Ramsay, Tim

ABSTRACTBackground and AimsWe aimed to assess the impact of setons on perianal fistula outcomes in patients with perianal fistulising Crohn's disease (PFCD) treated with anti‐TNF therapy.MethodsWe included patients treated with their first anti‐TNF therapy for PFCD after undergoing a pelvic MRI between 2005 and 2022 from 6 North American centres. Our exposure was one or more setons at the time of anti‐TNF therapy. Our primary outcome was major adverse fistula outcome (MAFO), a composite of repeat local surgical intervention, hospitalisation, or faecal diversion for PFCD, and our secondary outcome was fistula remission defined clinically. We used 1:1 cardinality matching and propensity score weighting to control for fistula severity based on centrally read MRIs, luminal characteristics, and concomitant therapies.ResultsOur analysis included 221 patients: 81 with setons and 140 without setons. After cardinality matching, our cohorts were balanced (standardised difference < 0.1 for all covariates). Patients with setons had similar rates of MAFO (HR 1.23; 95% CI, 0.68–2.21) and fistula remission at 6 months (OR, 0.81; 95% CI, 0.41–1.59) and 12 months (OR, 0.63; 95% CI, 0.31–1.27) compared to patients without setons. Our results remained stable when analysed by propensity score weighting and in a sensitivity analysis of patients who underwent an exam under anaesthesia. In patients with abscesses, there were lower rates of MAFO (HR, 0.49; 95% CI, 0.19–1.25) but not statistically significant in patients with setons.ConclusionsIn this multicentre, setons were not associated with improved fistula outcomes. Future prospective controlled studies are warranted.

Objectives To survey experts in Headache Medicine on their opinions regarding appropriate non‐inferiority margins for outcomes commonly used in migraine research. Methods Members of the American Headache Society and the Canadian Headache Society were invited to participate in the Non‐Inferiority Margins in Migraine Research (NIMM) survey. Adult and child neurologists with expertise in Headache Medicine were eligible to participate. The survey had a multiple choice format and comprised questions on respondent characteristics, eligibility, as well as expert opinion on non‐inferiority margins for outcomes commonly used in trials of both prophylactic and acute interventions for migraine. Results Ninety‐nine eligible respondents completed the survey. Most respondents were adult neurologists (84.9%) and 74% reported practicing in the USA. The following were the most commonly selected non‐inferiority margins: (1) change in monthly migraine attacks comparing baseline to the treatment period: 1 attack (39.4% selecting), (2) change in monthly migraine days comparing baseline to the treatment period: 1 day (44.4%), (3) change in average migraine intensity on a 4‐point scale comparing baseline to the treatment period: 1.0 (31.3%), (4) percentage of participants who are pain‐free 2 hours after the intervention: 5% (41.4%), (5) percentage of participants who have a migraine recurrence within 48 hours of treatment: 5% (42.4%), and (6) percentage of participants with sustained pain freedom: 5% (42.4%). Conclusions The results of the NIMM survey describe the opinions of a group of experts on appropriate non‐inferiority margins for outcomes commonly used in migraine clinical trials. There was significant variability in responses and lack of consensus on the choice of non‐inferiority margins. The survey did not incorporate the patient perspective and was not validated prior to distribution. Further work in this area is required in order to explore how to incorporate clinical considerations into the selection of non‐inferiority margins for migraine research.

We review controversies associated with randomized controlled trials (RCTs) stopped early for apparent benefit (truncated RCTs or tRCTs) and present our groups’ perspective. Long-established theory, simulations and recent empirical evidence demonstrate that tRCTs will on average overestimate treatment effects, and this overestimation may be large, particularly when tRCTs have small number of events. Theoretical considerations and simulations demonstrate that on average, meta-analyses of RCTs with appropriate stopping rules will lead to only trivial overestimation of treatment effects. However, tRCTs will disproportionally contribute to meta-analytic estimates when tRCTs occur early in the sequence of trials with few subsequent studies, publication of nontruncated RCTs is delayed, there is publication bias, or tRCTs result in a ‘freezing’ effect in which ‘correcting’ trials are never undertaken. To avoid applying overestimates of effect to clinical decision-making, clinicians should view the results of individual tRCTs with small sample sizes and small number of events with skepticism. Pooled effects from meta-analyses including tRCTs are likely to overestimate effect when there is a substantial difference in effect estimates between the tRCTs and the nontruncated RCTs, and in which the tRCTs have a substantial weight in the meta-analysis despite themselves having a relatively small number of events. Such circumstances call for sensitivity analyses omitting tRCTs.