Healthcare resource utilization and production loss in vedolizumab-treated inflammatory bowel disease patients: results from the Swedish prospective multicentre SVEAH study
Linda Ryen, Isabella Visuri, Sara Karlqvist, Carolina Malmgren, Daniel Bergemalm, Carl Eriksson
TL;DR
This study analyzed the healthcare costs and productivity losses of IBD patients in Sweden treated with vedolizumab, finding high direct costs but lower indirect costs for those who continued treatment.
Contribution
The study provides new empirical data on the economic burden of vedolizumab-treated IBD patients in a real-world clinical setting.
Findings
The mean annual direct cost for IBD patients was €24,305, with medication being the largest cost driver (64%).
Patients who continued vedolizumab had significantly lower indirect costs (€3,044) compared to those who discontinued (€8,927).
Perianal disease and high baseline disease activity in Crohn’s disease were associated with increased direct costs.
Abstract
Data on direct and indirect annual costs for inflammatory bowel disease (IBD) patients treated with vedolizumab are limited. To evaluate the total annual direct healthcare costs and indirect costs among IBD patients treated with vedolizumab. A prospective observational multicentre study involving 286 patients with Crohn’s disease (CD; n = 169) or ulcerative colitis (UC; n = 117) who started vedolizumab therapy during 2015–2017 at 21 hospitals across Sweden. Data on direct and indirect costs were collected during a 3-year follow-up period. Direct costs were measured as healthcare resource utilization including medication, hospital admissions and hospital-based outpatient visits. Indirect societal costs were measured as production losses from sick leave and disability pension. Data were obtained from the Swedish Quality Register for IBD and through linkage with national registers. Data…
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Taxonomy
TopicsInflammatory Bowel Disease · Microscopic Colitis · Eosinophilic Esophagitis
Introduction
Inflammatory bowel disease (IBD) is a chronic idiopathic inflammatory disorder of the gastrointestinal tract. The two main types of IBD are Crohn’s disease (CD) and ulcerative colitis (UC). IBD is associated with significant morbidity and may lead to complications such as strictures, fistulas, infections and cancer, which impose a significant economic burden on society and the healthcare system. Although recent studies have shown a rapidly increasing incidence of IBD in newly industrialized countries in the Middle East, Asia and South America, the highest prevalence is still found in Northern Europe and North America.^ 1 ^ For example, in Örebro, Sweden, the prevalence of IBD in 2010 was 741 per 100,000 inhabitants.^2,3^
The primary aim of medical management is to induce and maintain remission, with the long-term goals of preventing disability, surgery and colorectal cancer.^ 4 ^ Biological agents have become the mainstay of therapy for patients with severe IBD and for those with mild to moderate disease who do not respond to or cannot tolerate conventional treatment.
In 2014, vedolizumab, a monoclonal antibody targeting α4β7 integrin, received approval from the European Medical Agency for treating moderate to severe CD and UC, based on evidence from the GEMINI studies.^5?–7^ The prospective observational multicentre SVEAH study revealed significant clinical effectiveness of vedolizumab in Swedish routine care, even though 88% of the patients had been exposed to anti-tumour necrosis factor (anti-TNF) therapy at the start of treatment. However, vedolizumab is expensive, potentially exceeding €10,000 per treatment-year depending on the country, healthcare system and dosage.
Although biologics have proven effective in achieving clinical remission, enhancing work productivity and reducing hospitalization and surgery rates, there is evidence to suggest that healthcare costs related to IBD have increased over the past few decades, primarily due to escalating medication expenses.^ 8 ^ Conversely, it is well known that work disability is a common consequence of IBD. Previous studies have demonstrated that productivity losses represent a significant portion of the societal costs associated with IBD.^ 9 ^
In this study, we aimed to estimate the direct (medication, hospital admissions and costs for hospital-based outpatient visits) and indirect societal costs (productivity losses from sick leave and disability pension) for a well-characterized cohort of vedolizumab-treated patients with IBD.
Materials and methods
Patients
SVEAH was a nationwide prospective multicentre study conducted at 21 Swedish hospitals (13 regional and 8 university hospitals) between 2015 and 2021. The study population and design of the study are described in detail elsewhere.^10,11^ In short, eligible patients were ⩾18 years old and had active IBD at the start of vedolizumab. Active CD was defined as the presence of symptoms together with ulcers on colonoscopy or signs of active disease on magnetic resonance imaging, C-reactive protein (CRP) > lowest limit of detection, high-sensitivity CRP >2.87 mg/l or faecal calprotectin >200 µg/g. Active UC was defined as the presence of symptoms and a Mayo endoscopic subscore of ⩾2.^ 12 ^ Exclusion criteria were contraindications to vedolizumab or prior exposure to the drug.
Written informed consent was obtained from all participants included in the study. Vedolizumab was administrated intravenously. No predetermined dosing schedule was applied, and the treating physician was permitted to adjust the dose or dosing interval at any time.^10,11^ All patients were followed for 3 years. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (Supplemental Material).^ 12 ^
Direct costs
The patients were followed up using an electronic case report form (eCRF) integrated with the Swedish Quality Registry for Inflammatory Bowel Disease (SWIBREG).^ 13 ^ Through the use of the Swedish personal identity number,^ 14 ^ we were able to link the study population to other Swedish health data registers. Inpatient and outpatient data were retrieved from the National Patient Register, which has almost complete coverage of all non-primary care outpatient visits from 2001 onwards, including all outpatient visits to gastroenterologists, paediatric gastroenterologists and surgeons.^15,16^
Valuation of the resources used for providing inpatient and outpatient care was performed using the diagnosis-related groups (DRGs) constructed by the Swedish Association of Local Authorities and Regions. Each healthcare episode in the National Patient Register is categorized into a DRG code reflecting the amount of resources used considering diagnoses, treatments, procedures and length of hospital stay. Each DRG has a relative weight and an economic value assigned based on cost per patient administrative data.^17,18^ National retrospective weights from 2022 were used along with an economic value based on the 2022 agreement for debiting out-of-county patients in Region Örebro County. Costs for all healthcare were included in the calculations, not just costs related to IBD.
Data on medication use were collected through the study eCRF, as well as through linkage to SWIBREG^ 13 ^ and the Prescribed Drug Register, which ensured nearly 100% coverage.^ 19 ^ Non-prescription drugs were not included. Costs for prescription drugs were directly available from the Prescribed Drug Register, and the total cost was included in the estimations whether it was paid by the government or by the patient (prescription of medicines above SEK 2400 (approximately €200) per year is provided free of charge for the patient). For infusion drugs (vedolizumab, infliximab and the induction dose of ustekinumab), the coverage is insufficient, and data on their use were obtained from SWIBREG. Based on the number of doses from SWIBREG, the cost was estimated using the yearly prices negotiated at Örebro University Hospital.
All costs were converted to 2022 prices and presented in Euros. Cost estimations are presented in this article for years 1, 2 and 3 after inclusion in the study. To identify predictors of resource utilization, direct costs were analysed based on factors such as age, sex, disease duration, presence of extra-intestinal manifestations, Montreal classification and medical or surgical treatments. Additionally, the results were stratified based on baseline clinical disease activity (Harvey–Bradshaw index or partial Mayo Clinic score) and the reasons for initiating vedolizumab treatment, according to the following criteria: (1) patients with a primary non-response to the most recent anti-TNF therapy; (2) patients who discontinued the most recent anti-TNF due to adverse drug reactions, loss of response or other reasons and (3) patients naïve to anti-TNF.
Indirect costs
Indirect costs were defined as production losses due to absence from paid work. Estimations were based on sick leave and disability pension payments provided by the Social Insurance Agency, which were available through the Swedish Longitudinal Integrated Database for Health Insurance and Labour Market Studies (LISA).^ 20 ^ The Swedish social insurance system offers compensation for both sick leave and disability pensions, either partially or fully. During the study period, no compensation was provided for the first day of sick leave, while days 2–14 were covered by the employer. Hence, only absences from work lasting longer than 14 days were included in the estimations.
The costs associated with productivity losses due to sick leave (>14 days) or permanent disability pension were estimated based on the total number of sick leave days, valued by the average monthly salary in Sweden for 2022, including social fees (€3575*1.3142), corresponding to a production loss of €154 per day of sick leave. The data in LISA are available for each calendar year. Since all costs were estimated annually based on each individual’s inclusion date, and thus do not correspond to calendar years, sick leave was assumed to be evenly distributed across the year. It should be noted that 1 day of sick leave does not necessarily correspond to 1 full working day; that is, a full-time worker and a part-time worker will both have 14 full days of sick leave if they are absent for 14 days. This introduces a risk of overestimating production losses; but on the other hand, absences shorter than 14 days were not included. Since there was a delay when producing LISA, information for 2020 was not available at the time of data retrieval for this study, and so sick leave data for patients entering the study in 2017 were not available for year 3 after inclusion. All patients of working age included in 2017 contributed data to the cost analyses for years 1 and 2 but were excluded from the analysis for year 3.
Statistics
All costs are presented in Euro (€), inflation-adjusted to the year 2022. Continuous data are presented as mean with standard deviation (SD) or as median and interquartile range (IQR), and categorical data are expressed as frequencies and percentages. Differences between groups were assessed with the Mann–Whitney U test, Kruskal–Wallis test or chi-square test as appropriate. All tests were two-tailed, and p-values of <0.05 were considered statistically significant. Statistical analyses were performed using version 25.0 of IBM SPSS Statistics for Windows (IBM Corp., Armonk, NY, USA) or version 16.1 of STATA for Windows (StataCorp LLC, College Station, TX, USA).
Results
The study population consisted of 286 patients with IBD (CD: n = 169; UC: n = 117) initiating vedolizumab between April 1, 2015 and November 31, 2017.^11,21^ Demographic and clinical characteristics of the study population are summarized in Table 1. During the 3-year follow-up period, 131 patients (CD: n = 83; UC: n = 48) discontinued the treatment for various reasons (evidence of its lack of or loss of response: n = 97; adverse drug reaction: n = 14; pregnancy: n = 4; other reasons: n = 16; Figure 1).
Table 1.: Baseline demographics and clinical characteristics of patients with Crohn’s disease and ulcerative colitis. 21
Flow diagram of the study.
The total direct healthcare cost for the cohort during the 3-year study period was €20,853,974, with €13,391,457 (64%) spent on medications (of which €12,802,692 (95%) was on biologics), €4,109,190 (20%) on hospital admissions and €3,353,327 (16%) on outpatient care (Figure 2(a)). The mean annual follow-up cost was €24,305 (SD: €10,391) for all individuals with IBD, €24,873 (SD: €10,917) for patients with CD and €23,484 (SD: €9566) for patients with UC (p = 0.24). No difference was observed between male (€24,506; SD: €10,331) and female patients (€24,080; SD: €10,491; p = 0.87) or between smokers (€22,269; SD: €10,073) and non-smokers (€24,432; SD: €10,434; p = 0.80; Figure 2).
Mean total direct costs for men and women diagnosed with Crohn’s disease (CD) (a) or ulcerative colitis (UC) (c) and mean indirect costs (CD, b; UC, d), years 1–3 following start of treatment with vedolizumab. Error bars represent 95% confidence intervals.
Overall, the mean direct cost per patient-year of follow-up decreased from €31,126 (SD: €15,020) in year 1 to €21,454 (SD: €13,220) in year 2 (p < 0.01) and €20,226 (SD: €14,751) in year 3 (p = 0.04). Similar patterns were observed when stratifying by subtype of IBD (data not shown). The direct costs were similar in patients who continued vedolizumab for the entire study period (€24,401; SD: €8283) and those who discontinued treatment (€24,192; SD: €12,466; p = 0.12).
Direct healthcare cost in patients with CD
During the 3-year follow-up, the total direct healthcare cost for the 169 patients with CD was €12,611,059, with €8,054,979 (64%) spent on medications (of which €7,856,458 was on biologics), €2,432,598 (19%) on hospital admissions and €2,123,482 (17%) on hospital-based outpatient care (Figure 3(a)–(c)). The median number of days admitted to hospital during the 3-year study period was 2 (IQR: 0–12), and the median number of visits to outpatient care (including doctor visits, nurse visits, infusion visits, dietician consultations and counsellor visits combined) was 18 (IQR: 10–30).
Mean cost of hospital admissions for patients with Crohn’s disease (CD) (a) and ulcerative colitis (UC) (d), outpatient visits (b, CD; e, UC) and medication (c, CD; f, UC) for men and women, years 1–3 following the start of treatment with vedolizumab. Error bars represent 95% confidence intervals.
At the individual level, comparable annual follow-up costs were observed when the results were stratified by age, sex, smoking status, disease location, prior treatments and reasons for discontinuation of the last anti-TNF treatment (Table 2). In contrast, statistically significantly higher costs were observed among patients with perianal disease, in patients with moderate to severe clinical disease activity, and in patients without concurrent corticosteroids at initiation of therapy.
Table 2.: Annual direct cost among patients with Crohn’s disease, divided by baseline demographics and clinical characteristics.
Direct healthcare cost in patients with ulcerative colitis
During the 3-year follow-up, the total direct healthcare cost for the 117 patients with UC was €8,242,916, with €5,336,478 (65%) spent on medications (of which €4,946,233 was on biologics), €1,676,592 (20%) on hospital admissions and €1,229,846 (15%) on hospital-based outpatient care (Figure 3(d) and (e)). The median number of days admitted to hospital during the 3-year study period was 1 (IQR: 0–10), and the median number of visits to outpatient care (nurse visits and doctor visits combined) was 14 (IQR: 8–26).
At the individual level, comparable annual follow-up costs were observed when the results were stratified by age, sex, smoking status, disease extent, prior treatments, clinical disease activity at baseline and reasons for discontinuation of the last anti-TNF treatment (Table 3). The only baseline variable that seemed to be associated with costs in patients with UC was the concurrent use of immunomodulator treatment.
Table 3.: Annual direct cost among patients with ulcerative colitis, divided by baseline demographics and clinical characteristics.
Indirect societal costs
As the data in the LISA register have a long delay, we can only report indirect costs (productivity losses from sick leave and disability pension) for all patients during the first 2 years of follow-up. At study entry, 247 (86%) patients were of working age (<65 years). During the study period, the mean annual number of lost workdays was 46 (SD: 103; median: 0; IQR: 0–22) for patients with CD and 25 (SD: 69; median: 0; IQR: 0–9) for patients with UC, corresponding to mean productivity loss costs of €7098 (SD: €15,838) for patients with CD and €3775 (SD: €10,603) for patients with UC (p = 0.32; Figure 1). The number of sick days was unevenly distributed among the participants, and about 50% of participants had no sick days during the follow-up period.
No significant differences were observed between men (30 days; SD: 77; median: 0; IQR: 0–11 and €4612; SD: €11,826) and women (45 days; SD: 104; median: 0; IQR: 0–20 and €6999; SD: €16,061; p = 0.82).
In year 3, data on sick leave and disability pension were available for 180 (75%) of the 239 (84%) patients who were still of working age. Over the course of the study, the number of sick days declined from 53 (SD: 108; median: 0; IQR: 0–37) in year 1 to 33 (SD: 96; median: 0; IQR: 0–0) in year 2 and 37 (SD: 99; median: 0; IQR: 0–0) in year 3 (p < 0.01).
Direct and indirect costs for patients with IBD who continued versus discontinued vedolizumab
The median treatment duration for the 131 patients who discontinued vedolizumab was 8.1 months (IQR: 3.8–15.3). The most common alternative treatments after discontinuation of vedolizumab included bowel surgery (n = 59), ustekinumab (n = 35), adalimumab (n = 20), golimumab (n = 15) infliximab (n = 8), tofacitinib (n = 7) and certolizumab pegol (n = 1) with each patient potentially receiving one or more of these treatments.
No statistically significant difference in total direct healthcare costs was observed between patients who continued (€73,204; SD: €24,849) versus discontinued vedolizumab (€72,575; SD: €37,397; p = 0.122). However, there were substantial differences in how the costs were distributed: Patients who discontinued treatment had more outpatient visits, more days admitted to hospital, and underwent more major surgeries, whereas patients who continued treatment had higher medication costs (Table 4). Among patients continuing vedolizumab, the mean number of lost workdays and productivity loss costs was 20 days (SD: 64; median: 0; IQR: 0–1) and €3044 (SD: €9922), compared to 58 days (SD: 112; median: 0; IQR: 0–55) and €8927 (SD: € 17,171) among those who discontinued treatment (p < 0.01; Table 4; Figure 4). Overall, the total cost of production losses over the first 2 years was €3,282,528 for the entire cohort, comprising €943,583 for patients who continued vedolizumab (n = 155) and €2,338,945 for those who discontinued treatment (n = 131).
Table 4.: Direct and indirect costs for patients with IBD who continued versus discontinued vedolizumab.
Mean total direct (a) and indirect (b) costs for patients with Crohn’s disease (CD) or ulcerative colitis (UC) (c and d) by continuation of vedolizumab, years 1–3 following start of treatment with vedolizumab. Error bars represent 95% confidence intervals.
Discussion
In this prospective observational multicentre study, we assessed the total societal costs for a cohort of highly treatment-resistant IBD patients treated with vedolizumab, who represent a significant economic burden on the healthcare system. About 90% of this population had been exposed to anti-TNF therapy, and nearly half of those with CD had undergone at least one intestinal resection.
We found a high mean direct annual follow-up cost of €24,305, with the cost peaking in the first year of vedolizumab treatment and decreasing in the second and third years.^ 22 ^ Comparing patients who continued vedolizumab treatment (n = 155) with those who discontinued (n = 131), total direct healthcare costs did not differ significantly. However, substantial differences were observed in the cost distribution: patients who continued treatment had higher medication costs, whereas those who discontinued incurred higher costs related to hospital admissions, surgeries and outpatient visits. In contrast, patients who continued treatment had significantly lower indirect costs (i.e. costs due to productivity losses from sick leave and disability pensions) likely due to better disease control.
Unlike studies from the pre-biologic era,^23?–25^ where surgery was the primary driver of healthcare costs, we found that medication constituted the largest portion (64%) of direct costs, while hospital admissions, including surgery costs, accounted for only 20% and outpatient care made up 16%. This aligns with other comprehensive reports.^9,26?–28^ For example, the COIN study, which evaluated the cost of IBD across 14 Dutch hospitals, found that medication costs accounted for up to 71% of the cost in CD and 59% in UC, while hospitalization and surgery contributed 19% and less than 1%, respectively.^ 27 ^
IBD is associated with significant morbidity, and numerous studies have shown that costs related to sick leave and disability often surpass direct healthcare expenses.^9,29,30^
In a recent Swedish study, the total annual societal cost was estimated at 14,136 (≈ €13,288) for a patient with UC.^ 9 ^ These figures are somewhat lower than those in this study, which included a selected group of patients with therapy-refractory IBD. A key difference between the studies is that in the present study only about 15% of the total costs were indirect costs associated with sick leave and disability pension, compared to nearly 60% in the previous study.^ 9 ^ The SVEAH study demonstrated that vedolizumab had high clinical effectiveness in Swedish practice, with a steroid-free clinical remission rate of nearly 50% after 1 year.^11,21^ However, we cannot conclude from the current findings whether the drug itself reduced the need for sick leave and disability pension or whether the study population incidentally consisted of generally healthy individuals, apart from their IBD, with a high work capacity.
In CD, the presence of perianal disease and high disease activity were associated with slightly higher direct costs, while concurrent corticosteroid treatment at the start of vedolizumab surprisingly appeared to be linked to slightly lower costs. In patients with UC, costs were marginally higher for those using immunomodulators in addition to vedolizumab.
We had expected higher costs in individuals using corticosteroids, as steroid use is often a marker of more severe disease in observational studies (confounding by indication). However, there was a non-statistically significant association between corticosteroid use at treatment initiation and clinical remission after 52 weeks in the original SVEAH study (odds ratio: 2.04; 95% confidence interval: 0.84–4.91).^ 21 ^ We cannot provide a definitive explanation for this observation, but vedolizumab has a relatively long onset time in patients with CD, and corticosteroids may have prevented patients from prematurely discontinuing their treatment.
This study included a diverse group of patients from both regional hospitals and university centres, encompassing individuals who would have been excluded from the GEMINI trials, thereby reflecting the real-world use of vedolizumab in clinical practice. Other key strengths include the prospective data collection using an eCRF integrated within SWIBREG, and the availability of data from nationwide registers with comprehensive coverage.
By nature, cost-of-illness studies are descriptive and do not aim to offer direct information on the comparative cost-effectiveness of various treatments or to test specific hypotheses. However, by identifying and quantifying the relative contributions of different components to the overall economic burden of a disease, these studies can provide valuable insights into the potential cost implications of new treatments.
The main limitation of our study is the absence of data on items and services not captured in national registers, such as primary care visits, rehabilitation stay, sick leave periods shorter than 14 days and presenteeism (i.e. when employees are physically present at work but are unable to perform at full capacity due to illness). As a result, our cost estimates are likely to underestimate the true total costs. Unfortunately, the absence of a control group in this study limits the ability to compare the cost-effectiveness of different treatments based on our data. The relatively small sample size of our study population limited our ability to perform detailed cost analyses in smaller, yet clinically relevant subgroups, such as patients treated with combination therapies involving methotrexate or mercaptopurine, as well as those discontinuing vedolizumab due to adverse events. Additionally, since we used DRG codes instead of International Classification of Diseases (ICD) codes, we were unable to quantify the incidence of specific adverse events associated with vedolizumab. However, costs for managing these events (e.g. emergency care, hospitalizations, diagnostics and specialist visits) are included in the total cost estimates, as they are captured in the aggregated healthcare utilization through the DRG system. Using DRG weights to measure and value resource use may be perceived as imprecise because the estimated costs do not capture the full variation between patients. However, the DRG system in Sweden is clinically integrated and updated annually, with retrospective DRG weights designed to estimate resource use.^ 31 ^
Conclusion
This is the first study to evaluate the mean annual cost for IBD patients treated with vedolizumab in Swedish clinical practice. High direct costs were seen, primarily driven by medication expenses, while indirect costs related to sick leave and disability pensions were lower than in previous studies, especially for patients continuing therapy. Increased costs were associated with perianal disease and high disease activity in CD, and with concomitant use of immunomodulators in UC.
Supplemental Material
sj-docx-1-tag-10.1177_17562848251352023 – Supplemental material for Healthcare resource utilization and production loss in vedolizumab-treated inflammatory bowel disease patients: results from the Swedish prospective multicentre SVEAH studySupplemental material, sj-docx-1-tag-10.1177_17562848251352023 for Healthcare resource utilization and production loss in vedolizumab-treated inflammatory bowel disease patients: results from the Swedish prospective multicentre SVEAH study by Linda Ryen, Isabella Visuri, Sara Karlqvist, Carolina Malmgren, Daniel Bergemalm and Carl Eriksson in Therapeutic Advances in Gastroenterology
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