Indomethacin with or without prophylactic pancreatic stent placement to prevent pancreatitis after ERCP: a randomised non-inferiority trial.

BACKGROUND: The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention. METHODS: In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete. FINDINGS: Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6-6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups. INTERPRETATION: For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement. These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines. FUNDING: US National Institutes of Health.

Sex-specific disparities in COVID-19 outcomes.

Objectives: Sex-specific disparities in morbidity and mortality of COVID-19 illness are not well understood. Neutralizing antibodies (Ab) may protect against severe COVID-19 illness. We investigated the association of sex with disease progression and SARS-CoV-2 Ab response. Methods: In this exploratory analysis of the phase 3, multicenter, randomized, placebo-controlled Convalescent Plasma in Outpatients (C3PO) trial, we examined whether sex was associated with progression to severe illness, defined as a composite of all-cause hospitalization, emergency/urgent care visit, or death within 15 days from study enrollment. Patients had a positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test, symptom onset within 7 days, stable condition for emergency department discharge, and were either ≥50 years old or had at least one high-risk feature for disease progression. Patients received blinded convalescent plasma or placebo in a 1:1 fashion and were evaluated on days 15 and 30 after infusion. Blood samples were collected on day 0 (pre-/post-infusion), 15, and 30 to measure Ab levels with the Broad Institute using the Plaque Reduction Neutralization Test assay. Results: Of 511 patients enrolled (median age 54 [Iinterquartile range 41-62] years, 46% male, 66% white, 20% black, 3.5% Asian), disease progression occurred in 36.7% of males and 25.9% of females (unadjusted risk difference 10.8%, 95% confidence interval [CI], 2.8-18.8%). Sex-disparities did not persist when adjusted for treatment group, age, viremic status, symptom onset, and tobacco use (adjusted risk difference 5.6%, 95% confidence interval [CI], -2.2% to 13.4%), but were present in the subgroup presenting 3 or more days after symptom onset (adjusted risk difference 12.6%, 95% CI, 3.4% to 21.9%). Mean baseline Ab levels (log scale) available for 367 patients were similar between sexes (difference 0.19 log units, 95% CI, -0.08 to 0.46). The log-scale mean increase from baseline to day 15 after adjusting for treatment assignment and baseline levels was larger in males than females (3.26 vs. 2.67). A similar difference was noted when the groups were subdivided by outcome. Conclusions: Progression of COVID-19 was similar in males and females when adjusted for age, tobacco use, and viremia status in this study. However, in the cohort presenting 3 or more days after symptom onset, COVID-19 outcomes were worse in males than females. Neutralizing Ab levels increased more in males but did not correlate with sex differences in outcomes.

An Expected Score Approach to Ordinal Outcomes in a Bayesian, Response Adaptive, Randomized Trial.

Ordinal outcomes are common in medicine and can be analyzed in many ways, but the distribution of ordinal data can present unique challenges. The proposed KESETT study is a three-armed, randomized trial comparing two doses of ketamine plus levetiracetam to levetiracetam alone for treating patients with benzodiazepine-refractory status epilepticus. A Bayesian, adaptive clinical trial is proposed employing an ordinal primary outcome at 60 minutes ranging from 1 (improving consciousness and seizure cessation) to 5 (life-threatening event/death). Based on a previous study, the ordinal outcome is expected to have a bimodal distribution, with the effect of treatment expected to be non-proportional across the outcome scale. As such, approaches relying on assuming proportionality of the odds are not appropriate. We propose for this scenario an analytic approach to compare ordinal outcomes using the expected score derived from the posterior distribution for each treatment group. This approach requires minimal assumptions, maintains the benefit of using the full ordinal scale, is interpretable, and can be used in a Bayesian analysis framework. We compare this new approach under multiple simulated scenarios to 3 traditional frequentist approaches. The new approach controls type I error and power, resulting in a sizable reduction in sample size relative to a non-parametric test.

Accounting for Liver Transplant in Acute Liver Failure Research.

Background and Aims: Acute liver failure (ALF) is a rare but serious disease with challenging clinical decisions, including the possibility of liver transplantation. Although there is interest in predicting who will need a transplant, that outcome is difficult to define as the decision to transplant includes many extraneous factors. The majority of research in this setting focuses on identifying factors that can provide guidance on a patient's likelihood of survival without a liver transplant. The question that arises is whether death and transplant should be combined as a poor outcome or should alternative approaches be used to account for transplant in this setting. Furthermore, does the approach to incorporating transplant information impact the accuracy of predicting survival. We aim to compare alternative analytic methods for the ALF setting to provide guidance to the clinical research community on how to handle transplant when the outcome of interest is survival without a transplant. Methods: Five analysis approaches are compared based on model performance using existing registry data from 2100 ALF patients: logistic regression with transplant as part of the outcome, logistic regression with transplant as a covariate, inverse probability weighting, survival analysis, and multiple imputation. Results: The various models exhibit comparable model fit with each providing advantages and challenges in implementation. Conclusion: There are alternative modeling approaches in the ALF setting, leaving researchers with multiple valid options for how to include transplant when examining factors that may influence transplant-free survival.