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Rigshospitalet - a part of Copenhagen University Hospital
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Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations

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  • Evan A Stein
  • Eldad J Dann
  • Albert Wiegman
  • Flemming Skovby
  • Daniel Gaudet
  • Etienne Sokal
  • Min-Ji Charng
  • Mafauzy Mohamed
  • Ilse Luirink
  • Joel S Raichlen
  • Mattias Sundén
  • Stefan C Carlsson
  • Frederick J Raal
  • John J P Kastelein
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BACKGROUND: Homozygous familial hypercholesterolemia (HoFH), a rare genetic disorder, is characterized by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and accelerated atherosclerotic cardiovascular disease. Statin treatment starts at diagnosis, but no statin has been formally evaluated in, or approved for, HoFH children.

OBJECTIVES: The authors sought to assess the LDL-C efficacy of rosuvastatin versus placebo in HoFH children, and the relationship with underlying genetic mutations.

METHODS: This was a randomized, double-blind, 12-week, crossover study of rosuvastatin 20 mg versus placebo, followed by 12 weeks of open-label rosuvastatin. Patients discontinued all lipid-lowering treatment except ezetimibe and/or apheresis. Clinical and laboratory assessments were performed every 6 weeks. The relationship between LDL-C response and genetic mutations was assessed by adding children and adults from a prior HoFH rosuvastatin trial.

RESULTS: Twenty patients were screened, 14 randomized, and 13 completed the study. The mean age was 10.9 years; 8 patients were on ezetimibe and 7 on apheresis. Mean LDL-C was 481 mg/dl (range: 229 to 742 mg/dl) on placebo and 396 mg/dl (range: 130 to 700 mg/dl) on rosuvastatin, producing a mean 85.4 mg/dl (22.3%) difference (p = 0.005). Efficacy was similar regardless of age or use of ezetimibe or apheresis, and was maintained for 12 weeks. Adverse events were few and not serious. Patients with 2 defective versus 2 negative LDL receptor mutations had mean LDL-C reductions of 23.5% (p = 0.0044) and 14% (p = 0.038), respectively.

CONCLUSIONS: This first-ever pediatric HoFH statin trial demonstrated safe and effective LDL-C reduction with rosuvastatin 20 mg alone or added to ezetimibe and/or apheresis. The LDL-C response in children and adults was related to underlying genetic mutations. (A Study to Evaluate the Efficacy and Safety of Rosuvastatin in Children and Adolescents With Homozygous Familial Hypercholesterolemia [HYDRA]; NCT02226198).

Original languageEnglish
JournalJournal of the American College of Cardiology
Volume70
Issue number9
Pages (from-to)1162-1170
Number of pages9
ISSN0735-1097
DOIs
Publication statusPublished - 29 Aug 2017

    Research areas

  • Adolescent, Anticholesteremic Agents, Child, Cholesterol, LDL, Cross-Over Studies, DNA, DNA Mutational Analysis, Dose-Response Relationship, Drug, Double-Blind Method, Female, Follow-Up Studies, Homozygote, Humans, Hyperlipoproteinemia Type II, Male, Mutation, Rosuvastatin Calcium, Treatment Outcome, Journal Article, Multicenter Study, Randomized Controlled Trial

ID: 52804251