Pediatric Heart Network - The Hospital for Sick Children, Toronto

儿科心脏网络 - 多伦多病童医院

• 批准号: 8486376
• 负责人: BRIAN W MCCRINDLE
• 金额: $ 32.39万
• 依托单位: HOSPITAL FOR SICK CHLDRN (TORONTO)
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8486376
• 关键词: Address; Adult; Age; Age-Months; Anticoagulants; Antiplatelet Drugs; Benefits and Risks; Blood Circulation; Blood Platelets; Blood Vessels; Cardiac; Catheterization; Cause of Death; Cessation of life; Child; Child Mortality; Childhood; Clinical; Clinical Trials; Coagulation Process; Common Ventricle; Data; Data Analyses; Decision Making; Diagnosis; Dose; Double-Blind Method; Drug Targeting; Drug effect disorder; Embolism; Enrollment; Event; Fibrin; Fontan Procedure; Freedom; Genetic; Genetic Polymorphism; Guidelines; Heart; Hemorrhage; Heparin; Hospitalization; Hospitals; Infant; Intervention; Lead; Length of Stay; Lesion; Low Prevalence; Measures; Medical History; Metabolism; Methodology; Minor; Monitor; Morbidity - disease rate; New Agents; Obstruction; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Physiology; Population; Prevalence; Prevention; Principal Investigator; Procedures; Property; Pulmonary Embolism; Pulmonary artery structure; Randomized; Relative (related person); Relative Risks; Repeat Surgery; Research; Residual state; Resources; Risk; Risk Reduction; Safety; Shunt Device; Site; Staging; Stenosis; Stratification; Stress; Stroke; Superior Vena Cava Syndrome; Testing; Therapeutic; Therapeutic Embolization; Thrombectomy; Thrombophilia; Thrombosis; Thrombus; Time; Transplantation; Ultrasonography; Venous; Venous Thrombosis; Warfarin; artery stenosis; base; clopidogrel; congenital heart disorder; drug metabolism; evidence base; hazard; high risk; improved; innovation; mortality; neonate; neurodevelopment; novel; palliative; prevent; primary outcome; response; risk benefit ratio; secondary outcome

DESCRIPTION (provided by applicant): Thrombosis and thrombosis-related complications are under-recognized, yet contribute important morbidity and mortality for children with congenital heart disease. Patients with functional single ventricle undergoing palliative staging procedures towards eventual Fontan procedure are at particularly high risk, with 40% having clinically important thrombosis events before reaching superior cavopulmonary connection (SCPC), and a further 28% having events up to Fontan. The use of thromboprophylaxis is limited by lack of a sufficient evidence base and suboptimal risk-benefit ratio of currently used agents. An innovative 2 step randomized double blind clinical trial utilizing new agents is proposed to rigorously address this significant problem. For Step 1, subjects with functional single ventricle who are expected to proceed to SCPC will be enrolled at the time of initial presentation and diagnosis, and randomized to prasugrel or dabigatrin after baseline thrombophilia and genetics assessment. Subjects will be monitored up to SCPC for the primary outcome of clinically important thrombosis events, as well as compliance and bleeding complications. For Step 2, remaining subjects will have their assigned study drug discontinued just before SCPC, and after SCPC will be randomized to prasugrel or dabigatran. Surveillance vascular ultrasound will be obtained 4-10 days after SCPC, and subjects will be followed to 18 months of age with monitoring for the primary outcome, compliance and bleeding complications. At 18 months of age, surveillance vascular ultrasound and neurodevelopmental assessment will be obtained. Competing risks methodology will be used for data analysis to determine relative hazard reduction for time-related clinically important thrombosis events both for Step 1 and Step 2. The study will have 85% power to detect a 25% and 33% relative risk reduction for Step 1 and Step 2, respectively. Risk (bleeding)/benefit (thrombosis prevention) ratios will be also be compared. Factors (thrombophilia, genetic polymorphisms) associated with thrombosis and risk/benefit will be explored. This study will be an important contribution to the evidence base, study the use of novel agents in a high risk population, and identify factors that will enable risk-stratification and improved outcomes. RELEVANCE: Patients with functional single ventricle (severe congenital heart disease), continue to have the highest rates of morbidity and mortality, and thrombosis is an important contributor that has not been adequately recognized or addressed. The proposed research will rigorously determine the risk and spectrum of thrombosis, test new agents for preventing thrombosis, and identify thrombophilia and genetic polymorphism factors that may lead to better targeting of interventions and overall improved outcomes.

描述（由申请人提供）： 血栓形成和血栓形成相关的并发症是认识不足，但贡献了重要的发病率和死亡率的儿童先天性心脏病。功能性单心室患者接受姑息性分期手术，最终进行Fontan手术的风险特别高，40%的患者在达到上级腔静脉连接（SCPC）之前发生了具有临床意义的血栓形成事件，另有28%的患者发生了Fontan事件。血栓预防的使用受到缺乏足够证据基础和目前使用药物的风险-受益比不佳的限制。一个创新的2步随机双盲临床试验，利用新的代理人提出严格解决这一重大问题。对于第1步，预计将进行SCPC的功能性单心室受试者将在初次就诊和诊断时入组，并在基线血栓形成倾向和遗传学评估后随机接受普拉格雷或达比加群酯治疗。将对受试者进行监测，直至SCPC，以了解具有临床意义的血栓形成事件的主要结局以及依从性和出血并发症。对于第2步，其余受试者将在SCPC前立即停用分配的研究药物，并在SCPC后随机接受普拉格雷或达比加群。将在SCPC后4-10天进行监测血管超声检查，并对受试者进行随访至18个月，监测主要结局、依从性和出血并发症。在18个月大时，将获得监测血管超声和神经发育评估。竞争风险方法将用于数据分析，以确定步骤1和步骤2中时间相关的临床重要血栓形成事件的相对风险降低。本研究将有85%的把握度检测到步骤1和步骤2的相对风险分别降低25%和33%。还将比较风险（出血）/受益（血栓形成预防）比。将探索与血栓形成和风险/获益相关的因素（血栓形成倾向、遗传多态性）。这项研究将对证据基础做出重要贡献，研究新型药物在高危人群中的使用，并确定能够进行风险分层和改善结局的因素。 相关性：功能性单心室（严重先天性心脏病）患者的发病率和死亡率仍然最高，血栓形成是一个尚未得到充分认识或解决的重要因素。拟议的研究将严格确定血栓形成的风险和范围，测试预防血栓形成的新药物，并确定可能导致更好的干预目标和总体改善结果的血栓形成倾向和遗传多态性因素。