Health care resource use and costs for Crohn ’ s disease before and after infliximab therapy

Division of Gastroenterology, University of Alberta, Edmonton, Alberta Correspondence: Dr Dustin E Loomes, Division of Gastroenterology, University of Alberta, Zeidler Ledcor Centre, Edmonton, Alberta T6G 2X8. Telephone 780-492-6941, fax 780-492-8121, e-mail dloomes@ualberta.ca Received for publication October 3, 2010. Accepted February 24, 2011 Over the past decade, the treatment of Crohn’s disease has changed remarkably, perhaps most notably with the introduction of antitumour necrosis factor monoclonal antibodies, the first of which was infliximab. Infliximab is approved for the treatment of moderate to severe luminal and fistulizing Crohn’s disease that is refractory to standard therapy, which includes corticosteroid and immunosuppressive medications (1). Although clinical trials have demonstrated the efficacy of infliximab for both induction (2,3) and maintenance (4,5) of remission, global availability remains restricted due to its cost (6). Crohn’s disease, however, is associated with considerable economic costs. Early age of onset, high morbidity, slightly reduced to near normal life expectancy and higher prevalence in industrialized first-world nations (with an estimated prevalence of 234 per 100,000 persons in Canada [7]) contribute to both high indirect costs (8) and direct costs (9). Furthermore, the top 7% of patients with Crohn’s disease are responsible for 50% of the total direct costs (10), the majority of which are associated with hospitalizations and surgeries (11,12). Several studies have demonstrated that infliximab decreases resource use (13-17) and, for some patients, infliximab may reduce health-related expenditures (13). However, some analyses have suggested that infliximab therapy may actually increase total costs overall (17), and perhaps more so in those who lose response to infliximab (18). Additionally, practice patterns with regard to infliximab use have changed over the past decade, due in part to the acceptance of maintenance dosing, widespread adoption of immunosuppressive medications that enhance the efficacy and durability of infliximab therapy, and a shift toward outpatient care (19). Therefore, the objective of the present study was to examine the economic and resource use benefits of infliximab therapy for the first time in patients with Crohn’s disease up to two years postinfusion therapy using patients who served as their own controls.

In all cases, infliximab use was in accordance with the Canadian Association of Gastroenterology guidelines for infliximab treatment in Crohn's disease (1).Patients who underwent previous treatment with other antitumour necrosis factor biological therapy for any indication, and who had a history of cancer with less than two years of documented disease-free state (other than resected cutaneous basal and squamous cell carcinoma or in situ cervical cancer) were excluded.
Retrospective analysis of patient charts was performed to gather baseline demographics.Disease subtype was not identified in five charts.
The primary end points were defined as direct resource use and health care costs before and after infliximab therapy.Health care resources and costs were divided into the following major categories: health care visit, endoscopy, radiology and therapeutic intervention; these categories were further subdivided into inpatient and outpatient services, and finally subdivided into various types of health care encounters.Some types of health care encounters were composed of multiple diagnoses or procedures.Nonsurgical management of inflammatory bowel disease (IBD)-related hospitalization was composed of management of IBD and of gastrointestinal obstruction.Minor surgeries were defined as less extensive esophageal, stomach and duodenal procedures, less extensive intestinal and rectal procedures, minor gastrointestinal procedures, abdominal laparoscopy, and anus and stomal procedures.Major surgeries were composed of major esophageal, stomach and duodenum procedures, major intestinal and rectal procedures, laparotomy, extensive gastrointestinal procedures, and gastrostomy and colostomy procedures.
Secondary outcomes were health care costs divided by the number of patients with Crohn's disease with fistulae or those without fistulae.
The inpatient costs in the current study, including direct patient care costs, administrative overhead, facility maintenance and other nonpatient care costs as measured by Case Mix Groups (CMG) and complexity modifier codes associated with each hospitalization, were derived from the Alberta Health and Wellness 2006 Annual Report, Health Costing In Alberta (21).Doctors' fees were calculated using the provincial fee schedule (22).Service categories were extrapolated from the Canadian Classification of Health Interventions codes that were included in each patient's hospital encounter information.There were no costs calculated for inpatient endoscopy and radiology because these were encompassed by the CMG code costs.Outpatient services included diagnostic tests, procedures and visits, but excluded costs of medications other than infliximab, as well as nonpatient care costs.Outpatient costs were extracted from the Ambulatory Care Classification System provincial costing database (21), which contains direct costs for each procedure and visit type, and were added to the corresponding doctors' fees.The cost of infliximab was calculated using the median patient dose of 400 mg, and a supplier cost of CAD$3,152 per 400 mg (Canadian supplier cost at August 2010).All costs in the tables have been standardized to 2005 United States dollars (23,24).The total number of infliximab doses were determined by a retrospective review of each patient's infusion records.
Statistical analysis was performed using the statistical software programs Stata/MP 11 (StataCorp LP, USA).Primary and secondary outcome analyses were compared using a paired t test.Demographics were analyzed by descriptive methods, and P<0.05 was considered to be statistically significant.

Patient demographics
The demographic characteristics of the patient population are summarized in Table 1.In the analysis of 66 patients who had available economic data one year before and after infliximab, 62.1% of the study population were women and 93.9% were Caucasian.The mean (± SD) age at the time of the first infliximab infusion was 42.0±11.6years.Length of time between diagnosis and first infusion of infliximab, and overall duration of Crohn's disease was 10.1±8.1 years and 15.8±8.7 years, respectively.The majority of patients had ileocecal (48.5%), colonic (36.4%) or ileal (15.2%) disease.The percentage of patients with fistulizing disease (47.0%) and nonfistulizing disease (45.5%) were comparable (note: in five records, it was not possible to confirm the presence or absence of fistulizing disease).Patients analyzed according to either one year or two years before and after infliximab were similar in all characteristics, with the exception of the mean percentage of patients on infliximab at the end of the study period (66.7% versus 56.4%), and the mean number of infliximab infusions per year (7.4±1.4 infusions versus 5.7±2.1 infusions).In the subgroup analysis of patients with or without fistulizing disease one year before and after infliximab, there was no difference in infliximab use (64.5% and 63.3%, respectively).

Health care resource use before and after infliximab use
Total health care resource use one year and two years before and after infliximab therapy were compared (Table 2).

Comparison of health care costs before and after infliximab therapy
Health care costs per patient one year and two years before and after infliximab therapy were compared (Table 3).

One-year analysis:
There was a reduction in total combined inpatient and outpatient costs (−$  1).There was an increase in outpatient visit costs ($233 [P<0.05]),but total outpatient costs did not change significantly (−$8 [P=0.97]).With the cost of maintenance infliximab added to the reduced total combined inpatient and outpatient costs, total direct costs trended up in the twoyear analysis ($16,117 [P=0.08]),although the cost per patient per year was lower than in the one-year before and after analysis.

Costs according to luminal or fistulizing disease subtype
Health care expenditures per patient were stratified according to the presence or absence of fistulizing disease (

DiSCuSSiOn
Infliximab is a mainstay of therapy for moderate to severe Crohn's disease due to its superior efficacy in the treatment of luminal ( 4) and fistulizing (5) disease over traditional therapies such as corticosteroids and immunosuppressive medications.However, despite this widespread use, the overall impact on health-related expenditures is unclear.
The results of the present study demonstrated a reduction in inpatient resource use and costs with infliximab therapy.This reduction may extend into the second year of treatment, despite an overall decrease in infliximab use over this time.The present analysis suggests, as do other similar studies (13,25), that this reduction in inpatient costs is largely driven by a decrease in hospitalizations, colonoscopies and surgeries.When the cost of infliximab is factored into the analysis, there was a net increase in overall direct costs, similar to the findings of Saro et al (17).However, in countries with a higher cost structure, such as the United States, a combined reduction of inpatient and outpatient costs by almost 50% after two years of treatment may very well translate into an overall cost savings with infliximab therapy.
The magnitude of health care cost savings in patients with fistulizing disease may be greater than for those without fistulizing disease.A greater decrease in hospitalizations and surgical interventions in patients with fistulizing disease has been previously suggested (15).In the present analysis, the decrease in combined inpatient and outpatient costs was only significant for patients with fistulizing disease, although combined costs did trend downward in the nonfistulizing subgroup.Both subgroups of patients showed similar downward trends in major surgeries.A recent study by Taxonera et al (26) did not demonstrate a difference in hospitalizations or surgeries between fistulizing and nonfistulizing subgroups.It is recognized that the present study was limited by its retrospective design and the lack of a traditional control group.However, given that the population studied was considered to be a representative sample and that infliximab is now of proven benefit for patients with Crohn's disease, using a control group would be neither ethical nor reasonable.The absence of outpatient drug costing data potentially limited some additional savings with infliximab.Although infliximab is recognized to be corticosteroid sparing in approximately one-third of patients (4), overall, the cost of corticosteroids are relatively low compared with the other direct costs involved.Infliximab use is not expected to result in cost savings of immunosuppressives as evidenced by the Study of Biologic and Immunomodulator Naive Pateints in Crohn's disease (SONIC) trial (27).
The current study only included responders to infliximab in the analysis because its objective was to examine patient costs before and after therapy.Patients excluded from the present analysis comprised a heterogenous group of patients who did not tolerate infliximab infusions or did not respond to induction therapy.The economic implications of including patients with a lack of response to infliximab or those that do not tolerate infliximab will lead to higher associated economic costs.
Perhaps the greatest limitation of the majority of economic studies to date is the lack of indirect costing data.Concessions made in career choices, disability compensation, early retirement and unemployment are all indirect costs to society that are difficult to quantify, but have been estimated to be responsible for 68% of overall health care expenditures (8).Crohn's disease is associated with a significantly decreased quality of life (28), and induction and maintenance of remission has been demonstrated to increase employment and normalize quality of life (16,29).Thus, the present analysis likely underestimated the true financial burden of Crohn's disease.Additional studies regarding the indirect costs of Crohn's disease are needed to elucidate the impact of infliximab on overall cost effectiveness.

Table 4
).The use of infliximab resulted in significant reductions in combined inpatient and outpatient costs (−$3,162 [P<0.05]) as well as inpatient costs (−$2,530 [P<0.05]) in patients with fistulizing disease, but not in patients

TabLe 4 Health care costs per patient stratified according to the presence or absence of fistulizing disease Resource Luminal disease with fistulae Luminal disease without fistulae Difference
Data presented as $.A-IFX After infliximab; B-IFX Before infliximab; NA Not available