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

## TL;DR

This study finds that placebo treatments may reduce delirium risk in high-risk patients, suggesting bias in current trial designs.

## Contribution

The novelty is identifying placebo effects in delirium prevention trials, which could influence future trial designs.

## Key findings

- SoC plus placebo was associated with a 40% lower risk of delirium compared to SoC alone.
- All-cause mortality did not differ significantly between SoC plus placebo and SoC alone.
- The study suggests a three-arm trial design to better assess placebo effects.

## Abstract

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.

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.

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.

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.

CRD42023488481.