Is Lovastatin Safe for Male Adolescents with HeFH?
Is Lovastatin Safe for Male Adolescents with HeFH?
By Sally Beattie, MS, RN, CS, GNP
Summary—Heterozygous familial hypercholesterolemia (HeFH) affects one of every 500 persons1 and is a devastating genetic defect manifested by excessive elevations in circulating low-density lipoprotein cholesterol (LDL-C), often at an early age. This leads to the premature onset of extensive coronary artery disease (CAD). HeFH is more prevalent in males, and, if left untreated, 23% of men experience a fatal coronary event by the age of 50, according to one study. Dietary intervention alone is frequently ineffective in reducing LDL-C for patients. In this study, researchers investigated the effect of lovastatin in adolescents with HeFH. They found LDL-C levels decreased significantly compared with placebo, and there were no adverse affects on growth, sexual maturation, serum hormone levels, or biochemical parameters of nutrition.2
HeFH is one of the most common autosomal dominant genetic disorders, often manifested in adolescence, and it is associated with tragic and devastating death at an early age. Serum cholesterol levels are about twice as high as normal (i.e. 300-400 mg/dl), which causes accelerated atherosclerosis. HeFH is more prevalent in males, and, if left untreated, 23% of men experience a fatal coronary event by age 50, according to one study.2 A compilation of data from five studies showed that approximately 75% of men with HeFH develop coronary disease, and 50% had a fatal myocardial infarction by age 60.1 The location and extent of coronary disease in HeFH patients suggest a poor prognosis. One study showed 70% of HeFH patients had triple-vessel CAD, and 32% had left main-vessel disease.3 Data on effects in the pediatric population, however, are limited.2
Researchers recently reported a one-year, multicenter, double-blind, placebo-controlled, randomized study testing the efficacy and safety of lovastatin in adolescents with HeFH.2 The study objective was to assess the lipid-lowering efficacy of lovastatin while monitoring growth, sexual maturation, and biochemical, nutritional, and endocrine parameters. (For the study’s clinical monitoring schedule, see table, p. 29.)
Table |
Research Study Clinical Monitoring Schedule
Each Visit:Source: Stein EA, Illingworth DR, Kwiterovich PO Jr., et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hyper cholesterolemia. JAMA 1999;281:137-144. _______________________________________________ |
Statins (3-hydroxy-3-methyglutaryl coenzyme A [HMG-CoA] reductase inhibitors) have been in widespread use in adults for more than a decade. In the adult population, these agents have been shown to be safe and effective for lowering total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. Large clinical trials have demonstrated significant reductions in cardiovascular mortality and morbidity associated with both primary and secondary prevention. In children and adolescents with severe HeFH in whom dietary intervention has been unsuccessful, bile acid sequestrants remain the drug of choice (although not federally approved for this use) because they are not systemically absorbed. However, their LDL-C lowering effects are only modest, and compliance is poor due to unpalatability.4
Study Design
This study recruited 132 adolescent boys (ages 10-17) with severe HeFH from 14 pediatric outpatient clinics in the United States and Finland. All had followed the American Heart Association (AHA) pediatric diet5 for at least four months, had elevated LDLs between 189mg/dl to 503mg/dl, and had at least one parent with LDL>189mg/dl.
After obtaining written parental or guardian consent, all eligible subjects received reinstruction about the AHA pediatric diet. Subjects continued the diet for eight more weeks and subsequently were randomized to receive active treatment or placebo. Within the treatment group, lovastatin was initiated at 10 mg/day and increased to 20 mg at week eight and then to 40 mg at week 16. Participants in the placebo arm received matching tablets. All tablets were taken immediately prior to the evening meal.
Monitoring took place every four weeks during the first 24 weeks and every six weeks during the second 24 weeks. Monitoring included clinical assessment laboratory measurements of blood lipids and hepatic transaminases.
Sexual maturation was evaluated using Tanner staging 6 and testicular volume at entry and after 24 and 48 weeks of treatment. All subjects continued to receive dietary review and reinforcement by a dietitian at weeks -8, -4, 0, 8, 16, 24, 30, 36, 42, and 48. Analysis was carried out on an intent-to-treat basis (n=132, 93% white); 110 subjects completed the entire study.
Study Results
The LDL-C levels of subjects taking lovastatin decreased significantly, compared with the levels of subjects taking placebo. With each doubling of the medication dosage, there was an approximate 6% additional lowering of LDL-C. It remained 25% lower than baseline at 48 weeks. Growth and sexual maturation did not differ significantly between the lovastatin and placebo groups at 24 and 48 weeks; serum hormone levels or biochemical measures of nutrition did not differ significantly, either. Serum vitamin E levels did go down in the treatment group consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation. Even with this reduction, however, levels remained within the accepted reference range.
There were no reported adverse effects on mental performance or the central nervous system, nor were there any apparent elevations in hepatic transaminases or creatine kinase increases with myalgia, the two most common concerns with statins in adults. The researchers acknowledged that although this study is the largest and longest to date and raised no safety or growth and development concerns, its limited size and duration precludes making predictions regarding safety and direct clinical benefit of lovastatin use in larger populations on longer therapy. It also did not provide data on adolescent girls. Researchers concluded that the lack of symptomatic adverse effects, together with the clinical and biochemical data, supports the tolerability of lovastatin in boys.
Implications for Practice
It has been shown that initiation of safe and effective drug therapy in identified at-risk pediatric populations may delay the onset of clinically manifest coronary artery disease. This study has clear implications for advanced practice nurses:
1. A careful family history is needed to guide providers in selective screening of children and adolescents for HeFH.
2. Pediatric patients requiring therapy need to be at least 10 years old; beyond that age, no clear consensus exists regarding the age at which drug therapy should be initiated.
3. The U.S. National Cholesterol Education Program Pediatric Treatment Panel recommends drug therapy be considered if, after appropriate diet intervention:
• LDL-C level remains >190mg/dl;
• or >160mg/dl with a family history of premature CAD ( • and/or two or more other cardiovascular disease risk factors exist.7
4. The presence of other risk factors (obesity, smoking, high blood pressure, and diabetes) must be addressed concurrently.
5. Until criteria for the most appropriate and efficacious drug therapy for pediatric HeFH are determined, consultation with a specialist is warranted.
References
1. Jorde L. Genes, Environment, and Common Diseases. In: McCance K, Huether S, eds. Pathophysiology: The Biologic Basis for Disease in Adults and Children. 3rd Edition. St. Louis: Mosby; 1998:163-64.
2. Stein EA, Illingworth DR, Kwiterovich PO Jr., et al. Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia. JAMA 1999;281:137-44.
3. Sugrue D, Thompson G, Oakley C, et al. Contrasting patterns of coronary atherosclerosis in normocholesterolaemic smokers and patients with familial hyper cholesterolaemia. BMJ 1981;283:1358-60.
4. Lambert M, Lupien P-J, Gagne C, et al. Treatment of familial hypercholesterolemia in children and adolescents: Effect of lovastatin. Pediatrics 1996;97:619-28.
5. Weidman W, Kwiterovich PO Jr, Jess MU, et al. AHA committee report: Diet in the healthy child. Circulation 1983;67:1411-14A.
6. Marshall W, Tanner J. Variations in the pattern of pubertal changes in boys. Arch Dis Child 1970; 45:13-23.
7. National Cholesterol Education Program. Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Bethesda, MD: National Heart, Lung, and Blood Institute; 1991: NIH pub lication 91-2732.
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