Cost-Effectiveness Analysis of Increased Adalimumab Dose Intervals in Crohn's Disease Patients in Stable Remission: The Randomized Controlled LADI Trial.

BACKGROUND AND AIMS: We aimed to assess cost-effectiveness of increasing adalimumab dose intervals compared to the conventional dosing interval in patients with Crohn's disease [CD] in stable clinical and biochemical remission. DESIGN: We conducted a pragmatic, open-label, randomized controlled non-inferiority trial, comparing increased adalimumab intervals with the 2-weekly interval in adult CD patients in clinical remission. Quality of life was measured with the EQ-5D-5L. Costs were measured from a societal perspective. Results are shown as differences and incremental net monetary benefit [iNMB] at relevant willingness to accept [WTA] levels. RESULTS: We randomized 174 patients to the intervention [n = 113] and control [n = 61] groups. No difference was found in utility (difference: -0.017, 95% confidence interval [-0.044; 0.004]) and total costs (-€943, [-€2226; €1367]) over the 48-week study period between the two groups. Medication costs per patient were lower (-€2545, [-€2780; -€2192]) in the intervention group, but non-medication healthcare (+€474, [+€149; +€952]) and patient costs (+€365 [+€92; €1058]) were higher. Cost-utility analysis showed that the iNMB was €594 [-€2099; €2050], €69 [-€2908; €1965] and -€455 [-€4,096; €1984] at WTA levels of €20 000, €50 000 and €80 000, respectively. Increasing adalimumab dose intervals was more likely to be cost-effective at WTA levels below €53 960 per quality-adjusted life year. Above €53 960 continuing the conventional dose interval was more likely to be cost-effective. CONCLUSION: When the loss of a quality-adjusted life year is valued at less than €53 960, increasing the adalimumab dose interval is a cost-effective strategy in CD patients in stable clinical and biochemical remission. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, number NCT03172377.

Continuation of Anti-TNF in Patients With Ulcerative Colitis in Remission Is Not Cost-effective Compared With Treatment Withdrawal: A Markov Model.

BACKGROUND AND AIMS: Anti-tumour necrosis factor alpha [anti-TNF] treatment accounts for 31% of health care expenditures associated with ulcerative colitis [UC]. Withdrawal of anti-TNF in patients with UC in remission may decrease side effects and infections, while promoting cost containment. Approximately 36% of patients relapse within 12-24 months of anti-TNF withdrawal, but reintroduction of treatment is successful in 80% of patients. We aimed to evaluate the cost-effectiveness of continuation versus withdrawal of anti-TNF in patients with UC in remission. METHODS: We developed a Markov model comparing cost-effectiveness of anti-TNF continuation versus withdrawal, from a health care provider perspective. Transition probabilities were calculated from literature, or estimated by an expert panel of 11 gastroenterologists. Deterministic and probabilistic sensitivity analyses were performed to account for assumptions and uncertainty. The cost-effectiveness threshold was set at an incremental cost-effectiveness ratio of €80,000 per quality-adjusted life-year [QALY]. RESULTS: At 5 years, anti-TNF withdrawal was less costly [-€10,781 per patient], but also slightly less effective [-0.04 QALY per patient] than continued treatment. Continuation of anti-TNF compared with withdrawal costs €300,390/QALY, exceeding the cost-effectiveness threshold. Continued therapy would become cost-effective if the relapse rate following anti-TNF withdrawal was ≥43% higher, or if adalimumab or infliximab [biosimilar] prices fell below €87/40 mg and €66/100 mg, respectively. CONCLUSIONS: Continuation of anti-TNF in UC patients in remission is not cost-effective compared with withdrawal. A stop-and-reintroduction strategy is cost-saving but is slightly less effective than continued therapy. This strategy could be improved by identifying patients at increased risk of relapse.

Evolution of Costs of Inflammatory Bowel Disease over Two Years of Follow-Up.

BACKGROUND: With the increasing use of anti-TNF therapy in inflammatory bowel disease (IBD), a shift of costs has been observed with medication costs replacing hospitalization and surgery as major cost driver. We aimed to explore the evolution of IBD-related costs over two years of follow-up. METHODS AND FINDINGS: In total 1,307 Crohn's disease (CD) patients and 915 ulcerative colitis (UC) patients were prospectively followed for two years by three-monthly web-based questionnaires. Changes of healthcare costs, productivity costs and out-of-pocket costs over time were assessed using mixed model analysis. Multivariable logistic regression analysis was used to identify costs drivers. In total 737 CD patients and 566 UC were included. Total costs were stable over two years of follow-up, with annual total costs of €7,835 in CD and €3,600 in UC. However, within healthcare costs, the proportion of anti-TNF therapy-related costs increased from 64% to 72% in CD (p<0.01) and from 31% to 39% in UC (p < 0.01). In contrast, the proportion of hospitalization costs decreased from 19% to 13% in CD (p<0.01), and 22% to 15% in UC (p < 0.01). Penetrating disease course predicted an increase of healthcare costs (adjusted odds ratio (adj. OR) 1.95 (95% CI 1.02-3.37) in CD and age <40 years in UC (adj. OR 4.72 (95% CI 1.61-13.86)). CONCLUSIONS: BD-related costs remained stable over two years. However, the proportion of anti-TNF-related healthcare costs increased, while hospitalization costs decreased. Factors associated with increased costs were penetrating disease course in CD and age <40 in UC.

Self-reported Health Care Utilization of Patients with Inflammatory Bowel Disease Correlates Perfectly with Medical Records.

BACKGROUND: Studies on the costs of health care in patients with inflammatory bowel disease (IBD) are increasingly conducted through the collection of self-reported data. We aimed to assess the concordance between estimated annual costs based on self-reported health care utilization and administrative data in IBD. METHODS: Consecutive patients with Crohn's disease or ulcerative colitis visiting the outpatient clinic were enrolled. Participants were asked to fill out a questionnaire on their IBD-specific health care utilization over the past year. Registered health care utilization over the same time period was extracted from medical records. Health care resources were multiplied by their unit prices to obtain costs. Cost estimates were compared, and correlation, sensitivity, and specificity were calculated. RESULTS: In total, 101 patients (70 Crohn's disease, 31 ulcerative colitis) were enrolled. Mean direct health care costs were &OV0556;4758 per year according to self-reported data and &OV0556;4866 according to administrative data (r = 0.97). Hospitalizations and diagnostics were relatively underreported with a sensitivity of 75% and 88%, and a specificity of 100% and 88%, respectively. One of 7 surgical procedures was overreported, and only 1 of 25 patients did not report the use of anti-tumor necrosis factor compounds. Suffering from a flare or having a pouch predicted a decreased recall with an adjusted odds ratio of 3.5 (95% confidence interval, 1.3-9.6) and 10.7 (95% confidence interval, 1.1-107.6), respectively. CONCLUSIONS: We report a high concordance between costs of self-reported health care utilization and administrative data over the past year in IBD. Self-reported health care utilization reliably measures the consumption of health care in IBD.

Comparison of Costs and Quality of Life in Ulcerative Colitis Patients with an Ileal Pouch-Anal Anastomosis, Ileostomy and Anti-TNFα Therapy.

BACKGROUND AND AIMS: More data are warranted on the economic impact of different treatment strategies in ulcerative colitis (UC) patients. We compared the costs and quality of life of UC patients with a pouch reconstruction, an ileostomy or anti-tumour necrosis factor α (TNFα) therapy. METHODS: UC patients filled out 3-monthly questionnaires for 2 years. Differences in 3-monthly healthcare costs, productivity costs and patient costs were tested using mixed model analysis. Quality of life was assessed employing the ) and the inflammatory bowel disease questionnaire (IBDQ). RESULTS: Out of 915 UC patients, 81 (9%) had a pouch and 48 (5%) an ileostomy, and 34 (4%) were on anti-TNFα therapy. Anti-TNFα-treated patients reported high UC related-healthcare costs per 3 months (€5350). Medication use accounted for 92% of healthcare costs. UC-attributable healthcare costs were 3-fold higher in ileostomy patients compared with pouch patients (€1581 versus €407; p < 0.01). Main cost drivers in ileostomy patients were healthcare costs and ileostomy supplies (2 and 23% of healthcare costs, respectively). In pouch patients, the main cost driver was hospitalization, accounting for 50% of healthcare costs. Productivity loss did not differ between pouch and ileostomy patients (€483 versus €377; p < 0.23), but was significantly higher in anti-TNFα-treated patients (€1085). No difference was found in IBDQ scores, but pouch patients were found to have higher quality-adjusted life years than ileostomy patients and anti-TNFα-treated patients (0.90 [interquartile range 0.78-1.00] versus 0.84 [0.78-1.00] and 0.84 [0.69-1.00], respectively; p < 0.01). CONCLUSION: Patients receiving anti-TNFα therapy reported the highest healthcare cost, in which medication use was the major cost driver. Ileostomy patients were three times more expensive than pouch patients due to frequent hospitalization and ileostomy supplies.

Multimodal treatment of perianal fistulas in Crohn's disease: seton versus anti-TNF versus advancement plasty (PISA): study protocol for a randomized controlled trial.

BACKGROUND: Currently there is no guideline for the treatment of patients with Crohn's disease and high perianal fistulas. Most patients receive anti-TNF medication, but no long-term results of this expensive medication have been described, nor has its efficiency been compared to surgical strategies. With this study, we hope to provide treatment consensus for daily clinical practice with reduction in costs. METHODS/DESIGN: This is a multicentre, randomized controlled trial. Patients with Crohn's disease who are over 18 years of age, with newly diagnosed or recurrent active high perianal fistulas, with one internal opening and no anti-TNF usage in the past three months will be considered. Patients with proctitis, recto-vaginal fistulas or anal stenosis will be excluded. Prior to randomisation, an MRI and ileocolonoscopy are required. All treatment will start with seton placement and a course of antibiotics. Patients will then be randomised to: (1) chronic seton drainage (with oral 6-mercaptopurine (6MP)) for one year, (2) anti-TNF medication (with 6MP) for one year (seton removal after six weeks) or (3) advancement plasty after eight weeks of seton drainage (under four months anti-TNF and 6MP for one year). The primary outcome parameter is the number of patients needing fistula-related re-intervention(s). Secondary outcomes are the number of patients with closed fistulas (based on an evaluated MRI score) after 18 months, disease activity, quality of life and costs. DISCUSSION: The PISA trial is a multicentre, randomised controlled trial of patients with Crohn's disease and high perianal fistulas. With the comparison of three generally accepted treatment strategies, we will be able to comment on the efficiency of the various treatment strategies, with respect to several long-term outcome parameters. TRIAL REGISTRATION: Nederlands Trial Register identifier: NTR4137 (registered on 23 August 2013).

A risk-profiling approach for surveillance of inflammatory bowel disease-colorectal carcinoma is more cost-effective: a comparative cost-effectiveness analysis between international guidelines.

BACKGROUND: Colonoscopic surveillance for neoplasia is recommended for patients with inflammatory bowel disease (IBD)-related colitis. However, data on cost-effectiveness predate current international guidelines. OBJECTIVE: To compare cost-effectiveness based on contemporary data between the surveillance strategies of the American Gastroenterological Association (AGA) and British Society of Gastroenterology (BSG). DESIGN: We constructed a Markov decision model to simulate the clinical course of IBD patients. SETTING: We compared the 2 surveillance strategies for a base case of a 40-year-old colitis patient who was followed for 40 years. PATIENTS: AGA surveillance distinguishes 2 groups: a high-risk group with annual surveillance and an average-risk group with biannual surveillance. BSG surveillance distinguishes 3 risk groups with yearly, 3-year, or 5-year surveillance. INTERVENTIONS: Patients could move from a no-dysplasia state with colonoscopic surveillance to 1 of 3 states for which proctocolectomy was indicated: (1) dysplasia/local cancer, (2) regional/metastasized cancer, or (3) refractory disease. After proctocolectomy, a patient moved to a no-colon state without surveillance. MAIN OUTCOME MEASUREMENTS: Direct costs of medical care, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. RESULTS: BSG surveillance dominated AGA surveillance with $9846 per QALY. Both strategies were equally effective with 24.16 QALYs, but BSG surveillance was associated with lower costs because of fewer colonoscopies performed. Costs related to IBD, surgery, or cancer did not affect cost-effectiveness. LIMITATIONS: The model depends on the accuracy of derived data, and the assumptions that were made to reflect real-life situations. Study conclusions may only apply to the U.S. health care system. CONCLUSION: The updated risk-profiling approach for surveillance of IBD colorectal carcinoma by the BSG guideline appears to be more cost-effective.

Effect of aging on healthcare costs of inflammatory bowel disease: a glimpse into the future.

BACKGROUND: Population aging is expected to result in a substantial additional burden on healthcare resources in the near future. We aimed to assess the current and future impact of aging on direct healthcare costs (DHC) attributed to inflammatory bowel disease (IBD). METHODS: Patients with IBD from a Dutch multicenter cohort filled out 3-monthly questionnaires for 2 years. Elderly (≥60 yr) and younger patients (18-60 yr) IBD were analyzed for differences in 3-monthly DHC, productivity losses, and out-of-pocket costs. Prevalence rates were obtained from a health insurance database. Estimates of annual DHC and prevalence rates were applied to the total Dutch adult population in 2011 and then projected to 2040, using predicted changes in population demography, prices, and volume. RESULTS: IBD-attributable DHC were lower in elderly than in younger patients with IBD with respect to 3-monthly DHC (&OV0556;359 versus &OV0556;978, P < 0.01), productivity losses (&OV0556;108 versus &OV0556;456, P < 0.01), and out-of-pocket costs (&OV0556;40 versus &OV0556;57, P < 0.01). Between 2011 and 2040, the percentage of elderly IBD patients in the Netherlands has been projected to rise from 24% to 35%. Between 2011 and 2040, DHC of the total IBD population in the Netherlands are projected to increase from &OV0556;161 to &OV0556;661 million. Population aging accounted for 1% of this increase, next to rising prices (29%), and volume growth (70%). CONCLUSIONS: Population aging has a negligible effect on IBD-attributable DHC of the IBD population in the near future, because the average costs incurred by elderly patients with IBD are considerably lower than those incurred by younger patients with IBD.

Healthcare costs of inflammatory bowel disease have shifted from hospitalisation and surgery towards anti-TNFα therapy: results from the COIN study.

OBJECTIVE: The introduction of anti tumour necrosis factor-α (anti-TNFα) therapy might impact healthcare expenditures, but there are limited data regarding the costs of inflammatory bowel diseases (IBD) following the introduction of these drugs. We aimed to assess the healthcare costs and productivity losses in a large cohort of IBD patients. DESIGN: Crohn's disease (CD) and ulcerative colitis (UC) patients from seven university hospitals and seven general hospitals were invited to fill-out a web-based questionnaire. Cost items were derived from a 3 month follow-up questionnaire and categorised in outpatient clinic, diagnostics, medication, surgery and hospitalisation. Productivity losses included sick leave of paid and unpaid work. Costs were expressed as mean 3-month costs per patients with a 95% CI obtained using non-parametric bootstrapping. RESULTS: A total of 1315 CD patients and 937 UC patients were included. Healthcare costs were almost three times higher in CD as compared with UC, €1625 (95% CI €1476 to €1775) versus €595 (95% CI €505 to €685), respectively (p<0.01). Anti-TNFα use was the main costs driver, accounting for 64% and 31% of the total cost in CD and UC. Hospitalisation and surgery together accounted for 19% and <1% of the healthcare costs in CD and 23% and 1% in UC, respectively. Productivity losses accounted for 16% and 39% of the total costs in CD and UC. CONCLUSIONS: We showed that healthcare costs are mainly driven by medication costs, most importantly by anti-TNFα therapy. Hospitalisation and surgery accounted only for a minor part of the healthcare costs.

Optimizing screening for tuberculosis and hepatitis B prior to starting tumor necrosis factor-α inhibitors in Crohn's disease.

BACKGROUND AND AIMS: Treatment with tumor necrosis factor-α (TNF-α) inhibitors in patients with Crohn's disease (CD) is associated with potentially serious infections, including tuberculosis (TB) and hepatitis B virus (HBV). We assessed the cost-effectiveness of extensive TB screening and HBV screening prior to initiating TNF-α inhibitors in CD. METHODS: We constructed two Markov models: (1) comparing tuberculin skin test (TST) combined with chest X-ray (conventional TB screening) versus TST and chest X-ray followed by the interferon-gamma release assay (extensive TB screening) in diagnosing TB; and (2) HBV screening versus no HBV screening. Our base-case included an adult CD patient starting with infliximab treatment. Input parameters were extracted from the literature. Direct medical costs were assessed and discounted following a third-party payer perspective. The main outcome was the incremental cost-effectiveness ratio (ICER). Sensitivity and Monte Carlo analyses were performed over wide ranges of probability and cost estimates. RESULTS: At base-case, the ICERs of extensive screening and HBV screening were €64,340 and €75,760 respectively to gain one quality-adjusted life year. Sensitivity analyses concluded that extensive TB screening was a cost-effective strategy if the latent TB prevalence is more than 12 % or if the false positivity rate of TST is more than 20 %. HBV screening became cost-effective if HBV reactivation or HBV-related mortality is higher than 37 and 62 %, respectively. CONCLUSIONS: Extensive TB screening and HBV screening are not cost-effective compared with conventional TB screening and no HBV screening, respectively. However, when targeted at high-risk patient groups, these screening strategies are likely to become cost-effective.

Effect of adalimumab on work productivity and indirect costs in moderate to severe Crohn's disease: a meta-analysis.

OBJECTIVE: To assess the effect of adalimumab on work productivity and indirect costs in patients with Crohn's disease (CD) using a meta-analysis of clinical trials. METHODS: Study-level results were pooled from all clinical trials of adalimumab for moderate to severe CD in which work productivity outcomes were evaluated. Work Productivity and Activity Impairment Questionnaire outcomes (absenteeism, presenteeism and total work productivity impairment [TWPI]) were extracted from adalimumab trials. Meta-analyses were used to estimate pooled averages and 95% CIs of one-year accumulated reductions in work productivity impairment with adalimumab. Pooled averages were multiplied by the 2008 United States national average annual salary ($44,101) to estimate per-patient indirect cost savings during the year following adalimumab initiation. RESULTS: The four included trials (ACCESS, CARE, CHOICE and EXTEND) represented a total of 1202 employed adalimumab-treated patients at baseline. Each study followed patients for a minimum of 20 weeks. Pooled estimates (95% CIs) of one-year accumulated work productivity improvements were as follows: -9% (-10% to -7%) for absenteeism; -22% (-26% to -18%) for presenteeism; and -25% (-30% to -20%) for TWPI. Reductions in absenteeism and TWPI translated into per-patient indirect cost savings (95% CI) of $3,856 ($3,183 to $4,529) and $10,964 ($8,833 to $13,096), respectively. CONCLUSION: Adalimumab provided clinically meaningful improvements in work productivity among patients with moderate to severe CD, which may translate into substantial indirect cost savings from an employer's perspective.

Performance of EUS-FNA for mediastinal lymphadenopathy: impact on patient management and costs in low-volume EUS centers.

BACKGROUND: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of mediastinal lymphadenopathy has been shown to be a valuable diagnostic tool in high-volume EUS centers (≥ 50 mediastinal EUS-FNA/endoscopist/year). Our goal was to assess the diagnostic accuracy of EUS-FNA and its impact on clinical management and costs in low-volume EUS centers (<50 mediastinal EUS-FNA/endoscopist/year). METHODS: Consecutive patients referred to two Dutch endoscopy centers in the period 2002-2008 for EUS-FNA of mediastinal lymphadenopathy were reviewed. The gold standard for a cytological diagnosis was histological confirmation or clinical follow-up of more than 6 months with repeat imaging. The impact of EUS-FNA on clinical management was subdivided into a positive impact by providing (1) adequate cytology that influenced the decision to perform surgery or (2) a diagnosis of a benign inflammatory disorder, and a negative impact which was subdivided into (1) false-negative or inconclusive cytology or (2) an adequate cytological diagnosis that did not influence patient management. Costs of an alternative diagnostic work-up without EUS-FNA, as established by an expert panel, were compared to costs of the actual work-up. RESULTS: In total, 213 patients (71% male, median age= 61 years, range = 23-88 years) underwent EUS-FNA. Sensitivity, specificity, and negative and positive predictive values were 89%, 100%, 80%, and 100%, respectively. EUS-FNA had a positive impact on clinical management in 84% of cases by either influencing the decision to perform surgery (49%) or excluding malignant lymphadenopathy (35%), and a negative impact in 7% of cases because of inadequate (3%) or false-negative (4%) cytology. In 9% of cases, EUS-FNA was performed without an established indication. Two nonfatal perforations occurred (0.9%). Total cost reduction was €100,593, with a mean cost reduction of €472 (SD = €607) per patient. CONCLUSIONS: Mediastinal EUS-FNA can be performed in low-volume EUS centers without compromising diagnostic accuracy. Moreover, EUS-FNA plays an important role in the management of patients with mediastinal lymphadenopathy and reduces total diagnostic costs.

Laparoscopic ileocolic resection versus infliximab treatment of distal ileitis in Crohn's disease: a randomized multicenter trial (LIR!C-trial).

BACKGROUND: With the availability of infliximab, nowadays recurrent Crohn's disease, defined as disease refractory to immunomodulatory agents that has been treated with steroids, is generally treated with infliximab. Infliximab is an effective but expensive treatment and once started it is unclear when therapy can be discontinued. Surgical resection has been the golden standard in recurrent Crohn's disease. Laparoscopic ileocolic resection proved to be safe and is characterized by a quick symptom reduction. The objective of this study is to compare infliximab treatment with laparoscopic ileocolic resection in patients with recurrent Crohn's disease of the distal ileum with respect to quality of life and costs. METHODS/DESIGN: The study is designed as a multicenter randomized clinical trial including patients with Crohn's disease located in the terminal ileum that require infliximab treatment following recent consensus statements on inflammatory bowel disease treatment: moderate to severe disease activity in patients that fail to respond to steroid therapy or immunomodulatory therapy. Patients will be randomized to receive either infliximab or undergo a laparoscopic ileocolic resection. Primary outcomes are quality of life and costs. Secondary outcomes are hospital stay, early and late morbidity, sick leave and surgical recurrence. In order to detect an effect size of 0.5 on the Inflammatory Bowel Disease Questionnaire at a 5% two sided significance level with a power of 80%, a sample size of 65 patients per treatment group can be calculated. An economic evaluation will be performed by assessing the marginal direct medical, non-medical and time costs and the costs per Quality Adjusted Life Year (QALY) will be calculated. For both treatment strategies a cost-utility ratio will be calculated. Patients will be included from December 2007. DISCUSSION: The LIR!C-trial is a randomized multicenter trial that will provide evidence whether infliximab treatment or surgery is the best treatment for recurrent distal ileitis in Crohn's disease. TRIAL REGISTRATION: Nederlands Trial Register NTR1150.