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.|
Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial.
|Journal Title||journal of the american college of cardiology|
|Publication Year Start||2017-01-01|
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.