Platform trials.

Platform trials focus on the perpetual testing of many interventions in a disease or a setting. These trials have lasting organizational, administrative, data, analytic, and operational frameworks making them highly efficient. The use of adaptation often increases the probabilities of allocating participants to better interventions and obtaining conclusive results. The COVID-19 pandemic showed the potential of platform trials as a fast and valid way to improved treatments. This review gives an overview of key concepts and elements using the Intensive Care Platform Trial (INCEPT) as an example.

Abnormal serum levels of magnesium, phosphate, and zinc in ICU patients-Characteristics, management, and outcomes: The WhyTrace cohort study.

BACKGROUND: Abnormal serum levels of magnesium, phosphate, and zinc appear common in intensive care unit (ICU) patients, but the epidemiology, management, and associations with outcomes are less well described. We described these factors and estimated associations with outcomes in a large dataset of Danish ICU patients. METHODS: We included adults who were acutely admitted to 10 general ICUs in Denmark between October 2011 and January 2018. From the dataset, we obtained characteristics of patients who had serum levels measured of magnesium, phosphate, or zinc, including data on supplementation. We used joint models with death as a competing outcome to estimate the associations between abnormal serum levels and time to successful extubation and, for magnesium, also incident tachyarrhythmia. RESULTS: We included 16,517 of 36,514 patients in the dataset. The cumulative probability of hypomagnesemia within 28 days was 64% (95% confidence interval [CI] 62-66); of hypophosphatemia 74% (95% CI 72-75); and of hypozincemia 98% (95% CI 98-98). Supplementation of magnesium was used in 3554 out of 13,506 (26%) patients, phosphate in 2115 out of 14,148 (15%) patients, and zinc in 4465 out of 9869 (45%) patients. During ICU stay, 38% experienced hypermagnesemia, 58% hyperphosphatemia, and 1% hyperzincemia. Low serum levels of magnesium, phosphate, and zinc were associated with shorter time to successful extubation, and high serum magnesium and phosphate and low serum zinc with the competing risk of increased mortality, but too few serum measurements made the results inconclusive. CONCLUSION: In this multicenter cohort study of acutely admitted ICU patients, most experienced low serum levels of magnesium, phosphate, or zinc during ICU stay, many received supplementation, and experiencing both low and high serum levels during ICU stay was not uncommon. Associations between serum levels and clinical outcomes appeared inconclusive because the data proved unfit for these analyses.

Patient-Important Outcomes Other Than Mortality in Contemporary ICU Trials: A Scoping Review.

OBJECTIVES: Randomized clinical trials (RCTs) conducted in adult ICU patients increasingly include patient-important outcomes other than mortality. This comes with challenges regarding outcome choices/definitions, handling of deceased patients and missing data in analyses, and choices of effect measures and statistical methods due to complex distributions. This scoping review aimed to characterize how these challenges are handled in relevant contemporary RCTs. DATA SOURCES: We systematically searched 10 selected journals for RCTs conducted primarily in adult ICU patients published between 1 January 2018 and 5 May 2022 reporting at least one patient-important outcome other than mortality, including "days alive without"…-type outcomes, functional/cognitive/neurologic outcomes, health-related quality of life (HRQoL) outcomes, and ordinal/other outcomes. STUDY SELECTION: Abstracts and full-texts were assessed independently and in duplicate by two reviewers. DATA EXTRACTION: Data were extracted independently and in duplicate by two reviewers using predefined and pilot-tested extraction forms and subsequently categorized to facilitate analysis. DATA SYNTHESIS: We included 687 outcomes from 167 RCTs, with 32% of RCTs using a patient-important outcome other than mortality as a (co-)primary outcome, most frequently "days alive without"…-type outcomes. Many different functional/cognitive/neurologic (103) and HRQoL (29) outcomes were reported. Handling of deceased patients varied, with analyses frequently restricted to survivors only for functional/cognitive/neurologic (62%) and HRQoL (89%) outcomes. Follow-up was generally longer and missing data proportions higher for functional/cognitive/neurologic and HRQoL outcomes. Most outcomes were analyzed using nonparametric tests (31%), linear regression/ t tests (27%), chi-square-like tests (12%), and proportional odds logistic regression (9%), often without presentation of actual treatment effects estimates (38%). CONCLUSIONS: In this sample of RCTs, substantial variation in practice and suboptimal methodological choices were observed. This calls for increased focus on standardizing outcome choices and definitions, adequate handling of missing data and deceased patients in analyses, and use of statistical methods quantifying effect sizes.

Heterogeneity of treatment effect of stress ulcer prophylaxis in ICU patients: A secondary analysis protocol.

BACKGROUND: In the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial, 3291 adult ICU patients at risk for gastrointestinal (GI) bleeding were randomly allocated to intravenous pantoprazole 40 mg or placebo once daily in the ICU. No difference was observed between the groups in the primary outcome 90-day mortality or the secondary outcomes, except for clinically important gastrointestinal bleeding. However, heterogeneity of treatment effect (HTE) not detected by conventional subgroup analyses could be present. METHODS: This is a protocol and statistical analysis plan for a secondary, post hoc, exploratory analysis of the SUP-ICU trial. We will explore HTE in one set of subgroups based on severity of illness (using the Simplified Acute Physiology Score [SAPS] II) and another set of subgroups based on the total number of risk factors for GI bleeding in each patient using Bayesian hierarchical models. We will summarise posterior probability distributions using medians and 95% credible intervals and present probabilities for different levels of benefit and harm of the intervention in each subgroup. Finally, we will assess if the treatment effect interacts with SAPS II and the number of risk factors separately on the continuous scale using marginal effects plots. CONCLUSIONS: The outlined post hoc analysis will explore whether HTE was present in the SUP-ICU trial and may help answer some of the remaining questions regarding the balance between benefits and harms of pantoprazole in ICU patients at risk of GI bleeding. CLINICALTRIALS. GOV REGISTRATION: NCT02467621.