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Enalapril to Prevent Cardiac Function Decline in Long-Term Survivors of Pediatric Cancer Exposed to Anthracyclines

From the Divisions of Pediatric Oncology, Biostatistics and Epidemiology, Cardiology, Department of Pediatrics, and the Center for Outcomes Research, Department of Anesthesiology and Critical Care Medicine, The Children's Hospital of Philadelphia and The University of Pennsylvania School of Medicine, Philadelphia, PA; The Divisions of Pediatric Cardiology, Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, OH; Division of Pediatric Cardiology, New York University of Medicine; and Department of Pediatric Cardiology, Memorial Sloan-Kettering Medical Center, New York, NY

Address reprint requests to Jeffrey H. Silber, MD, PhD, Center for Outcomes Research, Children's Hospital of Philadelphia, 3535 Market St, Suite 1029, Philadelphia, PA, 19104; e-mail: Silber{at}.chop.edu

PURPOSE: To determine whether an angiotensin-converting enzyme (ACE) inhibitor, enalapril, prevents cardiac function deterioration (defined using maximal cardiac index [MCI] on exercise testing or increase in left ventricular end-systolic wall stress [LVESWS]) in long-term survivors of pediatric cancer.

PATIENTS AND METHODS: This was a randomized, double-blind, controlled clinical trial comparing enalapril to placebo in 135 long-term survivors of pediatric cancer who had at least one cardiac abnormality identified at any time after anthracycline exposure.

RESULTS: There was no difference in the rate of change in MCI per year between enalapril and placebo groups (0.30 v 0.18 L/min/m²; P = .55). However, during the first year of treatment, the rate of change in LVESWS was greater in the enalapril group than in the placebo group (-8.59 v 1.85 g/cm²; P = .033) and this difference was maintained over the study period, resulting in a 9% reduction in estimated LVESWS by year 5 in the enalapril group. Six of seven patients removed from random assignment to treatment because of cardiac deterioration were initially treated with placebo (P = .11), and one has died as a result of heart failure. Side effects from enalapril included dizziness or hypotension (22% v 3% in the placebo group; P = .0003) and fatigue (10% v 0%; P = .013).

CONCLUSION: Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year; this reduction was maintained over the study period. Any theoretical benefits of LVESWS reduction in this anthracycline-exposed population must be weighed against potential side effects from ACE inhibitors when making treatment decisions.

Primarily funded by grant no. R01 HL-50424 from the National Heart, Lung, and Blood Institute. Other funding was obtained from the National Center for Research Resources, grant no. M01-RR-00240, and the National Cancer Institute, grant no. CA-16520.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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