The primary aim of this project is to determine whether the chronic administration of enalapril, an inhibitor of angiotensin converting enzyme (ACE), will reduce the progression of cardiac dysfunction in pediatric oncology patients who have received anthracyclines, and who are not currently on digoxin, diuretics or vasodilators for congestive heart failure (CHF). The project will include a randomized, double blind trial of enalapril versus placebo in approximately 168 patients at least 2 years off treatment with some cardiac dysfunction (without CHF) after receiving anthracyclines. Randomization will be stratified by total anthracycline dose, follow-up time from treatment, and age at time of treatment. We define cardiac dysfunction to include a fall in left ventricular shortening fraction (LVSF) as measured by echocardiogram, a moderate or severe abnormality on maximal cardiac index as measured on cycle ergometry testing, an abnormal LV ejection fraction (LVEF) by gated nuclear angiography, a prolonged QTc on ECG, or a history of exercise intolerance. All patients will receive the following baseline tests: (1) Maximal Cardiac Index (MCI) on cycle ergometry; (2) Echocardiogram/Doppler determined left ventricular end systolic wall stress (ESWS); (3) gated nuclear angiography (GNA) to determine left ventricular ejection fraction; (4) Holter monitor for 24 hour ECG monitoring. Patients will be randomized to either enalapril or placebo. Follow-up visits to ensure compliance and screen for side effects will be conducted. MCI and ESWS stress will be measured twice yearly, while all 4 tests will be repeated at the conclusion of the trial, after 4 to 5 years of treatment. The primary outcome variables will be the rate of decline in MCI and the rate of increase in ESWS. Secondary outcomes will be the change in LVEF and the incidence of arrhythmias.
The second aim i s to develop an algorithm to determine indications for enalapril use should we succeed in showing a treatment effect. This will require modeling the probability of cardiac dysfunction given patient characteristics at treatment, treatment type, cardiac status during treatment and at follow-up, and the development of cost effectiveness and medical decision making models testing the proposed algorithm.
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