Advances in transfusion medicine: gastrointestinal bleeding.

Gastrointestinal bleeding is a common medical and surgical emergency and is the second most common indication for red blood cell (RBC) transfusion in the UK. Most transfusion guidelines recommend the use of restrictive blood transfusion in stable gastrointestinal bleeding. This review explores the evidence supporting this practice, including whether it is safe in lower as well as upper gastrointestinal bleeding, and the risks of restrictive transfusion in patients with cardiovascular disease. There is a lack of evidence supporting the use of platelet and fresh frozen plasma transfusion in gastrointestinal bleeding. The aim of this review is to serve as a practical guide to transfusion in stable gastrointestinal bleeding.

Modern-day management of upper gastrointestinal haemorrhage.

Acute upper gastrointestinal haemorrhage (AUGIH) is a common medical emergency and can present with life threatening haemorrhage. In the U.K., there are 70,000 hospital admissions per year. In the majority of cases, the aetiology is non-variceal in origin, but in other cases it is due to variceal bleeding in patients with cirrhosis. It is also a leading indication for transfusion of blood components. This review explores recent randomised data on the efficacy and safety of red blood cell transfusion for AUGIH. In addition, the evidence base for use of other blood components and pro-haemostatic pharmacological agents is discussed, including acid suppression, antifibrinolytics and fibrinogen.

Meta-analysis: Intestinal ultrasound to evaluate colonic contents and constipation.

BACKGROUND: Constipation can be diagnosed clinically using the Rome criteria. Ultrasound (US), which lacks the radiation exposure of conventional X-ray, holds promise as a non-invasive tool to evaluate colonic contents and constipation. AIM: To examine the role of US in the assessment of constipation. METHODS: We performed a systematic search of Embase (OVID, 1984), Medline (Ovid, 1946), Cochrane Central, ClinicalTrials.gov and Australia New Zealand Clinical Trials Registry from database inception to 26 January 2024 according to PRISMA guidelines and prospectively registered with PROSPERO. All studies using US to assess constipation or colonic contents in either adults or children were included. Rectal diameter measurements were pooled in meta-analysis. Risk of bias was assessed using the Newcastle Ottawa Scales and Joanna Briggs Institute checklists. RESULTS: Of 12,232 studies screened, 51 articles (6084 patients; 3422 children) describing US to assess symptoms in patients with constipation were included. Most studies used Rome criteria to diagnose constipation. Rectal diameter was associated with clinical constipation in 29 paediatric studies (3331 patients). Meta-analysis showed the mean rectal diameter of constipated patients was significantly higher than controls (mean difference 12 mm, 95% confidence intervals (CI): 6.48, 17.93, p < 0.0001, n = 16 studies). Other features of constipation on US included posterior acoustic shadowing and echogenicity of luminal contents. CONCLUSION: US is an appealing imaging modality to assess luminal contents and constipation. Further well-designed studies are required to validate US metrics that accurately identify constipation.

National audit of the use of surgery and radiological embolization after failed endoscopic haemostasis for non-variceal upper gastrointestinal bleeding.

BACKGROUND: Following non-variceal upper gastrointestinal bleeding (NVUGIB), 10-15 per cent of patients experience further bleeding. Although surgery has been the traditional salvage therapy, there is renewed interest in transcatheter arterial embolization (TAE). This study examined the use, clinical characteristics and outcomes of patients receiving salvage surgery or TAE after failed endoscopic haemostasis for NVUGIB. METHODS: A UK national audit of upper gastrointestinal bleeding was undertaken in May and June 2007. A logistic regression model was used to identify clinical predictors of endoscopic failure. RESULTS: Data were analysed from 4478 patients involving 212 UK centres. Some 533 (11·9 per cent) experienced further bleeding, of whom 163 (30·6 per cent) proceeded to salvage therapy with surgery (97), TAE (60) or both (6). Among surgical patients (mean age 71 years), 66·0 per cent (68 of 103) had a Rockall score of at least 3 and emergency surgery was carried out between midnight and 08.00 hours in 21 per cent, with a consultant surgeon present in 89 per cent of operations. Some 9 per cent of patients had further bleeding after TAE, resulting in later surgery. The mortality rate was 29 per cent after surgery, 10 per cent after TAE and 23·2 per cent among those with further bleeding after the index endoscopy that was managed by endoscopy alone. The strongest predictors of endoscopic failure were coagulopathy (odds ratio 3·27, 95 per cent confidence interval 2·37 to 4·53) and a haemoglobin level of 10 g/dl or less (odds ratio 2·22, 1·71 to 2·87, for haemoglobin 8-10 g/dl). CONCLUSION: Salvage surgery and embolization are required in fewer than 4 per cent of patients with NVUGIB. The high postoperative mortality rate, reflecting age, co-morbidity and severity of bleeding, warrants a prospective study to establish the effectiveness and safety of TAE as an alternative to surgery in the management of bleeding after failure of endoscopic therapy.

Outcomes following acute nonvariceal upper gastrointestinal bleeding in relation to time to endoscopy: results from a nationwide study.

BACKGROUND AND STUDY AIMS: Despite the established efficacy of therapeutic endoscopy, the optimum timeframe for performing endoscopy in patients with nonvariceal upper gastrointestinal bleeding (NVUGIB) remains unclear. The aim of the current audit study was to examine the relationship between time to endoscopy and clinical outcomes in patients presenting with NVUGIB. PATIENTS AND METHODS: This study was a prospective national audit performed in 212 UK hospitals. Regression models examined the relationship between time to endoscopy and mortality, rebleeding, need for surgery, and length of hospital stay. RESULTS: In 4478 patients, earlier endoscopy ( < 12 hours) was not associated with a lower mortality or need for surgery compared with later ( > 24 hours) endoscopy (odds ratio [OR] for mortality 0.98, 95 % confidence interval [CI] 0.88 - 1.09 for endoscopy > 24 hours vs. < 12 hours; P = 0.70). In patients receiving therapeutic endoscopy, there was a nonsignificant trend towards an increase in rebleeding associated with later endoscopy (OR 1.13, 95 %CI 0.97 - 1.32 for endoscopy > 24 hours vs. < 12 hours), with the converse seen in patients not requiring therapeutic endoscopy (OR 0.83, 95 %CI 0.73 - 0.95 for endoscopy > 24 hours vs. < 12 hours; interaction P = 0.003). Later endoscopy ( > 24 hours) was associated with an increase in risk-adjusted length of hospital stay (1.7 days longer, 95 %CI 1.39 - 1.99 vs. < 12 hours; P < 0.001). CONCLUSIONS: Earlier endoscopy was not associated with a reduction in mortality or need for surgery. However, it was associated with an increased efficiency of care and potentially improved control of hemorrhage in higher risk patients, supporting the routine use of early endoscopy unless specific contraindications exist. These results may help inform the debate about emergency endoscopy service provision.

Mortality from acute upper gastrointestinal bleeding in the United kingdom: does it display a "weekend effect"?

OBJECTIVES: An increased mortality in patients presenting to hospital at weekends has been observed for several medical conditions. The aim of this study is to examine the relationship between weekend presentation to hospital following acute upper gastrointestinal bleeding and mortality. METHODS: Data were collected on 6,749 patients presenting to 212 UK hospitals. A logistic regression model was used to examine the relationship between weekend presentation to hospital and mortality. RESULTS: Patients presenting at the weekend were more likely to present with shock (39% vs. 36%), hematemesis (41% vs. 38%), and receive red cell transfusion (42% vs. 39%). Only 38% of those presenting at weekends underwent endoscopy within 24 h compared with 55% admitted on weekdays (adjusted odds ratio (OR)=0.47, 95% confidence interval (CI)=0.41-0.54), although the proportion of all patients receiving endoscopic therapy was identical at weekends compared with weekdays (24%). After adjustment for confounders, there was no evidence of a difference between weekend and weekday mortality (OR=0.93; 95% CI=0.75-1.16). Similar results were seen when restricting the analysis to those patients who underwent endoscopy (n=5,004) (OR=0.87, 95% CI=0.65-1.16). There was no difference in the OR for mortality for weekend compared with weekday presentation between patients presenting to hospitals with an out-of-hours (OOH) endoscopy rota compared with those presenting to hospitals without such a facility. CONCLUSIONS: In this large prospective study of acute upper gastrointestinal bleeding in the United Kingdom, there was no increase in mortality for weekend vs. weekday presentation despite patients being more critically ill and having greater delays to endoscopy at weekends. Provision of an OOH endoscopy service at weekends in the remaining UK hospitals may not lead to further reductions in case fatality, although a reduction in OOH endoscopy provision from current levels could lead to an increase in mortality at weekends.

Systematic review with meta-analysis: prevalence, risk factors and costs of aminosalicylate use in Crohn's disease.

BACKGROUND: Aminosalicylates are the most frequently prescribed drugs for patients with Crohn's disease (CD), yet evidence to support their efficacy as induction or maintenance therapy is controversial. AIMS: To quantify aminosalicylate use in CD clinical trials, identify factors associated with use and estimate direct annual treatment costs of therapy. METHODS: MEDLINE, Embase and CENTRAL were searched to April 2017 for placebo-controlled trials in adults with CD treated with corticosteroids, immunosuppressants or biologics. The proportion of patients co-prescribed aminosalicylates in placebo arms was pooled using a random-effects model. Meta-regression was used to identify factors associated with aminosalicylate use. Annual treatment costs were estimated using the 2016 Ontario Drug Benefit Program. RESULTS: Forty-two induction and 10 maintenance trials were included. The pooled proportion of patients co-prescribed aminosalicylates was 44% [95% CI: 39%-49%] in induction trials and 49% [95% CI: 35%-64%] in maintenance trials. There was substantial to considerable heterogeneity (I2  = 86.0%, 91.8% for induction and maintenance trials, respectively). In multivariable meta-regression, aminosalicylate use has decreased over time in induction trials (OR 0.50 [95% CI: 0.34-0.74] per 10-year increment). While a decline has been seen over time, 35% of CD patients were still using aminosalicylates in contemporary trials from the last 5 years. The estimated annual cost for the lowest price mesalazine (mesalamine) formulation is approximately $32 million for the Canadian CD population. CONCLUSIONS: Over one-third of CD patients entering clinical trials are still co-prescribed aminosalicylates. A definitive trial is needed to inform the conventional practice of using aminosalicylates as CD maintenance therapy.

Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis.

BACKGROUND: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. AIMS: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study-level covariates on these rates. RESULTS: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P < 0.0001, per 10% increase in corticosteroid use). CONCLUSIONS: Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field.

HLA-DQA1-HLA-DRB1 polymorphism is a major predictor of azathioprine-induced pancreatitis in patients with inflammatory bowel disease.

BACKGROUND: Azathioprine (AZA)-induced pancreatitis is an unpredictable and dose-independent adverse event affecting 2%-7% of patients with inflammatory bowel disease (IBD) patients treated with AZA. There are no tools in clinical practice to identify at-risk individuals; however, a genome wide association study (GWAS) identified a strong association between the Class II HLA gene region polymorphism (rs2647087) and thiopurine-induced pancreatitis. AIM: To independently confirm the findings of the GWAS in an IBD cohort, to evaluate its utility in clinical practice and to offer a novel AZA treatment algorithm for IBD based on pharmacogenomic principles. METHODS: A retrospective cohort study evaluated 373 AZA-exposed IBD patients from a tertiary care academic centre in London, Canada. Due to the limited number of patients taking mercaptopurine (MP), such patients were not included this cohort. All subjects underwent screening for the single nucleotide polymorphism (SNP) rs2647087 mapped to the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype and were sub-divided based on the presence (n = 13) or absence (n = 360) of an AZA-induced pancreatitis diagnosis. The risk of AZA-induced pancreatitis was assessed based on rs2647087 genotype. RESULTS: The risk of pancreatitis during AZA-therapy was highly predictable and genotype dependent: 0.53% for wild type (A/A), 4.25% (OR = 4.19, 95% CI 1.02-36.45, P = 0.044) for heterozygous (A/C), and 14.63% (OR = 15.83, 95% CI 3.80-145.26, P = 0.0001) for homozygous variant (C/C) patients. CONCLUSIONS: The class II HLA region (at rs2647087) is an important marker of AZA-induced pancreatitis risk. We propose a simple and clinically implementable algorithm based on rs2647087 and TPMT genotypes for AZA selection and dosing for patients with IBD.

An expert consensus to standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Crohn's disease.

BACKGROUND: Fibrotic stricture is a common complication of Crohn's disease (CD) affecting approximately half of all patients. No specific anti-fibrotic therapies are available; however, several therapies are currently under evaluation. Drug development for the indication of stricturing CD is hampered by a lack of standardised definitions, diagnostic modalities, clinical trial eligibility criteria, endpoints and treatment targets in stricturing CD. AIM: To standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Chron's disease. METHODS: An interdisciplinary expert panel consisting of 15 gastroenterologists and radiologists was assembled. Using modified RAND/University of California Los Angeles appropriateness methodology, 109 candidate items derived from systematic review and expert opinion focusing on small intestinal strictures were anonymously rated as inappropriate, uncertain or appropriate. Survey results were discussed as a group before a second and third round of voting. RESULTS: Fibrotic strictures are defined by the combination of luminal narrowing, wall thickening and pre-stenotic dilation. Definitions of anastomotic (at site of prior intestinal resection with anastomosis) and naïve small bowel strictures were similar; however, there was uncertainty regarding wall thickness in anastomotic strictures. Magnetic resonance imaging is considered the optimal technique to define fibrotic strictures and assess response to therapy. Symptomatic strictures are defined by abdominal distension, cramping, dietary restrictions, nausea, vomiting, abdominal pain and post-prandial abdominal pain. Need for intervention (endoscopic balloon dilation or surgery) within 24-48 weeks is considered the appropriate endpoint in pharmacological trials. CONCLUSIONS: Consensus criteria for diagnosis and response to therapy in stricturing Crohn's disease should inform both clinical practice and trial design.

Reliability of histologic assessment in patients with eosinophilic oesophagitis.

BACKGROUND: The validity of the eosinophilic oesophagitis (EoE) histologic scoring system (EoEHSS) has been demonstrated, but only preliminary reliability data exist. AIM: Formally assess the reliability of the EoEHSS and additional histologic features. METHODS: Four expert gastrointestinal pathologists independently reviewed slides from adult patients with EoE (N = 45) twice, in random order, using standardised training materials and scoring conventions for the EoEHSS and additional histologic features agreed upon during a modified Delphi process. Intra- and inter-rater reliability for scoring the EoEHSS, a visual analogue scale (VAS) of overall histopathologic disease severity, and additional histologic features were assessed using intra-class correlation coefficients (ICCs). RESULTS: Almost perfect intra-rater reliability was observed for the composite EoEHSS scores and the VAS. Inter-rater reliability was also almost perfect for the composite EoEHSS scores and substantial for the VAS. Of the EoEHSS items, eosinophilic inflammation was associated with the highest ICC estimates and consistent with almost perfect intra- and inter-rater reliability. With the exception of dyskeratotic epithelial cells and surface epithelial alteration, ICC estimates for the remaining EoEHSS items were above the benchmarks for substantial intra-rater, and moderate inter-rater reliability. Estimation of peak eosinophil count and number of lamina propria eosinophils were associated with the highest ICC estimates among the exploratory items. CONCLUSION: The composite EoEHSS and most component items are associated with substantial reliability when assessed by central pathologists. Future studies should assess responsiveness of the score to change after a therapeutic intervention to facilitate its use in clinical trials.

Systematic review: the safety of vedolizumab for the treatment of inflammatory bowel disease.

BACKGROUND: Vedolizumab specifically recognises the α4ß7 integrin and selectively blocks gut lymphocyte trafficking: potentially, it offers gut-specific immunosuppression. AIM: To review the safety of vedolizumab and summarise post-marketing data to assess if any safety concerns that differ from registration trials have emerged. METHOD: A systematic bibliographic search identified six registration trials and nine cohort studies. RESULTS: Integrated data from registration trials included 2830 vedolizumab-exposed patients (4811 person-years exposure [PYs]) and 513 placebo patients. This reported lower exposure-adjusted incidence rates of infection (63.5/100 PYs; 95% CI: 59.6-67.3) and serious adverse events (20.0/100 PYs; 95% CI: 18.5-21.5) compared to placebo (82.9/100 PYs; 95% CI: 68.3-97.5) and (28.3/100 PYs 95% CI: 20.6-35.9) respectively. Higher, but statistically insignificant rates of enteric infections occurred in vedolizumab-exposed patients (7.4/100 PYs; 95% CI: 6.6-8.3) compared to placebo (6.7 PYs; 95% CI: 3.2-10.1). Six post-marketing cohort studies (1049 patients, 403 PYs) demonstrated rates of infection of 8% (82/1049); enteric infection of 2% (21/1049) and adverse events of 16% (166/1049). Multivariate analysis in one cohort study suggested increased risk of surgical site infection with perioperative VDZ. Human experience in pregnancy is limited. CONCLUSIONS: Post-marketing data confirm the excellent safety of vedolizumab observed in registration trials. The signal of post-operative complications should be interpreted with caution, but warrants further study. Although comparative studies are needed, Vedolizumab may be a safe alternative in patients who best avoid systematic immunosuppression, including those pre-disposed to infection, malignancy or the elderly.

Systematic review with meta-analysis: faecal microbiota transplantation for the induction of remission for active ulcerative colitis.

BACKGROUND: Faecal microbiota transplantation (FMT) is emerging as a novel therapy for ulcerative colitis (UC). Interpretation of efficacy of FMT for UC is complicated by differences among studies in blinding, FMT administration procedures, intensity of therapy and donor stool processing methods. AIM: To determine whether FMT is effective and safe for the induction of remission in active UC. METHODS: Medline (Ovid), Embase and the Cochrane Library were searched from inception through February 2017. Original studies reporting remission rates following FMT for active UC were included. All study designs were included in the systematic review and a meta-analysis performed including only randomised controlled trials (RCTs). RESULTS: There were 14 cohort studies and four RCTs that used markedly different protocols. In the meta-analysis of RCTs, clinical remission was achieved in 39 of 140 (28%) patients in the donor FMT groups compared with 13 of 137 (9%) patients in the placebo groups; odds ratio 3.67 (95% CI: 1.82-7.39, P<.01). Clinical response was achieved in 69 of 140 (49%) donor FMT patients compared to 38 of 137 (28%) placebo patients; odds ratio 2.48 (95% CI: 1.18-5.21, P=.02). In cohort studies, 39 of 168 (24%; 95% CI: 11%-40%) achieved clinical remission. CONCLUSIONS: Despite variation in processes, FMT appears to be effective for induction of remission in UC, with no major short-term safety signals. Further studies are needed to better define dose frequency and preparation methods, and to explore its feasibility, efficacy and safety as a maintenance agent.

Review article: dose optimisation of infliximab for acute severe ulcerative colitis.

BACKGROUND: Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. AIM: To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. METHODS: We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies. RESULTS: Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. CONCLUSIONS: Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.

The development of a magnetic resonance imaging index for fistulising Crohn's disease.

BACKGROUND: Magnetic resonance imaging (MRI) is the gold standard for assessment of perianal fistulising Crohn's disease (CD). The Van Assche index is the most commonly used MRI fistula index. AIMS: To assess the reliability of the Van Assche index, and to modify the instrument to improve reliability and create a novel index for fistulising CD. METHODS: A consensus process developed scoring conventions for existing Van Assche index component items and new items. Four experienced radiologists evaluated 50 MRI images in random order on three occasions. Reliability was assessed by estimates of intraclass correlation coefficients (ICCs). Common sources of disagreement were identified and recommendations made to minimise disagreement. A mixed effects model used a 100 mm visual anologue scale (VAS) for global severity as outcome and component items as predictors to create a modified Van Assche index. RESULTS: Intraclass correlation coefficients (95% confidence intervals) for intra-rater reliability of the original and modified Van Assche indices and the VAS were 0.86 (0.81-0.90), 0.90 (0.86-0.93) and 0.86 (0.82-0.89). Corresponding ICCs for inter-rater reliability were 0.66 (0.52-0.76), 0.67 (0.55-0.75) and 0.58 (0.47-0.66). Sources of disagreement included number, location, and extension of fistula tracts, and rectal wall involvement. A modified Van Assche index (range 0-24) was created that included seven component items. CONCLUSIONS: Although "almost perfect" intra-rater reliability was observed for the assessment of MRI images for fistulising CD using the Van Assche index, inter-rater reliability was considerably lower. Our modification of this index should result in a more optimal instrument.

Randomised non-inferiority trial: 1600 mg versus 400 mg tablets of mesalazine for the treatment of mild-to-moderate ulcerative colitis.

BACKGROUND: High concentration mesalazine formulations are more convenient than conventional low concentration formulations for the treatment of ulcerative colitis (UC). AIM: To compare the efficacy and safety of 1600 mg and 400 mg tablet mesalazine formulations. METHODS: Patients with mild-to-moderate active UC (Mayo Clinic Score >5; N=817) were randomised to 3.2 g of oral mesalazine, administered as two 1600 mg tablets once, or four 400 mg tablets twice daily. We hypothesised that treatment with the 1600 mg tablet was non-inferior (within a 10% margin) to the 400 mg tablet for induction of clinical and endoscopic remission at week 8. Open-label treatment with the 1600 mg tablet continued for 26-30 weeks based on induction response. Predictors of treatment response were also explored. RESULTS: At week 8, remission occurred in 22.4% and 24.6% of patients receiving the 1600 mg and 400 mg tablets, respectively (absolute difference -2.2%, 95% CI: -8.1% to 3.8%, non-inferiority P=.005). Endoscopic and histopathologic disease activity, leucocyte concentration and age were significantly associated with clinical remission (P=.022, .042, .014 and .023, respectively). At week 38, 43.9% (296/675) of patients who continued treatment with the 1600 mg formulation were in remission, including 70.3% (142/202) of patients who received a reduced dose of mesalazine (1.6 g/d). The overall incidence of serious adverse events was low. CONCLUSIONS: Induction therapy with 3.2 mg mesalazine using two 1600 mg tablets once-daily was statistically and clinically non-inferior to a twice-daily regimen using four 400 mg tablets (NCT01903252).

Systematic review with meta-analysis: placebo rates in induction and maintenance trials of Crohn's disease.

BACKGROUND: Minimising placebo response is essential for drug development. AIM: To conduct a meta-analysis to determine placebo response and remission rates in trials and identify the factors affecting these rates. METHODS: MEDLINE, EMBASE and CENTRAL were searched from inception to April 2014 for placebo-controlled trials of pharmacological interventions for Crohn's disease. Placebo response and remission rates for induction and maintenance trials were pooled by random-effects and mixed-effects meta-regression models to evaluate effects of study-level characteristics on these rates. RESULTS: In 100 studies containing 67 induction and 40 maintenance phases and 7638 participants, pooled placebo remission and response rates for induction trials were 18% [95% confidence interval (CI) 16-21%] and 28% (95% CI 24-32%), respectively. Corresponding values for maintenance trials were 32% (95% CI 25-39%) and 26% (95% CI 19-35%), respectively. For remission, trials enrolling patients with more severe disease activity, longer disease duration and more study centres were associated with lower placebo rates, whereas more study visits and longer study duration was associated with higher placebo rates. For response, findings were opposite such that trials enrolling patients with less severe disease activity and longer study duration were associated with lower placebo rates. Placebo rates varied by drug class and route of administration, with the highest placebo response rates observed for biologics. CONCLUSIONS: Placebo rates vary according to whether trials are designed for induction or maintenance and the factors influencing them differ for the endpoints of remission and response. These findings have important implications for clinical trial design in Crohn's disease.