Authors' objectives: Cascade testing the relatives of people with familial hypercholesterolaemia is an efficient approach to identifying familial hypercholesterolaemia. The cascade-testing protocol starts with identifying an index patient with familial hypercholesterolaemia, followed by one of three approaches to contact other relatives: indirect approach, whereby index patients contact their relatives; direct approach, whereby the specialist contacts the relatives; or a combination of both direct and indirect approaches. However, it is unclear which protocol may be most effective. The objectives were to determine the yield of cases from different cascade-testing protocols, treatment patterns, and short- and long-term outcomes for people with familial hypercholesterolaemia; to evaluate the cost-effectiveness of alternative protocols for familial hypercholesterolaemia cascade testing; and to qualitatively assess the acceptability of different cascade-testing protocols to individuals and families with familial hypercholesterolaemia, and to health-care providers. Cascade testing among relatives of index cases is the most efficient and cost-effective approach to identifying people with familial hypercholesterolaemia (FH). The cascade-testing protocol starts with identifying the first patient in the family with FH (index case) and is followed by one of three approaches: indirect approach, whereby the patient with FH contacts their relatives; direct approach, whereby the genetic specialist contacts the relatives; or a combination of both direct and indirect approaches. The National Institute for Health and Care Excellence (NICE) recommend that, once FH is genetically confirmed in index cases, FH cascade testing should be offered to first- then second-degree relatives using streamlined genetic testing for pathogenic variants identified in the index case. Alternative protocols include testing of first- and second-degree relatives simultaneously, rather than sequentially, and also consider the role of non-genetic markers for FH status among relatives. However, it is currently unclear how FH cascade-testing services should be configured to improve the number of relatives identified while offering value for money.

Authors' results and conclusions: Systematic review of protocols: based on data from 4 of the 24 studies, the combined approach led to a slightly higher yield of relatives tested [40%, 95% confidence interval (CI) 37% to 42%] than the direct (33%, 95% CI 28% to 39%) or indirect approaches alone (34%, 95% CI 30% to 37%). The PASS databases identified that those contacted directly were more likely to complete cascade testing.

Authors' methods: This study comprised systematic reviews and analysis of three data sets: PASS (PASS Software, Rijswijk, the Netherlands) hospital familial hypercholesterolaemia databases, the Clinical Practice Research Datalink (CPRD)–Hospital Episode Statistics (HES) linked primary–secondary care data set, and a specialist familial hypercholesterolaemia register. Cost-effectiveness modelling, incorporating preceding analyses, was undertaken. Acceptability was examined in interviews with patients, relatives and health-care professionals. Systematic reviews were not used in the economic analysis, as relevant studies were lacking or of poor quality. As only a proportion of those with primary care-coded familial hypercholesterolaemia are likely to actually have familial hypercholesterolaemia, CPRD analyses are likely to underestimate the true effect. The cost-effectiveness analysis required assumptions related to the long-term cardiovascular disease risk, the effect of treatment on cholesterol and the generalisability of estimates from the data sets. Interview recruitment was limited to white English-speaking participants. Yield of cases Effectiveness of contact strategies for cascade testing among relatives for familial hypercholesterolaemia (systematic review 1) This review was performed to quantify the effectiveness of different contact approaches in cascade testing. A total of 2347 titles and abstracts were screened, with 217 screened at full-text stage. Twenty-four non-comparative studies were included, of which 12 used a direct approach, 7 used an indirect approach and 5 used a combination of both. Although evidence is very limited, the combined approach resulted in more relatives being tested for FH [40%, 95% confidence interval (CI) 37% to 42%, one study] than either the direct or indirect approaches (direct: 33%, 95% CI 28% to 39%, one study; indirect: 34%, 95% CI 30% to 37%, two studies). The systematic reviews on contact strategies identified a few low-quality studies and no relevant studies on diagnostic accuracy. These could not be used in the cost-effectiveness analysis. The CPRD primary care data set defined FH as patients coded with FH in primary care. We acknowledge that this may not be accurate. The major limitations of the cost-effectiveness analyses related to the assumptions required, namely about the generalisability of the available data to FH patients and FH services, about the effect of cholesterol burden on CVD risk and long-term CVD risk. Hence, there is uncertainty about the generalisability of the cost-effectiveness results to clinical practice. Furthermore, patient recruitment for interviews was limited to white English-speaking patients, and genetic counsellors were not available for interviews. These findings are consistent with the NICE guideline recommendations. The further elaboration on the most effective protocol, specifically testing first-and second-degree relatives simultaneously, may be considered in future updates to the FH guidelines.

Project Status: Completed

URL for project: https://www.journalslibrary.nihr.ac.uk/programmes/hta/15/134/02

Year Published: 2023

URL for published report: https://www.journalslibrary.nihr.ac.uk/hta/CTMD0148

URL for additional information: English

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: England, United Kingdom

DOI: 10.3310/CTMD0148

Organisation Name: NIHR Health Technology Assessment programme

Contact Address: NIHR Journals Library, National Institute for Health and Care Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK

Contact Name: journals.library@nihr.ac.uk

Contact Email: journals.library@nihr.ac.uk