1240
Original article
Length of hospital stay and associated hospital costs with infliximab versus cyclosporine in severe ulcerative colitis Mark Löwenberga,*, Nicolette W. Duijvisb,*, Cyriel Ponsioena, Gijs R. van den Brinka,b, Paul Fockensa and Geert R.A.M. D’Haensa Background Cyclosporine and infliximab (IFX) seem equally effective as rescue therapy in hospitalized patients with severe ulcerative colitis (UC), although associated hospital stay and costs may differ. Aim The aim of this study was to compare the duration of hospital stay and associated costs from initiation of rescue therapy to time of discharge in hospitalized patients with corticosteroid-refractory UC receiving cyclosporine or IFX. Colectomy rates after 6 months were used as the outcome parameter for treatment success. Patients and methods Hospital records of patients admitted between November 2003 and August 2012 at a tertiary referral center were analyzed. Results Forty-two patients were included (cyclosporine group: 26 patients; IFX group: 16 patients). Patient characteristics were comparable, with the exception that cyclosporine-treated patients more often had a pancolitis (89 vs. 63%, P = 0.046). The median length of hospital stay was 11.0 (interquartile range 7.75–13.25) versus 4.0 days (interquartile range 4.0–5.75) in the cyclosporine and IFX group (P < 0.01), respectively. The mean in-hospital costs were significantly higher in the cyclosporine-treated versus IFX-treated patients (6121 vs. 4853 euros, P < 0.05), whereas the total costs up to 3 months after initiation of
Introduction Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon characterized by mucosal ulceration, rectal bleeding, diarrhea, and abdominal pain. Up to 25% of UC patients experience a severe flare requiring urgent hospitalization [1,2]. Acute severe UC is a potentially lifethreatening condition, with estimated rates of urgent colectomy up to 40% [2]. Intravenous corticosteroids are the first-line treatment for attacks of severe UC, which is effective in about 60% of cases [3,4]. Around 15–60% of UC patients have corticosteroid-refractory disease [3–5]. Clinical guidelines recommend cyclosporine A (CsA) or infliximab (IFX) as rescue therapy in UC patients who fail to respond within 3–5 days to systemic corticosteroids. CsA and IFX are rapidly effective agents and the decision on which one to select as rescue therapy in daily practice is often guided by center preference and the physician’s personal experience. CsA is a calcineurin inhibitor that inhibits proliferation and cytokine production of T-helper lymphocytes. The first 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
rescue therapy were significantly higher in the IFX group (6787 vs. 9983 euros, P < 0.01). There were no significant differences in colectomy rates at 6 months (23 and 31% for cyclosporine and IFX, P = 0.50). More side-effects were observed during treatment with cyclosporine. Conclusion Length of hospital stay and in-hospital costs have been reduced significantly since the introduction of IFX as rescue therapy for severe UC instead of cyclosporine. However, the total treatment costs are higher in IFX-treated patients. Eur J Gastroenterol Hepatol 26:1240–1246 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:1240–1246 Keywords: costs, cyclosporine, infliximab, length of hospital stay, ulcerative colitis a Department of Gastroenterology and Hepatology and bTytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
Correspondence to Mark Löwenberg, MD, PhD, Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Tel: + 31 20 5667621; fax: + 31 20 6917033; e-mail: [email protected] *Mark Löwenberg and Nicolette W. Duijvis contributed equally to the writing of this article. Received 21 May 2014 Accepted 18 July 2014
placebo-controlled study that reported on the efficacy of intravenous CsA as rescue therapy in UC was published 20 years ago [6]. A dose-finding trial showed that 2 mg/kg body weight of CsA was equally effective as 4 mg/kg/day [7]. However, long-term follow-up of CsA-treated patients has shown a high colectomy rate, up to 88% after 7 years [8]. CsA treatment has been associated with hypertension, seizures, nephrotoxicity, and hypomagnesemia. Therefore, patients who receive treatment with CsA require intensive monitoring, including measurement of CsA blood concentrations [9]. The chimeric antitumor necrosis factor antibody IFX is effective as induction and maintenance therapy in patients with moderate to severe UC [10], and also in hospitalized patients with severe corticosteroidrefractory UC [11,12]. The drug has become an established therapeutic option for UC during the last decade. A recent study showed that CsA was not better as compared with IFX in hospitalized UC patients who failed 5 days of intravenous corticosteroids, showing comparable efficacy outcomes with both regimens ranging from DOI: 10.1097/MEG.0000000000000187
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Hospital stay and costs of IFX vs. CsA in UC Löwenberg et al. 1241
40 to 46% at 98 days [13]. All patients were hospitalized for 8 days; thus, the impact of treatment on length of hospital stay and associated treatment costs could not be assessed in this trial. The aim of the current study was to assess length of hospital stay and associated treatment costs in patients admitted for corticosteroid-refractory UC receiving treatment with CsA or IFX.
Patients and methods Patient selection and eligibility
All patients included in the study were identified using the local hospital database. We identified patients hospitalized for severe corticosteroid-refractory UC and treated with intravenous CsA (2 mg/kg/day) or IFX (5 mg/kg) between November 2003 and August 2012 at a single tertiary referral center [Academic Medical Center (AMC), Amsterdam]. Severe UC was defined as the need for hospitalization, on the basis of the ECCO guidelines (statement 5D) [14]. Patients had to have (bloody) diarrhea more than six times daily and should have signs of systemic toxicity (e.g. tachycardia, fever, low hemoglobin level, or high sedimentation rate). Corticosteroidrefractory disease was defined as failing 3–5 days of corticosteroids. Therapy failure was defined as acute colectomy or relapse of the disease that resulted in a change in the therapeutic regime or complete cessation of rescue therapy. In case of signs of a toxic megacolon, patients were immediately redirected to the surgeon as this is a strong indication for acute colectomy. Patients were excluded if they received IFX for any other indication, or if the diagnosis was equivocal for possible Crohn’s disease, indeterminate colitis, or infectious colitis. Forty-two patients fulfilled these criteria and in all of these patients complete follow-up was available. Treatment
There is no standard protocol at the AMC outlining when to initiate treatment with CsA or IFX in patients with severe UC, although in most cases (including all patients in our cohort), this decision is based on the Oxford recommendations [15], meaning that UC patients failing 3–5 days of intravenous corticosteroids move on to further treatment options. According to the ECCO guidelines, the next step would include rescue treatment with calcineurin inhibitors, such as CsA or tacrolimus, or antitumor necrosis factor antibodies [14]. There are no standardized criteria for hospital discharge; hence, all patients admitted and treated at our center for severe UC were discharged on the basis of the physician’s judgment, irrespective of the received rescue treatment. All patients were treated following our standard protocol for the respective treatments. Patients receiving intravenous CsA were administered 2 mg/kg body weight/day. Dose adjustments were made to obtain blood concentrations within the therapeutic range (150–350 μg/l) and inhospital treatment was continued until a clinical response was seen. The patient was then switched to oral
CsA for a period of 3 months. Maintenance treatment further on is usually azathioprine or 6-mercaptopurine, which is initiated during hospital admission or at discharge. IFX was started at 5 mg/kg per infusion. Remission-induction therapy with IFX consists of three infusions at weeks 0, 2, and 6. The patient was discharged after a clinical response was seen. Subsequent infusions with IFX were administered in an outpatient setting, with the potential to shorten the treatment interval or increase the IFX dose if required, which is in line with current treatment guidelines and the IFX drug label. Data collection
Hospital records were reviewed retrospectively. The following information was collected: age, sex, smoking status, extent of disease, duration of disease before admission, medication at time of admission, failed medication, length of hospital stay, side-effects due to rescue therapy, and colectomy rate. We chose to analyze colectomy rates after 6 months as the outcome parameter for treatment success, as colectomies that fall outside this time window are less likely to correlate with this specific event of rescue therapy because of possible confounding factors, such as alterations in the treatment regime. End-points
The primary end-point was duration of hospital stay from the initiation of rescue therapy with CsA or IFX to the date of discharge. Secondary end-points included hospital costs for CsA-treated and IFX-treated patients and total treatment costs associated with outpatient treatment up to 3 months after initiation of rescue therapy. Hospital costs were based on admission costs, drug costs, and laboratory tests (trough level measurements). Outpatient costs were based on drug costs and, in case of treatment with IFX, admission costs at the infusion unit. In case of an acute colectomy because of immediate failing of rescue therapy, the number of days that the patient was admitted at the surgical ward was included. The costs of the colectomy itself have not been included in the analysis. To investigate treatment outcomes, colectomy rates were analyzed with a follow-up of 6 months. Economic costs as a result of work leave because of hospitalization were not taken into account. Cost analysis
Drug costs, hospitalization costs, and costs of outpatient treatment were calculated on the basis of drug prices using the Dutch pharmacotherapeutic compass that contains a wide spectrum of pharmaceutical information, including costs of the prescription of all drugs available in the Netherlands. Intravenous treatment with CsA costs 9.31 euros per day and CsA blood level measurements cost 19 euros for one test. Measurements of CsA blood concentrations are performed every other day until the patient is switched to oral CsA, according to the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1242 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 11
treatment protocol. Orally administered CsA costs 7.40 euros per day, on the basis of an average necessary dose of 150 mg twice daily. A vial of 100 mg IFX cost 647 euros in the Netherlands in 2010. IFX is dosed at 5 mg/kg body weight (induction scheme: 0–2–6 weeks). The mean body weight was 67.44 and 67.46 kg for IFX-treated and CsA-treated patients, respectively. Calculations have therefore been carried out on the basis of an average body weight of 70 kg per patient in both groups. Of note, at our tertiary referral center, IFX vials (containing 100 mg IFX per vial) are often shared between patients to reduce spillage. The reference price for hospitalization in a tertiary referral center in the Netherlands was 575 euros per day in the year 2010 (http://www.zorginstituutnederland.nl/binaries/ content/documents/zinl-www/documenten/publicaties/overigepublicaties/1007-handleiding-voor-kostenonderzoek/1007-handle iding-voor-kostenonderzoek/Handleiding+voor+kostenonderzoek. pdf). Admission costs at our day-care unit (in case of IFXtreated patients) are 300 euros per day. The following formulas have been used to calculate the hospitalization costs in both groups, in which Q represents the length of hospital stay in days. CsA hospital costs ¼ð9:31QÞþð190:5QÞþð575QÞ; which stands for (CsA costs) + (trough level measurements) + (admission costs), respectively. IFX hospital costs ¼ 2265þð575QÞ; which stands for IFX costs (70 kg × 5 mg/kg × 6.47 euros/ mg IFX, or 3.5 vials containing 100 mg IFX per vial) + admission costs. For total treatment costs, including outpatient treatment costs up to 3 months after initiation of rescue therapy, 666 euros were added to the CsA hospitalization costs, representing 90 days of oral CsA treatment. For IFX, 5130 euros was added to the IFX hospitalization costs, representing the costs of IFX infusions at week 2 and week 6, including day-care admission costs. Statistical analysis
The statistics used to describe the two patient populations are based on the mean and SD with respect to normally distributed data; otherwise, the median and interquartile range (IQR) were used. The significance of patient characteristics was analyzed using the χ2-test in case of categorical characteristics. To compare continuous characteristics, the Student t-test was used. To assess whether the outcome in hospitalization days was influenced by factors other than therapy, we carried out univariate analyses. All significant factors were subsequently used in a multivariate regression analysis. The Kaplan– Meier survival curve shows colectomy-free survival after hospital discharge comparing both treatment groups by the log rank test. Data were analyzed using SPSS
software version 20.0 (IBM SPSS Inc., Chicago, Illinois, USA). A P-value of lower than 0.05 was considered significant.
Results Baseline characteristics
A total of 42 patients (median age 37 years; 43% women) were included in the analysis, of whom 26 patients were treated with CsA and 16 patients with IFX. Patients’ characteristics in both groups were comparable, as shown in Table 1. Patients receiving CsA were treated between 2003 and 2012, and patients in the IFX group received treatment with IFX between 2006 and 2012. The median duration of disease was 2.0 (IQR 1.3–8.0) versus 4.0 (IQR 0.0–7.3) years, and 19.2 versus 31.3% of patients were smokers in the CsA and the IFX group, respectively. Three patients treated with CsA and four patients treated with IFX were already receiving thiopurines at the time of admission, which they continued during rescue treatment. All other CsA patients were started on thiopurines, except for one patient, who could not tolerate thiopurines. Three patients (one CsA patient and two IFX patients) were not on steroids at the time of admission, but all failed on steroids shortly before. CsA patients were started significantly more often on thiopurines compared with patients in the IFX group. The proportion of patients with a pancolitis was 89 versus 63% in the CsA and the IFX group (P = 0.046), respectively. The mean follow-up in months (from the date of discharge until April 2013) was 91.5 (IQR 56.5–102.3) in the CsA Table 1
Patient characteristics CsA
Number of patients 26 (n) Age 37 (21.0–43.0) Sex 11 ♀ (42) Median disease 2 (1.3–8.0) duration (years) Median follow-up 91.50 (56.50–102.25) (months) Smoking status Yes 5 (19.2) No 11 (42.3) Former smoker 5 (19.2) Unknown 5 (19.2) UC location (Montreal classification) Proctitis (E1) 1 (3.8) Left-sided colitis 1 (3.8) (E2) Pancolitis (E3) 23 (88.5) Unknown 1 (3.8) Co-medication at the time of admission Corticosteroids 25 (96) Admitted with 3 (12) thiopurines Started 22 (85) thiopurines Mesalamine 18 (69)
IFX
P-value
16 34 (20–43.50) 7 ♀ (44) 4 (0.0–7.3)
NS NS
34.50 (23.25–48.75)
NS NS
5 6 3 2
(31.3) (37.5) (18.7) (12.5)
0 6 (37.5)
NS < 0.01
10 (62.5) 0
< 0.05a NS
14 (87.5) 4 (25)
NS NS
6 (37.5)
0.002
12 (75)
NS
Values are represented as mean ± SD, median (IQR), or n (%). CsA, cyclosporine A; IFX, infliximab; IQR, interquartile range; UC, ulcerative colitis. a P-value (Pearson’s χ2) based on the presence of pancolitis.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Hospital stay and costs of IFX vs. CsA in UC Löwenberg et al. 1243
group and 34.05 (IQR 23.3–48.8) in the IFX group. The mortality rate in both groups was 0%.
Fig. 1
P
Original article
Length of hospital stay and associated hospital costs with infliximab versus cyclosporine in severe ulcerative colitis Mark Löwenberga,*, Nicolette W. Duijvisb,*, Cyriel Ponsioena, Gijs R. van den Brinka,b, Paul Fockensa and Geert R.A.M. D’Haensa Background Cyclosporine and infliximab (IFX) seem equally effective as rescue therapy in hospitalized patients with severe ulcerative colitis (UC), although associated hospital stay and costs may differ. Aim The aim of this study was to compare the duration of hospital stay and associated costs from initiation of rescue therapy to time of discharge in hospitalized patients with corticosteroid-refractory UC receiving cyclosporine or IFX. Colectomy rates after 6 months were used as the outcome parameter for treatment success. Patients and methods Hospital records of patients admitted between November 2003 and August 2012 at a tertiary referral center were analyzed. Results Forty-two patients were included (cyclosporine group: 26 patients; IFX group: 16 patients). Patient characteristics were comparable, with the exception that cyclosporine-treated patients more often had a pancolitis (89 vs. 63%, P = 0.046). The median length of hospital stay was 11.0 (interquartile range 7.75–13.25) versus 4.0 days (interquartile range 4.0–5.75) in the cyclosporine and IFX group (P < 0.01), respectively. The mean in-hospital costs were significantly higher in the cyclosporine-treated versus IFX-treated patients (6121 vs. 4853 euros, P < 0.05), whereas the total costs up to 3 months after initiation of
Introduction Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon characterized by mucosal ulceration, rectal bleeding, diarrhea, and abdominal pain. Up to 25% of UC patients experience a severe flare requiring urgent hospitalization [1,2]. Acute severe UC is a potentially lifethreatening condition, with estimated rates of urgent colectomy up to 40% [2]. Intravenous corticosteroids are the first-line treatment for attacks of severe UC, which is effective in about 60% of cases [3,4]. Around 15–60% of UC patients have corticosteroid-refractory disease [3–5]. Clinical guidelines recommend cyclosporine A (CsA) or infliximab (IFX) as rescue therapy in UC patients who fail to respond within 3–5 days to systemic corticosteroids. CsA and IFX are rapidly effective agents and the decision on which one to select as rescue therapy in daily practice is often guided by center preference and the physician’s personal experience. CsA is a calcineurin inhibitor that inhibits proliferation and cytokine production of T-helper lymphocytes. The first 0954-691X © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
rescue therapy were significantly higher in the IFX group (6787 vs. 9983 euros, P < 0.01). There were no significant differences in colectomy rates at 6 months (23 and 31% for cyclosporine and IFX, P = 0.50). More side-effects were observed during treatment with cyclosporine. Conclusion Length of hospital stay and in-hospital costs have been reduced significantly since the introduction of IFX as rescue therapy for severe UC instead of cyclosporine. However, the total treatment costs are higher in IFX-treated patients. Eur J Gastroenterol Hepatol 26:1240–1246 © 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. European Journal of Gastroenterology & Hepatology 2014, 26:1240–1246 Keywords: costs, cyclosporine, infliximab, length of hospital stay, ulcerative colitis a Department of Gastroenterology and Hepatology and bTytgat Institute for Liver and Intestinal Research, Academic Medical Center, Amsterdam, The Netherlands
Correspondence to Mark Löwenberg, MD, PhD, Department of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Tel: + 31 20 5667621; fax: + 31 20 6917033; e-mail: [email protected] *Mark Löwenberg and Nicolette W. Duijvis contributed equally to the writing of this article. Received 21 May 2014 Accepted 18 July 2014
placebo-controlled study that reported on the efficacy of intravenous CsA as rescue therapy in UC was published 20 years ago [6]. A dose-finding trial showed that 2 mg/kg body weight of CsA was equally effective as 4 mg/kg/day [7]. However, long-term follow-up of CsA-treated patients has shown a high colectomy rate, up to 88% after 7 years [8]. CsA treatment has been associated with hypertension, seizures, nephrotoxicity, and hypomagnesemia. Therefore, patients who receive treatment with CsA require intensive monitoring, including measurement of CsA blood concentrations [9]. The chimeric antitumor necrosis factor antibody IFX is effective as induction and maintenance therapy in patients with moderate to severe UC [10], and also in hospitalized patients with severe corticosteroidrefractory UC [11,12]. The drug has become an established therapeutic option for UC during the last decade. A recent study showed that CsA was not better as compared with IFX in hospitalized UC patients who failed 5 days of intravenous corticosteroids, showing comparable efficacy outcomes with both regimens ranging from DOI: 10.1097/MEG.0000000000000187
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Hospital stay and costs of IFX vs. CsA in UC Löwenberg et al. 1241
40 to 46% at 98 days [13]. All patients were hospitalized for 8 days; thus, the impact of treatment on length of hospital stay and associated treatment costs could not be assessed in this trial. The aim of the current study was to assess length of hospital stay and associated treatment costs in patients admitted for corticosteroid-refractory UC receiving treatment with CsA or IFX.
Patients and methods Patient selection and eligibility
All patients included in the study were identified using the local hospital database. We identified patients hospitalized for severe corticosteroid-refractory UC and treated with intravenous CsA (2 mg/kg/day) or IFX (5 mg/kg) between November 2003 and August 2012 at a single tertiary referral center [Academic Medical Center (AMC), Amsterdam]. Severe UC was defined as the need for hospitalization, on the basis of the ECCO guidelines (statement 5D) [14]. Patients had to have (bloody) diarrhea more than six times daily and should have signs of systemic toxicity (e.g. tachycardia, fever, low hemoglobin level, or high sedimentation rate). Corticosteroidrefractory disease was defined as failing 3–5 days of corticosteroids. Therapy failure was defined as acute colectomy or relapse of the disease that resulted in a change in the therapeutic regime or complete cessation of rescue therapy. In case of signs of a toxic megacolon, patients were immediately redirected to the surgeon as this is a strong indication for acute colectomy. Patients were excluded if they received IFX for any other indication, or if the diagnosis was equivocal for possible Crohn’s disease, indeterminate colitis, or infectious colitis. Forty-two patients fulfilled these criteria and in all of these patients complete follow-up was available. Treatment
There is no standard protocol at the AMC outlining when to initiate treatment with CsA or IFX in patients with severe UC, although in most cases (including all patients in our cohort), this decision is based on the Oxford recommendations [15], meaning that UC patients failing 3–5 days of intravenous corticosteroids move on to further treatment options. According to the ECCO guidelines, the next step would include rescue treatment with calcineurin inhibitors, such as CsA or tacrolimus, or antitumor necrosis factor antibodies [14]. There are no standardized criteria for hospital discharge; hence, all patients admitted and treated at our center for severe UC were discharged on the basis of the physician’s judgment, irrespective of the received rescue treatment. All patients were treated following our standard protocol for the respective treatments. Patients receiving intravenous CsA were administered 2 mg/kg body weight/day. Dose adjustments were made to obtain blood concentrations within the therapeutic range (150–350 μg/l) and inhospital treatment was continued until a clinical response was seen. The patient was then switched to oral
CsA for a period of 3 months. Maintenance treatment further on is usually azathioprine or 6-mercaptopurine, which is initiated during hospital admission or at discharge. IFX was started at 5 mg/kg per infusion. Remission-induction therapy with IFX consists of three infusions at weeks 0, 2, and 6. The patient was discharged after a clinical response was seen. Subsequent infusions with IFX were administered in an outpatient setting, with the potential to shorten the treatment interval or increase the IFX dose if required, which is in line with current treatment guidelines and the IFX drug label. Data collection
Hospital records were reviewed retrospectively. The following information was collected: age, sex, smoking status, extent of disease, duration of disease before admission, medication at time of admission, failed medication, length of hospital stay, side-effects due to rescue therapy, and colectomy rate. We chose to analyze colectomy rates after 6 months as the outcome parameter for treatment success, as colectomies that fall outside this time window are less likely to correlate with this specific event of rescue therapy because of possible confounding factors, such as alterations in the treatment regime. End-points
The primary end-point was duration of hospital stay from the initiation of rescue therapy with CsA or IFX to the date of discharge. Secondary end-points included hospital costs for CsA-treated and IFX-treated patients and total treatment costs associated with outpatient treatment up to 3 months after initiation of rescue therapy. Hospital costs were based on admission costs, drug costs, and laboratory tests (trough level measurements). Outpatient costs were based on drug costs and, in case of treatment with IFX, admission costs at the infusion unit. In case of an acute colectomy because of immediate failing of rescue therapy, the number of days that the patient was admitted at the surgical ward was included. The costs of the colectomy itself have not been included in the analysis. To investigate treatment outcomes, colectomy rates were analyzed with a follow-up of 6 months. Economic costs as a result of work leave because of hospitalization were not taken into account. Cost analysis
Drug costs, hospitalization costs, and costs of outpatient treatment were calculated on the basis of drug prices using the Dutch pharmacotherapeutic compass that contains a wide spectrum of pharmaceutical information, including costs of the prescription of all drugs available in the Netherlands. Intravenous treatment with CsA costs 9.31 euros per day and CsA blood level measurements cost 19 euros for one test. Measurements of CsA blood concentrations are performed every other day until the patient is switched to oral CsA, according to the
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1242 European Journal of Gastroenterology & Hepatology 2014, Vol 26 No 11
treatment protocol. Orally administered CsA costs 7.40 euros per day, on the basis of an average necessary dose of 150 mg twice daily. A vial of 100 mg IFX cost 647 euros in the Netherlands in 2010. IFX is dosed at 5 mg/kg body weight (induction scheme: 0–2–6 weeks). The mean body weight was 67.44 and 67.46 kg for IFX-treated and CsA-treated patients, respectively. Calculations have therefore been carried out on the basis of an average body weight of 70 kg per patient in both groups. Of note, at our tertiary referral center, IFX vials (containing 100 mg IFX per vial) are often shared between patients to reduce spillage. The reference price for hospitalization in a tertiary referral center in the Netherlands was 575 euros per day in the year 2010 (http://www.zorginstituutnederland.nl/binaries/ content/documents/zinl-www/documenten/publicaties/overigepublicaties/1007-handleiding-voor-kostenonderzoek/1007-handle iding-voor-kostenonderzoek/Handleiding+voor+kostenonderzoek. pdf). Admission costs at our day-care unit (in case of IFXtreated patients) are 300 euros per day. The following formulas have been used to calculate the hospitalization costs in both groups, in which Q represents the length of hospital stay in days. CsA hospital costs ¼ð9:31QÞþð190:5QÞþð575QÞ; which stands for (CsA costs) + (trough level measurements) + (admission costs), respectively. IFX hospital costs ¼ 2265þð575QÞ; which stands for IFX costs (70 kg × 5 mg/kg × 6.47 euros/ mg IFX, or 3.5 vials containing 100 mg IFX per vial) + admission costs. For total treatment costs, including outpatient treatment costs up to 3 months after initiation of rescue therapy, 666 euros were added to the CsA hospitalization costs, representing 90 days of oral CsA treatment. For IFX, 5130 euros was added to the IFX hospitalization costs, representing the costs of IFX infusions at week 2 and week 6, including day-care admission costs. Statistical analysis
The statistics used to describe the two patient populations are based on the mean and SD with respect to normally distributed data; otherwise, the median and interquartile range (IQR) were used. The significance of patient characteristics was analyzed using the χ2-test in case of categorical characteristics. To compare continuous characteristics, the Student t-test was used. To assess whether the outcome in hospitalization days was influenced by factors other than therapy, we carried out univariate analyses. All significant factors were subsequently used in a multivariate regression analysis. The Kaplan– Meier survival curve shows colectomy-free survival after hospital discharge comparing both treatment groups by the log rank test. Data were analyzed using SPSS
software version 20.0 (IBM SPSS Inc., Chicago, Illinois, USA). A P-value of lower than 0.05 was considered significant.
Results Baseline characteristics
A total of 42 patients (median age 37 years; 43% women) were included in the analysis, of whom 26 patients were treated with CsA and 16 patients with IFX. Patients’ characteristics in both groups were comparable, as shown in Table 1. Patients receiving CsA were treated between 2003 and 2012, and patients in the IFX group received treatment with IFX between 2006 and 2012. The median duration of disease was 2.0 (IQR 1.3–8.0) versus 4.0 (IQR 0.0–7.3) years, and 19.2 versus 31.3% of patients were smokers in the CsA and the IFX group, respectively. Three patients treated with CsA and four patients treated with IFX were already receiving thiopurines at the time of admission, which they continued during rescue treatment. All other CsA patients were started on thiopurines, except for one patient, who could not tolerate thiopurines. Three patients (one CsA patient and two IFX patients) were not on steroids at the time of admission, but all failed on steroids shortly before. CsA patients were started significantly more often on thiopurines compared with patients in the IFX group. The proportion of patients with a pancolitis was 89 versus 63% in the CsA and the IFX group (P = 0.046), respectively. The mean follow-up in months (from the date of discharge until April 2013) was 91.5 (IQR 56.5–102.3) in the CsA Table 1
Patient characteristics CsA
Number of patients 26 (n) Age 37 (21.0–43.0) Sex 11 ♀ (42) Median disease 2 (1.3–8.0) duration (years) Median follow-up 91.50 (56.50–102.25) (months) Smoking status Yes 5 (19.2) No 11 (42.3) Former smoker 5 (19.2) Unknown 5 (19.2) UC location (Montreal classification) Proctitis (E1) 1 (3.8) Left-sided colitis 1 (3.8) (E2) Pancolitis (E3) 23 (88.5) Unknown 1 (3.8) Co-medication at the time of admission Corticosteroids 25 (96) Admitted with 3 (12) thiopurines Started 22 (85) thiopurines Mesalamine 18 (69)
IFX
P-value
16 34 (20–43.50) 7 ♀ (44) 4 (0.0–7.3)
NS NS
34.50 (23.25–48.75)
NS NS
5 6 3 2
(31.3) (37.5) (18.7) (12.5)
0 6 (37.5)
NS < 0.01
10 (62.5) 0
< 0.05a NS
14 (87.5) 4 (25)
NS NS
6 (37.5)
0.002
12 (75)
NS
Values are represented as mean ± SD, median (IQR), or n (%). CsA, cyclosporine A; IFX, infliximab; IQR, interquartile range; UC, ulcerative colitis. a P-value (Pearson’s χ2) based on the presence of pancolitis.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Hospital stay and costs of IFX vs. CsA in UC Löwenberg et al. 1243
group and 34.05 (IQR 23.3–48.8) in the IFX group. The mortality rate in both groups was 0%.
Fig. 1
P
