Evaluating protocols for identifying and managing patients with FH

Familial Hypercholesterolaemia (FH) is a common inherited cause of raised cholesterol, affecting up to 320,000 people in the UK. However, over 80% of individuals are not identified, leading to many avoidable heart attacks and early deaths. Use of cholesterol lowering medication can prevent over half of these premature heart attacks.

National (NICE) guidelines recommend general practitioners (GPs) identify people with possible FH by using cholesterol levels, family information and physical examination. If FH seems likely, the GP should refer patients to a specialist to confirm diagnosis, usually by genetic testing. If FH is confirmed, treatment should be given and their relatives contacted for genetic testing – known as “cascade” testing.

Implementation of NICE recommendations for cascade testing FH has been very limited to date. Existing cost-effectiveness analyses of FH identification protocols (UK and internationally) have focused on whether or not specific protocols for cascading are cost-effective. Commissioners and policy makers are uncertain about whether current designs for cascading programmes represent the best value for money. In particular, they have questioned whether tighter criteria for cascading could offer better value for money, and whether current service designs offer value for money in terms of maximising the number of relatives tested. This reflects recognition amongst commissioners and policymakers that previous cost-effectiveness results were subject to significant limitations and evidential uncertainties. Department of Health, through NICE, recognised this gap leading to a scoping review by the NIHR Health Technology Assessment (HTA). As a result NIHR HTA commissioned this current NIHR project to address these limitations by comparing a wide range of protocols for cascade testing and addressing a wide range of evidential uncertainties and develop economic models to evaluate the cost-effectiveness of cascade testing in the NHS with the aim of informing the implementation of the most cost-effective and acceptable protocol of care for these patients. This project relies on using existing cohorts and registries, routine NHS data and secondary care service data to inform the parameterisation and structure of the models.

The study team propose in this programme of research to evaluate treatment patterns and short- and long-term cardiovascular outcomes and the NHS costs of patients with FH. The outputs of this linkage request will result in providing the most accurate and up-to-date outcome of FH patients to date. Data on cases managed in primary and secondary care will be linked to data on treatment patterns and cholesterol response. This will provide a rich and accurate source of information to parameterise and inform the structure of the short and long-term economic models, the main deliverable within the HTA programme of work. In order to do this, the study requires Hospital Episode Statistics Accident & Emergency, Hospital Episode Statistics Outpatients, Hospital Episode Statistics Admitted Patient Care. The study has requested multiple years of data to make sure it can model the full life-course of an FH patient, to include both their outcomes across follow-up and health care utilisation. Only then, can the study address all the current gaps in the evidence and capture all events in secondary care as well as conduct economic costing on a patient's health care utilisation over an extended period of time. This means this source of data will be essential in developing the most robust economic model outcomes to inform commissioners and policy-makers on the impacts of various cascade screening strategies as accurately as possible.

Below are all the stakeholders that are involved with the project, with detail as to their activities for the purpose of this project. There is no work in this programme of research taking place outside the UK. All processing activities are within bona-fide UK academic institutions which abide by the highest levels of Data Protection laws and Information Governance rules. No data or specific tools/analysis involving usage of data will be shared with any third parties. Only publication output on the aggregate results of the analysis will be widely disseminated in peer-reviewed journals, conferences, reports, and official HTA monograph.

University of Nottingham: This is the lead organisation submitting the application and carrying out the research. Their role is as a Data Controller given the remit and aims of the project and as a Data Processor as they will receive the pseudonymised dataset from UCL and will conduct the analysis from the linked data (Simon-Broome Registry to HES).

University of York: This is a collaborating institution carrying out the research. Their role is as a data controller given their involvement in the aims and remit of the project and as a Data Processor as they will receive the pseudonymised dataset from UCL and will conduct the analysis from the linked data (Simon-Broome to HES).

UCL: This is a collaborating institution. They are the data guardian and Data Controller for the consented Simon-Broome registry dataset. They will submit the patient identifiers to NHS Digital for linkage of the Simon-Broome to requested HES datasets and receive the pseudonymised linked dataset from NHS digital.

HeartUK: This is a charity involved in promoting the Simon-Broome registry database and follow-up studies using the cohort. The steering group at HeartUK oversees and approves access to use the Simon-Broome registry for research in the public interest. They are not a Data Controller or Data Processor as they will not process, control, or store any of the data and not involved with the aims the research. It provides the forum (I.e. meeting space in London) for hosting the Simon Broome steering group (members are UK academics).

BHF: The British Heart Foundation support patient involvement and will support dissemination of the aggregated results and publications. They are not a Data Controller or Data Processor. They will only see aggregated data with small numbers suppressed (in line with the HES Analysis Guide) in the final report once published, and any publications and dissemination via conference presentations, posters, etc.

Data Flow Process

The Simon-Broome register is a register of consenting patients held at University College London (UCL) within their data safe-haven. UCL is the Data Controller for the Simon-Broome Registry. The original Simon-Broome data set includes identifiable variables which will be provided to NHS Digital by UCL for linkage to HES - forename, surname, date of birth, NHS number, postcode, unique study identifier. Gender will also be provided for analysis, and ethnicity is permitted on the same basis. This process is in line with the other current study which includes ongoing linkage of the Simon-Broome data set to Civil Registrations (Deaths) data (NIC 300282), though there will be no linkage between the data released under the different agreements. NHS Digital will then conduct the linkages to the HES datasets (Admitted Patient Care, Accident and Emergency, Outpatients) and return the linked pseudonymised data to UCL removing all the identifiable variables in the Simon-Broome dataset of forename, surname, date of birth, NHS number, postcode and gender. UCL will store the dataset in their safe-haven.

As the cohort is already flagged by NHS Digital for NIC 300282, there will be no new flow of identifiers for this agreement.

Linkage of the HES data to any other dataset, including data released under a different agreement, is not required or permitted under this agreement.

UCL will send a copy of the pseudonymised dataset to the Universities of Nottingham and York, as per the approved secure data transfer protocol specified in the CAG support, ethics approval and HTA protocol.

Data access

All HTA research team members involved with accessing, processing, and analysis of the data are directly employed staff members by their respective institutions (University of Nottingham, University of York, and University College London). There is no data access or processing activities occurring outside of the UK.

All organisations party to this agreement must comply with the Data Sharing Framework Contract requirements, including those regarding the use (and purposes of that use) by “Personnel” (as defined within the Data Sharing Framework Contract i.e.: employees, agents and contractors of the Data Recipient who may have access to that data).

Outputs of the research

The main result (outputs) will be the parametric survival regressions for economic modelling and the cost of hospitalisations. Whilst individual patient level data is required to assist with populating the model, the data used in the modelling is not identifiable as. The data will be used to generate predictions of the proportion of individuals experiencing relevant clinical events over time within the economic model and their costs. This will allow estimates of lifetime costs and QALYs to be generated by the model. The models, along with a full representation of their uncertainty (derived using the variance-covariance matrix for each event) will be incorporated within the model. Outputs will contain only aggregate level data with small numbers suppressed in line with HES analysis guide.

As well as completing NIHR HTA monograph (expected publication date in 2021), standard dissemination strategies, of peer-reviewed open access primary care, public health, cardiovascular and genetic publications and conference presentations, will be further prioritised. The project will target submitting its work high impact medical journals such as the British Medical Journal, European Heart Journal, Heart, Atherosclerosis, Circulation, or JAMA (the Journal of the American Medical Association) in 2020. No personal data will be used in the write-up or publication of results. Descriptive statistics will only be at the aggregate level with small numbers suppressed in line with HES analysis guide.

Target audience of outputs

The audience of the research outputs are patients, the public, charity groups, policymakers at the Department of Health, Public Health England, NICE. These outputs (publications, reports, monographs) will be made open access (freely available) to all audience members at the end of the study (likely to be 2021). No outputs will be used for any commercial purposes.

The project will ensure that findings are highlighted to the public, patients, and policymakers (NHS, Department of Health, Public Health England and NICE) in partnership with third sector voluntary organisations (Heart UK and British Heart Foundation - BHF). The project has bi-annual meetings with HEART UK and BHF to keep them updated on the study progress and any new potential findings, and having early conversations with Department of Health and Public Health England on a dissemination strategy. This will likely involve a published NIHR Signal in 2021. In the UK, the data controllers are active current contributors to NICE guidelines for FH and will ensure the outputs of this cost-effectiveness analysis inform updated NICE guideline recommendations and quality standards.

The project will also work with the International FH foundation, US CDC Office of Public Health Genomics and European collaborators, and international advisers in Australia, USA and Europe to ensure the analysis informs international guidelines recognising potential differences between international settings. These discussions will occur at the end of the study in 2020 when the project has economic models developed.

All outputs and publications contain only aggregated data with small numbers suppressed in line with the HES Analysis Guide.

The project will support Heart UK to organise patient and health professional focus groups to help refine findings and produce digital dissemination strategies (e.g. involving website, email, Facebook, Twitter or similar). This will occur towards end of the study in 2019-2020. The project is running some 2-3 consensus development groups with HEART UK/BHF in 2020 to interpret and analyse the findings from a patient and stakeholder prospective. Working closely with HEART UK and BHF, the project will develop a disseminate study from the study to the wider public by:

- Networking with existing and potential FH service commissioners across England, e.g. national NHS commissioners workshop

- Presenting study findings in a way that makes sense to managerial and commissioning audiences, e.g. publish articles in NHS professional and health service commissioner journals

- Sharing learning of early implementers of FH services

- Scoping the possibility of producing a FH toolkit incorporating advice on FH service design and a revised costing template for FH services that is generalizable to the English NHS, based on CCG geographies.

The project anticipates that the dissemination strategy will be fully implemented in 2021, with all the publications in the public domain.

Benefits to patients from this data release

If patients with familial hypercholesterolaemia (FH) are not identified they can die at an early age from myocardial Infarction and other cardiovascular disease. It has been well-established that patients with FH who are not diagnosed and treated will have a 50% chance of coronary mortality by 50 years of age in men and 60 years of age in women. At a population level, the UK is incredibly poor at diagnosing FH with close to 80% under diagnosis. This accounts for anywhere from 120,000 to 180,000 individuals currently in the general population who do not know they are affected. Hence, improving the current low detection rate of FH is urgently needed. One of the most cost-effective solutions is to develop protocols of efficient cascade testing to identify affected relatives, especially younger relatives, and to initiate early statin treatment to lower LDL cholesterol will prevent and reduce premature mortality, and long-term coronary morbidity. Available service data highlight the major extent of the problem. National audits show only around one affected relative is identified for each index case. To improve identification and health outcomes for these patients, evidence-based protocols need to be implemented. This data release of using one highest quality and well-established FH disease registries known internationally and linking outcomes to HES will provide the longest follow-up to date. This will allow for novel research to be generated on the long-term outcomes for patients affected by FH and the impact of treatment in real-world settings (as knowledge of impact of treatment for FH is limited to trials). Many patient representatives who themselves have FH, from partner charities, Heart UK and the British Heart Foundation, have expressed a dire need to understand the effectiveness of treatment on long-term outcomes and how these outcomes can inform the development of more effective and efficient ways to cascade screen for relatives.

Benefits to health care practitioners on data release

Many health care practitioners, in particular in primary care commissioners, are still unaware of the magnitude of under-diagnosis, how to identify, or manage FH in current clinical practice. The research outputs, once published, will improve awareness among practitioners and patients, leading to improved compliance anticipated by 2022. Further, the economic model will improve the identification of FH through revised shared care protocols to be reviewed by the next NICE review of the FH guidelines 2024, leading to commissioning of evidence-based FH cascade screening programmes and, ultimately, saving lives.

Benefits to the policy-makers and NHS commissioners from this data release

Cascade testing recommendations exist for the UK but policy-makers have acknowledged they do not reflect the current evidence base, which has evolved significantly since guidance was issued in 2008. Hence, this research project was commissioned by the Department of Health and HTA. There is significant uncertainty regarding whether cascade testing is cost-effective and how it should be implemented. As a result, cascade testing protocols are often piecemeal with variable implementation of services in the UK. To support commissioners deciding on whether to implement a new cascade testing service, or modify an existing service, there is an urgent need for new cost-effectiveness modelling that collates and synthesizes the best available current evidence, evaluates the overall impacts of cascade testing for all affected individuals and answers key questions about how the service should be designed to offer the best possible value for money.

These outputs, which are expected to be published in by 2021, will allow the identification of the most cost-effective design for a FH cascade testing protocol in the NHS which will likely result in a change in the current ways cascade testing in implemented in the UK. The project will inform future NICE implementation for FH cascade testing based on the economic model, to support analysis of the cost, outcomes and savings associated with implementing FH cascade services at local level. Combined with findings from the proposed qualitative research, this work will provide valuable practical information to health care decision makers involved in commissioning or running FH services regarding the appropriate use of NHS resources.

Yielded Benefits is not a requirement for new applications.