doi: 10.1161/ATVBAHA.107.143644
© 2007 American Heart Association, Inc.
Editorials |
Summary of the American Heart Association’s Scientific Statement on Drug Therapy of High-Risk Lipid Abnormalities in Children and Adolescents
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.
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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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1. McCrindle BW, Urbina EM, Dennison BA, Jacobson MS, Steinberger J, Rocchini AP, Hayman LL, Daniels SR. Drug therapy of high-risk lipid abnormalities in children and adolescents. Circulation. 2007; 115: 1948–1967.
2. de Jongh S, Lilien MR, op’t RJ, Stroes ES, Bakker HD, Kastelein JJ. Early statin therapy restores endothelial function in children with familial hypercholesterolemia. J Am Coll Cardiol. 2002; 40: 2117–2121.
3. Wiegman A, Hutten BA, de Groot E, Rodenburg J, Bakker HD, Buller HR, Sijbrands EJ, Kastelein JJ. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial. JAMA. 2004; 292: 331–337.
4. American Academy of Pediatrics. National Cholesterol Education Program: Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992; 89: 525–584.
5. Kavey RE, Allada V, Daniels SR, Hayman LL, McCrindle BW, Newburger JW, Parekh RS, Steinberger J. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2006; 114: 2710–2738.
6. Tonstad S, Knudtzon J, Sivertsen M, Refsum H, Ose L. Efficacy and safety of cholestyramine therapy in peripubertal and prepubertal children with familial hypercholesterolemia. J Pediatr. 1996; 129: 42–49.[CrossRef][Medline] [Order article via Infotrieve]
7. McCrindle BW, O’Neill MB, Cullen-Dean G, Helden E. Acceptability and compliance with two forms of cholestyramine in the treatment of hypercholesterolemia in children: a randomized, crossover trial. J Pediatr. 1997; 130: 266–273.[CrossRef][Medline] [Order article via Infotrieve]
8. Tonstad S, Sivertsen M, Aksnes L, Ose L. Low dose colestipol in adolescents with familial hypercholesterolaemia. Arch Dis Child. 1996; 74: 157–160.
9. McCrindle BW, Helden E, Cullen-Dean G, Conner WT. A randomized crossover trial of combination pharmacologic therapy in children with familial hyperlipidemia. Pediatr Res. 2002; 51: 715–721.[CrossRef][Medline] [Order article via Infotrieve]
10. de Jongh S, Ose L, Szamosi T, Gagne C, Lambert M, Scott R, Perron P, Dobbelaere D, Saborio M, Tuohy MB, Stepanavage M, Sapre A, Gumbiner B, Mercuri M, van Trotsenburg AS, Bakker HD, Kastelein JJ. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin. Circulation. 2002; 106: 2231–2237.
11. Knipscheer HC, Boelen CC, Kastelein JJ, van Diermen DE, Groenemeijer BE, van den EA, Buller HR, Bakker HD. Short-term efficacy and safety of pravastatin in 72 children with familial hypercholesterolemia. Pediatr Res. 1996; 39: 867–871.[Medline] [Order article via Infotrieve]
12. Lambert M, Lupien PJ, Gagne C, Levy E, Blaichman S, Langlois S, Hayden M, Rose V, Clarke JT, Wolfe BM, Clarson C, Parsons H, Stephure DK, Potvin D, Lambert J; the Canadian Lovastatin in Children Study Group. Treatment of familial hypercholesterolemia in children and adolescents: effect of lovastatin. Pediatrics. 1996; 97: 619–628.
13. Stein EA, Illingworth DR, Kwiterovich PO Jr, Liacouras CA, Siimes MA, Jacobson MS, Brewster TG, Hopkins P, Davidson M, Graham K, Arensman F, Knopp RH, DuJovne C, Williams CL, Isaacsohn JL, Jacobsen CA, Laskarzewski PM, Ames S, Gormley GJ. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial. JAMA. 1999; 281: 137–144.
14. Clauss SB, Holmes KW, Hopkins P, Stein E, Cho M, Tate A, Johnson-Levonas AO, Kwiterovich PO. Efficacy and safety of lovastatin therapy in adolescent girls with heterozygous familial hypercholesterolemia. Pediatrics. 2005; 116: 682–688.
15. McCrindle BW, Ose L, Marais AD. Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo–controlled trial. J Pediatr. 2003; 143: 74–80.[CrossRef][Medline] [Order article via Infotrieve]
16. Wheeler KA, West RJ, Lloyd JK, Barley J. Double blind trial of bezafibrate in familial hypercholesterolaemia. Arch Dis Child. 1985; 60: 34–37.
17. Colletti RB, Neufeld EJ, Roff NK, McAuliffe TL, Baker AL, Newburger JW. Niacin treatment of hypercholesterolemia in children. Pediatrics. 1993; 92: 78–82.[Medline] [Order article via Infotrieve]
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