Prevalence and management of familial hypercholesterolaemia in patients with chest pain admitted to hospital: a retrospective observational study.

OBJECTIVES: Patients with familial hypercholesterolaemia (FH) are genetically burdened by a lifelong elevation of the low-density lipoprotein cholesterol (LDL-C) level, putting them at a very high risk of premature ischaemic heart disease (IHD). This study aims to assess the prevalence of FH among patients admitted for IHD and the preventive treatment status before admission. DESIGN: Observational, retrospective, register-based study. SETTING: Individuals discharged with a diagnosis of IHD were enrolled consecutively throughout 2012-2016 from the cardiac care units of two hospitals in Copenhagen. PARTICIPANTS: 4223 individuals were discharged during the period. Inclusion criteria for further investigation were the availability of one measurement of LDL-C at the time of admission. In total, 2797 individuals were included for further investigation. There were no exclusion criteria. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary objective has been to determine the prevalence of FH in the population. The secondary objective has been to determine the use of lipid-lowering therapy and to which extend the individuals reach their treatment goal. RESULTS: Among the 2797 consecutive patients evaluated, the prevalence of potential FH was 7.7% (1: 13) and 6.8% (1:15) had probably or definite FH. The prevalence of FH was age-dependent: Among the 680 patients (24.3%) with premature IHD (men <55 years/women <60 years), 136 patients (20.0%) had potential FH and 21 (3.1%) had probable/definite FH. None were diagnosed and almost none attained their treatment goal. CONCLUSIONS: There is still a massive lack of recognition of FH in patients admitted to a cardiac care unit with a diagnosis of IHD. Despite a measured high LDL-C, the diagnosis was not made for any patients not even in patients who were admitted at an early age or had a previous cardiovascular event.

Measuring Costs of Cardiovascular Disease Prevention for Patients with Familial Hypercholesterolemia in Administrative Claims Data.

INTRODUCTION: Familial hypercholesterolemia is a common genetic condition that significantly increases an individual's risk of cardiovascular events such as heart attack, stroke, and cardiac death and is a candidate for population-wide screening programs. Economic analyses of strategies to identify and treat familial hypercholesterolemia are limited by a lack of real-world cost estimates for screening services and medications for reducing cardiovascular risk in this population. METHODS: We estimated the cost of lipid panel testing in patients with hyperlipidemia and the cost of statins, ezetimibe, and PCKS9 inhibitors in patients with familial hypercholesterolemia from a commercial claims database and report costs and charges per panel and prescription by days' supply. RESULTS: The mean cost for a 90-day supply for statins was $183.33, 2.3 times the mean cost for a 30-day supply at $79.35. PCSK9 inhibitors generated the highest mean costs among medications used by patients with familial hypercholesterolemia. CONCLUSIONS: Lipid testing and lipid-lowering medications for cardiovascular disease prevention generate substantial real-world costs which can be used to improve cost-effectiveness models of familial hypercholesterolemia screening and care management.

Assessment of ethnic inequalities in diagnostic coding of familial hypercholesterolaemia (FH): A cross-sectional database study in Lambeth, South London.

BACKGROUND AND AIMS: Differences in the perceived prevalence of familial hypercholesterolemia (FH) by ethnicity are unclear. In this study, we aimed to assess the prevalence, determinants and management of diagnostically-coded FH in an ethnically diverse population in South London. METHODS: A cross-sectional analysis of 40 practices in 332,357 adult patients in Lambeth was undertaken. Factors affecting a (clinically coded) diagnosis of FH were investigated by multi-level logistic regression adjusted for socio-demographic and lifestyle factors, co-morbidities, and medications. RESULTS: The age-adjusted FH % prevalence rate (OR, 95%CI) ranged from 0.10 to 1.11, 0.00-1.31. Lower rates of FH coding were associated with age (0.96, 0.96-0.97) and male gender (0.75, 0.65-0.87), p < 0.001. Compared to a White British reference group, a higher likelihood of coded FH was noted in Other Asians (1.33, 1.01-1.76), p = 0.05, with lower rates in Black Africans (0.50, 0.37-0.68), p < 0.001, Indians (0.55, 0.34-0.89) p = 0.02, and in Black Caribbeans (0.60, 0.44-0.81), p = 0.001. The overall prevalence using Simon Broome criteria was 0.1%; we were unable to provide ethnic specific estimates due to low numbers. Lower likelihoods of FH coding (OR, 95%CI) were seen in non-native English speakers (0.66, 0.53-0.81), most deprived income quintile (0.68, 0.52-0.88), smokers (0.68,0.55-0.85), hypertension (0.62, 0.52-0.74), chronic kidney disease (0.64, 0.41-0.99), obesity (0.80, 0.67-0.95), diabetes (0.31, 0.25-0.39) and CVD (0.47, 0.36-0.63). 20% of FH coded patients were not prescribed lipid-lowering medications, p < 0.001. CONCLUSIONS: Inequalities in diagnostic coding of FH patients exist. Lower likelihoods of diagnosed FH were seen in Black African, Black Caribbean and Indian ethnic groups, in contrast to higher diagnoses in White and Other Asian ethnic groups. Hypercholesterolaemia requiring statin therapy was associated with FH diagnosis, however, the presence of cardiovascular disease (CVD) risk factors lowered the diagnosis rate for FH.

Cost-effectiveness and Return on Investment of a Nationwide Case-Finding Program for Familial Hypercholesterolemia in Children in the Netherlands.

Importance: The Netherlands is one of the few countries that has a long-term history of active screening for familial hypercholesterolemia (FH), enabling health-economic analyses. Objective: To investigate cost-effectiveness and the return on investment (ROI) of a nationwide cascade case-finding and preventive treatment program starting with identification of FH in children and treatment, from both a societal and health care perspective. Design, Setting, and Participants: Cascade case-finding and early preventive treatment were modeled to simulate the progression of disease and costs of 10-year-olds suspected of having heterozygous FH over a lifetime. The model consisted of 3 health states: alive without coronary heart disease (CHD), alive with CHD, and deceased. Mendelian randomization analysis was used to quantify the risk of a first CHD event as a function of age and total lifetime exposure to low-density lipoprotein cholesterol. Cost-effectiveness was defined as €20 000 ($21 800) per QALYs (quality-adjusted life-years) gained, using incremental cost-effectiveness ratios (ICERs). All future benefits and costs were discounted annually by 1.5% and 4%, respectively. Interventions: The study compared 2 strategies: (1) cascade screening and initiation of treatment with statins in children (mean age, 10 years) and (2) no screening, later detection, and treatment. Main Outcomes and Measures: Outcome of interest included cost, detection, and successful treatment of FH in terms of life-years gained and QALYs. The clinical and cost outputs for each model in the 2 scenarios (early detection and treatment and later detection and treatment) were totaled to determine the overall cost-effectiveness and ROI attributed to implementation of the Dutch FH program. Results: In this model constructed to simulate the progression of FH in 1000 hypothetical 10-year-olds, from a health care perspective, the program would gain 2.53 QALYs per person, at an additional cost of €23 365 ($25 468) (both discounted). These equated to an ICER of €9220 ($10 050) per QALY gained. From the societal perspective, the detection and treatment program were cost saving over a lifetime compared with no cascade screening for FH. The ROI for the detection and treatment program for FH in children was €8.37 ($9.12). Conclusions and Relevance: The findings of this study suggest that the early detection and treatment program for FH in children may offer a good value for investment, being both health and cost saving. The findings and interpretations are conditional on assumptions inherent in the health economic model.

Enhancing the Detection and Care of Heterozygous Familial Hypercholesterolemia in Primary Care: Cost-Effectiveness and Return on Investment.

BACKGROUND: Heterozygous familial hypercholesterolemia (HeFH) is under-detected and undertreated. A general practitioner-led screening and care program for HeFH effectively identified and managed patients with HeFH. We evaluated the cost-effectiveness and the return on investment of an enhanced-care strategy for HeFH in primary care in Australia. METHODS: We developed a multistate Markov model to estimate the outcomes and costs of a general practitioner-led detection and management strategy for HeFH in primary care compared with the standard of care in Australia. The population comprised individuals aged 50 to 80 years, of which 44% had prior cardiovascular disease. Cardiovascular risk, HeFH prevalence, treatment effects, and acute and chronic health care costs were derived from published sources. The study involved screening for HeFH using a validated data-extraction tool (TARB-Ex), followed by a consultation to improve care. The detection rate of HeFH was 16%, and 74% of the patients achieved target LDL-C (low-density lipoprotein cholesterol). Quality-adjusted life years, health care costs, productivity losses, incremental cost-effectiveness ratio, and return on investment ratio were evaluated, outcomes discounted by 5% annually, adopting a health care and a societal perspective. RESULTS: Over the lifetime horizon, the model estimated a gain of 870 years of life lived and 1033 quality-adjusted life years when the general practitioner-led program was employed compared with standard of care. This resulted in an incremental cost-effectiveness ratio of AU$14 664/quality-adjusted life year gained from a health care perspective. From a societal perspective, this strategy, compared with standard of care was cost-saving, with a return on investment of AU$5.64 per dollar invested. CONCLUSIONS: An enhanced general practitioner-led model of care for HeFH is likely to be cost-effective.

How does cholesterol burden change the case for investing in familial hypercholesterolaemia? A cost-effectiveness analysis.

BACKGROUND AND AIMS: This study aimed to ascertain how the long-term benefits and costs of diagnosis and treatment of familial hypercholesterolaemia (FH) vary by prognostic factors and 'cholesterol burden', which is the effect of long-term exposure to low-density lipoprotein cholesterol (LDL-C) on cardiovascular disease (CVD) risk. METHODS: A new cost-effectiveness model was developed from the perspective of the UK National Health Service (NHS), informed by routine data from individuals with FH. The primary outcome was net health gain (i.e., health benefits net of the losses due to costs), expressed in quality-adjusted life years (QALYs) at the £15,000/QALY threshold. Prognostic factors included pre-treatment LDL-C, age, gender, and CVD history. RESULTS: If cholesterol burden is considered, diagnosis resulted in positive net health gain (i.e., it is cost-effective) 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. If cholesterol burden is not considered, diagnosis 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. CONCLUSIONS: Diagnosis and treatment of most people with FH results in large net health gains, particularly in those with higher pre-treatment LDL-C. Economic evaluations of FH interventions should consider the sensitivity of the study conclusions to cholesterol burden, particularly where interventions target younger patients, and explicitly consider prognostic factors such as pre-treatment LDL-C, age, and CVD history.

Cost-Effectiveness of Pediatric Universal Screening for Familial Hypercholesterolemia in Argentina.

OBJECTIVE: Our study aimed to evaluate the expected cost-effectiveness of pediatric universal screening for the early diagnosis of familial hypercholesterolemia in Argentina using a probabilistic model. METHODS: Two different healthcare technologies were compared: (1) Universal screening of hypercholesterolemia at 6 years of age and (2) previous diagnostic situation (comparator). The perspective of the public Argentine healthcare system funded by the National Ministry of Health was used, considering only direct costs. Effectiveness was evaluated in terms of the number of life-years gained (LYG) and quality-adjusted life-years (QALYs) obtained by identifying familial hypercholesterolemia through each of the screening strategies. Only direct costs of screening and treatment of each strategy were evaluated. The time horizon was extended to 60 years. Future avoided costs of prevented coronary events were also included. Cost-effectiveness was measured in terms of the incremental cost-effectiveness ratio (ICER) per LYG and QALYs. Different scenarios were evaluated: (1) only index case, (2) index case and first-degree relatives, and (3) index case and first-degree relatives measuring QALYs. Sensitivity studies were conducted. RESULTS: Each identified child complying with follow-up visits and treatment gains 8.14 life-years. The ICER values obtained were 1465.35 USD/LYG and 1726.50 USD/LYG when applying a discount rate of 5%. The ICER was 10%-17% of the gross domestic product per capita in Argentina (mean 2010-2019: 12 446 USD) and did not exceed the minimum annual retirement income. CONCLUSION: Pediatric universal screening for familial hypercholesterolemia could be considered a cost-effective health technology in Argentina.

Cost-effectiveness of population-wide genomic screening for familial hypercholesterolemia in the United States.

BACKGROUND: Population genomic screening for familial hypercholesterolemia (FH) in unselected individuals can prevent premature cardiovascular disease. OBJECTIVE: To estimate the clinical and economic outcomes of population-wide FH genomic screening versus no genomic screening. METHODS: We developed a decision tree plus 10-state Markov model evaluating the identification of patients with an FH variant, statin treatment status, LDL-C levels, MI, and stroke to compare the costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness of population-wide FH genomic screening. FH variant prevalence (0.4%) was estimated from the Geisinger MyCode Community Health Initiative (MyCode). Genomic test costs were assumed to be $200. Age and sex-based estimates of MI, recurrent MI, stroke, and recurrent stroke were obtained from Framingham risk equations. Additional outcomes independently associated with FH variants were derived from a retrospective analysis of 26,025 participants screened for FH. Sensitivity and threshold analyses were conducted to evaluate model assumptions and uncertainty. RESULTS: FH screening was most effective at younger ages; screening unselected 20-year-olds lead to 111 QALYs gained per 100,000 individuals screened at an incremental cost of $20 M. The incremental cost-effectiveness ratio (ICER) for 20-year-olds was $181,000 per QALY, and there was a 38% probability of cost-effectiveness at a $100,000 per QALY willingness-to-pay threshold. If genomic testing cost falls to $100, the ICER would be $91,000 per QALY. CONCLUSION: Population FH screening is not cost-effective at current willingness to pay thresholds. However, reducing test costs, testing at younger ages, or including FH within broader multiplex screening panels may improve clinical and economic value.

Population genomic screening of young adults for familial hypercholesterolaemia: a cost-effectiveness analysis.

AIMS: The aim of this study was to assess the impact and cost-effectiveness of offering population genomic screening to all young adults in Australia to detect heterozygous familial hypercholesterolaemia (FH). METHODS AND RESULTS: We designed a decision analytic Markov model to compare the current standard of care for heterozygous FH diagnosis in Australia (opportunistic cholesterol screening and genetic cascade testing) with the alternate strategy of population genomic screening of adults aged 18-40 years to detect pathogenic variants in the LDLR/APOB/PCSK9 genes. We used a validated cost-adaptation method to adapt findings to eight high-income countries. The model captured coronary heart disease (CHD) morbidity/mortality over a lifetime horizon, from healthcare and societal perspectives. Risk of CHD, treatment effects, prevalence, and healthcare costs were estimated from published studies. Outcomes included quality-adjusted life years (QALYs), costs and incremental cost-effectiveness ratio (ICER), discounted 5% annually. Sensitivity analyses were undertaken to explore the impact of key input parameters on the robustness of the model. Over the lifetime of the population (4 167 768 men; 4 129 961 women), the model estimated a gain of 33 488years of life lived and 51 790 QALYs due to CHD prevention. Population genomic screening for FH would be cost-effective from a healthcare perspective if the per-test cost was ≤AU$250, yielding an ICER of

Assessment of practical applicability and clinical relevance of a commonly used LDL-C polygenic score in patients with severe hypercholesterolemia.

BACKGROUND AND AIMS: Low-density lipoprotein cholesterol (LDL-C) levels vary in patients with familial hypercholesterolemia (FH) and can be explained by a single deleterious genetic variant or by the aggregate effect of multiple, common small-effect variants that can be captured in a polygenic score (PS). We set out to investigate the contribution of a previously published PS to the inter-individual LDL-C variation and coronary artery disease (CAD) risk in patients with a clinical FH phenotype. METHODS: First, in a cohort of 628 patients referred for genetic FH testing, we evaluated the distribution of a PS for LDL-C comprising 12 genetic variants. Next, we determined its association with coronary artery disease (CAD) risk using UK Biobank data. RESULTS: The mean PS was higher in 533 FH-variant-negative patients (FH/M-) compared with 95 FH-variant carriers (1.02 vs 0.94, p < 0.001). 39% of all patients had a PS equal to the top 20% from a population-based reference cohort and these patients were less likely to carry an FH variant (OR 0.22, 95% CI 0.10-0.48) compared with patients in the lowest 20%. In UK Biobank data, the PS explained 7.4% of variance in LDL-C levels and was associated with incident CAD. Addition of PS to a prediction model using age and sex and LDL-C did not increase the c-statistic for predicting CAD risk. CONCLUSIONS: This 12-variant PS was higher in FH/M- patients and associated with incident CAD in UK Biobank data. However, the PS did not improve predictive accuracy when added to the readily available characteristics age, sex and LDL-C, suggesting limited discriminative value for CAD.

Familial Hypercholesterolemia in Asia Pacific: A Review of Epidemiology, Diagnosis, and Management in the Region.

Familial hypercholesterolemia (FH) is a common genetic disease that is estimated to affect at least 15 million people in the Asia Pacific region. Affected individuals are at significantly increased risk of premature atherosclerotic cardiovascular disease. A literature review was undertaken to provide an overview of the epidemiology, diagnosis, and management of FH across the region.Currently, epidemiological data relating to FH are lacking across the Asia Pacific. Of the 15 countries and regions considered, locally conducted studies to determine FH prevalence were only identified for Australia, China, India, and Japan. Although practically all national clinical guidelines for dyslipidemia include some commentary on FH, specific guidelines on the management of FH are available for only one third of the countries and regions evaluated. Estimates of current FH diagnosis rates suggest that most affected individuals remain undiagnosed and untreated. Although innovative medications such as proprotein convertase subtilisin/kexin type 9 inhibitors have been approved and are available in most countries and regions considered, they are currently reimbursed in only one quarter.Despite these shortcomings, there is cause for optimism. Early experience with cascade screening in Hong Kong, India, and Vietnam has proven an effective means of identifying family members of probands, as has a reverse screening of family members of children with FH in China. FH registries are gaining momentum across the region, with registries now established in almost half of the countries and regions evaluated. This review concludes with a Call to Action on FH for Asia Pacific to engage healthcare professionals, improve public awareness, and form national FH alliances, comprising all relevant healthcare professional organizations, as a platform to expedite national quality improvement programs in the management of FH.

Feasibility and cost of FH cascade screening in Belgium (BEL-CASCADE) including a novel rapid rule-out strategy.

BACKGROUND: Familial hypercholesterolaemia (FH) is underdiagnosed in most countries. We report our first experience from a national pilot project of cascade screening in relatives of FH patients. METHODOLOGY: Participating specialists recruited consecutive index patients (IP) with Dutch Lipid Clinic Network (DLCN) score ≥6. After informed consent, the relatives were visited by the nurses to collect relevant clinical data and perform blood sampling for lipid profile measurement. FH diagnosis in the relatives was based on the DLCN and/or MEDPED FH (Make-Early-Diagnosis-to-Prevent-Early-Deaths-in-FH) criteria. RESULTS: In a period of 18 months, a total of 127 IP (90 with definite FH and 37 with probable FH) were enrolled in 15 centres. Out of the 270 relatives visited by the nurses, 105 were suspected of having FH: 31 with DCLN score >8, 33 with DLCN score 5-8 and 41 with MEDPED FH criteria. In a post-hoc analysis, another set of MEDPED FH criteria established in the Netherlands and adapted to Belgium allowed to detect FH in 51 additional relatives. CONCLUSION: In a country with no national FH screening program, our pilot project demonstrated that implementing a simple phenotypical FH cascade screening strategy using the collaboration of motivated specialists and two nurses, allowed to diagnose FH in 127 index patients and an additional 105 of their relatives over the two-year period. Newly developed MEDPED FH cut-offs, easily applicable by a nurse with a single blood sample, might further improve the sensitivity of detecting FH within families.

Cost-Effectiveness of Evolocumab Therapy for Myocardial Infarction: The Chinese Healthcare Perspective.

PURPOSE: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an indispensable lipid-lowering treatment option, but their cost-effectiveness has been questioned. This study aimed to perform a health economic evaluation of evolocumab versus placebo in patients with myocardial infarction (MI) in China. METHODS: A Markov cohort state-transition model was developed in decision analysis software to estimate the incremental cost-effectiveness ratio (ICER), defined as cost per quality-adjusted life-year (QALY) saved. The simulation subjects could undergo non-fatal MI and/or stroke, or vascular or non-vascular death event. We integrated the Chinese population-specific demographics and event rates with the risk reduction of evolocumab based on the FOURIER trial and/or lowering of low-density lipoprotein cholesterol (LDL-C). Age-related change, event costs and utilities were included from published sources. RESULTS: At its current list price [33,748 Chinese yuan (CNY) annually per person], the ICER for evolocumab therapy was 927,713 CNY per QALY gained when integrating the FOURIER trial with absolute reduction of LDL-C. The probability of cost-effectiveness of evolocumab versus placebo was 1.96%, with a generally accepted threshold of 212,676 CNY per QALY gained. A reduction in acquisition price by approximately 70% (to less than 10,255 CNY annually) was needed to be cost-effective. Alternative scenario analyses of therapeutic benefit showed that the ICER for evolocumab in MI patients with uncontrolled familial hypercholesterolemia (FH) was 187,736 CNY per QALY gained. CONCLUSION: Evolocumab in patients with MI was not cost-effective based on the price in 2019 in China; however, treatment with evolocumab was more favorable in MI patients with FH.

Awareness, treatment rates, and compliance to treatment in patients with serum LDL cholesterol higher than 250 mg/dL, and possible, probable, or definite familial hypercholesterolemia.

PURPOSE: Familial hypercholesterolemia (FH) is a genetic disease characterized by increased levels of low-density lipoprotein cholesterol (LDL-C). It is underdiagnosed and undertreated despite relatively high prevalance and significant association with increased mortality. We aimed to determine treatment status and compliance in patients with LDL-C ≥ 250 mg/dL and FH. DESIGN: Patients older than 18 years old and have a serum LDL-C ≥ 250 mg/dL between January 2010 to December 2016 were identified from the hospital database. A phone survey was performed. Demographic features, smoking status, alcohol use, exercise, cardiovascular disease (CVD), use of medication for dyslipidemia, and CVD and high cholesterol levels in the family were questioned. Dutch Lipid Clinical Network Criteria was used to classify patients. The study was registered to Clinicaltrials.gov in July 2020 (NCT04494464). RESULTS: 1365 patients with a LDL-C ≥ 250 mg/dL were identified. Patients that could not be reached and who refused to interview were excluded and the data of 367 patients were analyzed. There were 248 (67.6%) female and 119 (32.4%) male patients and mean age was 50.52 ± 11.66. LDL-C was ≥330 mg/dL in 50 (13.6%) and 250-329 mg/dL in 317 (86.4%) patients. Forty (10.9%) patients were classified as definite, 181 (49.3%) as probable and 146 (39.8%) as possible FH. 213 (58.0%) patients were not receiving lipid-lowering treatment, and 162 (76.1%) stated that medication was never recommended previously, 30 (14.1%) had stopped medication him/herself and 21 (9.8%) had stopped medication with the advice of the physician. Among patients with definite/probable FH, 84 (38.0%) had CVD and the rate of lipid-lowering drug use in these patients was 58.3%. CONCLUSION: A significant proportion of patients with LDL-C ≥ 250 mg/dL were not taking lipid-lowering drugs. Similar with many other studies, diagnosis, and treatment rates of FH patients were very low in our study. Further national studies are required to increase awareness of the disease in both physicians and patients.

Risk Factor Burden and Long-Term Prognosis of Patients With Premature Coronary Artery Disease.

Background Coronary artery disease (CAD) is increasing among young adults. We aimed to describe the cardiovascular risk factors and long-term prognosis of premature CAD. Methods and Results Using the Duke Databank for Cardiovascular Disease, we evaluated 3655 patients admitted between 1995 and 2013 with a first diagnosis of obstructive CAD before the age of 50 years. Major adverse cardiovascular events (MACEs), defined as the composite of death, myocardial infarction, stroke, or revascularization, were ascertained for up to 10 years. Cox proportional hazard regression models were used to assess associations with the rate of first recurrent event, and negative binomial log-linear regression was used for rate of multiple event recurrences. Past or current smoking was the most frequent cardiovascular factor (60.8%), followed by hypertension (52.8%) and family history of CAD (39.8%). Within a 10-year follow-up, 52.9% of patients had at least 1 MACE, 18.6% had at least 2 recurrent MACEs, and 7.9% had at least 3 recurrent MACEs, with death occurring in 20.9% of patients. Across follow-up, 31.7% to 37.2% of patients continued smoking, 81.7% to 89.3% had low-density lipoprotein cholesterol levels beyond the goal of 70 mg/dL, and 16% had new-onset diabetes mellitus. Female sex, diabetes mellitus, chronic kidney disease, multivessel disease, and chronic inflammatory disease were factors associated with recurrent MACEs. Conclusions Premature CAD is an aggressive disease with frequent ischemic recurrences and premature death. Individuals with premature CAD have a high proportion of modifiable cardiovascular risk factors, but failure to control them is frequently observed.

The Knowns and Unknowns of Contemporary Statin Therapy for Familial Hypercholesterolemia.

PURPOSE OF REVIEW: Statins are first-line therapy for lowering low-density lipoprotein (LDL) cholesterol in familial hypercholesterolemia (FH), particularly in heterozygous patients. We review advances and new questions on the use of statins in FH. RECENT FINDINGS: Cumulative evidence from registry data and sub-analyses of clinical trials mandates the value of statin therapy for prevention of atherosclerotic cardiovascular disease (ASCVD) in FH. Statins are safe in children and adolescents with FH, with longer term cardiovascular benefits. The potentially toxic effects of statins in pregnancy need to be considered, but no association has been reported in prospective cohort studies with birth defects. There is no rationale for discontinuation of statins in elderly FH unless indicated by adverse events. FH is undertreated, with > 80% of statin-treated FH patients failing to attain LDL cholesterol treatment targets. This may relate to adherence, tolerability, and genetic differences in statin responsiveness. Statin treatment from childhood may reduce the need for stringent cholesterol targets. Combination of statins with ezetimibe and PCSK9 inhibitors significantly improves the efficacy of treatment. Whether statin use could improve the clinical course of FH patients with COVID-19 and other respiratory infections remains an unsolved issue for future research. Statins are the mainstay for primary and secondary prevention of ASCVD in FH. Sustained long-term optimal statin treatment from an early age can effectively prevent ASCVD over decades of life. Despite their widespread use, statins merit further investigation in FH.

Health economic evaluation of screening and treating children with familial hypercholesterolemia early in life: Many happy returns on investment?

BACKGROUND AND AIMS: There are no studies that have specifically investigated the cost-effectiveness of cascade screening of children for heterozygous familial hypercholesterolemia (FH) and treatment of affected individuals with statins to prevent coronary heart disease (CHD). This study explores the cost-effectiveness of this strategy from the perspective of the Australian public healthcare system. METHODS: A lifetime Markov model with four health states (Alive without CHD, Alive with CHD, Dead from fatal CHD, and Dead from other causes) was developed to simulate the progression of ten-year-old children screened for FH and treated immediately with statins if found to have FH. The underlying prevalence of FH in this target population was assumed to be 56.8%, and the sensitivity and specificity of testing were 100%. The comparator was usual care, which assumed that subjects started statins spontaneously at a later point or when they experienced a cardiovascular event. The effect of reducing low-density lipoprotein cholesterol (LDL-C) on the risk of a first event at each age assumed that risk was proportional to total lifetime exposure and was implemented using Mendelian randomisation analysis data. Cost and other outcome data were sourced from published sources. Outcome of interests were costs in Australian dollars (AUD), life years gained (LYG) and quality-adjusted life years (QALYs) gained, as well as incremental cost-effectiveness ratios (ICERs) of costs per LYG and per QALY gained. All future costs and outcomes were discounted by 5% annually. RESULTS: Undiscounted results showed that compared with usual care, cascade screening of ten year-old children for FH and initiation of treatment of affected individuals saved 7.77 LYG and 7.53 QALYs per person over a lifetime. With 5% annual discounting, there were 0.97 LYG and 1.07 QALYs gained per person, at net reduction cost of -$1134. The cascade screening of ten-year-old children for FH and initiation of treatment compared to usual case was a cost saving approach. In 51.2% of iterations, screening and initiation with statin were cost saving and in 48.8% of iterations were cost-effective. In most of the one-way sensitivity and scenario analyses, the ICER stayed within the accepted Australian threshold. CONCLUSIONS: Compared to usual care, cascade screening of ten-year-old children for FH and treating affected individuals are likely to be cost saving.

Proportion of High-Risk/Very High-Risk Patients in Europe with Low-Density Lipoprotein Cholesterol at Target According to European Guidelines: A Systematic Review.

OBJECTIVE: Assess achievement of low-density lipoprotein cholesterol (LDL-C) targets in European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines. DESIGN: Systematic literature review. DATA SOURCES: Medline, EMBASE, Cumulated Index to Nursing and Allied Health Literature. ELIGIBILITY CRITERIA: Observational studies reporting LDL-C levels/target attainment, measured between 1 August 2006 to 31 August 2017, in European adults with established cardiovascular disease (CVD), diabetes with target organ damage, familial hypercholesterolaemia (FH) or 10-year risk of fatal CVD ≥ 5% (assessed by Systematic Coronary Risk Evaluation [SCORE]). DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted relevant studies and assessed study quality using the Risk of Bias for Non-Randomised Studies-Interventions (ROBINS-I) tool. Primary outcome was the proportion of patients achieving LDL-C targets in the 2011/2016 ESC/EAS guidelines. Where available, patient characteristics were presented as means weighted by sample size. The proportions of patients achieving LDL-C targets in the 5 years before and after publication of the 2011 guidelines were compared using a chi-square test. RESULTS: Across 81 eligible studies (303,534 patients), achievement of LDL-C < 1.8 mmol/L was poor among patients with established CVD (16%; range 9-56%) and at very high risk of CVD (SCORE ≥ 10% [18%; 14-25%]). In individuals with FH, SCORE 5-10%, or diabetes and target organ damage, LDL-C < 2.5 mmol/L was achieved by 15% (9-22%), 46% (21-55%) and 13% (6-34%), respectively. Comparing the 5 years before/after publication of the 2011 guidelines, target achievement increased significantly over time but remained suboptimal (LDL-C < 1.8, 22% versus 15%; LDL-C < 2.5, 68% versus 61%; both p < 0.001; established CVD group only). CONCLUSIONS: These data show suboptimal LDL-C control among European patients at high risk of CVD. Those at greatest overall risk (clinically established CVD or at least a 10% 10-year risk of fatal CVD) had the lowest achievement of 2011/2016 EAS/ESC LDL-C targets. With lower LDL-C targets advocated in 2019 ESC/EAS guidelines, this unmet need will increase. PROTOCOL REGISTRATION: PROSPERO registration number; CRD77844.

The characteristics of patients with possible familial hypercholesterolemia-screening a large payer/provider healthcare delivery system.

BACKGROUND: Familial hypercholesterolemia (FH) is an under-diagnosed condition. AIM: We applied standard laboratory criteria across a large longitudinal electronic medical record database to describe cross-sectional population with possible FH. METHODS: A cross-sectional study of Clalit Health Services members. Subjects who met the General Population MED-PED laboratory criteria, excluding: age <10 years, documentation of thyroid, liver, biliary or autoimmune diseases, a history of chronic kidney disease stage 3 or greater, the presence of urine protein >300 mg/l, HDL-C>80 mg/dl, active malignancy or pregnancy at the time of testing were considered possible FH. Demographic and clinical characteristics are described at time of diagnosis and at a single index date following diagnosis to estimate the burden on the healthcare system. The patient population is also compared to the general population. RESULTS: The study cohort included 12 494 subjects with out of over 4.5 million members of Clalit Health Services. The estimated prevalence of FH in Israel was found to be 1:285. These patients are notably positive for, and have a family history of, cardiovascular disease and risk factors. For most of them the LDL-C levels are not controlled, and only a quarter of them are medically treated. CONCLUSIONS: By using the modified MED-PED criteria in a large electronic database, patients with possible FH can be identified enabling early intervention and treatment.

A genetic risk score predicts coronary artery disease in familial hypercholesterolaemia: enhancing the precision of risk assessment.

Familial hypercholesterolaemia (FH) is associated with increased risk of coronary artery disease (CAD); however, risk prediction and stratification remain a challenge. Genetic risk scores (GRS) may have utility in identifying FH patients at high CAD risk. The study included 811 patients attending the lipid disorders clinic at Royal Perth Hospital with mutation-positive (n = 251) and mutation-negative (n = 560) FH. Patients were genotyped for a GRS previously associated with CAD. Associations between the GRS, clinical characteristics, and CAD were assessed using regression analyses. The average age of patients was 49.6 years, and 44.1% were male. The GRS was associated with increased odds of a CAD event in mutation-positive [odds ratio (OR) = 3.3; 95% confidence interval (CI) = 1.3-8.2; P = .009] and mutation-negative FH patients (OR = 1.8; 95% CI = 1.0-3.3; P = .039) after adjusting for established predictors of CAD risk. The GRS was associated with greater subclinical atherosclerosis as assessed by coronary artery calcium score (P = .039). A high GRS was associated with CAD defined clinically and angiographically in FH patients. High GRS patients may benefit from more intensive management including lifestyle modification and aggressive lipid-lowering therapy. Further assessment of the utility of the GRS requires investigation in prospective cohorts, including its role in influencing the management of FH patients in the clinic.