Consequences on Private Insurance Coverage

Abstract

Bedard et al. recently published a review on the impact of the 2013 American Academy of Orthopaedic Surgeons (AAOS) Clinical Practice Guideline (CPG) on intra-articular (IA) hyaluronic acid (HA) injections, also referred to as viscosupplementation, and concluded that there were subtle but important changes in the use of IA HA following the publication of the AAOS CPG and that these changes were warranted because of the high cost of the injections, given their questionable efficacy1. However, we believe that consideration of the additional data supports a different conclusion and that the CPG has had a more detrimental impact on patient care. We submit that continued endorsement of this guideline may not be in the best interest of patients or the health-care system. Accordingly, we believe that the 2013 AAOS CPG should be reconsidered and modified to include a more comprehensive and perhaps more objective treatise on the guidelines for the nonsurgical treatment of knee pain due to osteoarthritis (OA). The Impact In 2016, the total population of the United States was 320,372,000; an estimated 292,320,000 citizens were covered by some form of health insurance. Of these, approximately 216 million citizens were covered by private insurance (Table I), of whom 178 million were covered through employer-based insurance2. While Medicare, accounting for 53.4 million lives2, covers all approved uses of IA HA injections, 17 major insurance carriers (including the largest, Anthem Blue Cross and Blue Shield3) that account for nearly 64 million lives (29.6% of all private insurance-covered lives) do not pay for IA HA injections (Table II), citing the 2013 AAOS CPG as a primary reason. This decision of noncoverage means that patients pay, at a minimum, an estimated $1,600 for a course of 3 injections of Synvisc (Genzyme Biosurgery)4 (based on the average wholesale price of IA HA products, including $62.16 as the cost of administration per injection plus a Level-1 office visit as well as visits under the Current Procedural Terminology [CPT] codes 99213 or 99214 [first visit only] of $90 [approximately $1,400 for Synvisc-One]5) compared with an estimated $320 in copayment (assuming an average 20% copayment using Medicare fee-for-service as a standard)6 under insurance coverage. TABLE I - Summary of the U.S. Population Health-Care Coverage* Source of Population No. of Lives U.S. Population Total U.S. population 320,372,000 100.0% Uncovered by health insurance 28,052,000 8.8% Covered by health insurance 292,320,000 91.2% Medicare-covered lives 53,372,000 16.7% Medicaid-covered lives 62,303,000 19.4% Private insurance-covered lives 216,203,000 67.5% *Medicare and Medicaid-covered lives include the elderly and citizens with disabilities who qualify for dual coverage. TABLE II - Summary of the U.S. Health-Care-Covered Lives and Noncoverage of IA HA Injections Major Insurance Plans Not Covering IA HA Injections* Covered Lives Privately Insured U.S. Lives Total U.S. Lives Total private health insurance-covered lives 216,203,000 100.0% 67.5% BCBS (non-coverage)† 46,574,621 21.5% 14.5% Kaiser Health Plan U.S. 9,185,680 4.2% 2.9% Medicaid (NY, NC, OK) 8,137,430 3.8% 2.5% Total private health insurance not covering IA HA injections 63,897,731 29.6% 19.9% *Published coverage policies: Anthem Blue Cross and Blue Shield (BCBS); Kaiser Health Plan U.S.; New York Medicaid; North Carolina Medicaid; Oklahoma Medicaid; BCBS of California, Florida, Massachusetts, Kansas City and Kansas, New York (Health Now), Arkansas, and Rhode Island; Regence Blue Cross; Premera BCBS; Group Health Coop; and Lifewise Health Plan of Washington.†The BCBS association is a federation of 36 separate U.S. health insurance organizations and companies providing health insurance to >100 million lives. The plans denying coverage, primarily Anthem Blue Cross and Blue Shield (BCBS), have a dominating or partial market presence in the states of AK, CA, CO, CT, FL, GA, ID, IN, KS, KY, MA, ME, MO, NH, NV, NY, RI, OH, VA, WA, and WI. The AAOS CPG and coverage decisions do not acknowledge the recently reported economic and medical benefits associated with viscosupplementation (IA HA) use, including (1) delayed time to knee replacement7-9, (2) reduced pain medication usage (corticosteroids, nonsteroidal anti-inflammatory drugs [NSAIDs], and opioids)10, (3) better cost-effectiveness compared with standard-of-care treatments11, (4) improved function9, and (5) a favorable safety profile12-14. The Evidence The 2013 AAOS CPG was based on a meta-analysis of published HA clinical studies that met the CPG and systematic review working group inclusion criteria. The guideline concluded that HA injections demonstrated significant differences in pain relief compared with saline solution injections15. However, we believe that the AAOS CPG remains debatable since its evidence synthesis rules allowed only for the inclusion of Level-I evidence (randomized clinical trials) and not Level-III and Level-IV published evidence. This may deprive patients of access to additional treatment modalities16,17, and the subjective inclusion criteria (such as age, Kellgren-Lawrence grade, primary outcome measures, activity level, comorbidities, etc.) that are used for patient selection in randomized clinical trials have been shown to substantially affect research outcomes18. Additionally, the final negative recommendation (“We cannot recommend using hyaluronic acid for patients with symptomatic osteoarthritis of the knee”; strength of recommendation: strong) was based on the conclusion that the effect size was not “clinically significant,” which the AAOS defined as “a statistically significant difference in treatment effect where the lower limit of the 95% confidence interval is greater than the minimal clinically important improvement” (MCII; MCII values were based on the published literature)15. This conclusion may have been based on flawed methodology and interpretation of minimal clinically important differences (MCIDs) of patient-reported outcomes16. At present, there is no universal standard for calculating MCIDs (we are aware of as many as 9 published methods19), especially when comparing population-based studies with individual-based studies, which has led to often disparate methodological and/or interpretation problems. Although there is value in understanding the MCID for assessing clinical appropriateness, it is only 1 of many important clinical tools (such as patient-reported outcome instruments, clinical experience, clinical study designs, demographics and patient variability, comorbidities, physical functional state, quality of life [both psychological and social aspects], tolerability, convenience, availability, physician’s preference and experience, cost, alternative treatment options, etc.) for evaluating treatment safety and effectiveness20. At this point, basing the effectiveness of an intervention solely on such an evaluation may be considered shortsighted. Furthermore, meta-analysis examining the HA class may incorporate additional levels of bias. These biases may include (1) regulatory bias, resulting from inclusion of studies from nonapproved U.S. products; (2) historical bias, resulting from comparison of studies over decades; (3) effectiveness bias, resulting from exclusion of studies not using the currently accepted or adopted outcome measures or methodology; and (4) control bias, resulting from failure to distinguish between true placebo controls and active comparators (Table III). The issue of control bias is especially important when examining the comparative effect size of IA HA injections, given the recent reports of the clinical effectiveness of IA saline solution injections, which are typically used as control comparators (including arthrocentesis and the use of up to 4 g/day of acetaminophen) in HA studies21,22. The use of IA saline solution as a control comparator can diminish the net effect size of an IA HA intervention because the comparator is an active clinical intervention (arthrocentesis, saline solution injection of diluting pain mediators, and access to up to 4 g/day of acetaminophen) instead of a true placebo (control bias). Reliance on a single outcome measure also has been challenged, with a combination of patient-reported outcomes and responder analysis being proposed as a more appropriate standard for outcome assessment23. TABLE III - Types of Bias No. Bias Description 1 Regulatory Resulting from the inclusion of clinical studies of nonapproved U.S. products (products not approved may provide a negative bias) 2 Historical Resulting from the comparison of clinical trials over decades, which may have led to the exclusion of studies not meeting current practices and thereby may not include studies of the first approved products 3 Effectiveness Resulting from the exclusion of studies utilizing validated outcome measures at the time of design but not using the currently accepted or adopted outcome measures or methodology (excludes earlier studies) 4 Control Resulting from the failure to distinguish true placebo controls from active comparators (saline solution injections) We believe that the AAOS workgroup, in their CPG review, potentially applied a somewhat flawed methodology16 to make a strong recommendation against the use of IA HA, given that all of the evidence that we believe to be relevant should have been considered further. These selection biases can be easily tested, and we recommend stratifying these variables. The CPG concluded that the benefits were exceeded by the potential harm and/or the quality of the supporting evidence for this recommendation is high. However, results from clinical studies and postmarketing reports have demonstrated that IA HA injections are not harmful13,14. The adverse reactions that the CPG cite also are limited and seem to be restricted to a single product, which may be related to the chemical cross-linking manufacturing process24. Accordingly, we question the basis of the “strong” recommendation against the use of IA HA injections. In contrast, 2 of what we believe are the most comprehensive and perhaps least biased meta-analyses of HA effectiveness (based on affiliation or sponsorship: research sponsored by the Cochrane Collaboration25 and the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services26) concluded that IA HA injections were statistically superior to IA saline solution injections, with a clinically meaningful difference. Using a network meta-analysis, Bannuru et al. showed that IA HA injections have a clinical effect size that is 2 to 3 times greater than that of standard-of-care oral pain medications26 (Table IV). More importantly, Bannuru et al.27 and Altman et al.21 have shown that IA saline solution injections (a standard control comparator to IA HA injections in clinical trials) are not placebos but are active comparators (Table V) as their effect size is comparable with standard-of-care NSAIDs. Therefore, using IA saline solution as a placebo comparator could dilute and diminish the effect size that is observed with IA HA injections (control bias). TABLE IV - Intra-Articular HA Clinical Effect Size Versus Other Treatments for OA Knee Pain* Comparator Placebo APAP IA Saline Solution† Celebrex Naproxen Ibuprofen Diclofenac IA Steroids IA HA 0.63 0.45 0.34 0.30 0.25 0.19 0.11 0.02 *HA = hyaluronic acid, OA = osteoarthritis, APAP = acetaminophen, and IA = intra-articular.†IA saline solution control = arthrocentesis, dilution with saline solution injection, and prn (as needed) APAP. Adapted, with permission, from: Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015 Jan 6;162(1):46-54. TABLE V - Placebo Pill, IA Saline Solution, and Oral NSAID Effect Size for Treatment of Knee OA* Comparator APAP IA Saline Solution Celebrex Naproxen Placebo pill 0.18 0.29 0.33 0.38 APAP 0.11 0.15 0.20 IA saline solution† 0.04 0.09 Celebrex 0.05 *IA = intra-articular, NSAID = nonsteroidal anti-inflammatory drug, OA = osteoarthritis, and APAP = acetaminophen.†IA saline solution control = arthrocentesis, dilution with saline solution injection, and prn (as needed) APAP. Adapted, with permission, from: Bannuru RR, Schmid CH, Kent DM, Vaysbrot EE, Wong JB, McAlindon TE. Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis. Ann Intern Med. 2015 Jan 6;162(1):46-54. The Osteoarthritis Research Society International (OARSI) guidelines for the nonsurgical management of knee OA concluded that IA HA injections had an estimated effect size (standardized mean difference) of 0.37 to 0.46 for pain, based on “good quality of evidence,” which equaled or exceeded the effect size for NSAIDS28. However, based on some inconsistent conclusions among the meta-analyses and conflicting results regarding the safety of some IA HA products, the panel voted to recommend IA HA injections with an “uncertain” designation for knee-only OA and as “not appropriate” for multiple-joint OA28. In a 2011 meta-analysis that was included in the OARSI guidelines, IA HA demonstrated a small but statistically significant reduction in OA knee pain by week 4, with a peak at week 8 (reaching moderate clinical significance) and residual benefit until 24 weeks29. Another meta-analysis from 2012 found moderate benefits of IA HA for pain and physical function in knee OA, although sensitivity analyses, including analysis of only larger studies with adequate blinding, found only a small effect size for pain30. The differences in the conclusions between the 2011 and 2012 analyses could have been due to the exclusion of studies with a smaller sample size and the inclusion of an additional 5 unpublished studies that reported nonsuperiority of HA compared with placebo in the 2012 meta-analysis31. Furthermore, systematic reviews published after the AAOS and OARSI guidelines had been issued also have drawn inconsistent conclusions regarding the clinical utility of HA injections. A meta-analysis of double-blinded sham-controlled studies found no clinically important improvement in pain or other outcomes with HA treatment versus placebo32. In contrast, a 2018 systematic review showed “strong evidence” for clinically important treatment effects for knee OA when using IA HA formulations with a molecular mass between 1,500 kDa and >6,000 kDa compared with nonoperative treatments33. In the recent OARSI guidelines, IA HA was conditionally recommended in individuals with knee OA in all groups34. Furthermore, it was noted that IA HA may have beneficial effects on pain at week 12 of treatment and beyond, as well as a more favorable long-term safety profile compared with repeated IA corticosteroids34. Notably, the American Medical Society for Sports Medicine (AMSSM) recommended the use of HA for appropriate patients with knee OA based on the number of participants meeting the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) criteria, which are different and might be considered more relevant than methods used in the earlier AAOS CPG35. The continued contradictory recommendations from meta-analyses, together with a lack of treatment consensus among clinicians, underscore the need for well-designed, prospective, large population-based studies (pragmatic studies)36 to evaluate the real-world effectiveness of IA HA for knee OA and inform decision-makers regarding the comparative balance of benefits, burdens, and risks of IA HA. The Clinical Options The value (clinical benefit) and associated risk (safety) of IA HA in controlling OA knee pain should be compared with those of other nonsurgical treatments. Guidelines generally recommend exercise, weight loss, and physical therapy, followed by simple analgesics, NSAIDs, or other analgesics37. While some studies have shown these treatments to be cost-effective38,39, advocating the use of nonsurgical management plans for knee OA in the absence of workable blueprints and practical means of implementation of a clear and well-substantiated consensus on treatment algorithms will render most nonsurgical plans for knee OA ineffective in real-world situations. Oral Pain Medications Although acetaminophen is often the first oral pain medication that is recommended in treatment algorithms for OA knee pain, recent studies have concluded that there is no role for single-agent acetaminophen for the treatment of patients with chronic OA pain, irrespective of dose40,41. In addition, the potential toxicity associated with acetaminophen has further called into question its use based on this associated risk (potential safety profile)42. Although NSAIDs are used as standard nonsurgical treatment of chronic OA knee pain, while effective, safety issues associated with NSAIDs need to be carefully considered43-45, especially since patients with knee OA often have comorbidities that can exacerbate these adverse effects. Due to safety concerns, in 2005, the U.S. Food and Drug Administration (FDA) also required all NSAID (including cyclooxygenase-2 [COX-2]-selective inhibitor) manufacturers to include “black box” warnings highlighting the potential for increased risk of cardiovascular events and serious gastrointestinal bleeding46. Solomon et al. examined all-cause mortality for Medicare beneficiaries with a diagnosis of rheumatoid arthritis or OA who were receiving a nonselective NSAID or a selective COX-2 inhibitor45. The estimated all-cause mortality incidence was for nonselective NSAIDs and for selective COX-2 Furthermore, based on at least per in arthritis In contrast, there have been no reported with HA The regarding use for chronic pain management are and and are not a in the treatment Solomon et al. noted that the all-cause primarily from with for Medicare beneficiaries was Using the as this could to study at the American Academy of and reported that approximately 20% of individuals who are times per week and the of or in those with chronic pain is from the and Health Administration that million elderly patients in the U.S. drugs in which is to to million by Other IA injections can the of OA are which is when comorbidities and are of in patient IA injections are perhaps the most treatment for OA knee pain, and recent reviews have demonstrated moderate over 1 to 2 and over 4 to after the of While in studies have demonstrated effects of on there is clinical evidence that injections 3 the of This has recently been in a review by et in which the clinical data supporting the adverse events after IA Other IA injections, such as and some in the treatment of OA knee pain but are large clinical some results in published clinical studies, the and in the of as well as control of and appropriate have that conclusions are to make with to the of these into the nonsurgical treatment Furthermore, since of these are approved by the the used in their are as medical by a and are not the can be to patients and further limit their the that the evidence supporting the use of and other injections for the management of OA knee pain is the AAOS an recommendation regarding their use in to IA HA. We believe that a of as in this that IA HA injections can be a treatment to the in the management of OA knee Clinical have recommendations for the use of IA HA in patient a of clinical appropriate use criteria to the of patients for whom HA use is This group that the use of HA injections in OA knee treatment is appropriate for patients with or moderate knee OA who have not other or for those who have been with or have had an to other or pharmacologic for the The group also concluded that HA injections are in patients with a at the injection and/or an active This clinical selection is to that observed in other such as with in which a selection of patients is of and with injections for patients with where there is limited evidence to their long-term The of injection is of for and with the being In to injections, knee injections have been shown to have improved injection resulting in improved patient-reported outcomes and Summary We believe that the use of IA HA as of the nonsurgical treatment to not be While there may be some on the of HA injections, meta-analyses and systematic reviews their with minimal safety concerns, and studies have and to the in conclusions from is not in question is the safety profile of the in the patient with the lack of In addition, there is no issue with patient or as there is with oral pain We believe that a more to appropriate OA treatment be to the more recent recommendations to the outcomes of IA HA with better patient selection and earlier Furthermore, we believe that the of a and treatment such as HA not treatment as clinicians, and the of the AAOS CPG on IA HA

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