The role of randomized cluster crossover trials for comparative effectiveness testing in anesthesia: design of the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial

Abstract

Increasingly, clinicians and researchers recognize that studies of interventions need to evaluate not only their therapeutic efficacy (i.e., the effect on an outcome in ideal, controlled settings) but also their real-world effectiveness in broad, unselected patient groups. Effectiveness trials inform clinical practice by comparing variations in therapeutic approaches that fall within the standard of care. In this article, we discuss the need for studies of comparative effectiveness in anesthesia and the limitations of individual patient randomized-controlled trials in determining comparative effectiveness. We introduce the concept of randomized cluster crossover trials as a means of answering questions of comparative effectiveness in anesthesia, using the design of the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial (Clinicaltrials.gov identifier NCT03053869).

When and how should we cluster and cross over: methodological and ethical issues (letter 2)

“…In designing the Benzodiazepine-Free Cardiac Anesthesia for Reduction in Postoperative Delirium (B-Free) trial, we accounted for these methodological issues. 3 Cluster-randomized trials could result in inflated Type I error because analyses are conducted at the individual level but randomization is at the cluster level and members of the same cluster tend to have more similar responses than members of different clusters. Therefore, it is crucial to account for the effect of clustering in sample size considerations and in statistical analysis.…”

In reply: When and how should we cluster and cross over: methodological and ethical issues (letters 1 and 2)

“…In their article, Spence et al argue that cluster randomized crossover trials are ''the preferred method to evaluate questions of effectiveness'' in anesthesia, and that ''individual RCTs are not the preferred design.'' 1 To illustrate the utility of this design, the authors discuss the B-Free pilot trial and ''expect to begin the [full-scale] trial in the summer of 2018.'' 1 In our commentary, we argue, ''individual (not cluster) randomization is the gold standard study design to evaluate questions of both efficacy and effectiveness.''…”

“…1 To illustrate the utility of this design, the authors discuss the B-Free pilot trial and ''expect to begin the [full-scale] trial in the summer of 2018.'' 1 In our commentary, we argue, ''individual (not cluster) randomization is the gold standard study design to evaluate questions of both efficacy and effectiveness.'' 2 Our arguments are not specific to the B-Free trial since, to date, no protocol has been published.…”

“…But the institutional policy of benzodiazepine administration is an individual-level intervention, as it is divisible individually. Patients in the intervention arm will receive benzodiazepines ''unless there are contraindications'' 1 and refusal to consent should be a contraindication.…”

Loopholes in the Research Ethics System? Informed Consent Waivers in Cluster Randomized Trials with Individual‐Level Intervention

“…For instance, Spence and colleagues describe the B-Free trial, an individual-cluster trial (using a multiple period cluster crossover design) of benzodiazepine use in anesthesia. 14 The B-Free trial randomizes hospitals to liberal versus restrictive policies of benzodiazepine use during cardiac anesthesia to evaluate the impact on postoperative delirium. Spence et al argue that seeking informed consent from patients would introduce bias, particularly if one study arm were viewed as more desirable by potential participants.…”