AG

AA

bst

ract

sSa1108

Cost-Effectiveness of Golimumab Versus Infliximab and Adalimumab for theTreatment of Moderate to Severe Ulcerative ColitisKristian Thorlund, Eric Druyts, Steve Kanters, Shawn Eapen, Edward Mills

Introduction: The efficacy and safety of golimumab was elucidated in the recently publishedPURSUIT trial. Two other biologics, infliximab and adalimumab, are also available for thetreatment of UC. Based on an indirect treatment comparison, golimumab is comparable inefficacy and safety to infliximab, but generally less costly, and superior to adalimumab inefficacy in terms of sustaining clinical outcomes, but generally of similar cost. For this reason,a cost-effectiveness (CE) analysis comparing the three anti-TNF-α agents was warranted.Methods: A Markov Model was created to simulate patients over a 10 years. The firstadministered intervention was any of the three biologics. Key health states included clinicalremission, clinical response, and relapse. Upon relapsing the administered biologic, patientswere assumed to transition into ‘relapse management', in which continual IV steroids couldkeep patients in response until they became refractory. Patients would then undergo colec-tomy and enter ‘post-colectomy remission'. After colectomy patients could either be inremission or experience temporary colectomy complications. Utilities were assigned sepa-rately for states before and after colectomy. Canadian cost estimates were used for biologics,background treatment, and all in/out-patient costs for colectomy and safety outcomes.Uncertainty around transition probability and cost estimates were incorporated. Sensitivityanalyses included a societal perspective, varying discount rates and time horizons, and ‘realworld' transition probabilities. Analysis: The cost-effectiveness of golimumab was comparedwith conventional therapy and with infliximab and adalimumab. CE measures included totalcost and utility over 10 years, mean incremental cost and utility per year, incremental CEratios (ICERs), CE acceptability curves (CEACs) for golimumab and the CE frontier for allbiologics. Results: In all analyses golimumab yielded the lowest ICER. In the base case analysis,golimumab, infliximab, and adalimumab were associated with an ICERs of approximately$40,000/QALY, $80,000/QALY, and $100,000/QALY, respectively. The CEAC for golimu-mab showed that a willingness-to-pay threshold (WTPs) of $100,000/QALY was associatedwith a ~90% probability of being cost-effective. The cost-effectiveness frontier demonstratedthat WTP thresholds greater than $25,000 showed that golimumab had the greatest probabil-ity of being cost-effective. Golimumab and infliximab displayed extended dominance com-pared to adalimumab. Sensitivity analysis taking a societal perspective or using ‘real world'transition probabilities reduced the ICERs by 20-40% for all biologics. Conclusion: Overallgolimumab provides a cost-effective treatment option for patients who have had an inadequateresponse to conventional therapy for moderately to severely active ulcerative colitis.

Sa1109

Meta-Analysis of Duration of Exposure to Thiopurines in Association WithDevelopment of Lymphoma in Patients With Inflammatory Bowel DiseaseDavid Kotlyar, James D. Lewis, Ann Tierney, Wojciech Blonski, Javier P. Gisbert, MariaChaparro, Gary R. Lichtenstein

Background: Numerous large scale national studies have shown that the use of thiopurinesin patients with Inflammatory Bowel Disease increases their risk of developing lymphoma.The issue of whether duration of exposure to thiopurines increases lymphoma risk remainsa highly clinically relevant yet poorly characterized issue. Our group previously publisheda nationwide retrospective study of patients with IBD exposed to thiopurines, and did showa significant increase in risk with duration of exposure (Khan 2013). We have also previouslypublished a systematic review of individual cases of lymphoma in patients exposed tothiopurines with IBD (Kotlyar 2012), which did not show a pattern of increased risk withincreasing exposure time. However, no meta-analysis of population based studies has yetbeen performed evaluating if there is a relationship between the time of exposure anddevelopment of lymphoma Aims: To determine the standardized incidence ratio of lymphomain pts exposed to AZA/6-MP in population cohort studies in relation to the time of exposureto AZA/6-MP via a meta-analysis of all available data. Methods: We searched MEDLINE,EMBASE and the Cochrane Database for: "6-MP and lymphoma", "6-mercaptopurine andlymphoma", "thiopurines and lymphoma", "azathioprine and cancer and IBD", "azathioprineand malignancy and IBD", "azathioprine and lymphoma" and "lymphoproliferative andthiopurines". Included citations were population-based studies from nationwide databases,IBD cohort studies, evaluated cancer as an outcome, and pts. received AZA and/or 6-MP.Additionally a comprehensive search of the literature and abstracts from international meet-ings (2005-2013) was done. In our study additional data were extracted from the Spanishcollaborative database ENEIDA which was used in the study by Chaparro. Pooled standard-ized incidence ratios (SIRs) were generated and confidence intervals were based on thePoisson distribution. Results: There were 4,383 citations in total. Two citations (Khan 2013,Chaparro 2010) were included. In those with less than 1 year of thiopurine exposure, theSIR=1.16 (95% CI= 0.11-2.06), in those with 1-2 years of exposure, SIR=3.95 (95% CI=0.6-6.71), in those with 2-3 yrs of exposure SIR=3.36 (95% CI=0.82-5.90), and in thosewith >3 yrs of exposure SIR=3.73 (95% CI= 1.05-6.40). (Table 1). Conclusion: Other thanone case of lymphoma which developed within 2 months of treatment, which may havebeen concurrent, there was a lag time of at least 8 months prior to onset of lymphoma. Ofthe cases, 5 (23%) were <1 yr, 5 (23%) between 2-3 yrs, and 12 (55%) greater than 3 yrs.In addition, while less than 3 years of exposure time was not associated with significantlyincreased risk, those with more than 3 years of exposure had a significantly increased risk.Combined Estimates for SIR

S-202AGA Abstracts

Sa1110

Comparing the Effectiveness of Anti-TNF Agents for the Treatment of Crohn'sDisease: a Bayesian Network Meta-AnalysisRyan W. Stidham, Terrence Lee, Peter D. Higgins, Amar R. Deshpande, Daniel A.Sussman, Amit G. Singal, B. Joseph J. Elmunzer, Sameer D. Saini, Sandeep Vijan, AkbarK. Waljee

Background: Anti-tumor necrosis factor-alpha inhibitors (Anti-TNF) are effective therapiesfor the treatment of Crohn's disease, but their comparative efficacy is unknown. We performeda network meta-analysis comparing the efficacy of anti-TNF therapies in Crohn's disease (CD).Methods: After screening of 506 studies, reviewers independently extracted information from6 studies evaluating induction and 5 studies evaluating maintenance of clinical remissionor response in CD. Traditional meta-analysis (TMA) was used to compare each anti-TNFagent to placebo. Bayesian network meta-analysis (NMA) was performed using non-informedpriors to compare the effects of anti-TNF drugs using placebo as a common comparator.In addition, sample sizes for comparative effectiveness trials were calculated. Results: TMArevealed that infliximab (IFX), adalimumab (ADA), and certolizumab pegol (CZP) are effectivetherapies for CD (see Table 1). NMA of agents for induction of remission demonstrated nostatistically significant difference between IFX and ADA or CZP (see Table 2). NMA demon-strated superiority of ADA to CZP for induction of remission (RR 2.93, 95%CrI 1.21-7.75).While trends favored IFX over ADA and CZP, the 95% credible interval crossed 1 and wastherefore not statistically significant. IFX was ranked the most effective drug in 67% of thesimulations, while ADA was favored in 33% and CZP in 0% of simulations. NMA of anti-TNF agents for induction of response demonstrated no significant difference in efficacy. IFXwas ranked the most effective anti-TNF for induction of response in 87% of simulations,while ADA was favored in 12%, and CZP in 1% of simulations. NMA of maintenance ofremission demonstrated no statistical significance difference between anti-TNF agents. IFXwas ranked the most effective anti-TNF for maintenance of remission in 79% of simulations,while ADA was favored in 16%, and CZP in 5% of simulations. Insufficient data was availableto perform NMA for maintenance of response across anti-TNF agents. Sample size calculationssuggest that direct comparison of anti-TNF agents would require upwards of 5000 subjects.Conclusions: This study demonstrates that, compared to placebo, IFX, ADA and CZP areall effective in the treatment of Crohn's disease. NMA demonstrated that no single agent isclinically superior. However, amongst subcutaneous anti-TNF therapies, ADA was superiorto CZP for induction of remission. Simulations favored IFX as first line for induction ofremission and response, but did not reach statistical significance. In the absence of directcomparison data, when considering infused vs. subcutaneous therapies, factors includingcost and patient preference should help guide the choice of anti-TNF agents, as comparativeeffectiveness trials between the agents would be impractical.Table 1. Traditional meta-analysis of anti-TNF clinical efficacy against placebo in Crohn's dis-ease.

Table 2. Network meta-analysis comparing clinical efficacy between anti-TNF agents inCrohn's disease.

Sa1111

Site and Severity Degree of Small Bowel Stricture Do Not Predict Indicationfor Surgery in Crohn's DiseaseNadia Pallotta, Giuseppina Vincoli, Laura Candeloro, Rodolfo Calarco, Enrico Corazziari

Crohn's disease (CD) progression is characterized by the occurrence of intestinal stricturesoften requiring surgery. A cohort study showed that 22% of patients with stricturing CDunderwent surgery during a 5 years follow-up (FU) interval (1). It is not known whetherthe site and severity of stricture defined by its lumen diameter and length, affect the indicationfor surgery. Small intestine contrast ultrasonography (SICUS) compared to surgical findingshas been proven to accurately detect CD small bowel strictures (2) and can assess themaximal intestinal lumen distensibility. AIM. To evaluate in CD patients whether the site,lumen diameter, and length of stricture are associated to obstructive symptoms requiringsurgery. Methods & Subjects. Within a long-term prospective FU study that includes clinical,laboratory, and SICUS evaluation performed at regular time intervals independently fromsymptoms recurrence and preoperatively in those submitted to surgery, 190 CD patients(112 M, mean age 37 yrs) were evaluated. SICUS was performed after the ingestion of 375ml of macrogol oral solution. The association between the occurrence of obstructive symptomsrequiring surgery and site, lumen diameter, and length of strictures as well as clinical featuresof patients was assessed with Mann-Whitney U test and chi-square test. Results. During a8±2 yrs FU period 99 patients (53%) developed one or more strictures requiring surgeryin 30 (28%) (M 14, mean age 39 yrs) illness behavior (IB) B2 25, B3 5 and location (L) atdiagnosis, L1 17, L3 13, but not in 69 patients (M 44, mean age 40 yrs) IB B1 25, B2 39,B3 5 (p<.000 vs operated) and L at diagnosis L1 38, L3 26 L4 5. The agreement by K-statistics between SICUS and surgery in identifying presence, site and number of strictureswas 1 and 0.93, respectively. The site of strictures was ileo-cecal valve/anastomosis, terminal,

distal and proximal ileum in 15, 44, 11 and 11 of non-operated patients and 0, 24, 7 and6 in operated patients (ns). Length of strictures was 5.6±3.4 cm at surgery, 5.7±4.1 cm atSICUS (n.s). Pre-stenotic dilatation was present in 49/81(60%) and 15/37(40.5%) stricturesin non-operated and operated patients, respectively (n.s). The length and lumen diameterof strictures were 5±5 cm and 6±1 mm in non-operated and 6.6±5 cm and 5.2±1.8 mm inoperated patients (n.s), respectively. There was no significant difference in the stricture siteand location of CD at diagnosis, between operated and non-operated patients . Conclusions.Site, length, and degree of luminal narrowing of stricture do not differ between CD patientsrequiring and not requiring surgery. Severity of stricture does not appear to be the onlyfactor of obstructive symptoms requiring surgery. It is likely that other factors contributewith stricture to indicate surgery. 1) Cosnes J et al IBD 2002; 2) Pallotta N et al IBD 2011

Sa1112

Pre-Operative Diarrhea and Length of Distal/Terminal Ileal Resection Do NotPredict Post-Operative Diarrhea in Crohn's Disease PatientsNadia Pallotta, Giuseppina Vincoli, Laura Candeloro, Rodolfo Calarco, Enrico Corazziari

A partly prospective study(1) on Crohn's disease (CD) reported that incidence (37% ofpatients) of diarrhea increased with the length of ileum removed. However it is not knownwhether diarrhea developed de novo or preceded resection. AIM To prospectively evaluatein CD patients submitted to ileo-colon resection whether 1) the length, site and number ofresection are associated with post-operative diarrhea and 2) the diarrhea is de novo orprecedes surgery. METHODS & PATIENTS. Within a long-term prospective follow-up(FU) study, that includes laboratory and clinical evaluations recorded with a standardizedquestionnaire and performed at regular time intervals independently from symptom recur-rence, and preoperatively, 190 CD patients (112 M, mean age 37 yrs) were investigated.The association between diarrhea at 1 year after surgery and length of ileal resection, illnessbehavior, BMI and the presence of pre-operative diarrhea, was assessed with Student's t-Test and chi-square test. RESULTS. During a 8±2 yrs FU period 59 CD patients (F 31, atdiagnosis age 33.6±14 yrs, B1 4, B2 42, B3 13, L1 31, L3 28) were submitted to ileoterminal-cecal-ascending colon resection for obstruction (32), obstruction and abscess/fistulas(16), abscess (3) fistulas (4) intestinal perforation (4). Of the operated patients 25/59 (42%)developed diarrhea at 1 year FU and of these 14/25 required cholestyramine treatment(length of resected tract 37±12 cm vs 28±12 cm, p=0.07 vs non cholestyramine treatedpatients). The length of ileal resection did not differ between patients who developed diarrhea(D) and those who did not (ND) (35±16 cm, range 10-85 cm, median 30 cm vs 34±19cm, range 10-80 cm, median 25 cm). There was no difference in illness behavior and BMIat surgery and at 1 year FU between the two groups (D patients B1 2, B2, 19; B3 4, BMI22.3±3 (pre-operative) 23±3 (post); ND patients B1 2 B2 23; B3 9, BMI 21.5±3.5 (pre-operative) 23±3 (post), p=0.6). Five patients were previously submitted to ileo-cecal resection(2/5 in D patients and 3/5 ND patients, ns). Diarrhea preceded surgery in 34/59 (58%)patients; of these postoperatively 18/34 (53%) had diarrhea and 16/34 (47%) did not (n.s).Seven (28%) patients developed de novo diarrhea after surgery. CONCLUSIONS. In CDpatients submitted to distal-terminal ileum-right colon resection pre-operative diarrhea is afrequent occurrence independent from illness behavior. Postoperative diarrhea is not relatedto the length of ileal tract removed at least for resection not exceeding 85 cm. Preoperativediarrhea has equal chance to persist or regress after surgery. De novo diarrhea after surgeryoccurs in no more than a third of patients. 1) Cosnes J et al BJS 1994

Sa1113

In Crohn's Disease (CD) Patients Small Bowel Prestenotic Dilatation Is NotRelated to Severity Degree of StrictureNadia Pallotta, Giuseppina Vincoli, Laura Candeloro, Rodolfo Calarco, Enrico Corazziari

Crohn's disease (CD) patients can develop lifetime clinical symptoms of intestinal obstructionwhich require a proper diagnostic work-up. At imaging the definition of stricture is notstandardized, and the presence of pre-stenotic dilatation has been widely considered thehallmark of fibrotic stricture, often requiring surgery (1). Small intestine contrast ultrasonog-raphy (SICUS) has been proven to be as accurate as surgical assessment of small bowel (SB)strictures in CD (2). SICUS can measure the length and, for its distinctive ability anddifferently from TC and RMN to prolong the observation time, the maximal lumen distensibil-ity of the stenotic tract. Aim. To evaluate in CD patients whether: a) site, lumen diameterand/or length of SB stricture are associated to presence and severity degree of pre-stenoticdilatation and b) pre-stenotic dilatation is associated with indication to surgery. Methods &Subjects. Within a long-term prospective follow-up (FU) study 190 patients (M 112, meanage 37yrs) were evaluated. SICUS was performed at regular FU intervals and preoperativelyin patients undergoing surgery after the ingestion of 375 ml of macrogol oral solution. Theassociation between site, lumen diameter and length of strictures and presence and lumendiameter of pre-stenotic dilatation was assessed with Student's t-Test, chi-square test andlinear regression analysis. Results. During the FU 109/190 developed one or more stricturesand 40 underwent surgery for obstruction (30), obstruction and abscess/fistulas (7), fistulas(3). The site of strictures was ileo-cecal valve/anastomosis, terminal, distal and proximalileum in 15, 44, 11 and 11 of non-operated patients (M 44, B1 25, B2 39, B3 5, L1 38,L3 26 L4 5, mean age 40 yrs) and 0,36,9 and 7 in operated patients (M 19, B1 1 B2 32,B3 7, L1 22, L3 18, mean age 33 yrs). The agreement by K-statistics between SICUS andsurgical findings in identifying presence, site of strictures and pre-stenotic dilatation was 1and 0.93, respectively. Prestenotic dilatation was present in 49/81(60%) and 27/52 (52%)strictures in non-operated (NOP) and operated patients (OP), respectively (p=0.4). Thelength and lumen diameter of strictures were 5±5 cm and 6±1 mm in NOP and 6.6±5 cmand 6.6±1.8 mm in OP (n.s), respectively and 5.7±3 cm and 6.2±2 mm and 6±2 cm and5.4±2 mm in OP with and without prestenotic dilatation. There was no significant associationbetween length, lumen diameter, and site, of stricture and both presence and lumen diameterof prestenotic dilatation in OP and in NOP (p=0.7). Conclusions. Site, length, and lumendiameter of small bowel strictures are not statistically associated with prestenotic dilatation.Strictures with prestenotic dilatation are not associated with an increased probability to havea surgical indication. 1) Rieder F et al 2013;2) Pallotta N et al 2011

S-203 AGA Abstracts

Sa1114

The Cost of Medical Management, Surgery and Clinical Investigations in aEuropean Population-Based Inception Cohort From the Biological Era - AnECCO-Epicom StudyJohan Burisch, Natalia Pedersen, Silvija Cukovic-Cavka, John Kaimakliotis, Dana.Duricova, Olga Shonova, Ida Vind, Niels Thorsgaard, Vibeke Andersen, Jens F. Dahlerup,Riina Salupere, Kári R. Nielsen, Pia Manninen, Epameinondas V. Tsianos, KarinLadefoged, Yvonne Bailey, Renata D'Inca, Limas Kupcinskas, Svetlana Turcan, FernandoMagro, Adrian Goldis, Elena Belousova, Vicent Hernandez, Sven Almer, Jonas Halfvarson,Shaji Sebastian, Peter L. Lakatos, Ebbe Langholz, Selwyn H. Odes, Pia Munkholm

Background: Data on the cost of inflammatory bowel disease (IBD) care in population-basedcohorts are available for several Western European countries, but represent the era precedingwidespread use of biological therapy. The aim of this study was to assess the costs ofinvestigations and treatment during the first year following diagnosis in Eastern and WesternEurope. Methods: The EpiCom-cohort is a European prospective population-based cohortof unselected, uniformly diagnosed patients with IBD diagnosed in 2010 in 31 centres from14 Western and 8 Eastern European countries, covering 10 million in background population(1). Patients are followed every 3rd month from diagnosis and clinical data regarding i.e.medical treatment, surgery and investigations entered in a web-based database, www.epicom-ecco.eu. Costs during the first 12 months from diagnosis were calculated in Euro (€) usingthe Danish Health Costs Register representing the mean costs for hospital and out-patientprocedures in Denmark, as well as the prices for medicine in the capital region of Denmark.Results: 1,367 patients were followed-up, 710 with ulcerative colitis (UC), 509 with Crohn'sdisease (CD) and 148 with IBD unclassified (IBDU). Total expenditure for the cohort was€ 5,408,174 (Investigations: € 2,042,990 (38%), surgery: € 1,427,648 (26%), biologicals:€ 781,089 (14%), standard treatment (all other than biologicals): € 1,156,520 (22%)).Expenditures for CD, UC and IBDU in Eastern and Western Europe are shown in Table 1and the distribution of cumulative expenses during the first year of disease in Figure 1.Mean crude expenditure per patient in Western Europe (Eastern Europe) with CD where:investigations € 1,803 (€ 2,160) (p=0.44), surgery € 11,489 (€ 13,973) (p=0.14),standard treatment € 1,027 (€ 824) (p=0.51), biologicals € 7,376 (€ 8,307) (p=0.31).Mean crude expenditure per patient in Western Europe (Eastern Europe) with UC where:investigations € 1,189 (€ 1,518) (p<0.01), surgery €18,414 (€ 12,395) (p=0.18), standardtreatment € 896 (€ 798) (p<0.05), biologicals € 5,681 (€ 72) (p=0.51). Overall cost perIBD patient or the whole cohort was approx. € 4,000 with € 1,500 spent on investigations,€ 1,000 on surgery and standard medication respectively, and € 500 on biological therapy.Conclusion: In this population-based unselected cohort including indolent and severe casescosts during the first year of disease were high and mainly incurred by the large numberof investigative procedures and surgeries with however biological therapy accounting foralready more than 15% of costs. Long-term follow-up of the cohort is needed to assess thecost effectiveness of biological agents. References: 1. Burisch J, et al. East-West gradient inthe incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort.Gut 2013:in press.Table 1. Total cost (Euros) for resources used in the first year of follow-up of 1,367 patientswith inflammatory bowel disease

CD, Crohn's disease; UC, ulcerative colitis; IBDU, Inflammatory bowel disease unclassified

Figure 1. Distribution of cumulative expenses for (A) Crohn's disease and (B) ulcerativecolitis patients during the first year from diagnosis in a European inception cohort

Sa1115

Natural History of Non-Severe Inflammatory Bowel Diseases At DiagnosisCyrielle Pirard, Edouard Louis, Reenaers Catherine

INTRODUCTION: Crohn's disease (CD) and ulcerative colitis (UC) are progressive diseasescharacterized by the occurrence of complications requiring immunomodulators and surgery.Few data are available for the prevalence and the factors associated with long-term non-severe (NS) inflammatory bowel diseases. AIMS&METHODS: Our aim was to assess thenatural history of NS CD and NC UC at diagnosis and to identify predictive factors of mildevolution over the long term. A retrospective study of the IBD patients registred in thedatabase of the university hospital of Liège, Belgium. NS CD was defined as the absence of

AG

AA

bst

ract

s