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Efficacy of Rosuvastatin in Children With Homozygous Familial Hypercholesterolemia and Association With Underlying Genetic Mutations.

Abstract 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.
PMID
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Authors

Mayor MeshTerms

Mutation

Keywords

apheresis

low-density lipoprotein cholesterol

low-density lipoprotein receptor

pediatrics

statins

Journal Title journal of the american college of cardiology
Publication Year Start




PMID- 28838366
OWN - NLM
STAT- MEDLINE
DA  - 20170825
DCOM- 20170901
LR  - 20170901
IS  - 1558-3597 (Electronic)
IS  - 0735-1097 (Linking)
VI  - 70
IP  - 9
DP  - 2017 Aug 29
TI  - Efficacy of Rosuvastatin in Children With Homozygous Familial
      Hypercholesterolemia and Association With Underlying Genetic Mutations.
PG  - 1162-1170
LID - S0735-1097(17)38003-8 [pii]
LID - 10.1016/j.jacc.2017.06.058 [doi]
AB  - 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).
CI  - Copyright (c) 2017 American College of Cardiology Foundation. Published by
      Elsevier Inc. All rights reserved.
FAU - Stein, Evan A
AU  - Stein EA
AD  - Metabolic and Atherosclerosis Research Center, Cincinnati, Ohio. Electronic
      address: [email protected]
FAU - Dann, Eldad J
AU  - Dann EJ
AD  - Rambam Health Care Campus, Haifa, Israel.
FAU - Wiegman, Albert
AU  - Wiegman A
AD  - Department of Paediatrics and Vascular Medicine, Academic Medical Center,
      University of Amsterdam, Amsterdam, the Netherlands.
FAU - Skovby, Flemming
AU  - Skovby F
AD  - Department of Clinical Genetics, University Hospital, and Institute of Clinical
      Medicine, University of Copenhagen, Copenhagen, Denmark.
FAU - Gaudet, Daniel
AU  - Gaudet D
AD  - ECOGENE-21 Clinical and Translational Research Center and Lipidology Unit,
      Department of Medicine, Universite de Montreal, Chicoutimi, Quebec, Canada.
FAU - Sokal, Etienne
AU  - Sokal E
AD  - Universite Catholique de Louvain, Cliniques St. Luc, Service de Gastroenterologie
      et Hepatologie Pediatrique, Brussels, Belgium.
FAU - Charng, Min-Ji
AU  - Charng MJ
AD  - Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
FAU - Mohamed, Mafauzy
AU  - Mohamed M
AD  - Hospital Universiti Sains Malaysia (HUSM), Clinical Trial Unit, Level 2,
      Kelantan, Malaysia.
FAU - Luirink, Ilse
AU  - Luirink I
AD  - Department of Paediatrics and Vascular Medicine, Academic Medical Center,
      University of Amsterdam, Amsterdam, the Netherlands.
FAU - Raichlen, Joel S
AU  - Raichlen JS
AD  - AstraZeneca Pharmaceuticals LP, Gaithersburg, Maryland.
FAU - Sunden, Mattias
AU  - Sunden M
AD  - AstraZeneca Gothenburg, Molndal, Sweden.
FAU - Carlsson, Stefan C
AU  - Carlsson SC
AD  - AstraZeneca Gothenburg, Molndal, Sweden.
FAU - Raal, Frederick J
AU  - Raal FJ
AD  - Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences,
      University of Witwatersrand, Johannesburg, South Africa.
FAU - Kastelein, John J P
AU  - Kastelein JJP
AD  - Department of Paediatrics and Vascular Medicine, Academic Medical Center,
      University of Amsterdam, Amsterdam, the Netherlands.
LA  - eng
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PL  - United States
TA  - J Am Coll Cardiol
JT  - Journal of the American College of Cardiology
JID - 8301365
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Cholesterol, LDL)
RN  - 83MVU38M7Q (Rosuvastatin Calcium)
RN  - 9007-49-2 (DNA)
SB  - AIM
SB  - IM
MH  - Adolescent
MH  - Anticholesteremic Agents/administration & dosage
MH  - Child
MH  - Cholesterol, LDL/blood/*genetics
MH  - Cross-Over Studies
MH  - DNA/*genetics
MH  - DNA Mutational Analysis
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - Female
MH  - Follow-Up Studies
MH  - Homozygote
MH  - Humans
MH  - Hyperlipoproteinemia Type II/blood/*drug therapy/genetics
MH  - Male
MH  - *Mutation
MH  - Rosuvastatin Calcium/*administration & dosage
MH  - Treatment Outcome
OTO - NOTNLM
OT  - apheresis
OT  - low-density lipoprotein cholesterol
OT  - low-density lipoprotein receptor
OT  - pediatrics
OT  - statins
EDAT- 2017/08/26 06:00
MHDA- 2017/09/02 06:00
CRDT- 2017/08/26 06:00
PHST- 2017/05/02 [received]
PHST- 2017/06/16 [revised]
PHST- 2017/06/29 [accepted]
AID - S0735-1097(17)38003-8 [pii]
AID - 10.1016/j.jacc.2017.06.058 [doi]
PST - ppublish
SO  - J Am Coll Cardiol. 2017 Aug 29;70(9):1162-1170. doi: 10.1016/j.jacc.2017.06.058.