A formulary restriction policy in a Medicare population was associated with lower celecoxib utilization; however, higher gastrointestinal- and arthritis-related medical costs were observed.
To compare the incidence of serious gastrointestinal (GI) complications and associated medical costs in a population with either osteoarthritis (OA) or rheumatoid arthritis (RA) enrolled in Medicare plans with celecoxib formulary restrictions versus plans without such restrictions.
This study was a retrospective cohort analysis of Medicare members in plans with and without celecoxib restrictions. Members diagnosed with OA or RA were identified and followed for 1 year.
The restricted group had higher levels of nonselective nonsteroidal anti-inflammatory drug use (51% vs 40%; P <.001), and celecoxib use was double in the unrestricted group (16% vs 8%; P <.001). The incidence of a serious GI complication was slightly higher in the restricted group (5.4% vs 4.6%; P <.001). The adjusted mean serious GI complication—related cost for the restricted group was more than 15 times higher than that for the nonrestricted group ($1559 [95% confidence interval (CI) $1341-$1811] vs $101 [95% CI $87-$117]); adjusted mean arthritis-related medical costs were $5733 per year (95% CI $5097-$6448) for the restricted group and $3170 (95% CI $2816-$3569) for the unrestricted group.
The restricted group had significantly less use of celecoxib, indicating that restriction was effective at reducing celecoxib utilization. Although limitations exist when comparing populations from different health plans, and the underlying causes of serious GI complications are multifactorial, the restricted group had a higher
incidence of serious GI complications and higher costs related to serious GI complications and arthritis.
(Am J Manag Care. 2011;17(7):503-512)
This study compared the incidence of serious gastrointestinal (GI) complications and associated GI- and arthritis-related medical costs between Medicare plans with and without formulary restriction policies for celecoxib.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of osteoarthritis (OA) and rheumatoid arthritis (RA).1-3 The most common adverse events experienced by NSAID users are gastrointestinal (GI) related. Adverse GI events can range from very minor dyspepsia to life-threatening GI bleeding or perforation.4,5 The major risk factors for GI complications related to NSAID use include history of GI bleed, concomitant use of anticoagulants, use of 2 or more NSAIDs, history of peptic ulcer, high-dose NSAID, age >60 years, severe illness, Helicobacter pylori infection, and concomitant use of corticosteroids.6 Lanas et al indicated that individuals over the age of 75 years are considered to be at high risk and their risk equals that of persons with a history of peptic ulcer disease.7 It has been estimated that more than 90% of all NSAIDs prescribed are for individuals over the age of 65 years.6 It is well documented that the elderly experience significant and serious GI complications with NSAIDs.7,8
Celecoxib, a selective cyclo-oxygenase (COX-2) inhibitor NSAID, has been shown to be as effective as traditional nonselective NSAIDs (nsNSAIDs), 9 although the product labeling for all NSAIDs carries the same GI and cardiovascular warning. The majority of traditional nsNSAIDs have generic equivalents available, while there are no COX-2 generic equivalents. Many health plans, in an effort to control costs, have implemented utilization management techniques such as tier placement, prior authorization, or step therapy to decrease utilization of COX-2 agents.10-12 In 2004, Briesacher et al found that members in a 3-tier pharmacy benefit design with arthritis and serious GI comorbidity were less likely to use a COX-2 agent compared with those with a 1-tier pharmacy benefit.13 Johnson et al evaluated the impact of NSAID formulary restriction on medical costs.14 They showed that the more restrictive formularies led to higher hospitalizations for OA and RA members and higher total healthcare costs for RA members.14 Although these approaches have the ability to lower pharmacy costs by decreasing utilization, very little has been published to show the impact of the restrictions on medical outcomes. Since 2007, some Medicare Advantage and Prescription Drug Plans have used various formulary management strategies to restrict the use of celecoxib. Humana health plans have used a step-therapy policy with prior authorization restriction. That is, in order to get celecoxib covered through their prescription benefit, Humana Medicare members must have tried and failed with 2 prescription-strength nsNSAIDs on the preferred drug list in the previous 6 months or must satisfy at least 1 of the following secondary criteria: currently on a prescription-strength GI medication, anticoagulant or antiplatelet therapy, bisphosphonate, chronic oral corticosteroid, or antineoplastic agent. If neither of these criteria are satisfied, the member’s provider could file a prior authorization request.
The purpose of this study was to compare the incidence of serious GI complications and associated medical costs in an elderly Medicare population with OA and/or RA enrolled in plans with restrictions on celecoxib versus plans without restrictions on celecoxib.
This retrospective study used a cohort design to identify and track members with arthritis who were covered under a Medicare Advantage or Medicare Supplemental plan. Two groups were identified for comparison: (1) restricted celecoxib coverage and (2) unrestricted celecoxib coverage. The study design was approved by an institutional review board.
All members with coverage through a Medicare Advantage or Medicare Supplemental health benefit plan who were continuously enrolled during an observation period 365 days prior to and after the index date and who were between 65 and 90 years of age on the index date were included in the study. Members who met either of the following 2 criteria were excluded from the study: (1) diagnosis of familial adenomatous polyposis during the preindex or follow-up period (defined as International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 211.3 in any diagnosis field on a medical claim) or (2) diagnosis of ankylosing spondylitis during the preindex or follow-up period (defined as ICD-9- CM code 720.0 in any diagnosis field on a medical claim).
The restricted celecoxib group was identified from Humana’s Medicare population using medical, pharmacy, and eligibility data. The unrestricted celecoxib group was identified using the MarketScan Medicare Supplemental and Coordination of Benefits Database from Thomson Reuters. Unrestricted status was based on participating in a plan that did not have a prior authorization/step therapy requirement for celecoxib. Thomson Medstat associates assigned the unrestricted status specific to each member for each calendar year. To assign this indication, members were first grouped by drug plan and year. Details on celecoxib coverage by plan and year were determined using Fingertip Formulary (Fingertip Formulary LLC, Glen Rock, New Jersey), Epocrates (Epocrates Inc, San Mateo, California), or the plans’ Web sites. When information was not available, the proportion of celecoxib fills relative to all drug fills was used as a proxy for restriction. Members enrolled in plans with <1.5% fills for celecoxib were tagged as restricted. Only members enrolled in a plan with an unrestricted status during their entire study period were considered for inclusion.
The study period was January 1, 2006, to December 31, 2008. Members who met all of the following criteria were included in the study: medical claim with an ICD-9-CM diagnosis code in any of the first 3 diagnosis fields for OA (715.x) or RA (714.x or v82.1) between January 1, 2007, and December 31, 2007. The service date of the first claim was defined as the index date. Those members who met the inclusion criterion were observed for 12 months prior to their index date and 12 months after their index date.
Pharmacy and medical claims with service dates that occurred during the individual subjects’ 24-month observation period were used to identify the outcomes of interest for the study. The composite primary end point of a serious GI complication was defined as a GI bleed or perforation (Table 1). Serious GI complications were further identified as upper or lower in nature. The relevant codes were selected based on published literature and expert opinion. The time until a serious GI complication was calculated as the number of days between the index date and service date on the medical claim.
Serious GI complication—related total medical per member per year (PMPY) costs during the follow-up period included the total outpatient and inpatient medical costs where the primary or secondary diagnosis code was for a serious GI complication. Arthritis-related total medical PMPY costs in the follow-up period included the total outpatient and inpatient medical costs where the primary or secondary diagnosis code was for RA or OA. Both plan-paid and member out-of-pocket costs were included in the calculation of serious GI- and arthritis-related medical costs. Gastroprotective and gastrotoxic medication utilization was evaluated using the pharmacy claims for the member. Arthritis treatment utilization was also evaluated (Table 2). An RxRisk-V score, which is an enhancement of the Chronic Disease Score,15,16 was calculated using pharmacy utilization during the 12 months prior to the index date. The unweighted version used in this analysis was calculated using a simple count of drugs in unique drug categories. The score can range from 0 to 27.17-19
Bivariate descriptive analyses were conducted on all study variables. The t test or Wilcoxon rank-sum methods were utilized for comparing continuous variables, and X2 tests were utilized for the categorical variables. The baseline characteristics (demographic, clinical, and drug utilization patterns) were compared between the celecoxib-restricted and celecoxibunrestricted groups. Statistical significance was set at P <.05.
Cox proportional hazard models were used to compare the restricted and unrestricted groups on the risk of serious GI complications. Time until a serious GI complication was the dependent (outcome) variable used in the model. The independent (predictor) variables used in the model were age, sex, region, OA/RA, use of medications or clinical conditions that increase risk of GI complications, and use of gastroprotective medications. Members were censored if they did not have a serious GI complication by the end of their follow-up period. Collinearity among the covariates was assessed, and based on the results there were no significant correlations between the covariates. Time-dependent covariates were included in the models to assess the proportional hazards assumption.
Generalized linear models (GLMs) using a gamma distribution as their probability distribution and log-link as their link function were used to compare the medical costs of serious GI complications and arthritis for the groups. The usefulness of the GLMs for modeling the medical costs is their ability to handle nonconstant variance (heteroscedasticity) and avoid having to retransform log-transformed costs (a common strategy for handling highly skewed medical cost data).19 The covariates used in the models were the same as those used in the proportional hazard model. Members with zero costs (related to serious GI complications or arthritis) during the follow-up period had $1 added to their costs. Models provided the adjusted estimates of mean cost for each of the groups. SAS version 9.2 (SAS Institute Inc, Cary, North Carolina) was used for all statistical analyses.
A total of 172,118 members met the inclusion criteria, with 86,011 members in the restricted group and 86,107 in the unrestricted group. Table 3 shows the results of the application of the inclusion/exclusion criteria for the groups. shows the baseline characteristics for the groups. The majority of members in both groups were female, with approximately 33% of both groups being male. Large differences were seen in the geographic regions between the restricted and unrestricted groups. The majority of members in the restricted group were located in the South and Midwest regions (70% and 23%, respectively). A more even distribution was seen in the unrestricted group between the Midwest, South, and West regions (29%, 37%, and 28%, respectively). The mean age for each of the groups was similar (75 years), although found to be statistically significantly different (P <0.01) due to the large sample sizes of the groups. The restricted and unrestricted groups showed an equal distribution of members with a diagnosis of OA (88%), RA (5.3%), and OA with RA (6%). The unrestricted group had more members with a prior history of a GI bleed (4.4% vs 2.1%). There were slightly more members with a history of H pylori infection in the restricted group (0.6% vs 0.4%). The unrestricted group had a slightly higher RxRisk-V score (5.9 vs 3.8).
With respect to the utilization of gastroprotective medications, more members in the unrestricted group had a claim(s) for a proton pump inhibitor (PPI) (37% vs 32%; P <.01), whereas more members in the restricted group had a claim(s) for a histamine H2-receptor antagonist (H2RA) (13% vs 8%; P <.01). Compared with the unrestricted group, the restricted group had more claims for drugs recognized as gastrotoxic: nsNSAIDs (51% vs 40%) and oral glucocorticosteroids (33% vs 29%). More utilization of bisphosphonates, antiplatelets, anticoagulants, and heparin was seen in the unrestricted group. As expected, fewer members used celecoxib in the restricted group compared with the unrestricted group (8% vs 16%). The unrestricted group also utilized more nonbiologic and biologic disease-modifying antirheumatic drugs.
The members in the restricted group had a slightly higher risk for a serious GI complication compared with the unrestricted group (5.4% vs 4.6%; P <.01 ). This translates into a higher relative risk (1.17 [95% confidence interval (CI) 1.12-1.21]) in the restricted group, although the absolute difference in risk was small (0.8%). While we agree that the clinical relevance of this finding is debatable due to the small difference, the difference was statistically significant, and given the prevalence of arthritis in the Medicare population, it could translate into significant outcome and cost differences between the 2 groups, as examined in subsequent sections. While no differences existed in lower GI complications between the groups, the incidence of upper GI complications was higher in the restricted group (1.0% vs 0.7%; P <.01). Both groups were similar with respect to time until a serious GI complication occurred. The average number of days until a serious GI event occurred was 167 days from the index date.
Cox proportional hazard models were also used to predict the risk of serious GI complications. After controlling for demographic and clinical characteristics and medications that impact the risk for a serious GI complication, the restricted group still showed a higher risk for a serious GI complication (hazard ratio 1.69; 95% CI 1.60-1.78), confirming the results of the unadjusted results. Covariates associated with an increased risk were age, prior GI bleed, H pylori diagnosis, RxRisk score, and sucralfate use. Those associated with a decreased risk were OA (vs OA and RA combined), and PPI, H2RA, glucocorticosteroid, oral bisphosphonate, antineoplastic, antiplatelet, anticoagulant, heparin, and celecoxib use (). A sensitivity analysis was performed by excluding members with a prior GI bleed. The results from the proportional hazards were similar (hazard ratio 1.63; 95% CI 1.54-1.73).
A second Cox proportional hazards model evaluating any gastroprotective therapy use and level of exposure was applied. Gastroprotective therapy use was defined as a member using a PPI, H2RA, sucralfate, or misoprostol between the index date and the end of their follow-up period. Gastroprotective therapy use was higher in the unrestricted group than the restricted group (36% vs 28%; P <.0001). The level of exposure was the number of claims made by the member during the period. The results of the Cox regression model indicated that users of any versus no gastroprotective therapy (dichotomous predictor) had more than 2.2 times the risk for a serious GI complication of nonusers (). However, the increase in the number of gastroprotective therapy refills was associated with a 20% decrease in the risk for a serious GI complication.
The unadjusted mean serious GI complication medical costs PMPY were $146 and $29 for the restricted and unrestricted groups, respectively. The unadjusted arthritisrelated medical PMPY costs were higher for the restricted group ($1436 vs $764; P <.0001). Table 8 presents the results from the generalized linear regression models for serious GI complication—related and arthritis-related medical costs after controlling for age, sex, geographic region, underlying clinical conditions, and drug utilization. The adjusted mean PMPY costs for serious GI complications were $1559 vs $101 (P <.0001) for the restricted and unrestricted groups, respectively, across the entire arthritis patient population. A second GLM model was used to compare the serious GI complication costs between the restricted and unrestricted groups for the subset of arthritis members with a serious GI complication only. This model showed that among those with a serious GI complication, the adjusted serious GI complication PMPY costs were 4 times higher in the restricted group compared with the unrestricted group ($4025 vs $1028, P <.0001). The model for arthritis-related medical PMPY costs showed that the adjusted costs for the restricted group were 80% higher than those for the unrestricted group.
This study compared the incidence of serious GI complications and disease-related expenditures in 2 groups of members covered under a Medicare Advantage or Medicare Supplemental plan who were diagnosed with OA or RA. The groups differed in terms of whether or not the health plan that administered the drug coverage benefit had a restriction (ie, step therapy edit) in place for celecoxib. Overall the groups were similar in terms of age and sex. However, large differences were seen in the geographic regions represented in each of the groups. The analyses indicated that region did not have an impact on serious GI event rates, but there was an impact on the costs associated with treating serious GI complications and arthritis. This could be due to variations in treatment patterns and reimbursement rates between regions. Both groups were also similar with respect to the prevalence of OA, RA, or both conditions. As would be expected, the level of celecoxib utilization was much lower in the restricted group.
Several other studies in Medicaid populations have demonstrated that prior authorization programs have a significant impact on reducing the utilization of COX-2 inhibitors with an expected increase in nsNSAID utilization.10,20,21 However, to our knowledge, no study has examined the association between restrictions and serious GI complications in a Medicare population. This association is important because for most health plans, age greater than 65 years is one of the risk factors indicating that the restriction should not be enforced (ie, members should be able to receive celecoxib). In spite of having this risk factor, only 8% of the restricted group received celecoxib, which is cause for concern and raises questions about factors influencing prescriber behavior. Future studies could focus on the outcomes observed in those individuals who are directly impacted by a formulary restriction policy to determine what alternative therapies, if any, are used if the decision is made to avoid or bypass the step therapy or prior authorization process.
Another key finding that may have an impact on the incidence of GI complications was the difference in utilization of PPIs. The unrestricted group had higher levels of PPI use. It was confirmed that the restricted plan also has some formulary restrictions on PPIs, which might explain some of this difference. Other studies have shown that PPIs are used more often with COX-2 inhibitors than nsNSAIDs.22 Although this relationship was not directly analyzed in this study, it could be an underlying reason why PPI use was higher in the unrestricted group. Interestingly, the unrestricted plan members also utilized more of nonbiologic and biologic disease-modifying antirheumatic drugs, even though the incidence of RA in both groups was similar. The increased use and resulting effectiveness of these agents could be an underlying factor for the lower arthritis-related medical costs in the unrestricted group.
First, the study was observational, so it was unable to identify a causal relationship between formulary restriction policy and serious GI complications and treatment
costs. Second, cumulative medication exposure was not accounted for when evaluating gastrotoxic/gastroprotective medication exposure. There could be significant differences between the therapeutic categories included in the analysis in terms of the cumulative amount of exposure required to impact the risk for a GI complication. For example, 30 days of continuous NSAID therapy may put a member at higher risk than 30 days of continuous antiplatelet therapy; however, based on presence of claims they are given equal weighting. Third, another clinical limitation is that other GI bleed risk factors were unaccounted for (eg, residing in a skilled nursing facility, where the likelihood of being sedentary may be higher and thus put the member at a higher risk for a serious GI complication). Fourth, the study was unable to account for confounding by health plan benefit structure. The restricted group consisted of members enrolled in a Medicare Advantage plan, whereas the nonrestricted group consisted of members enrolled in a Medicare Supplemental plan. The types of individuals enrolled in these types of plans could differ in terms of benefit structure. Lastly, members enrolled in a capitated (at-risk) benefit were not excluded. Providers commonly submit encounter claims only for their capitated members. The lack of reliable payment information for these members may have affected the cost analysis.
We found that that the Medicare population that belonged to plans with celecoxib formulary restriction policies in place had significantly lower celecoxib utilization, indicating that the restriction was effective at reducing utilization. However, after statistically controlling for underlying clinical risk factors, being in the restricted group was associated with a higher risk for experiencing a serious GI complication during the 1-year follow-up period. Being in the restricted group also was associated with higher serious GI-related and arthritis-related medical costs. Our findings underscore the importance of evaluating formulary restriction policies in terms of both the costs related to adverse clinical outcomes and the immediate intended benefits in terms of drug cost savings produced.
Author Affiliations: From Competitive Health Analytics, Inc (AML, ATB) Louisville, KY; Pfizer Inc (AVJ, JCC, RJS, MCD), New York, NY.
Funding Source: This study was funded by Pfizer, Inc.
Author Disclosures: Dr Louder reports employment and stock ownership with Humana, which has a utilization management restriction policy in place for celecoxib. Dr Joshi, Dr Cappelleri, Mr Deminski, and Dr Sanchez report that they are employed by Pfizer, the maker of Celebrex. Dr Joshi and Mr Deminski also report holding stock in the company. Dr Ball reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.
Authorship Information: Concept and design (AML, AVJ, ATB, JCC, MCD, RJS); acquisition of data (AML, ATB); analysis and interpretation of data (AML, AVJ, ATB, JCC, MCD, RJS); drafting of the manuscript (AML, JCC, RJS); critical revision of the manuscript for important intellectual content (AVJ, ATB, JCC, MCD, RJS); statistical analysis (AML, JCC); obtaining funding (AVJ, ATB, RJS); administrative, technical, or logistic support (AVJ); and supervision (AVJ).
Address correspondence to: Anthony M. Louder, PhD, RPh, Competitive Health Analytics, 325 West Main St, WFP6W, Louisville, KY 40202. E-mail: email@example.com.
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