Reducing risk of Anthracycline-related heart failure after childhood cancer

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.