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Release Date: July 20, 2004; Valid for credit through July 20, 2005

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July 20, 2004 — Statins are safe and effective for children with familial hypercholesterolemia, according to the results of a double-blind, randomized trial published in the July 21 issue of JAMA. This disorder is characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-c) beginning at birth.

"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," write Albert Wiegman, MD, PhD, from the University of Amsterdam in the Netherlands, and colleagues. "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."

Between December 1997 and October 1999, 214 children with familial hypercholesterolemia, aged 8 to 18 years, were randomized to receive pravastatin, 20 to 40 mg/day, or placebo for two years. Before receiving study medication, all children began a fat-restricted diet and were encouraged to participate in regular physical activity.

In the pravastatin group, mean carotid IMT showed a trend toward regression compared with baseline (-0.010 ± 0.048 mm; P = .049). In the placebo group, there was a trend toward progression (+0.005 ± 0.044 mm; P = .28). The mean change in IMT between the two groups was significant (0.014 ± 0.046 mm; P = .02).

Mean change in LDL-c levels was a 24.1% reduction in the pravastatin group, and a 0.3% increase in the placebo group (P < .001). Growth, maturation, hormonal levels, and muscle and liver enzymes were similar in both groups.

Study limitations were possible confounding by healthy lifestyle and diet, use of a surrogate marker of future vascular disease rather than clinical endpoints, and lack of generalizability to children with other causes of increased atherosclerotic risk.

"We were able to show that statin treatment improved the lipoprotein profile toward more physiological levels and we observed regression of carotid IMT. This shows that the increased arterial wall thickness progression found in children with familial hypercholesterolemia is reversible," the authors write. "Although this trial in children with familial hypercholesterolemia has, to our knowledge, the most extensive follow-up to date, data on even longer-term safety and efficacy of statin therapy in children are needed."

The Zorg Onderzoek Nederland and Bristol-Myers Squibb Inc. supported this study.

In an accompanying editorial, Antonio M. Gotto, Jr., MD, DPhil, from Weill Medical College of Cornell University in New York, NY, suggests that most children with familial hypercholesterolemia may need drug therapy. However, Dr. Gotto recognizes that potential risks of therapy must be considered in young patients.

"In the case of familial hypercholesterolemia, the promise of reducing future cardiovascular morbidity and mortality, as well as future demands on acute care and more expensive preventive approaches, would make aggressive treatment of high-risk young patients a worthwhile long-term initiative," Dr. Gotto writes. "Appropriate targeting of lifestyle and drug therapies will optimize primary prevention in this group at demonstrated risk for early disease."

Dr. Gotto is a consultant for AstraZeneca, Bristol-Myers Squibb Co., Kowa, Merck & Co. Inc., Merck-Schering Plough, Novartis, Pfizer Inc., and Reliant Pharmaceuticals.

JAMA. 2004;292:331-337, 377-378

Learning Objectives for This Educational Activity

• Evaluate pediatric complications of familial hypercholesterolemia.
• Describe the efficacy and adverse events associated with using pravastatin in children.

Clinical Context

Familial hypercholesterolemia can produce markedly elevated cholesterol levels in children, even in its heterozygous form. LDL-c levels are usually more than 190 mg/dL in this genotype. This high cholesterol level can produce atherosclerosis even in childhood. In a study comparing 201 children between the ages of 8 and 18 years with heterozygous familial hypercholesterolemia and their unaffected siblings, carotid IMT was significantly higher in the children with hypercholesterolemia. This study by the same authors of the current research, which appeared in the Jan. 31, 2004, issue of The Lancet, also showed that increased carotid IMT was not only associated with LDL-c levels, but older age and male sex as well. Familial hypercholesterolemia has also been linked to endothelial dysfunction in prepubertal children, further increasing the risk for later cardiovascular events.

An editorial by Gotto that accompanies the current article describes previously used treatments for familial hypercholesterolemia in children, including LDL-c apheresis and bile-acid sequestrants. These treatments are complex and poorly tolerated. The authors of the current study performed a placebo-controlled trial to determine the efficacy of pravastatin in reducing carotid IMT in children heterozygous for familial hypercholesterolemia while also examining the safety of the drug.

Study Highlights

• Children between the ages of 8 and 18 years were recruited from one center in the Netherlands if they had a clinical or molecular diagnosis of familial hypercholesterolemia. All had at least two fasting LDL-c values of at least 155 mg/dL, while triglyceride levels were less than 350 mg/dL.
• Children were excluded from study participation if they were positive for homozygous familial hypercholesterolemia or had hypothyroidism, liver disease, or elevation of serum muscle enzymes.
• All children were instructed to follow a fat-restricted diet and continue regular exercise. In addition, they were randomized to receive either pravastatin (10 mg in the evening for children younger than 14 years and 20 mg for children older than 14 years) or matching placebo. Evaluation was performed by blinded study personnel for 2 years following randomization.
• The main study outcome measure was carotid IMT progression for the 2-year study period. Lipid levels and sex steroids along with measures of growth and development were also followed. Liver enzymes and creatinine phosphokinase were assessed to monitor for drug toxicity.
• 106 participants were randomized to the pravastatin group, and 108 received placebo. 96% of children had the diagnosis of familial hypercholesterolemia confirmed with genetic analysis. The mean age of subjects was 13 years old, and baseline LDL-c levels were 239 and 237 mg/dL for the pravastatin and placebo groups, respectively. Total cholesterol, blood pressure, and smoking prevalence were similar between groups.
• All but 3 children had follow-up data available through 2 years. Dietary compliance was fair in both groups.
• After 2 years, mean carotid IMT regressed by 0.010 mm in the pravastatin group compared with a progression of 0.005 mm in the placebo group, a significant difference.
• LDL-c levels declined by 24.1% in the pravastatin group but increased by 0.3% in the placebo group after 2 years of therapy. Other measurements of the lipid profile did not significantly change in subjects treated with pravastatin.
• Pravastatin caused no adverse event when compared with placebo in children's academic performance, growth, body mass index, age at menarche, or Tanner staging.
• Measurements of cortisol, follicle-stimulating hormone, luteinizing hormone, thyrotropin, and 17B-estradiol (females) and testosterone (males) levels were similar between treatment groups through 2 years of follow up.
• Pravastatin was not associated with any significant increase in liver enzymes. One child developed an asymptomatic elevation of creatinine phosphokinase levels with pravastatin that resolved after withholding treatment.

Pearls for Practice

• Familial hypercholesterolemia, even in its heterozygous form, can produce evidence of atherosclerosis in children.
• Pravastatin is effective in reducing carotid IMT in children for a two-year period. Pravastatin therapy was associated with few significant adverse effects during this study interval.

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This article is intended for primary care physicians, pediatricians, pediatric endocrinologists, and other specialists who care for children with familial hypercholesterolemia.

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News Author

Laurie Barclay, MD
Freelance writer for Medscape Medical News

Disclosure: Dr. Barclay has reported no significant financial interests.

Clinical Reviewer

Gary Vogin, MD
Senior Medical Editor, Medscape

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CME Author

Charles Vega, MD, FAAFP
Assistant Clinical Professor, Associate Residency Program Director, Department of Family Medicine, University of California, Irvine

Disclosure: Dr. Vega has disclosed that he has received grants for educational activities from Pfizer.

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