Age-dependent heterogeneity in the efficacy of prophylaxis with enoxaparin against catheter-associated thrombosis in critically ill children

危重儿童依诺肝素预防导管相关血栓形成效果的年龄依赖性异质性

• 批准号: 10297366
• 负责人: EDWARD VINCENT FAUSTINO
• 金额: $ 80.06万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297366
• 关键词: 1 year old; 17 year old; Address; Adult; Age; Anticoagulants; Bayesian Analysis; Bayesian Method; Bayesian Modeling; Biological Markers; Blood coagulation; Catheters; Cessation of life; Child; Child Development; Childhood; Clinical; Clinical Trials; Clinical Trials Design; Coagulation Process; Critical Illness; Critically ill children; Deep Vein Thrombosis; Development; Dose; Enoxaparin; Event; Funding; Generations; Goals; Hemorrhage; Heterogeneity; Hospitalized Child; Hour; Incidence; Infant; National Institute of Child Health and Human Development; Nested Case-Control Study; Observational Study; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Plasma; Prevention strategy; Prophylactic treatment; Randomized; Randomized Clinical Trials; Research Priority; Risk; Risk Factors; Safety; System; Testing; Therapeutic; Thrombin; Thrombosis; Thrombus; Time; Treatment Efficacy; Ultrasonography; Venous; age effect; age related; arm; clinically relevant; improved; innovation; prevent; prophylactic; treatment as usual; venous thromboembolism

PROJECT SUMMARY Pediatric venous thromboembolism (VTE), which is predominantly deep venous thrombosis (DVT), is a top contributor to harm in hospitalized children. Critical illness and central venous catheter (CVC) are the most important risk factors for VTE in children. Among critically ill children, the risk of CVC-associated DVT (CADVT) is as high as 54% with 72% of cases in infants <1-year old. Given that VTE is generally preventable in adults with pharmacologic prophylaxis, national initiatives are ongoing to prevent VTE in children. However, the incidence of pediatric VTE has not decreased in 2 decades. Due to paucity of age-appropriate evidence on its efficacy against CADVT, pharmacologic prophylaxis is uncommon in children. Extrapolation of evidence from adults is not appropriate because the coagulation system changes significantly with age. We recently completed a Bayesian phase 2b randomized clinical trial funded by NICHD. In this trial, we randomized critically ill children to early administration of prophylactic dose of enoxaparin, the most commonly used anticoagulant for prophylaxis, or usual care. Prophylaxis with enoxaparin appeared to reduce the risk of CADVT by half. In post hoc analyses, the reduction was limited to older children ≥1-year old. The goal of the proposed Catheter-Related Early Thromboprophylaxis with Enoxaparin (CRETE) Studies is to investigate this newly identified age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of CADVT in critically ill children. To achieve this goal, we aim (1) to confirm the efficacy and safety of early administration of prophylactic dose of enoxaparin in reducing the risk of CADVT in critically ill older children; (2) to determine the efficacy and safety of early administration of therapeutic dose of enoxaparin in reducing the risk of CADVT in critically ill infants; and, (3) to probe the mechanisms that underly the age-dependent heterogeneity in the efficacy of enoxaparin in reducing the risk of CADVT in critically ill children. We will conduct 2 multicenter Bayesian explanatory randomized clinical trials in parallel to address Specific Aims 1 and 2. Depending on age, subjects will be randomized to different doses of enoxaparin vs usual care. Subjects will be systematically assessed for the development of CADVT using ultrasonography and clinically for bleeding. Using plasma obtained from subjects in the 2 trials, we will conduct an exploratory mechanistic nested case-control study to address Specific Aim 3. Biomarkers of the different mechanisms underlying CVC-associated thrombus formation, particularly thrombin generation, will be compared between subjects with and without CADVT. We will use Bayesian methods to improve the efficiency in the conduct and analyses of these studies. The proposed CRETE Studies address NICHD’s research priorities on child development, critical illness, therapeutics and innovative clinical trial design. They will provide high-quality age-appropriate evidence that will inform preventive strategies against CADVT and decrease harm in hospitalized children.

项目摘要 儿科静脉血栓栓塞症（VTE），主要是深静脉血栓形成（DVT），是一种 对住院儿童造成伤害的最大因素。危重病和中心静脉导管（CVC）是最多的 儿童VTE的重要危险因素。在重症儿童中，CVC相关DVT（CADVT）的风险 高达54%，其中72%的病例发生在1岁以下的婴儿中。由于成人的静脉血栓栓塞通常是可以预防的， 通过药物预防，国家正在采取措施预防儿童静脉血栓栓塞。但 儿童静脉血栓栓塞的发病率在20年内没有下降。由于缺乏与年龄相适应的证据， 对CADVT的疗效，药物预防在儿童中并不常见。外推证据， 成年人不适合，因为凝血系统随年龄变化很大。我们最近 完成了由NICHD资助的贝叶斯2b期随机临床试验。在这项试验中，我们随机 危重患儿早期给予预防性剂量的依诺肝素，最常用 抗凝剂预防或常规护理。用依诺肝素预防似乎可以降低 CADVT减半。在事后分析中，降低仅限于≥1岁的大龄儿童。的目标 一项建议的依诺肝素导管相关早期血栓预防（CRETE）研究就是要研究这一点 新发现的依诺肝素降低CADVT风险的疗效的年龄依赖性异质性， 重症患儿。为了实现这一目标，我们的目标是（1）确认早期给予 预防性剂量的依诺肝素在降低重症大龄儿童CADVT风险中的作用;（2）确定 早期应用治疗剂量依诺肝素降低老年人CADVT风险的有效性和安全性 危重婴儿;和，（3）探讨机制，在年龄依赖性异质性的基础上， 依诺肝素降低危重患儿CADVT风险的有效性我们将进行2个多中心 贝叶斯解释性随机临床试验平行解决特定目标1和2。取决于 年龄，受试者将随机接受不同剂量的依诺肝素与常规治疗。受试者将系统地 使用超声检查和临床出血评估CADVT的发展。使用等离子体 从2项试验的受试者中获得，我们将进行一项探索性机制巢式病例对照研究， 具体目标3. CVC相关血栓不同机制的生物标志物 将在患有和不患有CADVT的受试者之间比较凝血酶形成，特别是凝血酶生成。我们 将使用贝叶斯方法来提高这些研究的执行和分析效率。的 拟议的CRETE研究解决了NICHD在儿童发育，危重疾病， 创新的临床试验设计。他们将提供高质量的适龄证据， 将告知预防CADVT的策略，并减少住院儿童的伤害。