Familial hypercholesterolemia (FH) is a prevalent (1:500 individuals) inherited disorder that strongly predisposes to premature atherosclerosis and subsequent cardiovascular disease.1 In children with FH, atherosclerosis progression is observed before puberty.2
Consequently, guidelines for FH treatment advocate initiation of statins in children as young as 8 years.3 However, long-term efficacy and safety data for statin therapy initiated during childhood do not exist. We followed up a cohort of children with FH receiving statin therapy until adulthood.
We conducted a cohort study of 214 children heterozygous for FH, living in the Netherlands, aged 8 to 18 years, who were randomized between 1997 and 1999 into a single-center, 2-year, double-blind, placebo-controlled trial of pravastatin.4 Results showed a significant regression of carotid intima-media thickness (IMT) after statin treatment compared with placebo.
After the trial, all children received pravastatin (20-40 mg/d) and were followed up until March 2011 along with 95 unaffected siblings. Patients were instructed to adhere to the Step 2 diet. During follow-up, several patients switched to other statins. After 10 years, all participants underwent a physical examination, fasted blood sample, assessment of family and medical history, including the occurrence of adverse events, and measurement of carotid IMT, a validated marker of atherosclerosis.5
The study protocol was approved by the University of Amsterdam Academic Medical Center institutional review board and all participants gave written informed consent.
Efficacy outcome measures were carotid IMT and lipid profiles at follow-up. Safety assessment included growth, maturation, level of education, adverse events, and laboratory test results (aspartate and alanine aminotransferases, creatinine kinase, estimated glomerular filtration rate, and C-reactive protein).
Linear regression models were used to evaluate (1) differences in carotid IMT between patients with FH and unaffected siblings (adjusted for sex, age, blood pressure, and body mass index [BMI]) and (2) the association between carotid IMT and age at statin initiation (adjusted for sex, BMI, baseline carotid IMT, and duration of follow-up). Family relations were taken into account with generalized estimating equations.
P values are 2-sided, and significance was set at P < .05. Analyses were performed with SPSS version 11.5 (SPSS Inc).
Ten-year follow-up was achieved in 194 (91%) patients with FH and 83 (87%) siblings, all aged 18 to 30 years. The main reasons for nonattendance were “not motivated/too busy” and “living abroad.” Participant characteristics at baseline and after follow-up did not differ significantly between patients with FH and siblings, except for lipid profiles (Table 1).
After 10 years, mean carotid IMT was still significantly greater in patients with FH compared with siblings (0.480 mm [95% CI, 0.472-0.489 mm] vs 0.469 mm [95% CI, 0.459-0.480 mm], respectively; P = .02). In contrast, progression of carotid IMT from baseline was similar in both groups (patients with FH, 0.039 mm [95% CI, 0.032-0.046 mm] vs siblings, 0.037 mm [95% CI, 0.032-0.042 mm]; P = .52). In patients with FH, age at statin initiation was significantly associated with carotid IMT at follow-up (regression coefficient, 0.003 mm [SE, 0.001 mm]; P = .009).
Of the patients with FH, 163 (84%) were still using lipid-lowering medication. Of the patients who were prescribed lipid-lowering therapy, 142 (79%) took 80% or more of their medication in the preceding month. Three patients discontinued statin therapy due to adverse events. Rhabdomyolysis or other serious major adverse events were not reported. Laboratory safety parameters did not differ between patients with FH and siblings (Table 2). Also, no differences in growth, maturation, or educational level were noted (Tables 1 and 2).
To our knowledge, this study reports the longest follow-up in statin-treated children with FH and includes a control group of unaffected siblings, which minimizes genetic and environmental variation between groups. Long-term statin treatment initiated during childhood in patients with FH was associated with normalization of carotid IMT progression. Moreover, earlier statin initiation was associated with thinner carotid IMT at follow-up. No serious adverse events were reported during follow-up.
The safety of statin therapy is supported by extensive evidence in adults.6 In children, only short-term safety has been established. However, our long-term follow-up study lacks statistical power to detect rare events.
The low-density lipoprotein levels of patients with FH at follow-up did not meet current treatment standards and carotid IMT was thicker than in unaffected siblings. More robust lipid-lowering therapy or earlier initiation of statins may be required to completely restore arterial wall morphology and avert cardiovascular events later in life in this high-risk population.
Corresponding Author: Barbara A. Hutten, PhD, MSc, Department of Clinical Epidemiology, Biostatistics, and Bioinformatics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands (email@example.com).
Author Contributions: Drs Kusters and Hutten had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Wiegman and Hutten share last authorship position in the byline.
Study concept and design: Avis, Kastelein, Hutten.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Kusters, Avis, Hutten.
Critical revision of the manuscript for important intellectual content: Avis, de Groot, Wijburg, Kastelein, Wiegman, Hutten.
Statistical analysis: Kusters, de Groot, Hutten.
Obtained funding: Avis, Hutten.
Administrative, technical, or material support: Kusters, Avis, de Groot, Kastelein, Hutten.
Study supervision: Wijburg, Kastelein, Wiegman, Hutten.
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kastelein reported being a recipient of the Lifetime Achievement Award of the Netherlands Heart Foundation (project number 2010T082); and receiving lecture grants from Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, ISiS, Merck Sharp Dohme, Novartis, Pfizer, Regeneron, Roche, and sanofi. No other disclosures were reported.
Funding/Support: The AfterTen study is supported by grant 2009B059 from the Dutch Heart Foundation.
Role of the Funder/Sponsor: The Dutch Heart Foundation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Contributions: We are grateful to all children who participated in this study. We would also like to thank Johan Gort, BSc (Department of Vascular Medicine, Academic Medical Center), for performing all ultrasound measurements; Harry R. Büller, MD, PhD (Department of Vascular Medicine, Academic Medical Center), for reading the manuscript and providing comments; and the following members of the AfterTen study group for their help with the grant application (Maud N. Vissers, PhD, Department of Vascular Medicine, Academic Medical Center), interpretation of safety parameters (A. S. Paul van Trotsenburg, MD, PhD, Department of Pediatrics, Academic Medical Center), and assessment of compliance (Ellen M. Smets, PhD, Department of Medical Psychology, Academic Medical Center). None of the persons named received compensation for their contributions to the study.
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