642271

research-article2016

CARXXX10.1177/1947603516642271CartilageBannuru et al.

Clinical Paper

Safety of Repeated Injections of Sodium Hyaluronate (SUPARTZ) for Knee Osteoarthritis: A Systematic Review and Meta-Analysis

Cartilage 2016, Vol. 7(4) 322­–332 © The Author(s) 2016 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1947603516642271 cart.sagepub.com

Raveendhara R. Bannuru1, Christopher R. Brodie2, Matthew C. Sullivan1, and Timothy E. McAlindon1

Abstract Objective. Though there is no consensus on its efficacy, knee osteoarthritis is symptomatically managed with intra-articular hyaluronic acid (IAHA). Recent reports suggest that IAHA may delay the need for total knee replacement, with the magnitude of delay proportional to the number of injection series. However, the safety of repeated injection series is reported to vary between commercial products. This report describes a systematic review of safety data on repeated treatment courses of SUPARTZ. Design. We performed a systematic search of MEDLINE, Cochrane database, EMBASE, Web of Science, Google Scholar, and unpublished data. We included all human randomized controlled trials or observational studies with adverse event (AE) data for SUPARTZ in knee osteoarthritis. Two independent reviewers extracted data and evaluated study quality. Data were analyzed separately for the first and subsequent series of injections. Results. The primary sources for repeated-injection data on SUPARTZ were a postmarket registry (N = 7404), 4 prospective studies (N = 127 total), and a retrospective study (N = 220). None of the sources reported increased frequency or severity of AEs with repeated injections. In the registry, 95% of multiple-injection-series patients who reported an AE did so during the first series. None of the AEs was serious, and most resolved spontaneously without medical intervention. The overall adverse event rate after repeat courses of SUPARTZ was 0.008 (95% confidence interval: 0.001-0.055). Conclusions. Multiple courses of SUPARTZ injections appear to be at least as safe, and probably safer, than the first course. This study supports the safety of repeat courses of SUPARTZ injections for knee osteoarthritis. Keywords hyaluronic acid, knee osteoarthritis, safety, repeated injection, systematic review

Introduction Osteoarthritis (OA) is a progressive disorder characterized by structural damage to the joints that affects hundreds of millions of people worldwide.1 This painful and debilitating condition accounted for an overall loss of 17 million disability-adjusted life years worldwide in 2010.2 OA symptoms are most common in the knee joint, and in developed countries, end-stage OA is often treated with total knee replacement (TKR). The procedure is generally effective, but patients may experience persistent pain and serious complications.3-5 In the United States, the number of TKR procedures has doubled in the past 10 years, outpacing increases in causative factors such as obesity and population aging.6 That increase was greatest among younger patients, with TKR tripling in those between 45 and 64 years of age.6 These trends represent a significant public health and economic burden.

Less severe forms of knee OA are commonly managed symptomatically with intra-articular injections of hyaluronic acid (IAHA).7-10 There are currently 8 HA products approved by the Food and Drug Administration (FDA) and sold in the United States as viscosupplements for the treatment of OA pain. These HA preparations are derived either from avian sources (chicken combs) or from bacterial fermentation, and differ with regard to molecular weight, HA concentration/amount delivered, and number of injections 1

Center for Treatment Comparison and Integrative Analysis, Division of Rheumatology, Tufts Medical Center, Boston, MA, USA 2 Bioventus LLC, Durham, NC 27703, USA Corresponding Author: Raveendhara R. Bannuru, Center for Treatment Comparison and Integrative Analysis (CTCIA), Tufts Medical Center, 800 Washington Street, #406, Boston, MA 02111, USA. Email: [email protected]

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Bannuru et al. Table 1.  Characteristics of US Food and Drug Administration–Approved HA Viscosupplement Products.

HA Product

US Distributor

Origin

Molecular Weight (kDa)

Euflexxa Gel-One Hyalgan Monovisc Orthovisc Synvisc Synvisc-One SUPARTZ

Ferring Zimmer Fidia DePuy Synthes DePuy Synthes Sanofi Sanofi Bioventus

Bacteria Avian Avian Bacteria Bacteriaa Avian Avian Avian

2,400-3,600 N.D. (Cross-linked) 500-730 N.D. (Cross-linked) 1,000-2,900 6,000 (Cross-linked) 6,000 (Cross-linked) 620-1,170

Injections per Treatment Course (N)

Total HA per Treatment Course (mg)

3 1 3-5 1 3-4 3 1 3-5

60 30 60-100 88 90-120 48 48 75-125

ND = not described; HA = hyaluronic acid. a Original avian origin.

per treatment course (see Table 1). Four of the HA products comprise formulations of unmodified sodium hyaluronate (Euflexxa, Hyalgan, Orthovisc, and SUPARTZ), while the others are treated with cross-linking procedures, which increase molecular weight, and may enhance residence time (half-life) in the joint. Thus, while the half-life of unmodified HA (sodium hyaluronate) is on the order of 1 day, the half-life of cross-linked hylans (i.e., Synvisc) may range up to several days.11 However, cross-linked HAs have also been associated with increased adverse effects such as inflammatory reactions, which may potentially be attributable to the chemical cross-linking process employed and/or increased half-life.12 In a recent review and meta-analysis of randomized, saline-controlled trials of US-approved HA products, Strand et al.13 observed that IA injection of such products is safe and efficacious over 26 weeks. With one exception, the HA treatments in the 29 studies assessed included a single cycle (course) of injections. In a previous review and metaanalysis, Rutjes et al.8 reported an increased risk for serious adverse events in patients with knee OA treated with various HA supplements. In that analysis, however, and in contrast to the analysis by Strand et al.,13 the treatment association of reported serious adverse events was not evaluated. Recent data have suggested that the use of HA may delay the need for TKR.14-16 Thus, Altman et al.16 reported that the use of IAHA was associated with an average delay of up to 3 years in the time to TKR. The magnitude of the delay was proportional to the number of HA injection series. The economic benefits of delaying the time to a TKR procedure have recently been demonstrated in studies describing the long-term cost-effectiveness of HA treatments per quality-adjusted life years (QALY) relative to TKR.17,18 The safety of repeated injection series has not been established for all HA products, and at least one study has reported a significantly higher number of adverse events in patients receiving more than one course of treatment.19 Other reports

have not found evidence of increased risk in multiple series of IAHA injections,20,21 raising the possibility that the relative safety of repeat injections may vary between HA products. Preclinical studies have also evaluated the potential inflammatory and/or immunological effects of different HA preparations, following subcutaneous injection. In a mouse model, local air pouch membrane inflammation was observed for both cross-linked and non-crosslinked HAs, whereas only cross-linked HA elicited an antibody-mediated response.22 In a guinea pig model wherein animals were sensitized with multiple injections of HA, crosslinked HA elicited a delayed-type hypersensitivity reaction.23 Here we report the results of a systematic review of published safety data on 1 US-approved HA product, SUPARTZ, in order to compare adverse events during the first course of injections to those that occur during the second and subsequent courses. SUPARTZ has been marketed in Japan since 1987 and in the United States since 2001. The product has been sold in 22 countries under the names SUPARTZ, Artz, ArtzDispo, or Artzal. Though the efficacy and safety of single course of SUPARTZ has already been established, its safety after repeat courses is not well established.24,25 Therefore, the aim of this study was to review in a systematic fashion the safety of repeat courses of SUPARTZ injections in the management of knee OA.

Methods The properties of HA viscosupplements available in the US market (see Table 1) were compiled by electronically surveying peer reviewed citations and distributor information sources. SUPARTZ is an avian-derived product composed of a solution of purified, high molecular weight (620-1,170 kDa) sodium hyaluronate. Each 1 mL of SUPARTZ contains 10 mg of HA dissolved in physiological saline (1.0% solution).

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Data Sources and Search Strategy We performed a systematic electronic literature search for peer reviewed citations investigating the safety of intraarticular injections of SUPARTZ in the management of knee OA. We searched MEDLINE, the Cochrane Central Register of Controlled Trials, EMBASE, Web of Science, and Google Scholar from database inception to 15 October 2015 using the following search terms: “osteoarthritis,” “hyaluronic acid,” SUPARTZ, Artz, ArtzDispo, and Artzal. In addition to our electronic literature search, we actively searched for unpublished data by contacting SUPARTZ’s manufacturer and experts in the field. We also searched the FDA Premarket Approval Application (PMA) database for unpublished data on SUPARTZ, along with competitive IAHAs for comparative safety profiles. All searches were limited to human studies. We placed no restrictions on publication language; relevant non–English language articles were translated.

Inclusion and Exclusion Criteria Two independent reviewers screened abstracts and full text articles to determine eligibility. Patient inclusion criteria were adults diagnosed with knee OA. Eligible trials were human randomized controlled trials and observational studies which reported adverse event data for intra-articular injection of SUPARTZ in knee OA patients. We excluded animal and in vitro studies, conference abstracts, and studies which did not provide adverse event data.

Outcome Measures and Time Points Our primary outcome measure was overall incidence of adverse events. We also examined adverse events reported separately by type and severity.

Data Extraction After an a priori training exercise, 2 reviewers independently and in a blinded manner evaluated the studies and extracted data into a standardized electronic data extraction form. Any discrepancies in data extraction between the 2 reviewers were resolved by consensus. The disagreement rate across all entire extracted data was 2%. Information on characteristics of included participants (including number of participants, age, gender, OA grade, and disease duration), study characteristics (study design, study inclusion and exclusion criteria, number of injections administered, and duration of treatment), and adverse events was extracted from each study.

Risk of Bias of Included Studies Two reviewers blinded to one another’s assessments evaluated the quality of eligible studies. The Cochrane risk of

Cartilage 7(4) bias tool was used to assess the quality of randomized controlled trials.26 Trials were assessed based on comparability of study groups at baseline, randomization procedure, allocation concealment, participant and assessor blinding, and whether analysis was intention-to-treat. The NewcastleOttawa Scale was used to assess the quality of observational studies.27 This scale assesses a study on 3 broad perspectives: selection of the study groups; comparability of the groups; and ascertainment of the exposure or health outcome of interest. The studies were graded as poor (0-3 stars), moderate (4-6), or high (7-9) quality. We also assessed the quality of observational studies using Coleman score.28

Analytic Approach First Course Data.  We qualitatively summarized the data on the adverse events after the first course of SUPARTZ. We compared the adverse event rates between SUPARTZ and placebo groups in order to establish a reference or baseline for expected adverse events. Subsequent Course Data. We qualitatively synthesized the data on the adverse events after multiple courses of SUPARTZ and presented it in the order of best available evidence. The data was pooled across all studies using a random-effects model.29 Heterogeneity among the included studies was tested using Cochrane Q test and was quantified using I2 statistic.30

Results Our literature search yielded 1087 articles (Fig. 1). 1070 articles were excluded after abstract and full-text screening because they did not meet our inclusion criteria. Of the 17 eligible articles, 6 observational studies looked at the safety of repeat courses of SUPARTZ; 6 randomized controlled trials (RCTs) and 1 integrated analysis comprising 5 more RCTs (a total of 11 RCTs) examined the safety of a single course of SUPARTZ injections.

Adverse Event Rates After the First Course of SUPARTZ We identified a total of 11 randomized placebo-controlled trials reporting on adverse events after the first course of SUPARTZ (Table 2). Nine of these trials were published separately.31-39 Three of these separately published trials37-39 and 2 other unpublished trials40 were included in a patientlevel meta-analysis.41 Integrated Safety Analysis. In the 5 trials included in the patient-level integrated safety analysis, a total of 1,155

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Bannuru et al.

events was detected in comparison with placebo. Another trial reported treatment-related arthralgia in 16% of patients receiving SUPARTZ compared with 7% of patients receiving placebo.36 In 5 trials reporting the total rates of adverse events, the percentage of patients reporting ranged from 61% (vs. 50% for placebo)35 to 0% (vs. 0% for placebo).34 In the 6 trials, 7 participants receiving SUPARTZ (1.6%) and 10 receiving placebo (2.5%) withdrew due to adverse events. One trial which categorized adverse event incidence by organ system, reported that the most frequently occurring adverse events were musculoskeletal disorders (including arthralgia, arthropathy, and skeletal pain), occurring in 23% of the SUPARTZ group and 21% of the placebo group.36 In summary, adverse events after the first course of SUPARTZ were similar in characteristics and severity to those observed in the placebo group.

Adverse Event Rates After Multiple Courses of SUPARTZ We identified a total of 6 observational studies examining the safety of repeat courses of SUPARTZ. The characteristics of the repeat-course SUPARTZ studies are described in Table 3. Figure 1.  Flow diagram summarizing trial search and selection.

patients with knee OA were enrolled; 619 received either 3 or 5 SUPARTZ injections, while 536 received “placebo” saline injections and were followed at least up to 13 weeks.41 The rates of discontinuation due to adverse events were similar across active (SUPARTZ) and control groups in both the individual trials and integrated analysis: 1.8% of those receiving SUPARTZ and 3.2% receiving control injections discontinued treatment early due to an adverse event. The most common adverse event noted was arthralgia. Other common adverse events included injection site disorders arthropathy/arthrosis/arthritis, back pain, nonspecific pain, and headaches (Fig. 2). No adverse events were reported to be serious and all resolved without sequelae, and none were considered by the investigators to be related to SUPARTZ. Eight allergic reactions were reported in the 5 RCTs; none of these were judged by the investigators to be related to HA injections. They included hay fever, a cutaneous allergy to adhesive tape, and an allergic reaction to an intramuscular injection of diclofenac. No deaths were reported from this treatment among any of these 5 trials. Other Randomized Evidence. Six other RCTs reported adverse events data in 832 participants on a single course of SUPARTZ or placebo injections. In 5 of these trials,31-35 no statistically significant increase in treatment-related adverse

Post–Market Surveillance Data. A post–market surveillance study performed in Japan evaluated data from a total of 7,404 patients with knee OA who received intra-articular injections of SUPARTZ (Table 3).42 Of these cases, 3,614 (49%) received more than 1 treatment course (5 injections). That study compiled data prospectively from January 12, 1987 to January 11, 1993, from 675 medical institutions and evaluated the safety, effectiveness and utility of SUPARTZ injections for the knee and shoulder. This review includes only safety data pertaining to those subjects receiving injections in the knee. In this study, an adverse event was defined as an event that the treating physician assessed as related to SUPARTZ. General safety was assessed by the treating physician in person using the presence or absence of adverse events after each injection, the type and degree of symptoms, and clinical laboratory results that assessed liver, biliary, and metabolic function. Laboratory tests were conducted at the end of each course of treatment; baseline data were not collected. SUPARTZ was well tolerated in this population, with only 37 of 7,404 patients (0.5%) reporting 58 adverse events. Adverse events occurred most frequently (53 out of 58) during the first course of treatment (i.e., 1-5 injections), and typically occurred within a few hours of injection. Twenty-three out of 31 adverse event cases occurred within several hours of the injection, and only 2 occurred later than 1 day after injection. Thirty-five of 37 (95%) adverse event cases were reported during the first injection course. The

326

RCT

RCT

RCT

RCT

RCT

RCT

RCT

RCT

RCT

RCT

Shichikawa and Ogawa, 198332 Japan

Puhl et al., 1993a37 Germany

Dahlberg et al., 199433 Sweden

Lohmander et al., 1996a38 Sweden

Karlsson et al., 200235 Sweden

Wu et al., 199734 Japan

Day et al., 2004a39 Australia

Rolf et al., 200536 Sweden

UKa40 (unpublished)

Francea40 (unpublished)

254

231

272

240

 90

246

240

52

209

228

107

Study N

Exclusion Criteria

Moderate/severe joint Radiographic knee space narrowing; OA with pain on synovial effusion movement Radiographic knee OA Severe joint space with pain on exercise narrowing; synovial effusion Radiographic knee OA; Inflammatory joint age 40-75 yrs diseases, excessive effusion (≥100 mL) Inflammatory joint Knee pain and diseases, any other cartilage abnormality conditions that diagnosed by might interfere with arthroscopy treatment Radiographic OA, VAS Previous intra-articular knee fracture, RA pain> 10 mm, age 40-75 yrs Radiographic knee OA, Ahlback grade III-IV, VAS pain ≥40mm prior intra-articular fracture Mild/moderate early Marked joint narrowing, OA; exercise pain varus/vulgus deformity Complete loss joint Mild/moderate OA; space loss; severe pain on walking; age malalignment; RA 40-75 yrs Knee OA; age ≥35; VAS Bilateral symptomatic walking pain ≥40 mm OA; RA; BMI >40kg/ m2 Synovial effusion >50 mL Radiographic OA; moderate pain >3 months Radiographic OA; VAS Severe effusion (tight, global pain ≥35 mm distending effusion)

Inclusion Criteria

65

61

54

62

69

71

58

45

61

nd

62

Mean Age (Years)

68

57

40

59

28

65

56

nd

64

76

83

% Female

3 or 5

5

3

5

5

3

5

5

5

5

5

No. of Weekly Injections

5 weeks/13 weeks

5 weeks/25 weeks

3 weeks/52 weeks

5 weeks/18 weeks

5 weeks/26 weeks

3 weeks/26 weeks

5 weeks/20 weeks

5 weeks/52 weeks

5 weeks/14 weeks

5 weeks/6 weeks

5 weeks/6 weeks

Treatment/Study Duration

nd

nd

I-III (Outerbridge)

nd

nd

I-II (Ahlback)

I-II (Ahlback)

nd

nd

nd

nd

OA Grade

nd

nd

8

nd

2

nd

nd

nd

nd

nd

nd

OA Duration (Years)

Cochrane Risk of Bias Tool

Uncertain

Low

Low

Low

Low

Paracetamol

Co-proxamol

Paracetamol (2 g/day)

Low

Uncertain

Uncertain

Paracetamol and other Low analgesics

None

Paracetamol (4 g/day)

Simple analgesics and NSAIDs

nd

Prior paracetamol

Prior anti-inflammatory Low medication

Prior physical therapies Low

Co-medications Permitted

RCT = randomized controlled trial; OA = osteoarthritis; NSAID, nonsteroidal anti-inflammatory drug; nd = no data; yr(s) = year(s); VAS = visual analog scale; RA = rheumatoid arthritis; High = high risk of bias; Uncertain = uncertain risk of bias; Low = Low risk of bias. a Study was included in the Strand et al. (2006) integrated safety analysis.41

Shichikawa et al., 1983 Japan

RCT

Study Type

31

Study Authors, Year, Country

Table 2.  Characteristics of Studies Reporting Adverse Events in Single-Course SUPARTZ Treatment.

Bannuru et al.

Figure 2.  Frequency of adverse events reported in an integrated analysis of 5 randomized controlled trials (RCTs) that examined one series of SUPARTZ versus one series of saline control injections (N = 1155). Reference: Table VII from Strand et al.41

incidence of adverse events among patients who received more than one course of injections was 0.06% (2/3614). One patient reported 1 reaction during the second course, and 1 patient reported 4 reactions between the third and fourth course of injections. The specific reactions in these 2 cases were not described. The 37 affected patients reported a total of 58 adverse events, of which 83% (48 of 58) occurred at the injection site. Local reactions included pain (29), swelling (16) and redness (3). Other reactions were rash (3), itching (1), increased serum glutamic oxaloacetic transaminase (2), increased serum glutamic-pyruvic transaminase (3), and increased alkaline phosphatase (1). The incidence and nature of these reactions are described in the current US labeling for the product. Of those reporting adverse events, 21 cases (54%) continued SUPARTZ treatment; 5 of these continuing patients experienced subsequent local site reactions. An age-stratified analysis comparing subjects younger than 65 years with older patients found no age-related differences in the incidence of adverse events. In summary, the rate of adverse events was very low, and most events appeared during the first course of treatment. These few events were mostly mild in severity and localized to the injection site. No deaths were reported from this treatment. The quality of this study was assessed as moderate. Prospective Data. We found 4 uncontrolled prospective studies from Japan, which included a total of 127 knee OA patients receiving repeated courses of SUPARTZ (>5 injections).43-46 The characteristics of these studies are presented in Table 3. The quality of these studies varied, but was moderate overall. All 4 studies examined patients who received repeated courses of SUPARTZ (i.e., >5 injections). After the first course, subsequent injections were administered every 1 to

327 4 weeks as determined by symptom persistence. The average duration of treatment across all 4 studies was 12.4 months (range 4-35 months). Two of the 4 studies (N = 77 total43,46) conducted full laboratory analyses at baseline, again at intermediate stages (in 1 study at 5 weeks, and in another every 6 months), and also at the conclusion of treatment. Laboratory tests included hematology (red blood cells, white blood cells, hemoglobin, hematocrit, platelets, and erythrocyte sedimentation rate), clinical chemistry (GOT, GPT, Al-P, creatinine, and blood urea nitrogen), and urinalysis (protein, sugar, urobilinogen, and sediments). Three of the 4 studies described explicit methods for monitoring the incidence, severity, cause, and outcome of adverse events.43,45,46 No adverse events or abnormal lab results related to SUPARTZ use were reported in any of the prospective studies. One study reported that a 69-year-old patient complained of mild injection site pain at every administration, but the authors did not classify this complaint as a side effect, and the patient continued to receive injections.43 The total number of treatments for this specific patient was not specified, but the range of total injections for the study was 8 to 23. In summary, the evidence from these 4 moderatequality, prospective, uncontrolled studies (n = 127) suggests that multiple courses of injections pose no additional safety concerns above and beyond those associated with a single course. Retrospective Data. One retrospective study conducted in the United States analyzed 303 OA knees from 220 patients47 and examined the safety and effectiveness of 2 or more courses of SUPARTZ injections (Table 3). Although all patients received more than 1 course of SUPARTZ, adverse events were reported beginning with the first injection of the first course. Only the total number of events was reported; the authors did not separately list adverse events that occurred after the sixth injection or second course. Thus, this review did not compare the number of reactions during the first course versus subsequent courses. The authors classified adverse events as related, possibly related, or not related to the injection, and also categorized the severity of adverse events as mild, moderate, or severe. Reactions that did not interfere with routine activity were defined as mild. Moderate reactions were defined as those that interfered with routine activity but responded to symptomatic therapy or rest. Severe reactions were defined as those that interfered with routine activities despite symptomatic treatment and required medical or surgical treatment or hospitalization. A total of 26 adverse events were reported (20 mild and 6 moderate) in 303 knees from 220 patients. Twenty-five of 26 were considered possibly related to the injection. Only 1 event was determined to be definitely related to the injection, with the patient reporting pain that interfered with

328

Study Type

Study N Knee OA with pain on exercise

Inclusion Criteria

nd

nd

Knee OA

Knee OA

Marked narrowing of joint space; large amount of effusion; IA injection in previous 2 weeks; other serious health complications; pregnant and lactating women Previous study drug allergy; pregnant/ lactating women

Marked narrowing of joint space; large amount of effusion; IA injection in previous 2 weeks; other serious health complications nd

Exclusion Criteria

71 (35-99)

60 = 78%

74.5

76

79

73

63 (28-79)

67 (36-83)

77

63

67 (40-87)

71

% Female

nd

≤5 = 51%; 6-10 = 32%; 11-19 = 11%; ≥20= 6%

38 (16-106)

18 (8-32)

5 or more

14 (8-23)

Mean Number of Injections (Range)

a

OA = osteoarthritis; nd = no data; IA = intra-articular. A Newcastle-Ottawa score of 0-3 indicates poor methodological quality, 4-6 indicates moderate quality, and 7-9 indicates high quality.

Ueno et al., Postmarketing 7404 199542 Japan safety assessment study Whitman Retrospective 220 (303 47 et al., 2010 cohort study knees) USA

Hashimoto Prospective 34 patients Definite et al., 199246 cohort study diagnosis (35 of mild/ knees) Japan moderate OA

Yoh et al., Prospective 35 patients Knee OA on 198944 Japan cohort study X-ray (48 knees) Suzu and Prospective 15 Knee OA Hirasawa, cohort study with pain on 45 1990 Japan motion

Igarashi et al., Prospective 43 198343 Japan cohort study

Study Authors, Year, Country

Mean Age, Years (Range)

Table 3.  Characteristics of Studies Reporting Adverse Events in Multiple-Course SUPARTZ Treatment.

nd

nd

70% >1 year

OA Duration

93% >1 1 mild; 9 moderate; year 5 severe

nd

OA Grade

Prior antiinflammatory agents and physical therapies

nd

Prior antiinflammatory agents and physical therapies

nd

nd

nd

11

71

6

1

57

70

70

6

5

60

67

4

5

NewcastleOttawa Coleman Quality Score a Co-medications Score (0-9) (0-100)

6 months to Prior anti32-152 (mean of 78) 9 mild; 20 inflammatory moderate; 3 years 1 agents and month 5 severe physical therapies nd Mild to nd nd severe

16-78 (mean of 54)

≥26 (mean of 65)

13-40 (mean of 26)

Treatment Duration (Weeks)

Bannuru et al.

329

Figure 3.  Adverse event rate after repeat courses of SUPARTZ.

walking for 3 days and requiring bed rest. This reaction was 1 of 6 moderate adverse events, with the others including arthralgia (2), swelling (1), stiffness (1), and fainting (1). The 20 mild events included skin ecchymosis (11), pain (5), swelling (2), blistering (1), and nausea (1). All adverse events, mild and moderate, resolved spontaneously and without medical intervention. In summary, this retrospective study from the United States found a higher incidence (8.6%) of overall adverse events than found in a large Japanese registry (0.5%), but did not distinguish between the events occurring after first and repeat courses. Meta-Analysis Results. After pooling the data from all the studies, the overall adverse event rate after repeat courses of SUPARTZ was 0.008 with a 95% confidence interval ranging between 0.001 and 0.055 (Fig. 3). There were 8 events per 1,000 patients (0.08%). The heterogeneity among the studies was high (I2 = 73%). The heterogeneity among the included studies was high because they were conducted in different countries at different time periods, and also there were differences in the number of injections, and the length of follow up.

Discussion This study supports the safety of repeat courses of SUPARTZ injections for knee OA. The adverse events in the first course of SUPARTZ were similar in characteristics and severity to those observed in the placebo group. Moreover, adverse events were mostly mild in severity and typically subsided quickly. The incidence of adverse events in repeat courses of SUPARTZ was lower than first-course treatment.

The results of the post–market surveillance study were consistent with results from the 4 prospective, uncontrolled studies that described the results of 6 or more injections of SUPARTZ.42-46 Although there was heterogeneity in terms of the number of injections administered (range 8-106, average 23.3), the safety outcomes were similar. No adverse events were reported for any of the 127 treated patients. Two of the studies conducted full laboratory workups at baseline, during treatment, and at the conclusion of treatment. None of the 77 patients43,46 examined showed abnormal laboratory values related to SUPARTZ treatment. This evidence suggests that repeated SUPARTZ use did not negatively affect hepatic, renal, or metabolic function. Compared with the available safety data on repeat courses of other hyaluronic acid treatments, the incidence of adverse events following repeat courses of SUPARTZ was low. Open-label studies examining repeat courses of the FDA approved intra-articular hyaluronic acid products Euflexxa and Monovisc reported an overall adverse events rate of 43.8% and 49.6%, respectively,48,49 which were considerably higher than the adverse events rates reported in the SUPARTZ studies we examined.42-47 The incidence of treatment-related adverse events was reported as 4.1%, 5.2%, and 5.0% to 16.8% for Euflexxa, Synvisc-One, and Monovisc, respectively.48-50 These rates are higher than those reported in the Japan-based SUPARTZ studies (0.5%), but are similar to the adverse events incidence found in the US-based SUPARTZ study. Of note, one course of SynviscOne or Monovisc consists of only a single injection, whereas a course of SUPARTZ consists of 5 injections (see Table 1); nevertheless, the incidence of adverse events associated with these treatments was similar to or greater than the incidence of SUPARTZ-related adverse events. Studies examining

330 multiple treatment courses with Hyalgan also found no evidence of increased adverse events following repeat treatment.51 Cultural differences could also explain the discrepancy between the Japanese observational data and those from Western countries (the 5 RCTs were conducted in Australia, France, Germany, Sweden, and the United Kingdom). Social norms may reduce adverse-event disclosure or reporting in Japan relative to other nations. In support of this hypothesis, Igarashi43 noted that although no adverse events occurred among their 43 patients, “One woman of 69 years old complained of mild pain at every administration in injected region but was not regarded as a side effect, while her impression was ‘Improve’ and the improvement of symptoms was ‘Moderate.’” The authors did not consider this woman’s experience to qualify as an adverse event, although such a reaction would be deemed an adverse event under the US criteria. Regardless of cultural differences, no study reported an increase by any standard in the frequency or severity of adverse events associated with 6 or more injections of SUPARTZ®. One other aspect to be noted here is that these studies have been published over a period of 30 years, and the adverse event reporting methodologies have changed overtime. The newer studies using more stringent reporting methodologies might report more adverse events than those observed in this set of studies. Limitations of this review include the quality of available evidence on repeat injection courses of IAHA products. The data regarding the safety of repeat SUPARTZ injections was drawn from observational cohort studies of moderate methodological quality. Because long-term randomized clinical trials are expensive and pose feasibility concerns such as high study attrition, such studies are infrequently conducted and observational studies often provide the best available source of data for the safety of treatments in long-term follow-up. Thus, postmarketing studies such as those in this review provide one of the strongest sources of long-term safety data on pharmaceutical treatments. In summary, there is no evidence of increasing—or even equivalent—risk associated with multiple courses of SUPARTZ. Registry data suggest that patients are most likely to experience adverse events following the first injection of SUPARTZ, with 95% of adverse events occurring within the first course of 5 injections. Most of the adverse events that did occur were mild to moderate and resolved without medical intervention.

Conclusion Adverse events to SUPARTZ are rare in patients who have already received one course of SUPARTZ therapy. Data suggest subsequent courses of injections are at least as safe, and probably safer, than the first course. There is no evidence of increased risk associated with a high frequency of

Cartilage 7(4) SUPARTZ use. Thus, this study provides necessary and sufficiently valid scientific evidence to offer reasonable assurance of the safety of SUPARTZ for multiple courses of injection. Acknowledgments and Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RRB reports personal fees from Bioventus. CRB is an employee of Bioventus. MS declares no competing interests. TEM reports personal fees from Bioventus, and grants from Croma, Flexion Therapeutics, National Institutes of Health, and Agency for Healthcare Research and Quality outside the submitted work.

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