Osteoarthritis (OA) of the knee has emerged as one of the main causes of disability in the United States. Although no currently known cure of OA can reverse the progression of the disease, total knee replacement (TKR) is an effective and definitive treatment. However, TKR is an invasive procedure with potential risk for serious complications, and it has imposed high costs on the US healthcare system, with expenses accounting for hospital expenditures of TKR estimated at $28.5 billion in 2009.1Alternative low-risk therapies that can delay or obviate TKR are valuable to a number of patients, especially the poor candidates for surgery or those who wish to avoid TKR.
Intra-articular (IA) hyaluronic acid (HA) injections have been available as a safe and effective treatment option to alleviate pain and to improve joint functions.2 Results of randomized double-blind controlled clinical trials have demonstrated the pain-relieving effect of IA HA injections.3-5 Furthermore, a recent network meta-analysis comparing various pharmacologic interventions for knee OA has confirmed the efficacy of IA HA injections, which outperformed other interventions when compared with oral placebos.6,7 IA therapies are more effective than oral therapies for knee OA pain, with IA HA injections demonstrating the most pain reduction, potentially due to the benefit associated with needle injection and aspiration. Recent experimental studies have also suggested that IA HA may provide cartilage protection, reduce inflammation, and boost the viscosity of synovial fluid;8 IA HA may also exert therapeutic effects by inhibiting bone formation in OA patients.9,10 HA possesses the potential to delay or obviate TKR. Previous research with a case series review of patients in an orthopedic specialty practice reported that the use of IA HA injections in patients with grade IV OA delayed TKR substantially.11 One study analyzed retrospective medical claims data from a single private insurer and discovered potential evidence for the modest benefit of IA HA injections in delaying TKR.12
More detailed research work on a large sample of patients with knee OA and the requirement of TKR as a condition for inclusion using US administrative claims data has demonstrated the TKR-delaying effects of IA HA injections in comparison with a control group without claims for IA HA injections.13,14 This study also uses real-world US administrative data but utilizes a different approach by starting with a sample of patients with knee OA and evidence of IA HA injections and then assessing the effect of repeated courses of HA treatment on the delay of TKR, without TKR as a mandatory condition for inclusion. All patients with knee OA within the time window were included, regardless of the need for TKR compared with previous studies which only considered patients who ultimately received TKR. Safety information and effectiveness information were examined to achieve a balanced risk-benefit assessment. We also analyzed how multiple courses of HA treatment and other potentially relevant covariates at baseline affected the risk of receiving TKR in a multivariate survival model. We aimed to achieve a realistic assessment of the clinical utility of HA injections in delaying TKR in a real-world setting using both safety and effectiveness data.
METHODS
DATA SOURCE
A retrospective cohort observational study using IMS Health’s PharMetrics Plus Health Plan Claims Database was conducted by identifying knee OA patients with claims indicating initiation of HA injection at an index date during the selection period (July 1, 2007 to June 30, 2010). All common HA agents in the US market during this period (Euflexxa, Hyalgan, Orthovisc, Supartz, and Synvisc) were selected via the corresponding J-codes and pooled for investigation of HA class effects. The follow-up period was 36 months, post-index date of the initial HA injection. Outcomes were measured, and adverse events were identified during this period. The time window for identification of adverse events was within 2 weeks from any injection during the course of therapy (evidence of an emergency room visit and/or physician office visit with requisite code). The data during the 12-month pre-index baseline period from the claims database was used to obtain information about baseline patient characteristics, such as age, gender, type of coverage, physician specialty, Charlson Comorbidity Index (CCI), major comorbidities, and major medications of interest commonly used among patients with knee OA.
STUDY SAMPLE SELECTION
The eligible patients required an outpatient claim indicating the initiation of HA injection. The date of the first claim for the patient within the selection window was defined as their index date. Patients had to be ≥18 years of age in the year of their index date. They had to present at least 1 clinical knee OA diagnosis at any point in the 12-month pre-index period (including the index date), and only patients who were continuously enrolled from 12 months pre-index to 36 months post-index date were evaluated. Among these patients (approximately 1.4 million), the following were excluded to minimize complications in data analysis and interpretation: patients with evidence of any HA use in the pre-index period; patients with evidence of a different kind of HA index medication in the post-index period; patients with evidence of TKR within 30 days of the index event during the post-index period; patients with evidence of 2 different kinds of HA index medications on the index date; and patients with evidence of diagnosis of hip OA, fibromyalgia, rheumatoid arthritis, lupus, or gout during the pre-index period.
Five patient cohorts were defined according to the number of courses of IA HA injections over the entire post-index period.
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