Targeting High-Risk Young Patients for Statin Therapy
Authors: Antonio M. Gotto, Jr
Journal: JAMA (2004)

FAMILIAL HYPERCHOLESTEROLEMIA IS THE GENETIC model for the role of hypercholesterolemia in the pathology of coronary heart disease (CHD), with a frequency of heterozygous familial hypercholesterolemia of 1 in 500. Most heterozygous familial hypercholesterolemia patients have low-density lipoprotein cholesterol (LDL-C) values that are greater than 190 mg/dL (4.91 mmol/L), and premature heart disease is a usual occurrence. Therefore, physicians may classify familial hypercholesterolemia patients as being at high coronary risk and may begin preventive efforts as early as childhood, with lifestyle therapy as the foundation of any regimen. A healthful diet, antismoking, and exercise are important messages for all children; however, because of their genetic predisposition for elevated LDL-C, young persons with familial hypercholesterolemia may require a degree of cholesterol modification that lifestyle measures alone generally cannot provide. In such cases, a more aggressive approach is justified, but the options are limited. The extracorporeal procedure of LDL apheresis is reserved generally for patients with familial hypercholesterolemia and extreme elevation of LDL-C that is unresponsive to drug therapy. Thus, pharmacologic intervention likely will be needed in the majority of children with familial hypercholesterolemia. Prior to the advent of the statins, bile-acid sequestrants were considered the preferred drug approach in young people. Despite their poor palatability, these agents have a nonsystemic mode of action. In recent years, the proliferation of evidence that demonstrates the clinical cardiovascular benefits of statins has placed these drugs at the forefront of lipid therapies. Combinations of statins with bile-acid sequestrants or with the novel cholesterol absorption inhibitor ezetimibe in adult familial hypercholesterolemia patients have shown complementary actions. Shortterm studies in young familial hypercholesterolemia patients have suggested good tolerability and lipid modification with statin monotherapy. A small, 1-year study of 20 girls and boys aged 10 to 17 years with familial hypercholesterolemia who were treated with simvastatin, 5 to 20 mg/d, titrated to achieve an LDL-C level less than 170 mg/dL (4.39 mmol/L), is representative and reported a 36% reduction in LDL-C at the highest dosage, with a few adverse events that resolved on their own. In this issue of JAMA, Wiegman et al report the results of a 2-year efficacy study of pravastatin, 20 to 40 mg/d, compared with placebo in 214 children with heterozygous familial hypercholesterolemia. The mean age of the children was 13 years. Baseline total cholesterol and LDL-C were approximately 300 mg/dL (7.76 mmol/L) and 238 mg/dL (6.15 mmol/L), respectively. Active treatment produced a 24% reduction in LDL-C. Treatment was associated with an attenuation of progression of carotid intima-medial thickness that was illustrated by a trend toward regression in the pravastatin-treated group compared with a trend toward progression in the placebo group. The difference in intimamedial thickness between the groups achieved statistical significance (P=.02). However, the study does not provide longer-term safety data. Clinical end-point studies that prove that aggressive treatment of young patients with familial hypercholesterolemia leads to cardiovascular benefit also are lacking. When to begin treatment and at what intensity in children with familial hypercholesterolemia has been a subject of debate. Guidelines endorse the consideration of drug treatment in high-risk young adults and children as young as 10 years old after an ample trial of lifestyle therapy alone. On the other hand, given the paucity of data about the longterm impact of early treatment in the young, it is possible that delaying the start of drug therapy until after adolescence still may translate into future coronary protection. The psychosocial and economic repercussions for the child that follow a diagnosis of a chronic disease should also be taken into consideration. However, the results of Wiegman et al are in concordance with those of other studies in reporting no significant impact on developmental measures or safety with using statins in children who have entered puberty. At least 1 study offered evidence that a familial hypercholesterolemia diagnosis may increase the