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Canadian Journal of Cardiology

Contemporary Trends in the Management and Outcomes of Patients With Familial Hypercholesterolemia in Canada: A Prospective Observational Study

  • Liam R. Brunham
    Correspondence
    Corresponding author: Dr Liam R. Brunham, Centre for Heart Lung Innovation, Providence Health Care Research Institute, University of British Columbia, Rm 166, 1081 Burrard St, Vancouver, British Columbia V6Z 1Y6, Canada. Tel.: +1-604-682-2344, ext 63929; fax: +1-604-806-8351.
    Affiliations
    Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, British Columbia, Canada

    Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Centre for Heart Lung Innovation, Providence Health Care Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • Lubomira Cermakova
    Affiliations
    Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, British Columbia, Canada

    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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  • Terry Lee
    Affiliations
    Centre for Health Evaluation and Outcome Sciences, Providence Health Care Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • Ida Priecelova
    Affiliations
    Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, British Columbia, Canada
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  • Karine Alloul
    Affiliations
    Sanofi-Aventis Canada, Inc, Laval, Quebec, Canada
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  • Marilyn de Chantal
    Affiliations
    Sanofi-Aventis Canada, Inc, Laval, Quebec, Canada
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  • Gordon A. Francis
    Affiliations
    Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, British Columbia, Canada

    Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    Centre for Heart Lung Innovation, Providence Health Care Research Institute, University of British Columbia, Vancouver, British Columbia, Canada
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  • Jiri Frohlich
    Affiliations
    Healthy Heart Program Prevention Clinic, St. Paul's Hospital, Vancouver, British Columbia, Canada

    Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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Open AccessPublished:September 02, 2016DOI:https://doi.org/10.1016/j.cjca.2016.08.016

      Abstract

      Background

      Heterozygous familial hypercholesterolemia (HeFH) is one of the most common genetic diseases in the world and an important cause of premature cardiovascular (CV) disease. The purpose of this study was to characterize the clinical features, current treatment patterns, and CV outcomes of patients with HeFH in British Columbia, Canada.

      Methods

      We conducted a longitudinal observational study of patients with HeFH attending a specialized lipid clinic. We collected data on lipid levels, medication use, and CV events at baseline and last follow-up.

      Results

      We recruited 339 patients with clinically diagnosed HeFH, with a total of 3700 person-years of follow-up. The mean low-density lipoprotein cholesterol (LDL-C) level was 5.9 mmol/L at baseline and 3.7 mmol/L at last follow-up. Use of lipid-lowering therapy (LLT) increased from 35.7% at baseline to 84.7% at last follow-up. A ≥ 50% reduction in LDL-C level was achieved in 34.5% of patients, and an LDL-C level ≤ 2 mmol/L was seen in 8.3%. The overall CV event rate in this cohort was 33.5/1000 person-years. Among patients who had a CV event during follow-up, 59% experienced a recurrent event within 5 years.

      Conclusions

      These data contribute to our understanding of contemporary trends in the management of patients with HeFH in Canada. Despite a majority of patients receiving LLT, few patients reached high-risk lipid targets. These data highlight important opportunities to improve the care of patients with HeFH.

      Résumé

      Introduction

      L’hypercholestérolémie familiale hétérozygote (HFhé) est l’une des maladies génétiques les plus fréquentes dans le monde et une cause importante de la survenue prématurée de la maladie cardiovasculaire (CV). Le but de la présente étude était de décrire les caractéristiques cliniques, les profils de traitement actuels et les issues CV des patients atteints de HFhé de la Colombie-Britannique, au Canada.

      Méthodes

      Nous avons mené une étude observationnelle longitudinale des patients atteints de HFhé qui participaient à une clinique spécialisée dans les lipides. Nous avons recueilli les données sur les concentrations de lipides, l’utilisation de médicaments et les événements CV au début et à la fin du suivi.

      Résultats

      Nous avons recruté 339 patients ayant reçu un diagnostic clinique de HFhé, soit un total de 3700 personnes-années de suivi. La concentration moyenne de cholestérol à lipoprotéines de faible densité (LDL-C) était de 5,9 mmol/l au début et de 3,7 mmol/l à la fin du suivi. L’utilisation de traitement hypolipémiant (TH) augmentait de 35,7 % au début à 84,7 % à la fin du suivi. Une réduction de la concentration du LDL-C ≥ 50 % était atteinte chez 34,5 % des patients, et une concentration du LDL-C ≤ 2 mmol/l était observée chez 8,3 %. Le taux global d’événements CV dans cette cohorte était de 33,5/1000 personnes-années. Parmi les patients qui subissaient un événement CV durant le suivi, 59 % subissaient un événement récurrent dans les 5 années suivantes.

      Conclusions

      Ces données contribuent à notre compréhension des tendances contemporaines dans la prise en charge des patients atteints de HFhé au Canada. Malgré une majorité de patients recevant le TH, quelques patients ont atteint des cibles lipidiques à risque élevé. Ces données mettent en évidence des opportunités importantes pour améliorer les soins des patients atteints de HFhé.
      Heterozygous familial hypercholesterolemia (HeFH) is one of the most common genetic diseases and causes significant morbidity and mortality.
      • Yuan G.
      • Wang J.
      • Hegele R.A.
      Heterozygous familial hypercholesterolemia: an underrecognized cause of early cardiovascular disease.
      HeFH is characterized by elevated low-density lipoprotein cholesterol (LDL-C) levels and an up to a 10-fold increased risk of premature cardiovascular disease (CVD) and death.
      • Gidding S.S.
      • Ann Champagne M.
      • de Ferranti S.D.
      • et al.
      The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association.
      • 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.
      Treatment with statin drugs is effective at lowering LDL-C levels and reducing cardiovascular (CV) risk in patients with HeFH.
      • Versmissen J.
      • Oosterveer D.M.
      • Yazdanpanah M.
      • et al.
      Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.
      Recent genetic data have reconfirmed the excess CV risk associated with HeFH-causing mutations, even compared with control patients with similar levels of LDL-C but without FH.
      • Khera A.V.
      • Won H.H.
      • Peloso G.M.
      • et al.
      Diagnostic yield of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
      HeFH is estimated to affect 1 in 500 individuals in Canada.
      • Genest J.
      • Hegele R.A.
      • Bergeron J.
      • et al.
      Canadian Cardiovascular Society position statement on familial hypercholesterolemia.
      However, the true prevalence is likely to be much greater. Population data from the United States suggests that HeFH affects 1 in 250 individuals,
      • de Ferranti S.D.
      • Rodday A.M.
      • Mendelson M.M.
      • et al.
      Prevalence of familial hypercholesterolemia in the 1999 to 2012 United States National Health and Nutrition Examination Surveys (NHANES).
      and population-based genetic screening in Denmark indicates that 1 in 217 individuals are affected.
      • Benn M.
      • Watts G.F.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217.
      However, only a small minority of patients with HeFH have been diagnosed. It is estimated that only 15% of patients with FH in British Columbia have been diagnosed,
      • Wong S.
      • Taraboanta C.
      • Francis G.A.
      • Ignaszewski A.
      • Frohlich J.
      The British Columbia Familial Hypercholesterolemia Registry.
      and worldwide only 1% of patients have been diagnosed.
      • Nordestgaard B.G.
      • 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: consensus statement of the European Atherosclerosis Society.
      Increasing the diagnosis of patients with HeFH and establishing national registries of patients with this condition have been identified as priorities by national expert panels in several countries.
      • Genest J.
      • Hegele R.A.
      • Bergeron J.
      • et al.
      Canadian Cardiovascular Society position statement on familial hypercholesterolemia.
      • Nordestgaard B.G.
      • 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: consensus statement of the European Atherosclerosis Society.
      • Robinson J.G.
      • Goldberg A.C.
      National Lipid Association Expert Panel on Familial Hypercholesterolemia
      Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
      An important knowledge gap related to HeFH is that we lack data on contemporary treatment patterns, lipid levels achieved, and CV outcomes in this patient population, including in the Canadian context. To address these gaps in knowledge, we established the British Columbia Familial Hypercholesterolemia Registry,
      • Wong S.
      • Taraboanta C.
      • Francis G.A.
      • Ignaszewski A.
      • Frohlich J.
      The British Columbia Familial Hypercholesterolemia Registry.
      • Allard M.D.
      • Saeedi R.
      • Yousefi M.
      • Frohlich J.
      Risk stratification of patients with familial hypercholesterolemia in a multi-ethnic cohort.
      part of a national Canadian FH registry. Here we report the initial results of the British Columbia Familial Hypercholesterolemia Registry.

      Methods

      The British Columbia Familial Hypercholesterolemia Registry is a longitudinal open observational study of patients diagnosed with HeFH. This study was approved by the Clinical Research Ethics Board of the University of British Columbia. All patients provided written informed consent.
      Between 2012 and 2015, we invited active patients followed in the Healthy Heart Program Prevention clinic at St. Paul's Hospital in Vancouver, Canada to participate in this study. This is the only specialized lipid clinic in the province of British Columbia, and it receives referrals from the lower mainland of British Columbia as well as from around the province. Patients were eligible if they were 18 years or older and had a clinical diagnosis of “definite” or “probable” HeFH, based on the Dutch Lipid Clinic Network Criteria (DLCNC) score, in which a score of 6-8 indicates “probable” FH and a score > 8 indicates “definite” FH.
      • Nordestgaard B.G.
      • 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: consensus statement of the European Atherosclerosis Society.
      Patients were excluded if they were unwilling or unable to sign the informed consent form or had a secondary cause of hypercholesterolemia (eg, nephrotic syndrome or untreated hypothyroidism).
      Treatment goals were defined by current national clinical practice guidelines.
      • Anderson T.J.
      • Gregoire J.
      • Hegele R.A.
      • et al.
      2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
      Demographic, clinical, physical examination, and laboratory data were collected from the patients' medical records and entered into a secure web-based study database. High-potency statin drugs were defined as rosuvastatin 20 mg or 40 mg, atorvastatin 40 mg or 80 mg, or simvastatin 80 mg. All other statin doses were deemed to be low or moderate potency. Baseline data were defined as data at the time of the first visit to the Healthy Heart Program. Follow-up data were defined as data at the time of the last clinic visit as of December 2015.

      Statistical analysis

      Baseline characteristics between “definite” and “probable” HeFH were compared using a 2-sample t test, χ2 test, or Fisher exact test as appropriate. The change in lipid-lowering therapy (LLT) from baseline to last follow-up was assessed by the McNemar test. The proportion of patients who achieved ≥ 50% reduction in LDL-C levels and the proportion that achieved a LDL-C level of < 2 mmol/L were compared across the subgroups indicated using a χ2 test or Fisher exact test, as appropriate. Paired t tests were used to compare the change in plasma lipid levels. CV events were defined as myocardial infarction (MI), acute coronary syndrome, percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), angina and transient ischemic attack (TIA), or stroke. A Kaplan-Meier estimator and P values based on the log-rank test were used to compare the probability of CV events across groups. Observed 10-year CVD risk was obtained from the Kaplan-Meier estimator and compared to the 10-year risk predicted by the Framingham Risk Score (FRS). P values and confidence intervals for the observed risk were obtained based on the asymptotic property of the log hazard.

      Results

      Patient characteristics

      We identified patients with clinically diagnosed HeFH who attended a large specialized lipid clinic in Vancouver, Canada. A total of 1281 patients were identified, 679 of whom provided informed consent to participate in the registry. Of these individuals, 448 patients met criteria for either “definite” or “probable” HeFH based on the DLCNC. One hundred nine patients were excluded because of age < 18 years or missing data; 339 patients were included in the final analysis (Fig. 1).
      Figure thumbnail gr1
      Figure 1Flowchart of patients. Shown are patients who were identified as potentially eligible, provided consent to participate, and were included in the final analysis. DLCNC, Dutch Lipid Clinic Network Criteria; HeFH, heterozygous familial hypercholesterolemia.
      The baseline characteristics of the registry participants are shown in Table 1. The mean age of patients at enrollment was 43.9 years, and 51.3% were women. The mean follow-up was 10.9 years, providing a total of 3700 person-years of follow-up. Clinical atherosclerotic cardiovascular disease (ASCVD) was present in 12.1% of patients with HeFH at baseline. Approximately one-third of patients had other CV risk factors, most commonly hypertension (25.5%), current smoking (4.7%), and diabetes mellitus (DM) (2.1%).
      Table 1Baseline characteristics of patients
      CharacteristicEntire cohortDefinite FHProbable FHP value
      P value is for comparison between “definite” and “probable” FH.
      N339233106
      Age, y, mean (SD)43.9 (13.2)42.6 (12.9)47.0 (13.4)0.004
      DLCNC score mean (SD)10.7 (4.5)12.6 (4.2)6.4 (0.5)< 0.001
      Male sex (%)165 (48.7)117 (50.2)48 (45.3)0.4
      Weight, kg (SD)74.8 (16.0)74.8 (16.4)75.0 (15.2)0.9
      BMI, kg/m2 (SD)26.2 (4.6)26.1 (4.6)26.6 (4.6)0.4
      Framingham Risk Score, median (IQR)8.0 (3.9-18.4)8.0 (4.0-18.5)7.7 (3.0-16.0)0.7
      ASCVD at baseline (%)41 (12.1)28 (12.0)13 (12.3)0.9
      CV risk factors (%)99 (30.3)75 (33.3)24 (23.5)0.07
       HTN (%)84 (25.5)62 (27.3)22 (21.6)0.3
       DM (%)7 (2.1)7 (3.1)0 (0.0)0.1
       Current smoker (%)16 (4.7)13 (5.6)3 (2.9)0.3
      TC, mmol/L, (SD)7.9 (1.8)8.0 (2.0)7.7 (1.4)0.2
      LDL-C, mmol/L, (SD)5.9 (1.8)6.0 (1.9)5.6 (1.3)0.046
      HDL-C, mmol/L, (SD)1.3 (0.4)1.3 (0.4)1.4 (0.4)0.01
      TG, mmol/L, (SD)1.6 (0.9)1.6 (0.9)1.7 (0.9)0.4
      ApoB, g/L (SD)1.6 (0.4)1.6 (0.5)1.5 (0.4)0.4
      Lp(a) (mg/L)567.5 (488.9)473.1 (504.3)608.7 (479.5)0.2
      Years of follow-up (SD)10.9 (8.8)12.2 (9.2)8.1 (7.3)< 0.001
      ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; DLCNC, Dutch Lipid Clinic Network Criteria Score; DM, diabetes mellitus; FH, familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; HTN, hypertension; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); TC, total cholesterol; TG, triglycerides.
      P value is for comparison between “definite” and “probable” FH.

      Lipid-lowering therapy use and cholesterol levels achieved

      Use of LLT at baseline and at last follow-up is shown in Table 2. At baseline, most patients were not receiving any form of LLT (64.3%). Only 25.9% of patients were receiving a statin drug and only 10.6% were receiving a high-potency statin drug at baseline. By the last follow-up, 77.8% of patients were receiving a statin drug, representing a 200% increase. Among these, 46.9% were receiving a high-potency statin drug, 37.2% were receiving a statin drug plus ezetimibe, and 9.7% were receiving a statin drug plus ezetimibe plus at least 1 other LLT.
      Table 2Use of lipid-lowering therapy at baseline and last follow-up
      Lipid-lowering agentsBaseline
      Percentages do not add up to 100% because the categories are not mutually exclusive.
      N (%)
      Last follow-up
      Percentages do not add up to 100% because the categories are not mutually exclusive.
      N (%)
      P value
      None218 (64.3)52 (15.3)< 0.001
      Statin drug88 (25.9)264 (77.8)< 0.001
      Low-potency statin drug52 (15.3)105 (31.0)< 0.001
      High-potency statin drug36 (10.6)159 (46.9)< 0.001
      Statin drug + ezetimibe15 (4.4)126 (37.2)< 0.001
      Statin drug + ezetimibe + other LLT0 (0)33 (9.7)ND
      Ezetimibe alone1 (0.3)4 (1.2)0.4
      Non-statin–drug LLT33 (9.7)23 (6.8)0.2
      LLT, lipid lowering therapy; ND, not determined.
      Percentages do not add up to 100% because the categories are not mutually exclusive.
      Plasma lipid levels at baseline and last follow-up for patients with complete data at both baseline and follow-up are shown in Table 3. Plasma LDL-C levels decreased by 33.3% from baseline to last follow-up, reflecting a substantial shift in the population distribution of plasma LDL-C levels (Fig. 2A). Plasma apolipoprotein B concentrations were reduced 24.7%. Plasma triglyceride levels decreased modestly, and HDL-C levels increased modestly. Few patients had levels of lipoprotein(a) measured at both baseline and follow-up, but among those who did, there was no significant change.
      Table 3Lipid levels at baseline and last follow-up
      VariableNo.Baseline
      Only patients with data at both entry and last follow-up were included.
      mean (SD)
      Last follow-up
      Only patients with data at both entry and last follow-up were included.
      mean (SD)
      Percent change
      Only patients with data at both entry and last follow-up were included.
      P value
      LDL-C (mmol/L)3045.9 (1.8)3.7 (1.5)−33.3% (29.2)< 0.001
      HDL-C (mmol/L)3101.3 (0.4)1.5 (0.5)10.7% (30.2)< 0.001
      TG (mmol/L)3041.6 (0.9)1.3 (0.8)−7.2% (48.5)0.01
      ApoB (g/L)991.6 (0.5)1.1 (0.4)−24.7% (25.3)< 0.001
      Lp(a) (mg/L) (normal < 300 mg/L)7760.9 (563.4)782.3 (625.2)11.6 (48.9)0.6
      ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); TG, triglycerides.
      Only patients with data at both entry and last follow-up were included.
      Figure thumbnail gr2
      Figure 2Lipid levels in patients with heterozygous familial hypercholesterolemia. (A) Histogram of low-density lipoprotein cholesterol (LDL-C) levels at baseline and recruitment. (B) Percentage of patients achieving a ≥ 50% reduction in LDL-C levels compared with baseline value. (C) Percentage of patients achieving LDL-C levels ≤ 2 mmol/L. ASCVD, atherosclerotic cardiovascular disease; HPS, high-potency statin; LPS, low-potency statin.
      Despite the majority of patients receiving LLT, only a minority of patients (35.8%) achieved a ≥ 50% reduction in plasma LDL-C levels (Fig. 2B), and even fewer achieved an LDL-C ≤ 2 mmol/L (8.3%) (Fig. 2C). Only 5.9% of patients achieved an LDL-C level ≤ 1.8 mmol/L, which is a proposed lipid target for patients with severe FH.
      • Santos R.D.
      • Gidding S.S.
      • Hegele R.A.
      • et al.
      Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel.
      The proportion of patients achieving these targets was similar in the subgroups with “definite” or “probable” FH and was greater among those treated with high-potency statin drugs compared with those receiving low-potency statin drugs, although this difference did not reach statistical significance (P = 0.02) (Fig. 2B). Although a similar proportion of patients with previous ASCVD achieved an LDL-C target of ≤ 2 mmol/L, fewer patients in this subgroup achieved a ≥ 50% reduction in LDL-C (Fig. 2C).

      Cardiovascular outcomes

      We investigated the time to first CV event among patients in this cohort. The overall event rate was 33.5/1000 person-years (Table 4). The survival rate in the overall cohort is shown in Figure 3A, with a 10-year CV event rate of 15%. The 10-year CV event rate was numerically higher in those with “definite” (16%) compared with “probable” (13%) HeFH (Fig. 3B), although this difference was not statistically significant (log-rank test P = 0.3). The CV event rate was significantly higher in men than in women (Fig. 3C) and was higher in patients with any other CV risk factor (hypertension, diabetes, or current smoker) compared with those with no other CV risk factor (Fig. 3D). The overall rate of TIA or stroke was low (10-year event rate, 0%) compared with the 10-year rate of MI (5%), PCI (7%), CABG (7%), or angina (5%).
      Table 4Cardiovascular events per 1000 person-years
      StratumAny CV eventMICABGPCIAnginaTIA/stroke
      Overall (n)33.56.56.511.97.61.1
      Female sex (n)12.81.72.23.93.91.1
      Male sex (n)53.211.110.519.511.11.1
      Age < 55 y (n)30.07.05.110.56.70.6
      Age ≥ 55 y (n)53.33.614.219.512.43.6
      Without HTN (n)27.35.64.89.66.80.4
      With HTN (n)48.58.710.417.39.52.6
      Without any risk factor (n)27.66.24.59.86.70.5
      With any risk factor (n)44.67.210.115.89.42.2
      Probable FH (n)18.71.25.85.84.71.2
      Definite FH (n)38.08.16.713.78.41.1
      CABG, coronary artery bypass grafting; CV, cardiovascular; FH, familial hypercholesterolemia; HTN, hypertension; MI, myocardial infarction; PCI, percutaneous intervention; TIA, transient ischemic attack.
      Figure thumbnail gr3
      Figure 3Kaplan-Meier survival curves for probability of survival free of cardiovascular events. In each box, the x-axis represents the time in years since baseline and the y-axis represents the event-free probability. Survival curves are shown for (A) all patients and patients stratified by (B) definite or probable heterozygous familial hypercholesterolemia (HeFH), (C) sex, and (D) presence or absence of other cardiovascular (CV) risk factors. Other CV risk factors include hypertension, smoking, or diabetes.
      We compared the observed rate of CV events at 10 years to the predicted risk of CVD developing based on the FRS among these patients (Table 5). Overall, the observed rate of CVD at 10 years was significantly higher than predicted based on the FRS (observed 15.4% vs predicted 11.1%; P = 0.04). The observed rate of CVD was numerically higher than the predicted rate across every subgroup examined. The difference was particularly evident for men (observed, 22.1% vs predicted, 13.1%; P = 0.006).
      Table 5Predicted compared with observed 10-year risk of cardiovascular disease
      GroupPredicted 10-year CVD risk (%, based on FRS)Observed 10 year CVD risk (%) (95% CI)P value
      Overall11.115.4 (11.2-20.9)0.04
      Female sex9.38.7 (4.8-15.4)0.8
      Male sex13.122.1 (15.3-31.3)0.006
      Age < 55 y9.213.1 (8.9-18.9)0.07
      Age ≥ 55 y17.926.0 (14.6-43.7)0.2
      Without HTN9.312.6 (8.3-19.0)0.2
      With HTN16.522.8 (14.3-35.0)0.2
      Without any risk factor8.912.3 (7.9-19.0)0.2
      With any risk factor16.322.0 (14.2-33.1)0.2
      Probable FH10.812.8 (6.5-24.2)0.6
      Definite FH11.316.0 (11.2-22.6)0.06
      CVD, cardiovascular disease; FH, familial hypercholesterolemia; FRS, Framingham Risk Score; HTN, hypertension.

      Recurrent cardiovascular events

      We next examined the probability of recurrent CV events among patients with a first CV event that occurred after baseline. The probability of having a second event by 1 year after a first CV event was 52% and increased to 59% by year 5, with most of the recurrent events occurring within the first year (Fig. 4). The risk of a recurrent CV event was significantly higher in men than in women but not significantly different among individuals with “definite” compared with “probable” HeFH and among those with or without any other CV risk factors.
      Figure thumbnail gr4
      Figure 4Kaplan-Meier survival curves for probability of survival free of a recurrent cardiovascular (CV) event. Only patients who had an initial event are included in this analysis. In each box, the x-axis represents the time, in years, since first CV event after baseline, and the y-axis represents the event-free probability. Survival curves are shown for (A) all patients and patients stratified by (B) definite or probable heterozygous familial hypercholesterolemia (HeFH), (C) sex, and (D) presence or absence of other CV risk factors. Other CV risk factors include hypertension, smoking, or diabetes.

      Discussion

      Here we present the initial results of the British Columbia Familial Hypercholesterolemia Registry with a total of 3700 person-years of follow-up. This represents, to our knowledge, the first Canadian study to report medication use, lipid levels achieved, and annualized CV outcomes in a contemporary population of patients with HeFH. Our results provide insight into the patterns of treatment and characteristics of patients with HeFH and identify gaps in delivery of care for these patients. They also point to opportunities for improvements in the management of this condition.
      We found that few patients (25.3%) were receiving statin drugs at the time of first assessment at a specialized lipid clinic, and even fewer (10.6%) were receiving high-potency statin drugs. This reinforces the critical importance of recognizing and diagnosing HeFH and suggests that the majority of patients who have not been diagnosed are not receiving appropriate therapy. The low rate of LLT use at baseline also points to a lack of awareness of the need for aggressive treatment in this group of patients and suggests an opportunity to increase public and health professional awareness about this condition. An important future direction of this work will be to initiate cascade screening to identify more patients with HeFH who would benefit from early and intensive treatment.
      Although a majority of patients were receiving appropriate therapy by the last follow-up—consisting of a statin drug, ezetimibe, and combination therapy—few patients achieved recommended lipid targets. It is notable that despite intensive therapy in our cohort, a ≥ 50% reduction in LDL-C level was achieved in only 34.5% of patients, and an LDL-C level of < 2 mmol/L was seen in only 8.3% of patients. These data are broadly consistent with the results of HeFH registries reported in other jurisdictions, including the United States,
      • deGoma E.M.
      • Ahmad Z.S.
      • O'Brien E.C.
      • et al.
      Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: Data from the CASCADE-FH Registry.
      Spain,
      • Perez de Isla L.
      • Alonso R.
      • Watts G.F.
      • et al.
      Attainment of LDL-cholesterol treatment goals in patients with familial hypercholesterolemia: 5-year SAFEHEART Registry follow-up.
      The Netherlands,
      • Pijlman A.H.
      • Huijgen R.
      • Verhagen S.N.
      • et al.
      Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands.
      the United Kingdom,
      • Hadfield S.G.
      • Horara S.
      • Starr B.J.
      • et al.
      Are patients with familial hypercholesterolaemia well managed in lipid clinics? An audit of eleven clinics from the Department of Health Familial Hypercholesterolaemia Cascade Testing project.
      and France.
      • Beliard S.
      • Carreau V.
      • Carrie A.
      • et al.
      Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects.
      Our results highlight the challenges of treating patients with HeFH in Canada in order to reach lipids targets, even with maximal-dose combination agents. This reinforces the important unmet need in our ability to effectively control cholesterol levels in patients with HeFH to prevent ASCVD.
      The mean reduction in LDL-C levels observed in our study (33.3%) was lower than that observed in a controlled interventional trial of rosuvastatin in patients with HeFH. In that study, forced titration to 80 mg per day of rosuvastatin resulted in a mean 57.9% reduction in LDL-C levels.
      • Stein E.A.
      • Strutt K.
      • Southworth H.
      • et al.
      Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia.
      This reinforces the central role of high-intensity statin drugs as the mainstay of treatment of HeFH. The addition of ezetimibe has been demonstrated to further reduce LDL-C levels in patients with HeFH.
      • Pitsavos C.
      • Skoumas I.
      • Tousoulis D.
      • et al.
      The impact of ezetimibe and high-dose of statin treatment on LDL levels in patients with heterozygous familial hypercholesterolemia.
      • Pisciotta L.
      • Fasano T.
      • Bellocchio A.
      • et al.
      Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.
      The lesser reduction in LDL-C levels observed in our trial may reflect the over-representation of patients referred to our speciality lipid clinic because of statin-drug intolerance.
      Building on the established role of statin drugs and ezetimibe, the recent approval of therapeutic antibodies that inhibit proprotein convertase subtilisin kexin 9 (PCSK9) represents an important development in the ability to further lower LDL-C in patients with HeFH.
      • Navarese E.P.
      • Kolodziejczak M.
      • Schulze V.
      • et al.
      Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis.
      Both evolocumab and alirocumab have been studied in patients with HeFH,
      • Kastelein J.J.
      • Ginsberg H.N.
      • Langslet G.
      • et al.
      ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia.
      • Raal F.J.
      • Stein E.A.
      • Dufour R.
      • et al.
      PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.
      and they demonstrate reductions in LDL-C levels of 50%-70% compared with placebo when added to background statin-drug therapy. While these agents hold great promise for achieving greater lipid lowering in patients with HeFH, additional studies are needed to establish the long-term clinical impact of these therapies.
      The overall prevalence of ASCVD in our cohort at last follow up was 23%, which is broadly similar to that reported in HeFH registries in the United States and Denmark but higher than that reported in a French cohort.
      • 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.
      • deGoma E.M.
      • Ahmad Z.S.
      • O'Brien E.C.
      • et al.
      Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: Data from the CASCADE-FH Registry.
      • Beliard S.
      • Carreau V.
      • Carrie A.
      • et al.
      Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects.
      Despite aggressive medical therapy, the overall CV risk in our study population was high (10-year event rate, 15%). The rate of acute MI in this population (769/100,000/y in those 20-55 years) substantially exceeds by a factor of 10 the rate of hospitalization for MI in the province of British Columbia as a whole in similarly aged individuals (58/100,000 in the year 2009 for the age group 20-55 years).
      • Izadnegahdar M.
      • Singer J.
      • Lee M.K.
      • et al.
      Do younger women fare worse? Sex differences in acute myocardial infarction hospitalization and early mortality rates over ten years.
      The CV event rate was particularly high in patients with a first CV event. This is consistent with data from a registry of patients with HeFH from the United Kingdom, which showed that patients with HeFH and a history of a CV event are at the highest risk of event recurrence and suggests that this subpopulation requires particular focus to reduce the burden of CV events.
      • Neil A.
      • Cooper J.
      • Betteridge J.
      • et al.
      Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study.
      Despite aggressive treatment, the observed CVD risk was significantly higher than that predicted by the FRS in this population. This reinforces the high risk conferred by lifelong exposure to high LDL-C levels, which is not captured in standard-risk engines and may be underestimated in patients with HeFH. This also speaks to the important and ongoing need for early identification and diagnosis of these patients to allow earlier initiation of treatment. Interestingly, the risk of stroke or TIA was low in this population (0% at 5 years). Whether HeFH increases the risk for stroke is unclear.
      • Hutter C.M.
      • Austin M.A.
      • Humphries S.E.
      Familial hypercholesterolemia, peripheral arterial disease, and stroke: a HuGE minireview.
      Our results are consistent with the results of a recent meta-analysis that suggested that the risk of stroke among patients with HeFH in the statin-drug era is low.
      • Barkas F.
      • Elisaf M.
      • Milionis H.
      Statins decrease the risk of stroke in individuals with heterozygous familial hypercholesterolemia: a systematic review and meta-analysis.
      There was a high burden of other CV risk factors in this cohort, most commonly hypertension. Importantly, the presence of any CV risk factor was a significant driver of CV risk among these patients (Fig. 3D). This points to the importance of comprehensive CV risk assessment and prevention strategies among patients with HeFH. In contrast, the prevalence of DM was low, at 2.1% overall, and 0% among patients with “definite” HeFH. This compares with a prevalence of DM among the general Canadian population aged 40-44 years of 4.0%.
      • Public Health Agency of Canada
      Diabetes in Canada: Facts and figures from a public health perspective.
      The low frequency of DM in our cohort is consistent with previous data reporting a low prevalence of DM among patients with HeFH,
      • Besseling J.
      • Kastelein J.J.
      • Defesche J.C.
      • Hutten B.A.
      • Hovingh G.K.
      Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus.
      which may relate to lower rates of cholesterol uptake by pancreatic beta cells in the presence of defective LDL receptors.
      • Kruit J.K.
      • Kremer P.H.
      • Dai L.
      • et al.
      Cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) and cholesterol uptake via the LDL receptor influences cholesterol-induced impairment of beta cell function in mice.

      Limitations

      There are several limitations to our study that deserve consideration. Our study recruited patients from only a single centre in British Columbia. Although referrals to the Healthy Heart Program are received for patients from around the province, it is likely that our sample under-represents patients from rural or northern areas of British Columbia. Second, we used clinically diagnosed rather than molecularly confirmed HeFH as our inclusion criteria. It is likely that some patients meeting these criteria may have phenocopies of HeFH, such as polygenic hypercholesterolemia or familial combined hypercholesterolemia. Nevertheless, this reflects the reality of patients with HeFH in Canada, the majority of whom have not undergone genetic testing. A future direction of this work will be to examine the subgroup of those patients in whom a molecular diagnosis of HeFH is confirmed. A third limitation is that our definition of CV events did not include death. However, the number of deaths was small (n = 2) and is unlikely to have significant impact on our findings. Finally, we did not collect data on other phenotypes that may be of interest, such as aortic valve calcification.
      • ten Kate G.J.
      • Bos S.
      • Dedic A.
      • et al.
      Increased aortic valve calcification in familial hypercholesterolemia: prevalence, extent, and associated risk factors.

      Conclusions

      Our results fill a gap in knowledge regarding contemporary trends in the management of patients with HeFH in a context of statin-drug use in Canada. Despite aggressive use of LLT and combination therapy, the lipid targets in the majority of these patients remain higher than the recommended levels, and the prevalence of ASCVD is high. These findings point to important opportunities to improve the care of patients with HeFH and reduce the burden of disease in this high-risk population.

      Acknowledgements

      We would like to thank the patients who participated in the British Columbia Familial Hypercholesterolemia Registry. We also wish to thank Mr Joe Comeau for expert database assistance and generation of the Canadian Familial Hypercholesterolemia Registry database.

      Funding Sources

      This study was supported by a research grant from Sanofi-Aventis Canada. The British Columbia Familial Hypercholesterolemia Registry was supported by Pfizer Canada, Sanofi-Aventis Canada, and Amgen Canada. L.R.B. was supported by a Heart & Stroke Foundation of Canada National New Investigator award.

      Disclosures

      K.A. and M.D.C. are employees of Sanofi-Aventis Canada, Inc. The other authors have no conflicts of interest to disclose.

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