Nicholas E Burr

Folic Acid Supplementation May Reduce Colorectal Cancer Risk in Patients With Inflammatory Bowel Disease : A Systematic Review and Meta-Analysis.

Goals: To evaluate the role of folic acid supplementation in colorectal cancer (CRC) chemoprevention in patients with inflammatory bowel disease (IBD). Background: CRC is a serious complication of IBD. Folic acid supplementation has been shown to be chemopreventative in sporadic CRC. Patients with IBD are at risk of folate deficiency though intestinal malabsorption and also competitive inhibition by concurrent sulfasalazine use. To date, there have been several studies reporting on folic acid supplementation in patients with IBD and CRC. Study: We searched electronic databases for studies reporting folic acid use and CRC incidence in patients with IBD. We produced a pooled hazard ratio with 95% confidence intervals using a random-effects model. Preplanned subgroup analyses were performed to explore for any potential sources of heterogeneity. Results: Ten studies reporting on 4517 patients were included. We found an overall protective effect for folic acid supplementation on the development of CRC, pooled hazard ratio=0.58 (95% confidence interval, 0.37-0.80). There was low to moderate heterogeneity among studies, I2=29.7%. Subgroup analyses suggested that folic acid use was protective in hospital-based studies, studies from North America and those that were performed before folate fortification of foods in 1998. Conclusions: CRC remains an important complication of IBD. Chemoprevention is an attractive strategy and folic acid as a cheap, safe, and well-tolerated supplement may have a role. Focused prospective studies are required to precisely define any potential effect.

Risk of gastrointestinal bleeding with direct oral anticoagulants: a systematic review and network meta-analysis

BACKGROUND Direct oral anticoagulants are increasingly used for a wide range of indications. However, data are conflicting about the risk of major gastrointestinal bleeding with these drugs. We compared the risk of gastrointestinal bleeding with direct oral anticoagulants, warfarin, and low-molecular-weight heparin. METHODS For this systematic review and meta-analysis, we searched MEDLINE and Embase from database inception to April 1, 2016, for prospective and retrospective studies that reported the risk of gastrointestinal bleeding with use of a direct oral anticoagulant compared with warfarin or low-molecular-weight heparin for all indications. We also searched the Cochrane Library for systematic reviews and assessment evaluations, the National Health Service (UK) Economic Evaluation Database, and ISI Web of Science for conference abstracts and proceedings (up to April 1, 2016). The primary outcome was the incidence of major gastrointestinal bleeding, with all gastrointestinal bleeding as a secondary outcome. We did a Bayesian network meta-analysis to produce incidence rate ratios (IRRs) with 95% credible intervals (CrIs). FINDINGS We identified 38 eligible articles, of which 31 were included in the primary analysis, including 287 692 patients exposed to 230 090 years of anticoagulant drugs. The risk of major gastrointestinal bleeding with direct oral anticoagulants did not differ from that with warfarin or low-molecular-weight heparin (factor Xa vs warfarin IRR 0·78 [95% CrI 0·47-1·08]; warfarin vs dabigatran 0·88 [0·59-1·36]; factor Xa vs low-molecular-weight heparin 1·02 [0·42-2·70]; and low-molecular-weight heparin vs dabigatran 0·67 [0·20-1·82]). In the secondary analysis, factor Xa inhibitors were associated with a reduced risk of all severities of gastrointestinal bleeding compared with warfarin (0·25 [0.07-0.76]) or dabigatran (0.24 [0.07-0.77]). INTERPRETATION Our findings show no increase in risk of major gastrointestinal bleeding with direct oral anticoagulants compared with warfarin or low-molecular-weight heparin. These findings support the continued use of direct oral anticoagulants. FUNDING Leeds Teaching Hospitals Charitable Foundation.

Does aspirin or non-aspirin non-steroidal anti-inflammatory drug use prevent colorectal cancer in inflammatory bowel disease?

AIM To determine whether aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs) prevent colorectal cancer (CRC) in patients with inflammatory bowel disease (IBD). METHODS We performed a systematic review and meta-analysis. We searched for articles reporting the risk of CRC in patients with IBD related to aspirin or NA-NSAID use. Pooled odds ratios (OR) and 95%CIs were determined using a random-effects model. Publication bias was assessed using Funnel plots and Eggers test. Heterogeneity was assessed using Cochrans Q and the I (2) statistic. RESULTS Eight studies involving 14917 patients and 3 studies involving 1282 patients provided data on the risk of CRC in patients with IBD taking NA-NSAIDs and aspirin respectively. The pooled OR of developing CRC after exposure to NA-NSAIDs in patients with IBD was 0.80 (95%CI: 0.39-1.21) and after exposure to aspirin it was 0.66 (95%CI: 0.06-1.39). There was significant heterogeneity (I (2) > 50%) between the studies. There was no change in the effect estimates on subgroup analyses of the population studied or whether adjustment or matching was performed. CONCLUSION There is a lack of high quality evidence on this important clinical topic. From the available evidence NA-NSAID or aspirin use does not appear to be chemopreventative for CRC in patients with IBD.

Efficacy of pharmacological therapies for the treatment of opioid-induced constipation: systematic review and network meta-analysis

Objective Opioids are increasingly prescribed in the West and have deleterious GI consequences. Pharmacological therapies to treat opioid-induced constipation (OIC) are available, but their relative efficacy is unclear. We performed a systematic review and network meta-analysis to address this deficit in current knowledge. Design We searched MEDLINE, EMBASE, EMBASE Classic and the Cochrane central register of controlled trials through to December 2017 to identify randomised controlled trials (RCTs) of pharmacological therapies in the treatment of adults with OIC. Trials had to report a dichotomous assessment of overall response to therapy, and data were pooled using a random effects model. Efficacy and safety of pharmacological therapies was reported as a pooled relative risk (RR) with 95% CIs to summarise the effect of each comparison tested and ranked treatments according to their P-score. Results Twenty-seven eligible RCTs of pharmacological therapies, containing 9149 patients, were identified. In our primary analysis, using failure to achieve an average of ≥3 bowel movements (BMs) per week with an increase of ≥1 BM per week over baseline or an average of ≥3 BMs per week, to define non-response, the network meta-analysis ranked naloxone first in terms of efficacy (RR=0.65; 95% CI 0.52 to 0.80, P-score=0.84), and it was also the safest drug. When non-response to therapy was defined using failure to achieve an average of ≥3 BMs per week, with an increase of ≥1 BM per week over baseline, naldemedinewas ranked first (RR=0.66; 95% CI 0.56 to 0.77, P score=0.91) and alvimopan second (RR=0.74; 95% CI 0.57 to 0.94, P-score=0.71). Conclusion In network meta-analysis, naloxone and naldemedine appear to be the most efficacious treatments for OIC. Naloxone was the safest of these agents.

Colonic lesion characterization in inflammatory bowel disease: A systematic review and meta-analysis

AIM To perform a systematic review and meta-analysis for the diagnostic accuracy of in vivo lesion characterization in colonic inflammatory bowel disease (IBD), using optical imaging techniques, including virtual chromoendoscopy (VCE), dye-based chromoendoscopy (DBC), magnification endoscopy and confocal laser endomicroscopy (CLE). METHODS We searched Medline, Embase and the Cochrane library. We performed a bivariate meta-analysis to calculate the pooled estimate sensitivities, specificities, positive and negative likelihood ratios (+LHR, -LHR), diagnostic odds ratios (DOR), and area under the SROC curve (AUSROC) for each technology group. A subgroup analysis was performed to investigate differences in real-time non-magnified Kudo pit patterns (with VCE and DBC) and real-time CLE. RESULTS We included 22 studies [1491 patients; 4674 polyps, of which 539 (11.5%) were neoplastic]. Real-time CLE had a pooled sensitivity of 91% (95%CI: 66%-98%), specificity of 97% (95%CI: 94%-98%), and an AUSROC of 0.98 (95%CI: 0.97-0.99). Magnification endoscopy had a pooled sensitivity of 90% (95%CI: 77%-96%) and specificity of 87% (95%CI: 81%-91%). VCE had a pooled sensitivity of 86% (95%CI: 62%-95%) and specificity of 87% (95%CI: 72%-95%). DBC had a pooled sensitivity of 67% (95%CI: 44%-84%) and specificity of 86% (95%CI: 72%-94%). CONCLUSION Real-time CLE is a highly accurate technology for differentiating neoplastic from non-neoplastic lesions in patients with colonic IBD. However, most CLE studies were performed by single expert users within tertiary centres, potentially confounding these results.

Increasing Prescription of Opiates and Mortality in Patients With Inflammatory Bowel Diseases in England

Background & Aims The prescription of opiate medications is increasing. Individuals with inflammatory bowel diseases (IBD) can develop serious complications from opiate use, but few data are available on the prescription of these drugs to patients with IBD. We examined trends in prescriptions of opiates and their association with all‐cause mortality in individuals with IBD. Methods We performed a retrospective cohort study of 3517 individuals with Crohn’s disease (CD) and 5349 with ulcerative colitis (UC) using the primary care database ResearchOne, which holds de‐identified clinical and administrative information from the health records of approximately 6 million persons (more than 10% of the total population) in England. We explored trends in prescriptions of all opiates, codeine, tramadol, or strong opiates, separately from 1990 through September 14, 2014. Associations between opiates and all‐cause mortality were examined using propensity score‐matched analysis. Results There was a statistically significant increase in the prescription of opiate medications, with 10% of subjects receiving an opiate prescription from 1990 through 1993 compared to 30% from 2010 through 2013 (chi‐square for trend, P < .005). Prescription of strong opiates was significantly associated with increased premature mortality of patients with CD (heavy use) or UC (moderate or heavy use). There was a significant association between heavy use of any opiate or codeine alone and premature mortality of patients with UC. Use of tramadol alone, or in combination with codeine, was not associated with premature mortality in patients with CD or UC. Conclusions In an analysis of primary care patients with IBD in England, we found prescriptions for opiate drugs to have increased significantly from 1990 through 2013. Heavy use of strong opiates among patients with IBD associates with increased all‐cause premature mortality.

Commentary: the association between low-dose aspirin use and the incidence of colorectal cancer

*Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA. Department of Epidemiology and Community Health, Virginia Commonwealth University and McGuire VA Medical Center, Richmond, VA, USA. Department of Quantitative Health Sciences, University of Massachusetts Medical School, Worcester, MA, USA. E-mail: jsbajaj@vcu.edu

Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis

BACKGROUND Several new treatments for Clostridium difficile infections have been investigated. We aimed to compare and rank treatments for non-multiply recurrent infections with C difficile in adults. METHODS We did a random effects network meta-analysis within a frequentist setting to obtain direct and indirect comparisons of trials. We searched MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for published and unpublished trials from the creation of these databases until June 30, 2017. We included randomised controlled trials of treatments for non-multiply recurrent infections with confirmed C difficile in adults (at least 18 years) that reported both primary cure and recurrence rates, and we used the Cochrane Risk of Bias tool to appraise trial methods. For our analysis, we extracted the total numbers of patients with primary cure and recurrence from published and unpublished reports. The primary outcome was sustained symptomatic cure, defined as the number of patients with resolution of diarrhoea minus the number with recurrence or death. FINDINGS Of 23 004 studies screened, 24 trials, which comprised 5361 patients and 13 different treatments, were included in the analysis. The overall quality of evidence was rated as moderate to low. For sustained symptomatic cure, fidaxomicin (odds ratio 0·67, 95% CI 0·55-0·82) and teicoplanin (0·37, 0·14-0·94) were significantly better than vancomycin. Teicoplanin (0·27, 0·10-0·70), ridinilazole (0·41, 0·19-0·88), fidaxomicin (0·49, 0·35-0·68), surotomycin (0·66, 0·45-0·97), and vancomycin (0·73, 0·56-0·95) were better than metronidazole. Bacitracin was inferior to teicoplanin (0·22, 0·06-0·77) and fidaxomicin (0·40, 0·17-0·94), and tolevamer was inferior to all drugs except for LFF571 (0·50, 0·18-1·39) and bacitracin (0·67, 0·28-1·58). Global heterogeneity of the entire network was low (Cochrans Q=15·70; p=0·47). INTERPRETATION Among the treatments for non-multiply recurrent infections by C difficile, the highest quality evidence indicates that fidaxomicin provides a sustained symptomatic cure most frequently. Fidaxomicin is a better treatment option than vancomycin for all patients except those with severe infections with C difficile and could be considered as a first-line therapy. Metronidazole should not be recommended for treatment of C difficile. FUNDING None.

Assessing the efficacy of peripherally acting µ-opioid receptor antagonists (PAMORAs) in the treatment of opioid-induced constipation: authors reply

We thank Chedid and Camilleri for their carefully composed letter,1 and are delighted to have provoked further debate about the relative efficacy of drugs acting on µ-opioid receptors in the treatment of opioid-induced constipation (OIC) with our network meta-analysis.2 In fact, we had also written to another journal concerning a recent network meta-analysis examining this issue,3 which had reported erroneously that subcutaneous methylnaltrexone appeared to perform better than other medications for OIC.4 The authors confirmed in their reply to our letter that they had mistakenly included redundant data from duplicate publications of the same two randomised-controlled trials (RCTs) of methylnaltrexone in this meta-analysis,5 likely accounting for their findings.4 …

Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis

BACKGROUND & AIMS Several secretagogues have been approved for the treatment of irritable bowel syndrome with constipation (IBS-C). However, their relative efficacy is unclear because there have been no head-to-head randomized controlled trials. We conducted a network meta-analysis to compare their efficacies in patients with IBS-C. METHODS We searched MEDLINE, EMBASE, EMBASE Classic, and the Cochrane Central Register of Controlled Trials through June 2018 to identify randomized controlled trials assessing the efficacy of secretagogues in adults with IBS-C. Trials included in the analysis reported a dichotomous assessment of overall response to therapy, and data were pooled using a random-effects model. Efficacy and safety of secretagogues were reported as a pooled relative risk with 95% confidence interval to summarize the effect of each comparison tested, and treatments were ranked according to their P score. RESULTS We identified 15 eligible randomized controlled trials of secretagogues that included 8462 patients. Linaclotide, lubiprostone, plecanatide, and tenapanor were superior to placebo for the treatment of IBS-C. Linaclotide (290 μg once daily) was ranked first in efficacy based on the end point recommended by the Food and Drug Administration for trials in IBS-C, the primary end point used in each trial, abdominal pain, and complete spontaneous bowel movements. Tenapanor (50 mg twice daily) was ranked first for decreasing bloating. Total numbers of adverse events were significantly larger with linaclotide (290 and 500 μg once daily) and plecanatide (3 mg once daily) compared with placebo. However, plecanatide 6 mg once daily ranked first for safety. Diarrhea was significantly more common with all drugs, except lubiprostone (8 μg twice daily). Nausea was significantly more common in patients who received lubiprostone. CONCLUSIONS In a network analysis of randomized controlled trials of secretagogues for IBS-C, we found all drugs to be superior to placebo. Efficacy was similar among individual drugs and dosages for most end points. However, data were extracted at the 12-week time point, so the long-term relative efficacy of these drugs is unknown.