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When economy meets physiopathology: A novel cost-effectiveness model finally considers the cumulative effect of LDL cholesterol burden

  • Luiz Sérgio Fernandes de Carvalho
    Correspondence
    Corresponding author. Laboratory of Data for Quality of Care and Outcomes Research (LaDa:QCOR), Universidade Católica de Brasília, QS 07, Lote 01, Taguatinga Sul, Brasília, DF, 71966-700, Brazil.
    Affiliations
    Laboratory of Data for Quality of Care and Outcomes Research (LaDa:QCOR), Universidade Católica de Brasília, DF, Brazil
    Aramari Apo Institute, Brasília, DF, Brazil
    HEOR, Clarity Healthcare Intelligence, Jundiaí, SP, Brazil
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  • Andrea Dias Stephanus
    Affiliations
    Laboratory of Data for Quality of Care and Outcomes Research (LaDa:QCOR), Universidade Católica de Brasília, DF, Brazil
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  • Mariana Savedra Pfitzner
    Affiliations
    HEOR, Clarity Healthcare Intelligence, Jundiaí, SP, Brazil
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      Keywords

      Familial hypercholesterolemia (FH) is a prevalent hereditary autosomal dominant lipoprotein metabolic disorder marked by increased levels of LDL-cholesterol (LDL-C) and a higher risk of developing early cardiovascular disease [
      • Safarova M.S.
      • Kullo I.J.
      My approach to the patient with familial hypercholesterolemia.
      ]. Heterozygotic FH affects 1 in 250–300 individuals worldwide, and less than 1% of those subjects have been diagnosed to date [
      • Brunham L.R.
      • Ruel I.
      • Aljenedil S.
      • Rivière J.-B.
      • et al.
      Canadian cardiovascular society position statement on familial hypercholesterolemia: update 2018.
      ,
      • Ramaswami U.
      • Humphries S.
      Familial hypercholesterolaemia: what's new?.
      ].
      Early screening helps prevent or delay coronary artery disease (CAD) by guiding proper treatment to lower the high cholesterol burden associated with lifelong cardiovascular risk. According to the most recent recommendations, LDL-C should be reduced in adults with FH to 50% of baseline values, or to achieve 2.5 mmol/l (100 mg/dL) [
      • Santos R.D.
      Screening and management of familial hypercholesterolemia.
      ,
      • Tokgozoglu L.
      • Kayikcioglu M.
      Familial hypercholesterolemia: global burden and approaches.
      ]. However, in clinical practice, adherence to these recommendations is low for several reasons, including the effectiveness of lipid-lowering therapies (LLTs), genetic background, medical education, as well as the costs of screening and therapies.
      FH phenotype is highly heterogeneous even among heterozygotes. Among them, high-dose statins and ezetimibe will reduce LDL-C levels by 25–65% [
      • Postmus I.
      • Trompet S.
      • Deshmukh H.A.
      • et al.
      Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
      ]. Genetic variations affect the therapeutic efficacy of lipid-lowering drugs, with SORT1/CELSR2/PSRC1 and PCSK9 mutations being related with improved responses and mutations in the ApoE, LPA, and SLCO1B1 genes being associated with decreased responses [
      • Postmus I.
      • Trompet S.
      • Deshmukh H.A.
      • et al.
      Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
      ,
      • Feng Q.
      • Wei W.Q.
      • Chung C.P.
      • et al.
      The effect of genetic variation in PCSK9 on the LDL-cholesterol response to statin therapy.
      ,
      • Santos P.C.J.L.
      • Pereira A.C.
      Type of LDLR mutation and the pharmacogenetics of familial hypercholesterolemia treatment.
      ].
      In fact, less than 12% of individuals with FH actually reach optimal LDL-C levels. Of those not reaching LDL-C goals, 70% are on high-intensity statin plus ezetimibe, and in 30%, the main reason for goal achievement failure was the acceptance of a higher target level of LDL-C by the treating physician [
      • Perez de Isla L.
      • Alonso R.
      • Watts G.F.
      • Mata N.
      • et al.
      Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up.
      ]. Although several novel LLTs such as bempedoic acid and PCSK9 inhibitors are available, the access to these therapies is not always trivial and medical education can also be an issue. In the real world, the availability of such treatments does not necessarily convert into prescriptions and goal accomplishment [
      • Perez de Isla L.
      • Alonso R.
      • Watts G.F.
      • Mata N.
      • et al.
      Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART registry follow-up.
      ].
      To justify an effort, it is innate to think that the benefit must outweigh the cost. However, (i) when the benefit is not immediately clear or (ii) when marginal gains decrease by adding new therapies or (iii) when the cost scales in a non-linear fashion (i.e. the cost to reduce 1 mmol/L of LDL-C is much lower in statin-naïve individuals than in those taking high-dose statins plus ezetimibe [
      • Nherera L.
      • Calvert N.W.
      • Demott K.
      • et al.
      Thorogood, Cost-effectiveness analysis of the use of a high-intensity statin compared to a low-intensity statin in the management of patients with familial hypercholesterolaemia.
      ]), it is difficult to make clinicians conscious of the benefit of achieving LDL-C goals. To improve the quality of care for people with FH, the concept of cost-benefit or cost-effectiveness must be stressed and must be consistent with disease mechanistic framework.
      The average lifetime levels of LDL-C multiplied by the number of years lived define the atherosclerotic burden of any individual. The cumulative LDL-C over years is highly associated with CAD when above 160mmol (Fig. 1). This is not a new concept [
      • Starr B.
      • Hadfield S.G.
      • Hutten B.A.
      • et al.
      Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing.
      ,
      • Huijgen R.
      • Hutten B.A.
      • Kindt I.
      • et al.
      Discriminative ability of LDL-cholesterol to identify patients with familial hypercholesterolemia: a cross-sectional study in 26,406 individuals tested for genetic FH.
      ], however, it is not well defined the optimal screening and treatment window to avoid crossing the threshold of cumulative LDL-C associated with higher risk of CAD. Available cost-effectiveness studies did not consider the impact of cholesterol burden, ignoring such physiopathological component.
      Fig. 1
      Fig. 1LDL-C load and optimal windows for initiating therapy throughout life in relation to net health gain in homozygous, heterozygous, and non-FH individuals.
      The cumulative LDL cholesterol burden of individuals with CAD is typically 160 mmol (data derived from Refs. [
      • Nherera L.
      • Calvert N.W.
      • Demott K.
      • et al.
      Thorogood, Cost-effectiveness analysis of the use of a high-intensity statin compared to a low-intensity statin in the management of patients with familial hypercholesterolaemia.
      ,
      • Starr B.
      • Hadfield S.G.
      • Hutten B.A.
      • et al.
      Development of sensitive and specific age- and gender-specific low-density lipoprotein cholesterol cutoffs for diagnosis of first-degree relatives with familial hypercholesterolaemia in cascade testing.
      ]). Optimal treatment windows for heterozygous FH consider the threshold to obtain a net health gain superior to 1 QALY (given cost-effectiveness threshold of £15,000/QALY) as reported by Faria et al. [
      • Faria R.
      • Saramago P.
      • Cox E.
      • et al.
      How Does Cholesterol Burden Change the Case for Investing in Familial Hypercholesterolaemia? A Cost-Effectiveness Analysis.
      ]. In non-FH individuals, we also consider the LDL-C levels necessary to accumulate 100mmol over 25 years (from 30 to 55 years) and the exposure to normal levels of LDL-C during childhood and adolescence (∼1.8–2.2 mmol/L from 2 to 19 years) according to LDL-C nomograms in several populations [
      • Xiao P.
      • Huang T.
      • Yan Y.
      • et al.
      China Child and Adolescent Cardiovascular Health (CCACH) investigators. Performance of gender- and age-specific cut-points versus NCEP pediatric cutpoints in dyslipidemia screening among Chinese children.
      ,
      • Balder J.W.
      • Lansberg P.J.
      • Hof M.H.
      • et al.
      Pediatric lipid reference values in the general population: the Dutch lifelines cohort study.
      ,
      • Bibbins-Domingo K.
      • Grossman D.C.
      • Curry S.J.
      • et al.
      Screening for lipid disorders in children and adolescents: US preventive services task force recommendation statement.
      ,
      • Daniels S.R.
      • Greer F.R.
      Lipid screening and cardiovascular health in childhood.
      ,
      • Jolliffe C.J.
      • Janssen I.
      Distribution of lipoproteins by age and gender in adolescents.
      ]. CAD: coronary artery disease, FH: familial hypercholesterolemia, LDL-C: low-density lipoprotein; LLT: lipid-lowering therapies, QALY: quality-adjusted life years.
      In this issue of Atherosclerosis, Faria et al. [
      • Faria R.
      • Saramago P.
      • Cox E.
      • et al.
      How Does Cholesterol Burden Change the Case for Investing in Familial Hypercholesterolaemia? A Cost-Effectiveness Analysis.
      ] evaluated the impact of the cholesterol burden in the incremental cost-effectiveness for screening and treating individuals with FH at different ages and baseline cardiovascular risk. The authors found that when LDL-C burden is considered, in all individuals with pre-treatment LDL-C ≥ 4 mmol/L, and in those with pre-treatment LDL-C ≥ 2 mmol/L aged ≥50 years or who have CVD history had positive net health gains from diagnosis and treatment at the cost-effective threshold of £15,000/QALY.
      If cholesterol burden is not considered, diagnosis and treatment resulted in lower net health gain, but still positive in children aged 10 years with pre-treatment LDL-C ≥ 6 mmol/L and adults aged 30 years with pre-treatment LDL-C ≥ 4 mmol/L. Higher LDL-C levels and longer age at diagnosis result in greater net health improvements, which raises the risk of CAD in those individuals.
      The cumulative lifetime burden of LDL-C highlights the importance of early intervention. The new economic models by Faria et al. [
      • Faria R.
      • Saramago P.
      • Cox E.
      • et al.
      How Does Cholesterol Burden Change the Case for Investing in Familial Hypercholesterolaemia? A Cost-Effectiveness Analysis.
      ] and net health gains with early diagnosis and treatment are highly consistent with existing physiopathological models. With the new data, it is possible to ascertain an optimal treatment window for heterozygous FH at 10–18 years with LDL-C ≥ 6 mmol/L, considering the threshold to obtain a net health gain superior to 1 QALY (given cost-effectiveness threshold of £15,000/QALY) (Fig. 1). If left untreated, a heterozygous FH individual reaches a risky LDL-C burden at 25-45 years-old [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Humphries S.E.
      • et al.
      European Atherosclerosis Society Consensus Panel, Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
      ]. If diagnosed and treated appropriately with LLT in the optimal time window, life expectancy will increase by 8–10 years [
      • Faria R.
      • Saramago P.
      • Cox E.
      • et al.
      How Does Cholesterol Burden Change the Case for Investing in Familial Hypercholesterolaemia? A Cost-Effectiveness Analysis.
      ].
      Although the model was based in a cohort of individuals with FH, there is a considerable proportion of individuals with pre-treatment LDL-C levels between 2 and 4 mmol/L, what may indicate non-FH were also included in CPRD-FH cohort. This information stands as a limitation to whole model as an FH-specific model, but also permit a reasonable extrapolation to non-FH individuals. With the data by Faria et al. it is also possible to consider an optimal treatment window for the general population at 30–35 years with LDL-C ≥ 4 mmol/L. Three key reasons justify this window: (i) it provides a net health gain superior to 1 QALY (given cost-effectiveness threshold of £15,000/QALY); (ii) most non-FH individuals will reach a LDL-C burden of 60–70 mmol at their 30–35 years [
      • Xiao P.
      • Huang T.
      • Yan Y.
      • et al.
      China Child and Adolescent Cardiovascular Health (CCACH) investigators. Performance of gender- and age-specific cut-points versus NCEP pediatric cutpoints in dyslipidemia screening among Chinese children.
      ,
      • Balder J.W.
      • Lansberg P.J.
      • Hof M.H.
      • et al.
      Pediatric lipid reference values in the general population: the Dutch lifelines cohort study.
      ,
      • Bibbins-Domingo K.
      • Grossman D.C.
      • Curry S.J.
      • et al.
      Screening for lipid disorders in children and adolescents: US preventive services task force recommendation statement.
      ,
      • Daniels S.R.
      • Greer F.R.
      Lipid screening and cardiovascular health in childhood.
      ,
      • Jolliffe C.J.
      • Janssen I.
      Distribution of lipoproteins by age and gender in adolescents.
      ]; (iii) if a 30-year old individual carries a LDL-C level of 4mmol/L for 25 years, there is a high propensity of reaching the risky 160 mmol threshold at 55 years. With this window for diagnosis and treatment, life expectancy is projected to be increased by 4–7.5 years [
      • Faria R.
      • Saramago P.
      • Cox E.
      • et al.
      How Does Cholesterol Burden Change the Case for Investing in Familial Hypercholesterolaemia? A Cost-Effectiveness Analysis.
      ].
      These findings can guide the development of diagnostic guidelines that focus on people with various features (e.g., cascade screening versus universal screening with LDL-C in childhood). The cost-effectiveness model can also be easily modified to assess new treatments and medications that may result in greater LDL-C reductions but higher costs, as well as to use inputs from other countries to provide country-specific results.
      Limitations are well acknowledged by the study authors, but it is noteworthy that these findings might not apply to those who have homozygous FH. In addition, CPRD-FH cohort data had follow-up data limited to 10 years, leading to extrapolation of long-term cardiovascular risk with limited validity. Given the variation in management approaches across the country and over time, as well as individual LDL-C responses, another area of ambiguity is to the impact of diagnosis and therapy on LDL-C and post-diagnostic monitoring expenses.
      In conclusion, the novel economic models developed by Faria et al. are highly consistent with the physiopathological background of FH and atherosclerotic artery disease. More specifically, the study helps to define the ideal windows for screening and treatment to maximize lifespan at the lowest cost to society. Of course, the model is designed to the UK healthcare system. As so, due to the substantial variation in the organization of healthcare systems between countries, optimal cholesterol thresholds for screening and treatment might be country-specific and may be defined with appropriate local economic data.

      Financial support

      This work was supported by grant 310718/2021–0 from the Brazilian National Research Council (CNPq, Brazil), grants 371/2021 and 585/2022 from Fundação de Apoio a Pesquisa do Distrito Federal (FAPDF, Brazil), and grant 2019/09068–3 from Fundaço de Amparo a Pesquisa do Estado de São Paulo (FAPESP, Brazil).

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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