Armenian Saro H, Hudson Melissa M, Chen Ming Hui, Colan Steven D, Lindenfeld Lanie, Mills George, Siyahian Aida, Gelehrter Sarah, Dang Ha, Hein Wendy, Green Daniel M, Robison Leslie L, Wong F Lennie, Douglas Pamela S, Bhatia Smita
Department of Population Sciences, City of Hope, 1500, East Duarte Road, Duarte, CA, 91010-3000, USA.
Department of Epidemiology and Cancer Control, St. Jude Children's Research Hospital, Memphis, TN, USA.
BMC Cardiovasc Disord. 2016 Oct 4;16(1):187. doi: 10.1186/s12872-016-0364-6.
Anthracyclines are widely used in the treatment of childhood cancer. One of the well-recognized side-effects of anthracycline therapy is dose-dependent cardiomyopathy that may progress to heart failure (HF) years after completion of cancer-directed therapy. This study will evaluate the efficacy of low-dose beta-blocker (carvedilol) for HF risk reduction in childhood cancer survivors at highest risk for HF. The proposed intervention has the potential to significantly reduce chronic cardiac injury via interruption of neurohormonal systems responsible for left ventricular (LV) remodeling, resulting in improved cardiac function and decreased risk of HF. The intervention is informed by previous studies demonstrating efficacy in pediatric and adult non-oncology populations, yet remains unstudied in the pediatric oncology population.
METHODS/DESIGN: The primary objective of the trial is to determine impact of the intervention on echocardiographic markers of cardiac remodeling and HF risk, including: LV wall thickness/ dimension ratio (LVWT/D; primary endpoint), as well as LV ejection fraction, volume, and blood biomarkers (natriuretic peptides, galectin-3) associated with HF risk. Secondary objectives are to establish safety and tolerability of the 2-year course of carvedilol using: 1) objective measures: hepatic and cardiovascular toxicity, treatment adherence, and 2) subjective measures: participant self-reported outcomes. Two hundred and fifty survivors of childhood cancer (diagnosed <21 years of age), and previously treated with high-dose (≥300 mg/m) anthracyclines will be enrolled in a randomized, double-blind, placebo controlled trial. After baseline assessments, participants will be randomized in a 1:1 ratio to low-dose carvedilol (maximum dose: 12.5 mg/day) or placebo. Carvedilol or placebo is up-titrated (starting dose: 3.125 mg/day) according to tolerability.
When completed, this study will provide much-needed information regarding a physiologically plausible pharmacological risk-reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF.
ClinicalTrials.gov; NCT02717507.
蒽环类药物广泛应用于儿童癌症的治疗。蒽环类药物治疗公认的副作用之一是剂量依赖性心肌病，在癌症导向治疗结束数年之后可能进展为心力衰竭（HF）。本研究将评估低剂量β受体阻滞剂（卡维地洛）对HF风险最高的儿童癌症幸存者降低HF风险的疗效。拟实施的干预措施有可能通过中断负责左心室（LV）重塑的神经激素系统，显著减少慢性心脏损伤，从而改善心脏功能并降低HF风险。此前的研究已证实该干预措施在儿科和成人非肿瘤人群中有效，但在儿科肿瘤人群中尚未进行研究。
方法/设计：该试验的主要目的是确定干预措施对心脏重塑和HF风险的超声心动图标志物的影响，包括：左心室壁厚度/内径比（LVWT/D；主要终点），以及左心室射血分数、容积和与HF风险相关的血液生物标志物（利钠肽、半乳糖凝集素-3）。次要目的是通过以下方式确定卡维地洛2年疗程的安全性和耐受性：1）客观指标：肝脏和心血管毒性、治疗依从性，以及2）主观指标：参与者自我报告的结果。250名儿童癌症幸存者（诊断时年龄<21岁），且此前接受过高剂量（≥300mg/m）蒽环类药物治疗，将被纳入一项随机、双盲、安慰剂对照试验。在基线评估后，参与者将按1:1的比例随机分配至低剂量卡维地洛（最大剂量：12.5mg/天）或安慰剂组。卡维地洛或安慰剂根据耐受性进行滴定（起始剂量：3.125mg/天）。
本研究完成后，将为HF风险高的儿童癌症幸存者提供一种生理上合理的降低风险的药物策略所需的重要信息。
ClinicalTrials.gov；NCT02717507。
