Title: Lipid-modifying therapy in children with familial hypercholesterolemia
Funder: Department of Health and Social Care

Abstract: BACKGROUND: People with familial hypercholesterolaemia (FH) have raised cholesterol levels in their blood from birth. Cholesterol is a type of fat our bodies need but having raised levels over a long time causes heart disease, such as heart attacks. To prevent future heart disease, guidelines recommend starting cholesterol-reducing medication, usually statins, by age 10. However, there are still unanswered questions about what is the right age and cholesterol level at which to start statins to prevent heart disease later in life. Important considerations are: avoiding side effects, giving best value for money for the health service, and ensuring that treatment is acceptable for children/young people and their families._x000D_ _x000D_ We will answer these questions by:_x000D_ 1. Measuring health benefits and risks of starting cholesterol-reducing medication in childhood and adolescence (“Clinical effectiveness”)_x000D_ 2. Exploring the “Acceptability” of this medication for children/young people, families and healthcare professionals_x000D_ 3. Assessing value for money, through calculating the costs and benefits of starting medications at various ages and the savings produced by preventing early heart disease (“Cost-effectiveness”)_x000D_ _x000D_ DESIGN & METHODS:_x000D_ (1) “Clinical effectiveness”: we will follow children/young people with FH over time, to confirm how well medications work in reducing cholesterol and measure any side effects. We will use a national FH patient register, records from general practices across the country and previous studies. Finally, we will identify average cholesterol levels from young people without FH, which will indicate how far cholesterol levels should be reduced with treatment in children/young people with FH. _x000D_ _x000D_ (2) “Acceptability”: Using questionnaires repeated over time, we will ask young people how regularly they take their medication. We will also arrange interviews to ask the views of children/young people with FH, their families and healthcare professionals about how acceptable it is to start medication early, and the information families need to support their ongoing treatment._x000D_ _x000D_ (3) “Cost-effectiveness”: We will find out the costs of starting cholesterol-reducing medication and how often children/young people are seen by doctors and nurses. Using the study findings above and information on how cholesterol affects later risk of heart disease, we can calculate the value for money of starting treatment at different ages and cholesterol levels.

Lay abstract: BACKGROUND: Around 1 in 250 people have familial hypercholesterolaemia (FH) with raised low density lipoprotein-cholesterol (LDL-C) from birth, increasing the risk of premature cardiovascular disease. National guidance recommends starting lipid-lowering treatment (LLT) at age 10 years, yet evidence for the age and LDL-C thresholds at which to initiate LLT is limited, leading to the commissioned call for the RESEARCH QUESTIONS:_x000D_ _x000D_ What is the clinical and cost-effectiveness of LLT in children with FH in the UK? How are these affected by the age of commencing treatment and different thresholds of LDL-C for commencing treatment? _x000D_ _x000D_ OBJECTIVES to answer research questions:_x000D_ _x000D_ 1. Estimate absolute and relative reductions in LDL-C, and in cumulative LDL-C, achieved in current practice with LLT, and whether these vary by age and LDL-C at initiation of LLT_x000D_ _x000D_ 2. Estimate the incidence of side-effects and adverse events associated with LLT_x000D_ _x000D_ 3. Estimate LLT adherence at different ages and characterise reasons for variations in adherence_x000D_ _x000D_ 4. Understand the views of children and young people (CYP), their families and healthcare professionals, on information needs for starting LLT at different ages, and how these influence treatment acceptability, monitoring, and adherence_x000D_ _x000D_ 5. Estimate the impact of initiating LLT at different ages on the costs of managing FH over the short-term in CYP_x000D_ _x000D_ 6. Estimate long-term health outcomes and NHS costs of starting LLT at different ages and LDL-C thresholds to identify a cost-effective approach to management_x000D_ _x000D_ DESIGN & METHODS: _x000D_ Objectives 1 & 2: We will update the national Paediatric FH Register (PFHR) with new recruitment, retrospective clinical data and 3.5 years of prospective data, increasing the current 613 patients to over 1,300. We will also identify FH patients in the Clinical Practice Research Datalink (CPRD), and conduct evidence reviews for any remaining gaps. The Avon Longitudinal Study of Parents and Children (ALSPAC) cohort will provide average age-specific LDL-C levels across childhood in the general population that could be used as target LDL-C levels for treatment in FH._x000D_ _x000D_ Objectives 3 & 4: Repeated questionnaires sent to CYP on the PFHR will characterise LLT adherence over time, inform healthcare utilisation (for Obj 5), and inform sampling for qualitative interviews (Obj 4). Interviewing 40 CYP with FH and their families and 30 healthcare professionals will inform LLT acceptability and information needed to support monitoring. _x000D_ _x000D_ Objectives 5 & 6: We will estimate the healthcare costs of managing FH in CYP and the impact of initiating LLT. Synthesising information compiled across the study, we will develop a new cost-effectiveness model estimating long-term reductions in cardiovascular disease risk given observed LDL-C reductions in childhood. The model will compare the benefit-risk, short- and long-term health outcomes and costs of starting LLT at different ages and LDL-C thresholds. _x000D_ _x000D_ PROJECT TIMELINE: CPRD/ALSPAC analyses [3-12mths]; PFHR and questionnaire analyses [9-54]; Systematic and pragmatic evidence reviews [6-12 & 36-42]; Interview analyses [10-30]; Estimate costs [39-44]; Build cost-effectiveness model [45-56]_x000D_ _x000D_ IMPACT & DISSEMINATION: We will establish 2 new patient/stakeholder groups for this study bringing direct experience of FH (CYP Advisory Group (CYPAG) and Parent Advisory Group (PAG)). In partnership with these groups, charities including Heart UK, and health care professionals involved in FH care, we will widely disseminate findings with presentations and publications for various audiences. Impact will include updating national FH guidelines and informing commissioners and policymakers on service configuration.

Research activity codes: 6.1 PHARMACEUTICALS;7.1 INDIVIDUAL CARE NEEDS;8.2 HEALTH AND WELFARE ECONOMICS
Health categories: METABOLIC AND ENDOCRINE