Department of Perioperative Medicine, CHU Clermont-Ferrand, 58 Rue Montalembert, 63000, Clermont-Ferrand, France.
iGReD, CNRS, INSERM, Université Clermont Auvergne, Clermont-Ferrand, France.
Crit Care. 2023 Aug 1;27(1):303. doi: 10.1186/s13054-023-04562-y.
Ventilator-free days (VFDs) are a composite endpoint increasingly used as the primary outcome in critical care trials. However, because of the skewed distribution and competitive risk between components, sample size estimation remains challenging. This systematic review was conducted to systematically assess whether the sample size was congruent, as calculated to evaluate VFDs in trials, with VFDs' distribution and the impact of alternative methods on sample size estimation.
A systematic literature search was conducted within the PubMed and Embase databases for randomized clinical trials in adults with VFDs as the primary outcome until December 2021. We focused on peer-reviewed journals with 2021 impact factors greater than five. After reviewing definitions of VFDs, we extracted the sample size and methods used for its estimation. The data were collected by two independent investigators and recorded in a standardized, pilot-tested forms tool. Sample sizes were calculated using alternative statistical approaches, and risks of bias were assessed with the Cochrane risk-of-bias tool.
Of the 26 clinical trials included, 19 (73%) raised "some concerns" when assessing risks of bias. Twenty-four (92%) trials were two-arm superiority trials, and 23 (89%) were conducted at multiple sites. Almost all the trials (96%) were unable to consider the unique distribution of VFDs and death as a competitive risk. Moreover, significant heterogeneity was found in the definitions of VFDs, especially regarding varying start time and type of respiratory support. Methods for sample size estimation were also heterogeneous, and simple models, such as the Mann-Whitney-Wilcoxon rank-sum test, were used in 14 (54%) trials. Finally, the sample sizes calculated varied by a factor of 1.6 to 17.4.
A standardized definition and methodology for VFDs, including the use of a core outcome set, seems to be required. Indeed, this could facilitate the interpretation of findings in clinical trials, as well as their construction, especially the sample size estimation which is a trade-off between cost, ethics, and statistical power. Systematic review registration PROSPERO ID: CRD42021282304. Registered 15 December 2021 ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021282304 ).
无呼吸机天数（VFDs）作为重症监护试验的主要结局指标，其使用日益广泛。然而，由于组成部分之间的分布偏态和竞争风险，样本量估计仍然具有挑战性。本系统评价旨在系统评估试验中评估 VFDs 的样本量是否与 VFDs 的分布以及替代方法对样本量估计的影响相一致。
在 PubMed 和 Embase 数据库中进行了系统的文献检索，检索成人 VFDs 为主要结局的随机临床试验，检索时间截至 2021 年 12 月。我们重点关注影响因子大于 5 的同行评议期刊。在回顾了 VFDs 的定义后，我们提取了样本量及其估计方法。数据由两名独立的研究者收集，并记录在标准化的、经过试点测试的表格工具中。使用替代的统计方法计算样本量，并使用 Cochrane 偏倚风险工具评估偏倚风险。
在纳入的 26 项临床试验中，19 项（73%）在评估偏倚风险时存在“一些关注”。24 项（92%）试验为两臂优效性试验，23 项（89%）试验在多个地点进行。几乎所有试验（96%）都无法考虑 VFDs 和死亡的独特分布作为竞争风险。此外，VFDs 的定义存在显著的异质性，特别是在开始时间和呼吸支持类型方面。样本量估计方法也存在异质性，14 项（54%）试验使用了简单的模型，如 Mann-Whitney-Wilcoxon 秩和检验。最终，计算出的样本量相差 1.6 到 17.4 倍。
似乎需要一种标准化的 VFDs 定义和方法，包括使用核心结局集。实际上，这将有助于解释临床试验中的发现，并有助于其构建，特别是样本量估计，这是成本、伦理学和统计功效之间的权衡。系统评价注册 PROSPERO ID：CRD42021282304。于 2021 年 12 月 15 日注册（https://www.crd.york.ac.uk/prospero/display_record.php？ID=CRD42021282304）。
