OBJECTIVES: Cascade screening for familial hypercholesterolaemia (FH) refers to the systematic testing of relatives of people known to have FH (termed ‘indexes’). Cascade screening is cost-effective compared to no screening, but alternative screening strategies have not been studied. Our objective was to identify the cost-effective strategy to select indexes to cascade, and to contacting and testing their relatives.

METHODS: We developed a new cost-effectiveness model informed with routinely collected UK data from indexes and their relatives. Our decision tree model takes the UK National Health Service perspective and calculates, per index assessed to the cascade, the relatives diagnosed, cascade costs, quality-adjusted life years (QALYs), healthcare costs and incremental cost-effectiveness ratios (ICERs).

RESULTS: We compared 1792 strategies. The cost-effectiveness frontier was mostly formed by strategies which contacted 1^st and 2^nd degree relatives of indexes with genetic FH simultaneously and directly. The cost-effective strategy diagnoses relatives according to whether they were on lipid lowering treatment, cholesterol, and age, with some having confirmatory genetic testing – it diagnoses 52% affected relatives, at a cascade cost of £536; ICER = £13,996/QALY.

Sequential contact (i.e. contacting second degree relatives only when their first degree relative was diagnosed with FH), indirect contact via their index/relatives and genetically testing them diagnoses 36% of relatives, while direct and simultaneous contact with genetic testing diagnoses more relatives (56%); neither are in the cost-effectiveness frontier.

If genetic testing is not available, cascade screening remains cost-effective, diagnosing 41% of relatives (ICER=£5,603 vs no cascade).

Results are robust to alternative scenarios bar those affecting long-term benefits of diagnosis.

CONCLUSIONS: Simultaneous and direct contact of relatives of indexes with genetic FH and a mixed approach to testing relatives is cost-effective and achieves better outcomes than sequential and indirect contact. Identifying this strategy required systematic comparison of multiple alternatives, which is only achievable with cost-effectiveness modelling.