Effects of carvedilol on left ventricular function and oxidative stress in infants and children with idiopathic dilated cardiomyopathy: a 12-month, two-center, open-label study

Abstract

OBJECTIVES: This study was conducted to determine the effects of carvedilol adjunct to standard treatment on left ventricular function (LVF), estimated as ejection fraction (EF) and fractional shortening (FS) on echocardiography, in children with idiopathic dilated cardiomyopathy (DCM). A secondary end point was to characterize the antioxidant potential of carvedilol.

METHODS: Hospitalized children aged ≤16 years with clinically stable DCM and advanced congestive heart failure (HF) with modified New York Heart Association Classification for Children (NYHAC) functional classes II to IV and EF <40% were enrolled in this prospective, 12-month, 2-center, open-label study. Oral carvedilol was added to a standard regimen of an angiotensin-converting enzyme inhibitor, a diuretic, and digoxin in a dose-escalation design. Systolic and diastolic blood pressure (BP), heart rate (HR), and modified NYHAC were assessed before (baseline) and at 1, 3, 6, and 12 months of adjunct carvedilol treatment. EF and FS were analyzed before and at 6 and 12 months of carvedilol treatment. At each study visit, tolerability was assessed in terms of adverse events (AEs), treatment emergent signs and symptoms, physical examination including vital sign measurement (BP, HR, and body temperature), and laboratory analysis. Antioxidative enzyme activity was evaluated by measuring erythrocyte copper/zinc superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and glutathione reductase (GR) activity at baseline and 1, 3, 6, and 12 months of adjunct carvedilol treatment. For assessment of antioxidative enzyme activity, a control group comprised 29 age-matched healthy children.

RESULTS: Twenty-one children (12 boys, 9 girls; age range, 7 months to 16 years; 100% white) completed the study. Four patients discontinued carvedilol at the beginning of the study due to severe arrhythmia which required amiodarone therapy (2 patients), bradycardia and hypotension (1), and bronchospasm (1). Carvedilol (0.4 mg/kg/d in children ≤62.5 kg or 25 mg/d in children >62.5 kg) was associated with significant decreases from baseline in systolic BP (130 [4] vs 123 [3] mm Hg; P < 0.05), diastolic BP (85 [4] vs 77 [4] mm Hg; P < 0.05), and HR (81 [4] vs 65 [4] bpm; P < 0.001) after the first month of addition to standard therapy. At 6 months, there were significant improvements from baseline in EF (37.2% [2.4%] vs 50.2% [2.3%]; P < 0.001) and FS (18.37% [2.00%] vs 23.58% [0.90%]; P < 0.001). Modified NYHAC class was significantly improved in 80% of children (2.9 vs 2.3; P < 0.001) at 12 months. The highest dose of carvedilol (0.8 mg/kg/d in children ≤62.5 kg or 50 mg/d in children >62.5 kg) was well tolerated in all 21 children. No serious AEs that necessitated study drug discontinuation (tiredness, headache, vomiting) were observed. At baseline, mean (SE) erythrocyte SOD activity (2781 [116] vs 2406 [102] U/g Hb; P < 0.05) and GR activity (5.3 [0.3] vs 3.0 [0.2] μmol nicotinamide adenine dinucleotide phosphate [NADPH]/min/g Hb; P < 0.001) were significantly higher in children with DCM who received standard therapy compared with healthy controls.CAT activity (12.7[0.9] vs 18.5 [1.0]U/g Hb; P < 0.001) was significantly lower, while GSH-Px was unchanged. At 6 and 12 months of therapy, carvedilol plus standard treatment was associated with significant decreases from baseline in SOD (2516 [126] and 2550 [118], respectively, vs 2781 [116] U/g Hb; both, P<0.001) and GR (4.7 [0.3] and 4.1 [0.2], respectively, vs 5.3 [0.2] μmol NADPH/min/g Hb; P < 0.05 and P < 0.001) and increased CAT (16.9 [1.0] and 16.4 [0.7], respectively, vs 12.7 [0.9] U/g Hb; both, P < 0.001).

CONCLUSIONS: These pediatric patients with DCM treated for 12 months with carvedilol (up to 0.8 mg/kg/d in children ≤62.5 kg or 50 mg/d in children >62.5 kg) were found to have significant improvements in LVF and symptoms of HF. Twelve months of carvedilol therapy was associated with antioxidant enzyme activities near those observed in healthy children.

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Citation
Clin Ther. 2008 Apr;30(4):702-14