Multimodal lipid-lowering treatment in pediatric patients with homozygous familial hypercholesterolemia—target attainment requires further increase of intensity
- 401 Downloads
Familial hypercholesterolemia (FH) causes premature cardiovascular disease (CVD). Lipoprotein apheresis (LA) is recommended as first-line lipid-lowering treatment (LLT) for homozygous (ho) FH.
Efficacy of multimodal LLT including lifestyle counseling, drug treatment, and LA was analyzed in 17 pediatric hoFH or compound heterozygous (c-het) FH patients, who commenced chronic LA in Germany before the age of 18.
At time of diagnosis, mean low-density lipoprotein cholesterol (LDL-C) concentration was 19.6 mmol/l (756 mg/dl). Multimodal LLT resulted in 73% reduction of mean LDL-C concentration including a 62% contribution of LA. Only three children (18%) achieved mean LDL-C concentrations below the recommended pediatric target of 3.5 mmol/l (135 mg/dl). In 13 patients (76%) during chronic LA, neither cardiovascular events occurred nor was CVD progression detected clinically or by routine imaging techniques. In four patients (24%), cardiovascular events documented progression of CVD despite weekly LA, including one death due to coronary and cerebrovascular CVD which was not stabilized after commencing LA. Based on the mutational status, only 6 out of the 17 children were candidates for proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibition. Two already responded with further LDL-C decrease by 40%.
Next to drug therapy, regular LA is an essential component of LLT for approaching LDL-C targets in children with hoFH or c-hetFH, which was successful only in a minority of children. Progression of CVD morbidity and resulting mortality remain unresolved issues. Early and intensified multimodal LLT guided by risk factors beyond LDL-C concentration is needed to improve outcome.
KeywordsChildren Familial hypercholesterolemia LDL-cholesterol Lipoprotein apheresis prevention Treatment
Supported by German Society for Pediatric Nephrology (GPN)
Günter Klaus, Reinhard Klingel, and Andreas Heibges were mainly involved in analyzing the data and writing the manuscript. All clinical investigators gathered, documented, and summarized data from patients at their respective clinical sites and contributed equally to preparing the manuscript.
Funding of this study was part of an unrestricted research grant from Diamed, Cologne, Germany, to Apheresis Research Institute, covering costs of ethics votes and personal costs. No other costs were accounted for this study project.
Compliance with ethical standards
Ethical approval for the study had been obtained for every study site. All parents or legal guardians of the participating children and adolescents gave their written informed consent.
Conflict of interest statement
AH and RK are employees of Apheresis Research Institute, which received research grants from Diamed, Cologne Germany, and Asahi Kasei Medical, Tokyo Japan. JRS is funded by the Reinfried Pohl foundation and has served as medical adviser for MSD Germany, AMGEN, and Sanofi-Genzyme. In addition, he has received lecture fees by MSD, Sanofi-Genzyme, Synlab Academie, Novartis, and Berlin Chemie. For all other authors, no conflict of interest is declared.
- 1.Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Borén J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A, Panel EASC (2013) Familial hypercholesterolemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease. Eur Heart J 34:3478–3490CrossRefPubMedPubMedCentralGoogle Scholar
- 2.Santos RD, Gidding SS, Hegele RA, Cuchel MA, Barter PJ, Watts GF, Baum SJ, Catapano AL, Chapman MJ, Defesche JC, Folco E, Freiberger T, Genest J, Hovingh GK, Harada-Shiba M, Humphries SE, Jackson AS, Mata P, Moriarty PM, Raal FJ, Al-Rasadi K, Ray KK, Reiner Z, Sijbrands EJ, Yamashita S, International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel (2016) Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes-Endocrinol 4:850–861CrossRefPubMedGoogle Scholar
- 3.Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA, Kuivenhoven JA, Nordestgaard BG, Descamps OS, Steinhagen-Thiessen E, Tybjærg-Hansen A, Watts GF, Averna M, Boileau C, Borén J, Catapano AL, Defesche JC, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Ray KK, Stalenhoef AF, Stroes E, Taskinen MR, Wiegman A, Wiklund O, Chapman MJ, European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia (2014) Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 35:2146–2157CrossRefPubMedPubMedCentralGoogle Scholar
- 4.Sjouke B, Meeike Kusters D, Kindt I, Besseling J, Defesche JC, Sijbrands EJ, Roeters van Lennep JE, Stalenhoef AF, Wiegman A, de Graaf J, Fouchier SW, Kastelein JJ, Hovingh GK (2015) Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype–phenotype relationship, and clinical outcome. Eur Heart J 36:560–565CrossRefPubMedGoogle Scholar
- 5.Wiegman A, Gidding SS, Watts GF, Chapman MJ, Ginsberg HN, Cuchel M, Ose L, Averna M, Boileau C, Borén J, Bruckert E, Catapano AL, Defesche JC, Descamps OS, Hegele RA, Hovingh GK, Humphries SE, Kovanen PT, Kuivenhoven JA, Masana L, Nordestgaard BG, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos RD, Stalenhoef AF, Steinhagen-Thiessen E, Stroes ES, Taskinen MR, Tybjærg-Hansen A, Wiklund O, European Atherosclerosis Society Consensus Panel (2015) Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J 36:2425–2437CrossRefPubMedPubMedCentralGoogle Scholar
- 7.Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW, McCrindle B, Raal F, Rader D, Santos RD, Lopes-Virella M, Watts GF, Wierzbicki AS, American Heart Association Atherosclerosis, Hypertension, and Obesity in Young Committee of Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and Council on Lifestyle and Cardiometabolic Health (2015) The agenda for familial hypercholesterolemia. A scientific statement from the American Heart Association. Circulation 132:2167–2192CrossRefPubMedGoogle Scholar
- 10.Widhalm K, Binder CB, Kreissl A, Aldover-Macasaet E, Fritsch M, Kroisboeck S, Geiger H (2011) Sudden death in a 4-year-old boy: a near-complete occlusion of the coronary artery caused by an aggressive low-density lipoprotein receptor mutation (W556R) in homozygous familial hypercholesterolemia. J Pediatr 158:167CrossRefPubMedGoogle Scholar
- 11.Thompson GR, Blom DJ, Marais AD, Seed M, Pilcher GJ, Raal FJ (2017) Survival in homozygous familial hypercholesterolemia is determined by the on-treatment level of serum cholesterol. Eur Heart J. https://doi.org/10.1093/eurheartj/ehx317
- 13.Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, Chasman DI, Baber U, Mehran R, Rader DJ, Fuster V, Boerwinkle E, Melander O, Orho-Melander M, Ridker PM, Kathiresan S (2016) Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med 375:2349–2358CrossRefPubMedPubMedCentralGoogle Scholar
- 15.Chourdakis M, Buderus S, Dokoupil K, Oberhoffer R, Otfried Schwab KO, Wolf M, Zimmer KP, Koletzko B; for the German Society of Pediatrics (2015) S2k-guideline for diagnosis and treatment of dyslipidemias in children. Published online 2015 at www.awmf.org: AWMF-registry no 027-068 (document in German). http://www.awmf.org/leitlinien/detail/ll/027-068.html. Accessed 12 December 2017
- 16.France M, Rees A, Datta D, Thompson G, Capps N, Ferns G, Ramaswami U, Seed M, Neely D, Cramb R, Shoulders C, Barbir M, Pottle A, Eatough R, Martin S, Bayly G, Simpson B, Halcox J, Edwards R, Main L, Payne J, Soran H, for HEART UK Medical Scientific and Research Committee (2016) HEART UK. Statement on the management of homozygous familial hypercholesterolaemia in the United Kingdom. Atherosclerosis 255:128–139CrossRefPubMedGoogle Scholar
- 17.Klaus G, Pape L, Schmitt CP (2010) SOP Kinderdialyse: LDL-Apherese; Arbeitskreis Kinderdialyse der Gesellschaft für Pädiatrische Nephrologie (GPN) (document in German)Google Scholar
- 20.Heigl F, Hettich R, Lotz N, Reeg H, Pflederer T, Osterkorn D, Osterkorn K, Klingel R (2015) Efficacy, safety, and tolerability of long-term lipoprotein apheresis in patients with LDL- or Lp(a) hyperlipoproteinemia: findings gathered from more than 36,000 treatments at one center in Germany. Atheroscler Suppl 18:154–162CrossRefPubMedGoogle Scholar
- 21.Leigh SEA, Foster AH, Whittall RA, Hubbart CS, Humphries SE (2008) Update and analysis of the university college London low density lipoprotein receptor familial hypercholesterolemia database. Ann Hum Genet 72:485–498 updated at http://www.ucl.ac.uk/ldlr/LOVDv.1.1.0/. Accessed 12 December 2017CrossRefPubMedGoogle Scholar
- 29.Fernández-Friera L, Penalvo JL, Fernandez-Ortiz A, Ibañez B, López-Melgar B, Laclaustra M, Oliva B, Mocoroa A, Mendiguren J, Martínez de Vega V, García L, Molina J, Sánchez-González J, Guzmán G, Alonso-Farto JC, Guallar E, Civeira F, Sillesen H, Pocock S, Ordovás JM, Sanz G, Jiménez-Borreguero LJ, Fuster V (2015) Prevalence, vascular distribution, and multiterritorial extent of subclinical atherosclerosis in a middle-aged cohort. The PESA (Progression of Early Subclinical Atherosclerosis) Study. Circulation 131:2104–2113CrossRefPubMedGoogle Scholar
- 30.Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, Hoes AW, Jennings CS, Landmesser U, Pedersen TR, Reiner Ž, Riccardi G, Taskinen MR, Tokgozoglu L, Verschuren WM, Vlachopoulos C, Wood DA, Zamorano JL, Task Force Members (2016) 2016 ESC/EAS guidelines for the management of dyslipidaemias. Eur Heart J 37:2999–3058CrossRefPubMedGoogle Scholar
- 32.Roeseler E, Julius U, Heigl F, Spitthoever R, Heutling D, Breitenberger P, Leebmann J, Lehmacher W, Kamstrup PR, Nordestgaard BG, Maerz W, Noureen A, Schmidt K, Kronenberg F, Heibges A, Klingel R, Pro(a)LiFe-Study Group (2016) Lipoprotein apheresis for lipoprotein(a)-associated cardiovascular disease: prospective 5 years of follow-up and apolipoprotein(a) characterization. Arterioscler Thromb Vasc Biol 36:2019–2027CrossRefPubMedGoogle Scholar
- 33.Pérez de Isla L, Alonso R, Mata N, Fernández-Pérez C, Muñiz O, Díaz-Díaz JL, Saltijeral A, Fuentes-Jiménez F, de Andrés R, Zambón D, Piedecausa M, Cepeda JM, Mauri M, Galiana J, Brea Á, Sanchez Muñoz-Torrero JF, Padró T, Argueso R, Miramontes-González JP, Badimón L, Santos RD, Watts GF, Mata P (2017) Predicting cardiovascular events in familial hypercholesterolemia. The SAFEHEART registry. Circulation 135:2133–2144CrossRefPubMedGoogle Scholar
- 35.Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, ODYSSEY LONG TERM Investigators (2015) Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 16:1489–1499CrossRefGoogle Scholar
- 36.Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA, Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators (2015) Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 372:1500–1509CrossRefPubMedGoogle Scholar
- 37.Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR, FOURIER Steering Committee and Investigators (2017) Evolocumab and clinical outcomes in patients with cardiovascular disease. New Engl J Med 376:1713–1722CrossRefPubMedGoogle Scholar
- 38.Raal FR, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, Wasserman SM, Stein EA, TESLA Investigators (2015) Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 385:341–350CrossRefPubMedGoogle Scholar
- 39.Raal FJ, Hovingh GK, Blom D, Santos RD, Harada-Shiba M, Bruckert E, Couture P, Soran H, Watts GF, Kurtz C, Honarpour N, Tang L, Kasichayanula S, Wasserman SM, Stein EA (2017) Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diab Endocrinol 5:280–290CrossRefGoogle Scholar
- 40.Stefanutti C, Morozzi C, Di Giacomo S, Sovrano B2, Mesce D2, Grossi A (2016) Management of homozygous familial hypercholesterolemia in real-world clinical practice: a report of 7 Italian patients treated in Rome with lomitapide and lipoprotein apheresis. J Clin Lipidol 10:782–789CrossRefPubMedGoogle Scholar
- 41.Bruckert E, Kalmykova O, Bittar R, Carreau V, Béliard S, Saheb S, Rosenbaum D, Bonnefont-Rousselot D, Thomas D, Emery C, Khoshnood B, Carrié A (2017) Long-term outcome in 53 patients with homozygous familial hypercholesterolaemia in a single centre in France. Atherosclerosis 257:130–137CrossRefPubMedGoogle Scholar