Integrated Guidance for Enhancing the Care of Familial Hypercholesterolaemia in Australia

Familial hypercholesterolaemia (FH) is a dominant and highly penetrant monogenic disorder present from birth that markedly elevates plasma low-density lipoprotein (LDL)-cholesterol concentration and, if untreated, leads to premature atherosclerosis and coronary artery disease (CAD). There are approximately 100,000 people with FH in Australia. However, an overwhelming majority of those affected remain undetected and inadequately treated, consistent with FH being a leading challenge for public health genomics. To further address the unmet need, we provide an updated guidance, pre-sented as a series of systematically collated recommendations, on the care of patients and families with FH. These recommendations have been informed by an exponential growth in published works and new evidence over the last 5 years and are compatible with a contemporary global call to action on FH. Recommendations are given on the detection, diagnosis, assessment and management of FH in adults and children. Recommendations are also made on genetic testing and risk noti ﬁ cation of biological relatives who should undergo cascade testing for FH. Guidance on management is based on the con-cepts of risk re-strati ﬁ cation, adherence to heart healthy lifestyles, treatment of non-cholesterol risk factors, and safe and appropriate use of LDL-cholesterol lowering therapies, including statins, ezetimibe, PCSK9 inhibitors and lipoprotein apheresis. Broad recommendations are also provided for the organisation and development of health care services. Recommendations on best practice need to be underpinned by good clinical judgment and shared decision making with patients and families. Models of care for FH need to be adapted to local and regional health care needs and available resources. A comprehensive and realistic implementation strategy, informed by further research, including assess-ments of cost-bene ﬁ t, will be required to ensure that this new guidance bene ﬁ ts all Australian families with or at risk of FH. these investigations assess progression of root, myocardial ischaemia, aim of guiding management, therapy

Indisputable evidence confirms the causal role of low-density lipoprotein (LDL) particles in the initiation and development of atherosclerotic cardiovascular disease (ASCVD) [1,2]. The classical feature of familial hypercholesterolaemia (FH) is a marked elevation in plasma LDL-cholesterol concentration from birth due to highly penetrant monogenic defects that impair the hepatic clearance of LDL-cholesterol via the LDL receptor [3,4]. FH is the most common co-dominantly inherited cause of premature ASCVD, principally coronary artery disease (CAD). Accordingly, FH is characterised clinically by a personal and family history of hypercholesterolaemia and early CAD [3]. The genetically mediated risk of ASCVD starts to increase from birth and extends over the lifespan. If untreated, the accumulated burden of LDL-cholesterol accelerates the onset of CAD in both men and women of every race and ethnicity [1,3]. The contemporary care of FH provides an exemplar of the value of precision medicine in the prevention of premature ASCVD in families [3][4][5].

Importance of FH: Tier 1 Genomic Application
Recent epidemiological studies indicate that the overall prevalence of FH in the general population may be as high as 1 in 250 [6][7][8]. This implies that currently there are approximately 100,000 Australians living with the condition, one in five of whom are children. The prevalence of FH is especially high among people with premature ASCVD [7,8]. The Centers for Disease Control and Prevention have appropriately defined FH as a tier 1 genomic application [5,9], meaning that there is strong evidence that it is a preventable cause of premature disease and death, with significant potential for positive impact on public health and health care savings [7,8,10]. FH is more prevalent than other tier 1 genomic applications, such as hereditary breast and ovarian cancer and Lynch syndrome (hereditary non-polyposis colorectal cancer) [5,9]. However, in spite of the importance of FH, less than 10% of individuals (particularly children and adolescents) have been detected, and of those treated, over 80% do not attain guideline recommended LDL-cholesterol targets [3,5]. Targeting the detection of FH as a priority in children and the young could have the greatest impact on the prevention of ASCVD [11][12][13].

Guidelines, Position Statements and Models of Care on FH
The wide gaps in the care of FH have led to the publication of several international guidelines and position statements [11,[14][15][16][17][18][19]. The FH Australasia Network published one of the first models of care for FH in 2011 [17]. This model was conceived as an adaptive and integrated system, based on theoretical and evidence-based standards, providing the highest quality of health care services to patients and families with FH [17]. Such a framework allows the incorporation of evolving evidence to inform new standards of care, which form the basis for the present guidance. Our original model of care for FH [17] was significant in informing several international guidelines on FH [11,12]. It was updated by an international group of experts [18] and informed a scientific statement from the American Heart Association [11]. The 2014 integrated guidance [18] was assessed using the Appraisal of Guidelines for Research & Evaluation Instrument (AGREE-II) criteria by an independent group of international investigators and ranked as the leading contemporary guidance on FH [20].

Exponential Growth of Knowledge on FH: Review of Evidence
Since publication of the aforementioned guidelines, there has been an exponential growth in published works on several aspects of FH [3]. This includes the following: new knowledge on population prevalence [6][7][8]; screening methods [3,5,13,21] including use of non-fasting samples [22]; the role of primary care in detection and treatment [23]; new diagnostic gene technologies and genetic testing protocols [24]; methods for risk re-stratification, including estimation of lipoprotein(a) [25][26][27][28] and non-invasive cardiovascular imaging [3,29,30]; screening and treatment of children [12,31,32]; the safety and tolerability of statins [33,34]; the efficacy and application of new therapies (eg. PCSK9 inhibitors); management of homozygous FH including use of lipoprotein apheresis [35][36][37]; comprehensive health economic evaluations [38,39]; organisation of services [3], clinical registries [40][41][42]; role of advocacy and patient support groups [43]; and, definitions of research programs [3,11,44]. This evolving knowledge was reviewed systematically by representatives of the Writing Committee of this guidance in collaboration with international experts in the field in a period up to September 2019. As a consequence, two reviews have been published [3,5] which summarise the essential evidence which has enabled the development of the new recommendations on FH (see Tables 1-9; Appendices A and B; Supplementary Material: Tables 1-9; evidence for statements listed and referenced [ ). Additional relevant studies published in 2020 were also employed to support guidance statements. Beyond specific guidelines on FH [11,[14][15][16][17][18][19], our recommendations have also been based Integrated Guidance for Enhancing the Care of FH in Australia on new international guidelines for the primary and secondary prevention of ASCVD [49][50][51][52], as well as on metaanalyses and systematic reviews on the role of LDLcholesterol in the inception and development of ASCVD [2,53]. We acknowledge that several novel therapies are in development for managing FH [54][55][56][57][58]. However, with the exception of an angiopoietin-like protein 3 inhibitor for homozygous FH [58], none have been referred to in our recommendations. This is because these agents are still being tested in clinical trials and are not registered in Australia.

National Health Genomics Policy Framework
As reviewed elsewhere, the recommendations of the National Health Genomics Policy Framework [59] have also informed the recommendations for this new model of care for FH. Priority areas include patient-centred approaches, upskilling of the workforce in knowledge of genomics, costeffective use and evidence-based design of services, and the need for high-quality data collection [59]. Our new recommendations are aligned with the aforementioned priorities. They will accordingly enhance the strategic approach for incorporating genomics into the Australian health care system, as also exemplified by other inherited heart conditions [60]. Genetic testing for FH was listed on the Australian Medicare Benefits Schedule (MBS) in 2020 [61], based on recommendations by the national Medical Services Advisory Committee [62] that were informed by robust costeffectiveness data collated from an Australian specialist centre [38]. The present guidance includes specific

Methodology for Evidence-Based Recommendations
The quality of the new and diverse evidence in the literature was evaluated systematically by the assigned Writing Committee according to recommended protocols [45][46][47][48]. The totality of evidence was in turn systematically employed to inform specific recommendations on the individual components of the model of care of FH, accounting for preferences, values, circumstances and contexts where appropriate [63][64][65]. The process and basis for the grading of the evidence and recommendations are detailed in Appendices A and B [45][46][47][48]. Particular attention was given to include contributions from a wide spectrum of disciplines, consistent with a multi-disciplinary approach, with health consumers accounting for patient values and preferences [65,66]. The totality of published works employed to develop the evidenceinformed statements and recommendations are given in the Supplementary Material (Tables 1-9, statements' evidence references 1-332). It should be emphasised that the evidence for therapeutic interventions in FH was considered principally in respect of the effects on plasma LDL-cholesterol concentration, but where available, was also based on data on subclinical atherosclerosis and atherosclerotic cardiovascular outcomes [17,18]. As in previous publications [17,18], we considered that the absence of randomised controlled trials in FH should not diminish a strong recommendation for an intervention,  [65], we attempted to make our guidance statements as practicable and implementable as possible.

Spectrum of Classes of Recommendations and Levels of Evidence
We provide 140 statements in this new guidance on the care of FH; 80 more than in our earlier work on FH [17]. Of the total number of recommendations, 65.0% were classified as strong (class 1), 16.4% as moderate (class 2) and 18.6% as weak (class 3) (see Appendix C). Of overall evidence levels, 25.0% were high (level A), 43.6% were moderate (level B) and 31.4% were low (level C) (see Appendix C). High and moderate recommendations were generally supported by high and moderate levels of evidence (see Appendix C). The levels of evidence for this guidance are compatible with and surpass many other Australian clinical practice guidelines [65]. The evidence-poor components clearly demonstrate that many decisions in the care of FH patients need to be made with minimal or lower quality evidence and that further research may be required [3,11,44]. Compatible with the GRADE system [47], any apparent discordance between level of evidence and class of a recommendation reflected the perceived balance of benefits versus risks or harm by following the recommendation, as assessed by members of the Steering and Writing Committees (Appendices A and B). It also reflected that for certain statements further research was considered unlikely to change the class of recommendation [47]. Beyond the published works  3.6 Children and adolescents with heterozygous FH should ideally be reviewed by a paediatric specialist with expertise in lipidology and access to multi-disciplinary services 1 C 3.7 Genetic testing for FH should generally be offered to diagnose children after a pathogenic or likely pathogenic gene variant has been identified in a parent or first-degree relative (see 4.3 for genetic testing of children as index cases; see Table 5 for cascade testing and counselling)

The Real Challenge: Translation and Implementation of Models of Care
The updating of guidelines and models of care are well aligned with international calls to action on FH [10,68]. These have emphasised the need to enhance awareness, advocacy, screening, testing, diagnosis and treatment of FH, thereby solidifying and extending the 1999 WHO recommendations [69]. The critical challenge that remains is translating the recommendations in this new guidance into health policy and routine high-quality care for all individuals in the population [70][71][72]. Implementation science affords a unique opportunity for translating recommendations into routine practice to achieve maximal benefit for the population [71,73]. To optimise the care of FH within the contexts of the complex Australian health care system and advances in genomic medicine [59,74], an implementation strategy needs to account for the perspectives and needs of all patients, families, health care providers, stakeholder organisations, health policy makers and the broader community [70,75]. To have impact, implementation research is essential for improving the outcomes of FH patients over their lifespan [3,10,70]. Implementation has to be missiondriven to fully address the gaps between efficacious and delivered care [71]. This methodology must be embraced and adopted routinely to increase the impact of the new recommendations on improving the care of FH as a national health priority [10,70,75].     which may require addition of a PCSK9 inhibitor to a statin and ezetimibe, as well as the use of lipoprotein apheresis (see Table 8
DRS has received grants from Regeneron, Amgen, Astra-Zeneca, Amarin, Esperion, and Novartis, as well as personal fees from Amgen and Sanofi.
DAB has received honoraria from Amgen, Nestle and Sanofi. TB has received grants and honoraria from Amgen and Sanofi.
CKC has participated either as a participant or speaker in educational meetings sponsored by pharmaceutical companies that make lipid-lowering therapies.

Funding Sources
No funding from the pharmaceutical industry or other industry groups was obtained to support the development of this guidance on FH. ACM was supported by a Raine Clinician Research Fellowship. JP was supported by a Western Australian Health Translation Network (WAHTN) Early Career Fellowship and the Australian Government's Medical Research Future Fund.

Endorsements
This guidance has been endorsed by the Australian Atherosclerosis Society, Cardiac Society of Australia and New Zealand, National Heart Foundation (Australia), Australian Cardiovascular Alliance, Human Genetics Society of Australasia, European Atherosclerosis Society, International Atherosclerosis Society, FH Foundation, Heart UK, Asian-Pacific Society of Atherosclerosis and Vascular Disease, National Lipid Association (US) and the American Society of Preventive Cardiology.

Selection of Committees and Contributors
The Steering and Writing Committees were selected by board members of the Registry of FH Australasia Network (Australian Atherosclerosis Society, AAS) for having expertise in lipidology, cardiology, pathology, genetics, dietetics, endocrinology, general practice and paediatrics. Contributors were selected from a wide spectrum of medical and allied health specialties, including general practice, general internal medicine, genomic medicine, nursing, pharmacy practice, and health consumers from advocacy groups to account for variability in patient values and preferences; researchers with relevant expertise in genetics, implementation science, health economics and FH also contributed to the document.

Evidence Review
The Steering Committee decided collectively that the structure of and approach to this guidance should be based on a previous guidance on FH that had received a top ranking by an independent group employing the Appraisal of Guidelines for Research & Evaluation Instrument (AGREE-II) assessment criteria [20]. The evidence for the development of this new guidance was based on two peer-assessed reviews of FH [3,5], that were co-authored by members of the steering committee, as well as on additional published works. For the review papers, a literature search of the English language was undertaken between January 2014 and September 2019. The search employed the PubMed database with search string (all fields) "familial hypercholesterolemia" or "familial hypercholesterolaemia". GFW and JP assessed the titles and abstracts of all the articles identified and selected those that were most novel and valuable for informing the components of the model of care for FH. Additional published works were searched for using the above search terms in 2020 to generate relevant publications, which were also provided ad hoc by the Writing Committee and by individual contributors up to 31 May 2020.
To update the guidance, the Writing Committee employed these publications, as well as specialist clinical experience and expert opinion. The published works which informed the evidence and recommendations are shown in the Supplementary Material (Tables 1-9; 332 references). The first draft of the guidance statements was produced by GFW and JP. Four core workshops chaired by GFW were held by video conference between December 2019 and January 2020. The fourth workshop focussed exclusively on paediatric aspects of FH. The workshops include all members of the Steering Committee and members of the Writing Committee that covered the essential sub-specialties. The agenda focussed on discussion of the evidence and statement development, and consolidated the statements for each of the recommendations, which were designated both a Class of Recommendation and a Level of Evidence according to the protocol in Appendix B. (see Supplementary Material for references to the evidence supporting the statements). The totality of the evidence was assessed to inform the recommendations.

Document Review and Approval
The majority view (.80%) was employed to reach a consensus on the Class of Recommendation and Level of Evidence on the earlier drafts of the guidance. The statements were reviewed and edited by smaller sub-specialty working groups (specifically in genetic testing, cascade testing, risk notification, cardiovascular imaging, general practice and primary care). These discussions were arranged by the chair via telephone or email communication. All revised statements were subsequently circulated to all contributors for comment. Specific queries and disagreements with statements were resolved via telephone or email discussion with GFW, who then reached full agreement, via email and/or videoconference, with members of the Steering and the Writing Committees, as indicated by specialty. The writing committee examined the pre-final draft of the guidance and reached full consensus on the recommendations and wording of statements. All contributors reviewed and commented on evolving drafts of the document and approved the final version before submission.

Endorsements
Prior to publication, the full FH guidance with Supplementary Material was reviewed for endorsement by assigned members of the Cardiac Society of Australia and New Zealand (CSANZ), National Heart Foundation (Australia), Australian Cardiovascular Alliance, Human Genetics Society of Australasia, European Atherosclerosis Society, International Atherosclerosis Society, FH Foundation, Heart UK, Asian-Pacific Society of Atherosclerosis and Vascular Disease, National Lipid Association (US) and the American Society of Preventive Cardiology.   and Heart UK (https://www.heartuk.org.uk/genetic-conditions/secondary-hyperlipidaemia) websites.