Evolution of treatment targets in Crohn’s disease

Crohn’s disease is a chronic relapsing and remitting inflammatory disorder of the gastrointestinal tract, associated with significantly morbidity due to both symptoms and complications that have a considerable detrimental impact on a patient’s quality of life. An early treat to target approach with disease modifying agents has been shown to significantly improve long term outcomes, demonstrated by a number of therapeutic targets in a number of modalities. This review will outline the current treatment targets and measures of disease burden in Crohn’s disease

Pre-specification of statistical analysis approaches in published clinical trial protocols was inadequate

OBJECTIVES: Results from randomized trials can depend on the statistical analysis approach used. It is important to prespecify the analysis approach in the trial protocol to avoid selective reporting of analyses based on those which provide the most favourable results. We undertook a review of published trial protocols to assess how often the statistical analysis of the primary outcome was adequately prespecified. METHODS: We searched protocols of randomized trials indexed in PubMed in November 2016. We identified whether the following aspects of the statistical analysis approach for the primary outcome were adequately prespecified: (1) analysis population; (2) analysis model; (3) use of covariates; and (4) method of handling missing data. RESULTS: e identified 99 eligible protocols. Very few protocols adequately prespecified the analysis population (8/99, 8%), analysis model (27/99, 27%), covariates (40/99, 40%), or approach to handling missing data (10/99, 10%). Most protocols did not adequately predefine any of these four aspects of their statistical analysis approach (39%) or predefined only one aspect (36%). No protocols adequately predefined all four aspects of the analysis. CONCLUSION: The statistical analysis approach is rarely prespecified in published trial protocols. This may allow selective reporting of results based on different analyses

Adjusting for multiple prognostic factors in the analysis of randomised trials

Background: When multiple prognostic factors are adjusted for in the analysis of a randomised trial, it is unclear (1) whether it is necessary to account for each of the strata, formed by all combinations of the prognostic factors (stratified analysis), when randomisation has been balanced within each stratum (stratified randomisation), or whether adjusting for the main effects alone will suffice, and (2) the best method of adjustment in terms of type I error rate and power, irrespective of the randomisation method. Methods: We used simulation to (1) determine if a stratified analysis is necessary after stratified randomisation, and (2) to compare different methods of adjustment in terms of power and type I error rate. We considered the following methods of analysis: adjusting for covariates in a regression model, adjusting for each stratum using either fixed or random effects, and Mantel-Haenszel or a stratified Cox model depending on outcome. Results: Stratified analysis is required after stratified randomisation to maintain correct type I error rates when (a) there are strong interactions between prognostic factors, and (b) there are approximately equal number of patients in each stratum. However, simulations based on real trial data found that type I error rates were unaffected by the method of analysis (stratified vs unstratified), indicating these conditions were not met in real datasets. Comparison of different analysis methods found that with small sample sizes and a binary or time-to-event outcome, most analysis methods lead to either inflated type I error rates or a reduction in power; the lone exception was a stratified analysis using random effects for strata, which gave nominal type I error rates and adequate power. Conclusions: It is unlikely that a stratified analysis is necessary after stratified randomisation except in extreme scenarios. Therefore, the method of analysis (accounting for the strata, or adjusting only for the covariates) will not generally need to depend on the method of randomisation used. Most methods of analysis work well with large sample sizes, however treating strata as random effects should be the analysis method of choice with binary or time-to-event outcomes and a small sample size

Resource consumption and management associated with monitoring of warfarin treatment in primary health care in Sweden

BACKGROUND: Warfarin is used for the prevention and treatment of various thromboembolic complications. It is an efficacious anticoagulant, but it has a narrow therapeutic range, and regular monitoring is required to ensure therapeutic efficacy and at the same time avoid life-threatening adverse events. The objective was to assess management and resource consumption associated with patient monitoring episodes during warfarin treatment in primary health care in Sweden. METHODS: Delphi technique was used to systematically explore attitudes, demands and priorities, and to collect informed judgements related to monitoring of warfarin treatment. Two separate Delphi-panels were performed in three and two rounds, respectively, one concerning tests taken in primary health care centres, involving 34 GPs and 10 registered nurses, and one concerning tests taken in patients' homes, involving 49 district nurses. RESULTS: In the primary health care panel 10 of the 34 GPs regularly collaborated with a registered nurse. Average time for one monitoring episode was estimated to 10.1 minutes for a GP and 21.4 minutes for a nurse, when a nurse assisted a doctor. The average time for monitoring was 17.6 minutes for a GP when not assisted by a nurse. Considering all the monitoring episodes, 11.6% of patient blood samples were taken in the individual patient's home. Average time for such a monitoring episode was estimated to 88.2 minutes. Of all the visits, 8.2% were performed in vain and took on average 44.6 minutes. In both studies, approximately 20 different elements of work concerning management of patients during warfarin treatment were identified. CONCLUSION: Monitoring of patients during treatment with warfarin in primary health care in Sweden involves many elements of work, and demands large resources, especially when tests are taken in the patient's home

The risks and rewards of covariate adjustment in randomized trials: an assessment of 12 outcomes from 8 studies

Adjustment for prognostic covariates can lead to increased power in the analysis of randomized trials. However, adjusted analyses are not often performed in practice

Uptake of endoscopic screening for gastroesophageal varices and factors associated with variceal bleeding in patients with chronic hepatitis C infection and compensated cirrhosis, 2005-2016:a national database linkage study

Background: Primary measures for preventing morbidity and mortality associated with bleeding gastroesophageal varices in cirrhotic patients include endoscopic screening.Aim: To identify factors associated with (a) screening and (b) first hospital admission for variceal bleeding among cirrhotic hepatitis C virus (HCV) patients attending specialist care in Scotland.Methods: The Scottish Hepatitis C Clinical Database was linked to national hospitalisation and deaths records to identify all chronic HCV patients diagnosed with compensated cirrhosis in 2005-2016 (n = 2741). The adjusted odds of being screened by calendar year period were estimated using logistic regression, and the adjusted hazard ratio (HR) of a first variceal bleed using Cox regression.Results: About 34% were screened within the period starting 12 months before and ending 12 months after cirrhosis diagnosis. The proportion screened was stable in 2005-2010 at 42%, declining to 37% in 2011-2013 and 26% in 2014-2016. Odds of screening were decreased for age-groups &lt;40 (OR = 0.61, 95% CI: 0.48-0.77) and 60+ years (OR = 0.67, 95% CI: 0.48-0.94), history of antiviral therapy (OR = 0.70, 95% CI: 0.55-0.89), and cirrhosis diagnosis in 2014-2015, compared with 2008-2010 (OR = 0.67, 95% CI: 0.52-0.86). Compared with 2008-2010, there was no evidence for an increased/decreased relative risk of a first variceal bleed in any other period, but viral clearance was associated with a lower risk (HR = 0.56, 95% CI: 0.32-0.97).Conclusions: Overall screening uptake following cirrhosis diagnosis was low, and the decline into the IFN-free therapy era is of concern. The stable bleeding risk over time may be attributable both to ongoing prevention initiatives and to changing diagnostic procedures creating a patient pool with milder disease in more recent years.</p

The cost of monitoring warfarin in patients with chronic atrial fibrillation in primary care in Sweden

BACKGROUND: Warfarin is used for the prevention of stroke in chronic atrial fibrillation. The product has a narrow therapeutic index and to obtain treatment success, patients must be maintained within a given therapeutic range (International Normalised Ratio;INR). To ensure a wise allocation of health care resources, scrutiny of costs associated with various treatments is justified. The objective of this study was to estimate the health care cost of INR controls in patients on warfarin treatment with chronic atrial fibrillation in primary care in Sweden. METHODS: Data from various sources were applied in the analysis. Resource consumption was derived from two observational studies based on electronic patient records and two Delphi-panel studies performed in two and three rounds, respectively. Unit costs were taken from official databases and primary health care centres. RESULTS: The mean cost of one INR control was SEK 550. The mean costs of INR controls during the first three months, the first year and during the second year of treatment were SEK 6,811, SEK 16,244 and SEK 8,904 respectively. CONCLUSION: INR controls of patients on warfarin treatment in primary care in Sweden represent a substantial cost to the health care provider and they are particularly costly when undertaken in home care. The cost may however be off-set by the reduced incidence of stroke

Standardisation of intestinal ultrasound scoring in clinical trials for luminal Crohn's disease

Background: Intestinal ultrasound (IUS) is a valuable tool for assessment of Crohn’s disease (CD). However, there is no widely accepted luminal disease activity index. / Aims: To identify appropriate IUS protocols, indices, items, and scoring methods for measurement of luminal CD activity and integration of IUS in CD clinical trials. / Methods: An expert international panel of adult and paediatric gastroenterologists (n = 15) and radiologists (n = 3) rated the appropriateness of 120 statements derived from literature review and expert opinion (scale of 1-9) using modified RAND/UCLA methodology. Median panel scores of 1 to ≤3.5, >3.5 to <6.5 and ≥6.5 to 9 were considered inappropriate, uncertain and appropriate ratings respectively. The statement list and survey results were discussed prior to voting. / Results: A total of 91 statements were rated appropriate with agreement after two rounds of voting. Items considered appropriate measures of disease activity were bowel wall thickness (BWT), vascularity, stratification and mesenteric inflammatory fat. There was uncertainty if any of the existing IUS disease activity indices were appropriate for use in CD clinical trials. Appropriate trial applications for IUS included patient recruitment qualification when diseased segments cannot be adequately assessed by ileocolonoscopy and screening for exclusionary complications. At outcome assessment, remission endpoints including BWT and vascularity, with or without mesenteric inflammatory fat, were considered appropriate. Components of an ideal IUS disease activity index were identified based upon panel discussions. / Conclusions: The panel identified appropriate component items and applications of IUS for CD clinical trials. Empiric evidence, and development and validation of an IUS disease activity index are needed

Complete histologic normalisation is associated with reduced risk of relapse among patients with ulcerative colitis in complete endoscopic remission

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153611/1/apt15568.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153611/2/apt15568_am.pd

Narrow-band Imaging for Detection of Neoplasia at Colonoscopy: a Meta-analysis of Data From Individual Patients in Randomized Controlled Trials

Background & Aims Adenoma detection rate (ADR) is an important quality assurance measure for colonoscopy. Some studies suggest that narrow band imaging (NBI) may be more effective at detection of adenomas than white-light endoscopy (WLE) when bowel preparation is optimal. We conducted a meta-analysis of data from individual patients in randomized controlled trials that compared the efficacy of NBI to WLE in detection of adenomas. Methods We searched MEDLINE, EMBASE, and Cochrane library databases, through April 2017, for randomized controlled trials that assessed detection of colon polyps by high-definition WLE vs NBI and from which data on individual patients was available. The primary outcome measure was ADR adjusted for bowel preparation quality. Multilevel regression models were used with patients nested within trials, and trial included as a random effect. Results We collected data from 11 trials, comprising 4491 patients and 6636 polyps detected. Adenomas were detected in 952/2251 (42.3%) participants examined by WLE vs 1011/2239 (45.2%) participants examined by NBI (unadjusted odds ratio [OR] for detection of adenoma by WLE vs NBI, 1.14; 95% CI, 1.01–1.29; P=.04). NBI outperformed WLE only when bowel preparation was best: adequate preparation OR, 1.07 (95% CI, 0.92–1.24; P=.38) vs best preparation OR, 1.30 (95% CI, 1.04–1.62; P=.02). Second-generation bright NBI had a better ADR than WLE (second-generation NBI OR, 1.28; 95% CI, 1.05–1.56; P=.02), whereas first-generation NBI did not. NBI detected more non-adenomatous polyps than WLE (OR, 1.24; 95% CI, 1.06–1.44; P=.008) and flat polyps than WLE (OR, 1.24; 95% CI, 1.02–1.51; P=.03). Conclusions In a meta-analysis of data from individual patients in randomized controlled trials, we found NBI to have a higher ADR than WLE, and that this effect is greater when bowel preparation is optimal