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Prevalence and management of familial hypercholesterolaemia in coronary patients: An analysis of EUROASPIRE IV, a study of the European Society of Cardiology

      Highlights

      • In patients with coronary heart disease the prevalence of FH is less well documented.
      • In the EUROASPIRE IV cohort of coronary patients the prevalence of potential FH was 8.3%. The risk factor profile of these patients was worse compared to the other patients.
      • The results underscore the need to promote the identification of FH in coronary patients and their families and to improve their management.

      Abstract

      Background

      Familial hypercholesterolaemia (FH) is a hereditary disorder predisposing to premature coronary heart disease (CHD) and is until now mainly diagnosed clinically on the basis of a classical phenotype. Its prevalence varies and is estimated around 1 in 200–500; in patients with established CHD the prevalence is less well documented.

      Methods and results

      In EUROASPIRE IV data were collected in coronary patients from 24 European countries by means of a standardized interview, bioclinical examination and venous blood sampling. Potential FH was estimated using an adapted version of the Dutch Lipid Clinic Network Criteria.
      Among the 7044 patients eligible for analysis, the prevalence of potential FH was 8.3%; 7.5% in men and 11.1% in women. The prevalence was inversely related to age with a putative prevalence of 1:5 in those with CHD <50 yrs of age in both sexes. Even among women aged 70 the prevalence was 1:10. Irrespective of age and gender, prevalence differed substantially between European regions; potential FH patients were more likely to smoke, had higher triglycerides levels and their blood pressure was less well controlled. The use of cardioprotective drugs and the prevalences of diabetes, obesity and central obesity were similar.

      Conclusions

      The prevalence of potential FH in coronary patients is high; the results underscore the need to promote identification of FH in CHD patients and to improve their risk factor profile.

      Keywords

      1. Introduction

      Dyslipidaemias represent a heterogeneous group of disorders that are related to genetic and environmental factors. Familial forms can arise from mutations in one or different genes. Already more than 40 years ago J.L Goldstein et al. [
      • Goldstein J.L.
      • Schrott H.G.
      • Hazzard W.R.
      • Bierman E.L.
      • Motulsky A.G.
      Hyperlipidemia in coronary heart disease II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia.
      ] had observed that three of these disorders – familial hypercholesterolaemia (FH), familial hypertriglyceridaemia and familial combined hyperlipidaemia – occurred in about 20% of survivors of a myocardial infarction below 60 yrs of age and in 7% of the older survivors. In this report attention is given to the prevalence and management of potential FH in a large group of coronary patients.
      FH is an autosomal co-dominant inherited disorder of lipoprotein metabolism characterized by high low density lipoprotein cholesterol (LDL-C) plasma levels from birth and an increased risk of premature coronary heart disease (CHD). Mutations in the gene encoding the LDL receptor (LDLR) are the most commonly identified in these patients although mutations in APOB and PCSK9 have also been shown to result in FH. Historically, FH has been diagnosed clinically and the classical phenotype of heterozygous FH was a patient with premature CHD, severely elevated LDL-C, a family history of premature CHD and tendon xanthomas. Genomic analysis to identify mutations in the LDLR, APOB or PCSK9 is readily available, but the application of genetic screening varies considerable across countries. Homozygous FH is rare requiring therapeutic interventions in the first decade of life and while the prevalence was believed to be ∼1 in 1million current estimates suggest that the figure could be as high as ∼1 in 250 000 [
      • Cuchel M.
      • Bruckert E.
      • Ginsberg H.N.
      • et al.
      Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the consensus panel on familial hypercholesterolaemia of the European Atherosclerosis Society.
      ,
      • Reiner Ž.
      Impact of early evidence of atherosclerotic changes on early treatment in children with familial hypercholesterolemia.
      ,
      • Sjouke B.
      • Kusters D.M.
      • Kindt I.
      • Besseling J.
      • Defesche J.C.
      • Sijbrands E.J.
      • Roeters van Lennep J.E.
      • Stalenhoef A.F.
      • Wiegman A.
      • de Graaf J.
      • Fouchier S.W.
      • Kastelein J.J.
      • Hovingh G.K.
      Homozygous autosomal dominant hypercholesterolaemia in the Netherlands: prevalence, genotype-phenotype relationship, and clinical outcome.
      ].
      Heterozygous FH (HeFH) is more common; historically its prevalence was estimated at 1 in 500 people; however, results from more recent studies suggest a higher prevalence up to 1 in 200–250 [
      • Nordestgaard B.J.
      • Chapman M.J.
      • Humphries S.E.
      • et al.
      Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease.
      ]. The phenotype of HeFH comprises particularly high levels of LDL-C in the range of 5–10 mmol/L (200–400 mg/dL) in adulthood. The identification of patients with HeFH is still very incomplete in Europe and different criteria have been proposed (the Simon Broome Register Diagnostic Criteria [
      • Scientific Steering Committee on behalf of the Simon Broome Register Group
      Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group.
      ], the MedPed/WHO Criteria [
      • WHO Familial Hypercholesterolemia Consultation Group
      Familial Hypercholesterolemia. Report of a WHO Consultation.
      ] and the Dutch Lipid Clinic Network (DLCN) Diagnostic Criteria [
      • Civeira F.
      Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia.
      ]) to aid diagnosis. These algorithms are mainly based on the measured LDL-C level, a positive family history of CHD, personal CHD history and physical signs. Patients with established CHD and HeFH are at particularly elevated risk of recurrent events and current management of these patients focuses on the use of potent statins and ezetimibe in order to reach at least a 50% reduction and/or an LDL-C level of <1.8 mmol/L (70 mg/dL). In patients where these targets cannot be reached by statins alone or in case of statin intolerance, other drug treatments or combinations have been suggested in clinical guidelines [
      • Reiner Z.
      • Catapano A.L.
      • De Backer G.
      • et al.
      ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and theEuropean Atherosclerosis Society (EAS).
      ].
      Recognizing potential FH patients is of importance for two reasons: firstly, the absolute lifetime cardiovascular risk is sharply increased in HeFH patients and the need for intensive preventive strategies to mitigate this risk are deemed crucial; secondly, by means of cascade screening unidentified affected relatives can be detected. A major challenge therefore in clinical practice is to raise awareness of potential HeFH and identify potential patient groups where HeFH is particularly over-represented which would in turn assist cascade screening.
      In order to address some of these uncertainties we aim to estimate the prevalence of clinical HeFH in a large group of patients with CHD who participated in the EUROASPIRE IV survey. Moreover, we compared these potential HeFH patients with the other patients with respect to different clinical characteristics and their management.

      2. Study population and methods

      2.1 The EUROASPIRE IV survey

      The design and methodology of the EUROASPIRE IV study have been described in detail [
      • Kotseva K.
      • Wood D.
      • De Bacquer D.
      • De Backer G.
      • Ryden L.
      • Jennings C.
      • Gyberg V.
      • on behalf of the EUROASPIRE Investigators
      EUROASPIRE IV: a European society of cardiology survey on the lifestyle, risk factor and therapeutic management in coronary patients from 24 European countries.
      ] The survey was performed in 24 European countries; patients aged ≥ 18 and <80 years who had been hospitalized for a coronary event (defined as an acute myocardial infarction, acute myocardial ischaemia or procedure [CABG, PCI]) between 6 months and 3 years before the interview, were eligible. They were invited to participate in an interview during which trained technicians collected information through standardized methods.
      Height and weight were measured in light indoor clothes without shoes (SECA scales 701 and measuring stick model 220). Obesity was defined as a body mass index ≥30 kg/m2.
      Waist circumference was measured using a metal tape applied horizontally at the point midway in the mid-axillary line between the lowest rim of the rib cage and the tip of the hip bone (superior iliac crest) with the patient standing. Central obesity was defined as a waist circumference ≥88 cm for women and ≥102 cm for men.
      Blood pressure was measured twice on the right upper arm in a sitting position using an automatic digital sphygmomanometers (Omron M6) and the mean was used for all analyses.
      Breath carbon monoxide was measured in ppm using a smokelyser(Bedfont Scientific, Model Micro +). Smoking at the time of interview was defined as self-reported smoking, and/or a breath carbon monoxide exceeding 10 ppm. Persistent smoking was defined as smoking at interview among patients reporting to be smokers in the month prior to the index event. Habitual physical activity was assessed by means of the International Physical Activity Questionnaire (IPAQ). High physical activity was defined as proposed in http://www.ipaq.ki.se/scoring.pdf.
      All patients were asked to come fasting for 10–12 h and the fasting time was recorded at interview. The analyses with LDL-C and triglycerides were limited to those patients fasting for at least 6 h. Venous blood samples were taken with the patients in a sitting position with light stasis into a tube containing clot activator (Venosafe, Terumo Europe, Leuven, Belgium) for lipid assays and into a potassium EDTA tube (Venosafe) for HbA1c assay. Serum was separated by centrifuging at 2000 g for 10 min at room temperature. After that serum was aliquoted into two bar-code-labelled tubes and stored together with whole EDTA blood tubes locally at a minimum of −70 °C and then transported frozen to the central laboratory where all measurements were performed on a clinical chemistry analyzer (Architect c8000; Abbott Laboratories, Abbott Park, Illinois, USA).
      Total cholesterol, high density lipoprotein cholesterol (HDL-C) and triglycerides were analysed in serum, and HbA1c in whole blood with the following methods: enzymatic method for total cholesterol, a homogenous method for direct measurement of HDL-C, an enzymatic glycerol phosphate oxidase method for triglycerides, and an immunoturbidimetric method for HbA1c. LDL-C was calculated according to Friedewald's formula; if the triglycerides level was >4 mmol/L patients were excluded from this analysis.
      The central laboratory was the Disease Risk Unit, National Institute for Health and Welfare, Helsinki, Finland, and is accredited by the Finnish Accreditation Service and fulfils the requirements of the standard SFS-EN ISO/IEC 17025:2005.
      The laboratory takes part in Lipid Standardization Program organized by CDC, Atlanta, Georgia, USA and External Quality Assessment Schemes organized by Labquality, Helsinki, Finland. During the course of the study, comprising two months in 2013, the coefficient of variation (mean ± SD) and systematic error (bias) (mean ± SD) were 1.3% ± 0.2 and 1.7% ± 1.1 for total cholesterol, 1.6% ± 0.5 and −1.5% ± 1.6 for HDL-C, 2.3% ± 0.1 and −1.2% ± 2.6 for triglycerides, and 1.9% ± 0.1 and 1.4% ± 0.2 for HbA1c, respectively.

      2.2 Diagnostic criteria for potential FH

      The prevalence of FH was estimated using a modified version of criteria used in the MedPed/WHO algorithm [
      • WHO Familial Hypercholesterolemia Consultation Group
      Familial Hypercholesterolemia. Report of a WHO Consultation.
      ] and by the DLCN [
      • Civeira F.
      Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia.
      ]; 2 points were given if the age at the index event was <55/60 years for men/women OR if self-reported age of first diagnosis of CHD was <55/60 years for men/women; 1 point was given for a positive family history of premature (<55/65 years for men/women) CVD. The presence of arcus cornealis or tendon xanthomata was not recorded in the EUROASPIRE IV survey. A large majority of the patients (85.7%) was on statin therapy at the moment of blood sampling. To estimate the “untreated” LDL-C plasma level in these patients, information on the current intake of statins was collected. Participants were asked to bring all the drugs that they were taking on a daily basis to the interview and the interviewer collected the data regarding the dose; in case the interview was done at the home of the patients, detailed information was also collected as to the type of statin and the dosage. At the interview there was one question on compliance: “In the past month how often did you take your medication?” Possible answers were: “all the time (100%); nearly all of the time (90%); most of the time (75%); about half of the time (50%); and less than half of the time (<50%)”.
      In the patients on statin therapy “untreated” LDL-C level was estimated by multiplying their LDL-C level on treatment with correction factors published by J. Besseling et al. [
      • Besseling J.
      • Kindt I.
      • Hof M.
      • et al.
      Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers.
      ] taking into consideration the kind of statin and the dosage; if ‘uncommon dosages’ were reported or for the combination of ezetimibe with statins other than simvastatin, correction factors were calculated by extrapolation. All these correction factors were further modified by taking the answers to the question on drug compliance into consideration: in those taking their drugs all the time the correction factors were used unaltered; in those taking their drugs nearly all of the time the weight of the correction factors were reduced by 10%, in those taking their medication most of the time by 25%, in those taking their drugs about half of the time by 50%, and in those taking their drugs less than half of the time by 75%.
      “Untreated LDL-C“ was then entered in the algorithm by giving 1 point to a corrected LDL-C of 4.0–4.9 mmol/L, 3 points to an LDL-C of 5.0–6.4 mmol/L, 5 points to a LDL-C of 6.5–8.4 mmol/L and 8 points to a LDL-C of 8.5 mmol/L or more.
      The result of this algorithm was interpreted as follows:
      • ‘unlikely FH’ ← Total score 0–2
      • ‘possible FH’ ← Total score 3–5
      • ‘probable FH’ ← Total score 6–8
      • ‘definite FH’ ← Total score >8
      The categories ‘ definite’ and ‘probable FH’ were combined into ‘potential FH’.

      3. Statistical methods

      Prevalences were given as percentages. Gender- and center-specific prevalences of potential FH were age-standardized according to the direct method using the total sample as reference. Groups of patients with and without potential FH were statistically compared according to multilevel logistic modelling. These hierarchical models accounted for the clustering of patients within centres. In addition, P-values were adjusted for potential confounding due to differences in distributions of gender and age at interview. A level of <0.05 was a priori chosen to indicate statistical significance. All analyses were performed by means of SAS statistical software release 9.1 (SAS Institute Inc., Cary, North Carolina, USA).

      4. Ethical procedures

      National coordinators were responsible for obtaining Local Research Ethics Committees approvals. Written informed consent was obtained from each participant by the investigator by a signed declaration. The research assistants signed in the Case Record Form to confirm that informed consent was obtained and stored the original signed declaration consent in the patient file.

      5. Results

      From the original cohort of 7998 participants, 746 were excluded because of missing LDL-C level at interview, 93 because of missing information on the use of statins, and 115 using lipid lowering drugs other than statins or ezetimibe. The distribution of the total FH score in the remaining 7044 patients (5335 men; 1709 women) is presented in Fig. 1: 587 patients (8.3%) had a score of 6 or more and 77 (1.1%) of more than 8.
      Figure thumbnail gr1
      Fig. 1Distribution (in %) of FH scores in 7044 EAIV patients.
      In Table 1 the prevalence is given for the different categories of FH for all patients, by gender and by age groups. The prevalence of potential FH was higher in women than in men and among those aged <60 yrs compared to the 60+. The mean age at interview of the group with potential FH was 58.2 years (SD 10.0) compared with 64.8 years (SD 9.3) in the other patients.
      Table 1Prevalence of unlikely, possible, probable, definite and potential FH.
      NFH classification
      UnlikelyPossibleProbableDefinitePotential
      All704460.1% (4234)31.6% (2223)7.2% (510)1.1% (77)8.3% (587)
      Men533562.4% (3330)30.1% (1607)6.7% (357)0.8% (41)7.5% (398)
      Women170952.9% (904)36.0% (616)9.0% (153)2.1% (36)11.1% (189)
      Age <60 years221232.5% (719)52.1% (1152)13.7% (304)1.7% (37)15.4% (341)
      Age ≥60 years483272.7% (3515)22.2% (1071)4.3% (206)0.8% (40)5.1% (246)
      The association between potential FH versus age and gender is further demonstrated in Fig. 2. The prevalence of potential FH was significantly higher in men than in women (p < 0.0001) and was 8 times greater in the patients aged <50 years compared to those aged 70+. Among women, even those aged between 60 and 69 years, the prevalence was about 1 in 10. The effect of age is likely due to the definition of potential FH where additional weight is given to younger patients who developed CHD prematurely. CHD had occurred prematurely in 78% and 73% of respectively male and female patients with potential FH as compared to 33% and 37% in the other male and female patients.
      Figure thumbnail gr2
      Fig. 2Prevalence of potential FH (in %) by age at interview and gender.
      In Table 2 age-standardized prevalences of potential FH are given by gender and centre. The difference by gender, standardized for age, is somewhat larger; the differences between centres are very large: the prevalence of potential FH varies from 3.4% in the Finish centres to 20.8% in the centres from Bosnia-Herzegovina.
      Table 2Age-standardized prevalence of potential FH by gender and centre.
      NAge-standardized
      Using age distribution of total sample as reference.
      prevalence of potential FH (95% CI)
      Men53357.1% (6.4%–7.8%)
      Women170912.1% (10.6%–13.7%)
      Belgium3295.0% (2.6%–7.3%)
      Bosnia Herzegovina11920.8% (13.5%–28.1%)
      Bulgaria1129.0% (3.7%–14.2%)
      Croatia4039.1% (6.3%–11.9%)
      Cyprus687.9% (1.5%–14.3%)
      Czech Republic4587.1% (4.8%–9.5%)
      Finland4383.4% (1.7%–5.1%)
      France3324.4% (2.2%–6.6%)
      Germany4933.5% (1.8%–5.1%)
      Greece443.8% (0.0%–9.5%)
      Ireland19210.3% (6.0%–14.6%)
      Latvia2789.9% (6.4%–13.4%)
      Lithuania43311.8% (8.8%–14.9%)
      Netherlands3936.1% (3.7%–8.5%)
      Poland35711.4% (8.1%–14.7%)
      Romania4828.8% (6.2%–11.3%)
      Russian Federation38413.8% (10.3%–17.2%)
      Serbia37312.2% (8.9%–15.5%)
      Slovenia2314.8% (2.1%–7.6%)
      Spain1634.1% (1.1%–7.2%)
      Sweden3304.9% (2.6%–7.2%)
      Turkey2078.9% (5.0%–12.7%)
      Ukraine23112.7% (8.4%–17.0%)
      United Kingdom1946.0% (2.6%–9.3%)
      a Using age distribution of total sample as reference.
      In Table 3 the prevalences of CHD risk factors are presented in the group with potential FH (probable/definite) compared to the other (unlikely/possible). Smoking was more prevalent among the patients with potential FH (P = 0.012); there were no differences in prevalence of obesity, central obesity, and self-reported diabetes. The proportion of patients with a low HDL-C was smaller in those with potential FH compared to the other patients. On the contrary the proportion with elevated triglyceride levels was greater among patients with potential FH.
      Table 3Prevalence of CHD risk factors in patients with potential FH.
      FH classificationSignificance
      Adjusted for age and gender.
      Unlikely/PossibleProbable/Definite
      Current smoking
      Self-reported smoking or CO in breath >10 ppm.
      14.8% (958/6457)25.0% (147/587)P = 0.012
      Self-reported diabetes26.6% (1710/6425)21.1% (123/584)P = 0.10
      Obesity
      Body Mass Index ≥30 kg/m2.
      36.6% (2358/6440)39.1% (228/583)P = 0.80
      Central obesity
      Waist circumference ≥102 cm for men or ≥88 cm for women.
      57.4% (3647/6349)59.8% (345/577)P = 0.64
      Low HDL
      HDL cholesterol <1 mmol/L for men and <1.2 mmol/L for women.
      36.8% (2374/6457)34.6% (203/587)P = 0.011
      High TG
      Fasting triglycerides ≥1.7 mmol/L.
      30.0% (1823/6087)46.2% (259/560)P < 0.0001
      a Self-reported smoking or CO in breath >10 ppm.
      b Body Mass Index ≥30 kg/m2.
      c Waist circumference ≥102 cm for men or ≥88 cm for women.
      d HDL cholesterol <1 mmol/L for men and <1.2 mmol/L for women.
      e Fasting triglycerides ≥1.7 mmol/L.
      f Adjusted for age and gender.
      In Table 4 control of CHD risk factors is presented between the groups. Patients with potential FH had their blood pressure less well controlled; among those who were smokers before the index event almost half had stopped smoking at the time of the interview in both groups; those with potential FH tended to be less physically active (P = 0.06); control of diabetes was comparable.
      Table 4Control of CHD risk factors in patients with potential FH.
      FH classificationSignificance
      Adjusted for age and gender.
      Unlikely/PossibleProbable/Definite
      SBP/DBP<140/90 mmHg62.8% (4050/6447)58.5% (343/587)P < 0.0001
      Quit smoking
      Stopped smoking since recruiting event.
      51.9% (965/1859)46.5% (120/258)P = 0.18
      High physical activity
      According to the IPAQ Short Form questionnaire.
      42.4% (2110/4982)40.7% (175/430)P = 0.06
      HbA1c <7% in diabetes
      HbA1c < 7% among patients with diabetes.
      53.8% (916/1702)57.7% (71/123)P = 0.21
      a Stopped smoking since recruiting event.
      b According to the IPAQ Short Form questionnaire.
      c HbA1c < 7% among patients with diabetes.
      d Adjusted for age and gender.
      In Table 5 the use of cardioprotective drugs is compared between the groups; there were no significant differences in the use of aspirin or other anti-platelet drugs, beta-blockers, angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB's).
      Table 5Use of cardioprotective drugs in patients with potential FH.
      FH classificationSignificance
      Adjusted for age and gender.
      Unlikely/PossibleProbable/Definite
      ASA94.2% (6081/6457)96.4% (566/587)P = 0.35
      Beta-blockers83.2% (5374/6457)85.7% (503/587)P = 0.48
      ACE inhibitor or ARB75.4% (4866/6457)76.3% (448/587)P = 0.35
      ASA: aspirin; ACE: angiotensin converting enzyme; ARB: angiotensin II receptor blockers.
      a Adjusted for age and gender.
      Among all the patients with potential FH 55% were on a high-intensity statin (atorvastatin 40 or 80 mg/d, rosuvastatin 20 or 40 mg/d, simvastatin 80 mg/d) compared to 31% in the other patients.

      6. Discussion

      Among the coronary patients of the EUROASPIRE IV survey the prevalence of potential FH was calculated at 8.3% or 1 in 12. The prevalence of FH in selected series in the literature varies from 1 in 200 to 1 in 2000 [
      • Marks D.
      • Thorogood M.
      • Neil H.A.
      • Humphries S.E.
      A review on the diagnosis, natural history and treatment of familial hypercholesterlaemia.
      ,
      • Hopkins P.N.
      • Toth P.P.
      • Ballantyne C.M.
      • Rader D.J.
      Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the national lipid association expert panel on familial hypercholesterolemia.
      ,
      • Neil H.A.
      • Hammond T.
      • Huxley R.
      • Matthews D.R.
      • Humphries S.E.
      Extent of underdiagnosis of familial hypercholesterolaemia in routine practice: prospective registry study.
      ]. In the Danish general population it was 1 in 200 according to the DLCN criteria [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease and cholesterol-lowering medication.
      ]. In the US population the prevalence of potential FH according to an adapted version of the DLCN criteria in the NHANES 1999–2012 data was 0.23% or 1 in 427 [
      • de Ferranti S.
      • Rodday A.M.
      • Mendelson M.
      • Wong J.B.
      • Leslie L.K.
      • Sheldrick R.C.
      What is the prevalence of familial hypercholesterolemia in the US?.
      ]. In a Chinese community, aged 20 yrs and above the prevalence of probable and definite FH according to modified DLCN criteria was 0.28% or 1 in 357 [
      • Shi Z.
      • Yuan B.
      • Zhao D.
      • et al.
      Familial hypercholesterolemia in China: prevalence and evidence of underdetection and undertreatment in a community population.
      ]. Among patients with established CHD however, the prevalence of potential FH is not clear. In a series of consecutive patients aged <60 years admitted with an acute myocardial infarction to hospitals in the Yorkshire region in 1995 and in whom cholesterol had been measured (n = 292), 36 cases of FH (12.3%) were identified [
      • Dorsch M.F.
      • Lawrance R.A.
      • Durham N.P.
      • Hall A.S.
      Familial hypercholesterolaemia is underdiagnosed after AMI.
      ]. This prevalence is slightly higher compared to the prevalence we found, which might be explained by a younger study population in the previous study.
      In our study the prevalence of potential FH was inversely related to age, and more so in men than in women; in men aged <50 years the prevalence was 22%. This association with age may largely be explained by the weight given to younger age of CHD in the DLCN Criteria; it could also be that patients with FH die earlier resulting in a decline of the prevalence of potential FH by age. However, the Copenhagen General Population Study did not show a relationship between age and FH [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease and cholesterol-lowering medication.
      ].The difference in the prevalence of potential FH by gender may partially be artificial due to the difference in defining premature CHD in men and women. But it could also be related to differences by gender in the interaction between different CHD risk factors.
      The higher prevalence of potential FH in women compared to men may reflect the later onset of CHD in women in general but also in those with FH [
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • Humphries S.E.
      Familial hypercholesterolemia and coronary heart disease: a huge association review.
      ]. In the Copenhagen General Population Study the prevalence of potential FH was also higher in the female population aged >60 years [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease and cholesterol-lowering medication.
      ].
      Large regional differences were observed in the prevalence of potential FH, independent of age. This might be explained by differences between the centers participating in this survey. Specifically, if only high-standard tertiary centers in a specific country were involved, recruiting more severely affected patients, the chance of diagnosing potential FH in this center would be higher. Differences in participating rates between regions may also have influenced the differences in prevalence of potential FH.
      In the US National Heart, Lung and Blood Institute's exome sequencing project (ESP) exome sequencing was used as a tool to identify genes contributing to early-onset myocardial infarction (MI) risk. The range of possible LDLR mutations with dysfunctional consequences went from 2.4 to 6.6% [
      • Do R.
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      • Kraus W.E.
      • Davies R.
      • Nikpay M.
      • Johansen C.T.
      • Wang J.
      • Hegele R.A.
      • Hechter E.
      • Marz W.
      • Kleber M.E.
      • Huang J.
      • Johnson A.D.
      • Li M.
      • Burke G.L.
      • Gross M.
      • Liu Y.
      • Assimes T.L.
      • Heiss G.
      • Lange E.M.
      • Folsom A.R.
      • Taylor H.A.
      • Olivieri O.
      • Hamsten A.
      • Clarke R.
      • Reilly D.F.
      • Yin W.
      • Rivas M.A.
      • Donnelly P.
      • Rossouw J.E.
      • Psaty B.M.
      • Herrington D.M.
      • Wilson J.G.
      • Rich S.S.
      • Bamshad M.J.
      • Tracy R.P.
      • Adrienne Cupples L.
      • Rader D.J.
      • Reilly M.P.
      • Spertus J.A.
      • Cresci S.
      • Hartiala J.
      • Wilson Tang W.H.
      • Hazen S.L.
      • Allayee H.
      • Reiner A.P.
      • Carlson C.S.
      • Kooperberg C.
      • Jackson R.D.
      • Boerwinkle E.
      • Lander E.S.
      • Schwartz S.M.
      • Siscovick D.S.
      • McPherson R.
      • Tybjaerg-Hansen A.
      • Abecasis G.R.
      • Watkins H.
      • Nickerson D.A.
      • Ardissino D.
      • Sunyaev S.R.
      • O'Donnell C.J.
      • Altshuler D.
      • Gabriel S.
      • Kathiresan S.
      Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.
      ]. These figures were comparable with estimates of the prevalence of FH in coronary patients based on an analysis of total cholesterol levels in 1973(1).
      Assuming that FH has been diagnosed in CHD patients, one would expect that an intensive treatment strategy was initiated to prevent recurrent CHD events. However, only 55% of them where on a high-intensity statin; this proportion may even be an overestimation due to the method for estimating ‘untreated’ LDL-C levels where higher correction factors are given to those on a high-intensity statin. This results in a higher likelihood to belong to the potential FH group. It was further hypothesized that among patients with potential FH the control of other CHD risk factors would have been better. Paradoxically, this was also not the case; smoking was more prevalent among potential FH patients, hypertension was less well controlled, and they were physically less active. No differences were found in prevalence of obesity, central obesity, diabetes and the control of diabetes. In contrast, lower levels of HDL-C were less frequently observed in potential FH patients, whereas high triglyceride levels occurred more often in them. Overall the CHD risk profile seemed to be worse in patients with potential FH.
      FH is well recognized as an important risk factor for developing accelerated atherosclerosis and its clinical consequences. For diagnosing FH in adults it is still recommended to use phenotypic assessment based on tools that have been developed; one of these are the DLCN Criteria. A numerical score is calculated based on the personal and family history of premature CHD, the blood level of LDL-C and the presence of arcus cornealis or tendon xanthomata. The relation of molecular genetic to the phenotypic identification of FH with the DLCN Criteria was subject of a Danish study [
      • Damgaard D.
      • Larsen M.L.
      • Nissen P.H.
      • et al.
      The relationship of molecular genetic to clinical diagnosis of familial hypercholesterolemia in a Danish population.
      ]; from these results it was concluded that possible FH should also be included as potential FH if one wants to identify most single gene mutation carriers. The statement “treat the phenotype but counsel the genotype” [
      • Humphries S.E.
      • Galton D.
      • Nicholls P.
      Genetic testing for familial hypercholesterolaemia: practical and ethical issues.
      ] is according to these observations still very relevant.
      The high prevalence of potential FH in CHD patients, especially in those aged <50 years, opens the opportunity to increase the detection rate among family members. When a suspicious case is detected family screening protocols are warranted. All those identified with potential FH should receive high-intensity statins; even then a large proportion will probably not reach the LDL-C goal of <1.8 mmol/L (70 mg/dL) and combination therapies should be considered in these patients. High intensity lipid-lowering therapy for these patients is recommended in both, the European ESC/EAS [
      • Reiner Z.
      • Catapano A.L.
      • De Backer G.
      • et al.
      ESC/EAS guidelines for the management of dyslipidaemias: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and theEuropean Atherosclerosis Society (EAS).
      ] as well as in the US ACC/AHA [
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • Bairey Merz C.N.
      • Blum C.B.
      • Eckel R.H.
      • Goldberg A.C.
      • Gordon D.
      • Levy D.
      • Lloyd-Jones D.M.
      • McBride P.
      • Schwartz J.S.
      • Shero S.T.
      • Smith Jr., S.C.
      • Watson K.
      • Wilson P.W.
      • Eddleman K.M.
      • Jarrett N.M.
      • LaBresh K.
      • Nevo L.
      • Wnek J.
      • Anderson J.L.
      • Halperin J.L.
      • Albert N.M.
      • Bozkurt B.
      • Brindis R.G.
      • Curtis L.H.
      • DeMets D.
      • Hochman J.S.
      • Kovacs R.J.
      • Ohman E.M.
      • Pressler S.J.
      • Sellke F.W.
      • Shen W.K.
      • Smith Jr., S.C.
      • Tomaselli G.F.
      2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      ] guidelines, since it can markedly improve their life expectancy [
      • Reiner Ž.
      A comparison of European and US guidelines for familial hypercholesterolaemia.
      ]. Screening for the phenotype of FH in patients with premature CHD should also be complemented by a search for other dyslipidaemias that may cause premature CHD. Clinicians should be suspicious of increased levels of Lp(a) or triglycerides in patients with premature CHD. It has been shown that Lp(a) is frequently elevated in FH patients [
      • Nordestgaard B.G.
      • Chapman M.J.
      • Ray K.
      • Borén J.
      • Andreotti F.
      • Watts G.F.
      • Ginsberg H.
      • Amarenco P.
      • Catapano C.
      • Descamps O.S.
      • Fisher E.
      • Kovanen P.T.
      • Kuivenhoven J.A.
      • Lesnik P.
      • Masana L.
      • Reiner Z.
      • Taskinen M.R.
      • Tokgözoglu L.
      • Tybjærg-Hansen A.
      Lipoprotein(a) as a cardiovascular risk factor: current status.
      ].
      There are some methodological considerations in our study. It has the advantage of large numbers with more than 7000 patients participated; CHD was well documented and by protocol consecutive series were identified and invited in each center; drug intake was carefully enquired by trained technicians not only regarding the kind of statin but also the dose. Furthermore, all lipid measurements were performed in one central laboratory, which allowed us to estimate the ‘untreated LDL-C’ level more carefully than in studies where a correction factor was applied in patients on statins independent of the kind and the dose [
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease and cholesterol-lowering medication.
      ]. Nonetheless, using these more specific correction factors may still be insufficient and could introduce inaccurate estimations of the ‘true untreated LDL-C’ at the level of the individual; indeed, the coefficients that have been proposed [
      • Besseling J.
      • Kindt I.
      • Hof M.
      • et al.
      Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers.
      ] are based on observations by MR Law [
      • Law M.R.
      • Wald N.J.
      • Rudnicka A.R.
      Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.
      ] where a fixed level of LDL-C of 4.8 mmol/L has been used as the baseline value; therefore these coefficients may be correct for estimating the untreated LDL-C of a group of patients but not for individuals with varying baseline levels. The coefficients that are used to estimate ‘untreated LDL-C levels’ in patients using statins have not been validated, which is a limitation of our analyses. The individual variability in treatment response, which is considerable, is not taken into account in this approach as well. Its origins are incompletely understood and do not only depend on compliance; differences in lipid-lowering response to statins have also been ascribed to genetic factors. There are also other reasons which all might influence the individual response to statin treatment [
      • Reiner Ž
      Resistance and intolerance to statins.
      ].
      This study has some other limitations such as the post hoc design of this analysis; given the cross-sectional design of the study it is not possible to interpret the proportion of patients at goal. A fully compliant patient at goal (with an LDL-C level of <1.8 mmol/L according to the guidelines) could never enter the ‘potential FH’ group even on the highest dose of a high intensity statin: i.e. on atorvastatin 80 mg/d he ends up with an untreated LDL-C of 1.7 × 2.12 = 3.77 resulting in 0 points according to the DNLC Criteria; even with a positive family history and premature personal history he ends up with only 3 points. The prevalence of FH may have been overestimated in the absence of analyses of gene variants; some of the patients could have polygenic hypercholesterolaemia and not FH.
      Last, the time of the interview after the index CHD event varied between 6 months and 3 years. During this timeframe, some patients might have experienced a second, fatal event which prevented them from participation in the EUROASPIRE IV survey. Since potential FH is a risk factor for CHD, it can be anticipated that these patients are more represented in the deceased patients. Theoretically, the prevalence of potential FH we found might be an underestimation.

      7. Conclusion

      Potential FH is highly prevalent among patients that have experienced a CHD event and control of other CHD risk factors seemed to be less optimal than in other patients. Our results should increase the awareness of this serious condition with high CHD risk among treating physicians, and should encourage them to treat all risk factors aggressively, as well as to actively search for related potential FH patients among family members.

      Disclosures

      GDB was a consultant on an advisory panel of MSD and consulted with Amgen. GKH is holder of a Veni grant (91612122) from the Dutch Science Organisation (NWO), and his department has received research grant/lecture/adboard fees on his behalf from Amgen, AstraZeneca, Sanofi, Pfizer and Roche. JJPK acted as a consultant and received honoraria from the following companies: Aegerion, Amgen, AstraZeneca, Atheronova, Boehringer Ingelheim, Catabasis, Cerenis, CSL Behring, Dezima Pharmaceuticals, Eli Lilly, Esperion, Genzyme, Isis, Merck, Novartis, Omthera, Pronova, Regeneron, Sanofi, The Medicines Company, UniQure, Vascular Biogenics and Vivus.
      KK had grant support from the European Society of Cardiology for the submitted work; financial activities outside the submitted work in the previous 3 years: travel grants for conferences from Roche and Boehringer Ingelheim.
      KR received honoraria for advisory boards, consultancy, steering committees and lectures from Pfizer, Astra Zeneca, Abbott, Roche, MSD, Sanofi, Amgen, Regeneron, Aegerion, Kowa, Novartis, Novo Nordisk, Boehringer Ingelheim, Daiichi Sankyo, Lilly.
      ŽR received honoraria for advisory boards, consultancy, and lectures from Sanofi, Amgen, Krka and Synageva. DW had grant support from the European Society of Cardiology for the submitted work. DW had the following financial activities outside the submitted work in the previous 3 years: honoraria for invited lectures or advisory boards: AstraZeneca, Merck Sharp and Dohme, Kowa Pharmaceuticals, Menarini, Zentiva; consultancy: Merck Sharp and Dohme.
      JC, JB and DDB have no interests to declare.

      Funding

      The EUROASPIRE IV survey was carried out under the auspices of the European Society of Cardiology, EURObservational Research Programme. The survey was supported through unrestricted research grants to the European Society of Cardiology from Amgen, AstraZeneca, Bristol-Myers Squibb and AstraZeneca, F. Hoffman-La Roche, GlaxoSmithKline, and Merck Sharp & Dohme. The sponsors of the EUROASPIRE surveys had no role in the design, data collection, data analysis, data interpretation, decision to publish, or writing the manuscript.

      Acknowledgements

      The EUROASPIRE Study Group is grateful to the administrative staff, physicians, nurses, and other personnel in the hospitals in which the survey was carried out and to all patients who participated in the surveys.

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      Linked Article

      • Europe aspires to set the record straight on familial hypercholesterolaemia
        AtherosclerosisVol. 241Issue 2
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          Familial hypercholesterolaemia (FH) is a co-dominantly inherited condition that markedly elevates plasma levels of low-density lipoprotein (LDL) cholesterol and induces premature coronary artery disease (CAD) [1]. Risk of CAD in FH may be significantly diminished through early detection and treatment of hypercholesterolaemia [1–3]. However, FH remains under-detected and under-treated worldwide [2].
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