|Home | About | Journals | Submit | Contact Us | Français|
Life expectancy in familial hypercholesterolaemia (FH) has been greatly improved by the advent of statin therapy. In the UK, however, these agents are not licensed for use in children. We approached 169 physicians responsible for lipid clinics for information on their practice in young patients, and valid responses were received from 54%.
A typical lipid clinic has only 3.5 patients aged under 16 with FH. In boys aged 10-15 years 65% of physicians were prepared to treat with bile acid sequestrants but only 23% with statins. There was greater reluctance to treat in girls of the same age, corresponding figures being 52% and 12%.
Despite the efficacy of statins in reducing low-density-lipoprotein cholesterol, these agents are little used in children with FH. Their safety and clinical efficacy should be assessed by a randomized double-blind trial.
Familial hypercholesterolaemia (FH) is an autosomal dominant disorder leading to high serum concentrations of low-density-lipoprotein (LDL) cholesterol. LDL catabolism is delayed usually as a consequence of a mutation of the LDL receptor gene.1-3 Heterozygous FH affects 1 in 500 people and in most cases is fully penetrant. In childhood, when cholesterol levels are generally low, FH is the most likely cause of hypercholesterolaemia. It can be diagnosed from soon after birth. In families in which FH is running, a cholesterol exceeding 6.8 mmol/L clearly indicates an affected child.
Heterozygous FH carries a high premature morbidity and mortality from coronary heart disease (CHD) in adulthood, particularly in early middle-age.5 Since the advent of statin therapy, the life expectancy in treated FH has dramatically increased.6 There is thus a cogent need to identify people with FH at an age when clinical manifestations of CHD are still preventable. Because the condition can be reliably detected in early childhood, there may be an argument for beginning treatment, including cholesterol-lowering medication, at that time. Bile acid sequestrating agents are generally considered safe in childhood7 but are poorly tolerated and therefore generally ineffective. One fibrate, fenofibrate, has been licensed for use in children but its major action is to lower triglycerides, with less effect on LDL cholesterol. The statins are highly effective in lowering LDL cholesterol and are well tolerated, but there is little reliable evidence about their safety in childhood.8,9 A randomized trial would be the best approach to determine both the safety of statins and their capacity to reverse surrogate indices of arterial disease such as carotid intima-media thickness (IMT) measured by ultrasonography. IMT has been shown to be abnormal in affected siblings with FH by the age of 18 years.10 In adults the progression of IMT has been shown to be slowed with effective statin therapy.11
To assess the feasibility of a trial in children it is essential to know what is current clinical practice, so as to ensure that there are no ethical or practical objections to randomizing children to placebo or statin therapy. The present study was undertaken to determine current practice in the UK. The investigation also covered young adults, because practice with regard to lipid-lowering medication in young women is also undergoing great change.
A questionnaire was sent to 169 physicians who were listed as having responsibility for lipid clinics in the UK. The questionnaires (available on request from PND) asked about the indications for lipid-lowering drug therapy in male and female patients aged up to 35 years with the clinical diagnosis of heterozygous FH. Of the 169 physicians, 3 did not have any patients aged less than 35 and 10 had retired or ran joint clinics with one of the other physicians contacted. 84 completed questionnaires were returned, representing a response rate in terms of eligible clinics of 54%.
Most of the children with familial hypercholesterolaemia attended clinics specializing in the treatment of lipid disorders; these clinics saw few other children. The median number of children under the age of 16 years at each clinic was 3.5 (interquartile range [IQR] 0-10). In the age range 16-35 years the median number was 15 (IQR 5-26) at each clinic.
At few clinics was lipid-lowering medication introduced in children aged less than 10 years, only 15% reporting this practice in boys and 11% in girls (Figure 1). However, by the age of 15 years the majority of clinics were employing lipid-lowering medication (65% in boys and 52% in girls); before the age of 20 years, but not thereafter, there was a tendency to delay lipid-lowering medication for longer in girls than in boys. Even though the age range spanned by the questionnaire was up to 35 years, some 30-40% of physicians were still unprepared to prescribe lipid-lowering drugs until the serum cholesterol exceeded 8 mmol/L (Figure 2). In their choice of lipid-lowering medication physicians showed a clear preference for bile acid sequestrants until the age of 16 years (Figure 3). The reluctance to use statins in younger patients was statistically significant with 65% (95% confidence interval 55-75) being prepared to use bile acid sequestrants in boys aged 10-15 years and only 23% (14-30) being prepared to use statins in boys of a similar age. Corresponding figures for girls were 52% (41-63) and 12% (5-19) (also significantly different). The reluctance to adopt statin therapy persisted with statistical significance until an older age in females so that, whilst 83% (75-91) of clinics would prescribe statins to young men aged 16-20 years, only 62% (71-72) would do so in young women in this age group.
Untreated heterozygous FH carries a high mortality.1 The increase in death rate relative to the general population is almost exclusively due to CHD occurring before the age of 60 years.5 The condition can result in angina or acute myocardial infarction in men from their early 20s. In affected women from the same family the clinical onset of CHD is typically some 9 years later, but can nonetheless be remarkably early in life.1,12 Even in the general population of countries such as the UK and USA, fatty streaks are common in childhood and raised atheromatous lesions are evident by early adulthood.13,14 In heterozygous FH children there is no autopsy series, but tests of endothelial dysfunction15 and carotid intima-media thickness by ultrasonography10 indicate that atherosclerosis is considerably more advanced than in children who have not inherited FH.
The only lipid-lowering medications licensed for use in children are bile acid sequestrating agents and fenofibrate. Bile acid sequestrants have the potential to lower serum cholesterol substantially16 and can decrease coronary heart disease risk,17 but are rarely tolerated in adequate doses, particularly in children. Fibrate drugs, although better tolerated, are relatively ineffective at lowering cholesterol as opposed to triglycerides. Statin drugs, which are much more effective18 and are well tolerated, are not currently licensed for use in children. The use of medication in patients under 16 years revealed by our survey seems to reflect this restriction, bile-acid sequestrants being the most frequently employed. Younger children were treated with statins even less frequently than with fibrates. Thus, with fewer than one-quarter of clinicians employing statins in patients aged less than 16 years, most children are denied effective LDL-lowering therapy—presumably because of concerns about safety, even though statins have proved generally safe in adults.18
In a survey with a response rate of 54% one must be cautious in drawing quantitative conclusions. However, even with allowance for response bias certain findings stand out. Specialist centres are attended by only a small number of children—an observation that may reflect a reluctance to confirm the diagnosis or to refer young people until adulthood.
Such reluctance might be justifiable if all that was on offer at a referral centre was unnecessary monitoring and the ineffective exhibition of lipid-lowering drug therapy. Whilst most clinicians were prepared to use drug therapy in children whose cholesterol was in the range 6-8 mmol/L, few of their patients could be expected to achieve levels of cholesterol less than 6 mmol/L with bile-acid sequestrant or fibrate therapy. An earlier study in the Oxford region revealed considerable underdiagnosis of FH in children and young adults.19
For girls effective treatment was even less likely to be given than for boys. A reason for this reluctance might be that physicians view CHD as a later complication in women. However, serum lipid levels and the extent to which preatheromatous and frankly atheromatous lesions develop are similar in boys and girls before adolescence.4,13,14,20,21 If drug treatment is delayed in girls beyond the age at which it is started in boys, the question arises as to when it should be commenced. The issue is complicated by considerations of pregnancy and contraception. Ideally, women receiving lipid-lowering drugs should have effective contraception. Although bile-acid sequestrants are not considered directly teratogenic, there is the possibility that they might cause neural tube defects via an associated folate deficiency. Women attempting to conceive could take folate supplements, but most in our experience choose to discontinue bile-acid sequestrant therapy—as they should be advised to do with fibrate and statin therapy. It seems from our survey that many centres begin statin therapy in women around the age of 20 years, well before most have any intention of starting a family. Coupled with the advice to discontinue statins and any lipid-lowering drug medication from the time they plan to conceive until after they have completed breast feeding, this policy would seem logical. Even if they are not to contemplate pregnancy until their 40s, women treated in this way will have had 20 years of effective statin therapy. Our survey was completed before ezetimibe became available in the UK, but clearly, if clinicians are concerned about statin toxicity in young people, it will be many years before ezetimibe has any major impact on prescribing practice in children, except in homozygous FH.22
The major finding of the present study is that clinicians are not using statins in childhood, despite their LDL-lowering efficacy. It would thus be reasonable to conduct a placebo-controlled trial of statin treatment in children with heterozygous FH. Children on both the active or placebo arm could receive add-in bile-acid sequestrant therapy according to clinicians' usual practice. The trial could be undertaken between the ages of 10 and 16 in both boys and girls. It should be powered to establish safety and LDL lowering, and could also have a non-invasive vascular end-point such as IMT. In view of the excess morbidity and mortality of FH in young adults and middle-aged people such a trial would yield important information.
We thank HEART UK and Professor S Humphries for making available a comprehensive list of lipid clinics in the UK, and Ms C Price for help in preparing the typescript.