Reducing risk of Anthracycline-related heart failure after childhood cancer

 描述(由申请人提供)：与年龄匹配的对照组相比，儿童癌症幸存者发生心力衰竭(HF)的风险是15倍。蒽环类药物与心力衰竭的风险之间存在强烈的剂量依赖关系；累积剂量在300-600 mg/m2时，发病率接近20%，而剂量600 mg/m2时，发病率超过30%。心衰后的预后很差；5年存活率为50%。%。近60%的儿童癌症幸存者有以前接触过蒽环类药物的病史。越来越多的幸存者，加上挽救了几十年的生命，使得我们必须制定战略，降低脆弱人群中发生心力衰竭的风险。蒽环类药物的心脏毒性被认为与自由基的形成引起的直接心肌损伤有关，自由基的形成启动了心肌重塑和随后的左心功能恶化。阻滞剂或血管紧张素转换酶(ACE)抑制剂已成功地用于在无症状左心功能障碍的成人非肿瘤性人群中预防心衰，以及在干预时具有心衰遗传易感性但心功能正常的儿童非肿瘤性人群中成功地预防心衰。与选择性更强的血管紧张素转换酶抑制剂相比，越来越多的证据支持使用第三代β受体阻滞剂，如卡维地洛(联合使用1、2、A1受体阻滞剂)，与选择性更高的血管紧张素转换酶抑制剂相比，可全面逆转暴露于大剂量(HD)-蒽环类药物(=300 mg/m2)后的心肌重塑。然而，照顾儿童癌症幸存者的临床医生不愿使用这些药物进行预防，这在很大程度上是因为缺乏进行良好管理的随机临床试验，这些试验可以为此类干预提供证据。我们提出了一项小剂量卡维地洛(β-受体阻滞剂)治疗儿童癌症幸存者的随机、安慰剂对照试验，以确定为期两年的卡维地洛对接受蒽环类药物治疗的儿童癌症幸存者的左心室厚度-内径比(LVT-D)的影响，这是一种已建立的心脏重塑和心衰风险的超声心动图标记物，也是本研究中衡量疗效的主要终点；其他超声心动图(左心室：容量、射血分数[EF]、质量/体积比、室壁应力、心脏收缩应变)、功能(V02Max)和血液生物标记物(钠尿肽、Galectin-3)测量心力衰竭风险将被包括为次要终点。此外，我们计划在这群幸存者中建立卡维地洛两年疗程的安全性和耐受性。拟议的干预有可能通过阻断负责左室重构的神经激素系统来显著减少持续的心脏损伤，从而改善心功能并降低心力衰竭的风险。完成后，这项研究将提供有关合理的药物干预预防暴露于蒽环类药物的癌症幸存者心脏重构的关键信息，这些幸存者是心衰的高危人群。

 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.