For Familial Hypercholesterolemia Research Articles

Application of implementation science for improving the utilization of an international clinical practice guidance on familial hypercholesterolemia

BACKGROUNDThe International Atherosclerosis Society (IAS) published an evidence-informed guidance for familial hypercholesterolemia (FH) that provides both clinical and implementation recommendations. We reference examples of strategies from the literature to explore how these implementation recommendations can be tailored into implementation strategies at the local-level for stakeholders guided by a framework proposed by Sarkies and Jones. METHODSFour authors of the IAS guidance selected two published exemplar implementation recommendations for detection, management, and general implementation. Each recommendation was described as an implementation strategy using Proctor's guidance for specifying and reporting implementation strategies. It recommends reporting the actor (who), action (what), action-target (who is impacted), temporality (how often), and dose (how much) for each implementation strategy. RESULTSDetection: A centralized cascade testing model, mobilized nurses (actor) to relative's homes, after the diagnosis of the proband (temporality), once (dose) to consent, obtain a blood sample and health information (action) on relatives (action-target). Management: A primary care initiative to improve FH management included an educational session (action) with clinicians (action-target), computer-based reminder message and message to patients to have their cholesterol screened once (dose) at a visit or outreach (temporality) by researchers (actor). General: A partnership between a statewide public pathology provider, local public hospital network, primary health network, government health ministry, and an academic university (actors) was established to implement a primary-tertiary shared care model (action) to improve the detection of FH (action-target). CONCLUSIONSWe demonstrate that implementation recommendations can be specified and reported for different local contexts with examples on monitoring, evaluation, and sustainability in practice.

Prognostic value of diagnostic criteria for familial hypercholesterolemia in men and women with dyslipidemia

Aim. To analyze the prognostic value of the Dutch Lipid Clinic Network (DLCN) and Simon Broome Register (SBR) screening criteria for familial hypercholesterolemia (FH) in men and women with dyslipidemia.Material and methods. The study included 1233 patients with dyslipidemia.Biomaterial samples from 421 patients were studied using Next Generation Sequencing (NGS) to identify FH-associated genes. Statistical analysis was carried out using the StatTech v program. 3.1.6 (OOO Stattekh, Russia).Results. The most significant factors for predicting the FH in men are the level of low-density lipoprotein cholesterol (LDL-C) (1,77 times), positive family history for coronary artery disease (CAD) (6,26 times), multivessel coronary artery disease (4,05 times); in women before menopause — LDL-C (1,77 times per 1 mmol/l) and/or family history of coronary artery disease (3,31 times), in menopausal women — total cholesterol level (1,79 times per 1 mmol/l), coronary artery disease (6,52 times) and/or family history of stroke (6,04 times), xanthomas (4,24 times). Acute myocardial infarction and/or coronary stenting, arcus senilis, extracranial artery atherosclerosis did not prove to be prognostically significant for FH diagnosis.Conclusion. Diagnostic criteria for potential FH vary among patient populations. Its diagnostic significance depends on sex, and in women, reproductive status.

Should Familial Hypercholesterolaemia Be Included in the UK Newborn Whole Genome Sequencing Programme?

The UK National Health Service (NHS) has recently announced a Newborn Genomes Programme (NGP) to identify infants with treatable inherited disorders using whole genome sequencing (WGS). Here, we address, for familial hypercholesterolaemia (FH), the four principles that must be met for the inclusion of a disorder in the NGP. Principle A: There is strong evidence that the genetic variants causing FH can be reliably detected. Principle B: A high proportion of individuals who carry an FH-causing variant are likely to develop early heart disease if left undiagnosed and not offered appropriate treatment. Principle C: Early intervention has been shown to lead to substantially improved outcomes in children with FH. Principle D: The recommended interventions are equitably accessible for all. FH meets all the Wilson and Jungner criteria for inclusion in a screening programme, and it also meets all four principles and therefore should be included in the Newborn Genomes Programme.

Cascade testing of children and adolescents for elevated Lp(a) in pedigrees with familial hypercholesterolaemia

Elevated plasma lipoprotein(a) [Lp(a)] is a common, inherited condition independently causing cardiovascular disease. Recent expert recommendations suggest opportunistically testing for elevated Lp(a) during cascade testing for familial hypercholesterolaemia (FH). We investigated the effectiveness of detecting elevated Lp(a) in 103 children and adolescents who were first-degree relatives of 66 adult index FH cases as part of an established FH cascade screening program. The yield of detection of elevated Lp(a) using a threshold of ≥30 mg/dL in children and adolescents was assessed. Cascade testing from FH index cases with elevated Lp(a) ≥50 mg/dL identified 1 case of Lp(a) ≥30 mg/dL for every 2 children or adolescents tested. In contrast, opportunistic screening from index cases with FH but normal Lp(a) levels demonstrated 1 case of Lp(a) ≥30 mg/dL for every 7.5 children or adolescents tested (p < 0.001). In conclusion, cascade testing for elevated Lp(a) from index cases with FH and elevated Lp(a) is effective in identifying new cases of elevated Lp(a).

Abstract 16434: 104-Week Safety and Effectiveness of Low-Density Lipoprotein Cholesterol-Lowering Therapy With Evolocumab in Patients With Familial Hypercholesterolemia/Hypercholesterolemia in Japan: Results of Post-Marketing Surveillance

Introduction: Evolocumab is the first monoclonal antibody against proprotein convertase subtilisin/kexin type 9 approved in Japan for familial hypercholesterolemia (FH) and hypercholesterolemia (HC). Aims: This study assessed the 104-week safety and effectiveness of low-density lipoprotein cholesterol (LDL-C)-lowering therapy with evolocumab in patients with FH (homo/heterozygous) and HC in a real-world setting in Japan. Methods: Overall, 3721 and 2792 patients (108 and 91 homozygous FH, 2007 and 1613 heterozygous FH, 1606 and 1088 HC) from 668 clinical sites comprised the safety and effectiveness analysis sets, respectively. Primary safety endpoints: incidence (%) and number of patients with adverse drug reactions and serious adverse events. Effectiveness endpoints: % change in LDL-C from baseline at Week 12 (n=2386, primary endpoint) and Weeks 4-104 (secondary endpoint). Results: Mean age: 63.2 years; female: 33.8%. The mean±SD follow-up duration was 545.5±218.8 days. Adverse drug reaction subject incidence was 5.2%. Serious adverse event subject incidence was 8.9% (330/3721). The adverse event incidences of myocardial infarction and stroke were 0.6% (n=23/3721) and 0.6% (n=21/3721; 0.3% ischemic stroke [n=12]/0.2% hemorrhagic stroke [n=9]), respectively. Table 1 shows adverse events by lowest achieved LDL-C levels. The mean±SD % change in LDL-C from baseline to Weeks 12 and 104 were –45.7%±28.2% (n=84) and –50.9±21.1% (n=48) in homozygous FH patients ( P &lt;0.001 vs baseline; two-sided paired t -test), –56.0%±28.9% (n=1440) and –54.5±28.3% (n=905) in heterozygous FH patients ( P &lt;0.001), and –63.3%±23.7% (n=862) and –60.8±28.1% (n=352) in HC patients ( P &lt;0.001), respectively. Conclusions: There were no trends between the lowest achieved LDL-C levels and adverse events in Japanese patients. Evolocumab was well tolerated and sustained LDL-C reduction in patients with FH and HC in a real-world clinical setting in Japan.

Feasibility, Efficacy, and Safety of Peripheral Venous Access for Chronic Double-Filtration Plasmapheresis with Regional Citrate Anticoagulation

Introduction: Peripheral venous access (PVA) is recommended as a first-line vascular approach for therapeutic plasmapheresis with centrifugation methods but not filtration, which usually requires high blood flow. We evaluated the feasibility, efficacy, and safety of double-filtration plasmapheresis (DFPP) with PVA, using ultrasound guidance and regional citrate anticoagulation (RCA), i.e., PVA-RCA-DFPP in patients undergoing chronic DFPP. Secondly, we assessed the number of central venous catheters (CVCs) avoided. Methods: A single-center retrospective study evaluated 22 adult patients on chronic DFPP to perform PVA-RCA-DFPP. They were classified into 3 groups: successful (i.e., completion of sessions with PVA), primary failure (i.e., no sessions completed), secondary failure (i.e., ≥1 session with PVA completed but secondary return with CVC or arteriovenous fistula). Results: Among the 22 patients included (64% men), 7 patients (32%) were classified as primary failures (2 patient refusals, 5 inadequate PVAs), 1 patient (5%) as a secondary failure (due to uncomfortable venipunctures), and 14 patients (64%) as successful. In the successful group including 12 patients treated for chronic inflammatory demyelinating polyneuropathy (CIDP) and 2 patients for familial hypercholesterolemia (FH) (2 patients), 116 sessions were performed, with a median treated plasma volume of 4.3 L [IQR 3.6–4.6] (45 mL/kg) for a median duration of 134 min [IQR 122–144], and a median blood flow of 94 mL/min [IQR 87–103]. For the CIDP group, 90% of sessions achieved a plasma volume >1 TPV, and for the FH group 91% of sessions achieved an LDLc reduction >60%. Eleven sessions out of 116 (9%) were interrupted, mostly due to PVA dysfunction (5/11) and circuit clotting (4/11). Session interruptions decreased significantly between each patient’s first and following sessions (29% to 7%, p = 0.009). Conclusion: Chronic PVA-RCA-DFPP can be performed safely and efficiently, avoiding the use of CVCs.

Predictors of cardiovascular disease in a familial hypercholesterolemia unit

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Screening and cascade screening for familial hypercholesterolemia (FH) is advised in patients with early coronary heart disease (ECHD) or high-risk dyslipidemia LDL-c &amp;gt;190 mg/dL without secondary cause. The diagnostic rates of FH by genetic testing are 5-9% in patients with ECHD and 2-5% in patients with high-risk dyslipidemia. Methods Observational retrospective study of a cohort of 615 patients over 18 years of age, included in an HF unit (177 index cases and 438 first-grade relatives). The population was divided into 201 (32.7%) patients with cardiovascular disease (CVD) (Group A), and 414 patients without CVD (Group B). Clinical characteristics, variables of the inclusion blood test in the HF unit and the lipid-lowering treatment implemented were compared. Results Group A patients were older, wiht a higher proportion of male, higher rates of hypertension and diabetes, higher body mass index (BMI), higher percentage of obese, and no difference in historical maximum LDL-c levels compared to Group B. Group A patients, as a result of CVD, receivedmore potent lipid-lowering treatment, had lower levels of LDL-c but without differences in meeting their LDL-c objective (45.7% vs 39%, p=0.19), presented a higher rate of small and dense LDL-c either measured by LDL-c/ApoB ratio &amp;lt;1.3 or Triglycerides/HDL-c &amp;gt;2, and lower HDL-c values with a higher percentage of values minor than 40 mg/dL in men and less than 45 mg/dL in women (HDL-c &amp;lt;40-45). Group A had higher lipoprotein (a) values and higher lipoprotein (a) &amp;gt;180 mg/dL (equivalent to FH), a higher proportion of chronic kidney desease and increased uric acid (table 1). Conclusions In a population of patients with suspected FH, the presence of CV risk factors (male sex, older age, high blood pressure, diabetes, obesity, chronic kidney desease), and atherogenic blood test (HDL&amp;lt;40-45, increased lipoprotein (a), increased uric acid, small and dense LDL-c) were associated with CVD. The detection of these in this patient population of patients should lead us to act early and aggressively to prevent the development of CV events.

Referral rate, profile and degree of control of patients with familial hypercholesterolemia: data from a single lipid unit from a Mediterranean area

BackgroundThe challenging rigorous management of hypercholesterolemia promotes referral to specialized units. This study explored the need, based on referral rate and cardiovascular (CV) risk factor control in patients evaluated for familial hypercholesterolemia (FH), for a lipid unit (LU).MethodsOver a four-year period, 340 referrals to our unit were analyzed to establish the lipid disorder referral rate. Moreover, 118 patients referred for potential FH during the period 2010–2018 (52.4 ± 13.9 years, 47.5% male, Caucasian, 26.3% obese, 33.1% smokers and 51.7% with some glycaemic alteration) were investigated. The Dutch Lipid Clinic Network (DLCN) score, type and dose of lipid-lowering drugs, lipid profile including lipoprotein (a) (Lp(a)) and the presence of plaques with carotid ultrasound (CU) were recorded.ResultsLipids represented 6.2% of referrals (38 patient-years) requiring a 2–3 h weekly monographic outpatient consultation. The potential FH sample displayed a DLCN score ≥ 6 in 78% and modifiable CV risk factors in 51%. Only 22% achieved tight disease control despite intensive treatment. The statin-ezetimibe combination treatment group achieved better goals (73.0% vs. 45.5%, P = 0.003), and the rosuvastatin group had a higher proportion of prediabetes (60.9% vs. 39.1%, P = 0.037). Neither CU plaque presence nor Lp(a) > 50 mg/dL was linked with established CV disease patients, but higher Lp(a) concentrations were detected between them (102.5 (26.3–145.8) vs. 25.0 (13.0–52.0) mg/dL, P = 0.012).ConclusionsThe referral rate, degree of control, and proportion of modifiable CV risk factors in FH patients demonstrate the need for LU in our area as well as optimize control and treatment.

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

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. 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. 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. 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. 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. 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). 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.

Update on Sitosterolemia and Atherosclerosis.

The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease. Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative.

Understanding how educational interventions improve treatment adherence in patients with familial hypercholesterolaemia: a systematic review

Effective treatments for familial hypercholesterolaemia (FH) offer patients the opportunity of normal life expectancy, but lifelong adherence to both lipid-lowering therapies and lifestyle measures is challenging, and thus, this is rarely achieved. The aim of this systematic review is to identify attributes of educational interventions that promote adherence to treatment in FH. A systematic literature search was undertaken using Medline, CINAHL, HMIC and Embase. Papers were included based upon pre-defined inclusion and exclusion criteria; the quality of each included paper was assessed using the MERSQI scoring system. Relevant data were extracted, and a narrative synthesis was created. Six relevant studies of varying methodological quality were found amongst 2963 papers identified during the search. In total, there were 619 patients with FH in the intervention arm of the relevant studies. All six studies showed a positive effect of education on adherence to FH treatment; however, only two papers observed a statistically significant effect. Assessment was limited to the short-term. Four themes were identified as important when using education to improve treatment adherence: involving family, patient empowerment, practical problem solving and use of information leaflets. Educational interventions improve short term treatment adherence in patients with FH. Successful interventions are those that involve the whole family, set practical problem solving tasks, and that use techniques to increase the patients self-efficacy. This should all be supported by contemporaneous provision of written, age-appropriate information. There were no studies looking at education and long-term adherence in FH patients, and more research is needed in this area.

Preliminary results from REALITY: a nation-wide study of a database with 1.8 million real-life patients to study atherosclerotic cardiovascular disease and familial hypercholesterolemia in Spain

Abstract Introduction Ischemic heart disease and stroke are the leading causes of premature death worldwide. Atherosclerotic cardiovascular disease (ASCVD) is the main determining factor for these and other life-threatening pathologies, such as peripheral artery disease (PAD). LDL-lowering therapies are the gold standard to prevent ASCVD. These treatments are also used for familial hypercholesterolemia (FH), a genetic disorder manifesting with high LDL levels. It is crucial to evaluate the management and level of LDL control in “real-life” patients with ASCVD and FH, but so far very few large-scale studies have focussed on these issues. REALITY is an observational retrospective study of ASCVD and FH in Spain. Purpose The goals of REALITY included the analysis of the demographic and clinical characteristics, comorbidities, and concomitant medication of patients with ASCVD and/or FH by a multidisciplinary group of experts. The lipid-lowering therapies used in Spain were assessed, and patient LDL levels were evaluated according to treatment intensity during the two-year follow-up period. Methods Electronic medical records were retrieved from the BIG-PAC® database that includes anonymized data of patients from seven health areas in Spain. The study population included patients presenting a new or recurrent episode of ASCVD (n=26,976) or a new diagnosis of FH (n=572) during the recruitment period (from 01/01/2017 to 31/12/2018). The index date was defined as the date of the event/diagnosis, and a 2-year follow-up was established. Results The average age was 69.9±11.5 for ASCVD patients and 60.1±12 for FH patients (59.4% and 48.6% males, respectively). The average Charlson index was 2.2±1.6 in ASCVD and 1.2±1.4 in FH. The comorbidities most frequently observed in ASCVD vs. FH were hypercholesterolaemia (55% vs. 100%), arterial hypertension (65% vs. 54%), diabetes mellitus (31% vs. 29%) and obesity (31% vs. 21%). Around 25% and 6% of patients with ASCVD and FH, respectively, presented CV events in the follow-up. During the 24-month period, the highest rate of ischemic heart disease was observed in patients with LDL levels of 55–69 mg/dL, whereas LDL levels below 55 mg/dL were associated with the highest incidence of PAD. The highest lipid biochemical reductions in ASCVD vs. FH were observed in total cholesterol (−52±17.4 vs. −53.5±21.3 mg/dL), triglycerides (−53±7.9 vs. −54.2±8.8 mg/dL) and LDL (−27.4±10.4 vs. −29±12.3 mg/dL). HDL levels showed an average increase of 8.5±2 vs. 9.3±2.5 mg/dL. Treatment intensity correlated with reduction of LDL levels in all ASCVD disease subgroups and FH patients (Table 1). Conclusions The results of REALITY provide an estimated clinical picture of ASCVD and FH in Spain. The impact of therapeutical approaches on LDL levels and the prevention of CV events were evaluated by a multidisciplinary group of experts. The findings of the study will help lower the burden of ASCVD and FH in Spain. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): REALITY study was sponsored by Novartis. Statistical analysis of the BIG-PAC® database was performed by Atrys Health. Medical writing and editing were provided by Medical Science Consulting. All funded by Novartis.

Dutch Nationwide Implementation Program for familial hypercholesterolemia case finding in children: a cost-effectiveness and return on investment analysis

Abstract Background The Netherlands is one of the few countries in the world that actively screen for familial hypercholesterolemia (FH). Objectives We investigated the return on investment (ROI) and cost-effectiveness of the Dutch nationwide implementation program for FH case-finding and preventive treatment in children compared to later detection and treatment from both a societal and healthcare perspective in the Netherlands. Methods Cascade case finding and early preventive treatment were modelled to simulate the progression of disease and costs of ten-year-olds suspected of having heterozygous FH (HeFH) over a lifetime. The model consisted of three health states: alive without coronary heart disease (CHD), alive with CHD, and dead. The decision was to compare the nationwide implementation program for FH cascade case-finding in children and immediate treatment with statins compared to “usual care” later detection and treatment. The prevalence of HeFH in this target population was 51.2% as per the Dutch Health Program for FH case-finding, and the sensitivity and specificity of testing was 100%. Contemporary Mendelian Randomisation Analysis data was used to quantify the risk of a first coronary heart disease event as a function of age and total lifetime exposure to low-density-lipoprotein cholesterol. Costs and outcome were sourced from the Dutch data and other published sources. ROI for the Dutch nationwide implementation program for FH case-finding and cost-effectiveness analyses using incremental cost-effectiveness ratios (ICERs) (cost per quality-adjusted life years (QALYs) gained), compared with current usual care were the main outcomes of interest. All future benefits and costs were discounted annually by 1.5% and 4% respectively. Results Over the lifetime horizon, the ROI for the Dutch nationwide implementation program for FH case-finding was €16.52 (i.e. every euro spent on the program resulted in a return of €16.52). From the societal perspective, the Dutch nationwide implementation program for FH case-finding and early treatment with statins was the dominant strategy (health improvement and cost saving) compared to usual care. From a healthcare perspective, the Dutch nationwide implementation program for FH case-finding and early treatment with statins would gain 2.64 QALYs per person, at an additional cost of €7,178 (both discounted). These equated to an ICER of €2,668 per QALY gained. Conclusions From the societal perspective, the the Dutch nationwide implementation program for FH case-finding represented excellent value for investment for Netherlands, being not only health saving but also cost saving form a societal perspective and cost effective from a healthcare perspective. Funding Acknowledgement Type of funding sources: None.

Awareness of positive genetic testing for familial hypercholesterolemia encourages better adherence to triple-combined lipid-lowering therapy

Background and Aims : To assess the impact of awareness of genetic testing for familial hypercholesterolemia (FH) on the adherence to the lipid-lowering therapy (LLT).Methods: Patients ≥18 y.o. with “probable” or “definite” FH according to the DLCN criteria were included (n=82). The study consists of three visits (follow-up is 6 months) with a block randomization with a 2:1 allocation ratio (with: without genetic testing). The results of genetic testing were reported at the second visit. Patients were divided into 3 groups: I - with "positive" genetic testing (n=38); II - with "negative" genetic testing (n=19); III - without genetic testing (n=25). Fisher's test was used for statistical analysis. The study was registered on ClinicalTrials (NCT04656028).Results: Individuals with FH variants knew more often their LDL-C target level (61.1% at visit 3 vs 26.3% at visit 2; p=0.004) and comparing with group II (17.6%) by visit 3 (p=0.006). There was no difference in the proportion of patients taking combined LLT (statin+ezetimibe+PCSK9i) at the first visit (5.3% at groups I and II, 12.0% at group III; p=0.556) and in the frequencies of its prescribing at the second visit (70.3% at group I, 52.6% at group II and 56.0% at group III; p=0.326). Only patients with FH variants began to take the combined LLT significantly more often by visit 3 (43.2% vs 5.3% at visit 1 (p <0.001)).Conclusions: Knowledge of positive genetic testing for FH contributes to a better knowing of the LDL-C target level and better adherence to the triple-combined LLT. Background and Aims : To assess the impact of awareness of genetic testing for familial hypercholesterolemia (FH) on the adherence to the lipid-lowering therapy (LLT). Methods: Patients ≥18 y.o. with “probable” or “definite” FH according to the DLCN criteria were included (n=82). The study consists of three visits (follow-up is 6 months) with a block randomization with a 2:1 allocation ratio (with: without genetic testing). The results of genetic testing were reported at the second visit. Patients were divided into 3 groups: I - with "positive" genetic testing (n=38); II - with "negative" genetic testing (n=19); III - without genetic testing (n=25). Fisher's test was used for statistical analysis. The study was registered on ClinicalTrials (NCT04656028). Results: Individuals with FH variants knew more often their LDL-C target level (61.1% at visit 3 vs 26.3% at visit 2; p=0.004) and comparing with group II (17.6%) by visit 3 (p=0.006). There was no difference in the proportion of patients taking combined LLT (statin+ezetimibe+PCSK9i) at the first visit (5.3% at groups I and II, 12.0% at group III; p=0.556) and in the frequencies of its prescribing at the second visit (70.3% at group I, 52.6% at group II and 56.0% at group III; p=0.326). Only patients with FH variants began to take the combined LLT significantly more often by visit 3 (43.2% vs 5.3% at visit 1 (p <0.001)). Conclusions: Knowledge of positive genetic testing for FH contributes to a better knowing of the LDL-C target level and better adherence to the triple-combined LLT.

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

Population genomic screening for familial hypercholesterolemia (FH) in unselected individuals can prevent premature cardiovascular disease. To estimate the clinical and economic outcomes of population-wide FH genomic screening versus no genomic screening. 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. 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. 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.

Impact of a Population Genomic Screening Program on Health Behaviors Related to Familial Hypercholesterolemia Risk Reduction.

Background:Limited information is available regarding clinician and participant behaviors after disclosure of genomic risk variants for familial hypercholesterolemia (FH) from a population genomic screening program.Methods:We conducted a retrospective cohort study of MyCode participants with an FH risk variant beginning 2 years before disclosure until January 16, 2019. We analyzed lipid-lowering prescriptions (clinician behavior), medication adherence (participant behavior), and LDL (low-density lipoprotein) cholesterol levels (health outcome impact) pre- and post-disclosure. Data were collected from electronic health records and claims.Results:The cohort included 96 participants of mean age 57 (22–90) years with median follow-up of 14 (range, 3–39) months. Most (90%) had a hypercholesterolemia diagnosis but no specific FH diagnosis before disclosure; 29% had an FH diagnosis post-disclosure. After disclosure, clinicians made 36 prescription changes in 38% of participants, mostly in participants who did not achieve LDL cholesterol goals pre-disclosure (81%). However, clinicians wrote prescriptions for fewer participants post-disclosure (71/96, 74.0%) compared with pre-disclosure (81/96, 84.4%); side effects were documented for most discontinued prescriptions (23/25, 92%). Among the 16 participants with claims data, medication adherence improved (proportion of days covered pre-disclosure of 70% [SD, 24.7%] to post-disclosure of 79.1% [SD, 27.3%]; P=0.05). Among the 52 (54%) participants with LDL cholesterol values both before and after disclosure, average LDL cholesterol decreased from 147 to 132 mg/dL (P=0.003).Conclusions:Despite disclosure of an FH risk variant, nonprescribing and nonadherence to lipid-lowering therapy remained high. However, when clinicians intensified medication regimens and participants adhered to medications, lipid levels decreased.

An LDLR missense variant poses high risk of familial hypercholesterolemia in 30% of Greenlanders and offers potential of early cardiovascular disease intervention.

SummaryThe common Arctic-specific LDLR p.G137S variant was recently shown to be associated with elevated lipid levels. Motivated by this, we aimed to investigate the effect of p.G137S on metabolic health and cardiovascular disease risk among Greenlanders to quantify its impact on the population. In a population-based Greenlandic cohort (n = 5,063), we tested for associations between the p.G137S variant and metabolic health traits as well as cardiovascular disease risk based on registry data. In addition, we explored the variant’s impact on plasma NMR measured lipoprotein concentration and composition in another Greenlandic cohort (n = 1,629); 29.5% of the individuals in the cohort carried at least one copy of the p.G137S risk allele. Furthermore, 25.4% of the heterozygous and 54.7% of the homozygous carriers had high levels (>4.9 mmol/L) of serum LDL cholesterol, which is above the diagnostic level for familial hypercholesterolemia (FH). Moreover, p.G137S was associated with an overall atherosclerotic lipid profile, and increased risk of ischemic heart disease (HR [95% CI], 1.51 [1.18–1.92], p = 0.00096), peripheral artery disease (1.69 [1.01–2.82], p = 0.046), and coronary operations (1.78 [1.21–2.62], p = 0.0035). Due to its high frequency and large effect sizes, p.G137S has a marked population-level impact, increasing the risk of FH and cardiovascular disease for up to 30% of the Greenlandic population. Thus, p.G137S is a potential marker for early intervention in Arctic populations.

Genetic Variant ABCC1 rs45511401 Is Associated with Increased Response to Statins in Patients with Familial Hypercholesterolemia.

Statins are the first-line treatment for familial hypercholesterolemia (FH), but response is highly variable due to genetic and nongenetic factors. Here, we explored the association between response and genetic variability in 114 Brazilian adult FH patients. Specifically, a panel of 84 genes was analyzed by exon-targeted gene sequencing (ETGS), and the functional impact of variants in pharmacokinetic (PK) genes was assessed using an array of functionality prediction methods. Low-density lipoprotein cholesterol (LDL-c) response to statins (reduction ≥ 50%) and statin-related adverse event (SRAE) risk were assessed in carriers of deleterious variants in PK-related genes using multivariate linear regression analyses. Fifty-eight (50.8%) FH patients responded to statins, and 24 (21.0%) had SRAE. Results of the multivariate regression analysis revealed that ABCC1 rs45511401 significantly increased LDL-c reduction after statin treatment (p < 0.05). In silico analysis of the amino-acid change using molecular docking showed that ABCC1 rs45511401 possibly impairs statin efflux. Deleterious variants in PK genes were not associated with an increased risk of SRAE. In conclusion, the deleterious variant ABCC1 rs45511401 enhanced LDL-c response in Brazilian FH patients. As such, this variant might be a promising candidate for the individualization of statin therapy.

Motivating cascade testing for familial hypercholesterolemia: applying the extended parallel process model for clinician communication.

Motivating at-risk relatives to undergo cascade testing for familial hypercholesterolemia (FH) is critical for diagnosis and lifesaving treatment. As credible sources of information, clinicians can assist in family communication about FH and motivate cascade testing uptake. However, there are no guidelines regarding how clinicians should effectively communicate with probands (the first person diagnosed in the family) and at-risk relatives. Individuals and families with FH can inform our understanding of the most effective communications to promote cascade testing. Guided by the extended parallel process model (EPPM), we analyzed the perspectives of individuals and families with FH for effective messaging clinicians can use to promote cascade testing uptake. We analyzed narrative data from interviews and surveys collected as part of a larger mixed-methods study. The EPPM was used to identify message features recommended by individuals and families with FH that focus on four key constructs (severity, susceptibility, response efficacy, self-efficacy) to promote cascade testing. Participants included 22 individuals from 11 dyadic interviews and 98 survey respondents. Participants described prioritizing multiple messages that address each EPPM construct to alert relatives about their risk. They illustrated strategies clinicians could use within each EPPM construct to communicate to at-risk relatives about the importance of pursuing diagnosis via cascade testing and subsequent treatment for high cholesterol due to FH. Findings provide guidance on effective messaging to motivate cascade testing uptake for FH and demonstrates how the EPPM may guide communication with at-risk relatives about genetic risk and motivate cascade testing broadly.

Abstract 078: Mid- To Long- Term Follow-up Care Insufficiencies From A Cross-sectional School- Based Cholesterol Screening Program

Introduction: The CARDIAC project surveyed cardiometabolic risk and risk for familial hypercholesterolemia (FH) through a school-based program, demonstrating the importance of universal blood cholesterol screening in children. At most, 10% of FH is diagnosed in the United States. Hypothesis: We hypothesize a disconnect between identification of risk factors and the follow-up care received by those children and young adults. Methods: Between 1998 and 2016, 60,404 5th grade children had their LDL-C levels assessed through venipuncture lipid panels. Of the 638 children who had an LDL-C ≥ 160mg/dl, indicative of probable FH, 395 were identified through EPIC EHR, phone calls, and mail surveys. WVU IRB approved verbal consent by participants. Information on their current status was obtained including medical care for their cholesterol, lipid-lowering medications (LLM), other medications, and family history of cardiac-related events. Results: Out of the 395 children identified, 174 were male and 221 were female. We had follow-up lipid panels for 58. Eight participants on a LLM had a follow-up LDL-C that was 57.5 +/- 50.1 mg/dl lower than the 5th grade level. Fifty subjects not on a LLM had an LDL-C that was 27.2 +//- 48.0 mg/dl lower than baseline. No follow-up LDL-C data was available on 33 participants who received a LLM. While only 41 children had ever taken a LLM, 56 participants were taking oral contraceptive, and 63 a psychotropic medicine. Only 1 participant was enrolled in the FH Registry. No subject was found with major adverse coronary event. Conclusion: Follow-up after screening demonstrated improved lipid levels in several subjects without known medication. Many subjects were receiving oral contraceptive agents and psychotropic medicines associated with dyslipidemia, usually without follow-up lipid panels. Roughly one-third of participants had unknown mid-term course. Epic EHR for WVU Health System found 393 subjects. The inability to document ongoing medical care in addition to demonstrated lack of care received by those who had an LDL greater than 160mg/dl shows that there is insufficient follow-up care for young people with probable FH. In conclusion, the data points to areas to improve, including better education for patients with this cardiometabolic risk factor. Education of health care professionals, telemedicine, patient-driven advocacy groups, EHRs that cover large catchments, and patient communication portals promise to better focus ongoing care for persons with abnormal lipid profiles.