Potential placebo bias in current trials of delirium prevention: a network meta-analysis of 86 randomized controlled trials

Aim: Numerous network meta-analyses (NMAs) have reported inconsistent findings on the efficacy of various pharmacologic treatments for delirium prevention in high-risk patients. A potential confounder was the study design—using a placebo control or standard-of-care (SoC) control. We reexamined the incident delirium between SoC plus placebo and SoC alone in randomized controlled trials (RCTs) on delirium prevention. Methods: We systematically searched for relevant RCTs on pharmacotherapies for delirium prevention from the inception of electronic databases through 30 November 2023. The primary outcome was delirium incidence, with secondary consideration given to all-cause mortality. We conducted a frequentist NMA using risk ratios (RRs) with 95% confidence intervals (CIs) as the effect size. Results: The NMA results from 86 RCTs (19,889 participants, with a mean age of 68.5 years, and a mean female proportion of 44.0%) revealed that SoC plus placebo was associated with a lower risk of incident delirium than SoC alone (RR, 0.60 [95% CI, 0.41–0.88]). The RR of all-cause mortality was not significant between these two study designs. Conclusion: We found placebo effects on the incidence of delirium in RCTs involving high-risk patients. Further RCTs should consider a three-arm, parallel design including both a placebo group and an SoC group to replicate our study findings. Trial Registration: CRD42023488481.