OBJECTIVES: Familial hypercholesterolemia (FH) is a genetic disorder that leads to premature cardiovascular disease if untreated. Although it was previously thought that cascade genetic screening for FH is not cost-effective in the US, the cost of genetic testing has decreased substantially while PCSK9 inhibitors, a novel new lipid-lowering treatment, have been approved for use in FH. This study aimed to re-examine whether cascade genetic screening or cascade lipid screening is cost-effective for first-degree relatives of adults diagnosed with heterozygous FH in the US, compared to no cascade screening, and whether follow-on treatment with statins plus PCSK9 inhibitors (PCSK9i) is cost-effective, compared to high-intensity standard-of-care treatment with statins plus ezetimibe (HI-SOC).

METHODS: A decision tree was used to evaluate disease detection with the three screening strategies, while a lifetime Markov model was used to evaluate disease progression in one-year cycles until death. We report the incremental cost-effectiveness ratios (ICER) in terms of costs and quality-adjusted life years (QALYs) between six screening and treatment strategies, considering the US societal perspective.

RESULTS: At a willingness-to-pay threshold of $150,000/QALY, cascade genetic screening, whether paired with HI-SOC or PCSK9i, is the most cost-effective screening strategy, dominating all other alternatives assessed. Compared to cascade genetic screening with HI-SOC, cascade genetic screening with PCSK9i is cost-effective with an ICER of $56,034/QALY. Results were robust in one-way and probabilistic sensitivity analyses. Baseline cholesterol levels, treatment-adjusted cholesterol levels, and diagnostic test sensitivities had the greatest impact on ICERs.

CONCLUSIONS: This study is the first to incorporate lower genetic testing costs, newly available information on diagnostic test accuracy, effects of novel treatments, disease prognosis, and increased cardiovascular risk in this population. The results support cascade genetic screening for FH with subsequent HI-SOC or PCSK9i treatment as an evidence-based intervention that dominates alternative strategies and provides good value relative to costs.