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Familial hypercholesterolemia (FH) is one of the more
common genetic diseases, affecting about 1 in 500 persons in its heterozygous
form (HeFH) and about 1 per 1 million persons in its most severe homozygous
form.1 This disease, in which high levels of low-density lipoprotein cholesterol
(LDL-C) are associated with early and often severe manifestations of coronary
heart disease (CHD), even in the absence of other risk factors, has served as
a paradigm for the atherogenicity of elevated LDL-C levels. The study of this
disorder has provided one of the scientific foundations for the National Cholesterol
Education Program (NCEP)2, 3 approach that makes LDL-C the primary target of
cholesterol-lowering treatment for the prevention of CHD. It is therefore ironic
that HeFH, the most common form of the disease, is often neglected or undertreated
in adults and children. This is particularly disappointing because screening
for this disorder by cholesterol measurement is simple and inexpensive, and
its diagnosis and management are well within the compass of most physicians.
FULL TEXT BELOW:
When Should Patients With Heterozygous Familial Hypercholesterolemia Be Treated?
Basil M. Rifkind, MD, FRCP; Beth Schucker, MS; David J. Gordon, MD, PhD
Familial hypercholesterolemia (FH) is one of the more common genetic diseases,
affecting about 1 in 500 persons in its heterozygous form (HeFH) and about 1
per 1 million persons in its most severe homozygous form.1 This disease, in
which high levels of low-density lipoprotein cholesterol (LDL-C) are associated
with early and often severe manifestations of coronary heart disease (CHD),
even in the absence of other risk factors, has served as a paradigm for the
atherogenicity of elevated LDL-C levels. The study of this disorder has provided
one of the scientific foundations for the National Cholesterol Education Program
(NCEP)2, 3 approach that makes LDL-C the primary target of cholesterol-lowering
treatment for the prevention of CHD. It is therefore ironic that HeFH, the most
common form of the disease, is often neglected or undertreated in adults and
children. This is particularly disappointing because screening for this disorder
by cholesterol measurement is simple and inexpensive, and its diagnosis and
management are well within the compass of most physicians.
As Stein et al4 point out in their study in this issue of THE JOURNAL, the clinical toll of HeFH, although less severe than that of the homozygous disorder, is nonetheless quite considerable. In a British study of men with HeFH,5 the risk of a first CHD event was 5% by age 30 years, 24% by age 40 years, 51% by age 50 years, 85% by age 60 years, and 100% by age 70 years. Thus, the rate of initial incidence of CHD among susceptible individuals is 20% (0.19/0.95) in the fourth decade, 36% (0.27/0.76) in the fifth decade, 69% (0.34/0.49) in the sixth decade, and 100% in the seventh decade. These incidence rates exceed the 2%-per-year threshold for cholesterol-lowering treatment set by the European guidelines6 from age 30 years onward and exceed the British-recommended 3%-per-year risk threshold after age 40 years.7 The corresponding figures in women are less compelling (0% by age 40 years, 12% by age 50 years, 58% by age 60 years, and 74% by age 70 years) but still leave little doubt that these women are at very high risk of CHD events by age 50 years. A US study of 116 kindreds with FH in which affected and unaffected siblings were compared gave similar results; the cumulative probability of fatal or nonfatal CHD by age 60 years was 52% in men with HeFH (vs 13% in men without HeFH) and 33% in women with HeFH (vs 9% in women without HeFH).8
Any lingering doubts about the preventive worth of cholesterol-lowering therapy have now been fully dispelled by the impressive and consistent findings of randomized trials in adults using drugs belonging to the 3-hydroxy-3-methylglutaryl coenzyme A reductase (statin) class. In the 5 largest of these trials, involving 30,817 participants, reductions of 18% to 25% in cholesterol levels were associated with significant reductions of 25% to 40% in rates of fatal and nonfatal coronary ischemic events.9-13 Although middle-aged men predominate in these trials, subgroup analyses suggest similar benefits in women, elderly persons, and patients with diabetes, hypertension, and a wide range of cholesterol levels. Corresponding reductions in cardiac revascularization procedures occurred. Mortality rates for noncardiovascular diseases were unaffected and all-cause mortality generally was reduced. With the availability of such safe and efficacious treatment, there is no reason not to lower cholesterol vigorously in adults with HeFH.
The picture for children is less clear. Trials to accurately assess the relative risks and benefits of cholesterol lowering in children are not feasible because the adverse sequelae of the disease are rare before adulthood. However, because it is well known that the atherosclerotic process begins in childhood and is accelerated in HeFH, it is generally recommended that children with HeFH be treated, despite uncertainties about drug treatment. Although the statin drugs have proven remarkably safe in adults, adult trials cannot provide data on growth and development. Also, considering that cholesterol-lowering therapy is a lifelong proposition, instituting these drugs in childhood implies decades of exposure, which conceivably might bring out low-level toxic effects that are not evident in the typical 5- to 7-year cholesterol-lowering trial. There also may be adverse psychological effects of identifying children with HeFH as "abnormal," and compliance may be difficult.
The study by Stein et al4 provides much needed initial information and begins to address some of the concerns of physicians who are considering statins for children with HeFH. These findings represent a rigorous evaluation based on a 1-year placebo-controlled trial and give assurance that lovastatin will lower LDL-C with no apparent adverse effects on growth or hormonal and nutritional status, at least in adolescent boys. However, although this trial was longer and larger than other statin studies in children,14, 15 the duration of the study was still very short relative to the length of time (perhaps lifelong) that most children with FH would require drug treatment, and the ability of the study to address the possibility of adverse effects on long-term growth and development is limited.
The safety evaluation in this study, although more ambitious than in prior studies, was not comprehensive, and some important safety issues, such as drug effects on cognitive function and psychosocial development, were not addressed at all. Although a 1-year study of 132 children has sufficient power to detect gross treatment differences in safety outcomes, more subtle differences may have gone unnoticed. The natural history data argue more strongly for early intervention in men than women, and data on the safety of treating adolescent girls and young women of childbearing age are not available. However, the authors do deserve credit for selecting relevant measures, including some that are quite difficult to study, such as sexual maturation.
There is little reason to expect that the cholesterol-lowering efficacy of the statins is less in children than in adults. Indeed, the LDL-C lowering reported by Stein et al4 was only slightly less than in comparable adult studies of lovastatin. However, the 20% dropout rate was relatively high, and the authors did not comment on drug compliance.
Although even the accelerated atherosclerosis of HeFH is generally silent until well into adulthood, the critical question centers on what is gained by initiating treatment of HeFH in childhood and whether any clinical benefits obtained outweigh the attendant risks and other costs (including economic costs) of the additional years of treatment. The measure of efficacy in this study, LDL-C lowering, is far removed in time from the clinical CHD end points of primary concern; therefore, these critical issues have not been addressed. Because clinical events are rare with this disorder during childhood and early adulthood, other measures are needed to assess the impact of treatment strategies initiated in childhood. Noninvasive methods of assessing atherosclerosis severity at different sites may allow future trials to address these issues without requiring unduly large numbers of children or excessively prolonged follow-up. Until such trials can be done, it seems prudent to identify and treat HeFH aggressively in adolescent boys, given the significant morbidity and mortality from CHD that occurs as early as the third decade of life. The appropriate strategy is less certain for women with HeFH, given their relatively delayed onset of clinical CHD sequelae and the paucity of safety data pertaining to conception and pregnancy.
The need for more studies in children has received increasing emphasis during the last few years. Professional societies and government agencies now agree that if medical treatments are proposed for children, the benefits and risks of the treatments must be evaluated in children. Biomedical researchers are now being asked to rethink their long-held reluctance to involve children in studies because of ethical, safety, and logistical concerns. Current policy of the National Institutes of Health requires participation of children in clinical trials unless scientifically or ethically contraindicated. The study by Stein et al4 clearly demonstrates the feasibility of conducting clinical trials of high scientific quality and rigor in children, as well as the need for future trials addressing the issues of long-term safety and efficacy of aggressive treatment strategies initiated early in the disease process in the young.
Author/Article Information
Author Affiliations: Division of Heart and Vascular Diseases, National Heart,
Lung, and Blood Institute, Bethesda, Md.
Corresponding Author and Reprints: David J. Gordon, MD, PhD, Division of Heart
and Vascular Diseases, National Heart, Lung, and Blood Institute, 6701 Rockledge
Dr, Suite 9044, Bethesda, MD 20892-7940.
Editorials represent the opinions of the authors and THE JOURNAL and not those
of the American Medical Association.
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