Main

FH(1), an autosomal dominantly inherited defect in cholesterol clearance, affects approximately one out of 450 individuals in western countries(2). There is general agreement that adults with FH should receive aggressive diet and drug treatment to lower their substantially increased risk of cardiovascular morbidity and mortality(3).

The onset of coronary artery disease in FH patients can be as premature as the third decade of life, and early initiation of drug treatment in these patients seems warranted. The necessity and benefit of lowering cholesterol in children with FH, however, is debated, and furthermore, treatment may be associated with unwanted side effects. Growth and maturation of (pre)-pubertal children could be negatively affected by modifying cholesterol synthesis. Moreover, results of recent trials suggest that, when treatment is postponed until adulthood, progression of atherosclerotic lesions can still be influenced(4–6).

On the other hand, it is well documented that, within the cohort of FH patients, some exhibit rapid disease progression with clinical manifestations of atherosclerosis, whereas others will develop CVD much later. Probably, additional and largely unknown, either acquired or congenital, risk factors may explain this difference(7). Therefore, it seems likely that the effects of early initiation of cholesterol-lowering treatment in younger individuals will have to be evaluated one time or another.

At the present time, the recommended therapeutic regimen for children with FH is restricted to bile acid binding resins in conjunction with a lipid-lowering diet(8). Long-term studies, however, reported modest reductions of approximately 12% of plasma total cholesterol with this regimen(9, 10), only slightly more effective than diet alone(11, 12), and essentially insufficient to modify the process of vessel wall damage. Although HMG-CoA reductase inhibitors, the drugs of choice in the treatment of adults with FH, have proven to be safe and effective in large scale clinical studies(3, 13), only a few small observational studies, concerning the use of these drugs in children, have been reported(10, 14). Although in these studies children were treated for more than 1 y, neither of these investigations included control patients or were large enough to address safety.

In the present placebo-controlled study, we investigated the 3-mo safety, tolerability, and efficacy of pravastatin in 72 randomly selected children, aged 8 to 16 y, with heterozygous FH.

METHODS

Study design. The aim of this double-blind, randomized, placebo-controlled study was to evaluate safety, tolerability, and efficacy of 12-wk pravastatin treatment in 72 children with FH. Children were stratified for age(15) into three groups of equal number;i.e. 8 to 10, 11 to 13, and 14 to 16 y. After a diet and placebo run-in period of 8 wk, patients were randomized to four treatment arms,i.e. daily pravastatin, 5, 10, or 20 mg, or placebo, and were seen monthly.

Prestudy diet was evaluated for a period of 5 d, using a computer questionnaire, and adjusted, if necessary, to comply with an intake of carbohydrate 50% energy, protein 20% energy, and fat 30%, with a unsaturated:saturated ratio of 2:1. The daily intake of cholesterol was less than 300 mg.

Written informed consent was obtained from one of the parents or guardians and from all children when they were 12 y or older. The protocol was approved by the Institutional Review Board.

Patients. Children with known heterozygous FH were eligible for the study. Heterozygous FH was defined as a plasma LDL cholesterol level above the 95th percentile for age and sex, during lipid-lowering diet. Moreover, hypercholesterolemia had to be present in siblings, parents, or grandparents, or clinical manifestations of premature atherosclerosis had to be present before the age of 50 y in first or second degree relatives. Children were excluded if they had undergone major surgery in the past 3 mo or when they used medication interfering with lipid metabolism (such as anticonvulsants, oral contraceptives, corticosteroids, fibric acid derivatives, or immunosuppressants). Furthermore, children with hepatic or renal dysfunction were not included in the study.

Safety and efficacy measurement. A physical examination was performed at entry and at the final visit. During the other visits adverse events and vital signs were recorded by physicians unaware of treatment allocation. At each visit, blood samples were drawn after an overnight fast. Laboratory safety parameters included routine hematology, biochemistry, and urinalysis. Also TSH, cortisol, and ACTH were measured before and after the treatment period. Plasma total and LDL cholesterol, triglycerides, HDL cholesterol, apo A1, apo B100, Lp(a), and VLDL cholesterol were measured to assess efficacy. Plasma LDL cholesterol was calculated using the Friedewald equation(16). Apo A1 and B100 were determined by an immuno-rate-nephelometric procedure using a polyclonal goat-anti-human antiserum and were calibrated on World Health Organization proposed international reference material(17). Lp(a) was determined by an electroimmunodiffusion procedure using a monospecific polyclonal goat antiserum and calibrated on immunostandard human serum(18). VLDL cholesterol was determined after separation by ultracentrifugation in a Cs-chloride solution, and cholesterol was quantified enzymatically in the supernatant(19). Treatment compliance was evaluated by tablet count.

Statistical analysis. Analyses of variance and covariance were used for between-group comparisons. Paired t tests were used to assess significance of changes from baseline within each treatment group. Baseline values as well as age were included as covariates in the analysis. For frequency data, Fisher's exact test was used. All results were analyzed on the basis of intention to treat.

RESULTS

Seventy-two children were randomized to the four treatment groups. Baseline characteristics were comparable with respect to sex, age, ethnicity, and lipoprotein profiles (Table 1). All patients completed the study according to protocol. Overall compliance with intake of study medication was excellent (93%) and comparable among the groups. Four children belonging to one family showed a poor compliance; they were equally distributed over the treatment groups.

Table 1 Baseline characteristics
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Safety results. Pravastatin was well tolerated. Adverse events, whether or not considered to be related to therapy, were equally distributed among the four treatment groups (Table 2). One patient, treated with pravastatin 5 mg had a rash, which spontaneously disappeared after a few days, while drug treatment was continued. Five children, two in the placebo and three in the pravastatin 10-mg group, reported a single episode of headache during the active treatment period, of which none was considered to be serious. In the placebo group, one headache occurred during a period of rhinitis, and one appeared to be related to school examinations. Similar reasons were reported by the children in the pravastatin 10-mg group, who experienced headaches. All headaches resolved spontaneously after 1 to 3 d. The gastrointestinal complaints all resolved without a change in medication. Finally, laboratory safety measurements, including plasma TSH, ACTH, cortisol, creatine phosphokinase, and liver enzyme levels, did not show significant changes in any of the groups between the end of the treatment period and baseline (data are shown in Table 3).

Table 2 Adverse events
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Table 3 Laboratory safety parameters
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Efficacy results. At week 12, both plasma total and LDL cholesterol levels were significantly reduced in all pravastatintreated groups (Fig. 1,A and B). The curves show that maximum effect was reached within 8 wk, regardless the dosage used. The plasma LDL cholesterol levels were not reduced below the 95th percentile for sex and age (Fig. 2), except for two children in the pravastatin 20-mg group and one child each in the 5- and 10-mg groups, respectively. Plasma HDL cholesterol and triglyceride levels did not change as compared from baseline, except for a mean HDL cholesterol level increase of 11% in the pravastatin 20-mg group (p < 0.01). Plasma VLDL cholesterol and apo B100 levels were reduced within all pravastatin-treated groups(p < 0.05 and p < 0.001; data shown for all lipid and lipoprotein parameters in Table 4). Plasma levels of apo A1 showed a trend toward improvement in the pravastatin 20-mg group. Lp(a) levels were not influenced by pravastatin treatment.

Figure 1
figure 1

Plasma total (A) and LDL (B) cholesterol change (95% C. I.) during treatment with pravastatin 5 (▪), 10 (□), or 20 (•) mg, or placebo (○). Changes were statistically significant in all treatment groups compared with baseline (p < 0.05).

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Figure 2
figure 2

Absolute plasma LDL cholesterol change (95% C.I.) ater treatment with pravastatin 5, 10, or 20 mg, or placebo. ▪, baseline;□, wk 12. Changes were statistically significant in all treatment groups compared with baseline (p < 0.01). Line = upper limit of normal for plasma LDL cholesterol level.

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Table 4 Lipoprotein mean percentage change from baseline(95% C.I.)
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DISCUSSION

Our study demonstrates that 12 wk of pravastatin treatment in children with FH is well tolerated and does not affect routine biochemical parameters or hormonal status, as reflected by TSH, ACTH, or cortisol. The latter is in agreement with previous studies in adults(20, 21). As expected, plasma total and LDL cholesterol levels showed a significant reduction, which appeared to be dose-related. In the pravastatin 20-mg group, mean plasma LDL cholesterol decreased by 33%, whereas in the 5- and 10-mg groups plasma LDL cholesterol was reduced by 23%. A similar dose-related response was observed in the relative reduction of plasma total cholesterol.

It should be noted that, in only a few children, plasma LDL cholesterol levels did fall below the 95th percentile for age and sex, which could be considered a minimum level for slowing down the atherosclerotic process. In fact, there is suggestive evidence from studies in adults that arrest or regression of atherosclerosis is obtained only when plasma LDL cholesterol levels are reduced below 2.5 mmol/L(3, 10). Although the children in the present study were treated for a relatively short period of time, it can be assumed that the decrease observed would remain constant, especially because a convenient once daily regimen favors compliance.

What would be the preferred strategy in children with FH? It is premature to suggest a general course of treatment in children with FH, because it is not yet known whether all subjects with FH need to be treated in childhood, to prevent premature CVD. There is indeed reason to believe that, among subjects with FH, specific high risk groups exist, with, for example very high cholesterol levels or an extensive family history of premature CVD,i.e. determinants of FH itself. Additional genetic risk factors for the development of CVD, such as hyperhomocysteinemia or high levels of Lp(a), might contribute to the high risk status of these subjects with FH(7). It will be necessary to identify these high risk subgroups at an early point in time and to demonstrate that these subjects have a more progressive atherosclerotic disease of their arteries and subsequently that plasma LDL cholesterol lowering to a predefined level results in the arrest or regression of atherosclerosis(22).

At present, the international recommended treatment for children with FH consists of a lipid-lowering diet in combination with bile acid-binding resins(8), which has been shown to be safe and effective. However, long-term experience with this regimen is very disappointing with respect to effective cholesterol lowering, due to a sharp decrease in drug intake compliance over time(23). Our study demonstrates that pravastatin, in an once daily dosage regimen, may be a useful agent in the treatment of high risk children with FH. Albeit, long-term safety and efficacy studies with HMG-CoA reductase inhibitors using dose titration, to reduce plasma LDL cholesterol levels below a predefined level, need to be performed. Furthermore, the role of combination therapy in these subjects should be assessed.

In conclusion, cholesterol-lowering treatment with pravastatin is safe, well tolerated, and effective in children with FH. However, before new treatment strategies in these children are to be considered, results of long-term studies have to be awaited.

Note: After acceptance of this manuscript we became aware of an independently performed study in which three statins (simva-, lova- and pravastatin) were compared in young rats(24). Clinical signs (myopathy, walking, body weight), plasma creatine kinase activity (as a measure of muscle damage), and histologic validation of muscle damage were used as parameters. It appeared that the lipophilic statins (simva- and lovastatin) caused a strong reduction in body weight, very high plasma creatine kinase activity, and myopathy, in a dose-dependent fashion. Simvastatin was most potent in this respect (15 mg/kg/d), whereas lovastatin produced these effects at higher doses (40-55 mg/kg/d). Pravastatin, a hydrophilic compound, did not produce any of these symptoms, except some loss in body weight. Even at extremely high doses (1000 mg/kg/d) no signs of a myopathy were observed. The conclusion is that young animals are more susceptible to adverse effects of simva- and lovastatin. These results and ours collectively suggest that for long-term safety studies in young children pravastatin may be the most suitable candidate.