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A Randomized Controlled Trial

Albert Wiegman, MD, PhD; Barbara A. Hutten, PhD; Eric de Groot, MD, PhD; Jessica Rodenburg, MD; Henk D. Bakker, MD, PhD; Harry R. Büller, MD, PhD; Eric J. G. Sijbrands, MD, PhD; John J. P. Kastelein, MD, PhD

JAMA. 2004;292:331-337.

Context  Children with familial hypercholesterolemia have endothelial dysfunction and increased carotid intima-media thickness (IMT), which herald the premature atherosclerotic disease they develop later in life. Although intervention therapy in the causal pathway of this disorder has been available for more than a decade, the long-term efficacy and safety of cholesterol-lowering medication have not been evaluated in children.

Objective  To determine the 2-year efficacy and safety of pravastatin therapy in children with familial hypercholesterolemia.

Design  Randomized, double-blind, placebo-controlled trial that recruited children between December 7, 1997, and October 4, 1999, and followed them up for 2 years.

Setting and Participants  Two hundred fourteen children with familial hypercholesterolemia, aged 8 to 18 years and recruited from an academic medical referral center in the Netherlands.

Intervention  After initiation of a fat-restricted diet and encouragement of regular physical activity, children were randomly assigned to receive treatment with pravastatin, 20 to 40 mg/d (n = 106), or a placebo tablet (n = 108).

Main Outcome Measures  The primary efficacy outcome was the change from baseline in mean carotid IMT compared between the 2 groups over 2 years; the principal safety outcomes were growth, maturation, and hormone level measurements over 2 years as well as changes in muscle and liver enzyme levels.

Results  Compared with baseline, carotid IMT showed a trend toward regression with pravastatin (mean [SD], –0.010 [0.048] mm; P = .049), whereas a trend toward progression was observed in the placebo group (mean [SD], +0.005 [0.044] mm; P = .28). The mean (SD) change in IMT compared between the 2 groups (0.014 [0.046] mm) was significant (P = .02). Also, pravastatin significantly reduced mean low-density lipoprotein cholesterol levels compared with placebo (–24.1% vs +0.3%, respectively; P<.001). No differences were observed for growth, muscle or liver enzymes, endocrine function parameters, Tanner staging scores, onset of menses, or testicular volume between the 2 groups.

Conclusion  Two years of pravastatin therapy induced a significant regression of carotid atherosclerosis in children with familial hypercholesterolemia, with no adverse effects on growth, sexual maturation, hormone levels, or liver or muscle tissue.

Author Affiliations: Departments of Vascular Medicine (Drs Wiegman, de Groot, Rodenburg, Büller, Sijbrands, and Kastelein), Paediatrics (Drs Wiegman and Bakker), and Clinical Epidemiology and Biostatistics (Dr Hutten), Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, University of Rotterdam, Rotterdam, the Netherlands (Dr Sijbrands).

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