创伤性出血试验样本量方法的系统评价和荟萃分析。

A systematic review and meta-analysis of sample size methodology for traumatic hemorrhage trials.

机构信息

From the Faculty of Medicine (J.G.), University of Ottawa, Ottawa, Ontario, Canada; Department of Medicine (J.G.), The Ottawa Hospital, Ottawa, Ontario, Canada; Department of Critical Care (S.M.F.), Lakeridge Health Corporation, Oshawa, Canada; Division of Critical Care, Department of Medicine (B.R.), McMaster University, Hamilton, Canada; Department of Health Research Methods (B.R.), Evidence, and Impact, McMaster University, Hamilton, Canada; Division of Acute Care Surgery, Department of Surgery (K.I.), University of Southern California, Los Angeles, California; Division of General Surgery, Department of Surgery (J.L., A.T.), University of Ottawa, Ontario, Canada; and Division of Critical Care, Department of Medicine (A.T.), University of Ottawa, Ontario, Canada.

出版信息

J Trauma Acute Care Surg. 2023 Jun 1;94(6):870-876. doi: 10.1097/TA.0000000000003944. Epub 2023 Mar 7.

DOI:10.1097/TA.0000000000003944

PMID:36879398

Abstract

BACKGROUND

Trauma hemorrhage remains the most common cause of preventable mortality in trauma. To guide clinical practice, RCTs provide high-quality evidence to inform clinical decision making. The clinical relevance and inferences made by RCTs are dependent on assumptions made during sample size calculation.

METHODS

To describe the quality of methodology for sample size determination, we conducted a systemic review RCTs evaluating interventions that aim to improve survival in adults with trauma-related hemorrhage. Estimated and actual outcome data are compared, including components of sample size determination.

RESULTS

A total of 13 RCTs were included. We noted a high rate of negative trial results (11 of 13 studies). Most studies were multi-center and conducted in North America, evaluating patients with blunt and penetrating injuries. The criteria for hemorrhagic shock varied across studies. All studies did not accurately estimate the mortality rate during sample size calculation. All but one study overestimated the mortality reduction during sample size calculation; the median absolute mortality reduction was 3%, compared with a target of 10%. Only the CRASH-2 study used a minimal clinically important different for treatment effect target. No RCTs employed prognostic enrichment. Most studies were terminated (8 of 13), mainly for futility.

CONCLUSION

Taken together, this review highlights that current clinical trial methodology is limited by imprecise control group risk estimates, overly optimistic treatment effect estimates, and lack of transparent justification for such targets. These limitations result in studies at high risk for futility and potentially premature abandonment of promising therapies. Given the high morbidity and mortality of trauma-related hemorrhage, we recommend that future conduct of trauma RCTs incorporate (1) prognostic enrichment to inform baseline risk, (2) justify target treatment differences based on clinical importance and realistic estimates of feasibility, and (3) be transparent and provide justification for the assumptions made.

LEVEL OF EVIDENCE

Systematic Review/Meta-Analysis; Level III.

摘要

背景

创伤性出血仍然是创伤患者中最常见的可预防死亡原因。为了指导临床实践，RCT 提供高质量的证据来为临床决策提供信息。RCT 的临床相关性和推论取决于样本量计算过程中的假设。

方法

为了描述样本量确定方法的质量，我们对评估旨在提高创伤相关出血成人存活率的干预措施的 RCT 进行了系统回顾。比较了估计和实际的结果数据，包括样本量确定的组成部分。

结果

共纳入 13 项 RCT。我们注意到阴性试验结果的比例很高（13 项研究中有 11 项）。大多数研究是多中心的，并且在北美进行，评估的是钝性和穿透性损伤的患者。出血性休克的标准在研究之间有所不同。所有研究在样本量计算中都没有准确估计死亡率。除了一项研究外，所有研究在样本量计算中都高估了死亡率降低程度；中位数绝对死亡率降低为 3%，而目标值为 10%。只有 CRASH-2 研究使用了治疗效果目标的最小临床重要差异。没有 RCT 采用预后富集。大多数研究（13 项中有 8 项）因无效而终止。

结论

总的来说，本综述强调了当前临床试验方法学受到以下因素的限制：对照组风险估计不精确、治疗效果估计过于乐观，以及缺乏对这些目标的透明论证。这些局限性导致研究具有很高的无效风险，并可能过早放弃有前途的治疗方法。鉴于创伤相关出血的高发病率和死亡率，我们建议未来进行创伤 RCT 时应考虑以下几点：（1）预后富集以告知基线风险；（2）根据临床重要性和现实可行性估计，为目标治疗差异提供正当理由；（3）透明并为所做的假设提供正当理由。