Effectiveness and Costs of Biologics in Veterans With Rheumatoid Arthritis

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The American Journal of Pharmacy Benefits, November/December 2015, Volume 12, Issue 11

This study applied a validated algorithm to estimate the effectiveness and costs of the index biologic used by 4696 US veterans with rheumatoid arthritis.

ABSTRACT

Objectives: An effectiveness algorithm that was validated with the Veterans Affairs Rheumatoid Arthritis Registry was used to compare effectiveness of different biologic disease-modifying antirheumatic drugs (DMARDs) and cost per effectively treated patient in the Veterans Health Administration (VHA).

Study Design: Effectiveness was estimated with the algorithm using VHA claims data for biologics (abatacept, adalimumab, etanercept, infliximab, or rituximab) newly initiated from 2008 to 2011.

Methods: Patients were considered effectively treated if they did not fail any of 6 algorithm criteria during 1 year of follow-up: 1) low treatment adherence; 2) biologic dose escalation; 3) biologic switch; 4) addition of nonbiologic DMARD; 5) new or increased oral glucocorticoid; and 6) more than 1 intra-articular glucocorticoid injection. Index biologic costs included medication and administration costs. Subgroup analyses were conducted by gender, smoking status, serologic status, and body mass index.

Results: The analysis included 4696 patients (mean age = 61 years; 87% male). The proportion of patients categorized as effectively treated was higher for subcutaneous biologics (adalimumab, 33.4%; etanercept, 32.3%) than for intravenous biologics (rituximab, 27%; infliximab, 26.4%; abatacept, 24.8%). Index biologic cost per effectively treated patient was lower for etanercept ($39,432) and adalimumab ($41,519) than for infliximab ($54,524), abatacept ($55,776), and rituximab ($58,260). Men had lower cost per effectively treated patient than did women ($40,745 vs $57,450). Outcomes were comparable within other subgroups.

Conclusions: In veterans with rheumatoid arthritis, the subcutaneous biologics adalimumab and etanercept had the highest proportions of patients categorized as effectively treated and the lowest costs per effectively treated patient.

Am J Pharm Benefits. 2015;7(6):280-289

PRACTICAL IMPLICATIONS

This study applied a validated algorithm to estimate effectiveness and costs of the index biologic used by 4696 US veterans with rheumatoid arthritis.

  • Compared with intravenous biologics (abatacept, infliximab, and rituximab), subcutaneous biologics (etanercept and adalimumab) had lower 1-year biologic costs, higher rates of effectiveness according to the algorithm, and lower costs per effectively treated patient.
  • Men had lower costs per effectively treated patient than women; outcomes were similar within other subgroups.
  • Previous studies in managed care settings used similar methods, but this was the first study to report comparable results in the unique setting of the Veterans Health Administration.

Approximately 1.3 million adults in the United States have rheumatoid arthritis (RA), an inflammatory autoimmune condition that primarily affects the synovial membrane in the joints of the body,1,2 causing inflammation in the joints and destruction of bone and cartilage.3,4 Biologics including abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab, and anakinra play an important role in the treatment of RA by helping to regulate the body’s inflammatory process and inhibiting joint damage.5,6 The biologics differ in their method of administration, dosing level, dosing schedule, and whether they are approved for first-line use after treatment failure with a nonbiologic disease-modifying antirheumatic drug (DMARD).7-15

Comparisons of effectiveness of different biologics and their costs in RA are critical for formulary decision makers to develop evidence-based formularies. Economic comparisons of biologics in RA have been published using managed care data,16-21 but only limited work has focused on the Veterans Health Administration (VHA).22 The VHA has a number of characteristics that make it difficult to generalize from managed care data, including a unique set of demographic characteristics (members are predominantly older men), physicians who are salaried rather than reimbursed on a fee-for-service basis, medication prices that are governed by the Federal Supply Schedule (FSS) and BIG 4 (Veterans Affairs [VA], Department of Defense, Coast Guard, and Public Health Service) pharmaceutical pricing rather than wholesale acquisition costs, and small or no patient co-payments.23 For these reasons, a detailed analysis of this population was expected to be informative for VHA decision makers, with potential application to other health systems.

Previous cost analyses for biologics in RA have been limited by the lack of information about effectiveness. Lower effectiveness leading to worse long-term outcomes with a biologic could offset any cost savings associated with that biologic. Curtis et al24 developed and validated a claims-based effectiveness algorithm using clinical outcomes in patients in the Veterans Administration Rheumatoid Arthritis (VARA) registry receiving biologic and nonbiologic DMARD therapy.

The algorithm uses data commonly available in claims data sets to estimate the effectiveness of biologics. The algorithm evaluates 6 criteria: adherence to the biologic, increases in biologic doses, switching biologics, adding a new nonbiologic DMARD, starting or increasing the dose of oral glucocorticoids, and the use of multiple intra-articular glucocorticoid joint injections. In the validation, the gold standard for effectiveness was a disease activity score using 28 joint counts (DAS28) of ≤3.2 units (the threshold for low disease activity) or improvement in DAS28 >1.2 units after 1 year of DMARD therapy. The DAS28 is a widely accepted metric of disease activity in RA that is commonly used both in clinical trials and in routine real-world settings. The sensitivity of the effectiveness algorithm was 75% and its specificity was 90%.24

The positive predictive value and negative predictive value of the effectiveness algorithm were 76% and 90%, respectively. Recent studies applied the algorithm to commercial claims databases to estimate effectiveness and biologic cost per effectively treated patient,25,26 but this approach has not been applied to the VHA, which is a large purchaser of biologic agents.

The objectives of this study were to compare the estimated effectiveness of different biologics in veterans with RA by using a published algorithm based on administrative data24 to assess the reasons for treatment failure and estimate biologic costs per effectively treated patient.

METHODS

Data Source

This study was approved by the University of Utah Institutional Review Board and the VA Research Service. All data were from the VA Medical System. Patient data, procedures, and text notes were obtained from the Corporate Data Warehouse (CDW) and accessed through the Veterans Informatics and Computing Infrastructure.

Outpatient-Dispensed DMARDs

Pharmacy dispensing data were obtained from CDW, Decision Support Services (DSS), and VA Pharmacy Benefits Management (PBM) Services. Because discrepancies were found in DMARD dispensing across the VHA data marts, a harmonization algorithm was developed to resolve such discrepancies that prioritized dispensing data found in multiple data sources based on source, with CDW first, PBM second, and DSS third. Priority was given to CDW because it is now considered production data; PBM now acquires their data from CDW and then applies data-cleaning algorithms; and DSS because it is now considered legacy data.

Since this study required careful tracking of average weekly dose to determine if a dose escalation occurred, accurate estimates of dosing were needed. In typical pharmacoepidemiological research, the dispensed quantity, unit strength, and days’ supply are used to estimate the prescribed average weekly dose. This approach, however, is unreliable for biologic DMARDs dispensed by the VHA system that are subcutaneously administered at home and for medications with complex weekly dosing schedules, such as methotrexate, because of known inconsistencies in pharmacy dispensing data.

The primary problem in the VHA setting is that the quantity dispensed is not well standardized; for example, the quantity dispensed for etanercept is at times listed differently at various VHA medical centers—dispensing of a box of 4 syringes of etanercept 50 mg may be listed as a quantity of 4 (meaning 4 syringes), or 1 (meaning 1 box of 4 syringes), or 200 (meaning 200 mg total per box). Fortunately, the VA CDW and PBM data contain some information on dispensed units in addition to the narrative medication schedules from prescriptions (sigs).

Determining dispensed quantity from sigs on a large scale is labor- and time-intensive, so an automated Natural Language Processing (NLP) tool was developed to extract and standardize the prescribed average weekly dose from the medication sig.27 This information was used with pharmacy dispensing data on days’ supply, unit dose, and quantity to generate the best estimate of average weekly dose. The process was validated by medical record review and comparison with the VARA registry.

Infused Biologic DMARDS

Similar to the limitations in the VHA discussed above for subcutaneous biologics, outpatient infusions of medications such as intravenous biologics are not consistently documented in structured VHA pharmacy dispensing or nurse Barcode Medication Administration data.22 Healthcare Common Procedure Coding System procedure codes intended for administrative billing provide information on outpatient infusions but they are not used consistently, which makes it difficult to compute the total infused dose.27 An NLP tool was developed to search for outpatient infusion notes and extract total infused dose of biologic DMARDs.28 The process was validated by chart review and comparison with the VARA registry.

Eligibility Criteria

US veterans receiving care within the VHA were included in the analysis if they had at least one claim between January 1, 2008, and December 31, 2011, for abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, or tocilizumab. Patients with a claim for subcutaneous abatacept were removed from the analysis because abatacept was approved only for intravenous use before the start of the study period. Subcutaneous tocilizumab and intravenous golimumab were not included in the analysis because they were not approved at any time during the study period.

The first claim for one of these biologics provided the definition for the patient’s index date and the index biologic. Patients were included only if they were enrolled in the VHA for at least 365 days before their index date. Patients were required to be aged at least 18 years on the index date and to have a diagnosis of RA (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 714.0x) on at least 1 claim in the 365 days prior to or 30 days after the index date.

Patients were excluded from the analysis if they had psoriasis (ICD-9-CM: 696.1), psoriatic arthritis (ICD-9-CM: 696.0), ankylosing spondylitis (ICD-9-CM: 720.0), Crohn’s disease (ICD-9-CM: 555.xx), ulcerative colitis (ICD-9-CM: 556.xx), juvenile idiopathic arthritis (ICD-9-CM: 714.3x), non-Hodgkin lymphoma (ICD-9-CM: 200.xx, 202.xx), or chronic lymphocytic leukemia (ICD-9-CM: 204.1x) on any claim in the 365 days prior to or 30 days after the index date. To limit the analysis to patients who newly initiated biologic therapy, established users of biologics (patients with any other biologic claim in the 180 days before the index date) were excluded from the analysis.

Other exclusion criteria were an index claim for a biologic before it received FDA approval for treatment of RA, claims for more than 1 biologic on the index date, and sparse use of VHA services (no claim within 180 days before the index date and between 10 and 24 months from index date, as a proxy for leaving VHA care). Biologic agents with a sample size <100 patients were not evaluated since the sample size was deemed too small to provide reliable estimates.

Algorithm Criteria for Effectiveness

Using the validated algorithm,24 the following 6 criteria were applied to each patient’s claims for the 1-year follow-up period (365 days) after the index date:

  • Low adherence to the index drug: a) for subcutaneous biologics (adalimumab and etanercept): medication possession ratio <80%, defined as the total days’ supply in the follow-up period divided by 365 days; and b) for intravenous biologics: fewer infusions than recommended in the FDA-approved dosing schedules (ie, <12 abatacept infusions, <7 infliximab infusions, or <4 rituximab infusions).
  • Increase in biologic dose during the follow-up period compared with the beginning dose: a) abatacept: >100 mg dose increase or >18 infusions total; b) adalimumab: frequency increase to 40 mg once weekly; c) etanercept: frequency increase to 50 mg twice weekly; d) infliximab: >100 mg dose increase (with each dose rounded up to the nearest 100 mg) or >10 infusions total; and e) rituximab: no escalation rule was applied.
  • Switch to a new biologic agent during the follow-up period.
  • Addition of a new nonbiologic DMARD during the follow-up period.
  • Oral glucocorticoids: a) initiation of chronic glucocorticoids for those with no oral glucocorticoid prescriptions during the 180 days pre-index; and b) increase by >20% in oral glucocorticoid dose (based on prednisone equivalent dose29) between months 7 and 12 post index for those who received any oral glucocorticoid prescription during the 180 days pre-index.
  • More than 1 parenteral or intra-articular glucocorticoid joint injection on unique days between 90 days and 1 year post index.

According to the algorithm, the index biologic was considered “effective” and the patient was considered to be “effectively treated” if none of the 6 criteria were met. The index biologic was considered “not effective” if at least 1 of the 6 criteria was met. The proportion of patients (95% CI) that failed each of the criteria was analyzed. Proportions (95% CI) were also calculated for effective and not effective index biologics.

Costs

Total costs of the index biologic in the first year (ie, between the index date and 365 days after the index date, inclusive) were calculated by summing the lowest contracted amount using VHA prices from the 2013 fiscal year based on the FSS and BIG 4 (eAppendix 1 [eAppendices available at www.ajmc.com]).30 These were the most recent costs available at the time of the study. Intravenous abatacept was $1.58 per mg, adalimumab was $16.77 per mg, etanercept was $6.61 per mg, infliximab was $4.85 per mg, and rituximab was $4.70 per mg. The cost for each outpatient pharmacy dispensing episode for subcutaneously injected medication was $25 and the infusion costs were $169.09 per administration. Costs of other medications used in the first year, such as DMARDs or other biologics, were not included in the cost calculations.

One-year biologic cost per patient was calculated for each biologic as the total cost for the index biologic divided by the number of patients who received that index biologic. The 1-year cost per effectively treated RA patient (ie, a patient who met the algorithm effectiveness rule) was estimated for each index biologic. The metric reflected total expenditures by the VHA for the index biologic divided by the number of patients effectively treated by that biologic. It was calculated as follows:

Cost per effectively treated patient = Total cost of index agent for all patients who index on it / Number of effectively treated patients on index agent

Subgroup Analysis

Subgroup analyses of effectiveness, biologic costs, and costs per effectively treated patient were stratified by the following baseline characteristics: gender (male or female), smoking status (current smoker or current nonsmoker), cyclic citrullinated peptide (CCP) (positive [>20 IU/mL] or negative), rheumatoid factor (positive [>20 IU/mL or >1:40 titer] or negative), and body mass index (≥30 kg/m2 or <30 kg/m2).

Statistical Analysis

Continuous data are presented as means and 95% CIs, and categorical variables are presented as proportions and 95% CIs. The focus on 95% CIs instead of P values provides evidence for the stability of estimates along with statistical significance. In general, when the 95% CIs do not overlap between 2 groups P <.05 and the 2 groups are considered significantly different.31,32

RESULTS

Patient Disposition

A total of 4696 patients met all inclusion and exclusion criteria (eAppendix 2), of whom 2069 (44.1%) started etanercept, 1989 (42.4%) started adalimumab, 267 (5.7%) started rituximab, 254 (5.4%) started infliximab, and 117 (2.5%) started abatacept. Eight patients who received subcutaneous abatacept in the first year were not analyzed. Fifty-seven patients who started anakinra, certolizumab, golimumab, and tocilizumab were not analyzed because of the small sample size (n <100 patients) for each of those agents.

Baseline Characteristics

Baseline demographic and clinical characteristics were comparable across index biologics (Table 1). Most patients (86.6%) were male and most patients were either white non-Hispanic (76.2%) or black non-Hispanic (13.1%). The mean age at baseline was 61 years and the mean body mass index was 29.7 kg/m2. Rheumatoid factor was positive (>20 IU/mL or >1:40 titer) for 60.5% of patients and CCP was positive (>20 IU/mL) for 46.8%; 33.5% of patients were current smokers.

Effectiveness According to the Algorithm

Rates of effectiveness according to the algorithm and reasons patients were categorized as not effectively treated are summarized in Table 2. The algorithm categorized 32% of patients as effectively treated overall. The proportion of patients categorized as effectively treated was higher for the subcutaneous biologics (adalimumab, 33.4%; etanercept, 32.3%) than for the intravenous biologics (rituximab, 27%; infliximab, 26.4%; abatacept, 24.8%).

Among the patients who were categorized as not effectively treated, the most commonly failed criterion was low adherence (50.1%), followed by adding a new DMARD (20.4%), having a new or increased oral glucocorticoid dose (17.9%), switching biologics (13.2%), increasing the biologic dose (4.5%), and having >1 glucocorticoid injection (2.2%). Many patients had more than 1 criterion for failure; criterion failure rates were comparable across index biologics for most of the criteria, except for increase in biologic dose (infliximab, 23.2%; abatacept, 6.8%; adalimumab, 6.3%; etanercept, 0.8%; rituximab could not be measured) and biologic switch (rituximab, 7.1%; other index biologics, 12.2% to 20.5%).

Biologic Costs

Biologic costs are presented overall and by index biologic in Figure 1. The 1-year biologic cost per patient in the first year after the index date, including all drug costs and administration costs for the index biologic, was $13,504 overall. Etanercept had the lowest 1-year biologic cost ($12,750), followed by abatacept ($13,825), adalimumab ($13,860), infliximab ($14,382), and rituximab ($15,710).

The 1-year index biologic cost per effectively treated patient was $42,247 overall. Etanercept had the lowest 1-year index biologic cost per effectively treated patient ($39,432), followed by adalimumab ($41,519), infliximab ($54,524), abatacept ($55,776), and rituximab ($58,260).

Subgroup Analysis

The main results of the subgroup analyses are provided in Table 3. Biologic costs and effectiveness were similar between smokers and nonsmokers, patients positive and negative for CCP at baseline, patients positive and negative for rheumatoid factor at baseline, and patients with body mass index ≥30 kg/m2 and <30 kg/m2 at baseline. Men and women had similar 1-year biologic costs ($13,682 for men and $12,350 for women), but men were more likely to be categorized as effectively treated (34% of men [95% CI, 32%-35%] and 21% of women [95% CI, 18%-25%]) and thus had a lower cost per effectively treated patient ($40,745 for men and $57,450 for women).

The overall rates of algorithm failure and the rates of failure for individual criteria are presented separately for men and women in Figure 2. The lower rate of effectiveness among women overall was not attributable to substantially greater failure of a single criterion, but instead it appeared to result from greater failure rates for each of the criteria among women compared with men. Full results for each subgroup analysis of effectiveness are provided in eAppendix 3.

DISCUSSION

In this analysis, the application of a validated claims-based algorithm24 to data for 4696 veterans with RA categorized 33% of patients who started adalimumab and 32% of patients who started etanercept as effectively treated with the subcutaneous biologic after 1 year of therapy compared with approximately 25% to 27% of patients who started intravenous biologic therapy with abatacept, infliximab, or rituximab.

The rank order for 1-year biologic cost per patient, regardless of effectiveness, from lowest to highest was etanercept, abatacept, adalimumab, infliximab, and rituximab. When effectiveness and costs were combined, the subcutaneous biologics had lower 1-year biologic costs per effectively treated patient compared with the intravenous biologics; the rank order for biologic cost per effectively treated patient from lowest to highest was etanercept, adalimumab, infliximab, abatacept, and rituximab.

These findings are consistent with those from recent analyses of commercial claims databases that used similar methods and found that the subcutaneous biologic etanercept had the highest rates of effectiveness according to the algorithm and the lowest cost per effectively treated patient.25,26 In the IMS PharMetrics Plus database, biologic cost per effectively treated patient, per the algorithm, was $50,141 for etanercept, $53,386 golimumab, $56,942 adalimumab, $73,516 abatacept, and $114,089 infliximab.25 In the MarketScan database, biologic cost per effectively treated patient, per the algorithm, was $49,952 for etanercept, $50,189 golimumab, $52,858 adalimumab, $71,866 abatacept, and $104,333 infliximab.26

Failure rates for the individual algorithm criteria were generally comparable between this study and the analyses of commercial claims databases. As in those analyses, the most common reason for failing the algorithm in this study was low adherence to the index biologic. Subjects could fail more than 1 algorithm criterion and the analysis was not designed to determine the order in which patients failed multiple criteria. Thus, it is possible that biologic switching in the first year, which occurred in more than 1 in 8 US veterans (13.2%), was a major contributor to nonadherence to the index biologic therapy.

Failure rates were comparable across the index biologics for most of the algorithm criteria, except for increase in biologic dose, which was failed by 23.2% of patients who received infliximab compared with 0.8% for etanercept, 6.3% for adalimumab, and 6.8% for abatacept. The intermittent dosing schedule for rituximab does not allow application of dose escalation criteria to rituximab as is possible with other biologic agents. The previous analyses of commercial claims databases reported similar results for this criterion.25,26

Dose escalation or more frequent administration of infliximab or adalimumab is common in clinical practice,33-38 and is consistent with dosing recommendations in the US labeling for infliximab and adalimumab. Formation of neutralizing antibodies to adalimumab and infliximab can lead to loss of clinical response over time in RA,39,40 and it may contribute to the need for dose escalation with these biologics. Neutralizing antibodies to etanercept have not been reported; non-neutralizing anti-etanercept antibodies have been reported but they do not appear to affect clinical safety or efficacy.41 Neutralizing and non-neutralizing anti-abatacept antibodies have been reported but they do not appear to affect clinical safety or efficacy.42

The 1-year biologic costs per effectively treated patient in this study were comparable with those in the analyses of commercial claims databases for all biologics except infliximab. The cost per effectively treated patient was highest for infliximab in every study, but it was greater than $100,000 in each of the analyses of commercially insured patients,25,26 compared with approximately $58,000 in this study of VHA patients. This appears to have resulted both from 1-year costs associated with starting infliximab therapy that were lower in this study of US veterans ($15,710) than in the studies of commercially insured Americans ($21,131), and a rate of effectiveness according to the algorithm that was higher in US veterans (27%) than in commercially insured patients (20% in each study).25,26

Subgroup analysis determined that men had higher rates of effectiveness and lower costs per effectively treated patient than women. The reason for this gender difference could not be determined from the data, but it aligns with other reports of gender differences. Women report worse scores for RA disease activity and function than men,43-46 which may explain why women are less likely than men to achieve remission,44-50 particularly in early RA.51

The current analysis was limited to VHA data, and exposure to biologic agents outside the VHA was not available. The VHA represents a unique set of patients who are predominantly male, elderly, and retired; results may not be generalizable to a commercially insured population. However, the objective of this study was to compare different biologics, specifically in the VHA, because other studies previously examined similar outcomes in commercially insured patients. This analysis was designed to identify patients who were biologic-naïve because they had no other biologic therapy claims in the previous 6 months, but the possibility of biologic therapy outside the VHA cannot be excluded.

More than 85% of VHA patients in this analysis started biologic therapy with the subcutaneous biologics adalimumab and etanercept. There are no national VHA formularies, treatment guidelines, or algorithms for biologic selection in RA. The usage patterns in this study were consistent with guidelines from the American College of Rheumatology,5,6 which recommend tumor necrosis factor inhibitors before other biologics.

The use of subcutaneous therapy, rather than intravenous therapy, by most of the patients in this study may reflect physician and patient preference for subcutaneous injections over intravenous infusions. It may also reflect geography, because VHA centers often cover a broad geographic region. Thus, VHA patients and physicians may prefer self-administration of subcutaneous biologics at home rather than intravenous therapy, which requires travel to the VHA.

Limitations

The following aspects of the study design may limit interpretation of the results. Estimates of biologic effectiveness were based on retrospective analysis of administrative claims, rather than a direct clinical measure. Thus, no medical records, patient ratings, or physician ratings of effectiveness were analyzed. However, the algorithm was developed and validated in a population of veterans, in which it had high positive and negative predictive value compared with the gold standard of DAS28 scores.24

The algorithm criterion for adherence does not distinguish patient noncompliance with prescribed biologic therapy from tapering, switching, or discontinuation of biologic therapy that was planned by the physician for reasons unrelated to effectiveness. This may explain why the failure rates for adherence were much higher than the failure rates for the other algorithm criteria.

Cost analyses in this study were limited to the total costs of the index biologic; approximately 1 in 8 patients switched to another biologic in the first year, and the costs of those subsequent biologics were not included in the analysis. In previous comparisons of biologic costs across indications that also attributed costs of subsequent biologics to the index biologic, etanercept had the lowest costs, followed by adalimumab and infliximab.20,21

The same order for biologic costs was seen in this study. Of these 3 biologics, etanercept had the lowest costs per effectively treated patient, followed by adalimumab and infliximab. Costs of nonbiologic DMARDs were not included in this analysis, but they were expected to be minimal compared with the biologic costs and similar across treatment groups. Because RA disease severity was not reported on the claims, it was not possible to adjust the analysis for disease severity.

CONCLUSIONS

In this study of a national VHA population, the subcutaneous biologics etanercept and adalimumab had lower 1-year biologic costs than intravenous biologics in veterans with RA, as well as higher rates of effectiveness according to the algorithm, which resulted in lower costs per effectively treated patient. Results for costs and effectiveness were similar across most patient subgroups. Men had higher rates of effectiveness and lower costs per effectively treated patient than women; further analysis would be required to understand the underlying reasons for these findings. Although previous studies used similar methods and reported similar outcomes in managed care populations, this study is the first to confirm that cost and effectiveness outcomes are similar in the national VHA population, despite its unique clinical and economic characteristics.

Acknowledgments

The authors wish to thank Jonathan Latham of PharmaScribe, LLC (whose work was funded by Amgen Inc), and Dikran Toroser of Amgen Inc for their assistance with the preparation and submission of the manuscript.

Author Affiliations: Veterans Affairs Salt Lake City Health Care System and University of Utah School of Medicine (BCS, C-CT, TH, JL, C-CL, GWC); University of Alabama at Birmingham (JRC); Amgen Inc (DHT, NS, DJH), Thousand Oaks, CA.

Funding Source: This work was funded by Immunex Corporation, a wholly owned subsidiary of Amgen Inc, and by Wyeth, which was acquired by Pfizer Inc in October 2009. Supplemental funding was provided by the Veterans Affairs Health Services Research and Development Award (HIR 08 204). Project title: VA Informatics and Computing Infrastructure (VINCI). This material is the result of work supported with resources and the use of facilities at the Veterans Affairs SLC IDEAS Center, Salt Lake City, Utah.

Author Disclosures: Drs Tang, Shah, and Harrison are employees and stockholders of Amgen Inc. Dr Sauer received an investigator initiated grant from Amgen to fund the majority of this work. Dr Lu received part of the traveling fund for attending an academic conference from the Amgen grant funding. Dr Curtis is a consultant for and he has also previously received grants and honoraria from Roche/Genentech, UCB, Janssen, CORRONA, Amgen, Pfizer, BMS, Crescendo, and AbbVie. Dr Cannon was the co-principle investigator for this Amgen funded study. The remaining authors report 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 (BCS, DJH, JL, C-CL, JRC, NS, GWC); acquisition of data (BCS, C-CT, TH, C-CL, JRC, GWC); analysis and interpretation of data (BCS, DJH, C-CT, TH, JL, JRC, NS, GWC, DT); drafting of the manuscript (BCS, JRC, NS); critical revision of the manuscript for important intellectual content (BCS, C-CT, DJH, C-CL, JRC, GWC, DT); statistical analysis (BCS, C-CT); obtaining funding (BCS, GWC); provision of patients or study materials (BCS); administrative, technical, or logistic support (BCS, JL, C-CL, GWC, DT); and supervision (GWC).

Send correspondence to: Brian C. Sauer, PhD; VA Salt Lake City IDEAS Center; Salt Lake City Health Care System, 500 Foothill Drive, Bldg 182; Salt Lake City, UT 84148. E-mail: brian.sauer@utah.edu. (Also contact for detailed protocol and program codes.)

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