Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries

M Doortje Reijman; Tycho R Tromp; Barbara A Hutten; G Kees Hovingh; Dirk J Blom; Alberico L Catapano; Marina Cuchel; Eldad J Dann; Antonio Gallo; Lisa C Hudgins; Frederick J Raal; Kausik K Ray; Fouzia Sadiq; Handrean Soran; Jaap W Groothoff; Albert Wiegman; D Meeike Kusters; Homozygous Familial Hypercholesterolaemia International Clinical Collaborators (HICC); Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis: an International Registry (CHAIN) consortia

doi:10.1016/S2352-4642(24)00073-7

Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries

Lancet Child Adolesc Health. 2024 May 14:S2352-4642(24)00073-7. doi: 10.1016/S2352-4642(24)00073-7. Online ahead of print.

Authors

M Doortje Reijman¹, Tycho R Tromp², Barbara A Hutten³, G Kees Hovingh⁴, Dirk J Blom⁵, Alberico L Catapano⁶, Marina Cuchel⁷, Eldad J Dann⁸, Antonio Gallo⁹, Lisa C Hudgins¹⁰, Frederick J Raal¹¹, Kausik K Ray¹², Fouzia Sadiq¹³, Handrean Soran¹⁴, Jaap W Groothoff¹, Albert Wiegman¹⁵, D Meeike Kusters¹; Homozygous Familial Hypercholesterolaemia International Clinical Collaborators (HICC); Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis: an International Registry (CHAIN) consortia

Affiliations

¹ Department of Paediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
² Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
³ Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands; Amsterdam Cardiovascular Sciences, Diabetes and Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
⁴ Department of Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands; Novo Nordisk, Søborg, Denmark.
⁵ Division of Lipidology, Department of Medicine and the Cape Heart Institute, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
⁶ IRCCS Multimedica, Milan, Italy; University of Milan, Milan, Italy.
⁷ Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁸ Blood Bank and Apheresis Unit, Rambam Health Care Campus, Haifa, Israel.
⁹ Sorbonne Université, INSERM, UMR 1166, Lipidology and Cardiovascular Prevention Unit, Department of Nutrition, APHP, Hôpital Pitié-Salpêtrière, Paris, France.
¹⁰ The Rogosin Institute, Weill Cornell Medical College, New York, NY, USA.
¹¹ Carbohydrate and Lipid Metabolism Research Unit, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.
¹² Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, School of Public Health, Imperial College London, London, UK.
¹³ Shifa Tameer-e-Millat University, Islamabad, Pakistan.
¹⁴ Department of Diabetes, Endocrinology and Metabolism, Manchester University NHS Foundation Trust and National Institute of Health Research/Wellcome Trust Clinical Research Facility, Manchester, UK.
¹⁵ Department of Paediatrics, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands. Electronic address: a.wiegman@amsterdamumc.nl.

PMID: 38759658
DOI: 10.1016/S2352-4642(24)00073-7

Abstract

Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence.

Methods: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis.

Findings: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037).

Interpretation: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life.

Funding: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.