Citations

Abstract Background We quantified loss of response (LOR) to vedolizumab (VDZ) in clinical practice and assessed the effectiveness of VDZ dose intensification for managing LOR. Methods Retrospective review (May 2014–December 2016) of a prospectively maintained inflammatory bowel disease (IBD) registry. Kaplan-Meier estimates were used to determine rates of LOR to VDZ . Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. Success of recapturing response (>50% reduction in symptoms from baseline) and remission (complete resolution of symptoms) after dose intensification was quantified. Results Cumulative rates for VDZ LOR were 20% at 6 months and 35% at 12 months, with slightly lower rates in Crohn’s disease than in ulcerative colitis (6 months 15% vs 18% and 12 months 30% vs 39%, P = 0.03). On multivariable analysis, LOR to a tumor necrosis factor (TNF) antagonist before VDZ use was associated with an increased risk for LOR to VDZ [hazard ratio (HR) 1.93; 95% confidence interval (CI) 1.25–2.97] in all patients. For Crohn’s disease patients specifically, higher baseline C-reactive protein concentration was associated with increased risk for LOR to VDZ (HR 1.01 per mg/dL increase, 95% CI 1.01–1.02). Shortening of VDZ infusion interval from 8 to every 4 or 6 weeks recaptured response in 49% and remission in 18% of patients. Conclusions LOR to a TNF antagonist before VDZ use and higher baseline C-reactive protein are important predictors of VDZ LOR. Treatment response can be recaptured in almost half of these patients with VDZ infusion interval shortening.

SummaryBackgroundThere are conflicting data on comparative effectiveness of adalimumab and infliximab in patients with Crohn's disease (CD).AimsTo compare the effectiveness and safety of adalimumab and infliximab in biologic‐naïve patients with CD, in a nationwide register‐based propensity score‐matched cohort study in Denmark.MethodsA total of 2908 Danish adults with CD had been treated with adalimumab or infliximab as their first biologic agent between 2005‐2014. By Cox regression, we compared rates of all‐cause hospitalisation, CD‐related hospitalisation, major abdominal surgery and serious infections after variable 2:1 propensity score matching, accounting for baseline disease characteristics, healthcare utilisation and use of CD‐related medications.ResultsAfter propensity‐score matching, we included 315 adalimumab‐ (34.9 ± 12.9 years, 41.9% males) and 512 infliximab‐treated (33.6 ± 12.6 years, 40.8% males) patients, with median disease duration 4.0 years; 36.9% had prior abdominal surgery. Over a median follow‐up 2.3 years after starting biological therapy, there were no significant differences in rate of CD‐related hospitalisation (hazard ratio [HR], 0.81 [95% CI, 0.55‐1.20]) or major abdominal surgery (HR, 1.24 [0.66‐2.33]) between adalimumab‐ and infliximab‐treated patients, though rate of all‐cause hospitalisation was lower in adalimumab‐treated patients (HR, 0.74 [0.56‐0.97]). There was no significant difference in incidence of serious infections requiring hospitalisation (HR, 1.06 [0.26‐4.21]). These results were stable in patients treated with biological monotherapy (all‐cause hospitalisation: HR, 0.75 [0.53‐1.05]; CD‐related hospitalisation: HR, 0.82 [0.51‐1.32], abdominal surgery: HR, 1.47 [0.63‐3.47]) or in combination with immunomodulators (all‐cause hospitalisation: HR, 0.70 [0.44‐1.11]; CD‐related hospitalisation: HR, 0.80 [0.42‐1.52], abdominal surgery: HR, 1.02 [0.39‐2.64]).ConclusionsIn this population‐based, propensity score matched, real‐life cohort study using administrative claims, there was no significant difference in effectiveness and safety of adalimumab and infliximab in biologic‐naïve patients with CD.

SummaryBackgroundThere are limited data to inform positioning of agents for treating moderate‐severe ulcerative colitis (UC).AimTo assess comparative efficacy and safety of different therapies as first‐line (biologic‐naïve) and second‐line (prior exposure to anti‐tumour necrosis factor(TNF)‐α) agents for moderate‐severe UC, through a systematic review and network meta‐analysis, and appraise quality of evidence (QoE) using grading of recommendations, assessment, development and evaluation (GRADE) approach.MethodsWe identified randomised controlled trials (RCTs) in adults with moderate‐severe UC treated with anti‐TNF agents, anti‐integrin agents and janus kinase (JAK) inhibitors, as first‐line or second‐line agents, and compared with placebo or another active agent. Efficacy outcomes were induction/maintenance of remission and mucosal healing; and safety outcomes were serious adverse events and infections. Network meta‐analyses were performed, and ranking was assessed using surface under the cumulative ranking (SUCRA) probabilities.ResultsIn biologic‐naïve patients (12 trials, no head‐to‐head comparisons), infliximab and vedolizumab were ranked highest for induction of clinical remission (infliximab: odds ratio [OR], 4.10 [95% confidence intervals [CI], 2.58‐6.52]; SUCRA,0.85; vedolizumab:SUCRA,0.82) and mucosal healing (infliximab:SUCRA,0.91; vedolizumab:SUCRA,0.81) (moderate QoE). In patients with prior anti‐TNF exposure (4 trials, no head‐to‐head comparisons), tofacitinib was ranked highest for induction of clinical remission (OR, 11.88 [2.32‐60.89]; SUCRA, 0.96) and mucosal healing (moderate QoE). Differences in trial design limited comparability of trials of maintenance therapy for efficacy. Vedolizumab was ranked safest in terms of serious adverse events (SUCRA, 0.91), and infection (SUCRA, 0.75) in maintenance trials.ConclusionsInfliximab and vedolizumab are ranked highest as first‐line agents, and tofacitinib is ranked highest as second‐line agent, for induction of remission and mucosal healing in patients with moderate‐severe UC, based on indirect comparisons. Head‐to‐head trials are warranted to inform clinical decision‐making with greater confidence.

Abstract Background Efforts towards antibiotic stewardship help reduce risk of Clostridium difficile infection (CDI) but there is a need to delineate antibiotic choices to reduce CDI risk. Tetracyclines may be associated with a low risk for CDI but the evidence is conflicting. We conducted a systematic review and meta-analysis to determine the relationship between tetracyclines use and CDI. Methods A systematic search of Medline, Embase, and Web of Science was performed from January 1978 up to December 2016 including studies assessing the association between tetracyclines and CDI; compared with other antibiotics; to assess the risk of CDI after exposure to tetracyclines vs. other antibiotics. Study quality was assessed using the Newcastle-Ottawa scale. Weighted summary estimates were calculated using generalized inverse variance with random-effects model using Review Manager version 5.3 (Cochran Inc). Results Six studies; 4 case control and 2 cohort studies reported the association of CDI with tetracyclines or other antibiotics prior to CDI including patients from 1993 to 2012. Meta-analysis of all studies using the random-effects model demonstrated that tetracyclines were associated with decreased risk of CDI compared with other antibiotics (OR, 0.62; 95% CI, 0.47–0.81; P = .0005). There was significant heterogeneity among the studies, with an I2 of 53% (Figure 1). No publication bias was seen. Subgroup analysis of studies evaluating the risk of CDI with doxycycline only also demonstrated a decreased risk of CDI with doxycycline compared with other antibiotics (OR, 0.55; 95% CI, 0.40–0.75; P = 0.0002). A subgroup analysis based on CDI diagnosis definitions revealed a decreased risk of CDI with tetracyclines (OR, 0.59; 95% CI, 0.44–0.80; P = 0. 0006) in studies that used clinical definitions (presence of diarrhea with a positive stool test), but not among the studies that used ICD-9 codes for CDI diagnosis (OR, 0.95; 95% CI, 0.45–2.01; P = 0.90). Conclusion Tetracyclines are associated with a lower risk of developing CDI compared with other antibiotics. It is reasonable to use these over other antibiotics when appropriate (community acquired pneumonia, bronchitis, chlamydia, rickettsial or spirochetal infections) to reduce the risk of CDI. Forest plot demonstrating decreased odds of CDI with tetracyclines use by a random-effects model Disclosures All authors: No reported disclosures.

522 Background: Metformin inhibits mTOR and downstream pathways involved in cell proliferation and survival by inducing AMPK activation. Although its use has been associated with decreased risk of colorectal cancer (CRC), the effect of metformin on cancer related mortality is unclear. We performed a meta-analysis of published observational studies evaluating metformin use in patients with CRC and its association with overall and CRC-specific survival. Methods: Through a systematic search of PubMed and conference presentations (cut-off: August 2013), we identified 8 observational studies (18,537 total patients with CRC; 6242 CRC patients with DM) reporting the association between metformin use and survival after diagnosis of CRC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated using the random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: On meta-analysis, metformin use was associated with a 34% reduction in mortality in CRC patients as compared to non-use (adjusted HR, 0.66; 95% CI, 0.54-0.81), albeit with high heterogeneity (I2=66.9%). After exclusion of one study, which contributed to considerable heterogeneity, a 28% reduction in mortality was considered a more conservative, consistent effect estimate (adjusted HR, 0.72; 95% CI, 0.64-0.81), with minimal heterogeneity (I2=16.2%). On restricting analysis only to patients with DM, use of metformin (vs non-use) was associated with decreased all-cause mortality (6 studies; adjusted HR, 0.63; 95% CI, 0.49-0.81) and CRC-specific mortality (3 studies; adjusted HR, 0.66; 95% CI, 0.50-0.87). Conclusions: Based on meta-analysis of observational studies, the use of metformin in diabetic patients with CRC appears to be associated with reduced all-cause mortality and CRC-specific mortality. Further prospective investigation of metformin’s effect on outcome in CRC patients is warranted.

11 Background: Acid-suppressive medications, particularly proton pump inhibitors (PPI), may modify risk of esophageal adenocarcinoma (EAC) in patients with Barrett’s esophagus (BE). We performed a systematic review and meta-analysis of studies evaluating the association between PPIs and histamine receptor antagonists (H2RA) and risk of EAC or high-grade dysplasia (BE-HGD) in patients with BE. Methods: Through a systematic search up to June 2013, we identified 7 observational studies (5 cohort studies and 2 case-control studies; 2,813 patients with BE, 317 cases of EAC and/or BE-HGD, 84.4% PPI users) reporting the association between PPIs or H2RA and EAC in patients with BE. Summary odds ratio (OR) with 95% confidence intervals (CI) was estimated using random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: On meta-analysis, PPI use was associated with 71% reduction in EAC risk in patients with BE (adjusted OR, 0.29; 95% CI, 0.12-0.71). There was a trend toward a dose-response relationship with PPI use for >2 years protective against EAC [3 studies; PPI use >2 years vs. <2 years (as compared to no use): OR, 0.45 (0.19-1.06) vs. 1.09 (0.47-2.56)]. Considerable heterogeneity was observed in the overall analysis (I2=81%). On restricting analysis to 5 cohort studies, use of PPIs was consistently associated with a lower risk of EAC and/or BE-HGD (adjusted OR, 0.33; 95% CI, 0.19-0.58; I2=9%). H2RA use was not associated with decreased risk of EAC in patients with BE based on 2 studies (adjusted OR, 1.15; 95% CI, 0.77-1.72). Using a 67% summary risk reduction (derived from cohort studies) of EAC and/or BE-HGD with PPI use in patients with BE, and observed cumulative incidence rates of EAC and/or BE-HGD in patients with BE overall as 10.2 per 1,000 patient years, we estimate the number needed to treat with PPIs to prevent 1 case of EAC or BE-HGD in BE patients at 147. Conclusions: Based on meta-analysis of observational studies, the use of PPI, but not H2RA appears to be associated with a decreased risk of EAC and/or BE-HGD in patients with BE. PPI use should be considered in BE, and chemopreventive trials of PPIs in patients with BE are warranted.

686 Background: Preclinical evidence suggests that statins have anti-neoplastic properties by inhibiting cell proliferation, and inducing apoptosis. Statins may be associated with reduced risk of colorectal cancer (CRC), but their effect on CRC related mortality is unclear. We performed a meta-analysis of published observational studies evaluating statin use in patients with CRC and its association with overall and CRC-specific mortality. Methods: Through a systematic search upto August 2014, we identified 7 observational studies (64,773 patients with CRC;19.5% statin users) reporting the association between statin use and mortality in patients with CRC. Summary hazard ratio (HR) with 95% confidence intervals (CI) was estimated using the random effects model, and heterogeneity was measured using the inconsistency index (I2). Results: On meta-analysis, statin use was associated with a 26% reduction in all-cause mortality in CRC patients as compared to non-use (6 studies; adjusted HR, 0.74; 95% CI, 0.67-0.83) with minimal heterogeneity (I2=18%), after adjusting for age, sex and CRC stage. Only one study adjusted for concomitant metformin use. Five studies evaluated CRC-specific mortality; on meta-analysis, use of statins (vs non-use) was also associated with decreased CRC-specific mortality (adjusted HR, 0.74; 95% CI, 0.70-0.83; minimal heterogeneity, I2=17%). On limiting analysis to statin use after diagnosis of CRC, use of statins remained significantly associated with reduced CRC-specific mortality (3 studies; adjusted HR, 0.70; 95% CI, 0.60-0.81), but not overall mortality (4 studies; adjusted HR, 0.82; 95% CI, 0.64-1.05). On restricting analysis to studies, which adjusted for concomitant use of aspirin/NSAID, the inverse association between statin use and overall- (5 studies; adjusted HR, 0.74; 95% CI, 0.66-0.84) and CRC-specific mortality (4 studies; adjusted HR, 0.76; 95% CI, 0.69-0.84) remained significant. Conclusions: Based on this meta-analysis, statin use in patients with CRC may be associated with reduced all-cause and CRC-specific mortality. This observation merits prospective investigation of statins’ effect on outcome in CRC patients.

Liver fibrosis is the most important predictor of mortality in nonalcoholic fatty liver disease (NAFLD). Quantitative risk of mortality by fibrosis stage has not been systematically evaluated. We aimed to quantify the fibrosis stage–specific risk of all‐cause and liver‐related mortality in NAFLD. Through a systematic review and meta‐analysis, we identified five adult NAFLD cohort studies reporting fibrosis stage–specific mortality (0‐4). Using fibrosis stage 0 as a reference population, fibrosis stage–specific mortality rate ratios (MRRs) with 95% confidence intervals (CIs) for all‐cause and liver‐related mortality were estimated. The study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses statement. Included were 1,495 NAFLD patients with 17,452 patient years of follow‐up. Compared to NAFLD patients with no fibrosis (stage 0), NAFLD patients with fibrosis were at an increased risk for all‐cause mortality, and this risk increased with increases in the stage of fibrosis: stage 1, MRR = 1.58 (95% CI 1.19‐2.11); stage 2, MRR = 2.52 (95% CI 1.85‐3.42); stage 3, MRR = 3.48 (95% CI 2.51‐4.83); and stage 4, MRR = 6.40 (95% CI 4.11‐9.95). The results were more pronounced as the risk of liver‐related mortality increased exponentially with each increase in the stage of fibrosis: stage 1, MRR = 1.41 (95% CI 0.17‐11.95); stage 2, MRR = 9.57 (95% CI 1.67‐54.93); stage 3, MRR = 16.69 (95% CI 2.92‐95.36); and stage 4, MRR = 42.30 (95% CI 3.51‐510.34). Limitations of the study include an inability to adjust for comorbid conditions or demographics known to impact fibrosis progression in NAFLD and the inclusion of patients with simple steatosis and nonalcoholic steatohepatitis without fibrosis in the reference comparison group. Conclusion: The risk of liver‐related mortality increases exponentially with increase in fibrosis stage; these data have important implications in assessing the utility of each stage and benefits of regression of fibrosis from one stage to another. (H epatology 2017;65:1557‐1565).