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Results from pragmatic trials should reflect the comparative treatment effects encountered in patients in real-life clinical practice to guide treatment decisions. Therefore, pragmatic trials should focus on outcomes that are relevant to patients, clinical practice, and treatment choices. This sixth article in the series (see Box) discusses different types of outcomes and their suitability for pragmatic trials, design choices for measuring these outcomes, and their implications and challenges. Measuring outcomes in pragmatic trials should not interfere with real-world clinical practice to ensure generalizability of trial results, and routinely collected outcomes should be prioritized. Typical outcomes include mortality, morbidity, functional status, well-being, and resource use. Surrogate endpoints are typically avoided as primary outcome. It is important to measure outcomes over a relevant time horizon and obtain valid and precise results. As pragmatic trials are often open label, a less subjective outcome can reduce bias. Methods that decrease bias or enhance precision of the results, such as standardization and blinding of outcome assessment, should be considered when a high risk of bias or high variability is expected. The selection of outcomes in pragmatic trials should be relevant for decision making and feasible in terms of executing the trial in the context of interest. Therefore, this should be discussed with all stakeholders as early as feasible to ensure the relevance of study results for decision making in clinical practice and the ability to perform the study.

BackgroundPreventing central line-associated bloodstream infection (CLABSI) and catheter-associated urinary tract infection (CAUTI) remains challenging in intensive care units (ICUs).ObjectiveThe Agency for Healthcare Research and Quality Safety Program for ICUs aimed to reduce CLABSI and CAUTI in units with elevated rates.MethodsInvited hospitals had at least one adult ICU with elevated CLABSI or CAUTI rates, defined by a positive cumulative attributable difference metric (CAD >0) in the Centers for Disease Control and Prevention’s Targeted Assessment for Prevention strategy. This externally facilitated programme implemented by a national project team and state hospital associations included on-demand video modules and live webinars reviewing a two-tiered approach for implementing key technical and socioadaptive factors to prevent catheter infections, using principles and tools based on the Comprehensive Unit-based Safety Program. CLABSI, CAUTI and catheter use data were collected (preintervention 13 months, intervention 12 months). Multilevel negative binomial models assessed changes in catheter-associated infection rates and catheter use.ResultsOf 366 recruited ICUs from 220 hospitals in 16 states and Puerto Rico for two cohorts, 280 ICUs completed the programme including infection outcome reporting; 274 ICUs had complete outcome data for analyses. Statistically significant reductions in adjusted infection rates were not observed (CLABSI incidence rate ratio (IRR)=0.75, 95% CI 0.52 to 1.08, p=0.13; CAUTI IRR=0.79, 95% CI 0.59 to 1.06, p=0.12). Adjusted central line utilisation (IRR=0.97, 95% CI 0.93 to 1.00, p=0.09) and adjusted urinary catheter utilisation were unchanged (IRR=0.98, 95% CI 0.95 to 1.01, p=0.14).ConclusionThis multistate programme targeted ICUs with elevated catheter infection rates, but yielded no statistically significant reduction in CLABSI, CAUTI or catheter utilisation in the first two of six planned cohorts. Improvements in the interventions based on lessons learnt from these initial cohorts are being applied to subsequent cohorts.

This second article in the series on pragmatic trials describes the challenges in selection of sites for pragmatic clinical trials and the impact on validity, precision, and generalizability of the results. The selection of sites is an important factor for the successful execution of a pragmatic trial and impacts the extent to which the results are applicable to future patients in clinical practice. The first step is to define usual care and understand the heterogeneity of sites, patient demographics, disease prevalence and country choice. Next, specific site characteristics are important to consider such as interest in the objectives of the trial, the level of research experience, availability of resources, and the expected number of eligible patients. It can be advisable to support the sites with implementing the trial-related activities and minimize the additional burden that the research imposes on routine clinical practice. Health care providers should be involved in an early phase of protocol development to generate engagement and ensure an appropriate selection of sites with patients who are representative of the future drug users.

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