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Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy

Published:November 11, 2013DOI:https://doi.org/10.1016/j.jacl.2013.11.002

      Highlights

      • All patients with homozygous familial hypercholesterolemia (FH) and many with heterozygous FH remain far from treatment low-density lipoprotein (LDL) cholesterol goals.
      • The National Lipid Association recently recommended 4 additional patient segments for LDL apheresis.
      • Recently approved therapies hold promise in reducing the frequency of apheresis and also potentially the number of patients that may need apheresis.
      • LDL apheresis is the therapy of choice for patients with severe, refractory FH.
      • LDL apheresis remains an underused option for uncontrolled severe FH.

      Abstract

      Familial hypercholesterolemia (FH), an autosomal-dominant inherited disorder, can occur in either the heterozygous (HeFH) or homozygous (HoFH) state, and is characterized by high levels of serum low-density lipoprotein cholesterol (LDL-C). Although potent statins and maximally tolerated lipid-lowering therapy (LLT) have greatly reduced the risk of premature coronary heart disease (CHD) and death, all patients with HoFH and many with severe HeFH remain far from treatment goals and are thus at risk of cardiovascular disease. LDL apheresis is the treatment of choice for these patients but remains underutilized. No formal studies or epidemiologic data have estimated the prevalence of HoFH. An HeFH prevalence of 1:500 and a simplified Hardy–Weinberg equilibrium model was used to determine the probability of finding HoFH as 1:1 million in the general population. A US population of approximately 314.8 million was used to determine the number of cases of HoFH and HeFH. The following key parameters were used to estimate the prevalence of severe HeFH: baseline pretreatment LDL-C level and distribution of patients with FH, posttreatment LDL-C level and distribution after maximally tolerated LLT, and baseline percentage of patients with HeFH who have CHD. We assumed an HeFH prevalence of 1:500 and used statistics for a Gaussian distribution after the posttreatment means and standard deviations of LDL-C levels in patients with HeFH receiving maximally tolerated LLT, as has been documented by data from clinical trials and cross-sectional studies. These estimates do not include the statin-intolerant population. The objective of this analysis was to determine the prevalence of the US population with severe HeFH with or without CHD who still will be eligible for LDL apheresis despite maximally tolerated LLT. We estimated that there are 315 US patients with HoFH and 650,000 with HeFH. The estimated prevalence of the severe HeFH population eligible for apheresis is approximately 1:20,000 (range, 1:11,700–1:62,500). This estimate suggests that, based on the efficacy of maximally tolerated LLT and CHD status, approximately 15,000 (approximately 2.4%) of the 625,000 patients with HeFH who are maximally treated will still be eligible for LDL apheresis.

      Keywords

      Familial hypercholesterolemia (FH) is an autosomal co-dominant inherited disorder with a gene–dosage effect.
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      Mechanisms of disease: genetic causes of familial hypercholesterolemia.
      The clinical phenotype of FH is characterized by increased levels of serum low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B). Consequently, FH confers an increased risk of premature coronary heart disease (CHD), with significant rates of morbidity and mortality.
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      Persons affected by FH are typically either heterozygotes or homozygotes for the LDL receptor (LDLR) gene.
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      Phenotypic FH can also occur because of mutational defects in either the APOB gene (familial defective apolipoprotein B-100 [FDB]) or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene (FH type III).
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      Heterozygotes and homozygotes for the APOB and PCSK9 genes have been described.
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      The clinical homozygous FH (HoFH) phenotype may be due to a true genetic homozygote that has the same mutation on both alleles or may be due to a genetically compound heterozygote in which a different mutation is found at each allele.
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      Collectively, these monogenic inherited familial disorders result in phenotypic FH and are also referred to as autosomal dominant hypercholesterolemia (ADH).
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      Mutations in the LDL receptor adaptor protein 1 cause autosomal recessive hypercholesterolemia (ARH), which is extremely rare.
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      Rare genetic causes of autosomal dominant or recessive hypercholesterolaemia.
      Patients with ARH are similar to those with HoFH but with greater phenotypic variability.
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      • Trau L.M.
      Genetics, clinical phenotype, and molecular cell biology of autosomal recessive hypercholesterolemia.
      The estimated phenotypic prevalence of clinical heterozygous FH (HeFH; or heterozygous ADH), which is diagnosed on the basis of clinical symptoms and plasma cholesterol values, is approximately 1:500 persons in most Western countries. FH, or ADH, is one of the most frequent monogenic hereditary disorders in the general population.
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      Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.
      No formal studies or categorical epidemiologic data to estimate the prevalence of HoFH are available. On the basis of the HeFH prevalence of 1:500 and a simplified Hardy–Weinberg equilibrium, the probability of finding the homozygous form of FH is interpreted as 1:1 million in the general population [1/500 (mother) × 1/500 (father) × 1/4(child)].
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      In current literature, the prevalence of HoFH in the United States, the European Union, and globally is approximately 1:1 million.
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      Mechanisms of disease: genetic causes of familial hypercholesterolemia.
      • Vella A.
      • Pineda A.A.
      • O'Brien T.
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      • Goldberg A.C.
      • Hopkins P.N.
      • Toth P.P.
      • et al.
      Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
      With the use of this often-cited prevalence and assuming a US population of approximately 314.8 million, there are an estimated 315 cases of HoFH and 650,000 cases of HeFH in the United States.

      United States Census Bureau. U.S. and World Population Clock. 2012. Available at: http://www.census.gov/population/www/popclockus.html. Accessed February 13, 2013.

      Comprehensive molecular genetic analyses from various countries have found that 20% to 48% of patients with the clinical FH phenotype do not harbor a known causative mutation in the LDLR, APOB, or PCSK9 gene, and additional loci may contribute to a familial ADH-like phenotype.
      • Motazacker M.M.
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      • Huijgen R.
      • et al.
      Advances in genetics show the need for extending screening strategies for autosomal dominant hypercholesterolaemia.
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      • Hopkins P.N.
      • Toth P.P.
      • et al.
      Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
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      On the basis of the relative frequencies of the various genetic defects that cause HeFH, one can assume that the relative frequencies of homozygotes for these genes are also the same.

      Efficacy of statins and use of LDL apheresis

      Potent statins and maximally tolerated lipid-lowering therapy (LLT) used to treat patients with homozygous FH have greatly reduced the related risks of premature CHD and death, affording survival into the third and fourth decades of life.
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      Because these risks in FH are largely driven by very high LDL-C and apo B levels from birth,
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      Disorders of lipid metabolism.
      treatment strategies focus on early detection, reduction of these levels, and management of other risk factors.
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      Statins alone and in combination with other LLTs can lower LDL-C levels by an average of 25% in HoFH and 45% to 60% in HeFH.
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      Long-term treatment with pitavastatin (NK-104), a new HMG-CoA reductase inhibitor, of patients with heterozygous familial hypercholesterolemia.
      However, almost all patients with HoFH and a small proportion with HeFH continue to have dangerously high LDL-C levels, regardless of maximally tolerated LLT, and are at an excessively high risk of cardiovascular-related death.
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      These patients with severe FH can benefit from LDL apheresis, a procedure that rapidly produces marked reductions in LDL and apo B particles.
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      Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
      The use of LDL apheresis in severe FH is approved by the US Food and Drug Administration (FDA).
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      FDA criteria recommend LDL apheresis in patients who have failed prior treatment with dietary therapy and maximally tolerated LLT (defined as a trial of drugs from ≥2 separate classes of hypolipidemic agents) for ≥6 months and who have HoFH with LDL-C levels >500 mg/dL (>12.95 mmol/L), HeFH with LDL-C levels ≥300 mg/dL (≥7.76 mmol/L), or HeFH with LDL-C levels ≥200 mg/dL (≥5.2 mmol/L) plus documented CHD.

      FDA Premarket Approval (PMA) P910018 for Liposorber® LA-15 System. Rockville, MD; February 21, 1996.

      FDA Premarket Approval (PMA) P940016 for Heparin-Induced Extracorporeal Lipoprotein Precipitation (H.E.L.P.) Futura Apheresis System. Last updated November 2, 2012. Available at: http: \\clinical6\PCX\Genzyme\Mipomersen\2011 Plan\2011 Review Manuscripts\1185B Cumulative risk of CAD in patients with FH and Severe FH - Robinson & Vishwanath\References\FDA PMA P940016.mht. Accessed February 13, 2013.

      A prevalence estimate of the severe FH pool eligible for apheresis is not available.

      Apheresis-eligible population

      Current guidelines emphasize the need to aggressively lower LDL-C levels in patients with FH. Among heterozygous patients, the presence of CHD is an important parameter that drives the eligibility for apheresis. In 2011, the National Lipid Association recommended that 4 additional patient segments be considered candidates for LDL apheresis, including functional patients with (1) HoFH and LDL-C levels ≥300 mg/dL (≥7.76 mmol/L; or non–HDL-C ≥ 330 mg/dL [≥8.55 mmol/L]); (2) HeFH and LDL-C levels ≥300 mg/dL (≥7.76 mmol/L; or non-HDL-C ≥330 mg/dL [≥8.55 mmol/L]) and 0 to 1 risk factors; (3) HeFH and LDL-C levels ≥200 mg/dL (≥5.2 mmol/L; or non–HDL-C ≥ 230 mg/dL [≥5.96 mmol/L]) and high-risk characteristics (eg, ≥2 risk factors or high lipoprotein(a) levels ≥50 mg/dL [≥1.30 mmol/L] with the use of an isoform insensitive assay); and (4) HeFH with LDL-C levels ≥160 mg/dL (4.14 mmol/L; or non-HDL-C ≥190 mg/dL [≥4.92 mmol/L]) and very-high-risk characteristics (established CHD, other cardiovascular disease [CVD], or diabetes).
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      National Lipid Association guidelines also state that comprehensive risk assessment for CHD including the measurement of lipoprotein (a) [Lp(a)] levels and management of CHD are critical because the presence of multiple CHD risk factors is associated with dramatic acceleration in the development of atherosclerosis.
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      The recent joint guidelines from the European Atherosclerosis Society and the European Society of Cardiology on the management of dyslipidemias are complementary to the guidelines on CVD prevention in clinical practice and address not only clinicians interested in prevention, such as family physicians and cardiologists, but also specialists at lipid clinics or metabolic units who deal with dyslipidemias that are more difficult to classify and treat. The European Atherosclerosis Society/European Society of Cardiology guidelines state that rare patients with severe hyperlipidemias, especially HoFH and severe HeFH, require specialist evaluation and consideration of the need for LDL apheresis. This weekly or every-other-week technique removes LDL and Lp(a) from plasma during extracorporeal circulation.
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      Elevated levels of Lp(a) are substantial and independent risk factors for coronary disease. Treatment with statins does not adequately address the increased risks associated with high levels of Lp(a), and treatment options to reduce these levels are limited. Some centers in Germany recommend that apheresis be considered in patients with Lp(a) levels >60 mg/dL and progressive CHD, despite the optimal control of other risk factors. In 2010, 34% of 71 patients in the Berlin area underwent lipid apheresis because of an isolated Lp(a) elevation, 41% because of HoFH, and 25% because of therapy-refractory, severe hypercholesterolemia (LDL-cholesterol level >200 mg/dL).

      Rosada A, Kassner U, Vogt A, Willhauck M, Parhofer K, Steinhagen-Thiessen E. Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) levels reduce the incidence of cardiovascular events? [e-pub ahead of print July 25, 2013] Artif Organs. doi: 10.1111/aor.12135.

      Surprisingly, more than one-third of these apheresis treatments are performed in patients with isolated Lp(a) elevation.

      Rosada A, Kassner U, Vogt A, Willhauck M, Parhofer K, Steinhagen-Thiessen E. Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) levels reduce the incidence of cardiovascular events? [e-pub ahead of print July 25, 2013] Artif Organs. doi: 10.1111/aor.12135.

      The British HEART-UK LDL Apheresis Working Group
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      recommends considering apheresis in patients with Lp(a) levels >60 mg/dL and progressive CHD when the LDL-C is >125 mg/dL despite maximal drug therapy.
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      On the basis of the modest response to both statins and ezetimibe,
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      • et al.
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      • et al.
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      almost all LDLR homozygotes would be eligible for apheresis. Very few ARH homozygotes will be eligible for LDL apheresis because their posttreatment LDL-C levels often are <200 mg/dL (<5.2 mmol/L).
      • Arca M.
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      • et al.
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      Aggressive treatment with statins and other combination therapies in FDB homozygotes usually will result in LDL-C levels <200 mg/dL (<5.2 mmol/L).
      • Hansen P.S.
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      • Faergeman O.
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      No studies have yet been done specifically in PCSK9 homozygous patients.
      We estimate that only 189 to 252 LDLR homozygotes treated with maximally tolerated LLT will be eligible for apheresis. These numbers are based on the estimate of approximately 315 patients with HoFH (1:1 million of the US population of approximately 314.8 million

      United States Census Bureau. U.S. and World Population Clock. 2012. Available at: http://www.census.gov/population/www/popclockus.html. Accessed February 13, 2013.

      ), the assumption that ≥60% to 80% are LDLR homozygotes, and the ability of statins in combination with other LLTs to lower LDL-C levels to <200 mg/dL (<5.2 mmol/L) in FDB homozygotes and ARH homozygotes.
      Many patients with HeFH can achieve substantial reductions in LDL-C levels with LLTs, and life expectancy in aggressively managed patients can be increased by 10 to 30 years, especially if diagnosis is made early.
      • De Castro-Oros I.
      • Pocovi M.
      • Civeira F.
      The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations.
      Clinical trials with statins indicate that LDL-C concentrations can be lowered by 23% to 46% in patients with HeFH, and combined drug therapy can lower LDL-C levels by 26% to 66%.
      • Stein E.A.
      • Strutt K.
      • Southworth H.
      • Diggle P.J.
      • Miller E.
      HeFH Study Group
      Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia.
      • Kastelein J.J.
      • Akdim F.
      • Stroes E.S.
      • et al.
      ENHANCE investigators
      Simvastatin with or without ezetimibe in familial hypercholesterolemia.
      • Tasaki H.
      • Miyamoto M.
      • Kubara T.
      • et al.
      Cross-over trial of intensive monotherapy with atorvastatin and combined therapy with atorvastatin and colestimide for Japanese familial hypercholesterolemia.
      • Pisciotta L.
      • Fasano T.
      • Bellocchio A.
      • et al.
      Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.
      • Wierzbicki A.S.
      • Lumb P.J.
      • Semra Y.K.
      • Crook M.A.
      High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia.
      • Wierzbicki A.S.
      • Lumb P.J.
      • Cheung J.
      • Crook M.A.
      Fenofibrate plus simvastatin therapy versus simvastatin plus cholestyramine therapy for familial hypercholesterolaemia.
      • 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.
      • Huijgen R.
      • Abbink E.J.
      • Bruckert E.
      • et al.
      Triple Study Group
      Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial.
      • Kawashiri M.A.
      • Nohara A.
      • Noguchi T.
      • et al.
      Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia.
      Despite combination therapy, however, a small proportion of patients with HeFH will remain eligible for apheresis.
      Patients with severe FH, a small subset of the broader FH population, have LDL-C levels that are either ≥300 mg/dL (≥7.76 mmol/L) regardless of heart disease or ≥200 mg/dL (≥5.2 mmol/L) with evidence of atherosclerotic disease (eg, CHD, peripheral vascular disease, clinically evident carotid atherosclerotic disease, stroke, transient ischemic attack
      • Goldstein J.L.
      • Hobbs H.H.
      • Brown M.S.
      Familial hypercholesterolemia.
      • van der Graaf A.
      • Cuffie-Jackson C.
      • Vissers M.N.
      • et al.
      Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia.
      ) and are receiving maximally tolerated LLT, such as different combinations of statins, ezetimibe, bile acid sequestrants, and niacin.
      • Ito M.K.
      • McGowan M.P.
      • Moriarty P.M.
      Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
      In most countries, the extreme risk of CVD makes these patients eligible for apheresis.
      The purpose of this article is to estimate the prevalence of the US population with severe HeFH who will still be eligible for LDL apheresis despite maximally tolerated LLT and CHD status.

      Estimation of CHD in the proposed population

      HeFH is underrecognized and often underdiagnosed.
      • Rees A.
      Familial hypercholesterolaemia: underdiagnosed and undertreated.
      LLT generally is begun later in life when advanced atherosclerosis has already developed. Retrospective multicenter cohort studies have assessed the effect of LLT in patients with HeFH from various FH registries in the Netherlands (4 studies), the United Kingdom, the United States (the MEDPED [Make Early Diagnosis to Prevent Early Death] register), Canada, Italy, Spain, Portugal, Germany, and Greece (1 study), and Mexico.
      • Haddad L.
      • Day I.N.
      • Hunt S.
      • Williams R.R.
      • Humphries S.E.
      • Hopkins P.N.
      Evidence for a third genetic locus causing familial hypercholesterolemia. A non-LDLR, non-APOB kindred.
      • Pisciotta L.
      • Fasano T.
      • Bellocchio A.
      • et al.
      Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.
      • Wierzbicki A.S.
      • Lumb P.J.
      • Cheung J.
      • Crook M.A.
      Fenofibrate plus simvastatin therapy versus simvastatin plus cholestyramine therapy for familial hypercholesterolaemia.
      • Civeira F.
      • Castillo S.
      • Alonso R.
      • et al.
      Spanish Familial Hypercholesterolemia Group
      Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene mutation.
      • de Sauvage Nolting P.R.
      • Defesche J.C.
      • Buirma R.J.
      • Hutten B.A.
      • Lansberg P.J.
      • Kastelein J.J.
      Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemia.
      • Jansen A.C.
      • Aalst-Cohen E.S.
      • Tanck M.W.
      • et al.
      The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients.
      • Jansen A.C.
      • van Aalst-Cohen E.S.
      • Tanck M.W.
      • et al.
      Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia.
      Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group.
      • Bouhali T.
      • Brisson D.
      • St-Pierre J.
      • et al.
      Low plasma adiponectin exacerbates the risk of premature coronary artery disease in familial hypercholesterolemia.
      • Taira K.
      • Bujo H.
      • Kobayashi J.
      • Takahashi K.
      • Miyazaki A.
      • Saito Y.
      Positive family history for coronary heart disease and 'midband lipoproteins' are potential risk factors of carotid atherosclerosis in familial hypercholesterolemia.
      • Vaca G.
      • Vazquez A.
      • Magana M.T.
      • et al.
      Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia.
      • Bourbon M.
      • Alves A.C.
      • Medeiros A.M.
      • Silva S.
      • Soutar A.K.
      Investigators of Portuguese FH Study
      Familial hypercholesterolaemia in Portugal.
      • Dedoussis G.V.
      • Genschel J.
      • Bochow B.
      • et al.
      Molecular characterization of familial hypercholesterolemia in German and Greek patients.
      The average rate of CVD was 28% in these studies.
      In 1 study with 2400 patients with HeFH from 27 Dutch lipid clinics, approximately 33% presented with CVD.
      • Jansen A.C.
      • Aalst-Cohen E.S.
      • Tanck M.W.
      • et al.
      The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients.
      Similarly, a review of medical records showed that 33.2% of 1940 patients with HeFH from various Dutch lipid clinics had ≥1 cardiovascular event.
      • Jansen A.C.
      • van Aalst-Cohen E.S.
      • Tanck M.W.
      • et al.
      Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia.
      Similar percentages for patients with HeFH with CVD (38.6%) are available from a cross-sectional cohort of 409 patients with FH from the Simon Broome FH Register (United Kingdom).
      Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group.
      • Humphries S.E.
      • Whittall R.A.
      • Hubbart C.S.
      • et al.
      Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee
      Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.
      Of 951 genetically diagnosed patients from the Spanish FH Register, approximately 21% had CVD.
      • Civeira F.
      • Castillo S.
      • Alonso R.
      • et al.
      Spanish Familial Hypercholesterolemia Group
      Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene mutation.
      A smaller study from Italy with 65 patients with HeFH showed that 40% had CVD, and another smaller study from Japan with 97 patients with HeFH showed that 50% had CVD.
      • Pisciotta L.
      • Fasano T.
      • Bellocchio A.
      • et al.
      Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.
      In contrast, the lowest rate of patients with HeFH with CVD was 17% in a Dutch study of 1249 patients.
      • 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.
      On the basis of a median prevalence of 30% CVD at baseline, it can be concluded that the prevalence in HeFH populations ranges from 17% to 50%.
      • Haddad L.
      • Day I.N.
      • Hunt S.
      • Williams R.R.
      • Humphries S.E.
      • Hopkins P.N.
      Evidence for a third genetic locus causing familial hypercholesterolemia. A non-LDLR, non-APOB kindred.
      • Pisciotta L.
      • Fasano T.
      • Bellocchio A.
      • et al.
      Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.
      • 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.
      • Civeira F.
      • Castillo S.
      • Alonso R.
      • et al.
      Spanish Familial Hypercholesterolemia Group
      Tendon xanthomas in familial hypercholesterolemia are associated with cardiovascular risk independently of the low-density lipoprotein receptor gene mutation.
      • de Sauvage Nolting P.R.
      • Defesche J.C.
      • Buirma R.J.
      • Hutten B.A.
      • Lansberg P.J.
      • Kastelein J.J.
      Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemia.
      • Jansen A.C.
      • Aalst-Cohen E.S.
      • Tanck M.W.
      • et al.
      The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients.
      • Jansen A.C.
      • van Aalst-Cohen E.S.
      • Tanck M.W.
      • et al.
      Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia.
      Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group.
      • Bouhali T.
      • Brisson D.
      • St-Pierre J.
      • et al.
      Low plasma adiponectin exacerbates the risk of premature coronary artery disease in familial hypercholesterolemia.
      • Taira K.
      • Bujo H.
      • Kobayashi J.
      • Takahashi K.
      • Miyazaki A.
      • Saito Y.
      Positive family history for coronary heart disease and 'midband lipoproteins' are potential risk factors of carotid atherosclerosis in familial hypercholesterolemia.
      • Vaca G.
      • Vazquez A.
      • Magana M.T.
      • et al.
      Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia.
      • Bourbon M.
      • Alves A.C.
      • Medeiros A.M.
      • Silva S.
      • Soutar A.K.
      Investigators of Portuguese FH Study
      Familial hypercholesterolaemia in Portugal.
      • Dedoussis G.V.
      • Genschel J.
      • Bochow B.
      • et al.
      Molecular characterization of familial hypercholesterolemia in German and Greek patients.
      For our estimates, we chose a figure of 30% CVD in patients with HeFH at baseline, which represents the median value. In addition, a cross-sectional study from the Netherlands showed that among patients treated with maximally tolerated LLT with LDL-C goals of approximately 100 mg/dL (≥2.5 mmol/L), 30% with HeFH had a history of CVD.
      • 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.

      Estimation assumptions and parameters

      No estimate exists of the number of patients with FH who are eligible for apheresis. To obtain an estimate, we assume a prevalence of HeFH of 1:500 and use a Gaussian distribution after the posttreatment means and standard deviations (SDs) of LDL-C levels in patients receiving maximally tolerated LLT as documented in various studies.
      Published estimates of the size of the severe FH population do not exist because, to date, no therapy specifically targets this population. The broad FH prevalence data, which are more robust and globally converge at approximately 1:500, can be used as a basis for calculating population size.
      With the availability of data from clinical trials and cross-sectional studies that include patients with HeFH who have received maximally tolerated LLT, it is feasible to estimate the prevalence of severe FH.
      The key parameters that drive our methodology in estimating the prevalence of severe HeFH are as follows:
      • 1.
        Baseline pretreatment LDL-C level and associated distribution of patients with FH
      • 2.
        Observed posttreatment LDL-C levels
      • 3.
        Observed distribution (SD) of LDL-C levels after maximally tolerated LLT
      • 4.
        Percentage of patients with HeFH and CHD at baseline before treatment initiation

      Efficacy of LLTs in HeFH and estimation of eligibility for apheresis

      Numerous studies have tested the efficacy of maximally tolerated LLT in LDLR homozygotes and report only modest response to both statins and ezetimibe (Tables 1 and 2).
      • Stein E.A.
      • Strutt K.
      • Southworth H.
      • Diggle P.J.
      • Miller E.
      HeFH Study Group
      Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia.
      • Kastelein J.J.
      • Akdim F.
      • Stroes E.S.
      • et al.
      ENHANCE investigators
      Simvastatin with or without ezetimibe in familial hypercholesterolemia.
      • Marais A.D.
      • Raal F.J.
      • Stein E.A.
      • et al.
      A dose-titration and comparative study of rosuvastatin and atorvastatin in patients with homozygous familial hypercholesterolaemia.
      • Raal F.J.
      • Pappu A.S.
      • Illingworth D.R.
      • et al.
      Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.
      • Raal F.J.
      • Pilcher G.J.
      • Panz V.R.
      • et al.
      Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy.
      • Tsimihodimos V.
      • Miltiadous G.
      • Elisaf M.
      Therapy with statins is effective in some patients with homozygous familial hypercholesterolemia [letter].
      • Yamamoto A.
      • Sudo H.
      • Endo A.
      Therapeutic effects of ML-236B in primary hypercholesterolemia.
      • Laue L.
      • Hoeg J.M.
      • Barnes K.
      • Loriaux D.L.
      • Chrousos G.P.
      The effect of mevinolin on steroidogenesis in patients with defects in the low density lipoprotein receptor pathway.
      • Uauy R.
      • Vega G.L.
      • Grundy S.M.
      • Bilheimer D.M.
      Lovastatin therapy in receptor-negative homozygous familial hypercholesterolemia: lack of effect on low-density lipoprotein concentrations or turnover.
      • Raal F.J.
      • Pilcher G.J.
      • Illingworth D.R.
      • et al.
      Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia.
      • Tasaki H.
      • Miyamoto M.
      • Kubara T.
      • et al.
      Cross-over trial of intensive monotherapy with atorvastatin and combined therapy with atorvastatin and colestimide for Japanese familial hypercholesterolemia.
      • Pisciotta L.
      • Fasano T.
      • Bellocchio A.
      • et al.
      Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.
      • Wierzbicki A.S.
      • Lumb P.J.
      • Semra Y.K.
      • Crook M.A.
      High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia.
      • Wierzbicki A.S.
      • Lumb P.J.
      • Cheung J.
      • Crook M.A.
      Fenofibrate plus simvastatin therapy versus simvastatin plus cholestyramine therapy for familial hypercholesterolaemia.
      • 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.
      • Huijgen R.
      • Abbink E.J.
      • Bruckert E.
      • et al.
      Triple Study Group
      Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial.
      • Kawashiri M.A.
      • Nohara A.
      • Noguchi T.
      • et al.
      Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia.
      A summary of the various studies from the Netherlands, Italy, and 2 global studies that assessed the effects of mono, dual, and triple LLTs in patients with HeFH, which were mentioned previously, is provided in Table 2.
      • Stein E.A.
      • Strutt K.
      • Southworth H.
      • Diggle P.J.
      • Miller E.
      HeFH Study Group
      Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia.
      • Kastelein J.J.
      • Akdim F.
      • Stroes E.S.
      • et al.
      ENHANCE investigators
      Simvastatin with or without ezetimibe in familial hypercholesterolemia.
      • Tasaki H.
      • Miyamoto M.
      • Kubara T.
      • et al.
      Cross-over trial of intensive monotherapy with atorvastatin and combined therapy with atorvastatin and colestimide for Japanese familial hypercholesterolemia.
      • Pisciotta L.
      • Fasano T.
      • Bellocchio A.
      • et al.
      Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.
      • Wierzbicki A.S.
      • Lumb P.J.
      • Semra Y.K.
      • Crook M.A.
      High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia.
      • Wierzbicki A.S.
      • Lumb P.J.
      • Cheung J.
      • Crook M.A.
      Fenofibrate plus simvastatin therapy versus simvastatin plus cholestyramine therapy for familial hypercholesterolaemia.
      • 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.
      • Huijgen R.
      • Abbink E.J.
      • Bruckert E.
      • et al.
      Triple Study Group
      Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial.
      • Kawashiri M.A.
      • Nohara A.
      • Noguchi T.
      • et al.
      Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia.
      These patients already had CHD at baseline or during registration.
      Table 1HoFH and response to lipid-lowering therapy
      Reference, year of publication/countryDrug: doseHoFH genotypeNo. of patients/mean age, yStudy designDurationLDL-C level
      Baseline, mg/dL (mmol/L)Posttreatment, mg/dL (mmol/L)Mean percent reduction, %
      Marias et al,
      • Marais A.D.
      • Raal F.J.
      • Stein E.A.
      • et al.
      A dose-titration and comparative study of rosuvastatin and atorvastatin in patients with homozygous familial hypercholesterolaemia.
      2008/South Africa
      Rosuvastatin: 20, 40, 80 mg/d

      Atorvastatin: 80 mg/d
      HoFH LDLR: 17

      Compound HeFH: 21

      HeFH: 3

      No variant in LDLR: 2
      44/28Dose titration and statin efficacy comparison (N = 4 with portacaval shunts and N = 11 on apheresis)30 wk (first 18-wk dose escalation, last 12-wk double-blind, randomized, crossover, 80 mg/d)514 ± 116 (13.3 ± 3.0)415 ± 41 (10.7 ± 1.06)

      421 ± 44 (10.9 ± 1.14)
      19

      18
      Raal et al,
      • Raal F.J.
      • Pappu A.S.
      • Illingworth D.R.
      • et al.
      Inhibition of cholesterol synthesis by atorvastatin in homozygous familial hypercholesterolaemia.
      2000/South Africa
      Atorvastatin: 40, 80, 120, 160 mg/dHoFH LDLR or compound HeFH

      FH Afrik: 23

      CT2/CT2: 2

      FH 664/FH/664: 2

      Unknown: 8
      35/22Statin monotherapy dose escalation4 wk/dose31 ± 3.9 (0.8 ± 0.1)422 ± 19.3 (10.9 ± 0.5) (at 80 mg/d)28
      Raal et al,
      • Raal F.J.
      • Pilcher G.J.
      • Panz V.R.
      • et al.
      Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy.
      2011/South Africa
      Simvastatin, atorvastatin, rosuvastatin, LDL apheresis, plasma exchange

      Increasing dose of maximally tolerated statin
      HoFH LDLR: 70

      FH Afrik-1: 90

      FH Afrik-2: 37

      FH Afrik-3: 17

      P664L: 10

      APOB/LDLR: 1

      ARH: 1

      Compound HeFH: 58
      149/26.8Multiple increasing dose statins13.2 y439.6 (11.4)26.4
      Tsimihodimos et al,
      • Tsimihodimos V.
      • Miltiadous G.
      • Elisaf M.
      Therapy with statins is effective in some patients with homozygous familial hypercholesterolemia [letter].
      2000/Greece
      Lovastatin, pravastatin, simvastatin, fluvastatin, atorvastatin: NRHoFH G1775A Class V mutation: 55/NRMultiple statinsNR354 ± 75 (9.2 ± 1.9)Range: 420–472 (10.9–12.2)Before atorvastatin: 23.5
      Yamamoto et al,
      • Yamamoto A.
      • Sudo H.
      • Endo A.
      Therapeutic effects of ML-236B in primary hypercholesterolemia.
      1980/Japan
      Mevastatin (ML-236B; Compactin): 50–150 mg/dHoFH: 2

      HeFH: 1

      Suspected HeFH: 4

      CH: 4
      11/38

      (HeFH: 30 y; CH: 41 y, 44 y, 48 y, 71 y)
      Monotherapy4–8 wkNRNR27% (HeFH, N = 1; CH, N = 4)
      Laue et al,
      • Laue L.
      • Hoeg J.M.
      • Barnes K.
      • Loriaux D.L.
      • Chrousos G.P.
      The effect of mevinolin on steroidogenesis in patients with defects in the low density lipoprotein receptor pathway.
      1987/US
      Mevinolin: 20 mg, twice dailyHoFH: 6

      LDLR unknown: 1

      Cholesterol ester storage disease: 1
      7Monotherapy8 wkRange: 147–969 (3.8–25.1)NR21
      Uauy et al,
      • Uauy R.
      • Vega G.L.
      • Grundy S.M.
      • Bilheimer D.M.
      Lovastatin therapy in receptor-negative homozygous familial hypercholesterolemia: lack of effect on low-density lipoprotein concentrations or turnover.
      1988/US
      Lovastatin: 2 mg/kg dailyLDLR receptor-negative3MonotherapyNR370 ± 18 (9.6 ± 0.5)NRNo change
      Raal et al,
      • Raal F.J.
      • Pilcher G.J.
      • Illingworth D.R.
      • et al.
      Expanded-dose simvastatin is effective in homozygous familial hypercholesterolaemia.
      1997/South Africa
      Simvastatin: 40, 80, 160 mg/dHoFH and compound HeFH for Afrik-1, -2, -3: 9

      HeFH for Afrik-1: 1

      HoFH for exon 16 mutation: 2
      12/26Dose escalation18 wk14.8 [SE: 1.3] (572) (SE: 50.3)80 mg/d dose: 10.1 [SE: 1.0] (391) (SE: 38.7)160 mg/d dose: 31

      80 mg/d dose: 25
      APOB, apolipoprotein B gene; ARH, autosomal recessive hypercholesterolemia; CH, combined hyperlipidemia; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor gene; NR, not reported; SE, standard error; US, United States.
      Table 2Heterozygous familial hypercholesterolemia and response to lipid-lowering therapy
      Diagnostic criteria vary widely.
      Reference, year of publication/country(ies)Study designDrug: doseNDurationMean age, yLDL-C level
      Baseline, mg/dL (mmol/L)Posttreatment, mg/dL (mmol/L)Percent reduction, %
      Stein et al
      • Stein E.A.
      • Strutt K.
      • Southworth H.
      • Diggle P.J.
      • Miller E.
      HeFH Study Group
      Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia.
      /global
      Weighted-randomization, double-blind, parallel-group, forced titrationAtorvastatin: 20/40/80 mg

      Rosuvastatin: 20/40/80 mg
      187

      436
      18 wk48

      47
      292 ± 51 (7.56 ± 1.32)

      288 ± 49 (7.46 ± 1.27)
      154 ± 45 (3.99 ± 1.17)

      129 ± 46 (3.34 ± 1.19)
      48

      56
      Tasaki et al,
      • Tasaki H.
      • Miyamoto M.
      • Kubara T.
      • et al.
      Cross-over trial of intensive monotherapy with atorvastatin and combined therapy with atorvastatin and colestimide for Japanese familial hypercholesterolemia.
      2006/Japan
      Randomized crossover20 mg/d atorvastatin + 3 g/d colestimide

      40 mg/d atorvastatin (16 wk at 20 mg)
      172 × 16 wk54.1308 ± 53 (7.98 ± 1.37)145.6 ± 34.5 (3.77 ± 0.89)

      147.8 ± 19.4 (3.83 ± 0.50)
      25.9

      22.5
      Kastelein et al,
      • Kastelein J.J.
      • Akdim F.
      • Stroes E.S.
      • et al.
      ENHANCE investigators
      Simvastatin with or without ezetimibe in familial hypercholesterolemia.
      2008/global
      ENHANCE80 mg/d simvastatin monotherapy

      80 mg/d simvastatin + 10 mg/d ezetimibe
      363

      357
      24 mo45.7

      46.1
      317 ± 66.1 (8.21 ± 1.71)

      319 ± 65 (8.26 ± 1.68)
      192.7 ± 60.3 (4.99 ± 1.56)

      141.3 ± 52.6 (3.66 ± 1.36)
      39.1 ± 0.9

      55.6 ± 0.9
      Pisciotta et al,
      • Pisciotta L.
      • Fasano T.
      • Bellocchio A.
      • et al.
      Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.
      2007/Italy
      Simvastatin vs simvastatin + ezetimibeDaily 20 mg/40 mg simvastatin/atorvastatin monotherapy

      Daily 20 mg/40 mg simvastatin + 10 mg ezetimibe
      6512 wkMen: 51.4

      Women: 57.1
      335 ± 66.8 (8.53 ± 1.73)

      340 ± 63.8 (8.80 ± 1.65)
      209.5 ± 43.67 (5.42 ± 1.13)

      142.6 ± 27.8 (3.69 ± 0.72)
      36.7 ± 1.3

      56.7 ± 0.9
      Wierzbicki et al,
      • Wierzbicki A.S.
      • Lumb P.J.
      • Semra Y.K.
      • Crook M.A.
      High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia.
      1998/UK
      Atorvastatin vs simvastatin combinations80 mg/d atorvastatin

      40 mg/d simvastatin + 200 mg/d fenofibrate

      40 mg d simvastatin + 32 mg/d cholestyramine
      5412 wkRange: 18–70313 ± 90.4 (8.10 ± 2.34)165.5 ± 49.4 (4.28 ± 1.28)

      176.3 ± 36.7 (4.56 ± 0.95)

      197.6 ± 53.3 (5.11 ± 1.38)
      45.6 ± 15.5

      42 ± 12.2

      36 ± 14.4
      Wierzbicki et al,
      • Wierzbicki A.S.
      • Lumb P.J.
      • Cheung J.
      • Crook M.A.
      Fenofibrate plus simvastatin therapy versus simvastatin plus cholestyramine therapy for familial hypercholesterolaemia.
      1997/UK
      Simvastatin combination efficacy therapies40 mg/d simvastatin + 200 mg/d fenofibrate

      40 mg/d simvastatin + 32 mg/d cholestyramine
      296 moRange: 18–70320 ± 102 (8.23 ± 2.66)177.4 ± 37.1 (4.59 ± 0.96)

      192.5 ± 35.9 (4.98 ± 0.93)
      40.6 ± 20.5

      37.1 ± 21.9
      Pijlman et al,
      • 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.
      2010/Netherlands
      Observation cross-sectionalMax statin dose in combination with ezetimibe

      Dose, NR
      261NRMax tx: 53

      No max tx: 49
      251 ± 71 (6.5 ± 2.0)135 ± 46 (3.5 ± 1.2)47 achieved 50% LDL-C reduction
      Huijgen et al,
      • Huijgen R.
      • Abbink E.J.
      • Bruckert E.
      • et al.
      Triple Study Group
      Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial.
      2010/France, Germany, Netherlands, Sweden, UK
      Triple study colesevelam3.75 g/d colesevelam + 10 mg ezetimibe + maximum statin therapy

      10 mg ezetimibe + max statin therapy
      45

      41
      12 wk53.7

      51.8
      305 ± 73 (7.89 ± 1.89)

      324 ± 81 (8.39 ± 2.10)
      131 ± 30 (3.4 ± 0.8)

      147 ± 38.7 (3.8 ± 1.0)
      57

      55
      Kawashiri et al,
      • Kawashiri M.A.
      • Nohara A.
      • Noguchi T.
      • et al.
      Efficacy and safety of coadministration of rosuvastatin, ezetimibe, and colestimide in heterozygous familial hypercholesterolemia.
      2012/Japan
      Colestimide20 mg/d rosuvastatin + 10 mg/d ezetimibe + 3.62 g/d colestimide1732 wk63.9296.6 ± 36.8 (7.68 ± 0.95)100.1 ± 20.5 (2.59 ± 0.53)66
      ENHANCE, Effect of ezetimibe plus simvastatin versus simvastatin alone on atherosclerosis in the carotid artery; LDL-C, low-density lipoprotein cholesterol; max, maximum; NR, not reported; tx, treatment; UK, United Kingdom.
      Diagnostic criteria vary widely.
      For an estimate of the prevalence of the apheresis-eligible population, we considered only studies that included ≥2 separate classes of hypolipidemic agents. Older studies of moderate-dose simvastatin plus cholestyramine or fenofibrate were not used because of the modest efficacy of these drugs (<40%) in reducing LDL-C levels.
      • Wierzbicki A.S.
      • Lumb P.J.
      • Semra Y.K.
      • Crook M.A.
      High-dose atorvastatin therapy in severe heterozygous familial hypercholesterolaemia.
      • Wierzbicki A.S.
      • Lumb P.J.
      • Cheung J.
      • Crook M.A.
      Fenofibrate plus simvastatin therapy versus simvastatin plus cholestyramine therapy for familial hypercholesterolaemia.
      A crossover study of atorvastatin alone or with colestimide was not included because of the small number of patients (N = 17).
      • Tasaki H.
      • Miyamoto M.
      • Kubara T.
      • et al.
      Cross-over trial of intensive monotherapy with atorvastatin and combined therapy with atorvastatin and colestimide for Japanese familial hypercholesterolemia.
      On the basis of data in Table 2, it can be estimated that maximally tolerated LLT results in a ≥50% reduction in LDL-C levels in most patients with HeFH.
      • Goldberg A.C.
      • Hopkins P.N.
      • Toth P.P.
      • et al.
      Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
      With the use of statistics for a Gaussian distribution with the means and SDs described in these trials, it can be concluded that a maximum of 14.2% of patients with HeFH treated with maximally tolerated LLT will have LDL-C levels that remain >200 mg/dL (>5.2 mmol/L). Two studies (from the Netherlands and Italy) with information on CHD status and LDL-C levels after maximally tolerated LLT with 2 agents provide estimates of 0.8% of patients with severe HeFH and CHD and LDL-C levels >200 mg/dL (>5.2 mmol/L) and 2.4% with severe HeFH and CHD, despite maximally tolerated LLT.
      • Pisciotta L.
      • Fasano T.
      • Bellocchio A.
      • et al.
      Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients.
      • 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 proportion of patients with HeFH treated with maximally tolerated LLT who have LDL-C levels >200 mg/dL (>5.2 mmol/L) was approximately 8% in the Dutch study.
      • 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.
      Studies also show that, of the 8% to 14.2% (our estimate) of patients, 17% to 40% will also have CHD and therefore meet the criteria for severe HeFH and CHD, despite maximally tolerated LLT. To calculate the prevalence of patients with severe FH and LDL-C levels >200 mg/dL (>5.2 mmol/L) despite maximally tolerated LLT, we have assumed the median prevalence of CHD in this population to be approximately 30%.
      • Jansen A.C.
      • Aalst-Cohen E.S.
      • Tanck M.W.
      • et al.
      The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients.
      Assuming that 8% of patients with HeFH being treated have LDL-C levels >200 mg/dL (>5.2 mmol/L) and that 30% of those have preexisting CHD, we estimate that approximately 2.4% of HeFH is severe FH in which patients are eligible for apheresis. This percentage represents a prevalence of patients with severe FH and LDL-C levels >200 mg/dL (>5.2 mmol/L) and can be stated as 1:25,000, representing a maximum of 12,000 patients in the United States (Fig. 1).
      Figure thumbnail gr1
      Figure 1Gaussian distribution of the prevalence of severe familial hypercholesterolemia in patients eligible for apheresis is estimated at approximately 1:20,000 and may range from 1:11,700 to 1:62,500.
      • 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.
      CVD, cardiovascular disease; FH, familial hypercholesterolemia; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MAX LLT, maximally tolerated lipid-lowering therapy.
      Finally, the Gaussian distribution also indicates that approximately 0.01% to 0.3% of all patients with HeFH will have LDL-C levels ≥300 mg/dL (>7.8 mmol/L) after maximally tolerated LLT, regardless of CHD status, and will also meet the definition of apheresis-eligible severe HeFH. We estimate the prevalence of patients with severe FH with posttreatment LDL-C levels >300 mg/dL (>7.8 mmol/L) at <1:1 to 7.5:1 million. On the basis of this prevalence calculation and on posttreatment LDL-C levels, these patients with severe FH and LDL-C levels >300 mg/dL (>7.76 mmol/L) bear phenotypic resemblance to patients with HoFH and may be considered the functional equivalents of homozygous patients.

      Discussion

      Current therapies have substantially reduced the rates of morbidity and mortality associated with HoFH and HeFH, with statins being the cornerstone of treatment. Nevertheless, despite maximally tolerated LLT, almost all homozygous patients and a significant proportion of heterozygous patients remain at exceedingly high LDL-C levels. The evidence in the medical literature is sufficient to support that LDL apheresis offers an overall clinical benefit to both homozygous and heterozygous patients. Even so, LDL apheresis remains an underused option for uncontrolled severe FH. Conservatively, in the United States, <5% of patients with FH who are eligible are currently receiving LDL apheresis.
      • Moriarty P.M.
      LDL-apheresis therapy.
      In addition, assuming a prevalence of HoFH of 1:1 million in the general population and that all patients with HoFH are identified, the number of patients receiving apheresis should be greater. The prevalence of HoFH is greater in specific populations worldwide,
      • Austin M.A.
      • Hutter C.M.
      • Zimmern R.L.
      • Humphries S.E.
      Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.
      and the 1:1 million estimate may not take into account other phenotypic homozygotes such as double heterozygotes or patients with ARH. Without DNA analysis of FH genes, it is difficult to differentiate severely affected double and compound heterozygotes from homozygotes with milder disease.
      • Mabuchi H.
      • Nohara A.
      • Noguchi T.
      • et al.
      Hokuriku FH Study Group
      Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan.
      Therefore, our estimate of 315 patients with HoFH in the United States receiving maximally tolerated LLT who are eligible for apheresis may be an underestimate. Likewise, if all patients with HeFH were to be identified and treated, then approximately 15,000 of the potential 625,000 patients with HeFH in the United States would still be eligible for LDL apheresis.
      Several factors may positively or negatively affect the estimates presented in this article. These factors include the number of therapies within combination therapy, prevalence of CHD at baseline in patients with FH, actual prevalence of HeFH compared with the assumed prevalence of 1:500, and inclusion of the statin-intolerant population. All of our estimates use the prevalence of CHD at baseline. However, LDL-C itself is a continuous variable for CHD, and the prevalence of CHD at higher LDL-C levels is expected to be much greater than at lower levels. Dutch data corroborate this statement because the prevalence of CHD was 17% at baseline in the complete FH population being studied
      • Huijgen R.
      • Abbink E.J.
      • Bruckert E.
      • et al.
      Triple Study Group
      Colesevelam added to combination therapy with a statin and ezetimibe in patients with familial hypercholesterolemia: a 12-week, multicenter, randomized, double-blind, controlled trial.
      ; however, among patients who were maximally treated but had not reached the treatment goal of ≤100 mg/dL (≤2.5 mmol/L), the prevalence of CHD was much higher at 30%. Similarly in a cross-sectional Simon Broome British Heart Foundation study in white patients aged >18 years with treated HeFH, the prevalence of CHD was approximately 38.9%.
      • Humphries S.E.
      • Whittall R.A.
      • Hubbart C.S.
      • et al.
      Simon Broome Familial Hyperlipidaemia Register Group and Scientific Steering Committee
      Genetic causes of familial hypercholesterolaemia in patients in the UK: relation to plasma lipid levels and coronary heart disease risk.
      • Neil H.A.
      • Seagroatt V.
      • Betteridge D.J.
      • et al.
      Established and emerging coronary risk factors in patients with heterozygous familial hypercholesterolaemia.
      Hence, a more precise estimate would require determination of the exact prevalence of CHD in an FH-treated group with LDL-C levels >200 mg/dL (>5.2 mmol/L). To our knowledge, such data have not been published.
      Recent data from the general Danish population also show that the prevalence of HeFH itself is much higher (1:137) than the previously estimated 1:500,
      • 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.
      which would also have a great upward effect on our estimates.
      Most importantly, our estimates do not include the statin-intolerant population. In randomized controlled trials of non-FH populations, the incidence of statin-associated myopathy (any of a variety of muscle complaints, including myalgia, related to statins) is 1% to 5%.
      • Thompson P.D.
      • Clarkson P.
      • Karas R.H.
      Statin-associated myopathy.
      Indeed, if statin intolerance affects a similar percentage of the 625,000 patients with HeFH in the United States, the number of patients with HeFH who will present with LDL-C levels >200 mg/dL (>5.2 mmol/L) after dual nonstatin therapy will be great and have an upward effect on our estimates of the prevalence of severe FH. Not including the statin-intolerant population in our estimates of the prevalence of severe FH again leads us to believe that our estimate is conservative.
      In 2007, Thompson et al
      • Thompson G.R.
      HEART-UK LDL Apheresis Working Group
      Recommendations for the use of LDL apheresis.
      provided data from 5 European countries which showed the frequency of the use of LDL apheresis to treat refractory hypercholesterolemia. The estimated totals of patients receiving apheresis in Germany, Sweden, Italy, France, and the United Kingdom are 12, 3, 2, 2, and 0.6 per million, respectively. In 2007, the respective populations were 82.3, 9.1, 59.1, 63.4, and 60.8 million. Thus, approximately 1542 eligible patients of a total of 275 million Europeans were receiving apheresis. The calculated number of patients per population is highest in Germany, at 988, and lowest in the United Kingdom, at 36 patients. Because the frequency of FH is similar in all of these countries, the researcher states that these variations may be due to differences in clinical practice, commercial activity, or ability to pay.
      • Thompson G.R.
      HEART-UK LDL Apheresis Working Group
      Recommendations for the use of LDL apheresis.
      • Lanzieri G.
      Population and social conditions.
      In comparison, in the United States, an estimated 400 patients with severe elevations in LDL-C levels are receiving apheresis. Because only 40 centers in the United States provide LDL apheresis, access is a major problem, as are out-of-pocket costs to patients.
      • Ito M.K.
      • McGowan M.P.
      • Moriarty P.M.
      Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
      • Goldberg A.C.
      Novel therapies and new targets of treatment for familial hypercholesterolemia.
      Most US health care insurance companies cover LDL apheresis if the LDL-C level is >500 mg/dL in patients with homozygous FH, >300 mg/dL in patients without coronary artery disease, or >200 mg/dL in patients with coronary artery disease despite having 6 months of treatment with maximal cholesterol-lowering and dietary therapy.
      • Thompsen J.
      • Thompson P.D.
      A systematic review of LDL apheresis in the treatment of cardiovascular disease.
      Although it has not been explicitly stated in coverage plans, many US health care insurance companies also have considered an elevated Lp(a) when determining coverage for LDL apheresis. The US Tufts Health Plan recently extended the eligibility for apheresis to include patients with CHD and LDL-C levels >160 mg/dL (>4.14 mmol/L) on failure of all other treatments.

      TUFTS Health Plan. Medical Necessity Guidelines. LDL Apheresis. Document 1035179. December 28, 2012. Available at: http://www.tuftshealthplan.com/providers/pdf/mng/Low_Density_Lipid_Apheresis.pdf. Accessed February 13, 2013.

      If this population is also presumed to have FH, then our prevalence estimates of 1:20,000 of apheresis-eligible patients would increase greatly to approximately 11% of all patients with FH and CHD who received treatment with maximally tolerated LLT.
      New and emerging therapies with novel therapeutic targets to treat high LDL-C levels are in ongoing clinical trials. The approval of new therapies will likely decrease the need for LDL apheresis in patients with HoFH or severe HeFH. Apo B inhibitors (eg, mipomersen, which was approved in the United States in January 2013), microsomal triglyceride transfer protein (MTP) inhibitors (eg, lomitapide, which was approved in the United States in December 2012), and PCSK9 inhibitors have proven to be effective in lowering plasma LDL-C levels in combination with other maximally tolerated LLTs.
      • Goldberg A.C.
      Novel therapies and new targets of treatment for familial hypercholesterolemia.
      • Parhofer K.G.
      Mipomersen: evidence-based review of its potential in the treatment of homozygous and severe heterozygous familial hypercholesterolemia.

      FDA Approves New Orphan Drug Kynamro to Treat Inherited Cholesterol Disorder. FDA News Release. January 29, 2013. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm337195.htm. Accessed August 20, 2013.

      FDA Approves New Orphan Drug for Rare Cholesterol Disorder. FDA News Release. December 26, 2012. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333285.htm. Accessed August 20, 2013.

      Both ApoB inhibitors (eg, mipomersen) and MTP inhibitors (eg, lomitapide) may likely reduce the number of people eligible for apheresis or the frequency of LDL apheresis in patients already receiving the therapy. However, LDL apheresis has demonstrated benefit for cardiovascular outcomes,
      • Mabuchi H.
      • Nohara A.
      • Noguchi T.
      • et al.
      Hokuriku FH Study Group
      Molecular genetic epidemiology of homozygous familial hypercholesterolemia in the Hokuriku district of Japan.
      which has not yet been shown with either MTP inhibitors or ApoB inhibitors. Moreover, the precise order and sequence of the use of these agents in conjunction with or in lieu of apheresis is yet to be definitively established. Hence, it is unclear as to how the approval of these 2 agents will affect the number of patients eligible for receiving LDL apheresis or the frequency of LDL apheresis. Mipomersen was approved by the FDA as an adjunct to LLTs and diet to reduce apo B, LDL-C, total cholesterol, and non–HDL-C levels in patients with HoFH. However, until the approval and adoption of new pharmacotherapies for lowering LDL-C levels, LDL apheresis will continue to be the treatment of choice for patients with severe, refractory FH.

      Acknowledgments

      Editorial assistance in the development of this manuscript was provided by Connexion Healthcare (Newtown, PA). The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors (ICMJE), were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development.

      Financial disclosure

      Genzyme Corp (Cambridge, MA) funded editorial assistance supplied by Connexion Healthcare in the development of this manuscript. Mr R. Vishwanath was an employee of Genzyme Corporation at the time of this analysis. Dr L.C. Hemphill is involved in clinical trials for Genzyme.

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