Improving the global care of familial hypercholesterolaemia: Starting the ball rolling
2018; Elsevier BV; Volume: 277; Linguagem: Inglês
10.1016/j.atherosclerosis.2018.09.002
ISSN1879-1484
AutoresKausik K. Ray, Gerald F. Watts,
Tópico(s)Health Systems, Economic Evaluations, Quality of Life
ResumoIn 2013, a European Atherosclerosis Society (EAS) consensus panel concluded that familial hypercholesterolaemia (FH) was underdiagnosed and undertreated [[1]Nordestgaard B. Chapman M. Humphries S. et al.Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease (Consensus Statement of the European Atherosclerosis Society).Eur. Heart J. 2013; 34: 3478-3490Crossref PubMed Scopus (1786) Google Scholar]. Supported by international evidence [2Watts G.F. Gidding S. Wierzbicki A.S. et al.Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.Int. J. Cardiol. 2014; 171: 309-325Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 3Gidding S.S. Champagne M.A. de Ferranti S.D. et al.The agenda for familial hypercholesterolemia - a scientific statement from the American heart association.Circulation. 2015; : 132PubMed Google Scholar, 4Santos R.D. Gidding S.S. Hegele R.A. et al.Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial hypercholesterolemia panel.Lancet Diabetes & Endocrinology. 2016; 4: 850-861Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar, 5Goldberg A.C. Robinson J.G. Cromwell W.C. et al.Future issues, public policy, and public awareness of familial hypercholesterolemias: recommendations from the national lipid association expert panel on familial hypercholesterolemia.J. Clin. Lipidol. 2011; 5: S46-S51Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar], the expert panel also recognised the worldwide shortfall of data on the care of FH. To address this important demand, the Familial Hypercholesterolaemia Studies Collaboration (FHSC) was established under the auspices of the EAS in 2015. The primary aim of the FHSC is to improve global knowledge of the care of FH patients through the acquisition, curation and analysis of big data within a robust registry framework. The first publication hailed 'a call to arms' [[6]Vallejo-Vaz A.J. Kondapally Seshasai S.R. Cole D. et al.Familial hypercholesterolaemia: a global call to arms.Atherosclerosis. 2015; 243: 257-259Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar] to buttress critical gaps in the care of FH. The mission, aims and technical aspects of the FHSC registry have been published [[7]Vallejo-Vaz A.J. Akram A. Kondapally Seshasai S.R. et al.Pooling and expanding registries of familial hypercholesterolaemia to assess gaps in care and improve disease management and outcomes: rationale and design of the global EAS Familial Hypercholesterolaemia Studies Collaboration.Atherosclerosis Suppl. 2016; 22: 1-32Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar]. The registry harbours the largest global dataset on FH, derived from 70 countries across 6 continents. This issue of Atherosclerosis includes a thematic series of 41 peer-assessed articles on diverse aspects of the care of FH, including the overview FHSC report and 5 invited reviews from leading experts in the field. The opening article from the FHSC presents the outcome of a survey relating to awareness, prevalence, management and treatment of FH across member countries. The report highlights a general lack of information on the prevalence of FH in most of the participating countries, and universally low rates of identification [[8]Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).Atherosclerosis. 2018; 277: 234-253Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar]. Where data are available, figures concur with contemporary estimates [[9]Akioyamen L.E. Genest J. Shan S.D. et al.Estimating the prevalence of heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis.BMJ Open. 2017; 7e016461Crossref PubMed Scopus (197) Google Scholar]. The distribution of plasma cholesterol in the community and specific characteristics, such as gene founder effects and consanguinity, and population sampling methods clearly influence the frequency estimates and detection rates of FH [[8]Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).Atherosclerosis. 2018; 277: 234-253Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar]. The survey shows that the Dutch Lipid Network Score is the most popular diagnostic tool, followed by Simon Broome and MEDPED; a minority of countries use modified criteria [[2]Watts G.F. Gidding S. Wierzbicki A.S. et al.Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.Int. J. Cardiol. 2014; 171: 309-325Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar,[10]Zhou M. Zhao D. Familial hypercholesterolemia in Asian populations.J. Atherosclerosis Thromb. 2016; 23: 539-549Crossref PubMed Scopus (29) Google Scholar], highlighting the need for country-specific tools for FH diagnosis. Importantly, a critical observation is the lack of resources and funding to support best clinical practice in caring for FH. Genetic testing is not universally available and is used mostly to confirm clinical diagnosis; however, in the majority of cases, genetic testing is only self-funded or available in the context of research. About 30% of the countries surveyed offer genetic cascade screening mostly on a regional basis, with only a few at national level, but the funding formula is uncertain. Pharmacotherapies for manging FH are implemented in all countries, but are not universally reimbursed, re-imbursement criteria varying widely. High intensity statins are the standard of care, usually with add-on ezetimibe; in 4 countries, however, ezetimibe is not available. About 70% of the countries report availability of PCSK9-inhibitors, but use is restricted; 60% offer lipoprotein apheresis, but this is limited to one centralised or a few reference centres [[8]Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).Atherosclerosis. 2018; 277: 234-253Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar]. The subsequent papers add to the evolving corpus of information referred to above. Several countries report that the community prevalence of FH is 2-fold greater than previously recognised [11Corral P. Geller A.S. Polisecki E.Y. et al.Unusual genetic variants associated with hypercholesterolemia in Argentina.Atherosclerosis. 2018; 277: 254-259Google Scholar, 12Paragh G. Harangi M. Karányi Z. et al.Identifying patients with familial hypercholesterolemia using data mining methods in the Northern Great Plain region of Hungary.Atherosclerosis. 2018; 277: 260-264Google Scholar, 13Kutkiene S. Petrulioniene Z. Laucevicius A. et al.Lipid profile evaluation and severe hypercholesterolaemia screening in the middle-aged population according to nationwide primary prevention programme in Lithuania.Atherosclerosis. 2018; 277: 265-270Google Scholar, 14Harada P.H. Miname M.H. Benseñor I.M. et al.Familial hypercholesterolemia prevalence in an admixed racial society: sex and race matter. The ELSA-Brasil.Atherosclerosis. 2018; 277: 271-275Google Scholar, 15Pojskic L. Pojskic B. Familial hypercholesterolemia screening program in Bosnia and Herzegovina and cardiovascular morbidity.Atherosclerosis. 2018; 277: 276-279Google Scholar, 16Miserez A.R. Martin F.J. Spirk D. DIAgnosis and management of familial hypercholesterolemia in a nationwide design (DIAMOND-FH): Prevalence in Switzerland, clinical characteristics and the diagnostic value of clinical scores.Atherosclerosis. 2018; 277: 280-286Google Scholar]. This makes FH a public health issue that needs to be accordingly addressed. An expert review accepts the higher frequency of FH, but cautions that the data need to account for the method of diagnosis, ascertainment bias, gene founder effects, and consanguinity [[17]Vallejo-Vaz A.J. Ray K.K. Epidemiology of familial hypercholesterolaemia: community and clinical.Atherosclerosis. 2018; 277: 287-295Google Scholar]. Several of the clinical surveys indicated that FH remains largely undiagnosed and untreated [[12]Paragh G. Harangi M. Karányi Z. et al.Identifying patients with familial hypercholesterolemia using data mining methods in the Northern Great Plain region of Hungary.Atherosclerosis. 2018; 277: 260-264Google Scholar,18Lalić K. Rajković N. Popović L. et al.The effects of 3-year statin therapy and the achievement of LDL cholesterol target values in familial hypercholesterolemia patients: an experience from Serbia.Atherosclerosis. 2018; 277: 296-301Google Scholar, 19Dumitrescu A. Mosteoru S. Vinereanu D. et al.Preliminary data of familial hypercholesterolemia (FH) patients in Romania.Atherosclerosis. 2018; 277: 302-305Google Scholar, 20Rizos C.V. Elisaf M.S. Skoumas I. et al.Characteristics and management of 1093 patients with clinical diagnosis of familial hypercholesterolemia in Greece: data from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH).Atherosclerosis. 2018; 277: 306-311Google Scholar, 21Schmidt N. Dressel A. Grammer T.B. et al.Lipid-modifying therapy and low-density lipoprotein cholesterol goal attainment in patients with familial hypercholesterolemia in Germany: the CaReHigh Registry.Atherosclerosis. 2018; 277: 312-320Google Scholar, 22Vohnout B. Fábryová Ľ. Klabník A. et al.Treatment pattern of familial hypercholesterolemia in Slovakia: targets, treatment and obstacles in common practice.Atherosclerosis. 2018; 277: 321-324Google Scholar, 23van Delden X.M. Huijgen R. Wolmarans K.H. et al.LDL-cholesterol target achievement in patients with heterozygous familial hypercholesterolemia at Groote Schuur Hospital: minority at target despite large reductions in LDL-C.Atherosclerosis. 2018; 277: 325-331Google Scholar, 24Béliard S. Boccara F. Cariou B. et al.High burden of recurrent cardiovascular events in heterozygous familial hypercholesterolemia: the French Familial Hypercholesterolemia Registry.Atherosclerosis. 2018; 277: 332-338Google Scholar, 25Kayıkçıoğlu M. Tokgozoglu L. Dogan V. et al.What have we learned from Turkish familial hypercholesterolemia registries (A-HIT 1 and A-HIT 2)?.Atherosclerosis. 2018; 277: 339-344Google Scholar, 26Latkovskis G. Saripo V. Gilis D. Latvian registry of familial hypercholesterolemia: the first report of three-year results.Atherosclerosis. 2018; 277: 345-352Google Scholar, 27Vrablik M. Raslová K. Vohnout B. et al.Real-life LDL-C treatment goals achievement in patients with heterozygous familial hypercholesterolemia in the Czech Republic and Slovakia: results of the PLANET registry.Atherosclerosis. 2018; 277: 353-359Google Scholar], despite meeting all the classical criteria for screening. The prevalence of definite FH is probably 5-fold higher among younger patients with an acute coronary syndrome [[28]Harada-Shiba M. Ako J. Arai H. Prevalence of familial hypercholesterolemia in patients with acute coronary syndrome in Japan: results of the EXPLORE-J study.Atherosclerosis. 2018; 277: 360-366Google Scholar] and protocols for linking the detection of such patients to follow-up in specialist clinics and the cascade testing of relatives for FH have been proposed [[29]Descamps O.S. Van Caenegem O. Hermans M.P. et al.A Belgian consensus strategy to identify familial hypercholesterolaemia in the coronary care unit and its subsequent cascade screening and treatment: BEL-FaHST (The Belgium Familial Hypercholesterolaemia STrategy).Atherosclerosis. 2018; 277: 367-374Google Scholar]. The universal screening of children for FH has been championed in the UK and US [[30]Payne J. Williams S. Maxwell D. et al.Familial hypercholesterolaemia patient support groups and advocacy: a multinational perspective.Atherosclerosis. 2018; 277: 375-381Google Scholar], but only implemented and shown to be efficacious in Slovenia [[31]Groselj U. Kovac J. Sustar U. Universal screening for familial hypercholesterolemia in children: the Slovenian model and literature review.Atherosclerosis. 2018; 277: 382-390Google Scholar]. Universal screening of children, with reverse cascade testing of parents, has recently been shown to be cost-effective and deserves more consideration [[32]McKay A.J. Hogan H. Humphries S.E. et al.Universal screening at age 1–2 years as an adjunct to cascade testing for familial hypercholesterolaemia in the UK: a cost-utility analysis.Atherosclerosis. 2018; 275: 434-443Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar]. In WHO low-to-middle income countries, reverse cascade testing from a child with HoFH is an effective method of detecting high-risk family members [[33]Truong T.H. Kim N.T. Nguyen M.N.T. et al.Homozygous familial hypercholesterolaemia in Vietnam: case series, genetics and cascade testing of families.Atherosclerosis. 2018; 277: 391-397Google Scholar]. Few reports give attention to the role of primary care in screening. This last topic is well reviewed by Brett et al. [[34]Brett T. Qureshi N. Gidding S. Watts G.F. Screening for familial hypercholesterolaemia in primary care: time for general practice to play its part.Atherosclerosis. 2018; 277: 398-405Google Scholar] who emphasized the value of opportunistic screening employing electronic data extraction tools, as exemplified by a report from Lithuania [[35]Petrulionienė Ž. Gargalskaitė U. Kutkienė S. et al.Establishing a national screening programme for familial hypercholesterolaemia in Lithuania.Atherosclerosis. 2018; 277: 406-411Google Scholar]. Multiple approaches to detecting FH have been proposed; selective, opportunistic, systematic and universal strategies all have merits and are not mutually exclusive [[1]Nordestgaard B. Chapman M. Humphries S. et al.Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease (Consensus Statement of the European Atherosclerosis Society).Eur. Heart J. 2013; 34: 3478-3490Crossref PubMed Scopus (1786) Google Scholar,[2]Watts G.F. Gidding S. Wierzbicki A.S. et al.Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.Int. J. Cardiol. 2014; 171: 309-325Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar,[34]Brett T. Qureshi N. Gidding S. Watts G.F. Screening for familial hypercholesterolaemia in primary care: time for general practice to play its part.Atherosclerosis. 2018; 277: 398-405Google Scholar,[36]Martin A.C. Gidding S.S. Wiegman A. et al.Known and unknowns in the care of paediatric familial hypercholesterolaemia.J. Lipid Res. 2017; 58: 1765-1776Crossref PubMed Scopus (30) Google Scholar]. Whilst the Dutch Lipid Clinic Network criteria are most popular for diagnosing FH [[8]Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).Atherosclerosis. 2018; 277: 234-253Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar], lack of information assails making an accurate diagnosis of FH [[37]Casula M. Olmastroni E. Pirillo A. Catapano A.L. Evaluation of the performance of Dutch lipid clinic network score in an Italian FH population: the LIPIGEN study.Atherosclerosis. 2018; 277: 412-416Google Scholar]. Concordance with the Simon Broome and MED-PED criteria can also be moderate to low [[38]Ahmad Z.S. Andersen R.L. Andersen L.H. et al.US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry.J. Clin. Lipidol. 2016; 10: 1223-1229Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar]. The Canadian network has therefore developed a simple and robust algorithm for diagnosing FH [[39]Brunham L.R. Ruel I. Khoury E. et al.Familial hypercholesterolemia in Canada: initial results from the FH Canada national registry.Atherosclerosis. 2018; 277: 417-422Google Scholar]. Whether this could provide a new standard diagnosis for FH remains to be verified. Country-specific criteria for FH are essential, particularly since there can be wide geographical variation (e.g. Europe and US vs Asia) in the population percentile values for LDL-cholesterol concentrations [[8]Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).Atherosclerosis. 2018; 277: 234-253Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar,[10]Zhou M. Zhao D. Familial hypercholesterolemia in Asian populations.J. Atherosclerosis Thromb. 2016; 23: 539-549Crossref PubMed Scopus (29) Google Scholar]. A practical definition of homozygous FH is also required [[4]Santos R.D. Gidding S.S. Hegele R.A. et al.Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial hypercholesterolemia panel.Lancet Diabetes & Endocrinology. 2016; 4: 850-861Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar], noting the phenotypic diversity of condition [[40]Raal F.J. Sjouke B. Hovingh G.K. et al.Phenotype diversity among patients with homozygous familial hypercholesterolemia: a cohort study.Atherosclerosis. 2016; 248: 238-244Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar]. Best practice in precision medicine requires that the diagnosis of FH be confirmed genetically [[41]Sturm A.C. Knowles J.W. Gidding S.S. et al.Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel.J. Am. Coll. Cardiol. 2018; 72: 662-680Crossref PubMed Scopus (252) Google Scholar]. Several countries have therefore undertaken their own genetic studies, supported in some cases by international experts [[11]Corral P. Geller A.S. Polisecki E.Y. et al.Unusual genetic variants associated with hypercholesterolemia in Argentina.Atherosclerosis. 2018; 277: 254-259Google Scholar,[16]Miserez A.R. Martin F.J. Spirk D. DIAgnosis and management of familial hypercholesterolemia in a nationwide design (DIAMOND-FH): Prevalence in Switzerland, clinical characteristics and the diagnostic value of clinical scores.Atherosclerosis. 2018; 277: 280-286Google Scholar,[31]Groselj U. Kovac J. Sustar U. Universal screening for familial hypercholesterolemia in children: the Slovenian model and literature review.Atherosclerosis. 2018; 277: 382-390Google Scholar,[33]Truong T.H. Kim N.T. Nguyen M.N.T. et al.Homozygous familial hypercholesterolaemia in Vietnam: case series, genetics and cascade testing of families.Atherosclerosis. 2018; 277: 391-397Google Scholar,[37]Casula M. Olmastroni E. Pirillo A. Catapano A.L. Evaluation of the performance of Dutch lipid clinic network score in an Italian FH population: the LIPIGEN study.Atherosclerosis. 2018; 277: 412-416Google Scholar,42Alnouri F. Athar M. Al-Allaf F.A. et al.Novel combined variants of LDLR and LDLRAP1 gene causing severe familial hypercholesterolemia.Atherosclerosis. 2018; 277: 423-431Google Scholar, 43Greizy L. Bernal L.M. Gelvez N. et al.Mutational analysis of the LDLR gene in a cohort of Colombian families with familial hypercholesterolemia.Atherosclerosis. 2018; 277: 432-437Google Scholar, 44Hsiung Y.-C. Lin P.-C. Chen C.-S. et al.Identification of a novel LDLR disease-causing variant using capture-based next-generation sequencing screening of familial hypercholesterolemia patients in Taiwan.Atherosclerosis. 2018; 277: 438-445Google Scholar, 45Catarina Alves A. Benito-Vicente A. Medeiros A.M. et al.Further evidence of novel APOB mutations as a cause of familial hypercholesterolaemia.Atherosclerosis. 2018; 277: 446-454Google Scholar]. Genetic testing is important in countries with high rates of consanguinity [[42]Alnouri F. Athar M. Al-Allaf F.A. et al.Novel combined variants of LDLR and LDLRAP1 gene causing severe familial hypercholesterolemia.Atherosclerosis. 2018; 277: 423-431Google Scholar]. Next generation sequencing permits the detection of a wider spectrum of mutations [[11]Corral P. Geller A.S. Polisecki E.Y. et al.Unusual genetic variants associated with hypercholesterolemia in Argentina.Atherosclerosis. 2018; 277: 254-259Google Scholar,[16]Miserez A.R. Martin F.J. Spirk D. DIAgnosis and management of familial hypercholesterolemia in a nationwide design (DIAMOND-FH): Prevalence in Switzerland, clinical characteristics and the diagnostic value of clinical scores.Atherosclerosis. 2018; 277: 280-286Google Scholar,[44]Hsiung Y.-C. Lin P.-C. Chen C.-S. et al.Identification of a novel LDLR disease-causing variant using capture-based next-generation sequencing screening of familial hypercholesterolemia patients in Taiwan.Atherosclerosis. 2018; 277: 438-445Google Scholar,[45]Catarina Alves A. Benito-Vicente A. Medeiros A.M. et al.Further evidence of novel APOB mutations as a cause of familial hypercholesterolaemia.Atherosclerosis. 2018; 277: 446-454Google Scholar] that not only facilitate a definitive diagnosis of FH, but may also confirm polygenic hypercholestrerolaemia; this molecular diagnosis may predict a more adverse prognosis in FH or when isolated may be used to ration cascade testing [[46]Futema M. Bourbon M. Williams M. Humphries S.E. Clinical utility of the polygenic LDL-C SNP score in familial hypercholesterolemia.Atherosclerosis. 2018; 277: 455-461Google Scholar]. Genetic testing is acceptable and does not impair quality of life, which is more likely consequent on co-existent morbidities in FH [[47]Souto A.C. Miname M.H. Fukushima J. et al.Health related quality of life in individuals at high risk for familial hypercholesterolemia undergoing genetic cascade screening in Brazil.Atherosclerosis. 2018; 277: 462-467Google Scholar]. The clinical expression of FH is variable and cardiovascular (CV) risk equations have been described [[48]Pérez de Isla L. Alonso R. Mata N. et al.Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry.Circulation. 2017; 135: 2133-2144Crossref PubMed Scopus (204) Google Scholar]. Several reports show a high prevalence of non-cholesterol risk factors among patients with FH, implying the need to address targets beyond LDL-cholesterol [[18]Lalić K. Rajković N. Popović L. et al.The effects of 3-year statin therapy and the achievement of LDL cholesterol target values in familial hypercholesterolemia patients: an experience from Serbia.Atherosclerosis. 2018; 277: 296-301Google Scholar,[20]Rizos C.V. Elisaf M.S. Skoumas I. et al.Characteristics and management of 1093 patients with clinical diagnosis of familial hypercholesterolemia in Greece: data from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH).Atherosclerosis. 2018; 277: 306-311Google Scholar,23van Delden X.M. Huijgen R. Wolmarans K.H. et al.LDL-cholesterol target achievement in patients with heterozygous familial hypercholesterolemia at Groote Schuur Hospital: minority at target despite large reductions in LDL-C.Atherosclerosis. 2018; 277: 325-331Google Scholar, 24Béliard S. Boccara F. Cariou B. et al.High burden of recurrent cardiovascular events in heterozygous familial hypercholesterolemia: the French Familial Hypercholesterolemia Registry.Atherosclerosis. 2018; 277: 332-338Google Scholar, 25Kayıkçıoğlu M. Tokgozoglu L. Dogan V. et al.What have we learned from Turkish familial hypercholesterolemia registries (A-HIT 1 and A-HIT 2)?.Atherosclerosis. 2018; 277: 339-344Google Scholar, 26Latkovskis G. Saripo V. Gilis D. Latvian registry of familial hypercholesterolemia: the first report of three-year results.Atherosclerosis. 2018; 277: 345-352Google Scholar,[49]Pang J. Marais D. Blom D.J. Heterozygous familial hypercholesterolaemia in specialist centres in South Africa, Australia and Brazil: importance of early detection and lifestyle advice.Atherosclerosis. 2018; 277: 468-474Google Scholar]. Smoking remains a major driver of CV risk across all continents [[25]Kayıkçıoğlu M. Tokgozoglu L. Dogan V. et al.What have we learned from Turkish familial hypercholesterolemia registries (A-HIT 1 and A-HIT 2)?.Atherosclerosis. 2018; 277: 339-344Google Scholar,[49]Pang J. Marais D. Blom D.J. Heterozygous familial hypercholesterolaemia in specialist centres in South Africa, Australia and Brazil: importance of early detection and lifestyle advice.Atherosclerosis. 2018; 277: 468-474Google Scholar], providing a major mandate for coronary prevention in FH. Diabetes and hypertension are also major priorities and the prevention of obesity a critical lifestyle objective in children with FH. The roles of Lp(a) [[50]Alonso R. Andres E. Mata N. et al.Lipoprotein (a) levels in Familial Hipercholesterolaemia: an important predictor for cardiovascular disease independent of the type of LDL-receptor mutation.J. Am. Coll. Cardiol. 2014; 63: 1982-1989Crossref PubMed Scopus (233) Google Scholar], cardiac imaging [[51]Sijbrands E.J. Nieman K. Budoff M.J. Cardiac computed tomography imaging in familial hypercholesterolemia: implications for therapy and clinical trials.Curr. Opin. Lipidol. 2015; 26: 586-592Crossref PubMed Scopus (17) Google Scholar] and genetic testing [[41]Sturm A.C. Knowles J.W. Gidding S.S. et al.Clinical genetic testing for familial hypercholesterolemia: JACC scientific expert panel.J. Am. Coll. Cardiol. 2018; 72: 662-680Crossref PubMed Scopus (252) Google Scholar] in risk prediction are increasingly being recognised, but were not specifically covered in this first cluster of country reports. Lp(a) evidently needs to be accounted for when making the phenotypic diagnosis of FH [[52]Langsted A. Kamstrup P.R. Benn M. et al.High lipoprotein(a) as a possible cause of clinical familial hypercholesterolaemia: a prospective cohort study.The Lancet Diabetes & Endocrinology. 2016; 4: 577-587Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar] and its complex with PCSK9 in plasma [[53]Afanasieva O.I. Ezhov M.V. Razova O.A. Apolipoprotein(a) phenotype determines the correlations of lipoprotein(a) and proprotein convertase subtilisin/kexin type 9 levels in patients with potential familial hypercholesterolemia.Atherosclerosis. 2018; 277: 475-480Google Scholar] could partly explain the reduction in Lp(a) with PCSK9 mAbs against background statin therapy [[54]Watts G.F. Chan D.C. Somaratne R. et al.Controlled study of the effect of proprotein convertase subtilisin-kexin type 9 inhibition with evolocumab on lipoprotein (a) particle kinetics.Eur. Heart J. 2018; 39: 2577-2585Crossref PubMed Scopus (89) Google Scholar]. Therapeutic targets and novel therapies for FH are well reviewed by Raal et al. [[55]Raal F.J. Hovingh G.K. Catapano A.L. Familial hypercholesterolemia treatments: guidelines and new therapies.Atherosclerosis. 2018; 277: 481-490Google Scholar]. Reaching LDL-targets remains a universal challenge in managing FH [[18]Lalić K. Rajković N. Popović L. et al.The effects of 3-year statin therapy and the achievement of LDL cholesterol target values in familial hypercholesterolemia patients: an experience from Serbia.Atherosclerosis. 2018; 277: 296-301Google Scholar,[20]Rizos C.V. Elisaf M.S. Skoumas I. et al.Characteristics and management of 1093 patients with clinical diagnosis of familial hypercholesterolemia in Greece: data from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH).Atherosclerosis. 2018; 277: 306-311Google Scholar,23van Delden X.M. Huijgen R. Wolmarans K.H. et al.LDL-cholesterol target achievement in patients with heterozygous familial hypercholesterolemia at Groote Schuur Hospital: minority at target despite large reductions in LDL-C.Atherosclerosis. 2018; 277: 325-331Google Scholar, 24Béliard S. Boccara F. Cariou B. et al.High burden of recurrent cardiovascular events in heterozygous familial hypercholesterolemia: the French Familial Hypercholesterolemia Registry.Atherosclerosis. 2018; 277: 332-338Google Scholar, 25Kayıkçıoğlu M. Tokgozoglu L. Dogan V. et al.What have we learned from Turkish familial hypercholesterolemia registries (A-HIT 1 and A-HIT 2)?.Atherosclerosis. 2018; 277: 339-344Google Scholar, 26Latkovskis G. Saripo V. Gilis D. Latvian registry of familial hypercholesterolemia: the first report of three-year results.Atherosclerosis. 2018; 277: 345-352Google Scholar,[49]Pang J. Marais D. Blom D.J. Heterozygous familial hypercholesterolaemia in specialist centres in South Africa, Australia and Brazil: importance of early detection and lifestyle advice.Atherosclerosis. 2018; 277: 468-474Google Scholar] and requires not only overcoming cost and access barriers to PCSK9 inhibitors, but also addressing the beliefs and perceptions of patients concerning medication [[56]Hagger M.S. Hardcastle S.J. Hu M. et al.Effects of medication, treatment, and behavioral beliefs on intentions to take medication in patients with familial hypercholesterolemia.Atherosclerosis. 2018; 277: 491-499Google Scholar]. Treatment gaps and related gender and ethnic disparities in the use of statins and attainment of treatment targets have also been underscored by data from the CASCADE-FH Registry in the US [[57]deGoma E.M. Ahmad Z.S. O'Brien E.C. et al.Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH registry.Circ. Cardiovasc. Genet. 2016; 9: 240-249Crossref PubMed Scopus (140) Google Scholar,[58]Amrock S.M. Duell P.B. Knickelbine T. et al.Health disparities among adult patients with a phenotypic diagnosis of familial hypercholesterolemia in the CASCADE-FH™ patient registry.Atherosclerosis. 2017; 267: 19-26Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. The ideal LDL-targets for FH patients may require revision in light of new clinical outcome trials with PCSK9 inhibitors. Current lipid management guidelines will need updating in 2019 [[55]Raal F.J. Hovingh G.K. Catapano A.L. Familial hypercholesterolemia treatments: guidelines and new therapies.Atherosclerosis. 2018; 277: 481-490Google Scholar,[59]Landmesser U. Chapman M.J. Stock J.K. et al.New prospects for PCSK9 inhibition?.Eur. Heart J. 2018; 39: 2600-2601Crossref PubMed Scopus (8) Google Scholar]. Dedicated clinical services for FH can evidently achieve better treatment outcomes in FH [[22]Vohnout B. Fábryová Ľ. Klabník A. et al.Treatment pattern of familial hypercholesterolemia in Slovakia: targets, treatment and obstacles in common practice.Atherosclerosis. 2018; 277: 321-324Google Scholar,25Kayıkçıoğlu M. Tokgozoglu L. Dogan V. et al.What have we learned from Turkish familial hypercholesterolemia registries (A-HIT 1 and A-HIT 2)?.Atherosclerosis. 2018; 277: 339-344Google Scholar, 26Latkovskis G. Saripo V. Gilis D. Latvian registry of familial hypercholesterolemia: the first report of three-year results.Atherosclerosis. 2018; 277: 345-352Google Scholar, 27Vrablik M. Raslová K. Vohnout B. et al.Real-life LDL-C treatment goals achievement in patients with heterozygous familial hypercholesterolemia in the Czech Republic and Slovakia: results of the PLANET registry.Atherosclerosis. 2018; 277: 353-359Google Scholar,[31]Groselj U. Kovac J. Sustar U. Universal screening for familial hypercholesterolemia in children: the Slovenian model and literature review.Atherosclerosis. 2018; 277: 382-390Google Scholar]. In low-to-middle income countries there is a major need to improve the care for severe FH [[33]Truong T.H. Kim N.T. Nguyen M.N.T. et al.Homozygous familial hypercholesterolaemia in Vietnam: case series, genetics and cascade testing of families.Atherosclerosis. 2018; 277: 391-397Google Scholar] and international advocacy for government funding for apheresis and new therapies is paramount. However, even in countries where apheresis is funded [[25]Kayıkçıoğlu M. Tokgozoglu L. Dogan V. et al.What have we learned from Turkish familial hypercholesterolemia registries (A-HIT 1 and A-HIT 2)?.Atherosclerosis. 2018; 277: 339-344Google Scholar], homozygous FH patients remain non-receptive to this form of therapy. This emphasizes the importance of improving physician training and expertise and addressing patient perceptions and beliefs about treatment [[56]Hagger M.S. Hardcastle S.J. Hu M. et al.Effects of medication, treatment, and behavioral beliefs on intentions to take medication in patients with familial hypercholesterolemia.Atherosclerosis. 2018; 277: 491-499Google Scholar]. The optimal management of FH in pregnancy needs further delineation, but preliminary data from a selected series in South Africa suggests that statins may be used safely from the third or fourth month of pregnancy [[60]Botha T.C. Pilcher G.J. Wolmarans K. et al.Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: a retrospective review of 39 pregnancies.Atherosclerosis. 2018; 277: 500-505Google Scholar]. Lipoprotein apheresis, however, remains a cornerstone of management of women with FH and coronary artery disease during pregnancy [[61]Stefanutti C. Julius U. Watts G.F. et al.Toward an international consensus—integrating lipoprotein apheresis and new lipid-lowering drugs.J. Clin. Lipidol. 2017; 11 (e853): 858-871Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar]. Models of care for FH should ideally be integrated across medical disciplines [[2]Watts G.F. Gidding S. Wierzbicki A.S. et al.Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.Int. J. Cardiol. 2014; 171: 309-325Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar]. International guidelines recommend that most patients should be managed in primary care [1Nordestgaard B. Chapman M. Humphries S. et al.Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease (Consensus Statement of the European Atherosclerosis Society).Eur. Heart J. 2013; 34: 3478-3490Crossref PubMed Scopus (1786) Google Scholar, 2Watts G.F. Gidding S. Wierzbicki A.S. et al.Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.Int. J. Cardiol. 2014; 171: 309-325Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 3Gidding S.S. Champagne M.A. de Ferranti S.D. et al.The agenda for familial hypercholesterolemia - a scientific statement from the American heart association.Circulation. 2015; : 132PubMed Google Scholar], noting that FH is a public health issue that accordingly needs addressing through several approaches to screening in the community [[34]Brett T. Qureshi N. Gidding S. Watts G.F. Screening for familial hypercholesterolaemia in primary care: time for general practice to play its part.Atherosclerosis. 2018; 277: 398-405Google Scholar]. While general practitioners, or family doctors, are ideally suited to detecting cases and caring for families with FH, their knowledge and practice remain suboptimal, but this can be partly remedied through dedicated vocational training and accreditation in FH [[62]Azraiia A.B. Ramlia A.S. Ismail Z. Knowledge, awareness and practice regarding familial hypercholesterolaemia among primary care physicians in Malaysia: the importance of professional training.Atherosclerosis. 2018; 277: 506-514Google Scholar]. Brett et al. [[34]Brett T. Qureshi N. Gidding S. Watts G.F. Screening for familial hypercholesterolaemia in primary care: time for general practice to play its part.Atherosclerosis. 2018; 277: 398-405Google Scholar] outline a comprehensive research agenda for primary care that encompasses several epidemiological, clinical (diagnostics, risk prediction, intervention trials), patient-centric and service design aspects of FH. This template can be adapted to set more general research priorities for the FHSC network. Patient support groups and networks are essential for advocating critical improvements across the continuum of care of FH [[2]Watts G.F. Gidding S. Wierzbicki A.S. et al.Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation.Int. J. Cardiol. 2014; 171: 309-325Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar,[30]Payne J. Williams S. Maxwell D. et al.Familial hypercholesterolaemia patient support groups and advocacy: a multinational perspective.Atherosclerosis. 2018; 277: 375-381Google Scholar]. Their value is well reviewed by an international consortium representing countries across Europe and North America [[30]Payne J. Williams S. Maxwell D. et al.Familial hypercholesterolaemia patient support groups and advocacy: a multinational perspective.Atherosclerosis. 2018; 277: 375-381Google Scholar]. The many achievements of these patient networks to date encompass government support for screening programmes, development of risk prediction tools, improvements in access to new therapies, support for patient registries, and recognition of a new ICD-10 code for FH. Registries are important not only to raise awareness of FH, but also to garner information necessary for clinical trials and audits, for education of registrants and healthcare professionals, and for health service research and policy making [[8]Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).Atherosclerosis. 2018; 277: 234-253Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar,[63]Mehta R. Martagon A.J. Galan Ramirez G.A. et al.The development of the Mexican familial hypercholesterolemia (FH) national registry.Atherosclerosis. 2018; 277: 515-521Google Scholar]. FH registries reported in this series are at different stages of development [[16]Miserez A.R. Martin F.J. Spirk D. DIAgnosis and management of familial hypercholesterolemia in a nationwide design (DIAMOND-FH): Prevalence in Switzerland, clinical characteristics and the diagnostic value of clinical scores.Atherosclerosis. 2018; 277: 280-286Google Scholar,[18]Lalić K. Rajković N. Popović L. et al.The effects of 3-year statin therapy and the achievement of LDL cholesterol target values in familial hypercholesterolemia patients: an experience from Serbia.Atherosclerosis. 2018; 277: 296-301Google Scholar,[20]Rizos C.V. Elisaf M.S. Skoumas I. et al.Characteristics and management of 1093 patients with clinical diagnosis of familial hypercholesterolemia in Greece: data from the Hellenic Familial Hypercholesterolemia Registry (HELLAS-FH).Atherosclerosis. 2018; 277: 306-311Google Scholar,[21]Schmidt N. Dressel A. Grammer T.B. et al.Lipid-modifying therapy and low-density lipoprotein cholesterol goal attainment in patients with familial hypercholesterolemia in Germany: the CaReHigh Registry.Atherosclerosis. 2018; 277: 312-320Google Scholar,24Béliard S. Boccara F. Cariou B. et al.High burden of recurrent cardiovascular events in heterozygous familial hypercholesterolemia: the French Familial Hypercholesterolemia Registry.Atherosclerosis. 2018; 277: 332-338Google Scholar, 25Kayıkçıoğlu M. Tokgozoglu L. Dogan V. et al.What have we learned from Turkish familial hypercholesterolemia registries (A-HIT 1 and A-HIT 2)?.Atherosclerosis. 2018; 277: 339-344Google Scholar, 26Latkovskis G. Saripo V. Gilis D. Latvian registry of familial hypercholesterolemia: the first report of three-year results.Atherosclerosis. 2018; 277: 345-352Google Scholar, 27Vrablik M. Raslová K. Vohnout B. et al.Real-life LDL-C treatment goals achievement in patients with heterozygous familial hypercholesterolemia in the Czech Republic and Slovakia: results of the PLANET registry.Atherosclerosis. 2018; 277: 353-359Google Scholar,[31]Groselj U. Kovac J. Sustar U. Universal screening for familial hypercholesterolemia in children: the Slovenian model and literature review.Atherosclerosis. 2018; 277: 382-390Google Scholar,[37]Casula M. Olmastroni E. Pirillo A. Catapano A.L. Evaluation of the performance of Dutch lipid clinic network score in an Italian FH population: the LIPIGEN study.Atherosclerosis. 2018; 277: 412-416Google Scholar,[39]Brunham L.R. Ruel I. Khoury E. et al.Familial hypercholesterolemia in Canada: initial results from the FH Canada national registry.Atherosclerosis. 2018; 277: 417-422Google Scholar,[64]Shek A. Alieva R. Kurbanov R. et al.Burden of familial heterozygous hypercholesterolemia in Uzbekistan: time is muscle.Atherosclerosis. 2018; 277: 522-527Google Scholar]. Through the FHSC there are abundant opportunities for enabling the development of fledgling registries. This could take the form of providing support and advice on registry governance, standardization of data elements, interoperability and expansion of platforms, with the ultimate aim of curating and analysing the highest quality big data required for maximising impact on the care of FH. Integration with other large international registries remains a future objective [[48]Pérez de Isla L. Alonso R. Mata N. et al.Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry.Circulation. 2017; 135: 2133-2144Crossref PubMed Scopus (204) Google Scholar,[57]deGoma E.M. Ahmad Z.S. O'Brien E.C. et al.Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH registry.Circ. Cardiovasc. Genet. 2016; 9: 240-249Crossref PubMed Scopus (140) Google Scholar,[65]Bellgard M.I. Walker C.E. Napier K.R. et al.Design of the familial hypercholesterolaemia Australasia network registry: creating opportunities for greater international collaboration.J. Atherosclerosis Thromb. 2017; 24: 1075-1084Crossref PubMed Scopus (26) Google Scholar]. While a laudable initial set of papers is presented from the constituent member countries of the FHSC [[8]Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC).Atherosclerosis. 2018; 277: 234-253Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar], selected gaps in information and desirable data for future communications should be identified. More registry data are required on the care of children with FH [[36]Martin A.C. Gidding S.S. Wiegman A. et al.Known and unknowns in the care of paediatric familial hypercholesterolaemia.J. Lipid Res. 2017; 58: 1765-1776Crossref PubMed Scopus (30) Google Scholar], such an initiative being currently spearheaded by Humphries, Wiegman and colleagues [[66]Ramaswami U. Cooper J. Humphries S.E. The UK paediatric familial hypercholesterolaemia register: preliminary data.Arch. Dis. Child. 2016; 102: 255-260Crossref PubMed Scopus (35) Google Scholar,[67]Wiegman A. Gidding S.S. Watts G.F. et al.Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment.Eur. Heart J. 2015; 36: 2425-2437Crossref PubMed Scopus (507) Google Scholar]. The population frequencies of FH need to be more systematically defined and communicated. This will require that the phenotypic diagnostic criteria for FH be both standardised and adjusted for specific countries. The less rigorous criteria adopted by some registries mean that many patients may not have 'true' FH [[68]Ellis K.L. Pang J. Chan D.C. et al.Familial combined hyperlipidemia and hyperlipoprotein (a) as phenotypic mimics of familial hypercholesterolemia: frequencies, associations and predictions.J. Clin. Lipidol. 2016; 10: 1329-1337Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. More information on methods of risk stratification and the specific roles of measuring Lp(a) and cardiovascular imaging would be welcomed from countries where these tests are feasible. Data on the frequency of statin intolerance in FH patients are highly relevant [[69]Rosenson R.S. Baker S. Banach M. et al.Optimizing cholesterol treatment in patients with muscle complaints.J. Am. Coll. Cardiol. 2017; 70: 1290-1301Crossref PubMed Scopus (130) Google Scholar]. Reports on patient-centric perceptions and the outcome of health economic evaluations of the models of care for FH from individual countries would in time be particularly apposite [[70]Norman R. Watts G.F. Weintraub W. et al.Challenges in the health economics of familial hypercholesterolemia.Curr. Opin. Lipidol. 2016; 27: 563-569Crossref PubMed Scopus (9) Google Scholar]. There were only a handful of papers on homozygous FH, but this is will be more extensively covered by communications from the HoFH International Clinical Collaboration (HICC) registry headed by Raal, Hovingh and Cuchel [[71]Hartgers M. Cuchel M. Hovingh G. et al.Clinical, demographic and genetic characteristics of homozygous familial hypercholesterolemia patients worldwide: interim results from the hofh international clinical collaborators (HICC) registry.Atherosclerosis. 2018; : 275Google Scholar]. Finally, global and country-specific models of care for FH will necessarily metamorphose as new evidence accrues from the scientific and clinical community of researchers. Beyond the curating of high quality big data, the FHSC is uniquely placed to set and expand a wider research agenda for FH [[3]Gidding S.S. Champagne M.A. de Ferranti S.D. et al.The agenda for familial hypercholesterolemia - a scientific statement from the American heart association.Circulation. 2015; : 132PubMed Google Scholar,[36]Martin A.C. Gidding S.S. Wiegman A. et al.Known and unknowns in the care of paediatric familial hypercholesterolaemia.J. Lipid Res. 2017; 58: 1765-1776Crossref PubMed Scopus (30) Google Scholar]. In meeting this challenge, the FHSC will effectuate a global paradigm shift in care, consistent with its mission of 'a call to arms' [[6]Vallejo-Vaz A.J. Kondapally Seshasai S.R. Cole D. et al.Familial hypercholesterolaemia: a global call to arms.Atherosclerosis. 2015; 243: 257-259Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar] against the worldwide burden of cardiovascular disease imposed by under-detected and under-treated FH. Professor Ray reports personal fees from Abbvie, grants and personal fees from Amgen, personal fees from Astra Zeneca, grants and personal fees from Sanofi, grants and personal fees from Regeneron, grants and personal fees from MSD, grants and personal fees from Pfizer, personal fees from Medco, personal fees from Resverlogix, personal fees from Akcea, personal fees from Boehringer Ingelheim, personal fees from Novo Nordisk, personal fees from Takeda, personal fees from Kowa, personal fees from Cerenis, personal fees from Cipla, personal fees from Algorithm, from Esperion, outside the submitted work. Professor Watts reports research grants from Amgen, Sanofi and Regeneron, and honoraria for advisory boards from Amgen, Sanofi, Regeneron, Gemphire and Kowa, outside the submitted work.
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