Definition/impact
Familial hypercholesterolaemia (FH) is a disorder that causes severe elevation in plasma cholesterol and a high risk of premature coronary artery disease. Heterozygous FH (heFH) occurs in approximately 1 in 500 people, affects all race/ethnic groups, and leads to a greater than 50% chance of coronary heart disease by the age of 50 years in men and at least 30% in women by the age of 60 years. Homozygous FH (hoFH) occurs in approximately 1 in a million individuals, and is characterised by greater disease severity, with early death from coronary heart disease.1
Demographics
Our knowledge of the geographical distribution and epidemiology of hoFH and heFH is largely incomplete. Founder populations, or those with higher levels of consanguinity, exhibit a high prevalence of the condition.1 The quality and coverage of data necessary for optimally designing health systems to cater for specific sectors of society are, however, not yet available. The need for more epidemiological evidence is particularly high in countries such as Australia, where the urban and rural healthcare systems differ and where the geographical distribution of FH-carrying family pedigrees is yet to be mapped.
Diagnosis
Early interventions can reduce the incidence of coronary artery disease in FH.2 In Australia, less than 20% of cases of FH have been identified and those diagnosed remain inadequately treated.3 The use of cascade screening has proven effective,4 but is yet to be consistently and nationally coordinated and supported.5 A systematic approach to collecting health economic and clinical data from existing cascade screening and awareness programmes would enhance the planning, coordination and support for both current and future services.3
Genetic typing
The genetic basis of FH has been mapped to more than 1700 mutations, where low-density lipoprotein (LDL) receptor function ranges from completely absent to approximately 25% of normal receptor activity.6,7,8 Mutations in ApoB and proprotein convertase subtilisin/kexin type 9 (PCSK9) are less frequent causes of autosomal dominant hypercholesterolaemia. Diagnostic laboratories typically undertake DNA testing in the absence of coordinated, integrated information-based registries. Registry reporting of genetic typing would ensure access to an overview of genetic data and contribute to overarching efforts of clinical networks to develop and promulgate best practice.
Therapy
Clinical management predominately involves early prescription of statin therapies with or without ezetimibe to lower the plasma LDL-C level.9 However, in FH even high-potency statins with other agents do not allow attainment of recommended treatment targets for plasma LDL-C concentration. Statins can also have dose-dependent side effects, most notably skeletal muscle symptoms. Currently, other therapeutics for FH comprise fibrates and bile acid sequestrants (resins).9 An MTP inhibitor (lomitapide/Juxtapid, Aegerion Pharmaceuticals, Cambridge, MA, USA) and an oligonucleotide developed against Apo-B 100 mRNA (mipomersen) are also approved for hoFH.10 Mipomersen (marketed as Kynamro by Genzyme, Cambridge, MA, USA) is the first systemic oligonucleotide inhibitor to reach the market for hoFH.11 The safety and effectiveness of Kynamro and Juxtapid have not been established in patients with hypercholesterolaemia who do not have hoFH, and the effects of these two drugs on cardiovascular morbidity and mortality has not been determined. The development of other classes of therapeutic drugs (monoclonal antibodies and anti-sense oligonucleotides, small interfering RNAs, and inhibitory adnectins) that target the inhibition of PCSK9 is also under development and may become available. Overall, the efficacy and safety of most of these novel therapies have not been tested and clinical trials are needed. The pathways in healthcare that enable clinical trials for FH are poorly defined, necessitating better engagement and coordinated actions between relevant stakeholders.
Registry objectives
In a previous article, we reviewed the evidence supporting the treatment, models of care and health economics of FH.12 Registries can enhance the healthcare of FH and other conditions,13,14,15,16,17 particularly where there are evidence gaps for informing improvements. The World Health Organization definition of 'patient registry' is 'a file of documents containing uniform information about individual persons, collected in a systematic and comprehensive way, in order to serve a pre-determined scientific, clinical or policy purpose'.18 In the case of an FH registry, the population should include both affected and unaffected relatives of the index case so that the impact of cascade screening programmes can be captured, and to enable recruitment of cases and controls for observational studies.
Patient registries can be key instruments for clinical research and improving healthcare planning and patient care. The Simon Broome Register is an observational cohort that has been in operation in Britain since 1980 and has recruited, from 21 lipid clinics, over 3382 individuals with heFH. The outputs from this registry have allowed analyses of the natural history, evidence for treatment and provided data for health economic evaluations.19,20,21,22,23 The registry of the Medical Genetics Laboratory at Oslo University Hospital contains more than 4400 patients with a molecular genetic diagnosis of FH, and has been successfully used to examine pregnancy outcomes.24
Recognition of the need to improve outcomes for Australasians with FH has driven the establishment of an Australian and New Zealand Registry for Familial Hypercholesterolaemia (ANZRFH). The ANZRFH is intended to provide supporting infrastructure in four key areas: (i) address a current gap in the flow of data for measuring the quality of healthcare; (ii) support basic research through provision of high-quality, de-identified aggregate data; (iii) enable geographically equitable access to clinical trials; and (iv) promulgate information about best practice and care services, particularly as we enter the era of precision medicine.
In contrast to registries intended primarily for descriptive or social networking purposes, the ANZRFH design requires a high level of rigour to effectively address focused and specific analytical questions. The registry aims are the primary consideration for designing data collection, data elements, natural history studies, data security, organisation and governance, custodianship, ethics and privacy policy, information output and resource and funding.
Data for the ANZRFH will be collected across multiple sites, mostly from specialist lipid clinics and from laboratories that report genetic results. Innovations in web-based platforms allow for the ANZRFH to be highly interactive and accessible in geographically disparate locations, with multiple-level, private access for a range of user groups. Additional sites may be added to the registry to increase the coverage of the FH population, with user groups being assigned appropriate upload and access privileges. In this way, large general practice clinics with the local resources to upload and maintain the currency of their patient data may also participate in the Registry, irrespective of their geographical location. Given that each general practitioner (GP) on average will see no more than one or two cases of FH per year, GP entries will be exceptional and the ANZRFH will be centrally coordinated, in a manner consistent with approaches to cascade screening.
The choice of the minimum common data collection for the ANZRFH has been guided by clinical and laboratory experts, validity of data and a focus on identifying key indicators of quality of care. Table 1 provides a list of the common data items identified for inclusion in the ANZRFH. Engagement with other registries and clinical groups, both within Australia and globally, continues to be a key to ensuring harmonisation of the data elements and the pathways for their collection. The registry framework16 allows suitable customisation for modifying of these elements or addition of new data modules.
The ANZRFH enables different user groups, such as clinical and genetic service providers, to have their own secure access to the same system, irrespective of site location. User access is controlled by a password and can be tailored to allow specific and targeted rights to be assigned to individuals or groups. Access to extracts of de-identified aggregate data by research investigators or any other third party, including other registries, will be controlled through the advisory board, human research ethics committees and the data custodian, as illustrated in Figure 1.
The organisation and governance of the ANZRFH are being developed to meet the Australian government and international standards for data collection. Specifically, an Advisory Board, comprised of representatives of the FH clinical networks, patient advocacy and laboratory experts, has been convened.
Ethics
While the ANZRFH meets the standards and intent of a quality registry,25 it will also provide de-identified data and the opportunity for patients to volunteer for clinical trials. Registrants may also elect to receive information about advances in best practice and care services. For these reasons, a voluntary recruitment process, which seeks informed and prospective permission for the aforementioned options for participation, along with a description of the potential benefits and risks of signing up to these options, is being developed26 and will explicitly include the opportunity to collect genotyping data. Subsequent audit of recruitment will be included in the annual reports and will reveal the level of success of this approach and whether registrants elect to provide selective consent, for example, give permission to collect and use genotyping data and be contacted about advances in treatments, but not give permission about eligibility for clinical trials.
Information outputs
The ANZRFH will extract longitudinal clinical data intended to inform our understanding of the unmet needs in the care of FH. Accordingly, the ANZRFH will report on the long-term effects of treatments on patient outcomes that cannot be gauged from shorter duration clinical trials. The data will inform regional prevalence of FH, and will be used to measure the effectiveness of cascade screening. Furthermore, the ANZRFH will help develop precision medicine by providing an easy overview of the genetic variants associated with the manifestation of disease. Specifically, the genetic data can be used to identify eligibility for clinical trials for all classes of therapeutic drugs launched against molecular targets. The identity of potential volunteers will be communicated to the treating clinician for discussions with the registrant and their family. Only the clinicians from the ANZRFH will have access to the registrant.
Resources/funds
The potential resources and funds of existing registries are variable. Some disease registries are developed by specific research groups to serve a narrow research purpose, and are reliant on the resources and funds of the research centres for sustainability. Other registries may be developed and supported by patient advocacy groups, whereas others are owned and funded by the pharmaceutical industry. In Australia, clinical quality registries recognised as providing high-priority comparative clinical performance data may receive government funding through the Australian Commission on Safety and Quality in Healthcare. The ANZRFH is being developed collaboratively by partners across government, clinical networks and patient advocacy groups. There are no costs to registrants and there are no restrictions on the ANZRFH seeking additional funding to support all or parts of the stated aims. Sustainability is vital to ensuring that the ANZRFH achieves cumulative successes: potential sources of funding that have so far been identified include those arising from partnership enterprises across public, private and industry sectors.
Registry evaluation
The Australian Commission on Safety and Quality in Healthcare provides operating principles and technical standards for Australian Clinical Quality Registries. The purpose of these guidelines is to enhance the value of information from existing registries, assist establishment and maintenance of registries for measuring quality and suggest a best practice model for registries. The ANZRFH is designed to meet all of these operating principles and recommendations. The most accurate measure of success for any registry would be the degree to which that registry delivers on its stated objectives. The goals of the ANZRFH are summarised in Table 2, together with a proposed set of key performance indicators. It is notable that, in an era of website hits and social media such as Twitter, the circulation of information by and about the Registry may be amplified and measured. A responsibility of the Advisory Board will be to review these indicators and provide commentary on the performance in the ANZRFH.
The success of the ANZRFH in fulfilling its goals should be reported annually. The Advisory Board plays an important role in effectively managing the output of the registry, thereby ensuring its success. Investments in other registries have been demonstrated to be cost-effective for the health services.27,28 Accordingly, several expert groups, including the American Heart Association, have called for the expansion of their clinical registry programmes.29
Current and future trends in registries
To date, there are few national FH registries in only a few European countries, such as The Netherlands, Spain and the United Kingdom. Other national registries will soon be operational such as the United States and Canada. However, there are no global FH registries and inter-operability between existing FH registries remains challenging. Software packages are commercially available for clinical management and cascade screening, and some patient registries have been established. However, these efforts are fragmented and inaccessible to many FH stakeholders. Key areas for the effective implementation of a value-based approach to healthcare are clinician engagement, national infrastructure, high-quality data and outcome-based incentives.28 More should be done across all of these areas to coordinate and harmonise the collection and use of evidence on FH.
The impact of any registry is enhanced through strong networking between research centres, clinical services, other registries and health data systems. For example, the ANZRFH could provide de-identified aggregate data to the Australian National Genetic Heart Disease Registry.30 A federated style of registry development, which allows for optimal interaction across different registries, is being undertaken by the RD-CONNECT consortium (http://www.rd-connect.eu/). This international consortium is combining resources to construct a web-based platform that will enable networking with multiple rare disease registries through exchange of information contained in common data elements, common use of unique patient identifiers, harmonised ethical frameworks and patient consent forms, links with biobanks, and research that includes clinical trials. One of the enabling features of the RD-CONNECT registry platform is the use of open-source web-based solutions for enabling greater inter-operability between data collections. In this respect, the use of open-source technology to build the ANZRFH embraces the growing paradigm shift away from using commercial, proprietary-protected software. The ANZRFH will be fully inter-operable with RD-CONNECT.
The advisory board of the ANZRFH is now actively seeking additional partners to further explore the opportunities to harmonise and combine efforts that enhance the care of FH. Ongoing engagement with other FH-specific registries, local support groups, the International FH Foundations, the FH Foundation USA, clinical networks and healthcare providers has been very promising.
Conclusions
FH registries are being designed to coordinate the collection of evidence for enhancing healthcare, including improving diagnostics and therapeutics. The success of registries in achieving these goals is influenced by their inter-operability with other registries and their connectivity with clinical networks, healthcare services, researchers, patient advocacy groups and other data repositories. Converging technologies and innovations in bioinformatics, targeted policy directives and improved clinical networking in FH are combining to create the necessary conditions for the establishment of such high-impact registries. The development of the ANZFHR is only one example, among several, of FH registries under construction around the world. If a global network of interoperable, interconnected national registries for FH is achieved, it promises to significantly contribute towards the evidence-based enhancement in the worldwide care of FH.
References