Singh, Siddharth

We performed a systematic review with network meta‐analysis (NMA) to compare the efficacy of different approaches in primary prevention of esophageal variceal bleeding and overall survival in patients with cirrhosis with large varices. Thirty‐two randomized clinical trials (RCTs) with 3,362 adults with cirrhosis with large esophageal varices and no prior history of bleeding, with a minimum of 12 months of follow‐up, were included. Nonselective beta‐blockers (NSBB), isosorbide‐mononitrate (ISMN), carvedilol, and variceal band ligation (VBL), alone or in combination, were compared with each other or placebo. Primary outcomes were reduction of all‐cause mortality and prevention of esophageal variceal bleeding. Random‐effects NMA was performed and summary estimates were expressed as odds ratio and 95% confidence intervals (OR; CI). Quality of evidence was critically appraised using the Grading of Recommendations, Assessment, Development and Evaluation approach. Moderate quality evidence supports NSBB monotherapy (0.70; 0.49‐1.00) or in combination with VBL (0.49; 0.23‐1.02) or ISMN (0.44; 0.21‐0.93) for decreasing mortality in patients with cirrhosis with large esophageal varices and no prior history of bleeding. Moderate‐quality evidence supports carvedilol (0.21; 0.08‐0.56) and VBL monotherapy (0.33; 0.19‐0.55) or in combination with NSBB (0.34; 0.14‐0.86), and low‐quality evidence supports NSBB monotherapy (0.64; 0.38‐1.07) for primary prevention of variceal bleeding. VBL carries a higher risk of serious adverse events compared with NSBB.Conclusion:NSBB monotherapy may decrease all‐cause mortality and the risk of first variceal bleeding in patients with cirrhosis with large esophageal varices. Additionally, NSBB carries a lower risk of serious complications compared with VBL. Therefore, NSBB may be the preferred initial approach for primary prophylaxis of esophageal variceal bleeding.

SummaryBackgroundThere are limited data to inform positioning of agents for treating moderate‐severe Crohn's disease (CD).AimWe assessed comparative efficacy and safety of first‐line (biologic‐naïve) and second‐line (prior exposure to anti‐tumour necrosis factor [TNF]‐α) agents) biologic therapy for moderate‐severe CD, through a systematic review and network meta‐analysis, and appraised quality of evidence (QoE) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.MethodsWe identified randomised controlled trials (RCTs) in adults with moderate‐severe CD treated with approved anti‐TNF agents, anti‐integrin agents and anti‐IL12/23 agents, first‐line or second‐line, and compared with placebo or another active agent. Efficacy outcomes were induction and maintenance of clinical remission; 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.ResultsNo head‐to‐head trials were identified. In biologic‐naïve patients, infliximab (SUCRA,0.93) and adalimumab (SUCRA,0.75) were ranked highest for induction of clinical remission (moderate QoE). In patients with prior anti‐TNF exposure, adalimumab (SUCRA, 0.91; low QoE, in patients with prior response or intolerance to anti‐TNF agents) and ustekinumab (SUCRA, 0.71) were ranked highest for induction of clinical remission. In patients with response to induction therapy, adalimumab (SUCRA, 0.97) and infliximab (SUCRA, 0.68) were ranked highest for maintenance of remission. Ustekinumab had lowest risk of serious adverse events (SUCRA, 0.72) and infection (SUCRA, 0.71; along with infliximab, SUCRA, 0.83) in maintenance trials.ConclusionIndirect comparisons suggest that infliximab or adalimumab may be preferred first‐line agents, and ustekinumab a preferred second‐line agent, for induction of remission in patients with moderate‐severe CD. Head‐to‐head trials are warranted.

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.