Reducing risk of Anthracycline-related heart failure after childhood cancer

降低儿童癌症后与蒽环类药物相关的心力衰竭的风险

基本信息

批准号：
9103021
负责人：
Saro Armenian
金额：
$ 66.99万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9103021
关键词：
Address Adrenergic beta-Antagonists Adult Age Angiotensin-Converting Enzyme Inhibitors Anthracyclines Biological Markers Blood Cancer Survivor Cardiac Cardiotoxicity Cardiovascular system Caring Cessation of life Chest Child Childhood Childhood Cancer Treatment Clinical Trials Network Coronary Arteriosclerosis Coupled Deterioration Dimensions Dose Double-Blind Method EFRAC Early Intervention Endocrine system Enzyme Inhibition Exposure to Free Radical Formation Galectin 3 Generations Genetic Predisposition to Disease Health Heart Abnormalities Heart failure Hepatic Image Incidence Individual Injury Interruption Intervention Left Left Ventricular Dysfunction Left Ventricular Function Left Ventricular Remodeling Life Long-Term Survivors Lymphoma Malignant Childhood Neoplasm Measures Morbidity - disease rate Myocardial Myocardium Natriuretic Peptides Outcome Patient Self-Report Pediatric Oncology Pediatric Oncology Group Peptidyl-Dipeptidase A Phase Physiological Placebo Control Population Prevention Preventive Intervention Randomized Randomized Clinical Trials Recording of previous events Risk Risk Reduction Safety Stress Stroke Survival Rate Survivors Thick Time Toxic effect Ventricular Ventricular Remodeling Vulnerable Populations base carvedilol chemotherapy childhood cancer survivor clinical efficacy clinically relevant high risk improved malignant breast neoplasm mortality oncology patient population premature prevent randomized placebo controlled trial sarcoma treatment adherence

项目摘要

DESCRIPTION (provided by applicant): Childhood cancer survivors are at a 15-fold risk of developing heart failure (HF) compared to age-matched controls. There is a strong dose-dependent association between anthracyclines and risk of HF; the incidence approaches 20% at cumulative doses between 300-600 mg/m2, and exceeds 30% for doses >600 mg/m2. Outcome following HF is poor; 5-year survival rate is <50%. %. Nearly 60% of the childhood cancer survivors carry a history of prior anthracycline exposure. The growing number of survivors, coupled with the decades of life saved makes it imperative that we develop strategies to reduce the risk of HF in the vulnerable populations. Anthracycline cardiotoxicity is thought to be related to direct myocardial injury due to formation of free radicals, which initiates myocardia remodeling and subsequent left ventricular (LV) functional deterioration. ß-blockade or angiotensin-converting enzyme (ACE)-inhibition have been successfully used to prevent HF in adult non- oncology populations with asymptomatic LV dysfunction, as well as in pediatric non-oncology populations with genetic predisposition to HF, but with preserved cardiac function at the time of intervention. Increasing evidence supports the use of third generation ß-blockers such as carvedilol (combined ß1, ß 2, a1 blockade) to provide a comprehensive reversal of myocardial remodeling following exposure to high dose (HD)- anthracyclines (=300 mg/m2), when compared with the more selective ACE inhibitors. However, clinicians caring for childhood cancer survivors are reluctant to use these agents for prevention due in large part to the paucity of well-conducted randomized clinical trials that would provide the evidence for such an intervention. We propose a randomized, placebo-controlled trial of low-dose carvedilol (beta-blocker) in childhood cancer survivors treated with HD anthracyclines to determine the impact of a two-year course of carvedilol on LV Thickness-Dimension ratio (LV T-D) - an established echocardiographic marker of cardiac remodeling and HF risk in survivors of childhood cancer exposed to anthracyclines, and the primary endpoint for measuring efficacy in the study; additional echocardiographic (left ventricular: volume, ejection fraction [EF], mass/volume ratio, wall stress, systolic cardiac strain), functional (V02 Max), and blood biomarker (natriuretic peptides, galectin-3) measures of HF risk will be included as secondary endpoints. In addition, we plan to establish safety and tolerability of the two-year course of carvedilol in this populatio of survivors. The proposed intervention has the potential to significantly reduce ongoing cardiac injury via interruption of neuro-hormonal systems responsible for LV remodeling, resulting in improved cardiac function and decreased risk of HF. When completed, this study will provide critical information regarding plausible pharmacologic intervention for prevention of cardiac remodeling in anthracycline-exposed cancer survivors at highest risk for HF.

描述（由适用提供）：与年龄匹配的对照相比，儿童癌症存活率有15倍患心力衰竭（HF）的风险。蒽环类动物与HF风险之间存在很强的剂量依赖性关联。该事件的累积剂量在300-600 mg/m2之间接近20％，剂量> 600 mg/m2的剂量超过30％。 HF之后的结果很差； 5年生存率<50％。％。近60％的儿童癌症存活率具有先前的蒽环类暴露史。越来越多的生存，再加上挽救的数十年生命，我们必须制定策略来降低弱势群体中HF的风险。由于自由基的形成，蒽环类心脏毒性被认为与直接心肌损伤有关，该自由基的形成启动了心肌重塑和随后的左心室（LV）功能定义。 β-锁骨或血管紧张素转换酶（ACE）抑制作用已成功用于预防成人非对称的非对称LV功能障碍的成人非肿瘤学人群中的HF，以及在练习术时具有遗传性心脏的遗传性倾向的儿科非核心群体，具有遗传性倾向。越来越多的证据支持使用第三代car虫（例如卡维地醇（合并ß1，ß2，A1封锁）），以与更具选择性的ACE抑制剂相比，在暴露于高剂量（HD） - 蒽环类药物（= 300 mg/m2）之后，提供了心肌重塑的全面逆转。但是，携带儿童癌症存活的临床医生不愿使用这些药物来预防，这在很大程度上是由于缺乏良好的随机临床试验，这将为这种干预提供证据。 We proposed a randomized, placebo-controlled trial of low-dose carvedilol (beta-blocker) in childhood cancer survivals treated with HD anthracyclines to determine the impact of a two-year course of carvedilol on LV Thickness-Dimension Ratio (LV T-D) - an established echocardiographic marker of cardiac remodeling and HF risk in survivals of childhood cancer exposed to anthracyclines, and测量研究效率的主要终点；其他超声心动图（左心室：体积，射血分数[EF]，质量/体积比，壁应力，收缩期心脏应变），功能（V02 MAX）和血液生物标志物（NATRIURIETIC PEPPERS，GALECTIN-3）的HF风险度量将包括在内。此外，我们计划在这种生存的人群中建立两年的卡维il醇过程的安全性和耐受性。拟议的干预措施有可能通过中断负责LV重塑的神经激素系统的中断来显着减少持续的心脏损伤，从而改善心脏功能并改善HF的风险。完成后，这项研究将提供有关预防蒽环类癌症生存中心脏重塑的合理药理学干预措施的关键信息，其HF风险最高。