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Metabolic Unit, Choremio Goudi Research Institute, 1st Department of Pediatrics, Medical School University of Athens, Aghia Sofia Children's Hospital, Athens, Greece
This 3-year study enrolled children/adolescents aged 6–15 years with HeFH.
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Atorvastatin was effective, reducing LDL-C levels by 40%–45% in these patients.
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Atorvastatin was safe, well tolerated, and did not impact growth and development.
Background
The efficacy and safety of atorvastatin in children/adolescents aged 10–17 years with heterozygous familial hypercholesterolemia (HeFH) have been demonstrated in trials of up to 1 year in duration. However, the efficacy/safety of >1 year use of atorvastatin in children/adolescents with HeFH, including children from 6 years of age, has not been assessed.
Objective
To characterize the efficacy and safety of atorvastatin over 3 years and to assess the impact on growth and development in children aged 6–15 years with HeFH.
Methods
A total of 272 subjects aged 6–15 years with HeFH and low-density lipoprotein cholesterol (LDL-C) ≥4.0 mmol/L (154 mg/dL) were enrolled in a 3-year study (NCT00827606). Subjects were initiated on atorvastatin (5 mg or 10 mg) with doses increased to up to 80 mg based on LDL-C levels.
Results
Mean percentage reductions from baseline in LDL-C at 36 months/early termination were 43.8% for subjects at Tanner stage (TS) 1 and 39.9% for TS ≥2. There was no evidence of variations in the lipid-lowering efficacy of atorvastatin between the TS groups analyzed (1 vs ≥2) or in subjects aged <10 vs ≥10 years, and the treatment had no adverse effect on growth or maturation. Atorvastatin had a favorable safety and tolerability profile, and only 6 (2.2%) subjects discontinued because of adverse events.
Conclusions
Atorvastatin over 3 years was efficacious, had no impact on growth/maturation, and was well tolerated in children and adolescents with HeFH aged 6–15 years.
Influence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium.
Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing.
Familial hypercholesterolemia (FH) is a common inherited autosomal dominant disorder of lipoprotein metabolism characterized by reduced clearance of low-density lipoprotein cholesterol (LDL-C) from the circulation leading to elevations of LDL-C.
Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
In most cases (85%–90%), FH is caused by defects in the low-density lipoprotein-receptor (LDL-R) gene. Defects in the genes for apolipoprotein B (apoB) and proprotein convertase subtilisin/kexin type 9 account for about 5% and <5% of cases, respectively.
Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group.
Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study.
Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin.
An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia.
Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.
For example, studies conducted with atorvastatin in children/adolescents with HeFH were up to 1 year in duration with the impact on growth/development evaluated at 26 weeks.
Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.
Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.
Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
This 3-year study enrolling ∼250 subjects aged 6–15 years with genetically confirmed HeFH was therefore conducted to characterize the long-term efficacy and safety of atorvastatin and to assess the impact of this medication on growth and development. Also, as part of this work, we examined the impact of atorvastatin treatment on endothelial function in the brachial arteries assessed by flow-mediated dilation (FMD).
This was an optional exploratory study to assess the potential for a change in the FMD to act as a surrogate biomarker for the efficacy of LDL-C lowering as previously shown in a study with simvastatin therapy in children and adolescents with FH.
Standard protocol approvals, registrations, and patient consents
This open-label, multicenter, prospective study was conducted between March 30, 2009 and October 8, 2013 at 30 centers across 14 counties in compliance with the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines. In addition, all local regulatory requirements were followed. The protocol and the informed consent documents were reviewed and approved by the institutional review boards and/or independent ethics committees at each participating center. Parents or legal guardians provided informed consent. The subject could also sign a written consent form, if they were able to do so. The exact processes and procedures for attaining assent and consent varied between countries. However, all country-specific guidelines were complied with.
Study population
Girls and boys aged 6–15 years with genetically confirmed HeFH (those girls and boys who had no prior record of genetically confirmed HeFH underwent genetic testing pre-randomization to confirm whether they had HeFH). DNA was extracted from saliva or from blood, and the 18 exons and flanking regions of the LDL-R gene and exon 26 of the apoB gene were sequenced using SANGER methodology. Samples were also tested for large deletions or insertions in the LDL-R gene, using Multiplex Ligase-dependent Probe Amplification (MLPA) analysis (Details provided in Supplementary Material).
All those who did not have genetically confirmed HeFH were excluded. All patients also had to have an LDL-C of ≥4.0 mmol/L (154 mg/dL) for inclusion. Exclusion criteria included a history of active liver disease, hepatic dysfunction, or persistent elevations of serum transaminases >3× the upper limit of normal (ULN) or conditions likely to delay puberty. Pregnant or breastfeeding females, and females of childbearing potential not using adequate contraception, were excluded. Subjects with hypersensitivities to statins or receiving statin therapy within 4 weeks of randomization were excluded. However, a 4-week washout of lipid-lowering medication was permitted.
Study design
The doses of atorvastatin used in this study were based on the results of a study comparing the efficacy and safety of different starting doses of atorvastatin in adults with dyslipidemia
An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia.
Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.
In total, 272 subjects with HeFH were stratified into 2 cohorts according to their Tanner stage (TS) (1 or ≥2) at screening. Subjects aged 6 to <10 years (mostly TS 1) initiated therapy on atorvastatin 5 mg per day (a pediatric chewable formulation), and those aged 10 to 15 years (mostly TS ≥ 2) initiated treatment with atorvastatin 10 mg per day.
Subjects had their dose titrated based on an LDL-C target of <3.35 mmol/L (<130 mg/dL). Doses were increased from 5 to 10 to 20 mg or 10 to 20 to 40 mg per day. Titrations above 40 mg per day were permitted after discussions with the study sponsor. Subjects initiating treatment on atorvastatin 10 mg per day were permitted to decrease their dose if their LDL-C decreased to <2.59 mmol/L (100 mg/dL). Subjects with LDL-C <2.59 mmol/L on the 5 mg dose were discontinued. Atorvastatin was dispensed at visit 1 (day 0), and subjects were seen monthly until month 6 at which point they were seen every 6 months. TS assessments were made at screening and every 6 months.
Outcome assessments
The primary assessments were measures of growth and development (height, weight, body mass index [BMI], TS), efficacy (absolute and percentage change from baseline in LDL-C, total cholesterol [TC], triglycerides [TG], high-density lipoprotein cholesterol [HDL-C], apo A-1, apoB), tolerability, and safety. An exploratory secondary efficacy endpoint was change from baseline in FMD in a subset of subjects (see Supplemental Information). Subjects were required to fast for ≥10 hours before the collection of samples for lipid assessments. The incidence, severity, and potential causal relationship of treatment-emergent adverse events (AEs) were monitored alongside abnormal laboratory findings. Hematology, blood chemistry, and urinalysis were also evaluated at screening and throughout the study. AEs were classified as mild (does not interfere with subject's usual function), moderate (interferes to some extent with subject's usual function), or severe (interferes significantly with subject's usual function).
Statistical analysis
The full analysis set, defined as all subjects who received ≥1 doses of the study drug, was included in all analyses. No imputations were used for missing values. Subjects were categorized by TS 1 or ≥2 for analyses of lipid endpoints and safety/tolerability, and also by age <10 years and ≥10 years for some analyses. Height, weight, BMI and FMD were analyzed by gender. Analyses were performed using descriptive statistics. Demographic and baseline data were summarized as mean ± standard deviation (SD) for continuous variables. The mean dose of atorvastatin was calculated as the average dose per subject weighted by duration on each dose and the unweighted average calculated regardless of the duration on each dose and the mean maximum dose. The percentage of subjects receiving 5, 10, 20, 40, or 80 mg atorvastatin as their maximum dose stratified by TS and age was calculated. The percentage of subjects who attained an LDL-C goal of <3.35 mmol/L (<130 mg/dL) at each visit was also calculated.
Results
Study population
A total of 400 pediatric subjects were screened and 272 with a genetically confirmed diagnosis of HeFH were enrolled (87 subjects without a previously confirmed genetic diagnosis of HeFH were considered for genetic screening and 66 were screened of which 49 [74.2%] were confirmed positive for HeFH) (Fig. 1). This study was conducted at 30 centers worldwide, and the methodologies for genetic testing and the manner in which this information was collated differed both between centers and the central laboratory used to screen the patients without confirmed FH. Therefore, unfortunately, it has not been possible to collate this information for patients across the study. One subject was assigned to study treatment, but not treated, due to a protocol violation. The 271 subjects treated comprised 139 children at TS 1 and 132 adolescents at TS ≥2.
Overall, 206 subjects (76.0%) completed the study with 65 (24%) discontinuing. In subjects at TS1, the most frequent cause of discontinuation was no longer being willing to participate in the study, whereas for subjects at TS ≥2, the most common reason for discontinuation was “low LDL-C” (defined as LDL-C <2.59 mmol/L [100 mg/dL] in subjects receiving atorvastatin 5 mg; 12 subjects). Unfortunately, in some cases, investigators were unaware that subjects initiating treatment on 10 mg per day could be down-titrated to 5 mg per day; this knowledge may have prevented some of these discontinuations.
The mean age of children at TS 1 at baseline was 8.5 years (SD = 1.9), the majority were male (66.9%) and white (96.4%; Table 1). The adolescents at TS ≥2 at baseline had a mean age of 12.0 years (SD = 1.7), the majority were female (59.8%) and white (98.5%). Overall, 27.3% of subjects were aged 6–8 years, and 51.7% were aged ≤10 years at baseline.
Table 1Demographics and baseline characteristics
Characteristic
TS 1, Total (n = 139)
TS ≥2, Total (n = 132)
Age, y, n (%)
6–8
69 (49.6)
5 (3.8)
9–10
45 (32.4)
21 (15.9)
11–14
25 (18.0)
104 (78.8)
15–15
0
2 (1.5)
Mean
8.5
12.0
SD
1.9
1.7
Range
6–12
8–15
Gender, Male, n (%)
93 (66.9)
53 (40.2)
Race
White
134 (96.4)
130 (98.5)
Black
1 (0.7)
1 (0.8)
Asian/other
4 (2.9)
1 (0.8)
Weight, kg
Mean
33.8
49.4
SD
11.3
12.1
Range
17–75
26–82
BMI, kg/m2
Mean
18.1
20.3
SD
3.7
3.7
Range
12.6–30.7
13.8–33.7
Height, cm
Mean
135.0
155.1
SD
12.1
10.5
Range
109–162
132–184
Baseline LDL-C, mmol/L (mg/dL)
Mean
6.30 (243.62)
5.92 (228.93)
SD
1.31 (50.66)
1.16 (44.86)
BMI, body mass index; LDL-C, low-density lipoprotein cholesterol; SD, standard deviation.
The mean weighted and mean maximum doses were similar in the subjects at TS 1 and ≥2, whereas mean doses were consistently higher in the subjects aged ≥10 years vs those aged <10 years (Fig. 2A). Few subjects (18, 6.6%) received atorvastatin 80 mg during the study, and 12 subjects (8.6%) at TS 1 received this maximum dose (Fig. 2B). The median duration of treatment was 1085 days (interquartile range [IQR], 1035.0–1099.0) overall for all subjects, 1084.0 days (IQR, 1060.0–1099) for TS 1 and 1085.0 (IQR, 634.0–1099.35) for TS ≥2. Approximately 70% of subjects received concomitant medications, most commonly ibuprofen and paracetamol (Supplemental Table 1).
Figure 2(A) Mean unweighted, weighted, and maximum doses of atorvastatin received by children and adolescents with HeFH stratified by TS and age. (B) The percentage of subjects receiving atorvastatin 5, 10, 20, 40, or 80 mg as their maximum dose, all subjects, by TS and age. HeFH, heterozygous familial hypercholesterolemia; SE, standard error; TS, Tanner stage.
There was very little difference in the mean percentage changes from baseline in LDL-C in all subjects and those at TS 1 or ≥2 over the study duration (Fig. 3 and Table 2). Mean LDL-C levels were reduced by ∼35% from month 1 in all subject groups, with a further reduction to ∼45% at month 3. LDL-C levels were then maintained at this level to month 30. At month 36/early termination, the mean reduction in LDL-C in the TS 1 group remained at −43.8%, whereas in the TS ≥2 group, it decreased to −39.9%.
Figure 3Mean percentage change from baseline in LDL-C in all subjects with HeFH and by TS 1 and ≥2 and aged <10 and ≥10 years at baseline. HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; TS, Tanner stage.
A total of 52% of subjects aged <10 years attained the LDL-C target of <3.35 mmol/L (130 mg/dL) at month 3, and goal attainment remained above 50% for the duration of the study, peaking at 67.4% at month 18. For the age ≥10 years' cohort, 52% of subjects achieved this goal at month 2, and goal attainment remained above 50% for the duration of the study, peaking at 78% at month 30 (Fig. 4).
Figure 4Percentage of subjects aged <10 years or ≥10 years at baseline achieving LDL-C goal of <3.35 mmol/L (<130 mg/dL) at each study visit. LDL-C, low-density lipoprotein cholesterol.
The mean percentage reductions from baseline at month 36/early termination in TC, non–HDL-C, and apoB were comparable for subjects at TS 1 and TS ≥ 2 (Fig. 5 and Table 2). HDL-C levels decreased slightly (1.1%) from baseline at month 36/early termination in subjects at TS 1 and increased slightly (1.6%) in subjects at TS ≥ 2. Baseline TG levels were slightly higher in the TS ≥2 group when compared with the TS 1 group (0.980 vs 0.880 mmol/L [86.8 vs 77.9 mg/dL], respectively). A larger mean percentage reduction in TG level at month 36/early termination was observed in the TS ≥2 group than in the TS 1 group (−7.76% vs −0.70%). A modest reduction in apo-A1 levels was reported for both TS groups (−4.80% vs −1.95% for TS 1 and TS ≥2 at month 36/early termination, respectively).
Figure 5Mean percentage change from baseline in lipid parameters at month 36/early termination in all subjects with HeFH and by TS 1 and ≥2 at baseline. Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; HeFH, heterozygous familial hypercholesterolemia; TC, total cholesterol; TG, triglyceride; TS, Tanner stage.
The FMD profile showed no discernable trends in either male or female subjects (See Supplemental Information).
Development and growth
At the month 36/early termination visit, male subjects had increased in height from baseline by a mean of 11.0% vs a mean of 8.1% for female subjects. The mean height in female subjects increased from 145 cm (mean age, 10.6 years) at baseline to 157 cm (mean age, 13.1 years) at month 36/early termination. The mean height in male subjects increased from 144 cm (mean age, 9.9 years) to 161 cm (mean age, 12.7 years) at month 36/early termination. At the month 36/early termination, male subjects had increased in weight from baseline by a mean of 32.5% compared with 27.3% for female subjects.
The shift in TS over this 3-year study is shown in Figure 6. By month 36/early termination visit just 41 of 253 subjects (16.2%) were at TS 1 in comparison with 139 of 271 (51.3%) at baseline. Conversely, the percentage of subjects at TS 5 increased from 6.6% (18 of 271) at baseline to 25.3% (64 of 253) at study end.
Figure 6Changes in the percentage of subjects in each TS over 36 months/early termination among children and adolescents with HeFH receiving atorvastatin therapy. HeFH, heterozygous familial hypercholesterolemia; TS, Tanner stage.
The overall incidence of all-causality AEs was very similar in the TS 1 (81.3%) and TS ≥2 (79.5%) groups (Table 3). Most AEs were of mild or moderate intensity. There were no deaths. Overall, 21 patients (7.7%) reported a serious AE (SAE). Overall, 6 (2.2%) subjects discontinued because of AEs (Table 3). This included 4 subjects at TS 1 (1 subject experienced Ewing's sarcoma, 1 increase in blood bilirubin, 1 intravascular papillary endothelial hyperplasia, and 1 subject experienced abdominal pain, constipation, fatigue, and headache), and 2 subjects at TS ≥ 2 (1 subject experienced myalgia and 1 eosinophilia). A total of 24 (8.9%) subjects had their dose reduced or temporarily discontinued because of treatment-related AEs. All the treatment-related AEs were mild or moderate in intensity. The most commonly occurring all-causality AEs are shown in Table 3.
Table 3The percentage of subjects
Treatment-related AEs are shown in italics.
reporting all-causality and treatment-related AEs, discontinuations because of AEs, and the most commonly reported AEs by TS and overall
Type or category of AE
TS 1 (n = 139)
TS ≥2 (n = 132)
Total (n = 271)
Subjects with AEs
81.3, 40.3
79.5, 37.1
80.4, 38.7
Serious AEs
10.1, 0.7
5.3, 0
7.7, 0.4
Discontinued because of AE
2.9, 2.2
1.5, 1.5
2.2, 1.8
Dose of study medication reduced or temporarily discontinued
18.7, 7.9
15.2, 9.8
17.0, 8.9
Most frequently occurring AEs (≥10% all causality in any group)
Of the subjects with a SAE, 14 were from the TS 1 group, and 7 were from the TS ≥2 group (see Supplemental Information for full details of these SAEs). A single SAE considered to be treatment-related by the investigator was reported: a 9-year-old male receiving atorvastatin 80 mg experienced an SAE of Ewing's sarcoma on day 704 of the study. The subject was hospitalized as a result of this condition. There was no evidence of dose-related increase in the overall incidence of AEs or discontinuations/dose reduction of study medication (Supplemental Table 2, Supplemental Table 3).
There were no obvious trends, or dose-related trends, in the incidence of laboratory abnormalities. No subjects had aspartate aminotransferase or alanine aminotransferase levels >3× ULN. Overall, 23 subjects (8.6%) had creatine kinase (CK) of >2× ULN. The incidence of this abnormality was much greater in the TS ≥ 2 (17; 12.9%) than in the TS 1 group (6; 4.4%). One subject, a 14-year-old male, was reported with increased CK (10× ULN) as a SAE. This was thought to be related to hard physical exercise. Elevations in CK were observed in other male subjects after intense exercise and in both genders after viral infections. All the other AEs related to laboratory abnormalities were of mild or moderate intensity.
Discussion
This 3-year, open-label, prospective study enrolling very young subjects with HeFH demonstrated that atorvastatin was well tolerated and efficacious in children and adolescents (6–15 years at study entry). Furthermore, there was no evidence that treatment with atorvastatin had any clinically relevant effect on growth or maturation. Because endogenous steroid hormone production is derived from cholesterol, a potential concern is how statin therapy may affect sexual development in children and adolescents.
An earlier study demonstrated that treatment with lovastatin (20–40 mg/day) for 24 weeks had no effect on hormone levels or menstrual cycle length in adolescent girls with HeFH aged 10–17 years.
The TS shift from baseline during our 3-year trial was consistent with the normal trajectory for maturation and development. For example, movement to TS 2 occurs from age 11 years (range, 8–13 years) in females and slightly later in males (range, 9.5–13.5 years), and TS 5 is usually reached at 14–15 years in females (range, 13–18 years) and 15 years in males (range, 13.5–17 years).
The mean height in males followed the 1 z-score line. In both males and females, the mean increase in height over the 3-year study followed the same trajectory as this reference group.
There is increasing evidence that the administration of statins early in life is beneficial in preventing or reducing atherosclerosis in subjects with FH.
In this study, we observed that atorvastatin administration led to substantial reductions in LDL-C and other atherogenic lipid parameters. The reductions in LDL-C reached maximal levels of ∼45% at months 3 to 6 and then remained at this level throughout the follow-up period. There was a slight increase in LDL-C at month 36/early termination, possibly due to the inclusion of data from subjects who discontinued study medication early in the trial. Substantial reductions at month 36/early termination were also observed in apo B and non-HDL-C. There appeared to be no evidence of variations in the lipid-lowering efficacy of atorvastatin between the TS groups analyzed (1 vs ≥2) or in subjects aged <10 vs ≥10 years.
The reductions of LDL-C observed are in accordance with the findings from other clinical studies conducted in pediatric and adolescent populations in which atorvastatin and other statins have been administered.
Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin.
An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia.
Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.
Moreover, the early efficacy of atorvastatin in this study is consistent with that observed in a similar but smaller (n = 39) short-term (8-week) atorvastatin study in which doses of 5–20 mg per day were administered to children and adolescents with HeFH. In the small 8-week study, mean LDL-C reductions from baseline of 40.7% and 39.7% were observed at week 8 in subjects at TS 1 and ≥2, respectively.
An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia.
Similar reductions in LDL-C (40%) were observed at week 26 in a larger study (n = 187) in which atorvastatin (10–20 mg per day) was administered to children and adolescents with FH or severe hypercholesterolemia.
Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.
The slightly greater reductions in LDL-C observed in this (∼45%) vs the earlier studies (∼40%) might be related to the higher doses of atorvastatin permitted in this study (up to 80 mg per day).
Atorvastatin was shown in this 3-year study to have a favorable safety and tolerability profile. Only 6 (2.2%) patients discontinued because of AEs. Regarding the SAE of Ewing's sarcoma in a 9-year-old male receiving atorvastatin 80 mg, evidence that this was not associated with statin use comes from a meta-analysis of 26 clinical trials of statin therapy, containing over 170,000 participants, which demonstrated no increase in cancer incidence among subjects receiving statins.
Also, the etiology of Ewing's sarcoma suggests that it is very unlikely that the atorvastatin treatment was associated with this cancer.
No unexpected or new safety findings were observed despite 27.3% of the children enrolled being 6–8 years and 51.7% <10 years at the start of the study. The differences in AEs and treatment-related AEs were not considered to be clinically meaningful, irrespective of TS of the studied subjects. In addition, no clinically meaningful potential safety trends were noted. Moreover, the safety and tolerability profile observed in this study was qualitatively and quantitatively similar to that observed previously in both adult and pediatric populations.
An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia.
Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.
The 2013 and 2015 European Atherosclerosis Society consensus statements on FH and the clinical guidance from the National Lipid Association Expert Panel
Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
This recommendation differs from the 2011 US Integrated Guidelines for the CV Health and Risk Reduction in Children and Adolescents, which notes that children <10 years should not be treated with lipid-lowering medication unless they have LDL-C levels of ≥400 mg/dL (10.36 mmol/L).
This study is limited by its open-label design, lack of an active comparator and by the limited number of subjects who received the 80-mg dose of atorvastatin, which mean our safety data are too limited to draw any conclusions regarding this dose. An additional limitation is the lack of genetic information collated across this cohort of children with HeFH. However, the study has some notable strengths such as children as young as 6 years old being enrolled, a duration of 3 years and the utilization of measures of growth and maturation.
The results of this study suggest that atorvastatin in doses of 5–40 mg is effective and can be used safely in children with HeFH aged as young as 6 years. These findings together with observations from other studies, which have demonstrated that atherosclerotic changes are apparent in children with HeFH before the age of 8 years,
In conclusion, our study demonstrates the favorable efficacy, safety, and tolerability profile of atorvastatin in both children as young as 6 years and adolescent subjects, treated for a period of 3 years.
Acknowledgment
Medical writing support for the development of this manuscript was provided by Paul Oakley, MSc and Jon Edwards, PhD of Engage Scientific and was funded by Pfizer. We would like to thank the subjects who took part in this study and the following investigators: Belgium—Professor Etienne Sokal, Professor David Cassiman; Canada—Dr Claude Gagne, Dr Shayne Philip Taback; Germany—Professor Dr Med. Karl Otfried Schwab, Professor Dr Med. Elisabeth Steinhagen-Thiessen; Hungary—Professor Dr Gyorgy Fekete, Dr Istvan Reiber; Italy- Professor Marcello Arca, Professor Maurizio Averna; Poland—Dr Jolanta Sykut-Cegielska, Dr Danuta Kurylak; Russian Federation—Dr Galina Igorevna Obraztsova, Dr Olga Sergeevna Groznova, Dr Dmitry D. Zotov, Dr Marina Y. Scherbakova; Slovakia—Dr Jana Saligova, Dr Stefan Rosipal, Dr Pavol Simurka, Dr Anna Hlavata; Spain—Dr Cristina Luzuriaga Tomas, Dr Gemma Carreras Gonzalez, Dr Jose Pastor Rosado, Dr Jose Luis Diaz Diaz, Dr Rafael Jimenez Gonzalez, Dr Esther Piñan Lopez; Switzerland—Dr Med Jean-Marc Nuoffer; Turkey—Professor Dr Mahmut Coker, Professor Dr Turgay Coskun, Professor Dr Alev Hasanoglu; United States—Dr Anton Lee Duke, Dr Alberto Santiago-Cornier, Dr Mary Patricia McGowan, Dr Tala Dajani, Dr Peter O. Kwiterovich, Dr Janet Hope Silverstein, Dr Julie Brothers, and Dr Sarah Ballow Clauss.
Author contributions: Dr Breazna was involved in the design of the study, the analysis of the data, interpreted the findings, participated in drafting of the manuscript, and approved the final version of the article for submission. Dr Langslet recruited and treated patients enrolled in the study, interpreted the findings, participated in drafting of the manuscript, and approved the final version of the article for submission. Dr Drogari is the top recruiter and treated patients enrolled in the study, interpreted the findings, participated in drafting of the manuscript, and approved the final version of the article for submission.
Financial disclosure
Dr Breazna is an employee of Pfizer Inc. Dr Langslet has received Advisory Board and lecture fees from Amgen, Sanofi, Boehringer-Ingelheim, and Janssen. Dr Drogari's University Department has received fees from Sanofi for Dr Drogari's attending Advisory Boards.
Appendix.
Methods
This open-label, multicenter, prospective study was conducted at 30 centers in Belgium, Canada, Germany, Greece, Hungary, Italy, Norway, Poland, Russian Federation, Slovakia, Spain, Switzerland, Turkey, and the United States.
HeFH genetic testing was conducted using the following methodologies: DNA was extracted from saliva (collected in Oragene DNA sample collection kit, DNA Genotek) or from blood using the QiAmp Blood DNA Mini Kit (Qiagen, Germany), according to manufacturer instructions. The promoter region and all the 18 exons and flanking regions of the LDL-R gene were amplified by polymerase chain reaction, and exon 26 of the apoB gene was sequenced in an ABI 3730 DNA analyzer using SANGER methodology after polymerase chain reaction amplification of the DNA samples. Sequence analysis was carried out using SeqScape software, v2.6. Reference sequences for the genes analyzed were based on the hg19-GRCh37 genome assembly database (LDLR: Ref Seq NM_000527.5 and APOB: Ref Eeq NM_000384.2). Samples were also tested for large deletions or insertions, using the MLPA—Multiplex Ligase dependent Probe Amplification kit (MRC, Holland) and following manufacturer's instructions.
Flow-mediated dilatation (FMD) measurements were made using each center's validated peer-review and published FMD protocol. FMD measurements were made at baseline and at months 6, 12, 18, 24, 30, and 36. The lipid panel was assessed at screening and at months 1, 2, 3, 6, 12, 18, 24, 30, and 36. FMD data were based on collected measures (hyperemic and resting diameter) and calculated as follows: FMD (%) = (hyperemic diameter − resting diameter)/resting diameter × 100.
Results
Flow-mediated dilation
In an effort to measure the effects of low-density lipoprotein cholesterol (LDL-C) lowering on endothelial function, we applied the established method of ultrasonically measured FMD in a part of our study population. A total of 73 subjects (37 at Tanner stage [TS] 1 and 36 at TS stage ≥2) from four centers were included in the FMD substudy. The FMD profile showed no discernable trends in either male or female subjects with the mean percentage dilation exhibiting little change over the duration of this substudy (Supplemental Fig. 1), possibly due to issues both in the methodology and the study design. For example, only a small number of patients took part in this substudy. Also, it is possible that the methodology used varied between the four centers leading to inconsistent results. Finally, the blood vessel walls of the children and adolescents examined may not have been sufficiently thickened by atherosclerosis for a beneficial effect of statins to be observed. Additional studies may be required to evaluate whether treatment with statins can have an effect on FMD in children and adolescents with familial hypercholesterolemia (FH) and whether this technique is useful for measuring endothelial dysfunction and atherosclerosis in children.
Supplemental safety information
The serious adverse events reported by the subjects in the TS 1 group were myositis (this was not associated with abnormal CK values and the subject continued taking study medication), feeling abnormal/syncope, intravascular papillary endothelial hyperplasia, testicular appendage torsion, hemorrhoids, viral infection, appendicitis (2 subjects), bipolar disorder, appendix disorder, concussion, abdominal pain, ulna fracture, and Ewing's sarcoma. The serious adverse events reported by the subjects in the TS ≥2 group were syncope, limb injury, abdominal pain and vomiting, suicide attempt, lumbar and thoracic vertebral fracture, obesity, and type 1 diabetes mellitus.
Supplemental Figure 1Mean FMD in a subset of subjects over 36 months among children and adolescents with HeFH receiving atorvastatin therapy. FMD, flow-mediated dilation; HeFH, heterozygous familial hypercholesterolemia.
Influence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium.
Drug therapy of high-risk lipid abnormalities in children and adolescents: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee, Council of Cardiovascular Disease in the Young, with the Council on Cardiovascular Nursing.
Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group.
Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study.
Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized, double-blind, placebo-controlled trial with simvastatin.
An eight-week trial investigating the efficacy and tolerability of atorvastatin for children and adolescents with heterozygous familial hypercholesterolemia.
Efficacy and safety of atorvastatin in children and adolescents with familial hypercholesterolemia or severe hyperlipidemia: a multicenter, randomized, placebo-controlled trial.
Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
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