Initiating statin therapy in children with FH reduces subclinical and clinical atherosclerotic disease
20-Year Follow-up of Statins in Children with Familial HypercholesterolemiaLiterature - Luirink IK, Wiegman A, Kusters DM et al., - N Engl J Med 2019; 381:1547-1556. DOI: 10.1056/NEJMoa1816454
Introduction and methods
Patients with familial hypercholesterolemia (FH) are at high risk for premature CV disease, as a result of elevated LDL-c levels since birth, caused by mutations in genes encoding proteins involved in the LDL receptor metabolism . The first functional and morphologic changes of the arterial wall have been demonstrated to start in childhood [2,3]. An EAS consensus panel and the current ACC/AHA guidelines for FH therefore advise initiation of statins in children aged 8  or 10  years old, respectively.
The lipid-lowering effect of statins in children is well established , but good follow-up data on clinical outcomes in treated children are scarce. Also in adults with FH, the benefit of statin treatment in the prevention of CV disease has not adequately been established prospectively.
This study is a 20-year follow-up study of children with genetically defined FH who started statin therapy between the ages of 8 and 18 years old. It aims to study differential progression in both subclinical atherosclerosis and clinical CV disease, and to compare the outcomes between those with FH who started treatment in childhood and those with untreated FH and healthy persons. Subclinical atherosclerosis progression over time was assessed by comparing the carotid intima media thickness (cIMT) in patients with FH with their unaffected age-matched siblings. Follow-up lasted until adulthood, at an age when the affected parents may already have experienced an event. The incidence of CV disease among FH patients was compared with that among their parents with FH, who started statin therapy much later in life.
214 Children with FH who enrolled in a double-blind placebo-controlled trial that evaluated the 2-year efficacy and safety of pravastatin from 1997-1999  were eligible for this study. Moreover, 95 unaffected (confirmed by genetic testing) enrolled at the time as a control group, and they were also eligible now. About 20 years after initial enrollment, patients and their unaffected siblings were contacted again, and those who agreed to participate in the current study answered a questionnaire about medical history, lifestyle habits, medication use and family history, and they visited the clinic once.
- Mean duration of follow-up was 18 years (range: 15-21) and mean age at follow-up was 31.7 (SD: 3.2) years for patients with FH and 31.6 (SD: 3.0) years for their siblings (not significantly different).
- From baseline, patients with FH showed a decrease of 32% in LDL-c to 160.7 (SD: 72.6) mg/dL (or 4.16 mmol/L, SD: 1.88) at follow-up, and siblings an increase of 24% to 121.9 (SD: 37.0) mg/dL (or 3.15 mmol/L, SD: 0.96 mmol/L).
- 37 Patients with FH (20%) reached the LDL-c target of <100 mg/dL, and 8 had LDL <70 mg/dL.
- At baseline, cIMT was greater in patients with FH (mean: 0.446 mm, 95%CI: 0.439-0.453) than in their unaffected siblings (mean: 0.439, 95%CI: 0.430-0.449). Mean age and sex-adjusted difference: 0.012 (95%CI: 0.002-0.021).
- After 20 years, mean IMT was 0.555 mm (95%CI: 0.542-0.567) in those with FH, vs. 0.551 (95%CI: 0.531-0.570) in siblings (mean difference adjusted for age, sex, mean BP and baseline cIMT: 0.008, 95%CI: -0.009 to 0.026).
- During follow-up, rate of progression of cIMT was 0.0056 mm/yr in patients with FH and 0.0057 in unaffected siblings (mean difference adjusted for sex: -0.0001 mm/yr, 95%CI: -0.0010 to 0.0008).
- Of 156 parents with FH, 41 (26%) experienced a CV event before the age of 40 years.
- Cumulative CV disease-free survival at the age of 39 was 99% in patients with FH who initiated statin therapy in childhood, and 74% in their affected parents (HR, sex and smoking status-adjusted: 11:8, 3.0-107.0).
- None of the young adults taking statins since childhood died from CV disease during follow-up, as compared with 7% of affected parents, all from myocardial infarction.
This study shows that 20 years after enrollment in a pediatric statin trial, progression of cIMT in participants with genetically defined FH was similar to that in their unaffected siblings. Patients with FH who were treated since childhood showed a lower cumulative incidence of CV events and CV death than among their affected parents, who initiated statin therapy later in life.