Christopher Ma

Postoperative Complications and Mortality Following Colectomy for Ulcerative Colitis

BACKGROUND & AIMS Complications after colectomy for ulcerative colitis (UC) have not been well characterized in large, population-based studies. We characterized postoperative in-hospital complications, stratified them by severity, and assessed independent clinical predictors, including use of immunosuppressants. METHODS We performed population-based surveillance using administrative databases to identify all adults (≥18 y) who had an International Classification of Diseases-9th/10th revisions code for UC and a colectomy from 1996 to 2009. All medical charts were reviewed. The primary outcome was severe postoperative complications, including in-hospital mortality. Logistic regression was used to assess predictors of complications after colectomy and then restricted to patients undergoing emergent or elective surgeries. RESULTS Of the 666 UC patients who underwent a colectomy, a postoperative complication occurred in 27.0% and the mortality rate was 1.5%. Independent predictors of postoperative complications were age (for patients >64 vs 18-34 y: odds ratio [OR], 1.95; 95% confidence interval [CI], 1.07-3.54), comorbidities (>2 vs none: OR, 1.89; 95% CI, 1.06-3.37), and admission status (emergent vs elective colectomy: OR, 1.62; 95% CI, 1.14-2.30). Significant risk factors for an emergent colectomy included time from admission to colectomy (>14 vs 3-14 d: OR, 3.32; 95% CI, 1.62-6.80) and a preoperative complication (≥1 vs 0: OR, 3.04; 95% CI, 1.33-6.91). A prescription of immunosuppressants before colectomies did not increase the risk for postoperative complications. CONCLUSIONS Postoperative complications frequently occur after colectomy for UC, predominantly among elderly patients with multiple comorbidities. Patients who were admitted to the hospital under emergency conditions and did not respond to medical treatment had worse outcomes when surgery was performed 14 or more days after admission.

Systematic review: the short‐term and long‐term efficacy of adalimumab following discontinuation of infliximab

Background  Therapy with adalimumab has been shown to be effective in Crohn’s disease (CD) patients who have lost response or are intolerant to infliximab.

Postoperative complications following colectomy for ulcerative colitis: A validation study

BackgroundUlcerative colitis (UC) patients failing medical management require colectomy. This study compares risk estimates for predictors of postoperative complication derived from administrative data against that of chart review and evaluates the accuracy of administrative coding for this population.MethodsHospital administrative databases were used to identify adults with UC undergoing colectomy from 1996–2007. Medical charts were reviewed and regression analyses comparing chart versus administrative data were performed to assess the effect of age, emergent operation, and Charlson comorbidities on the occurrence of postoperative complications. Sensitivity, specificity, and positive/negative predictive values of administrative coding for identifying the study population, Charlson comorbidities, and postoperative complications were assessed.ResultsCompared to chart review, administrative data estimated a higher magnitude of effect for emergent admission (OR 2.52 [95% CI: 1.80–3.52] versus 1.49 [1.06–2.09]) and Charlson comorbidities (OR 2.91 [1.86–4.56] versus 1.50 [1.05–2.15]) as predictors of postoperative complications. Administrative data correctly identified UC and colectomy in 85.9% of cases. The administrative database was 37% sensitive in identifying patients with ≥ 1Charlson comorbidity. Restricting analysis to active comorbidities increased the sensitivity to 63%. The sensitivity of identifying patients with at least one postoperative complication was 68%; restricting analysis to more severe complications improved the sensitivity to 84%.ConclusionsAdministrative data identified the same risk factors for postoperative complications as chart review, but overestimated the magnitude of risk. This discrepancy may be explained by coding inaccuracies that selectively identifying the most serious complications and comorbidities.

Clinical, endoscopic and radiographic outcomes with ustekinumab in medically‐refractory Crohn's disease: real world experience from a multicentre cohort

Ustekinumab is a monoclonal antibody targeting interleukins‐12 and ‐23, with efficacy in Crohns disease (CD) demonstrated in clinical trials.

Inflammatory bowel disease patients who leave hospital against medical advice: predictors and temporal trends.

Background: Leaving hospital against medical advice (AMA) may have consequences with respect to health‐related outcomes; however, inflammatory bowel disease (IBD) patients have been inadequately studied. Thus, we determined the prevalence of self‐discharge, assessed predictors of AMA status, and evaluated time trends. Methods: We analyzed the 1995–2005 Nationwide Inpatient Sample (NIS) to identify 93,678 discharges with a primary diagnosis of IBD admitted to the hospital emergently and did not undergo surgery. We described the proportion of IBD patients who left AMA. Predictors of AMA status were evaluated using a multivariate logistic regression model and temporal trend analyses were performed with Poisson regression models. Results: Between 1995 and 2005, 1.31% of IBD patients left hospitals AMA. Crohns disease (CD) patients were more likely to leave AMA (adjusted odds ratio [aOR], 1.53; 95% confidence intervals [CI]: 1.30–1.79). Characteristics associated with leaving AMA included: ages 18–34 (aOR, 7.77, 95% CI: 4.34–13.89); male (aOR, 1.75; 95% CI: 1.55–1.99); Medicaid (aOR, 4.55; 95% CI: 3.81–5.43) compared to private insurance; African Americans (aOR, 1.34; 95% CI: 1.09–1.64) compared to white; substance abuse (aOR, 2.75; 95% CI: 2.14–3.54); and psychosis (aOR, 1.55; 95% CI: 1.13–2.14). The incidence rates of self‐discharge for CD patients were stable (P > 0.05) between 1995 and 1999, while they significantly (P < 0.0001) increased after 1999. In contrast, AMA rates for UC patients remained stable during the study period. Conclusions: Approximately 1 in 76 IBD patients admitted emergently for medical management leave the hospital AMA. These were primarily disenfranchised patients who may lack adequate outpatient follow‐up.

Long-term Maintenance of Clinical, Endoscopic, and Radiographic Response to Ustekinumab in Moderate-to-Severe Crohn's Disease: Real-world Experience from a Multicenter Cohort Study

Background: Ustekinumab is a monoclonal antibody targeting interleukins 12 and 23. While effective in clinical trials for Crohns disease (CD), long-term maintenance of response in the real-world setting is unclear. We aim to assess the efficacy of ustekinumab for maintaining clinical, endoscopic, and radiographic response in CD. Methods: A retrospective multicenter cohort study was performed on patients with CD achieving steroid-free clinical response to ustekinumab induction, and advanced onto a regularly scheduled maintenance ustekinumab regimen between 2011 and 2016. The primary outcome was loss of response, defined by an increase in Harvey Bradshaw Index of >3 points from baseline requiring ustekinumab dose escalation, reinduction, rescue corticosteroids, immunomodulators, surgery, or ustekinumab discontinuation. Multivariate Cox proportional hazards regression was used to identify clinical factors associated with loss of response. Results: One hundred four patients with CD achieving steroid-free response with ustekinumab induction were included; 92.3% (96/104) had previously failed antitumor necrosis factor therapy. Median follow-up was 57.2 weeks (interquartile range (IQR): 36.7–103.4). Cumulative probability of maintained response at 52 weeks was 71.8%. Sixty-seven patients (64.4%) maintained endoscopic or radiographic response. Thirty-five patients (33.7%) lost response at a median time of 47.4 weeks (IQR: 35.3–68.4). Dose escalation was required in 17 patients (16.3%); response was recaptured in 9/17 (52.9%). Nine patients (8.7%) required surgery. In Cox multivariate regression, concurrent immunomodulation was associated with reduced risk of loss of response (hazards ratio 0.39 (95% CI, 0.17–0.92)). Conclusions: Subcutaneous ustekinumab is an effective treatment option for maintaining long-term clinical, endoscopic, and radiographic response in patients with moderate-to-severe CD failing antitumor necrosis factor therapy.

Heterogeneity in Definitions of Endpoints for Clinical Trials of Ulcerative Colitis: A Systematic Review for Development of a Core Outcome Set

Background & Aims: Advances in development of therapeutic agents for ulcerative colitis (UC) have been paralleled by innovations in trial design. It would be useful to identify a core outcome set, to standardize outcome definitions for efficacy and safety in clinical trials. We performed a systematic review of efficacy and safety outcomes reported in placebo‐controlled randomized controlled trials of patients with UC. Methods: We searched MEDLINE, EMBASE, and the Cochrane Library from inception through March 1, 2017, for placebo‐controlled randomized controlled trials of adult patients with UC treated with aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules. We collected information on efficacy and safety outcomes, definitions, and measurement tools, stratified by decade of publication. Results: We analyzed data from 83 randomized controlled trials (68 induction and 15 maintenance) comprising 17,737 patients. Clinical or composite‐clinical efficacy outcomes were reported in all trials; the UC Disease Activity Index and Mayo Clinic Score were frequently used to determine clinical response or remission. We found substantial variation in definitions of clinical or composite‐clinical endpoints, with more than 50 definitions of response or remission. Endoscopic factors, histologic features, and fecal or serum biomarkers were used to determine outcomes in 83.1% (69 of 83), 24.1% (20 of 83), and 24.1% (20 of 83) of trials, respectively. A greater proportion of trials published after 2007 reported objective outcomes (96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized definitions of histologic or biomarker endpoints were found. Patient‐reported efficacy and quality‐of‐life outcomes were described in 25 trials (30.1%) and safety outcomes were reported in 77 trials (92.8%). Conclusion: In a systematic review, we found that despite recent advances in clinical trials methods, there is a great deal of variation in definitions of endpoints, including response and remission, in randomized controlled trials of patients with UC. Researchers should identify a core set of outcomes to standardize efficacy and safety reporting in UC clinical trials.Advances in drug development for ulcerative colitis (UC) have been paralleled by innovations in trial design. Development of a core outcome set (COS) to standardize outcome definitions and reporting in clinical trials is desirable. We aim to systematically review the efficacy and safety outcomes reported in UC placebo-controlled RCTs. We searched MEDLINE, EMBASE, and the Cochrane Library from inception through March 1, 2017 for placebo-controlled RCTs in adult patients with UC treated with aminosalicylates, immunosuppressants, corticosteroids, biologics, and oral small molecules. Efficacy and safety outcomes, definitions, and measurement tools were extracted and stratified by decade of publication. Eighty-three RCTs (68 induction, 15 maintenance) were included, enrolling 17,737 patients. Clinical or composite-clinical efficacy outcomes were reported in all trials; the Ulcerative Colitis Disease Activity Index (UCDAI) and the Mayo Clinic Score (MCS) were commonly used tools for assessing clinical response/remission. Remarkably, substantial variability in the definition of clinical or composite-clinical endpoints was observed with over 50 definitions of response or remission utilized. Endoscopic, histologic, and fecal/serum biomarker outcomes were reported in 83.1% (69/83), 24.1% (20/83), and 24.1% (20/83) of RCTs, respectively. A greater proportion of trials published after 2007 reported objective outcomes (96.5% endoscopic, 26.3% histologic, and 36.8% biomarker outcomes), but no standardized definitions of histologic or biomarker endpoints exists. Patient-reported efficacy and quality of life outcomes were described in 25 RCTs (30.1%) and safety outcomes were reported in 77 RCTs (92.8%). Despite recent advances in clinical trials methodology, important heterogeneity in reporting and variability in endpoint definitions still remains. A need exists to develop and validate a COS for UC clinical trials

Development of a core outcome set for clinical trials in inflammatory bowel disease: study protocol for a systematic review of the literature and identification of a core outcome set using a Delphi survey

Introduction Crohn’s disease (CD) and ulcerative colitis (UC), the main forms of inflammatory bowel disease (IBD), are chronic, progressive and disabling disorders of the gastrointestinal tract. Although data from randomised controlled trials (RCTs) provide the foundation of evidence that validates medical therapy for IBD, considerable heterogeneity exists in the measured outcomes used in these studies. Furthermore, in recent years, there has been a paradigm shift in IBD treatment targets, moving from symptom-based scoring to improvement or normalisation of objective measures of inflammation such as endoscopic appearance, inflammatory biomarkers and histological and radiographic end points. The abundance of new treatment options and evolving end points poses opportunities and challenges for all stakeholders involved in drug development. Accordingly, there exists a need to harmonise measures used in clinical trials through the development of a core outcome set (COS). Methods and analysis The development of an IBD-specific COS includes four steps. First, a systematic literature review is performed to identify outcomes previously used in IBD RCTs. Second, semistructured qualitative interviews are conducted with key stakeholders, including patients, clinicians, researchers, pharmaceutical industry representatives, healthcare payers and regulators to identify additional outcomes of importance. Using the outcomes generated from literature review and stakeholder interviews, an international two-round Delphi survey is conducted to prioritise outcomes for inclusion in the COS. Finally, a consensus meeting is held to ratify the COS and disseminate findings for application in future IBD trials. Ethics and dissemination Given that over 30 novel therapeutic compounds are in development for IBD treatment, the design of robust clinical trials measuring relevant and standardised outcomes is crucial. Standardising outcomes through a COS will reduce heterogeneity in trial reporting, facilitate valid comparisons of new therapies and improve clinical trial quality.

Surgical Rates for Crohn’s Disease are Decreasing: A Population-Based Time Trend Analysis and Validation Study

Objectives:Temporal changes for intestinal resections for Crohn’s disease (CD) are controversial. We validated administrative database codes for CD diagnosis and surgery in hospitalized patients and then evaluated temporal trends in CD surgical resection rates.Methods:First, we validated International Classification of Disease (ICD)-10-CM coding for CD diagnosis in hospitalized patients and Canadian Classification of Health Intervention coding for surgical resections. Second, we used these validated codes to conduct population-based surveillance between fiscal years 2002 and 2010 to identify adult CD patients undergoing intestinal resection (n=981). Annual surgical rate was calculated by dividing incident surgeries by estimated CD prevalence. Time trend analysis was performed and annual percent change (APC) with 95% confidence intervals (CI) in surgical resection rates were calculated using a generalized linear model assuming a Poisson distribution.Results:In the validation cohort, 101/104 (97.1%) patients undergoing surgery and 191/200 (95.5%) patients admitted without surgery were confirmed to have CD on chart review. Among the 116 administrative database codes for surgical resection, 97.4% were confirmed intestinal resections on chart review. From 2002 to 2010, the overall CD surgical resection rate was 3.8 resections per 100 person-years. During the study period, rate of surgery decreased by 3.5% per year (95% CI: −1.1%, −5.8%), driven by decreasing emergent operations (−10.1% per year (95% CI: −13.4%, −6.7%)) whereas elective surgeries increased by 3.7% per year (95% CI: 0.1%, 7.3%).Conclusions:Overall surgical resection rates in CD are decreasing, but a paradigm shift has occurred whereby elective operations are now more commonly performed than emergent surgeries.

Inflammatory bowel disease patients are frequently nonadherent to scheduled induction and maintenance infliximab therapy: A Canadian cohort study.

BACKGROUND Adherence to maintenance medication regimens in inflammatory bowel disease patients has traditionally been poor. Although infliximab has demonstrated efficacy in inducing and maintaining disease remission, adherence to regularly scheduled infliximab infusions is required to maintain therapeutic trough drug levels and prevent the development of anti-infliximab antibodies. OBJECTIVES To characterize patient adherence to regularly scheduled induction and maintenance infliximab infusions. METHODS A retrospective cohort study was conducted evaluating adult outpatients with Crohn disease or ulcerative colitis on an induction or maintenance regimen of regularly scheduled infliximab from 2008 to 2010 at the University of Alberta (Edmonton, Alberta). Nonadherence was defined by a discrepancy of >72 h between the scheduled date of infusion and the actual date of administration. Patients were defined as nonadherent if they received <80% of their infliximab infusions per schedule. RESULTS A total of 215 patients (173 Crohn disease, 42 ulcerative colitis) met the inclusion criteria. Patients received a median of 12.0 infliximab infusions (interquartile range 7.0 to 13.0) during the study period; 412 induction and 1837 maintenance infliximab infusions were administered. Of 140 patients, 109 (77.9%) were adherent to their infliximab induction regimen, while 68 of 215 (31.6%) were adherent to their infliximab maintenance regimen. One hundred ninety-eight of 215 (92.1%) patients received at least one delayed maintenance infliximab infusion and 20 (10.1%) received maintenance infusions, on average, >1 week late. CONCLUSIONS While three-quarters of patients are adherent to infliximab induction therapy, fewer than one-third remained adherent to their scheduled maintenance infliximab regimen.