David Faleck

Proton Pump Inhibitors Do Not Increase Risk for Clostridium difficile Infection in the Intensive Care Unit.

Objectives:Patients in the intensive care unit (ICU) frequently receive proton pump inhibitors (PPIs) and have high rates of Clostridium difficile infection (CDI). PPIs have been associated with CDI in hospitalized patients, but ICU patients differ fundamentally from non-ICU patients and few studies have focused on PPI use exclusively in the critical care setting. We performed a retrospective cohort study to determine the associations between PPIs and health-care facility-onset CDI in the ICU.Methods:We analyzed data from all adult ICU patients at three affiliated hospitals (14 ICUs) between 2010 and 2013. Patients were excluded if they had recent CDI or an ICU stay of <3 days. We parsed electronic medical records for ICU exposures, focusing on PPIs and other potentially modifiable exposures that occurred during ICU stays. Health-care facility-onset CDI in the ICU was defined as a newly positive PCR for the C. difficile toxin B gene from an unformed stool, with subsequent receipt of anti-CDI therapy. We analyzed PPIs and other exposures as time-varying covariates and used Cox proportional hazards models to adjust for demographics, comorbidities, and other clinical factors.Results:Of 18,134 patients who met the criteria for inclusion, 271 (1.5%) developed health-care facility-onset CDI in the ICU. Receipt of antibiotics was the strongest risk factor for CDI (adjusted HR (aHR) 2.79; 95% confidence interval (CI), 1.50–5.19). There was no significant increase in risk for CDI associated with PPIs in those who did not receive antibiotics (aHR 1.56; 95% CI, 0.72–3.35), and PPIs were actually associated with a decreased risk for CDI in those who received antibiotics (aHR 0.64; 95% CI, 0.48–0.83). There was also no evidence of increased risk for CDI in those who received higher doses of PPIs.Conclusions:Exposure to antibiotics was the most important risk factor for health-care facility-onset CDI in the ICU. PPIs did not increase risk for CDI in the ICU regardless of use of antibiotics.

Vedolizumab for Ulcerative Colitis: Treatment Outcomes from the VICTORY Consortium

OBJECTIVES: We aimed to quantify the safety and effectiveness of vedolizumab (VDZ) when used for UC, and to identify predictors of response to treatment. METHODS: Retrospective review (May 2014‐December 2016) of VICTORY Consortium data. Adults with follow‐up after starting VDZ for clinically active UC were included. Primary effectiveness outcomes were cumulative rates of clinical remission (resolution of all UC‐related symptoms) and endoscopic remission (Mayo endoscopic sub‐score 0). Key secondary effectiveness outcomes included cumulative rates of corticosteroid‐free remission and deep remission (clinical remission and endoscopic remission). Cox proportional hazard analyses were used to identify independent predictors of treatment effectiveness. Non‐response imputation (NRI) sensitivity analyses were performed for effectiveness outcomes. Key safety outcomes were rates of serious infection, serious adverse events, and colectomy. RESULTS: We included 321 UC patients (71% prior TNF&agr; antagonist exposure, median follow‐up 10 months). The 12‐month cumulative rates of clinical remission and endoscopic remission were 51% and 41%, respectively. Corresponding rates for corticosteroid‐free remission and deep remission were 37% and 30%, respectively. Using NRI, 12‐month rates were 20% (n = 64/321) for clinical remission, 17% (n=35/203) for endoscopic remission, 15% (n=30/195) for corticosteroid‐free remission, and 14% (n = 28/203) for deep remission. A majority of the patients without adequate follow‐up at 12 months who were deemed non‐responders using NRI had already achieved clinical remission (n = 70) or a significant clinical response (n=36) prior to 12 months. VDZ discontinuation prior to 12 months was observed in 91 patients, for lack of response (n =56), need for surgery (n=29), or adverse event (n=6). On multivariable analyses, prior exposure to a TNF&agr; antagonist was associated with a reduced probability of achieving clinical remission (HR 0.53, 95% CI 0.38–0.75) and endoscopic remission (HR 0.51, 95% CI 0.29–0.88). Serious adverse events and serious infections were reported in 6% and 4% of patients, respectively. Overall cumulative rates of colectomy over 12 months were 13%, with lower rates observed in patients naive to TNF&agr; antagonist therapy (2%) than those who had been exposed to TNF&agr; antagonists (19%). CONCLUSION: In this large real‐world cohort we observed that VDZ was well tolerated and effective in achieving key clinical outcomes.

Predictors and Management of Loss of Response to Vedolizumab in Inflammatory Bowel Disease

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 Crohns 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 Crohns 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.

Response to Goyal and Katner

appropriately. First, the study design of this study is cross-sectional, which could not disclose any causal relationship. Th e lack of statistical signifi cance may not necessarily imply that vitamin D does not play a role in NAFLD pathogenesis. Rather, it could be interpreted that vitamin D and other metabolic risk factors, especially BMI, are placed on the same causal pathway in the pathogenesis and highly correlated. Earlier this year, in the American Journal of Gastroenterology , Nelson et al. reported contradictory results that vitamin D defi ciency may be involved in pro-infl ammatory pathways of NASH and the degree of defi ciency is associated with increased severity on histology in 190 biopsy-proven NAFLD patients, using the Non-alcoholic Steatohepatitis Clinical Research Network cohort ( 3 ). Second, although the authors mention that there was no statistical diff erence in vitamin D levels between control and NAFLD patients, there is signifi cant diff erence in light skin races (64.1% in controls vs. 83.6% in NAFLD) and proportion of participants involved in metabolic and weight loss surgery program (30.8% in controls vs. 13.5% in NAFLD). Races with lighter skin and people without medical condition requiring metabolic and weight loss surgery programs tend to have higher vitamin D levels, possibly elevating the mean vitamin D level in NAFLD ( 4,5 ). In the methods section, the authors mention that they only used two-sided t -tests or Wilcoxon’s rank-sum tests for continuous predictors and chi-squared tests or Fisher’s exact tests for categorical variables to compare controls and NAFLD demographics without adjustment for these diff erences. Also, the number of patients in the study seems too low to generate enough power to detect any meaningful diff erence, especially in that there were only nine stage 4 fi brosis patients who had the lowest mean vitamin D level. Th ird, it is unclear in the methods section how they generated age, gender, and BMI-matched cohorts. Th is is important since there may be a potential selection bias if the study population is not enrolled consecutively. Given other existing contradictory results over vitamin D’s role in NAFLD and numerous evidence of vitamin D’s role in metabolic risk factors, it may be premature 3. Deshpande A , Pasupuleti V , Th ota P et al. Community-associated Clostridium diffi cile infection and antibiotics: a meta-analysis . J Antimicrob Chemother 2013 ; 68 : 1951 – 61 . 4. Dial S , Alrasadi K , Manoukian C et al. Risk of Clostridium diffi cile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies . Can Med Assoc J 2004 ; 171 : 33 – 8 . 5. Heidelbaugh JJ , Goldberg KL , Inadomi JM . Overutilization of proton pump inhibitors: a review of cost-eff ectiveness and risk [corrected] . Am J Gastroenterol 2009 ; 104 Suppl 2 : S27 – 32 .