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Hospital for Children and Adolescents, University of Helsinki (M.H., T.M., A.F., M.L., S.P., M.A.), 00029-HUS Helsinki, Finland; and Department of Children and Adolescents, University of Oulu (M.N.), 90029-OYS Oulu, Finland
Address all correspondence and requests for reprints to: Dr. Marjatta Antikainen, Hospital for Children and Adolescents, University of Helsinki, P.O. Box 281, FIN-00029 Helsinki, Finland. E-mail: marjatta.antikainen{at}hus.fi.
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Abstract |
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194 mg/dl (5 mmol/liter)] was reached. By 2, 4, 6, 12, and 24 months of treatment, the total cholesterol levels had, respectively, decreased by 19, 20, 23, 27, and 26%, and the low-density lipoprotein cholesterol levels had decreased by 25, 27, 29, 33, and 32% compared with the dietary baseline values. Seventeen percent of patients had lipid deposits (carotid plaque, xanthomas, or corneal arcus) at baseline, and 27% had deposits at 1 yr. The side effects were mild, and no clinically significant elevations in alanine aminotransferase, creatine kinase, or creatinine were seen. Growth and pubertal maturation remained normal in all subjects. In conclusion, pravastatin treatment was safe and well tolerated. The efficacy in children with slight or moderate hypercholesterolemia was satisfactory, but in children with severe hypercholesterolemia, it was insufficient. |
Introduction |
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HeFH is associated with increased morbidity of coronary heart disease (CHD) and with premature death (3). In men with untreated HeFH, the prevalence of CHD is 20% by 40 yr of age, 45% by 50 yr, and 75% by 60 yr, and the mortality is 23% by 50 yr (4, 5). Premature deposition of cholesterol in coronary arteries and development of tendon xanthomas are also characteristic for children with HeFH. By ages 10–19 yr, children with HeFH have carotid artery plaques, and their carotid intima media thickness is greater than that in control subjects (6, 7, 8).
In HeFH patients, dietary interventions that reduce saturated fat and cholesterol intake have been shown to be insufficient for reaching normocholesterolemia (9). Furthermore, dietary supplementation of stanols or sterols has only moderately decreased serum cholesterol levels (10, 11, 12, 13). Numerous studies have demonstrated that gradual progression of atherosclerosis begins in childhood, emphasizing the need for early intensive drug therapy. However, there is no consensus on the age at which drug therapy should be started (9, 14, 15, 16, 17). Because cholesterol is an essential structural component of cells; a precursor for steroid hormones, vitamin D metabolites, and bile acids; and an important factor in neural myelinization and brain growth, concerns about possible side effects of statins on growth, pubertal development, and endocrinological functions have restricted their use in prepubertal children. Furthermore, because fat-soluble vitamins are transported by lipoproteins, their reduction by statins has been suspected to lead to vitamin deficiencies. However, these arguments lack substantiation, and the U.S. Food and Drug Administration has approved pravastatin for treatment of HeFH in children more than 8 yr of age. After the completion of our study, Wiegman et al. (18) reported the 2-yr efficacy and safety of pravastatin therapy in children 8–18 yr of age. We recently reported the pharmacokinetics and short-term safety of pravastatin in HeFH children (19). The purpose of the present prospective study is to determine the efficacy and safety of pravastatin over the longer term, with particular reference to growth and development.
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Patients and Methods |
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The study was conducted between August 2001 and February 2004, and 35 children and adolescents (22 girls and 13 boys; age range, 4.1–18.5 yr) with HeFH were enrolled. The final number of patients was 30, because five patients did not complete the first year of follow-up by the end of the study and were thus excluded from the analysis: one patient discontinued after 6 months of therapy due to persistent abdominal pain (subsequently diagnosed as lactose intolerance), one patient discontinued at baseline due to lack of motivation, and three patients fell behind with the protocol. The diagnosis of HeFH was based on LDL receptor mutation analysis (1) or lymphocyte test results (20). Sixteen patients were positive for the HeFH-Helsinki LDL receptor mutation, six patients were positive for the HeFH-North Karelia LDL receptor mutation, two patients were positive for the HeFH-Turku LDL receptor mutation, and six patients had defective cholesterol intake in the lymphocyte test. Aside from HeFH, all of our patients were healthy, and before the study, none was taking daily medication. One patient had been smoking 20 cigarettes/d for 3 yr.
The criteria for an open, clinical, follow-up study were patient age more than 4 yr (by which time normal children have reached plateau cholesterol levels) (21) and serum total cholesterol concentration of 232 mg/dl (
6 mmol/liter) or greater regardless of an 8-wk dietary intervention. A dietary review by the same dietitian was performed for all patients at the first hospital visit. The dietary recommendations included a low-fat (energy from fat, <30% of total energy), reduced-saturated-fat (<10% of total energy), and low-cholesterol (<100 mg/d) diet, with supplementation of plant stanol or sterol esters (2.0 g/d). Compliance was controlled after 2 months of dietary intervention, at baseline before pravastatin therapy, and at each hospital visit during pravastatin intervention. Consecutive patients who fulfilled the inclusion criteria and accepted the study protocol were enrolled without selection. The family history of the participants was recorded. Pravastatin was started at 10 mg/d regardless of the patient’s age or body weight, with a forced titration by 10 mg at 2, 4, 6, and 12 months of follow-up (maximum dose, 50 mg) until the target cholesterol level [194 mg/d (5 mmol/liter)] was reached. The maximum dose was increased to 60 mg in the patients with exceptionally high total cholesterol levels [>271 mg/dl (>7 mmol/liter)] after administration of 50 mg pravastatin. Of 30 patients, 16 were followed for 1 yr, and 14 were followed for 2 yr. Pravastatin was selected because it is hydrophilic and causes fewer muscular side effects.
The study protocol was approved by the ethics committee of Helsinki University Hospital for Children and Adolescents. The National Agency for Medicines in Finland granted permission to treat the study group with pravastatin, although pravastatin is not generally approved for pediatric use in Finland. The rules of the European Agency guidance for clinical investigation of medicinal products in the pediatric population (ICH Topic E 11) were followed. Each of the patients participated on a voluntary basis. Written informed consent was obtained from the parents.
Lipids
The fasting concentrations of serum total, LDL, and high-density lipoprotein (HDL) cholesterol and of serum triglycerides were determined before and at 2, 4, 6, 12, and 24 months of treatment. The concentrations of serum total and HDL cholesterol and of serum triglycerides were analyzed enzymatically by use of Hitachi 917 or Modulator automatic analyzers with reagents and calibrators as recommended by the manufacturer (Roche, Basel, Switzerland). The interassay coefficients of variation for low and high serum cholesterol concentrations [128 mg/dl (3.3 mmol/liter) and 245 mg/dl (7.1 mmol/liter], HDL cholesterol concentrations [35 mg/dl (0.9 mmol/liter) and 62 mg/dl (1.6 mmol/liter)], and triglyceride concentrations [89 mg/dl (1.0 mmol/liter) and 177 mg/dl (2.0 mmol/liter)] were 2.1 and 1.8%, 2.2 and 2.7%, and 3.0 and 2.3%, respectively. The LDL cholesterol concentration was calculated using the formula of Friedewald et al. (22). The highest fasting concentrations, before dietary or drug interventions, of serum total, LDL, and HDL cholesterol and of serum triglycerides were recorded from the patient chart. The short-term efficacy results in 20 patients have been reported previously (19).
Growth
Height and weight were measured with a wall-mounted stadiometer and an electric scale at each visit. The height SD score (hSDS) was calculated according to the following equation: hSDS = (observed height – mean height for age/SD), where SD represents the SD for the normal population of the same chronological age and gender (23). The weight for height index (W/H), expressed as a percentage, was determined from the ratio of weight (kilograms) for height (centimeters) to the mean W/H in the normal population of the same chronological age and gender. Bone age determinations were made according to the Greulich-Pyle method by the same pediatric endocrinologist at each visit (24). Height for bone age was also calculated and expressed as an SDS (23). Growth, in relation to gender and pubertal stage, of each patient was individually evaluated by a pediatric endocrinologist using growth charts, clinical data (e.g. changes in 
hSDS and W/H, pubertal development, and time of menarche), hormonal results (estradiol and testosterone), and bone age measurements.
Development
Pubertal maturation was evaluated clinically using Tanner’s pubertal staging by the same pediatrician at each visit (25, 26). Early maturation was defined as development of sexual characteristics before 8 yr of age in girls and 9 yr of age in boys. Delayed puberty was defined as no signs of puberty at the age of 13 yr in girls and 14 yr in boys (2 SD above the mean of chronological age for the onset of puberty). The menstrual history in girls was recorded. Gonadal maturation in girls was assessed by ultrasonography by a pediatric gynecologist at baseline (in 13 girls), at 12 months (in nine girls), and at 24 months (in two girls). The ultrasonography was performed transabdominally through a distended bladder with an Aloka SSD-1100 ultrasound scanner (Aloka Co., Ltd., Tokyo, Japan) equipped with a 13-Hz probe. The length of the uterus was recorded. The ovarian volume was calculated by: thickness x length x width x 0.52. The ovarian structure was evaluated. Testis volume in boys was assessed by high resolution B-mode ultrasonography (using an ATL HD 5000 ultrasound scanner (ALT, Bothell, WA), equipped with a linear 5- to 12-MHz transducer) before treatment and at 12 and 24 months. The testis volume was calculated by: thickness x length x width x 0.52 (27).
Baseline and stimulated hormonal status was recorded at 0, 12, and 24 months, comprising baseline ACTH, testosterone, and estradiol levels and ACTH-stimulated cortisol secretion, GnRH, FSH, and LH secretion. In the GnRH stimulation test, the patient received a dose of 3.5 µg/kg (maximum dose, 100 µg) GnRH, and blood samples for LH and FSH measurements were collected at 0, 20, 30, and 60 min and at 0, 30, 60, and 90 min, respectively (28). In the ACTH stimulation test, the patient received a dose of 0.25 mg/1.73 m2 (maximum dose, 0.25 mg) ACTH, and blood samples for cortisol measurements were collected at 0, 60, and 120 min. All laboratory measurements were carried out according to the standards of the Helsinki University Central Hospital. Serum FSH and LH were quantitated with time-resolved ultrasensitive immunofluorometric assays (AutoDELFIA; Wallac, Turku, Finland). Serum estradiol, testosterone, and ACTH were measured by RIA (Wallac). Serum cortisol was quantitated with an enzyme immunoassay using reagents on the immunoanalyzer Immunol (Bayer, Tarrytown, NY).
The boys and girls were divided into subgroups (IA, prepubertal at baseline and at follow-up; IB, prepubertal at baseline and pubertal at follow-up; II, pubertal at baseline; III, postpubertal at baseline) according to results from the GnRH stimulation test and clinical examination: prepubertal was defined as Tanner stage 1 in clinical examination, and peak FSH dominant over peak LH in the GnRH stimulation test; pubertal was defined as peak LH dominant over FSH, and peak LH concentration above 6 IU/liter in the GnRH stimulation test; and postpubertal was defined as Tanner stage 5 in clinical examination and, in girls, menarche before study onset. The GnRH stimulation test was used because of its sensitivity to detect central puberty before clinical signs. Development, relative to age and gender, of each patient was individually evaluated by the use of clinical data (e.g. progression in puberty and time of menarche), hormonal results (GnRH stimulation test, estradiol, and testosterone) and changes in testis/ovarian and uterine volumes.
Adverse events and biochemical safety
The potential side effects of pravastatin were monitored using a questionnaire. Clinical examinations and safety parameter measurements, including alanine aminotransferase (ALT), creatine kinase (CK), and creatinine were performed before treatment and at 2, 4, 6, 12, and 24 months. Vitamins A, D, and E were determined before treatment and at 6, 12, and 24 months. Vitamins A and E were analyzed by HPLC (Hewlett-Packard, Waldbronn, Germany), 1.25-hydroxyvitamin D was determined by RIA (Wallac), and 25-hydroxyvitamin D was determined by RIA (DiaSorin, Stillwater, MN) or an HPLC method (29).
Ultrasonography of carotid artery and Achilles tendon
All examinations were performed by the same two pediatric radiologists, who were unaware of the clinical and laboratory characteristics. High resolution B-mode ultrasound of the carotid arteries and Achilles tendons was performed using an ATL HD 5000 ultrasound scanner equipped with a linear 5- to 12-MHz transducer. In the carotid artery ultrasound, the subjects were examined in the supine position, with the head turned slightly to the left. The right common carotid artery was scanned longitudinally, and the intima media thickness of the posterior vessel wall, 2 cm below bifurcation, was measured. Four frozen images were captured with the typical two-line pattern visualized from near and far walls, and the vessel was magnified using a high resolution box function. From each picture, three intima media thickness measurements were performed. Plaques from both common and internal carotid arteries were searched. In the Achilles tendon ultrasound, the subjects were examined in the prone position with their feet and ankles, at a 90° angle, extended past the examination table. The tendons were scanned both transversally and longitudinally, and four frozen images were captured. The Achilles tendon thicknesses right above the calcaneus and at 2 cm cranially were measured. Xanthomas (defined as hypoechoic lesions seen both longitudinally and transversally), if present, were measured and recorded.
Ophthalmology
All patients were seen by an ophthalmologist before and after 1 yr of pravastatin treatment; the corneas and eye grounds were examined for corneal arcus and retinal arterial changes, respectively.
Statistical analysis
Data are the mean ± SD in text and tables. The normality of the distribution was tested by Shapiro-Wilke’s W test. Statistical comparison of the normally distributed variables between the pretreatment and treatment phases was carried out by paired t test. If the distribution was skewed, the Wilcoxon signed-rank test was used. Statistical comparison of the normally distributed variables between different groups was carried out by t test for unpaired values and by the Mann-Whitney U test, if the distribution was skewed. Pearson’s correlation coefficients were calculated to evaluate degrees of linear association between normally distributed variables and Spearman’s rank correlation coefficients for nonparametric variables. The statistics software used was purchased from StatsDirect Ltd. (Cheshire, UK). P < 0.05 was considered statistically significant.
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Results |
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The baseline characteristics are shown in Table 1
. The mean age of our patients before treatment was 10.1 ± 3.4 yr (range, 4.1–18.5 yr). The mean height and weight were 140.6 ± 19.6 cm (range, 106.2–172.9 cm) and 38.6 ± 17.4 kg (range, 16.4–89.9 kg), respectively.
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In the 16 patients followed for only 1 yr, the maximum dose of pravastatin was 10 mg in two patients, 20 mg in two patients, 30 mg in one patient, and 40 mg in 11 patients. In those 14 who were followed for 2 yr, the maximum doses were 10 mg in one patient, 20 mg in four patients, 40 mg in two patients, 50 mg in four patients, and 60 mg in three patients [only those with total cholesterol >271 mg/dl (>7 mmol/liter) after 50 mg pravastatin].
Lipids
The lipid and lipoprotein concentrations before dietary intervention and before pravastatin therapy (during dietary intervention), and the changes in the concentrations caused by diet and pravastatin treatment are shown in Table 2. The dietary intervention produced statistically significant changes in total and LDL cholesterol concentrations [–10.7% (P < 0.0001) and –12.6% (P = 0.0001)]; the changes in HDL cholesterol concentrations and triglycerides were not statistically significant [0.4% (P = 0.841) and 19.2% (P = 0.728)]. The maximum efficacies of 10–60 mg pravastatin are demonstrated in Table 3. The total cholesterol concentrations were at the target level [194 mg/dl (5 mmol/liter)] in nine patients after 1 yr of pravastatin treatment and in five patients after 2 yr. In the patients with slight or moderate baseline hypercholesterolemia [total cholesterol, <310 mg/dl (<8 mmol/liter)], the total cholesterol levels at 1 and 2 yr were 201 ± 27 mg/dl [5.2 ± 0.7 mmol/liter; range, 151–259 mg/dl (3.9–6.7 mmol/liter)] and 194 ± 43 mg/dl [5.0 ± 1.1 mmol/liter; range, 147–283 mg/dl (3.8–7.3 mmol/liter)], respectively. In the patients with more severe baseline hypercholesterolemia [total cholesterol, 310 mg/dl (8 mmol/liter)], the total cholesterol levels at 1 and 2 yr were 255 ± 66 mg/dl [6.6 ± 1.7 mmol/liter; range, 186–364 mg/dl (4.8–9.4 mmol/liter)] and 271 ± 43 mg/dl [7.0 ± 1.1 mmol/liter; range, 209–321 mg/dl (5.4–8.3 mmol/liter)], respectively.
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The parameters for growth and development are presented in Table 4. Growth, as individually evaluated and related to age, gender, and pubertal stage, was normal in all patients. No statistically significant changes in hSDS during the first year of treatment were observed in prepubertal girls or boys (P = 0.09 and P = 0.64, respectively). In prepubertal girls (group IA), the mean height velocities according to the Tanner-Whitehouse velocity chart of height at 1 and 2 yr were at the 97th and 50th percentiles, respectively (30). In the girls in group IB, the respective height velocities were at the 92nd and 43rd percentiles, and in the girls in group II, they were at the 25th and 24th percentiles. In the girls in group III, normal deceleration of growth was observed at 1 and 2 yr (mean height velocity, 0.5 and 0.2 cm/yr, respectively). In the boys in group IA, the mean height velocities at 1 and 2 yr were at the 70th and 93rd percentiles, respectively. In the boys in group IB, the respective height velocities were at greater than the 97th and 83rd percentiles. At baseline, the two boys (9.8 and 10.7 yr of age) in group II were pubertal according to the GnRH stimulation test (LH dominant over FSH; peak LH, 6.7 IU/liter in both), but had prepubertal testicular volumes (<4 ml). Their mean height velocity at 1 yr was greater than the 97th percentile. However, at 2 yr, the height velocity of the one boy followed had normalized to approximately the 97th percentile. The growth of these two boys, as individually analyzed using growth charts, was normal, and no accelerated bone maturation was observed.
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The estradiol and testosterone concentrations, with reference values, are shown in Table 5 (31). No clinically significant changes in estradiol and testosterone concentrations were observed. The data from the GnRH stimulation test, used for pubertal characterization, are not shown. At baseline, no signs of early maturation or delayed puberty were observed. Pubertal development, as individually evaluated and related to age and gender, was normal in all patients. The measurements of uterus and ovaries or testicles, with reference values, are shown in Table 5 (32, 33, 34). The ovarian structure, related to age, was normal in all patients examined. The testis volumes of pubertal boys (groups IB and II) were low compared with reference values (33, 34). This might be due in part to a difference in definition, because the GnRH stimulation test can detect central puberty before clinical signs.
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. A statistically significant reduction in the ACTH levels was observed at 1 and 2 yr, and in the baseline and peak cortisol levels at 1 yr. The ACTH concentrations [range, 53–64 ng/liter (11.7–14.1 pmol/liter)] at baseline in three patients and at 1 yr in one patient were slightly higher than reference values [10–50 ng/liter (2.2–11.0 pmol/liter)]. However, their basal cortisol levels were normal. At 2 yr, the ACTH concentration [9 ng/liter (2.0 pmol/liter)] in one patient was slightly lower than the reference value [10–50 ng/liter (2.2–11.0 pmol/liter)], but the basal cortisol concentration [11 µg/dl (298 nmol/liter)] was normal. At 1 and 2 yr, the basal cortisol concentrations [range, 3.6–4.9 µg/dl (99–135 nmol/liter)] were below reference values [>5.4 µg/dl (>150 nmol/liter)] in five and two patients, respectively. However, their stimulated peak cortisol concentrations were normal. No clinical signs of hypocortisolism were observed.
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The adverse experiences are shown in Table 6. Most symptoms reported were mild, disappeared during the first months of therapy, and thus did not seem to be dose-related. The most common adverse experiences were headache and gastrointestinal symptoms, affecting 13% and 37% of the patients, respectively, at 2 months. However, headache and gastrointestinal symptoms were also common complaints before treatment, affecting 10% and 17% of the patients, respectively. Sleep disorder occurred in 10%, but no other social or psychological adverse experiences, i.e. depression, hyperactivity, or impaired school performance, were reported. One patient [total cholesterol, 197 mg/dl (5.1 mmol/liter)] discontinued treatment at 14 months due to diarrhea, which was subsequently diagnosed as a food allergy. Irregular pravastatin use was reported by two patients due to financial reasons and by three patients due to poor adherence to therapy.
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The ALT, CK, creatinine, and vitamin levels are shown in Fig. 2. No clinically notable serum creatinine, ALT, or CK levels were observed at 2, 4, 6, 12, or 24 months. At 6 months, the decrease in vitamin E concentrations was significant (P < 0.001), yet all concentrations were within reference values [0.5–1.7 mg/dl (12–40 µmol/liter)]. Two patients had vitamin A concentrations [at 6 months, 26 µg/dl (0.9 µmol/liter); at 12 months, 23 µg/dl (0.8 µmol/liter)] lower than recommended levels (27–86 µg/dl (1–3 µmol/liter)]. At 6 months, a significant increase was observed in 1,25-hydroxyvitamin D levels (P < 0.001).
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The baseline intima media thickness of the right carotid artery was 0.42 ± 0.04 mm (range, 0.33–0.52 mm). A nonsignificant increase in the intima media thickness of the right carotid artery was seen at 1 and 2 yr [mean change, 0.02 ± 0.06 mm; range, –0.10 to 0.15 mm (P = 0.08); and <0.01 ± 0.06 mm; range –0.09 to 0.09 mm (P = 0.96), respectively]. No statistically significant correlations were observed between the baseline intima media thickness of the right carotid artery and total, LDL, or HDL cholesterol concentrations or triglycerides (r = 0.16, P = 0.41; r = 0.26, P = 0.18; r = –0.26, P = 0.18; and r = –0.03, P = 0.89, respectively), nor were the correlations statistically significant between the 1-yr change in intima media thickness and that in LDL cholesterol levels (r = 0.34; P = 0.07). Before treatment, a carotid plaque was observed in one patient. During follow-up, one additional patient developed a plaque.
Before treatment, Achilles tendon xanthomas (3.0 and 4.3 mm) occurred in two patients. At 1 yr, the xanthomas in one patient had disappeared, and one additional patient had developed xanthoma (6.0 mm). At 2 yr, the xanthoma of the latter patient had disappeared. No significant change was seen in Achilles tendon thickness at 1–2 yr (data not shown).
Two patients had corneal arcus at baseline and at 1 yr of follow-up, and two patients developed changes during the first year of treatment. No retinal arterial changes were seen.
Altogether, nine patients (baseline age, 7.7–18.5 yr) developed lipid deposits (carotid plaques, xanthomas, or corneal arcus) before or during treatment. Of these patients, two were positive for the HeFH-Helsinki LDL receptor mutation, three for the HeFH-North Karelia LDL receptor mutation, and one for the HeFH-Turku LDL receptor mutation, and three had defective cholesterol intake in the lymphocyte test (1, 20). The baseline ages of these nine patients were significantly higher than those of subjects without lipid deposits (12.9 ± 3.4 vs. 8.9 ± 2.7 yr; P = 0.002), but there were no statistical differences in total, LDL, and HDL cholesterol and triglyceride concentrations (P = 0.757, P = 0.531, P = 0.347, and P = 0.850, respectively).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Several studies in children have addressed the short-term safety and tolerability of statins (9, 14, 15, 16, 17, 18, 19). Their long-term safety is not as thoroughly understood, yet 48-wk results regarding growth and development of adolescents receiving lovastatin or simvastatin treatment have been promising (16, 17). Furthermore, after the completion of our study, Wiegman et al. (18) reported no adverse effects during 2 yr of pravastatin therapy on the growth or sexual maturation of children and adolescents 8–18 yr of age. However, because pravastatin doses in the latter study were 20 mg in children less than 14 yr of age and 40 mg in adolescents more than 14 yr of age (18), the doses in our study, especially in younger children, were considerably higher. Also, the strength of our study is that the growth and development of individual patients were assessed in relation to age, pubertal stage, and gender. Furthermore, to our knowledge, no previous study has reported the safety and efficacy over the longer term in children younger than 8 yr on any statin (19). Nine of our patients were less than 8 yr of age, and the youngest was only 4 yr old. In these patients, pravastatin was safe and well tolerated. Pravastatin treatment did not delay pubertal development or cause hormonal disturbances at any age; progressions in Tanner staging, estradiol and testosterone levels, and volumes of gonads were normal. Furthermore, growth was not adversely affected. Although slight alterations in ACTH and cortisol levels were observed, they were of little clinical relevance, and no patient had signs of hypocortisolism. Our findings are therefore in line with those of previous studies in which no adverse effects on adrenal function were observed in patients receiving pravastatin treatment (39).
The side effects reported in our 2-yr follow-up were mostly mild and transient, and the discontinuation rates resembled those with placebo (17). No clinically notable CK, ALT, or creatinine concentrations were detectable. Although a statistically significant decrease in vitamin E levels was observed, the fat-soluble vitamins remained at clinically satisfactory levels. This is of importance, because fat-soluble vitamins are transported in association with lipoproteins, and their absorption and transportation with statins have yielded concerns.
In adults with HeFH, carotid artery plaque has been associated with CHD, and the thickness of intima media layers in carotid arteries has proven useful in estimating the efficacy of lipid-lowering therapy (40, 41). According to recent data, intensive high-dose statin therapy is required to delay the progression of coronary atherosclerosis in adults with HeFH and in non-HeFH patients with CHD (42, 43, 44, 45). Furthermore, the maximum effect on CHD could possibly be obtained with even more intensive therapy than currently recommended by international guidelines (42, 43, 44, 45). Men with HeFH not treated with statins until middle-age remain at increased risk of CHD and would probably benefit from earlier and more vigorous therapy (44, 45). In our patients, the mean intima media thickness did not decrease during pravastatin treatment; actually, a slight nonsignificant increase was seen. This effect is similar to that found in some previous studies with pravastatin (in contrast to atrovastatin or simvastatin), in which the progression of carotid intima media thickness has slowed or stabilized, but uncommonly reverted (46, 47, 48). Furthermore, 17% of patients had lipid deposits at baseline (carotid plaque, xanthomas, or corneal arcus), and 27% had lipid deposits at 1 yr. The most important risk factor predisposing to lipid deposits was patient age. Considering the results from adults and our findings suggesting that the development of atherosclerosis in HeFH may start even before puberty, early statin therapy aiming at normocholesterolemia seems crucial in HeFH children for primary prevention of CHD.
Our conclusion from this comprehensive endocrinological study of children is that pravastatin is safe and well tolerated, with no adverse effects on growth or pubertal maturation, as individually evaluated. The cholesterol-lowering efficacy in slight or moderate hypercholesterolemia is satisfactory. Additional studies are needed to assess the development and reversibility of atherosclerosis in children and adolescents with HeFH.
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Acknowledgments |
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Footnotes |
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First Published Online January 18, 2005
Abbreviations: ALT, Alanine aminotransferase; CHD, coronary heart disease; CK, creatine kinase; HDL, high-density lipoprotein; HeFH, heterozygous familial hypercholesterolemia; hSDS, height SD score; LDL, low-density lipoprotein; W/H, weight for height index.
Received August 3, 2004.
Accepted January 7, 2005.
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