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Familial hypercholesterolaemia: evolving knowledge for designing adaptive models of care

Abstract

Optimal care for familial hypercholesterolaemia (FH) requires patient-centred management, multidisciplinary teamwork, involvement of primary care practitioners, patient networks, support groups and high-quality clinical registries, implemented through models of care adapted to FH. Models of care — evidence-based and context-specific frameworks that aim to deliver the highest quality of care for patients and their families — allow the application of precision and multidisciplinary medicine to FH care and can serve as paradigms for the prevention of premature atherosclerotic cardiovascular disease in all at-risk patients and families worldwide. The exponential growth in the number of publications on diverse aspects of FH has provided new knowledge for developing essential elements of existing models of care. These elements include clinical diagnostic criteria and genetic testing; risk restratification strategies; LDL-cholesterol treatment targets; management protocols for children; care of women in pregnancy; use of pharmacotherapies, including ezetimibe and PCSK9 inhibitors; use of lipoprotein apheresis for severe FH; and addressing barriers to care. However, substantial gaps remain that need to be addressed by a broad research agenda, implementation strategies and global collaboration and advocacy, aimed at improving the uptake, cost-effectiveness and routine implementation of evidence-based standards. In this Review, we summarize the dramatic increase in knowledge that informs adaptive models of care, with an emphasis on articles published since 2014.

Key points

  • Effective identification of familial hypercholesterolaemia (FH) requires the coordination of several screening strategies, with an emphasis on early detection and a central role for primary care.

  • Clinical diagnostic criteria for FH can be imprecise and need refining with affordable genetic testing; detection of a pathogenic mutation has prognostic utility and allows cascade testing and the initiation of treatment in childhood.

  • Incident atherosclerotic cardiovascular disease is variable in FH and can be predicted by genetic and phenotypic factors, including LDL-cholesterol burden and non-invasive imaging methods.

  • Management entails the timely lowering of LDL-cholesterol burden by lifestyle modifications and the use of statins, followed by ezetimibe and PCSK9 inhibitors if required; women and children need special care, and lipoprotein apheresis is indicated in patients with severe FH.

  • Effective models of care require multidisciplinary teams, patient networks, registries and research programmes; implementation remains a major challenge.

  • The evidence reviewed can be used to design adaptive models of care for FH.

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Fig. 1: An example of a patient pathway integrated across primary and specialist care for heterozygous FH.
Fig. 2: Phenotypic and genetic spectrum of FH.
Fig. 3: Risk of CAD across categories of LDL-cholesterol level and FH-causing mutation status.
Fig. 4: Development and progression of atherosclerosis in FH.
Fig. 5: Sequential treatment pathway for adults with FH7.

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G.F.W. and J.P. researched data for the article, and all authors contributed to discussions of its content. G.F.W. wrote the manuscript, and all authors reviewed and edited it before submission.

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Correspondence to Gerald F. Watts.

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Competing interests

The authors received no financial support for the research, authorship or publication of this article. G.F.W. has received honoraria as a consultant on advisory boards and research grants from Amgen, Regeneron Pharmaceuticals and Sanofi. S.S.G. has received research grants from the US National Institutes of Health and is employed by the FH Foundation. P.M. has received research grants from Amgen and Sanofi. J.P. was supported by a WAHTN Early Career Fellowship and the Australian Government’s Medical Research Future Fund. D.R.S. has received grants from Amarin, Amgen, AstraZeneca, Espirion, Novartis and Regeneron Pharmaceuticals, as well as personal fees from Amgen and Sanofi. S.Y. has received grants and personal fees from Astellas Pharma, AstraZeneca, Bayer Yakuhin, Daiichi Sankyo, Hayashibara, Izumisano City, Japan Tobacco, Kaizuka City, Kaken Pharmaceutical, Kissei Pharmaceutical, Kowa, Kyowa Medex, Merck Sharp & Dohme, Mochida Pharmaceutical, the Japanese National Institute of Biomedical Innovation, Nippon Boehringer Ingelheim, Otsuka Pharmaceutical, Sanwa Kagaku Kenkyusho, Shionogi, Takeda Pharmaceutical and Teijin Pharma, as well as personal fees from Amgen Astellas BioPharma, Astellas Pharma, AstraZeneca, Bayer Yakuhin, Bristol-Myers Squibb, Daiichi Sankyo, Kaken Pharmaceutical, Medical Review, Merck Sharp & Dohme, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer Japan, Sanofi, Sanwa Kagaku Kenkyusho, Shionogi, Skylight Biotech, Takeda Pharmaceutical and Toa Eiyo. F.J.R. has received research grants from Amgen, Sanofi and Regeneron Pharmaceuticals, has participated in speakers’ bureaus for and received honoraria from Amgen, Regeneron Pharmaceuticals, Sanofi and The Medicines Company, and is a consultant on advisory boards for Amgen, Regeneron Pharmaceuticals, Sanofi and The Medicines Company. R.D.S. is a recipient of a scholarship from the Conselho Nacional de Pesquisa e Desenvolvimento Tecnologico (CNPq) process no. 303734/2018-3 and has received honoraria for consulting, research and speaker activities from Ache, Akcea, Amgen, AstraZeneca, Esperion, Kowa, Merck, Novo-Nordisk, Pfizer and Sanofi/Regeneron Pharmaceuticals. K.K.R. has received research grants from Amgen, Merck Sharp & Dohme, Pfizer, Regeneron and Sanofi, as well as honoraria for lectures, being a consultant on advisory boards and/or as a steering committee member from Amgen, AstraZeneca, Boehringer Ingelheim, Esperion, IONIS, Kowa, Lilly, Pfizer, Regeneron Pharmaceuticals, Sanofi, Takeda and The Medicines Company.

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Nature Reviews Cardiology thanks R. Hegele, L. Ose and E. Stein for their contribution to the peer review of this work.

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Review criteria

A search was undertaken of the literature published in the English language between January 2014 and September 2019. The search used the PubMed database with search string (all fields) ‘familial hypercholesterolemia’ or ‘familial hypercholesterolaemia’. Additional published studies were provided ad hoc by individual authors. G.F.W. and J.P. assessed the titles and abstracts of all the articles identified and selected those that were novel and most useful for informing the components of the model of care for familial hypercholesterolaemia. The other authors approved this selection and supplied additional articles that added value to those identified in the literature review.

Related links

ClinVar database: https://www.ncbi.nlm.nih.gov/clinvar/

European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration: https://www.eas-society.org/page/fhsc

European FH Patient Network: https://fheurope.org/

FH Foundation: https://thefhfoundation.org/

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Watts, G.F., Gidding, S.S., Mata, P. et al. Familial hypercholesterolaemia: evolving knowledge for designing adaptive models of care. Nat Rev Cardiol 17, 360–377 (2020). https://doi.org/10.1038/s41569-019-0325-8

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