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Keywords:

  • Crohn's disease;
  • healthcare costs;
  • infliximab;
  • adalimumab

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Background:

Anti-tumor necrosis factor (TNF) medications have similar efficacy in Crohn's disease (CD), but have not been compared in the real world. This study compared health costs and utilization for patients with CD newly initiating anti-TNF therapy with adalimumab (ADA) or infliximab (IFX) by using insurance data.

Methods:

CD patients initiating ADA or IFX therapy were identified from the MarketScan database. ADA and IFX groups were matched using a propensity score. The primary endpoint was direct costs of healthcare for the 6 months following initiation. The secondary endpoints compared healthcare utilization between groups.

Results:

After propensity matching, characteristics were similar between the ADA (n = 623) and IFX (n = 623) groups. During the 6-month interval following anti-TNF initiation, healthcare costs were significantly lower for ADA compared with IFX. Total healthcare cost was $18,885 for ADA and $24,355 for IFX, a difference in cost of $5,470 (P < 0.0001). CD-related costs made up the majority of the costs: $16,454 for ADA and $22,316 for IFX (P < 0.0001). The largest difference in cost was seen in outpatient visits: $2,082 difference between the two groups (P < 0.0001). Both all-cause and CD-related hospitalization decreased for both ADA and IFX groups. Emergency room and hospitalization use in the 6-month follow-up period was not statistically different between groups, although numerically slightly higher in the IFX group.

Conclusions:

Patients with CD using ADA had lower healthcare costs than patients using IFX; this difference was partly driven by outpatient medical costs. (Inflamm Bowel Dis 2012;)

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract that can be debilitating and result in a reduced quality of life.1 Studies have found that medications and hospitalizations account for the greatest part of the economic burden of the disease.2 Patients with CD have increased healthcare utilization compared with matched controls, resulting in significant indirect costs from work loss.3, 4 Patients with a higher severity of CD account for the overwhelming majority of these direct and indirect costs, with only 2% of CD patients accounting for 29% of CD-related charges.5

Effective medical therapy is the best way to improve quality of life for patients and prevent the sequelae of inflammation and complications of the disease. Anti-tumor necrosis factor (TNF) therapy has demonstrated efficacy for symptomatic improvement of CD as well as mucosal healing.6–9 Post-hoc analyses of clinical trial data have demonstrated that adalimumab (ADA) and infliximab (IFX) decreased the need for hospitalization and surgeries, two of the larger components of cost for CD-related healthcare.10–12 Given these findings, economic models have determined that maintenance therapy with ADA or IFX is cost-effective, and data from the CHARM and ACCENT trials have shown acceptable incremental cost profiles with ADA and IFX, respectively.13, 14

Given the similar clinical efficacy of ADA and IFX in clinical trials of anti-TNF-naïve patients with moderate-to-severe CD, the question becomes whether there are differences related to cost. In an earlier study, Markov modeling was employed to compare economic and quality-adjusted life years (QALY) outcomes with ADA and IFX.15 Although it is difficult to directly compare data from the CHARM and ACCENT I trials, utilization estimates from these studies show that ADA results in greater QALY than IFX; ADA is associated with lower drug and drug administration costs, less drug waste, and lower hospitalization rates than IFX.15 This study, however, compared information spanning two separate clinical trials; the results may not represent real-life conditions, and the patient groups were not treated in parallel.

Thus, the aim of the present study was to compare cost and healthcare utilization between the TNF-α-inhibiting medications ADA and IFX in a real-world setting among members of a large healthcare database. Patients were included in the analysis if they had established CD and were newly initiating therapy with either ADA or IFX.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

We evaluated subjects having at least two independent ICD-9-CM diagnoses of CD (555.x) between January 1, 2000 and March 30, 2009 among members of a large national healthcare database (Medstat MarketScan, Camarillo, CA). Patients with at least one claim for ADA or IFX infusion were identified by Healthcare Common Procedure Coding System (HCPCS: J0135 for ADA and J1745 for IFX) and National Drug Codes (NDC). These two sources of data were used to ensure complete subject capture; J-codes document medications administered in an office or infusion center, while the NDC code is used for medications dispensed from retail pharmacies. Specialty pharmacies may make claims by either J-code or NDC. The index date was defined as the first date of anti-TNF use. Included subjects had to be continuously eligible for at least 6 months prior to and 6 months following the index date of anti-TNF use. Subjects were deemed new users of TNF-α inhibitors if there were no other claims for any biologic agents including IFX, ADA, certolizumab pegol, or etanercept at any time prior to the index date. Use of natalizumab was also deemed a criterion for exclusion. Subjects were excluded if a diagnosis of ulcerative colitis was identified (ICD-9-CM 556.x) before the index date and in the follow-up period. Subjects who used index drugs before February 27, 2007, the date of Food and Drug Administration (FDA) approval for ADA, were also excluded to avoid the nonapproved indications for study drugs.

Subjects were separated into groups based on type of medication used (ADA vs. IFX) on the index date. ADA and IFX groups were matched 1:1 using a propensity score stratified by age range, region of residence, inpatient visit utilization, and systemic steroid use criteria at baseline in a fashion similar to that which has been previously described.2 The intent of the propensity score was to reduce confounding variables in our retrospective groups. We chose this method to account for prescriber bias regarding treatment choices related to patient disease severity. By propensity score matching, we may attribute results to medication/treatment differences as opposed to subject characteristics at baseline. Age range was set so that no two subjects in the same stratum were greater than 15 years apart in age. The propensity scores were obtained by estimating the probability that subjects would have been treated with ADA or IFX using a logistic regression model based on the following 26 criteria: age, insurance, region, sex, Charlson comorbidity index, anemia, asthma, cardiovascular diseases, chronic obstructive pulmonary disease, cognitive and psychic disorders, colorectal cancer, diabetes, eye disease, hypertension, malnutrition, rheumatoid arthritis, anal fissures, fistula (including perianal, intestinal, intestinovaginal, or postoperative), abscess, gastrointestinal hemorrhage, obstruction, occlusion, stenosis, stricture of intestine, tobacco use, conventional treatment with aminosalicylates, immunosuppressants, antibiotics, and emergency visits. This score gave each enrolled subject a similar likelihood of receiving ADA based on the detailed criteria and was calculated according to the following formula:

  • equation image

Calculation of the propensity scores between the ADA and IFX groups would permit the authors to compare the likelihood of receiving ADA in each group with respect to the 20 component criteria.

A comprehensive list of CD-related ICD-9-CM and Current Procedural Terminology (CPT) codes was compiled including codes for clinical diagnoses, medications, hospitalizations, emergency room (ER) visits, outpatient visits, laboratories, and procedures (see online Appendix). The direct cost associated with these characteristics was calculated at baseline (6-month lead-in period) and 6-month follow-up period (period postindex date). The cost for the items detailed in this comprehensive list was defined as the direct cost of CD-related healthcare. Consumption of these healthcare services was defined as CD-related healthcare utilization. The cost for hospital admissions lasting less than 23 hours was counted in the outpatient service category in order to capture short admissions solely for the purpose of anti-TNF administration in the outpatient group.

The primary outcome was 6-month direct cost of healthcare postindex date. We also compared healthcare utilization between groups during the 6-month follow-up interval. The main analysis was replicated among those with at least 1 year of postindex eligibility to compare the validity of the findings over a longer time period.

Statistical Analysis

Relative risk was calculated for proportions; relative risk difference was calculated for continuous variables. A Wilcoxon rank-sum test was used to compare continuous variables and cost difference between groups; the chi-square test was used to compare categorical variables.

Ethical Considerations

D.A. Sussman, N. Kubiliun, and M.T. Abreu were all members of the University of Miami and initiated the study idea, developed study design, had full access to data, and drafted the article. None of these authors received consulting or speaking fees in the past year from Abbott Laboratories or from Janssen Biotech. M. Lu was involved in coding information from the Marketscan database. P.M. Mulani, J. Chao, C. Gillis, and M. Yang are employees of Abbott Laboratories. M. Yang and J. Chao were involved with refinement of study design. All were involved in review of data output, revision of the article, and response to journal reviewers. The potential for bias was mitigated by development of study idea independently of industry with involvement of academic authors at the stages of study design and data interpretation. The article was drafted by the academic authors with revisions made at the discretion of the first author. No financial support was provided to support this study. This claims database analysis was determined not to constitute Human Subjects Research by the Institutional Review Board of the University of Miami.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Patient Demographics and Baseline Characteristics

In all, 1533 subjects met inclusion and exclusion criteria; 690 in the ADA group and 843 in the IFX group. Baseline characteristics before stratification were different between groups with respect to age, region of residence, history of anal fissures, gastrointestinal hemorrhage, and systemic steroid use (Table 1). After calculating the propensity score for each subject based on 20 CD-related criteria, subjects were stratified into the ADA and IFX groups based on age, region of residence, inpatient visit utilization, and systemic steroid use. The mean propensity score for the ADA group was 0.475, while the score for the IFX group was 0.452. The mean difference in propensity score between groups was 0.066, demonstrating similarity between groups. A total of 1246 subjects were included with 623 patients in each group.

Table 1. Baseline Characteristics of CD Patients by Index Therapy: Adalimumab vs. Infliximab
 AdalimumabInfliximabP-valuea
Baseline Characteristics[A][B][A] vs. [B]
  • a

    Wilcoxon rank-sum test is used to compare continuous variables; chi-square test was used to compare categorical variables.

  • b

    PPO, Preferred Provider Organization; HMO, Health Maintenance Organization; POS, Point of Service.

  • *

    Significant at 5% level.

Study sample (n)690843 
Demographic characteristics     
 Age on index date (mean, SD)39.813.035.114.7<0.0001*
 Male (n, %)30344%37544%0.8230
Census region (n, %)    <0.0001*
 Northeast and unknown41%20% 
 North central26939%25130% 
 South26338%39046% 
 West9614%10512% 
Insurance typeb (n, %)    0.2940
 PPO47569%57969% 
 HMO7811%9912% 
 POS588%8810% 
 Other/unknown7911%779% 
Comorbidity profile (n, %)     
I. CD-related comorbidities     
 Anemia12418%13116%0.2030
 Asthma274%273%0.4530
 Cardiovascular diseases223%283%0.8840
 Chronic obstructive pulmonary disease (COPD)152%172%0.8300
 Cognitive and psychic disorders7110%718%0.2100
 Colorectal cancer345%465%0.6430
 Diabetes mellitus304%233%0.0840
 Eye disease649%718%0.5580
 Hypertension7611%8911%0.7740
 Malnutrition122%142%0.9060
 Rheumatoid arthritis284%243%0.1930
II. CD-related symptom/CD-specific comorbidities     
 Anal fissures314%668%0.0080*
 Fistula558%8510%0.1530
 Abscess517%698%0.5650
 Gastrointestinal hemorrhage325%708%0.0040*
 Obstruction, occlusion, stenosis, stricture of intestine548%739%0.5560
III. Behavior related comorbidities     
 Tobacco use172%212%0.9730
Deyo-Charlson comorbidity index (mean, SD)0.260.710.220.610.3577
Prior CD-related conventional treatment (n, %)     
 Aminosalicylates29443%33139%0.1850
 Systemic steroids35852%35943%<0.0001*
 Immunosuppressors26338%28434%0.0720
 Antibiotics25237%27733%0.1330
Health care service utilization (n, %)     
 Inpatient (IP) visits14721%21225%0.0770
 Emergency room (ER) visits15022%19623%0.4810

After propensity matching, demographic, clinical, and healthcare utilization characteristics were similar between the ADA and IFX groups at baseline, including insurance type (Preferred Provider Organization [PPO], Health Maintenance Organization [HMO], or Point of Service [POS] plans), Deyo-Charlson comorbidity index, location of disease, complications of disease (stricturing, fistulizing, and abscess formation), prior treatment with corticosteroids and immunomodulators, and healthcare utilization as defined by inpatient, outpatient, and ER visits (Table 2).16

Table 2. Baseline Characteristics of Matched CD Patients by Index Therapy: Adalimumab vs. Infliximab
 AdalimumabInfliximabP-valuea
Baseline Characteristics[A][B][A] vs. [B]
  • a

    Wilcoxon rank-sum test is used to compare continuous variables; chi-square test was used to compare categorical variables.

  • b

    PPO, Preferred Provider Organization; HMO, Health Maintenance Organization; POS, Point of Service.

  • *Significant at 5% level.

Study sample (n)623623 
Demographic characteristics     
 Age on index date (mean, SD)38.8513.037.9513.30.2144
 Male (n, %)28045%27644%0.8200
Census region (n, %)    1.0000
 Northeast and unknown599%599% 
 North central23037%23037% 
 South24940%24940% 
 West8514%8514% 
Insurance typeb (n, %)    0.3210
 PPO42468%43670% 
 HMO7212%7612% 
 POS528%569% 
 Other/unknown7512%559% 
Comorbidity profile (n, %)     
I. CD-related comorbidities     
 Anemia11018%9315%0.1920
 Asthma244%173%0.2660
 Cardiovascular diseases183%193%0.8670
 Chronic obstructive pulmonary disease (COPD)142%132%0.8460
 Cognitive and psychic disorders599%559%0.6940
 Colorectal cancer305%376%0.3790
 Diabetes mellitus274%183%0.1720
 Eye disease579%528%0.6160
 Hypertension599%7512%0.1430
 Malnutrition122%102%0.6670
 Rheumatoid arthritis213%163%0.4040
II. CD-related symptom/CD-specific comorbidities     
 Anal fissures295%396%0.2120
 Fistula508%559%0.6100
 Abscess488%467%0.8300
 Gastrointestinal hemorrhage284%427%0.0850
 Obstruction, occlusion, stenosis, stricture of intestine518%589%0.4830
III. CD-sub type     
 Large intestine8313%9515%0.3310
 Small intestine10417%9615%0.5370
 Small intestine with large intestine30349%28646%0.3350
 Unspecified site13321%14623%0.3770
IV. Behavior related comorbidities     
 Tobacco use142%152%0.8510
Deyo-Charlson comorbidity index (mean, SD)0.250.710.210.570.8331
Prior CD-related conventional treatment (n, %)     
 Aminosalicylates26442%25942%0.7740
 Systemic steroids31350%31350%1.0000
 Immunosuppressors24239%21835%0.1590
 Antibiotics22736%20733%0.2340
Healthcare service utilization (n, %)     
 Inpatient (IP) visits13822%13822%1.0000
 Emergency room (ER) visits13422%14323%0.5400

In the lead-in period prior to use of TNF-α-inhibiting medications, mean total and CD-related prescription nonanti-TNF drug costs were higher in the ADA group ((ADA: $1,374 vs. IFX: $1,113, P < 0.0001) and (ADA: $648 vs. IFX: $585, P = 0.029), respectively) (Table 3). Mean total CD-related healthcare costs were also different between groups (ADA: $8,849 vs. IFX: $9,271, P = 0.0427), driven primarily by a higher medical service cost in the IFX group (ADA: $8,201 vs. IFX: $8,686, P = 0.016). Medical service costs were those dollars associated with medical care, including hospitalizations, ER visits, and outpatient costs, but excluding prescription drugs. These mean baseline cost differences ranging from $63 to $486 over 6 months ($10.50–81 per month) were considered not economically meaningful in the context of the total cost of healthcare for these subjects. Between 19%–24% of patients required inpatient admissions prior to anti-TNF therapy.

Table 3. Healthcare Utilization and Cost of Matched CD Patients Over the 6 Months Preindex Period, Descriptive Analysis: Adalimumab vs. Infliximab
 AdalimumabInfliximab 
 (N=623)(N=623) 
Healthcare Utilization and CostsaMean ± SD or N (%)Median (Q1; Q3)Mean ± SD or N (%)Median (Q1; Q3)P-valueb
  • aRelative risk is calculated for proportions; difference is calculated for continuous variables.

  • b

    Wilcoxon rank-sum test is used for comparing continuous variables; chi-square test was used for comparing categorical variables.

  • c

    Other medical cost includes costs associated with treatments not classified as inpatient visits, emergency visits, or outpatient visits. Other medical costs can include the costs associated with treatment at unlisted facility, patient's home, school, independent laboratory, mobile units, etc.

  • *

    Significant at 5% level.

6-Month healthcare utilization     
 Hospitalization     
  6-Month rate, any cause138 (22%)n/a138 (22%)n/a1.0000
  6-Month rate, CD-related125 (20%) 135 (22%) 0.4860
  Hospitalization days, any cause1.79 ± 5.30.0 (0.0; 0.0)2.08 ± 7.60.0 (0.0; 0.0)0.8290
  Hospitalization days, CD-related1.65 ± 5.20.0 (0.0; 0.0)2.04 ± 7.60.0 (0.0; 0.0)0.3852
  Number of hospital visits, any cause0.3 ± 0.70.0 (0.0; 0.0)0.33 ± 0.70.0 (0.0; 0.0)0.8434
  Number of hospital visits, CD-related0.27 ± 0.60.0 (0.0; 0.0)0.32 ± 0.70.0 (0.0; 0.0)0.3699
 Emergency room visit     
  6-Month rate, any cause134 (22%)n/a143 (23%)n/a0.5400
  6-Month rate, CD-related89 (14%) 102 (16%) 0.3070
 Outpatient visits     
  Number of outpatient visits, any cause9.92 ± 7.18.0 (5.0; 13.0)9.66 ± 7.78.0 (5.0; 12.0)0.2353
  Number of outpatient visits, CD-related5.36 ± 4.25.0 (3.0; 7.0)5.48 ± 3.75.0 (3.0; 7.0)0.1547
6-Month healthcare costs ($)     
 Prescription drugs costs     
  Total prescription drug cost$1,374 ± $2,420$825 ($142; $1,777)$1,113 ± $1,936$514 ($0; $1,637)<0.0001*
  Total CD-related drug cost$648 ± $867$325 ($0; $1,018)$585 ± $897$182 ($0; $859)0.0290*
 Medical service-related costs     
  Hospitalization$4,541 ± $23,031$0 ($0; $0)$4,405 ± $14,779$0 ($0; $0)0.9337
  Hospitalization, CD-related$4,170 ± $22,796$0 ($0; $0)$4,260 ± $14,677$0 ($0; $0)0.4646
  ER visit$287 ± $1,084$0 ($0; $0)$242 ± $797$0 ($0; $0)0.7261
  ER visit, CD-related$227 ± $1,014$0 ($0; $0)$165 ± $593$0 ($0; $0)0.4500
  Outpatient / office visit$4,706 ± $7,302$2,498 ($806; $5,326)$4,892 ± $6,880$2,454 ($813; $6,036)0.5901
  Outpatient / office visit, CD-related$3,583 ± $6,316$1,645 ($299; $3,767)$4,014 ± $6,294$1,726 ($400; $4,903)0.1096
  Other medical costsc$732 ± $10,723$0 ($0; $83)$315 ± $1,560$0 ($0; $82)0.8913
  Other medical costs, CD-relatedc$220 ± $1,503$0 ($0; $7)$248 ± $1,522$0 ($0; $12)0.4254
  Total medical service costs$10,265 ± $26,869$3,909 ($1,245; $11,139)$9,854 ± $16,805$4,536 ($1,530; $12,624)0.2960
  Total medical service costs, CD-related$8,201 ± $23,752$2,652 ($512; $8,425)$8,686 ± $16,307$3,497 ($833; $10,960)0.0161*
 Total healthcare costs     
  Total healthcare costs$11,640 ± $27,088$5,544 ($2,218; $13,056)$10,967 ± $17,019$5,625 ($2,273; $14,000)0.7531
  Total healthcare costs, CD-related$8,849 ± $23,772$3,455 ($1,173; $9,426)$9,271 ± $16,323$4,124 ($1,435; $11,641)0.0427*

Direct Cost of Healthcare After Initiation of Anti-TNF Therapy

We calculated the mean total healthcare costs for the 6 months after the patients initiated anti-TNF therapy. Despite the fact that patients were matched by propensity score and had similar characteristics prior to initiating anti-TNF therapy, mean total healthcare costs were $5,470 lower in the ADA group than the IFX group in the follow-up period ($18,885 vs. $24,355, respectively, P < 0.0001) (Table 4). The majority of the healthcare costs in these groups were CD-related; therefore, the difference existed for mean CD-related healthcare costs ($16,454 vs. $22,316, P < 0.0001). We excluded the cost of the index drugs in order to find the reason for the differences seen. When cost of drug was excluded, there continued to be a difference in the cost analysis (ADA $8,176 vs. IFX $11,955, respectively, P < 0.0001). Excluding the costs of study medication, total and CD-related medical service-related costs were lower in the ADA group (mean difference of $3,779 and $4,171, respectively, P < 0.0001 for both groups).

Table 4. Healthcare Utilization and Cost of Matched CD Patients over the 6 Months Post-Index Period, Descriptive Analysis: Adalimumab vs. Infliximab
 AdalimumabInfliximab 
 (N=623)(N=623)P-valueb
Healthcare Utilization and CostsaMean ± SD or N (%)Median (Q1; Q3)Mean ± SD or N (%)Median (Q1; Q3)[A] vs. [B]
  • aRelative risk is calculated for proportions; difference is calculated for continuous variables.

  • b

    Wilcoxon rank-sum test is used for comparing continuous variables; chi-square test was used for comparing categorical variables.

  • c

    Other medical cost includes costs associated with treatments not classified as inpatient visits, emergency visits, or outpatient visits. Other medical costs can include the costs associated with treatment at unlisted facility, patient's home, school, independent laboratory, mobile units, etc.

  • *

    Significant at 5% level.

6-Month healthcare utilization     
 Hospitalization     
  6-Month rate, any cause89 (14%)n/a102 (16%)n/a0.3070
  6-Nonth rate, CD-related81 (13%) 94 (15%) 0.2890
  Hospitalization days, any cause1.24 ± 5.30.00 (0.0; 0.0)1.78 ± 5.90.00 (0.0; 0.0)0.2198
  Hospitalization days, CD-related1.2 ± 5.20.00 (0.0; 0.0)1.71 ± 5.90.00 (0.0; 0.0)0.2255
  Number of hospital visits, any cause0.2 ± 0.60.00 (0.0; 0.0)0.25 ± 0.70.00 (0.0; 0.0)0.2690
  Number of hospital visits, CD-related0.19 ± 0.60.00 (0.0; 0.0)0.23 ± 0.60.00 (0.0; 0.0)0.2603
 Emergency room visit     
  6-Month rate, any cause113 (18%)n/a120 (19%)n/a0.6110
  6-Month rate, CD-related57 (9%) 62 (10%) 0.6300
 Outpatient visits     
  Number of outpatient visits, any cause8.84 ± 7.47.00 (4.0; 11.0)11.3 ± 7.39.00 (6.0; 14.0)<0.0001
  Number of outpatient visits, CD-related4.28 ± 4.14.00 (2.0; 6.0)7.22 ± 3.97.00 (5.0; 9.0)<0.0001
6-Month healthcare costs ($)     
 Index drug costs$10,709 ± $4,979$11,692 ($8,477; $13,311)$12,401 ± $20,834$10,701 ($5,646; $15,515)0.5416
 Prescription drugs costs-excluding index drug    
  Total prescription drug costs$1,334 ± $1,892$679 ($118; $1,762)$1,639 ± $6,341$419 ($0; $1,613)0.0004*
  Total CD-related drug costs$546 ± $916$86 ($0; $814)$857 ± $2,047$75 ($0; $793)0.3803
 Medical service-related costs excluding index drug    
  Hospitalization$3,357 ± $14,809$0 ($0; $0)$5,166 ± $24,762$0 ($0; $0)0.2556
  Hospitalization, CD-related$3,257 ± $14,770$0 ($0; $0)$4,961 ± $24,638$0 ($0; $0)0.2576
  ER visit$206 ± $906$0 ($0; $0)$278 ± $1,441$0 ($0; $0)0.6157
  ER visit, CD-related$136 ± $852$0 ($0; $0)$182 ± $1,330$0 ($0; $0)0.6903
  Outpatient / office visit$2,482 ± $4,088$1,035 ($315; $2,971)$4,565 ± $6,007$2,459 ($1,371; $5,194)<0.0001*
  Outpatient / office visit, CD-related$1,579 ± $3,544$354 ($102; $1,521)$3,659 ± $5,364$1,908 ($1,045; $3,698)<0.0001*
  Other medical costsc$797 ± $11,722$0 ($0; $47)$307 ± $1,545$0 ($0; $89)0.0971
  Other medical costs, CD-relatedc$227 ± $1,992$0 ($0; $0)$257 ± $1,503$0 ($0; $7)0.0107*
  Total medical service costs$6,842 ± $20,388$1,449 ($379; $4,734)$10,316 ± $25,995$3,222 ($1,725; $8,846)<0.0001*
  Total medical service cost, CD-related$5,199 ± $16,476$487 ($128; $2,953)$9,059 ± $25,597$2,355 ($1,276; $7,153)<0.0001*
 Total healthcare costs     
  Total healthcare costs$18,885 ± $21,049$14,979 ($11,568; $20,397)$24,355 ± $36,525$18,365 ($12,267; $25,868)<0.0001*
  Total healthcare costs, CD-related$16,454 ± $16,667$13,542 ($10,627; $17,247)$22,316 ± $32,578$16,874 ($11,156; $23,980)<0.0001*
 Total healthcare costs excluding index drug     
  Total healthcare costs$8,176 ± $20,822$2,851 ($1,118; $7,075)$11,955 ± $27,032$4,879 ($2,187; $11,732)<0.0001*
  Total healthcare costs, CD-related$5,745 ± $16,503$1,306 ($308; $3,644)$9,916 ± $25,672$3,251 ($1,508; $8,367)<0.0001*
 Total healthcare costs excluding index  drug and Remicade administration cost     
   Total healthcare costs$8,176 ± $20,822$2,851 ($1,118; $7,075)$10,748 ± $27,031$3,615 ($1,115; $10,022)0.0347*
   Total healthcare costs, CD-related$5,745 ± $16,503$1,306 ($308; $3,644)$8,710 ± $25,679$1,944 ($500; $7,148)<0.0001*

There was a numerical difference ($1,809) noted for the mean cost of hospitalizations between groups; hospitalization in the ADA group was less costly, though it was not statistically significant (P = 0.26). Excluding index medication cost, total prescription drug cost was lower in the ADA group ($1,334 vs. $1,639, P = 0.0004). This difference was not derived from medication costs for drugs commonly used to prevent infusion reactions with IFX. No difference was noted in the mean cost of concurrent CD-related medications (P = 0.38). IFX was more expensive than ADA; however, no statistically significant difference between the mean cost of TNF-α-inhibiting index medication was noted during the 6-month study period (ADA: $10,709 vs. IFX: $12,401, P = 0.54).

Lower medical service costs with ADA were driven mainly by a decreased cost of outpatient office visits (P < 0.0001). This subset of costs includes not only outpatient medical care but also the cost of medication administration (infusion for IFX) and infusion reactions. Deeper analysis confirmed that this mean cost difference was primarily due to infusion-related expenses for IFX ($338 vs. $1,518; P < 0.0001). No significant difference in hospitalization, number of hospital visits, and ER visits was noted between the ADA and IFX groups over 6 months for CD-related encounters (Table 4). We conclude that during the 6-month interval following anti-TNF initiation, mean healthcare costs were significantly lower for ADA compared with IFX therapy, largely due to the difference in medication administration costs for the intravenous infusion of IFX, coupled with numerically, but not significantly, higher hospitalization costs and drug costs.

Comparison of Costs Before and After Initiation of Anti-TNF Therapy

Costs and healthcare utilization were compared within groups between the pre- and postindex periods (Table 5). Mean total CD-related healthcare costs increased in both groups (ADA: $7,605 and IFX: $13,046, mean difference compared with baseline). When the index medication cost was excluded, mean total healthcare costs decreased by $3,464 in the ADA group, while cost persistently increased by $987 in the IFX group. When the cost of IFX administration was also excluded, mean total healthcare costs decreased by $219 as well in the IFX group. Mean total medical service costs decreased by $3,423 in the ADA group and increased by $461 in the IFX group.

Table 5. Differences in Healthcare Utilization and Cost of Matched CD Patients, Descriptive Analysis 6 Months Postindex Period vs. 6 Months Preindex Period: Adalimumab vs. Infliximab
 Adalimumab DifferenceInfliximab Difference 
 (N=623)(N=623) 
Healthcare Utilization and CostsPost-prePost-preP-valuea
  • a

    Wilcoxon rank-sum test is used for comparing continuous variables; chi-square test was used for comparing hospitalizations, and Cochran-Mantel-Haenszel was used for emergency room visits.

  • b

    Other medical cost includes costs associated with treatments not classified as inpatient visits, emergency visits, or outpatient visits. Other medical costs can include the costs associated with treatment at unlisted facility, patient's home, school, independent laboratory, mobile units, etc.

6-Month healthcare utilization   
 Hospitalization   
  6-Month rate, any cause (%)−7.9%−5.8%0.3067
  6-Month rate, CD-related (%)−7.1%−6.6%0.6298
  Hospitalization days, any cause (mean ± SD)−0.54 ± 6.46−0.30 ± 8.500.7035
  Hospitalization days, CD-related (mean ± SD)−0.45 ± 6.34−0.33 ± 8.460.9960
  Number of hospital visits, any cause (mean ± SD)−0.10 ± 0.77−0.09 ± 0.820.6362
  Number of hospital visits, CD-related (mean ± SD)−0.09 ± 0.72−0.09 ± 0.790.9607
 Emergency room visit   
  6-Month rate, any cause (%)−3.4%−3.7%0.6875
  6-Month rate, CD-related (%)−5.1%−6.4%0.7261
 Outpatient visits   
  Number of outpatient visits, any cause (mean ± SD)−1.07 ± 6.231.64 ± 6.54<0.0001
  Number of outpatient visits, CD-related (mean ± SD)−1.08 ± 4.021.73 ± 4.15<0.0001
6-Month healthcare costs ($)   
 Prescription drugscCosts (mean ± SD)   
  Total prescription drug cost−$41 ± $1,863$526 ± $6,0930.5008
  Total CD-related drug cost−$102 ± $958$272 ± $1,9530.0488
 Medical service-related costs excluding index drug  (mean ± SD)  
  Hospitalization−$1,184 ± $25,811$761 ± $25,9070.5472
  Hospitalization, CD-related−$913 ± $25,553$701 ± $25,7460.8623
  ER visit−$81 ± $881$35 ± $1,3870.8825
  ER visit, CD-related−$92 ± $778$17 ± $1,2310.5546
  Outpatient / office visit−$2,223 ± $7,344−$327 ± $7,337<0.0001
  Outpatient / office visit, CD-related−$2,004 ± $6,319−$354 ± $6,741<0.0001
  Other medical costs b$65 ± $2,290−$8 ± $1,5840.1137
  Other medical costs, CD-related b$7 ± $2,029$9 ± $1,5370.0530
  Total medical service costs−$3,423 ± $26,897$461 ± $27,213<0.0001
  Total medical service costs, CD-related−$3,002 ± $26,596$373 ± $26,788<0.0001
 Total healthcare costs (mean ± SD)   
  Total healthcare costs$7,245 ± $27,300$13,388 ± $37,3150.0006
  Total healthcare costs, CD-related$7,605 ± $26,830$13,046 ± $33,5560.0009
 Total healthcare costs excluding index drug  (mean ± SD)   
  Total healthcare costs−$3,464 ± $27,041$987 ± $28,068<0.0001
  Total healthcare costs, CD-related−$3,104 ± $26,629$645 ± $26,735<0.0001
 Total healthcare costs excluding index drug and  Remicade administration cost (mean ± SD)   
   Total healthcare costs−$3,464 ± $27,041−$219 ± $28,1540.0809
   Total healthcare costs, CD-related−$3,104 ± $26,629−$561 ± $26,8070.1398

All-cause hospitalizations decreased by 7.9% in the ADA group and by 5.8% in the IFX group (P = 0.3067) (Table 5). For CD-related issues, utilization of hospitalization decreased by 7.1% in the ADA group and by 6.6% in the IFX group. The mean number of hospital stay in days and number of hospital visits decreased in both groups (ADA: −0.54 days; −0.10 visits and IFX: −0.30 days; −0.09 visits). All-cause and CD-related hospitalizations, ER visits, and outpatient visits cost less in the post period for subjects in the ADA group (Table 5). In the IFX group, only outpatient office visits cost less than the lead-in period. The increased costs of IFX administration offset the cost savings for outpatient services; hospitalizations and ER visits in the postindex period for IFX, despite the reduction of hospitalization utilization in the follow-up period compared with the lead-in period for IFX. Average CD-related prescription drug costs (excluding TNF-α-inhibiting medications) decreased by $102 over 6 months in the ADA group but increased by $272 in the IFX group and this difference was statistically significant, albeit by a very small amount (P = 0.0488).

Differences in Healthcare Costs for a Period of 12 Months After Initiation of Anti-TNF Therapy

We chose as our primary study endpoint to examine the first 6 months of healthcare costs with a secondary endpoint of 6-month healthcare utilization because of concerns related to changes in health plans and a smaller number of subjects. However, we wished to understand whether the trends observed in the first 6 months continued to hold true during the first year. The detailed cost and utilization analysis was repeated for those subjects having complete data during a 12-month follow-up interval. In all, 769 subjects met inclusion and exclusion criteria; 296 in the ADA group and 473 in the IFX group. After applying the propensity score, a total of 592 subjects were included with 296 patients in each group.

The cost and utilization results (Table 6) were largely similar to the 6-month analysis. Average outpatient costs, total medical service costs, and total healthcare costs excluding the index drug, however, were significantly lower in the ADA cohort compared with IFX cohort. Hospitalization, number of hospital visits, number of hospital days, and ER visits were similar between the IFX and ADA cohorts. The average total index drug costs were also significantly lower in the ADA cohort when compared with the IFX cohort.

Table 6. Healthcare Utilization and Cost of Matched CD Patients over the 12 Months PostIndex Period, Descriptive Analysis: Adalimumab vs. Infliximab
 AdalimumabInfliximabDifferenceaP-valueb
 (n=296)(n=296)[A]-[B] or
Healthcare Utilization and Costs[A][B][A]/[B][A] vs. [B]
  • a

    Relative risk is calculated for proportions; difference is calculated for continuous variables.

  • b

    Wilcoxon rank-sum test is used for comparing continuous variables; chi-square test was used for comparing categorical variables.

  • c

    Other medical cost includes costs associated with treatments not classified as inpatient visits, emergency visits, or outpatient visits. Other medical costs can include the costs associated with treatment at unlisted facility, patient's home, school, independent laboratory, mobile units, etc.

  • *

    Significant at 5% level.

12-Month healthcare utilization   
 Hospitalization    
  12-Month rate, any cause (n, %)76 (26%)74 (25%)1.030.8500
  12-Month rate, CD-related (n, %)68 (23%)65 (22%)1.050.7680
  Hospitalization days, any cause (mean ± SD)2.29 ± 6.22.75 ± 7.3-0.460.9398
  Hospitalization days, CD-related (mean ± SD)2.14 ± 6.12.52 ± 7.2-0.380.9266
  Number of hospital visits, any cause (mean ± SD)0.4 ± 0.90.39 ± 0.80.010.8681
  Number of hospital visits, CD-related (mean ± SD)0.36 ± 0.80.33 ± 0.80.030.7641
 Emergency room visit    
  12-Month rate, any cause (n, %)87 (29%)73 (25%)1.190.1950
  12-Month rate, CD-related (n, %)44 (15%)40 (14%)1.100.6380
 Outpatient visits    
  Number of outpatient visits, any cause (mean ± SD)18.07 ± 14.122.25 ± 13.7-4.18<0.0001
  Number of outpatient visits, CD-related (mean ± SD)7.97 ± 7.212.23 ± 5.8-4.26<0.0001
12-Month healthcare costs ($)    
 Index drug costs (mean ± SD)$18,330 ± $7,928$19,881 ± $40,174-$1,5500.0005*
 Prescription drugs costs excluding index drug (mean ± SD)   
  Total prescription drug costs$2,810 ± $3,778$4,758 ± $17,778-$1,9480.3133
  Total CD-related drug costs$993 ± $1,408$2,254 ± $4,468-$1,2610.2874
 Medical service-related costs excluding index drug (mean ± SD)  
  Hospitalization$6,655 ± $20,020$8,569 ± $38,009-$1,9140.9784
  Hospitalization, CD-related$6,164 ± $19,613$8,111 ± $37,846-$1,9470.9037
  ER visit$407 ± $1,396$330 ± $869$780.4188
  ER visit, CD-related$242 ± $1,243$178 ± $712$640.7489
  Outpatient / office visit$5,443 ± $8,998$9,172 ± $11,676-$3,729<0.0001*
  Outpatient / office visit, CD-related$2,971 ± $5,335$6,728 ± $10,020-$3,757<0.0001*
  Other medical costsc$556 ± $2,898$1,153 ± $7,862-$5970.2121
  Other medical costs, CD-relatedc$378 ± $2,841$549 ± $2,867-$1710.0666
  Total medical service costs$13,061 ± $24,800$19,224 ± $48,897-$6,163<0.0001*
  Total medical service cost, CD-related$9,755 ± $22,561$15,566 ± $39,625-$5,811<0.0001*
 Total healthcare costs (mean ± SD)    
  Total healthcare costs$34,202 ± $26,680$43,863 ± $74,009-$9,6620.0035*
  Total healthcare costs, CD-related$29,078 ± $23,680$37,701 ± $56,314-$8,6230.0011*
 Total healthcare costs excluding index drug  (mean ± SD)    
  Total healthcare costs$15,871 ± $26,040$23,982 ± $52,935-$8,111<0.0001*
  Total healthcare costs, CD-related$10,748 ± $22,682$17,820 ± $39,822-$7,072<0.0001*

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Currently, there are three FDA-approved TNF-α-inhibiting biologic medications for CD: IFX, ADA, and certolizumab pegol. IFX and ADA are approved for induction and maintenance of remission in CD, whereas certolizumab pegol is approved for maintenance of response. For our study we did not include certolizumab pegol because it was only approved in April 2008; we would not have had sufficient patients with a 6-month lead-in and 6-month follow-up to reach statistically meaningful conclusions. The original clinical trials of IFX and ADA for the treatment of CD enrolled patients with similar Crohn's Disease Activity Index (CDAI) scores. The rates of remission and response are comparable, although comparing across studies has inherent bias. The finding that both IFX and ADA reduce the hospitalization rates to a similar extent in the current study speaks to similar efficacy of the medications. Because of these similarities in action it is important to understand other factors that may influence choice of biologic therapy.

One difference between IFX and ADA or certolizumab pegol is the need for intravenous administration. IFX requires the placement of an intravenous catheter for at least a 2-hour infusion. Our study found that the costs associated with IFX in the 6 months after initiation of a biologic were higher than ADA and that the largest difference was due to infusion-related costs. In this analysis, we found that the average number of IFX infusions administered during the 6 months was 3.7; the expected number would have been five infusions if all subjects successfully completed induction and continued on maintenance therapy. Although there was no information in the database on dose (mg) used, we speculate that patients receiving fewer infusions may have not had a benefit from IFX or developed a side effect. The same scenario should be true of ADA, i.e., there is a certain rate of primary nonresponse that effects all anti-TNF medications. Importantly, healthcare utilization during the same period was similar between groups, with fewer hospitalizations, surgeries, and ER visits in the follow-up period than prior to use of TNF-α-inhibiting medications. Thus, as expected, patients who are on effective therapy for CD utilize less healthcare.

Although a minority of CD patients require hospitalization or surgery, these patients account for the majority of total CD-related health costs.17 Surgical procedures on patients with high disease severity consume ≈75% of overall CD-related charges and reimbursements.18 These more severe patients require more optimal medical therapy, as patients in remission have fewer hospitalizations and surgeries.19 Decreased hospitalizations and surgeries have been repeatedly demonstrated for the TNF-α-inhibiting medications IFX20–23 and ADA.24–26 Indeed, our study found that both medications decreased hospitalization rates and ER visits to a similar extent.

The total cost of healthcare was increased in both the ADA and IFX groups; this is likely due to the fact that the short-term change in hospitalization rates over 6 months was not enough to offset the cost of medications during this time period. Both all-cause and CD-related hospitalizations decreased for both the ADA and IFX groups. ER and hospitalization use in the 6-month follow-up period was similar between groups.

The data presented here represent the short-term influence of ADA and IFX on costs and healthcare utilization. Although we believe this is an important comparison, longer-term data would be ideal to guide clinical decisions. We were able to extend the comparison between ADA and IFX to 12 months, but given the relatively recent FDA approval of ADA for use in CD, 12 months was the longest period of follow-up for which meaningful data could be interpreted. In addition, patients change insurance plans, which again limits longer time comparisons. The most striking difference between groups was the cost of outpatient office visits, which consisted of IFX infusions and physician charges for medication administration. Healthcare utilization was similar in both groups after index medication initiation. One conclusion that should not be made from this study is that fewer outpatient visits for CD patients is a goal. It may be that patients receiving self-injectable medications should be visiting the physician more often to monitor labs as well as to monitor treatment adherence. At least in this short-term analysis, there was no evidence of worse outcomes due to fewer physician visits as evidenced by ER visits or hospitalizations in the postmedication intervals. Although TNF-α-inhibiting medications in general are associated with multiple side effects, they are considered safe based on clinical experience and meta-analyses.27, 28 However, some patients prescribed self-injectable medications may not return for routine office visits; the safety of medication continuation despite patient lack of visit adherence in particular has not been evaluated.

One interesting question relates to the cost of dose intensification during the postindex interval. CD patients on TNF-α-inhibiting medications lose response and require an increase in dose or shortening of dosing intervals. One study reported that 54.3% of patients on IFX require dose intensification over 30 months, comprised of dose increases, shortening of the interval, or both.29 This phenomenon of dose intensification is observed for both ADA and IFX. Further study on the rate of dose intensification for TNF-α-inhibiting medications is needed to permit analysis of the impact on cost of intensification over time. The influence of the commercial availability of measurable drug antibodies and trough levels to TNF-α-inhibiting medications on dosing changes and cost will also be worthy of study.

An important cost that cannot be extracted from the database is the out-of-pocket expense for healthcare consumers. The litany of commercially available healthcare plans results in a range of unpredictable costs to the patient; these factors certainly influence the healthcare provider's choice of treatment class and/or medication. Our study raised the interesting question of why higher costs of hospitalization and ER costs exist for patients using IFX as opposed to ADA. Our study included observation admissions (those lasting less than 23 hours) as outpatient claims data, so hospital admissions for the purpose of IFX administration should have been excluded. This finding should be verified by future investigations.

Our study has several limitations. The present investigation is a database study. Patients were excluded if they were exposed to an anti-TNF in the 6-month period leading up to initiation of ADA or IFX, but it is conceivable that they were on anti-TNF in the distant past as part of another insurance plan not included in the MarketScan database. We speculate that patients in our study using ADA were more likely to have been on IFX in the remote past (i.e., were anti-TNF exposed) than patients initiating IFX simply because IFX has been available longer, and ADA is approved for patients who have lost response to IFX in addition to naïve patients. This bias against ADA likely makes the study conclusions more conservative. Despite using the propensity score to balance patient characteristics between groups, the ultimate factors underlying health provider choice of medication cannot be determined with our study design. The intent of the propensity score is to reduce the influence of intangible confounding variables from creating unknown differences between groups, in much the same way that randomization accounts for these confounders in a prospective study. We attempted to make the two groups as similar as possible with these matching techniques. Of note, rates for tobacco use among study subjects was far lower than would be expected based on prior reports among CD patients; this is a manifestation of using a healthcare provider-dependent ICD-9-CM-based strategy to identify tobacco use in a retrospective population. The authors presume that providers are unlikely to report tobacco use by ICD-9-CM unless the patient is actively undergoing treatment for a tobacco-related disorder. The Marketscan database also heavily represents the South and North Central United States; accordingly, there may be differences in prescribing practices in other regions that would have led to different conclusions, limiting the ability to generalize study results. On the other hand, patients generally do receive IFX in an outpatient setting where there exists physician supervision; these costs are unlikely to be very different based on region. Additionally, the direct costs of ADA administration are expected to be small. For example, the investigators were unable to directly account for costs generated by patients receiving ADA in their physician's office or requiring home nursing visits.

The present study is the first head-to-head, real-world comparison of costs and healthcare utilization between ADA and IFX. Previous comparisons of these two medications were models not based on real costs and raised further research questions. We believe this study addresses some of those questions. Unfortunately, a direct, prospective comparison is unlikely to occur. Further investigation into the long-term cost difference between ADA and IFX is warranted given the chronic nature of CD. A study of prescribing practices and dose intensification on healthcare costs and utilization is also warranted.

REFERENCES

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Supporting Information

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. REFERENCES
  7. Supporting Information

Additional Supporting Information may be found in the online version of this article.

Please note: Wiley Blackwell is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.