{'fraction_non_alphanumeric': 0.034570355643914294, 'fraction_numerical': 0.015352330461674397, 'mean_word_length': 5.05685618729097, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
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. Electronic supplementary material The online version of this article (doi:10.1007/s12325-016-0331-8) contains supplementary material, which is available to authorized users.


INTRODUCTION
As one of the leading causes of disability, osteoarthritis (OA) decreases overall quality of life for those suffering from the disease and represents a substantial financial burden on the economy [1,2]. The direct and indirect costs of arthritis were estimated to be $126 billion in the United States in 2003, and with the prevalence of the disease rising, these values will only continue to increase [3,4]. With prevalence and costs related to OA trending upwards, the need to find cost-effective management strategies to control the impact of the disease on patient quality of life becomes increasingly important.
During the early stages of knee OA, conservative management including weight loss, the use of ambulatory aids, simple analgesics and nonsteroidal anti-inflammatory drugs (NSAIDS) is the first line of treatment; however, as the disease progresses and the joint becomes increasingly painful, the effectiveness of these treatment options becomes limited [5].
By the end stages of OA, total knee arthroplasty (TKA) is often necessary to address the degradation of the joint and the associated symptoms which severely limit day-to-day function [5]. TKA procedures are costly, with an inpatient TKA costing approximately $20,000, and a revision TKA costing approximately $25,000 [6]. The total cost for all TKA procedures in the US for 2012 was over $11 billion [7]. The younger a patient is when undergoing primary TKA, the more likely that a revision TKA will be necessary in the future [8].
Therefore, it is important to use adjunct treatment methods to delay the progression of disease symptoms and bridge the gap to costly arthroplasty procedures.
Intra-articular (IA) hyaluronic acid (HA) injections have been used to relieve symptoms of knee OA and have the potential to delay the need for TKA [9, 10]. There is a general lack of understanding about the intrinsic properties of various IA-HA products and the effect they have on overall effectiveness. Evidence has demonstrated an increased efficacy of high molecular weight (HMW) HA products over low molecular weight HA products, and improved safety outcomes of biological fermentation-derived HA products (Bio) compared to avian-derived HA products [11,12]. While there is uncertainty regarding the differences in intrinsic properties of IA-HA products compared to one another, even less is known regarding their cost-effectiveness.
While previous literature has examined the individual cost-effectiveness of specific IA-HA products, previous studies have not compared the cost-effectiveness across several IA-HA products [13,14]. Therefore, the purpose of this study is to examine and compare the cost-utility of different IA-HA products relative to conventional care, as well as to one another.

Treatment Utility Scores
Utility scores for the treatments were determined by converting Western Ontario

Cost-Utility Analysis
Cost-utility ratios were valued as the cost per quality-adjusted life years (QALY) gained. To determine the number of QALY gained by the treatment, the average baseline utility score of a given treatment was subtracted from the average 6-month post-treatment utility score, with the assumption that if participants had not received the treatment, there would be no QALY gained or lost through the 6-month period, and no cost would be incurred as they did not receive any treatment.
Incremental cost-effectiveness ratios (ICERs) were determined to compare the treatment options with one another. These were calculated using the formula (C B -C A )/ (Q B -Q A ), where C B and C A represent the cost of treatment B and treatment A, respectively, and Q B and Q A represent the QALY gained for treatment B and treatment A, respectively. A treatment is considered cost-effective if it falls below the willingness-to-pay threshold, which has ranged from $50,000/QALY to $150,000/ QALY in the literature, and is considered dominant if it is both more effective and less costly compared to the alternative [25,26]. For the purpose of this study, a willingness-to-pay threshold of $50,000/QALY was chosen, as this is the most conservative estimate. The ICERs of all treatments were calculated compared to conventional care, as well as to the IA-HA product yielding the greatest effect with respect to QALY gained. Data abstraction and analysis was conducted using Microsoft Excel (Version 2010, Microsoft, Redmond, WA, USA).

Sensitivity Analyses
A one-way sensitivity analysis was performed to determine the robustness of the results and was performed in each of the stepwise analyses performed in this study. For the cost-utility of each individual product, sensitivity analyses were performed by changing the price of treatment by ±20%, and by changing the utility score of the treatment by ±20%. When determining the difference in cost-utility of products in comparison to conventional care and to one another, the costs and utility scores of the HA products were once again adjusted for sensitivity analysis by ±20% before the ICER was performed.

Utility Scores
The utility score of patients who received Euflexxa improved by 0.145 QALY, increasing from 0.482 QALY before treatment to 0.627 QALY after treatment at 6 months (  as it provided a greater QALY improvement and was also less expensive (Table 4).

Sensitivity Analysis
Sensitivity analysis was conducted using two methods, by adjusting the price as well as the utility scores of HA products by ±20%, respectively. Acceptable cost-utility for all five products did not change when cost or utility score was changed by either increasing or decreasing by 20%, as all products remained below the willingness-to-pay threshold of $50,000/QALY gained (Table 5). Euflexxa retained the lowest cost-utility ratio across all analyses, and Hyalgan had the highest cost-utility ratio across all analyses.
When examining the ICERs compared to conventional care, the sensitivity analysis revealed no changes within the relationships between any HA product and conventional care when adjustments were made to cost of treatment or the product utility score.
Differences were seen in the ICER when comparing Euflexxa to other HA products; however, across all sensitivity analyses, Euflexxa remained a cost-effective option ( Table 6). Results of cost-effectiveness did not

DISCUSSION
The purpose of this study was to determine how the cost-effectiveness of various IA-HA products differs from one another, and to also compare the cost-effectiveness results to those of conventional care for knee OA. This study The need for cost-effective treatments for knee OA is extremely important due to the increasing prevalence and incidence of the disease, which will create an increasingly large burden upon the healthcare system in the United States [1][2][3][4]. With the high cost of primary TKA and even higher cost of revision TKA, a cost-effective treatment which can delay