Carvedilol in Preventing Heart Failure in Childhood Cancer Survivors
Heart failure [HF], is one of the leading causes of late morbidity and premature death after successful treatment of childhood cancer with anthracycline chemotherapy. In fact, childhood cancer survivors are at a 15-fold increased risk of developing HF compared to age-matched healthy controls. The risk is higher among those exposed to anthracyclines at a young age, and among those with concomitant exposure to chest radiation. This anthracycline-related cardiotoxicity presents as a continuum from asymptomatic structural or functional cardiac abnormalities detected on imaging studies, to clinically symptomatic HF. There is a strong dose-dependent relationship between anthracycline chemotherapy exposure and HF risk. The incidence of symptomatic HF is < 5% with cumulative anthracyclines exposure of < 300 mg/m²; approaches 20% at doses between 300 and 600 mg/m²; and exceeds 30% for doses > 600 mg/m². Overall, nearly two-thirds of children exposed to high-dose (HD) anthracyclines (300 mg/m²) develop asymptomatic cardiac abnormalities; these individuals are at risk for developing HF. Outcome following anthracycline-related HF is poor; 5-year overall survival rate is < 50%. Nearly 60% of all childhood cancer survivors carry a history of prior anthracycline exposure. The decades of life saved among the rapidly growing anthracycline-exposed childhood cancer survivors, makes it imperative that we develop strategies (informed by the pathogenic basis of anthracycline-related cardiotoxicity) to reduce the risk of HF in the vulnerable populations. Anthracycline cardiotoxicity results from direct cardiac injury due to formation of free radicals; this injury initiates cardiac remodeling and subsequent deterioration of left ventricular (LV) function. 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 a genetic predisposition to HF (but with preserved cardiac function at the time of intervention). There is increasing evidence supporting a comprehensive reversal of parameters used to measure cardiac remodeling, with the use of third generation ß-blockers such as carvedilol (combined ß1, ß 2, 1 blockade) when compared with ACE inhibitors (afterload reduction alone) following exposure to cardiotoxic agents (such as HD-anthracyclines). However, despite clear physiologic rationale, as well as evidence of clinical efficacy in non-oncology populations, clinicians are reluctant to use pharmacologic intervention in childhood cancer survivors, primarily due to a paucity of randomized clinical trials that would provide evidence for benefit from such an intervention. We address this gap in the proposed trial: a randomized, double-blind, placebo-controlled Phase 2b trial in asymptomatic childhood cancer survivors with prior exposure to HD-anthracyclines ( 300 mg/m2). This study will provide critical information regarding a physiologically plausible pharmacological risk reduction strategy for childhood cancer survivors at high risk for developing anthracycline-related HF. The proposed intervention has the potential to significantly reduce ongoing cardiac injury via interruption of neurohormonal systems responsible for 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. The intervention will rely on reproducible and clinically relevant echocardiographic and blood biomarkers of early cardiac remodeling. Finally, the proposal leverages the well-established clinical trials network of the Children¿s Oncology Group (COG), allowing participation by geographically diverse patient populations.