Health Economic Assessments of Hyaluronic Acid Treatments for Knee Osteoarthritis: A Systematic Review.

INTRODUCTION: Hyaluronic acid (HA) use to treat knee osteoarthritis (OA) has been extensively investigated in the literature. There are also multiple economic assessments comparing intra-articular HAs with oral anti-inflammatory medicines and other conservative measures (NSAIDs), as well as different types and formulations of HA. Owing to the broad landscape of evidence across this area, it is important to further understand the empirical data comparing HA products, as well as the health economic implications that exist between commercially available HAs. This systematic review aims to identify and summarize the available evidence comparing commercially available HA products in the USA, as well as the health economic evidence and socioeconomic outcomes associated with HA use for knee OA. METHODS: A systematic literature review within the OVID Medline, Embase, HealthStar, and Cochrane EBM HTA databases was conducted. Articles were screened for eligibility, and a qualitative summary of the findings was provided based on specific themes: (1) trials comparing the safety and/or efficacy of two or more HA products in knee OA, (2) economic/cost analyses of HA use in knee OA, and (3) studies investigating healthcare resource utilization in patients treated with HA for knee OA. RESULTS: The search strategy identified 398 studies, 27 of which were deemed eligible: 21 health economic analyses with US relevance and six head-to-head trials of HA products available in the USA, cumulatively assessing 5,782,156 patients with knee OA. The evidence demonstrates a clear distinction between high and low molecular weight HAs, as both efficacy and cost analyses provided favorable results for the high molecular weight options. In all but one cost analysis, HA use was a cost-effective option when compared to routine nonoperative care, captured in administrative databases, which typically included NSAID use and/or corticosteroids. HA saw benefits in delaying the need for total knee arthroplasty (TKA), decreasing the use of rescue medication, and limiting the need for additional corticosteroid injection. The included evidence highlights that the treatment's cost-effectiveness is improved when HA is utilized in earlier stages of the disease, as opposed to when HA is reserved for late stages of knee OA. Additionally, among HAs, Bio-HA and Hylan G-F 20 evidence made up the majority of available literature with beneficial efficacy and cost outcomes. Head-to-head evidence between them indicated similar pain outcomes; however, Bio-HA required less rescue with acetaminophen and had fewer joint effusions in this comparison. CONCLUSIONS: The available efficacy and safety data as well as health economic analyses on the use of HA for knee OA management suggest that there are economic benefits of this treatment option. From a healthcare system perspective, the body of HA literature summarizes favorable costs profile, decreased opioid and corticosteroid use as rescue medication, and a delay to the need for TKA in patients who have HA included in their treatment regimen.

Association Between Bio-Fermentation Derived Hyaluronic Acid and Healthcare Costs Following Knee Arthroplasty.

Background: Limiting access to intra-articular knee injections, including hyaluronic acid (HA), has been advocated as a cost-containment measure in the treatment of knee osteoarthritis. The association between presurgical injections and post-surgical complications such as early periprosthetic joint infection and revision remained to be investigated. This study evaluated pre- and post-surgical costs and rates of post-surgical complications in knee arthroplasty (KA) patients with or without prior HA use. Methods: Commercial and Medicare Supplemental Claims Data (IBM MarketScan Research Databases) from January 1, 2012 to December 31, 2018 were used to identify unilateral KA patients. Those who completed a course of bio-fermentation derived HA (Bio-HA) as the first-line HA therapy comprised of the test group (n = 4091), while the control group did not use HA prior to KA (n = 118,659). Using multivariable regression with propensity score (PS) weighting, overall healthcare costs, readmission rates, and revision rates were assessed at six months following KA. Results: Healthcare costs following KA were significantly lower for the Bio-HA group ($10,021 ± $22,796) than No HA group ($12,724 ± $32,966; PS p < 0.001). Bio-HA patients had lower readmission rates (8.9% vs 14.0%; PS p < 0.001) and inpatient costs per readmitted patient ($43,846 ± $50,648 vs $50,533 ± $66,150; PS p = 0.005). There were no differences in revision rate for any reason (Bio-HA: 0.78% vs No HA: 0.67%; PS p = 0.361) and with PJI (Bio-HA: 0.42% vs No HA: 0.33%; PS p = 0.192). Costs in the six months up to and including the KA were similar for both groups (Bio-HA: $49,759 ± $40,363 vs No HA: $50,532 ± $43,183; PS p = 0.293). Conclusion: Bio-HA use prior to knee arthroplasty did not appear to increase overall healthcare costs in the six months before and after surgery. Allowing access to HA injections provides a non-surgical therapeutic option without increasing cost or risk of post-surgical complications.

Changes in prescription pain medication and intra-articular corticosteroid utilization after intra-articular bio-fermentation derived hyaluronic acid use in patients undergoing multimodal pain management.

BACKGROUND: Multiple interventions may be used to treat symptomatic knee osteoarthritis (OA), but concerns have been raised about the safety and efficacy of some therapies. Clinical trials have shown that hyaluronic acid (HA) can provide pain relief up to 6 months and possibly to 12 months, while real-world data has shown that pain medication and intra-articular corticosteroid (CS) injection utilization are reduced within 6 months after HA. OBJECTIVE: To examine changes in prescription pain medication and CS utilization during 1 year after multimodal therapy that included high molecular weight, bio-fermentation derived HA (Bio-HA) use for knee OA. METHODS: Commercial and Medicare Supplemental claims data (IBM MarketScan Research Databases) (1 January 2012, through 31 December 2018) was used to identify unilateral Bio-HA patients using multimodal therapy (any combination of CS injection, opioids, and non-opioid pain medication). Monthly therapy utilization was compared in the 12 months after Bio-HA therapy initiation to the 4-month intra-multimodal period. RESULTS: A total of 13,999 patients underwent Bio-HA therapy with concurrent multimodal therapy. The number of filled opioid prescriptions decreased from 2,913.0/month to 2,861.5/month after Bio-HA, with a reduction in mean monthly prescriptions from 0.60 to 0.43 per user (p < 0.001). A number of opioid days supplied also decreased from 48,914/month to 39,730/month, with a decrease from 10.1/month to 6.0/month per user (p < 0.001). Bio-HA patients had prescription pain medication-free days for 71% of the time post-multimodal period compared to 53% during the intra-multimodal period (p < 0.001). The proportion of patients with CS injections after Bio-HA decreased from 53.8% to 29.6% (p < 0.001). Total monthly CS injections decreased from 2,292 to 663. CONCLUSIONS: Our data suggest that high molecular weight Bio-HA, as part of multimodal therapy, may be effective in providing longer-term pain relief with the reduction in pain therapy (CS injections and opioids) and increase in prescription pain medication-free days.

Delay to TKA and Costs Associated with Knee Osteoarthritis Care Using Intra-Articular Hyaluronic Acid: Analysis of an Administrative Database.

BACKGROUND: Total knee arthroplasty (TKA) is a surgical treatment for patients with knee osteoarthritis (KOA) that no longer experience symptom relief from non-operative or pharmacologic treatments. Non-operative KOA management aims to address patient symptoms and improve function, as well as forestall or mitigate the large costs associated with TKA. The primary objective of this study was to examine the relationship between intra-articular hyaluronic acid (IA-HA) treatment and delaying TKA in patients with KOA compared to patients not receiving IA-HA, as well as to identify differences in KOA-related costs incurred among patients who received or did not receive IA-HA. METHODS: This was a retrospective analysis of an administrative claims database from October 1st, 2010 through September 30th, 2015. Kaplan-Meier survival analysis was conducted to determine the TKA-free survival of patients who received IA-HA, stratified by the number of injection courses received versus those who did not receive any IA-HA. Median KOA-related costs per year were calculated for 2 comparisons: (1) patients who received IA-HA versus patients who did not receive IA-HA, among patients who eventually had TKA, and (2) patients who received IA-HA versus patients who did not receive IA-HA, among patients who did not have TKA. RESULTS: A total of 744 734 patients were included in the analysis. A delay to TKA was observed after IA-HA treatment for patients treated with IA-HA compared to those who did not receive IA-HA. At 1 year, the TKA-free survival was 85.8% (95% CI: 85.6%-86.0%) for patients who received IA-HA and 74.1% (95% CI: 74.0%-74.3%) for those who did not receive IA-HA. At 2 years, the TKA free survival was 70.8% (70.5%-71.1%) and 63.7% (63.5%-63.9%) in the 2 groups, respectively. Patients treated with multiple courses of IA-HA demonstrated an incremental increase in delay to TKA with more courses of IA-HA, suggesting that the risk of TKA over the study time period is reduced with additional IA-HA courses. The hazard ratio for the need of TKA was 0.85 (95% CI 0.84-0.86) for a single course and 0.27 (95% CI 0.25-0.28) for ⩾5 courses, both compared to the no IA-HA group. In patients that eventually had TKA, the median KOA-related costs were lower among those who received IA-HA before their TKA ($860.24, 95% CI: 446.65-1722.20), compared to those who did not receive IA-HA ($2659.49, 95% CI: 891.04-7480.38). For patients who did not have TKA, the median and interquartile range (IQR) KOA-related costs per year were similar for patients who received IA-HA compared with those who did not. CONCLUSION: These results demonstrate that within a large cohort of KOA patients, individuals who received multiple courses of IA-HA had a progressively greater delay to TKA compared to patients who did not receive IA-HA treatment. Also, for patients who progressed to TKA, IA-HA treatment was associated with a large reduction in KOA-related healthcare costs. Based on these results, multiple, repeat courses of IA-HA may be beneficial in substantially delaying TKA in KOA patients, as well as minimizing KOA-related healthcare costs.

Knee Osteoarthritis Treatment Costs in the Medicare Patient Population.

BACKGROUND: Several nonoperative options have been recommended for the treatment of knee osteoarthritis (OA), with varying degrees of evidence. Adhering to the American Academy of Orthopaedic Surgeons clinical practice guidelines has been suggested to decrease direct treatment costs by 45% in the year before knee arthroplasty, but this does not consider the cost of the entire episode of care, including the cost of surgery and postsurgery care. OBJECTIVES: To analyze the total treatment costs after a diagnosis of knee OA, as well as the proportion of arthroplasty interventions as part of the total knee OA-related costs, and whether the total costs differed for patients who received intra-articular hyaluronic acid and/or had knee arthroplasty. METHODS: We identified patients newly diagnosed with knee OA using the 5% Medicare data sample from January 2010 to December 2015. Patients were excluded if they were aged <65 years, had incomplete claim history, did not reside in any of the 50 states, had claim history <12 months before knee OA diagnosis, or did not enroll in Medicare Part A and Part B. The study analyzed knee OA-related costs from a payer perspective in terms of reimbursements provided by Medicare, as well as the time from the diagnosis of knee OA to knee arthroplasty for patients who had knee arthroplasty, and the time from the first hyaluronic acid injection to knee arthroplasty for those who received the injection. We compared patients who received hyaluronic acid and those who did not receive hyaluronic acid injections. Patients who received hyaluronic acid injection who subsequently had knee arthroplasty were also compared with those who did not have subsequent knee arthroplasty. RESULTS: Of the 275,256 patients with knee OA, 45,801 (16.6%) received a hyaluronic acid injection and 35,465 (12.9%) had knee arthroplasty during the study period. The median time to knee arthroplasty was 16.4 months for patients who received hyaluronic acid versus 5.7 months for those who did not receive hyaluronic acid. Non-arthroplasty-related therapies and knee arthroplasty accounted for similar proportions of knee OA-related costs, with hyaluronic acid injection comprising 5.6% of the total knee OA-related costs. For patients who received hyaluronic acid injections and subsequently had knee arthroplasty, hyaluronic acid injection contributed 1.8% of the knee OA-related costs versus 76.6% of the cost from knee arthroplasty. Patients who received hyaluronic acid injections and did not have knee arthroplasty incurred less than 10% of the knee OA-related costs that patients who had surgery incurred. CONCLUSION: Although limiting hyaluronic acid use may reduce the knee OA-related costs, in this study hyaluronic acid injection only comprised a small fraction of the overall costs related to knee OA. Among patients who had knee arthroplasty, those who received treatment with hyaluronic acid had surgery delayed by a median of 10.7 months and associated costs for a significant period. The ability to delay or avoid knee arthroplasty altogether can have a substantial impact on healthcare costs.

Knee OA cost comparison for hyaluronic acid and knee arthroplasty.

BACKGROUND: Limiting treatment to those recommended by the American Academy of Orthopaedic Surgeon Clinical Practice Guidelines has been suggested to decrease costs by 45% in the year prior to total knee arthroplasty, but this only focuses on expenditures leading up to, but not including, the surgery and not the entire episode of care. We evaluated the treatment costs following knee osteoarthritis (OA) diagnosis and determined whether these are different for patients who use intra-articular hyaluronic acid (HA) and/or knee arthroplasty. METHODS: Claims data from a large commercial database containing de-identified data of more than 100 million patients with continuous coverage from 2012 to 2016 was used to evaluate the cumulative cost of care for over 2 million de-identified members with knee OA over a 4.5-year period between 2011 and 2015. Median cumulative costs were then stratified for patients with or without HA and/or knee arthroplasty. RESULTS: Knee OA treatment costs for 1,567,024 patients over the 4.5-year period was $6.60 billion (mean $4210/patient) as calculated by the authors. HA and knee arthroplasty accounted for 3.0 and 61.5% of the overall costs, respectively. For patients who underwent knee arthroplasty, a spike in median costs occurred sooner for patients without HA use (around the 5- to 6-month time point) compared to patients treated with HA (around the 16- to 17-month time point). CONCLUSIONS: Non-arthroplasty therapies, as calculated by the authors, accounted for about one third of the costs in treating knee OA in our cohort. Although some have theorized that limiting the use of HA may reduce the costs of OA treatment, HA only comprised a small fraction (3%) of the overall costs. Among patients who underwent knee arthroplasty, those treated with HA experienced elevated costs from the surgery later than those without HA, which reflects their longer time to undergoing knee arthroplasty. The ability to delay or avoid knee arthroplasty altogether can have a substantial impact on the cost to the healthcare system.

Cost-Effectiveness of Treating Early to Moderate Stage Knee Osteoarthritis with Intra-articular Hyaluronic Acid Compared to Conservative Interventions.

INTRODUCTION: Evidence has demonstrated greater benefit of intra-articular hyaluronic acid (IA-HA) within earlier stages of knee osteoarthritis (OA) rather than waiting for patients to have progressed to later stages of disease progression. High molecular weight (HMW) HA has also been shown to be more effective than low molecular weight (LMW) HA products in mild to moderate knee OA, providing an important distinction to make within the class of IA-HA therapies. The purpose of this study is to evaluate the cost-effectiveness of treating patients with knee OA with HMW HA compared to LMW and conservative treatment, while taking into account disease stage. METHODS: Decision analytic models were created for early/moderate, as well as late stage knee OA. Models for late stage knee OA were created by assuming a range of response rates to IA-HA treatments from 10% to 50%. These models included conservative treatment using physical therapy/exercise, braces/orthosis, and medications such as non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics. The models compared the cost per quality adjusted life year (QALY) gained for these treatments to the use of either LMW or HMW HA. Incremental cost-effectiveness ratios (ICERs) were calculated for each treatment in relation to HMW HA. RESULTS: When evaluating treatment in early to moderate knee OA, HMW HA was dominant over LMW HA and physical therapy/exercise, as it was less expensive and provided greater benefit. HMW HA was cost-effective versus braces/orthosis and NSAID/analgesic medications based on a willingness to pay threshold of $50,000. In the model of 50% response rate to IA-HA for late stage OA, HMW HA remained cost-effective in comparison to physical therapy/exercise and braces/orthosis at a willingness to pay threshold of $50,000; but not NSAID/analgesic medications. In the worst-case scenario of a 10% responder rate to IA-HA, HMW HA was no longer cost-effective in any circumstance. CONCLUSION: IA-HA, particularly HMW formulations, demonstrate cost-effectiveness when compared to conservative treatment options and LMW HA in patients with early/mid stage knee OA. The cost-effectiveness of HMW HA in patients with later stage knee OA was not as apparent, particularly because of the uncertainty in the proportion of patients with late stage OA who have a meaningful improvement after receiving IA-HA. This cost-effectiveness finding supports the use of IA-HA in patients with early and moderate knee OA, as the benefits of IA-HA are apparent within the patient population with mild to moderate knee OA. The findings of this study suggest that there is a potential cost savings benefit as a result of utilizing HMW HA in earlier stages of knee OA as opposed to later stages. FUNDING: Ferring Pharmaceuticals Inc.

Cost-Effectiveness of Different Forms of Intra-Articular Injections for the Treatment of Osteoarthritis of the Knee.

INTRODUCTION: Osteoarthritis (OA), as one of the leading causes of disability, decreases the quality of life for those suffering from the disease and creates a substantial financial burden. Intra-articular hyaluronic acid (HA) can provide relief from the symptoms of OA and multiple HA products are prescribed. The purpose of this study is to examine the single payer cost-effectiveness of various HA products in the treatment of knee OA. METHODS: A single payer economic evaluation was conducted comparing Synvisc(®) (Sanofi, USA), Durolane(®) (Bioventus, USA), Hyalgan(®) (Fidia Pharma Inc., USA), Supartz™ (Bioventus, USA), and Euflexxa(®) (Ferring Pharmaceuticals Inc., USA). Utility scores for HA products were obtained by extracting Western Ontario and McMaster Universities Arthritis Index pain, stiffness and function from randomized controlled trials and converting them to health utilities index mark 3 scores. The cost of a treatment included the cost of the HA injection, cost of a knee injection procedure and cost of a doctor's visit for each required injection. Cost-utility in 2015 USD per quality-adjusted life years (QALY) saved was calculated for each HA product, and incremental cost-effectiveness ratios were calculated to compare the effectiveness of HA products to one another and to conventional care. RESULTS: When compared to conventional care, all investigated HA products were cost-effective, assuming a willingness-to-pay threshold of $50,000/QALY gained. The HA product Euflexxa had the most favorable cost-utility ratio ($5785.52/QALY) when compared to all other HA brands. CONCLUSION: The present study showed several HA products to be cost-effective in comparison to conventional care, with Euflexxa having the most favorable cost/QALY gained ratio compared to the other HA products. FUNDING: Ferring Pharmaceutics Inc.

Hyaluronic Acid Injections in Medicare Knee Osteoarthritis Patients Are Associated With Longer Time to Knee Arthroplasty.

BACKGROUND: Few nonoperative treatment options for knee osteoarthritis (OA) are available, but there is ongoing debate about the effectiveness of intra-articular (IA) hyaluronic acid (HA) injections. We investigated whether the formulation of IA HA, or its combined use with IA corticosteroid (CS), may be contributing to some of the reported variation in clinical outcomes. METHODS: The 5% Part B Medicare data (2005-2012) were used to identify knee OA patients who underwent knee arthroplasty (KA). The time from diagnosis of OA to KA was compared between patients with (HA) and without (no HA) IA HA use, using quantile regression with propensity score adjustment. These were further stratified by type of IA HA. Patient factors associated with time to KA were also assessed using Cox regression. RESULTS: The "HA" cohort was associated with a longer time to KA of 8.7 months (95% confidence interval: 8.3-9.1 months; P < .001) compared with the "no HA" cohort, with extended time to KA in the bioengineered Euflexxa IA HA cohort. Patient factors associated with longer time to KA included women, younger patients, minority patients, patients with fewer comorbidities, and IA CS injection use. Patients with both IA HA and IA CS had an additional 6.3 months (95% confidence interval: 5.5-7.0 months; P < .001) to KA over those with only IA HA. CONCLUSION: In a large cohort of elderly patients undergoing KA, there was a significant longer time from diagnosis of OA to KA in those receiving IA HA. It is unclear if the extended time may lead to less KA utilization.