Practice Guidelines

Familial hypercholesterolaemia: summary of NICE guidance

BMJ 2008; 337 doi: http://dx.doi.org/10.1136/bmj.a1095 (Published 27 August 2008) Cite this as: BMJ 2008;337:a1095
  1. Anthony S Wierzbicki, consultant chemical pathologist1,
  2. Steve E Humphries, British Heart Foundation professor of cardiovascular genetics2,
  3. Rubin Minhas, coronary heart disease clinical lead3
  4. on behalf of the Guideline Development Group
  1. 1St Thomas’ Hospital, London SE1 7EH
  2. 2Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Royal Free and University College London Medical School, London WC1E 6JJ
  3. 3Medway Primary Care Trust, Gillingham ME8 0NJ
  1. Correspondence to: R Minhas fh{at}rubin.icom43.net

    Why read this summary?

    The estimated prevalence of familial hypercholesterolaemia in the United Kingdom is 1 in 500. Heterozygous familial hypercholesterolaemia carries a high risk of premature coronary heart disease (>50% risk in men by the age of 50 years and >30% in women by 60 years), but the condition is underdiagnosed. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on diagnosing and managing familial hypercholesterolaemia.1

    Recommendations

    NICE recommendations are based on systematic reviews of best available evidence. When minimal evidence is available, recommendations are based on the guideline development group’s opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets.

    Diagnosis

    • Consider the possibility of familial hypercholesterolaemia in adults with raised cholesterol (total cholesterol concentration typically >7.5 mmol/l), especially if they have a personal or family history of premature coronary heart disease. [Based on the experience of the Guideline Development Group]

    • Make the diagnosis using the Simon Broome criteria: a combination of family history of coronary heart disease (at age <60 years in a first degree relative or <50 years in a second degree relative), clinical examination (specifically tendon xanthomata), and total cholesterol concentration >7.5 mmol/l or low density lipoprotein cholesterol >4.9 mmol/l. [Based on one observational study of moderate quality]

    • Confirm the diagnosis by referral to a specialist with expertise in familial hypercholesterolaemia. [Based on the experience of the Guideline Development Group]

    Management in primary care

    • Offer lifestyle advice, especially on smoking cessation.

    • Start treatment with a high intensity statin (such as simvastatin 80 mg or appropriate doses of atorvastatin and rosuvastatin) to achieve a >50% reduction in low density lipoprotein cholesterol concentrations, increasing to the maximum tolerated dose if necessary. [Based on one high quality randomised controlled trial using a surrogate outcome and health economic modelling of cost effectiveness]

    • Consider ezetimibe monotherapy if statin use is limited by intolerance. []Based on the NICE Technology Appraisal 1322]

    • Consider administering ezetimibe alongside the initial statin treatment if the serum total or low density lipoprotein cholesterol concentration is not appropriately controlled. [Based on NICE Technology Appraisal2]

    • Refer patients to a specialist with expertise in familial hypercholesterolaemia if low density lipoprotein cholesterol concentrations are not reduced by >50% or if patients are at particularly high risk—that is, with established coronary heart disease, a family history of early disease, or more than two cardiovascular risk factors. [Based on the experience of the Guideline Development Group]

    • Offer patients a referral to a cardiologist for evaluation of coronary heart disease if they have a family history of early disease or more than two cardiovascular risk factors. [Based on the experience of the Guideline Development Group]

    • Do not use risk estimation tools (such as the Framingham algorithm) for people with familial hypercholesterolaemia. [No tools for estimating cardiovascular risk have been developed for this population]

    • Offer all patients specialist referral for “cascade testing”—that is, conducting DNA testing or measuring cholesterol concentration if a genetic mutation is not found to identify relatives affected with familial hypercholesterolaemia. [Based on health economic modelling of cost effectiveness]

    Specialist management

    • Elicit a family history of hypercholesterolaemia and premature coronary heart disease, and note smoking history, to confirm a dominant pattern of inheritance and to construct a formal pedigree (showing inheritance of hypercholesterolaemia and coronary heart disease) so that cholesterol and DNA tests can be offered. [Based on the experience of the Guideline Development Group]

    • Advise patients on the implications of familial hypercholesterolaemia, the risk of coronary heart disease, and treatment options and provide information about patient support groups, such as Heart UK (www.heartuk.org.uk) and the British Heart Foundation (www.bhf.org.uk). [Based on the experience of the Guideline Development Group]

    • When a gene mutation that causes familial hypercholesterolaemia is identified in a patient, use DNA tests to identify their affected relatives. If a gene mutation is not identified in the patient, then measure their relatives’ sex and age specific low density lipoprotein cholesterol concentrations to confirm the diagnosis (do not use the Simon Broome criteria). [Based on health economic modelling of cost effectiveness]

    • Encourage patients to inform relatives of their potential risk and to facilitate cascade testing, which may involve referral by their own general practitioner. [Based on the experience of the Guideline Development Group]

    • Review all patients annually to assess the progress of cascade testing, update family histories, and note any changes in status for coronary heart disease. Make regular efforts to complete any outstanding cascade testing. [Based on the experience of the Guideline Development Group]

    Special considerations

    Women with familial hypercholesterolaemia

    • Combined oral contraceptives are not generally contraindicated for women taking lipid modifying drugs. However, because of a potential, small increased risk of cardiovascular events, consider other forms of contraception. [Based on the experience of the Guideline Development Group]

    • Do not advise against pregnancy or breast feeding. However, lipid modifying medication should be stopped three months before trying to conceive and should not be taken during pregnancy because of the potential risk of fetal abnormalities. If conception occurs while the woman is taking lipid modifying drugs, stop treatment immediately and offer an urgent referral to an obstetrician. [Based on low quality evidence of teratogenicity from observational studies and on the experience of the Guideline Development Group]

    Children and young people

    • Refer children and young people to a specialist with expertise in familial hypercholesterolaemia in this age group and in an appropriate setting. [Based on England’s national service framework for children, young people, and maternity services3 and the experience of the Guideline Development Group]

    • In children at risk of familial hypercholesterolaemia because of an affected parent, offer a DNA test by the age of 10 years if the family mutation is known; otherwise measure low density lipoprotein cholesterol concentration, but repeat this measurement after puberty to exclude familial hypercholesterolaemia. [Based on the experience of the Guideline Development Group]

    • For children with familial hypercholesterolaemia, consider treatment with a statin licensed for the appropriate age group; usually, do this by the age of 10 years, although earlier or later treatment may be needed after an individualised assessment. [Based on high quality evidence from short term studies of the efficacy and safety of statins in children and on the experience of the Guideline Development Group]

    • Routinely monitor growth and pubertal development in children and young people. [Based on the experience of the Guideline Development Group]

    Overcoming barriers

    Adequate funding is needed for training healthcare professionals how to communicate with patients about familial risk and DNA testing. To ensure the delivery of systematic care (such as cascade testing), education and training are necessary to ensure that consistent information is given by different healthcare professionals. Software is needed for managing pedigree information and coordination of cascade testing across regional and local health service boundaries. Patient information and education will be important. NICE has developed tools to help organisations implement this guideline.1

    Further information on the guidance

    Background

    This is the first systematic guideline incorporating clinical and cost effectiveness for the identification and management of familial hypercholesterolaemia. The guideline recommends a strategy of cascade testing (DNA testing and cholesterol testing) for identifying people with familial hypercholesterolaemia. It also includes recommendations for the pharmacological treatment of children, young people, and adults and for apheresis for people with severe heterozygous familial hypercholesterolaemia and homozygous familial hypercholesterolaemia.

    Methods

    The Guideline Development Group followed standard NICE methodology for the development of this guidance (www.nice.org.uk/page.aspx?o=114219). The multidisciplinary guideline group comprised patient representatives and healthcare professionals with expertise in the treatment of familial hypercholesterolaemia in primary care and secondary care, paediatrics, public health, health economics, systematic reviews, nursing, and information science.

    The group conducted a systematic review of the literature, assessed the quality of the literature, and qualitatively synthesised the included evidence as it related to both clinical and cost effectiveness. The group also developed new health economic models to determine the cost effectiveness of high intensity statin treatment and also for cascade testing using a strategy of combined DNA and cholesterol testing.

    The guideline went through an external consultation with stakeholders. The development group then assessed stakeholders’ comments and modified the guideline appropriately. An independent Guideline Review Panel assessed the appropriateness of the responses to the stakeholders.

    NICE has produced three different versions of the guideline: a full version, a quick reference guide, and a version for patients and the public. All versions are available from the NICE website.1

    Future research

    Future research has been recommended in the following areas:

    • What is the clinical effectiveness and cost effectiveness of identifying a patient with familial hypercholesterolaemia (defined by DNA testing) from general practice registers and from secondary care registers?

    • What is the clinical effectiveness and safety of differing doses of lipid modifying treatment in children with familial hypercholesterolaemia?

    • What are the appropriate indications, effectiveness, and safety of apheresis in patients with heterozygous familial hypercholesterolaemia?

    • What are the implications of familial hypercholesterolaemia for the safety of a woman during pregnancy, and what are the risks of fetal malformations attributable to pharmacological treatments?

    • What is the utility of routine cardiovascular evaluation for asymptomatic people with familial hypercholesterolaemia?

    Notes

    Cite this as: BMJ 2008;337:a1095

    Footnotes

    • This is one of a series of BMJ summaries of new guidelines, which are based on the best available evidence; they highlight important recommendations for clinical practice, especially where uncertainty or controversy exists.

    • The members of the Guideline Development Group were Leo Nherera, Elisabeth Shaw, Meeta Kathoria, Gill Ritchie, Vanessa Nunes, Dawn Davies, Philip Lee, Ian McDowell, Andrew Neil, Nadeem Qureshi, Philip Rowlands, Mary Seed, Helen Stracey, Margaret Thorogood, and Melanie Watson. ASW was a co-opted expert in the guideline development group. SEH was scientific adviser to the group, and RM was the group’s chairman.

    • Contributors: All authors contributed to writing and revising this article, and they all approved the final manuscript. RM is the guarantor.

    • Funding: The National Collaborating Centre for Primary Care was commissioned and funded by the National Institute for Health and Clinical Excellence to write this summary.

    • Competing interests: SEH is funded by the British Heart Foundation. RM has received lecture honorariums and travel grants from AstraZeneca, Solvay, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, and Sanofi-Aventis, but none during the past three years. ASW has received grant support, lecture honorariums, and travel grants from Abbott, Amarin, Solvay, GlaxoSmithKline, Merck kGA, Merck Sharp & Dohme, Pfizer, Sanofi-Aventis and Takeda.

    • Provenance and peer review: Commissioned; not externally peer reviewed.

    References