <td>-18.67,         |                |
|     |          |             | p&lt;0.0001</td>    |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | <td>--</td>         |                |
|     |          |             | </tr>               |                |
|     |          |             | </tbody>            |                |
|     |          |             | </table>            |                |
|     |          |             |                     |                |
|     |          |             | wb=weight bearing   |                |
|     |          |             | \*Heterogeneity     |                |
|     |          |             | noted               |                |
|     |          |             |                     |                |
|     |          |             | -Significant        |                |
|     |          |             | difference was      |                |
|     |          |             | noted in walking    |                |
|     |          |             | pain at 5-13 weeks  |                |
|     |          |             | but not 1-4 weeks.  |                |
|     |          |             | No difference in    |                |
|     |          |             | overall pain at 1-4 |                |
|     |          |             | weeks.              |                |
|     |          |             |                     |                |
|     |          |             | -Response was       |                |
|     |          |             | measured in a       |                |
|     |          |             | number of other     |                |
|     |          |             | methods with some   |                |
|     |          |             | showing benefit of  |                |
|     |          |             | treatment vs.       |                |
|     |          |             | placebo most often  |                |
|     |          |             | at 1-4 and/or 5-13  |                |
|     |          |             | weeks and in some   |                |
|     |          |             | cases 14-26 weeks.  |                |
|     |          |             |                     |                |
|     |          |             | -Trials comparing   |                |
|     |          |             | Hylan DF-20 to      |                |
|     |          |             | steroids            |                |
|     |          |             | demonstrated a      |                |
|     |          |             | benefit of Hylan at |                |
|     |          |             | 5-13 and 14-26      |                |
|     |          |             | weeks.              |                |
|     |          |             |                     |                |
|     |          |             | -One trial          |                |
|     |          |             | comparing Artz to   |                |
|     |          |             | Hylan GF-20 did not |                |
|     |          |             | show a difference.  |                |
|     |          |             |                     |                |
|     |          |             | **Orthovisc:** 14   |                |
|     |          |             | trials, several are |                |
|     |          |             | unpublished. Mean   |                |
|     |          |             | Jadad score 2.9     |                |
|     |          |             |                     |                |
|     |          |             | Orthovisc vs.       |                |
|     |          |             | Placebo:            |                |
|     |          |             |                     |                |
|     |          |             |   -------           |                |
|     |          |             | ---- -------------  |                |
|     |          |             | ------------ ------ |                |
|     |          |             | ------- ----------- |                |
|     |          |             |   W                 |                |
|     |          |             | eeks:      1-4      |                |
|     |          |             |       5-13          |                |
|     |          |             | 14-26         45-52 |                |
|     |          |             |                     |                |
|     |          |             |   WO                |                |
|     |          |             | MAC Pain  -4.36,    |                |
|     |          |             |      -5.40,       - |                |
|     |          |             | 4.41,        -5.30, |                |
|     |          |             |                     |                |
|     |          |             |        p\<0.0001\*  |                |
|     |          |             |   p\<0.00001   p\<0 |                |
|     |          |             | .0007\*   p\<0.0001 |                |
|     |          |             |                     |                |
|     |          |             |   \% more     Ove   |                |
|     |          |             | rall,               |                |
|     |          |             |                     |                |
|     |          |             |   effective   23-   |                |
|     |          |             | 45%                 |                |
|     |          |             |                     |                |
|     |          |             |   vs. plac          |                |
|     |          |             |                     |                |
|     |          |             |                     |                |
|     |          |             |                     |                |
|     |          |             |   WOMAC       -7.20 |                |
|     |          |             | ,        -12.87,    |                |
|     |          |             |    -10.88,       NS |                |
|     |          |             |   Function    p\<   |                |
|     |          |             | 0.0001     p\<0.000 |                |
|     |          |             | 1    P=0.0005       |                |
|     |          |             |                     |                |
|     |          |             |   \% more     Ove   |                |
|     |          |             | rall,               |                |
|     |          |             |                     |                |
|     |          |             |   effective   16-   |                |
|     |          |             | 42%                 |                |
|     |          |             |                     |                |
|     |          |             |   vs. plac          |                |
|     |          |             |                     |                |
|     |          |             |                     |                |
|     |          |             |                     |                |
|     |          |             |                     |                |
|     |          |             |  Pt. Global  -20, p |                |
|     |          |             | =0.003  -20,        |                |
|     |          |             |   NS            \-- |                |
|     |          |             |   Assess            |                |
|     |          |             |            p=0.0002 |                |
|     |          |             |                     |                |
|     |          |             |   (WMD)             |                |
|     |          |             |                     |                |
|     |          |             |                     |                |
|     |          |             |   -------           |                |
|     |          |             | ---- -------------  |                |
|     |          |             | ------------ ------ |                |
|     |          |             | ------- ----------- |                |
|     |          |             |                     |                |
|     |          |             | \*Heterogeneity     |                |
|     |          |             | noted               |                |
|     |          |             |                     |                |
|     |          |             | -No safety issues   |                |
|     |          |             | noted.              |                |
|     |          |             |                     |                |
|     |          |             | -Several trials     |                |
|     |          |             | investigated        |                |
|     |          |             | Orthovisc vs. other |                |
|     |          |             | HAs. In general,    |                |
|     |          |             | there were no       |                |
|     |          |             | consistent          |                |
|     |          |             | differences or      |                |
|     |          |             | advantages between  |                |
|     |          |             | products.           |                |
+-----+----------+-------------+---------------------+----------------+
| M   | [Sear    | a\. Studies | a-b. 7 out of 35    | a\. The        |
| edi | ch:]{.un | assessing   | studies were        | authors        |
| na^ | derline} | benefit     | included. Three     | concluded from |
| 20^ | PubMed   | from HA or  | using WOMAC and 4   | the            |
|     | (195     | Hylan       | using Lequesne. One | meta-analysis  |
|     | 0-2004), | treatments  | meta-analysis was   | that HA may    |
|     | CINAHL   | were        | performed on all 3  | improve        |
|     | (198     | included if | using WOMAC and 2   | short-term     |
|     | 2-2004), | they used   | using Lequesne. A   | relief of pain |
|     | Medline  | WOMAC or    | separate analysis   | and            |
|     | (196     | Lequesne    | was performed for   | functionality  |
|     | 6-2004). | Index to    | each of the         | as measured by |
|     | Hand     | measure     | remaining 2 studies | the Lequesne   |
|     | search   | outcomes.   | using the Lequesne  | index but did  |
|     | of       |             | Index.              | not appear to  |
|     | re       | b\. All     |                     | affect pain or |
|     | ferences | data were   | **HA vs. placebo**  | disability in  |
|     | lists    | converted   | (Difference between | those studies  |
|     | for all  | into a      | groups)             | using WOMAC as |
|     | r        | percent of  |                     | the measure of |
|     | etrieved | the total   |   -------------     | improvement.   |
|     | studies. | possible    | --- --------------- | Stiffness was  |
|     |          | score for   | -- ---------------- | improved vs.   |
|     | [Includ  | each        |   **WOMAC           | placebo. Based |
|     | ed:]{.un | outcome     | **        **Statist | upon their     |
|     | derline} | measurement | ically   **95% CI** | findings, they |
|     | Efficacy | to allow    |                     | state that     |
|     | studies  | for         |  Significant        | there is no    |
|     | ev       | comparison  |                     | sufficient     |
|     | aluating | between     |  Result**           | reason to      |
|     | HA vs.   | results of  |                     | either         |
|     | saline   | the WOMAC   |   Pain              | recommend or   |
|     | in       | and         |       N             | not recommend  |
|     | jections | Lequesne    |      -0.6043-5.4755 | HA             |
|     | as the   | Index.      |                     | viscos         |
|     | control  | (Unclear if |   Disability        | upplementation |
|     | and in   | this method |       N             | for OA of the  |
|     | OA of    | is valid)   |      -0.8282-4.8619 | knee.          |
|     | the      |             |                     |                |
|     | knee.    | c\. Effect  |   Stiffness         | b\.            |
|     | Also use | sizes were  |        Y            | Limitations of |
|     | of the   | calculated. |       2.1780-8.7955 | the            |
|     | WOMAC or |             |                     | meta-analysis  |
|     | Lequesne | d\. Authors |   **Leque           | include narrow |
|     | Index to | were        | sne       **Statist | inclusion of   |
|     | measure  | contacted   | ically   **95% CI** | studies versus |
|     | outcomes | for missing |   Index**           | other          |
|     | and      | i           |  Significant        | meta-analyses, |
|     | study    | nformation. |                     | conversion of  |
|     | p        |             |  Result**           | data into a    |
|     | roviding | e\. Quality |                     | percent of the |
|     | means    | of each     |   Up to 6 mo        | total possible |
|     | and      | included    | nths   Y            | score for each |
|     | standard | study was   |       1.2315-2.6268 | outcome        |
|     | dev      | assessed    |   post-treatment    | measurement    |
|     | iations. | using the   |                     | using a method |
|     | . RCTs   | Ph          |                     | described by a |
|     | i        | ysiotherapy |   6 months or       | "statistical   |
|     | nvolving | Evidence    |  \>   N             | consultant"    |
|     | humans   | Database    |      -0.8489-8.7955 | and an         |
|     | and      | (PEDro)     |   post-treatment    | algorithm      |
|     | p        | rating      |                     | developed by   |
|     | ublished | scale.^22^  |   -------------     | one of the     |
|     | in       |             | --- --------------- | authors.       |
|     | English  | f\. Tests   | -- ---------------- | Unsure if      |
|     | were     | for         |                     | their methods  |
|     | i        | homogeneity | c\. Effect sizes    | are valid.     |
|     | ncluded. | between     | were not different  |                |
|     | Means    | studies     | between placebo and |                |
|     | and      | were not    | HA groups on change |                |
|     | standard | reported.   | from baseline to    |                |
|     | de       | Authors     | post-treatment.     |                |
|     | viations | seemed to   |                     |                |
|     | were     | assume      | d\. No requests for |                |
|     | needed   | homogeneity | missing information |                |
|     | to       | between     | were returned.      |                |
|     | perform  | studies     |                     |                |
|     | sta      | based upon  | e\. PEDro rating    |                |
|     | tistical | study       | scale was used to   |                |
|     | tests.   | inclusion   | assess quality and  |                |
|     |          | and         | the average score   |                |
|     | 2        | exclusion   | was 8.2 out of 10.  |                |
|     | r        | criteria.   |                     |                |
|     | eviewers |             | f\. Data was stated |                |
|     | indep    | g\.         | to be homogenous    |                |
|     | endently | Publication | between studies.    |                |
|     | selected | bias was    |                     |                |
|     | studies  | not         |                     |                |
|     | for      | addressed.  |                     |                |
|     | in       |             |                     |                |
|     | clusion, |             |                     |                |
|     | p        |             |                     |                |
|     | erformed |             |                     |                |
|     | s        |             |                     |                |
|     | earches, |             |                     |                |
|     | ab       |             |                     |                |
|     | stracted |             |                     |                |
|     | data and |             |                     |                |
|     | scored   |             |                     |                |
|     | method   |             |                     |                |
|     | ological |             |                     |                |
|     | quality. |             |                     |                |
+-----+----------+-------------+---------------------+----------------+
| Rei | [Sear    | [Direct     | [Direct Comparison  | Authors        |
| che | ch:]{.un | Comparison  | Studies of HA vs.   | conclude that  |
| nba | derline} | Studies of  | Hylan:]{.underline} | based upon     |
| ch^ | Cochrane | HA vs.      |                     | their          |
| 21^ | CTR,     | Hylan:]{    | 13 trials met       | meta-analysis, |
|     | Medline, | .underline} | inclusion criteria, | the evidence   |
| *   | EMBase,  |             | 11 published in     | does not       |
| *HA | Cinahl   | a\. If a    | full and 2 as       | support an     |
| vs  | from     | study       | abstracts only.     | advantage of   |
| Hy  | i        | presented   | Trial duration      | the hylan over |
| lan | nception | data on     | ranged from 3 weeks | the HA         |
| c   | through  | more than   | to 1 year (median 6 | products.      |
| omp | 11-06.   | one pain    | months) and 2,085   | However, from  |
| ari | Hand     | scale, the  | patients receiving  | their          |
| son | searched | highest on  | HA or Hylan.        | meta-analysis  |
| s** | co       | the         |                     | of ADEs,       |
| (   | nference | hierarchy   | a-d. Pooled effect  | flares and     |
| dir | proc     | of pain     | size-0.27 (95% CI   | joint          |
| ect | eedings, | related     | -0.55 to 0.01) with | effusions,     |
| and | te       | outcomes    | a high degree of    | there might be |
| ind | xtbooks, | was used.   | heterogeneity       | some           |
| ire | r        | If pain was | between studies     | disadvantages  |
| ct) | eference | assessed at | (I^2^=88%)          | of the Hylan   |
|     | lists,   | more than   |                     | vs. the HAs.   |
|     | etc.     | one time    | Effect sizes were   |                |
|     |          | point, the  | smaller in those    | There was      |
|     | [Includ  | final       | trials with         | significant    |
|     | ed:]{.un | assessment  | adequate            | heterogeneity  |
|     | derline} | or max of 6 | concealment (n=2),  | between        |
|     | RCT or   | months      | blinding of         | included       |
|     | qu       | pos         | patients (n=6) and  | trials and     |
|     | asi-RCTs | t-treatment | in trials using     | most of the    |
|     | (blinded | was used.   | intent-to-treat     | trials were    |
|     | or       |             | analysis (n=1) and  | judged to be   |
|     | un       | b\. Effect  | heterogeneity was   | of poor        |
|     | blinded) | sizes were  | lower between these | quality.       |
|     | c        | calculated  | trials.             |                |
|     | omparing | by dividing |                     |                |
|     | intra-a  | the         | There did not       |                |
|     | rticular | differences | appear to be an     |                |
|     | in       | in mean     | impact of source or |                |
|     | jections | values at   | origin of HA (avian |                |
|     | of HA    | the end of  | vs. bacterial) and  |                |
|     | with     | the trial   | Hylan.              |                |
|     | Hylan in | across      |                     |                |
|     | patients | treatment   | There was no        |                |
|     | with OA  | groups by   | evidence that       |                |
|     | of the   | the pooled  | molecular weight of |                |
|     | knee.    | standard    | the HA vs. Hylan    |                |
|     | Two      | deviation   | impacted effect     |                |
|     | r        | co          | size.               |                |
|     | eviewers | rresponding |                     |                |
|     | de       | to Cohen's  | e\. A high degree   |                |
|     | termined | d. If this  | of heterogeneity    |                |
|     | eli      | could not   | was found in the    |                |
|     | gibility | be          | analysis in which   |                |
|     | of       | calculated, | all data were       |                |
|     | trials.  | differences | pooled.             |                |
|     |          | in mean     |                     |                |
|     | 2 of 4   | changes     | f\. Meta-analysis   |                |
|     | r        | from        | of local ADEs,      |                |
|     | eviewers | baseline to | Flares and joint    |                |
|     | assessed | end of      | effusions:          |                |
|     | quality  | trial as a  |                     |                |
|     | of       | proxy       | -   6 trials with 7 |                |
|     | met      | measure,    |     comparisons     |                |
|     | hodology | otherwise   |     contributed to  |                |
|     | (con     | app         |     the             |                |
|     | cealment | roximations |     meta-analysis   |                |
|     | of       | were made.  |     of [local       |                |
|     | t        | **A         |                     |                |
|     | reatment | negative    |   ADEs]{.underline} |                |
|     | all      | effect size |     (e.g. pain,     |                |
|     | ocation, | indicated   |     swelling,       |                |
|     | blinding | superiority |     warming or      |                |
|     | and      | of hylan    |     severe          |                |
|     | a        | vs. HA. An  |     inflammatory    |                |
|     | nalyses, | effect size |     reactions): RR  |                |
|     | etc.)    | of -0.30    |     1.91 of Hylan   |                |
|     |          | was         |     (95% CI         |                |
|     |          | considered  |     1.04-3.39) vs.  |                |
|     |          | clinically  |     HA with low     |                |
|     |          | relevant.** |     statistical     |                |
|     |          |             |     heterogeneity   |                |
|     |          | c\.         |     I^2^=28%        |                |
|     |          | Ran         |                     |                |
|     |          | dom-effects | -   3 trials with 4 |                |
|     |          | me          |     comparisons     |                |
|     |          | ta-analysis |     contributed to  |                |
|     |          | was used to |     the             |                |
|     |          | pool effect |     meta-analysis   |                |
|     |          | sizes and   |     of flares: RR   |                |
|     |          | relative    |     2.04 (95% CI    |                |
|     |          | risks and   |     1.18-3.53)      |                |
|     |          | to          |     Hylan vs. HA    |                |
|     |          | calculate   |     and no          |                |
|     |          | the         |     statistical     |                |
|     |          | statistical |     heterogeneity   |                |
|     |          | he          |     I^2^=0%         |                |
|     |          | terogeneity |                     |                |
|     |          | (I^2^).     | -   2 trial with 3  |                |
|     |          | I^2^ of 25, |     comparisons     |                |
|     |          | 50 and 75%  |     contributed to  |                |
|     |          | indicates   |     the             |                |
|     |          | low,        |     meta-analysis   |                |
|     |          | moderate    |     of joint        |                |
|     |          | and high    |     effusions: RR   |                |
|     |          | degree of   |     2-40 (95% CI    |                |
|     |          | het         |     1.21-4.76)      |                |
|     |          | erogeneity, |     Hylan vs. HA    |                |
|     |          | re          |     with moderate   |                |
|     |          | spectively. |     heterogeneity   |                |
|     |          |             |     (I^2^=36%)      |                |
|     |          | d\.         |                     |                |
|     |          | Univariate  | [Indirect           |                |
|     |          | ran         | Comparison of HA    |                |
|     |          | dom-effects | vs.                 |                |
|     |          | meta        | Hylan:]{.underline} |                |
|     |          | -regression |                     |                |
|     |          | analysis    | a\. 31 trials       |                |
|     |          | was used to | (n=3983 patients)   |                |
|     |          | determine   | were included       |                |
|     |          | whether     |                     |                |
|     |          | effect      |   ---------         |                |
|     |          | sizes were  |  ---------- ------- |                |
|     |          | affected by |                     |                |
|     |          | the         |    **Effect   **95% |                |
|     |          | following:  |                     |                |
|     |          | allocation  |     Size**     CI** |                |
|     |          | c           |                     |                |
|     |          | oncealment, |   Overall           |                |
|     |          | blinding of |    -0.64      -1.25 |                |
|     |          | patients    |                     |                |
|     |          | and         |                  to |                |
|     |          | therapists, |                     |                |
|     |          | follow-up   |               -0.02 |                |
|     |          | duration    |                     |                |
|     |          | and MW of   |   Trials            |                |
|     |          | standard    |    0.23       -0.31 |                |
|     |          | HAs.        |   \>200 pts         |                |
|     |          |             |             to 0.77 |                |
|     |          | e\.         |                     |                |
|     |          | Cochrane Q  |   Trials            |                |
|     |          | was used to |    -1.19      -1.91 |                |
|     |          | determine   |   \<20              |                |
|     |          | he          | 0 pts            to |                |
|     |          | terogeneity |                     |                |
|     |          |             |               -0.46 |                |
|     |          | f\.         |   ---------         |                |
|     |          | Me          |  ---------- ------- |                |
|     |          | ta-analysis |                     |                |
|     |          | of ADEs and | -   Statistically   |                |
|     |          | flares      |     significant     |                |
|     |          |             |     difference      |                |
|     |          | [Indirect   |     between trial   |                |
|     |          | Comparison  |     size and        |                |
|     |          | of HA vs.   |     corresponding   |                |
|     |          | Hylan:]{    |     effect size     |                |
|     |          | .underline} |     with the larger |                |
|     |          |             |     studies         |                |
|     |          | a\.         |     favoring HA and |                |
|     |          | Indirect    |     the smaller     |                |
|     |          | comparison  |     trials favoring |                |
|     |          | of HA and   |     Hylan. Overall, |                |
|     |          | Hylan:      |     statistical     |                |
|     |          | Effect      |     heterogeneity   |                |
|     |          | sizes taken |     I^2^=72%        |                |
|     |          | from trials |                     |                |
|     |          | in which HA | Quality of included |                |
|     |          | or hylans   | trials was          |                |
|     |          | were        | generally poor      |                |
|     |          | compared to |                     |                |
|     |          | placebo.    |                     |                |
|     |          | This        |                     |                |
|     |          | analysis    |                     |                |
|     |          | was         |                     |                |
|     |          | undertaken  |                     |                |
|     |          | since a     |                     |                |
|     |          | couple of   |                     |                |
|     |          | the other   |                     |                |
|     |          | me          |                     |                |
|     |          | ta-analysis |                     |                |
|     |          | inferred    |                     |                |
|     |          | that there  |                     |                |
|     |          | may be a    |                     |                |
|     |          | greater     |                     |                |
|     |          | benefit of  |                     |                |
|     |          | the hylan   |                     |                |
|     |          | vs. HA      |                     |                |
|     |          | products.   |                     |                |
+-----+----------+-------------+---------------------+----------------+

ADEs=adverse events, ADLs=activities of daily living, ASPID=adjusted sum
of pain intensity difference, CL vs N-CL=cross-linked vs.
non-cross-linked, CTR=controlled trials register, FID=functional index
difference, HA=hyaluronic acid, IA=intra-articular, PID=pain intensity
difference, Pla=placebo, RCT=randomized controlled trial, SFID=sum
functional index difference, SPID=sum pain intensity difference,
\*Effect size: small effect size 0.2-0.5 is roughly similar to the
effect of NSAIDs, large effect size 1-1.8 is similar to that observed
with a knee replacement.