Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:982-985
doi: 10.1161/ATVBAHA.107.143644
(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:982.)
© 2007 American Heart Association, Inc.
Summary of the American Heart Association’s Scientific Statement on Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents
Brian W. McCrindle for the Writing Group
From the Division of Cardiology, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, Ontario, Canada.
Correspondence to Dr Brian McCrindle, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. E-mail brian.mccrindle{at}sickkids.ca
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Introduction
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Drug therapy of lipid abnormalities in children and adolescents
has been surrounded with controversy. Much of the debate is
about the evidence that intervening in asymptomatic youth will
reduce disease morbidity or mortality in adulthood. There is
also particular concern that the increasing prevalence of lipid
abnormalities associated with the epidemic of pediatric obesity
will lead to a generation of children taking long-term medication
for lifestyle-related issues. The Writing Group, therefore,
sought to examine the current state of evidence and guidelines
and to provide clarifications and modifications, which are detailed
in their Scientific Statement.
1
See Circulation. 2007;115:1948–1967
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Imperative for Intervention
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A substantial body of evidence now exists to assert that the
atherosclerotic process begins in childhood and is associated
with the recognized cardiovascular risk factors. Pathologic
studies, such as the Pathobiological Determinants of Atherosclerosis
in Youth (PDAY) Study, have shown strong associations with the
extent of early atherosclerotic lesions and levels of risk factors,
including lipid abnormalities. An important observation from
pathology studies has been the geometric association between
increasing number of risk factors and the extent of lesions,
which has important implications in view of the increasing prevalence
of risk factor clustering associated with obesity and the metabolic
syndrome. Population-based studies, such as the Bogalusa Heart
Study and the Muscatine Study, find increasing trends in adiposity
and associated risk factors in youth, and that both risk factors
and obesity track into adulthood. These studies demonstrate
associations between lipid abnormalities and noninvasively measured
markers of early atherosclerosis. Recent clinical trials have
shown that effective lowering of LDL-cholesterol levels in youth
with familial or severe hypercholesterolemia is associated with
improvement and even regression of early markers.
2,3 This evidence
informs the imperative for the identification and effective
treatment of children and adolescents with high-risk lipid abnormalities.
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Clinical Studies of Drug Therapy in Children
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There have been several well-designed clinical trials that have
explored the short-term efficacy and safety of lipid-lowering
drug therapy in children with familial hypercholesterolemia
or severe hypercholesterolemia (
Table 1). These studies have
primarily used existing guidelines to define inclusion and exclusion
criteria, often included a double-blind, placebo-controlled,
randomized phase, and were of 1 or 2 years duration. The focus
has been primarily on the bile-acid–binding resins and,
more recently, the statins. These studies find similar safety
and efficacy as do studies in adults. The bile-acid–binding
resins have been associated with poor tolerability and compliance
in children and with limited effectiveness in achieving lipid-lowering
targets. Based on these findings, statins are now recommended
as first-line therapy for those children and adolescents who
meet criteria for drug therapy to lower LDL-cholesterol levels.
Initiation, monitoring, titration and maintenance are similar
for adults. However, statin use in the pediatric population
requires particular attention to ongoing monitoring of growth,
maturation and development, counseling and assurance of appropriate
contraception in females, and drug interactions. Concomitant
maintenance of therapeutic healthy lifestyle behaviors and the
prevention of obesity are also essential. Further studies are
needed to document long-term compliance, safety and effectiveness,
as well as the clinical impact on the atherosclerotic disease
process. Rigorous pediatric studies should be performed for
all drugs used to treat lipid abnormalities.
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Existing Guidelines and Challenges
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Existing guidelines primarily derive from an Expert Panel convened
by the National Cholesterol Education Program, which published
their discussion and recommendations in 1992.
4 They advocated
a population-based approach aimed at downward shifting of cholesterol
levels primarily through adoption of a fat-reduced and cholesterol-restricted
prudent diet. They also advocated a screening algorithm aimed
at identifying individuals with very high levels of LDL-cholesterol.
Screening was initiated on the basis of family history of premature
atherosclerotic cardiovascular disease or events or important
hypercholesterolemia. Based on LDL-cholesterol levels, recommendations
were made regarding subsequent monitoring, further investigation,
and implementation of a more rigorous dietary intervention.
Selected individuals with persistent and more extreme elevations
of LDL-cholesterol would be eligible for consideration of drug
therapy only after the age of 10 years (
Table 2). Bile-acid–binding
resins were recommended as first-line therapy.
There have been several concerns and challenges regarding these guidelines, particularly in light of newer evidence. There has been increasing recognition of the limitations of screening based on family history, and the increasing prevalence of lipid abnormalities because of the pediatric obesity epidemic. The guidelines did not address racial, ethnic, age and gender-specific differences that might influence screening cut-point levels and differences in disease risk. As more evidence has accumulated there has been increased awareness of the interaction of lipid abnormalities with other risk factors and high-risk disease states; thus, there needs to be some flexibility and integration of the guidelines.5 Ongoing experience with the recommended bile-acid–binding resins has been discouraging, whereas short-term clinical trials of the statins have shown excellent safety and efficacy, in addition to a positive effect on noninvasive measures of early atherosclerosis.2,3
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Current Modifications
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Current modifications are provided in
Table 2. The major changes
include an adjuvant focus on pediatric overweight and obesity,
the recognition of statins as first-line drug therapy, and the
incorporation of flexibility into initiation decisions based
on the presence of other important risk factors and high-risk
disease states.
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Conclusions
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Although a perfect chain of evidence may never exist to show
that management of lipid abnormalities in youth leads to a subsequent
reduction of cardiovascular disease, events and mortality in
adults, several links in the chain are well established. This
statement highlights those links and the evidence supporting
them, and establishes the imperative and guidelines for treating
children and adolescents with high-risk lipid abnormalities
with safe and effective drug therapy.
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Acknowledgments
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Members of the writing group included: Elaine M. Urbina, MD;
Barbara A. Dennison, MD; Marc S. Jacobson, MD; Julia Steinberger,
MD, MS; Albert P. Rocchini, MD; Laura L. Hayman, PhD, RN; Stephen
R. Daniels, MD, PhD.
Disclosures
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References
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Introduction
Imperative for Intervention