Clinical Topic A-Z Clinical Speciality

Hypercholesterolaemia - familial

Hypercholesterolaemia - familial
D006938Hyperlipoproteinemia Type II
CardiovascularEndocrine and metabolic
2009-03-02Last revised in March 2009

Hypercholesterolaemia - familial - Summary

Familial hypercholesterolaemia (FH) is characterized by a high cholesterol concentration in the blood, present from birth and caused by an inherited genetic defect, leading to early development of atherosclerosis and coronary heart disease.

Most affected individuals have heterozygous FH: they have inherited a defective gene for FH from one parent only.

The prevalence of heterozygous FH in the UK population is estimated to be 1 in 500.

Suspect FH if:

Total cholesterol concentration is greater than 7.5 mmol/L.

There is a family history of premature coronary heart disease.

Tendon xanthomata are present.

All children and young people (up to 15 years of age) with suspected or confirmed FH should be managed by a specialist.

If FH is suspected in an adult, two measurements of plasma lipid concentrations (including low-density lipoprotein cholesterol [LDL-C] concentration) are required, preferably after a fast of at least 10 hours.

Secondary hypercholesterolaemia should be excluded.

The Simon Broome criteria are used to make a diagnosis of heterozygous FH.

Definite FH can be diagnosed in an adult with:

Total cholesterol greater than 7.5 mmol/L, low-density lipoprotein cholesterol (LDL-C) concentration greater than 4.9 mmol/L, and tendon xanthomata (or evidence of tendon xanthomata in a first- or second-degree relative), or

An identified genetic mutation for familial hypercholesterolaemia.

Possible FH can be diagnosed in an adult with total cholesterol greater than 7.5 mmol/L, LDL-C greater than 4.9 mmol/L, and at least one of the following:

Family history of myocardial infarction: before 60 years of age in a first-degree relative, or before 50 years of age in a second-degree relative.

Family history of raised total cholesterol: greater than 7.5 mmol/L in an adult first- or second-degree relative, or greater than 6.7 mmol/L in a child, brother, or sister younger than 16 years of age.

Referral to a specialist is recommended for all adults diagnosed with heterozygous familial hypercholesterolaemia (FH) for confirmation of the diagnosis and initiation of cascade testing (identification of affected relatives).

Adults at particularly high risk of a coronary event should also be managed by a specialist. Particularly high risk is defined as any of the following:

Established coronary heart disease (CHD).

Family history of premature CHD.

Two or more other cardiovascular disease risk factors (such as male gender, smoking, hypertension, or diabetes).

Cardiovascular disease risk assessment tools should not be used to guide management.

Management of adults with FH involves:

Offering lifestyle advice.

Treating blood pressure where appropriate and considering aspirin if aged over 40 years (unlicensed for primary prevention).

Prescribing a high intensity statin to achieve a target reduction in low-density lipoprotein cholesterol (LDL-C) concentration of greater than 50% from baseline.

Referring to a specialist if statins are contraindicated or not tolerated.

Lipid-lowering medication should be stopped 3 months before attempting to conceive due to the potential risk of fetal malformation if taken during the first trimester.

Lipid-lowering medication, except bile acid sequestrants (resins), is not recommended during lactation.

Have I got the right topic?

1months3060monthsBoth

This CKS topic is based on the National Institute for Health and Care Excellence (NICE) guideline, Identification and management of familial hypercholesterolaemia [NICE, 2008].

This CKS topic covers the detection and management in primary care of adults and children with homozygous or heterozygous familial hypercholesterolaemia (or familial primary type IIa hyperlipoproteinaemia).

This CKS topic does not cover the management of people with secondary hypercholesterolaemia, non-familial (polygenic) hypercholesterolaemia, combined hyperlipidaemia, hypertriglyceridaemia, type III hyperlipoproteinaemia, or sitosterolaemia (phytosterolaemia).

There are separate CKS topics on Antiplatelet treatment, CVD risk assessment and management, Hypertension - not diabetic, Lipid modification - CVD prevention, MI - secondary prevention, Obesity, and Smoking cessation.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in March 2009

November 2012 — minor update. The links to the electronic medicines website (www.medicines.org.uk) have been updated.

December 2010 — minor update. Following the publication of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial [SEARCH Collaborative Group, 2010], the Supporting evidence section has been updated. Issued in December 2010.

June 2010 — minor update. Following a review of the data from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial [Clinical Trial Service Unit, 2008], the Medicines and Healthcare products Regulatory Agency (MHRA) has advised that simvastatin 80 mg should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks [MHRA, 2010]. Issued in June 2010.

October 2009 — minor update. A reminder from the MHRA [MHRA, 2009] that aspirin is not licensed for use in primary prevention of vascular events has been added. Issued in October 2009.

November 2008 to March 2009 — this is a new CKS topic. The evidence base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

Update

New evidence

Evidence-based guidelines

No new evidence-based guidelines since 1 November 2008.

HTAs (Health Technology Assessments)

No new HTAs since 1 November 2008.

Economic appraisals

No new economic appraisals relevant to England since 1 November 2008.

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Ademi, Z., Watts, G.F., Juniper, A., and Liew, D. (2013) A systematic review of economic evaluations of the detection and treatment of familial hypercholesterolemia. International Journal of Cardiology 167(6), 2391-2396. [Abstract]

O'Gorman, C.S., Higgins, M.F., and O'Neill, M.B. (2009) Systematic review and meta-analysis of statins for heterozygous familial hypercholesterolemia in children: evaluation of cholesterol changes and side effects. Pediatric Cardiology 30(4), 482-489. [Abstract]

Qin, Y., Niu, K., Zeng, Y., et al. (2013) Isoflavones for hypercholesterolaemia in adults (Cochrane Review). The Cochrane Library. Issue 6. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Undela, K., Gudala, K., Malla, S. and Bansal, D. (2013) Statin use and risk of Parkinson's disease: a meta-analysis of observational studies. Journal of Neurology 260(1), 158-165. [Abstract]

Undela, K., Srikanth, V., and Bansal, D. (2012) Statin use and risk of breast cancer: a meta-analysis of observational studies. Breast Cancer Research and Treatment 135(1), 261-269. [Abstract]

Vuorio, A., Kuoppala, J., Kovanen, P.R., et al. (2010) Statins for children with familial hypercholesterolemia (Cochrane Review). The Cochrane Library. Issue 7. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Primary evidence

Randomized controlled trials published since the last revision of this topic:

Meuwese, M.C., de Groot, E., Duivenvoorden, R., et al. (2009) ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial. JAMA 301(11), 1131-1139. [Abstract] [Free Full-text]

Raal, F.J., Santos, R.D., Blom, R.D., et al. (2010) Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 375(9719), 988-1006. [Abstract]

Observational studies published since the last revision of this topic:

Farzadfar, F., Finucane, M.M., Danaei, G., et al (2011) National, regional, and global trends in serum total cholesterol since 1980: systematic analysis of health examination surveys and epidemiological studies with 321 country-years and 3·0 million participants. Lancet 377(9765), 578-586. [Abstract]

Pletcher, M.J., Bibbins-Domingo, K., Liu, K., et al. (2010) Nonoptimal lipids commonly present in young adults and coronary calcium later in life: the CARDIA (Coronary Artery Risk Development in Young Adults) study. Annals of Internal Medicine 153(3), 137-146. [Abstract] [Free Full-text]

A cohort study has been published since the last revision of this topic:

Civeira, F., Rose, E., Harauta, E., et al. (2008) Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia. American Journal of Cardiology 102(9), 1187-1193. [Abstract]

New policies

No new national policies or guidelines since 1 November 2008.

New safety alerts

August 2012: The Medicines and Healthcare products Regulatory Agency (MHRA) have issued updated advice on drug interactions and contraindications in simvastatin:

Reference: MHRA (2012) Simvastatin: updated advice on drug interactions - updated contraindications. Drug Safety Update 6(1), S1. [Free Full-text]

January 2012: The Medicines and Healthcare products Regulatory Agency (MHRA) has issued the following advice for healthcare professionals:

There is sufficient evidence to support an association between statin use and new onset diabetes.

The risk appears to be mainly in people already at increased risk of developing diabetes.

Raised fasting blood glucose at baseline is a key risk factor. Other risk factors include a history of hypertension, raised triglycerides, and a raised body mass index at baseline.

Patients at risk should be monitored both clinically and biochemically according to national guidelines.

The level of risk of new onset diabetes may vary between statins. However, there is insufficient evidence to confirm or exclude an increased risk for any particular statin.

The reduced vascular risk from statin therapy outweighs any risk of diabetes, including in people at increased risk of developing diabetes, and those with pre-existing diabetes at baseline: statin treatment should not be stopped.

Reference: MHRA (2012) Statins: risk of hyperglycaemia and diabetes. Drug Safety Update 5(6), A2. [Free Full-text (pdf)]

May 2010: The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that:

There is an increased risk of myopathy associated with high-dose (80 mg) simvastatin.

Simvastatin 80 mg should be considered only in patients with sever hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.

Prescribers may wish to review patients taking simvastatin 80 mg at the next review visit to take into account the new evidence.

Patients who are currently taking simvastatin 80 mg should not stop taking their medicine. However, they should be advised to contact their doctor immediately if they experience unexplained muscle pain, tenderness, or weakness.

Reference: MHRA (2010) Simvastatin: increased risk of myopathy at high dose (80 mg). Drug Safety Update 3(10), 7. [Free Full-text (pdf)]

Changes in product availability

No changes in product availability since 1 November 2008.

Goals and outcome measures

Goals

To identify people who may have familial hypercholesterolaemia (FH) and to take the appropriate steps for a diagnosis to be made

To refer all people with a provisional diagnosis of FH to a specialist with expertise in FH for confirmation of the diagnosis

To refer adults with confirmed heterozygous FH at particularly high risk of a coronary event to a specialist with expertise in FH

To prescribe appropriate doses of cholesterol lowering drugs

To provide lifestyle advice

To appropriately refer women who are pregnant or who are considering pregnancy

Background information

Definition

What is it?

Familial hypercholesterolaemia (FH) is characterized by high cholesterol concentration in the blood, present from birth and caused by an inherited genetic defect, leading to early development of atherosclerosis and coronary heart disease.

Most affected individuals have heterozygous FH: they have inherited a defective gene for FH from one parent only.

Rarely, an affected individual will have homozygous FH: they have inherited a defective gene from both parents.

[NICE, 2008]

Causes

What causes it?

Familial hypercholesterolaemia (FH) has an autosomal dominant pattern of inheritance: children of a person with FH have a 50% risk of inheriting the disease [NICE, 2008].

Prevalence

How common is it?

The prevalence of heterozygous familial hypercholesterolaemia (FH) in the UK population is estimated to be 1 in 500, which means that about 110,000 people in the UK are affected.

The prevalence of homozygous FH is one person per million.

[NICE, 2008]

Complications

What are the complications?

When untreated:

More than 50% of men with familial hypercholesterolaemia (FH) develop coronary heart disease by 50 years of age.

About 30% of women with FH develop coronary heart disease by 60 years of age.

[Marks et al, 2003]

Diagnosis

Diagnosis of familial hypercholesterolaemia

Recognition

When should I suspect familial hypercholesterolaemia?

Suspect familial hypercholesterolaemia (FH) in:

Adults with total cholesterol concentrations greater than 7.5 mmol/L.

People with a family history of premature coronary heart disease (before 60 years of age in a first-degree relative, or before 50 years of age in a second-degree relative).

People with tendon xanthomata.

Additional information

Additional information

Tendon xanthomata:

Appear in people with heterozygous FH from 20 years of age onwards (unless the person was started on a statin early in life), but are often evident in homozygous FH from childhood.

May be difficult to detect.

Are hard, non-tender, nodular enlargements of tendons.

Are most commonly found on the dorsum (knuckles) of the hands and in the Achilles tendons, and may rarely be present on the extensor hallucis longus and triceps tendons.

Feel hard because they are fibrotic, and may become inflamed in the Achilles tendons (sometimes presenting as chronic Achilles tenosynovitis, which may be exacerbated by a statin).

Do not appear yellow; the overlying skin is of normal colour.

Are highly suggestive of FH:

But their absence does not exclude FH.

Other types of xanthomata (such as xanthelasmata on the eyelids) and premature corneal arcus may occur in people with FH, but are less specific.

[WHO, 1998; Winder et al, 1998; Warrell et al, 2003; Moruisi et al, 2006]

Basis for recommendation

Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

Assessment

What should I do if familial hypercholesterolaemia is suspected?

If familial hypercholesterolaemia (FH) is suspected in an adult:

Take two measurements of plasma lipid concentrations (including low-density lipoprotein cholesterol [LDL-C] concentration), preferably after a fast of at least 10 hours.

Look for tendon xanthomata.

Take a family history (if possible) of myocardial infarction and raised cholesterol.

Exclude secondary hypercholesterolaemia:

An underlying cause can usually be detected from the history and examination, and by checking thyroid stimulating hormone, fasting blood glucose concentration, renal function, electrolytes, and liver function tests.

An underlying condition or drug may be exacerbating primary FH, and serum lipids should be rechecked (if possible) after the condition has resolved or the drug has been stopped.

To confirm a diagnosis of FH, see Diagnosis in adults.

If FH is suspected in a child or young person (up to 15 years of age):

Diagnosis in children and young people should be made by a specialist:

Either do an initial assessment in primary care as for adults, or refer to a specialist for the initial assessment to be carried out.

Ideally, referral will be to a specialist with particular expertise in FH in children and young people. If unavailable locally, refer to a specialist with expertise in FH (usually at a lipid or metabolic clinic).

Diagnosis should be made by 10 years of age or at the earliest opportunity thereafter.

Additional information

Additional information

Causes of secondary hypercholesterolaemia

The following may cause hypercholesterolaemia (without hypertriglyceridaemia):

Hypothyroidism (see the CKS topic on Hypothyroidism).

Cholestatic liver disease (such as primary biliary cirrhosis).

Nephrotic syndrome.

Cushing's syndrome.

Drugs:

Androgens.

Ciclosporin.

Anti-retrovirals (protease inhibitors).

Anorexia nervosa.

The following may also cause hypercholesterolaemia, but, usually, hypertriglyceridaemia would also be present:

Diabetes mellitus or obesity (although hypertriglyceridaemia alone is the more common presentation). See the CKS topics on Diabetes - type 2 and Obesity.

Pregnancy.

Renal dialysis or advanced renal failure.

Monoclonal gammopathy.

Excess alcohol consumption.

HIV infection.

Drugs:

Thiazide diuretics.

Glucocorticoids.

Retinoic acid derivatives.

Beta-blockers.

Anti-retrovirals (protease inhibitors, nucleoside analogue reverse transcriptase inhibitors such as stavudine).

[Warrell et al, 2003; Aronson, 2006; Bhatnagar et al, 2008]

Basis for recommendation

Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

The need for fasting when checking serum lipids is based on expert opinion [Bhatnagar et al, 2008]; the calculation of LDL-C is based on the assumption of fasting samples and triglyceride levels less than 4.5 mmol/L (the opinion of a CKS expert reviewer).

The method suggested for detecting an underlying cause is based on expert opinion in a textbook [Kumar and Clark, 1994].

Diagnosis in adults

How do I confirm a diagnosis in adults?

Use the Simon Broome criteria to make a diagnosis of heterozygous familial hypercholesterolaemia (FH):

Diagnose definite FH in an adult with:

Total cholesterol greater than 7.5 mmol/L, low-density lipoprotein cholesterol (LDL-C) concentration greater than 4.9 mmol/L, and tendon xanthomata (or evidence of tendon xanthomata in a first- or second-degree relative), or

An identified genetic mutation for familial hypercholesterolaemia.

Diagnose possible FH in an adult with total cholesterol greater than 7.5 mmol/L, LDL-C greater than 4.9 mmol/L, and at least one of the following:

Family history of myocardial infarction: before 60 years of age in a first-degree relative, or before 50 years of age in a second-degree relative.

Family history of raised total cholesterol: greater than 7.5 mmol/L in an adult first- or second-degree relative, or greater than 6.7 mmol/L in a child, brother, or sister younger than 16 years of age.

Consider a clinical diagnosis of homozygous FH in adults with LDL-C greater than 13 mmol/L.

Refer to a specialist with expertise in FH for confirmation of the diagnosis.

Basis for recommendation

Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

NICE recommend the use of the Simon Broome diagnostic criteria. These are validated criteria, recommended by NICE because their development was based on a UK population, and they are simpler to use than other criteria with a comparable or better positive likelihood ratio [National Collaborating Centre for Primary Care, 2008b].

Diagnosis in children and young people

How do I confirm a diagnosis in children and young people?

Use the Simon Broome criteria for children (which differ from the criteria for adults in terms of the lipid concentrations) to make a diagnosis of familial hypercholesterolaemia (FH) in children and young people (up to 15 years of age):

Diagnose definite FH in a child or young person with:

Total cholesterol greater than 6.7 mmol/L, low-density lipoprotein cholesterol (LDL-C) greater than 4.0 mmol/L, and tendon xanthomata (or evidence of tendon xanthomata in a first- or second-degree relative), or

An identified genetic mutation for FH.

Diagnose possible FH in a child or young person with total cholesterol greater than 6.7 mmol/L, LDL-C greater than 4.0 mmol/L, and at least one of the following:

Family history of myocardial infarction: before 60 years of age in a first-degree relative, or before 50 years of age in a second-degree relative.

Family history of raised total cholesterol: greater than 7.5 mmol/L in an adult first- or second-degree relative or greater than 6.7 mmol/L in a child, brother, or sister younger than 16 years.

Consider a clinical diagnosis of homozygous FH in children and young people with LDL-C greater than 11 mmol/L.

Refer to a specialist for confirmation of the diagnosis.

Ideally, referral will be to a specialist with particular expertise in FH in children and young people. If unavailable locally, refer to a specialist with expertise in FH (usually at a lipid or metabolic clinic).

Diagnosis should be made by 10 years of age or at the earliest opportunity thereafter.

Basis for recommendation

Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

NICE recommend the use of the Simon Broome diagnostic criteria. These are validated criteria, recommended by NICE because their development was based on a UK population, and they are simpler to use than other criteria with a comparable or better positive likelihood ratio [National Collaborating Centre for Primary Care, 2008b].

Management

Management

Scenario: Management : covers the management of people with a diagnosis of FH confirmed by a specialist.

Scenario: Management

Scenario: Management of familial hypercholesterolaemia

1months3060monthsBoth

Management of adults with heterozygous FH

How do I manage adults with confirmed heterozygous familial hypercholesterolaemia?

Refer all adults diagnosed with heterozygous familial hypercholesterolaemia (FH) on the basis of the Simon Broome criteria to a specialist with expertise in FH for confirmation of the diagnosis and initiation of cascade testing.

Adults with confirmed heterozygous FH at particularly high risk of a coronary event should also be managed by a specialist with expertise in FH. Particularly high risk is defined as any of the following:

Established coronary heart disease (CHD).

Family history of premature CHD (first-degree relative before 60 years of age, or second-degree relative before 50 years of age).

Two or more other cardiovascular disease risk factors (such as male gender, smoking, hypertension, or diabetes).

Consider a routine referral to a cardiologist for evaluation for possible CHD if either of the following are present:

A family history of CHD in early adulthood.

Two or more other cardiovascular disease risk factors (such as male gender, smoking, hypertension, or diabetes).

If managing an adult with confirmed heterozygous FH in primary care:

Do not use cardiovascular disease risk assessment tools to guide management because people with FH are already at a high risk of premature CHD.

Consider doing a baseline electrocardiogram (ECG).

Offer lifestyle advice in addition to medication.

Treat with cholesterol-lowering medication (see Cholesterol lowering in adults with heterozygous FH).

Consider treating people with FH and sustained systolic blood pressure greater than 140 mmHg and/or diastolic blood pressure greater than 90 mmHg with blood pressure lowering medication, to achieve a target blood pressure of less than 140/90 mmHg (see the CKS topic on Hypertension - not diabetic):

A higher threshold (160/100 mmHg) for treatment could be considered for people without other risk factors who are either 40 years of age or younger or have been treated to target with cholesterol-lowering medication since childhood.

A lower target blood pressure, such as less than 140/85 mmHg, is recommended by some experts.

Consider starting aspirin 75 mg daily in adults older than 40 years of age if there are no contraindications. See the CKS topic on Antiplatelet treatment.

The age to start aspirin may be brought forward or delayed, depending on whether the person has been treated to target with cholesterol-lowering medication since childhood.

Women may be less likely than men to benefit from aspirin.

Note that aspirin is not licensed for primary prevention of cardiovascular disease.

If in doubt about the use of blood pressure lowering medication and aspirin, seek advice from a specialist with expertise in FH.

Additional information

Additional information

Cascade testing

This involves identification of affected relatives by DNA testing (if available) and/or measuring low-density lipoprotein cholesterol (LDL-C) concentration.

In families in which a mutation is identified, the mutation (and not LDL-C) should be used to identify affected relatives.

In the absence of DNA diagnosis, diagnosis in relatives of an affected individual should be by age- and gender-specific criteria for LDL-C concentration. The Simon Broome criteria should not be used for diagnosis of affected relatives following cascade testing.

It is envisaged that cascade testing should include first-, second-, and, where possible, third-degree relatives, as part of a nationwide, family-based follow-up system.

[NICE, 2008]

Basis for recommendation

Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008], and a summary of NICE guidance published in the British Medical Journal, which helps to define the role of primary care [Wierzbicki et al, 2008].

However, there is no clear guidance from NICE on the use in primary care of blood pressure lowering and antiplatelet medication specifically in people with familial hypercholesterolaemia (FH) [NICE, 2004; NICE, 2006; NICE, 2008].

Blood pressure

Recommendations regarding the threshold for, and target of, blood pressure lowering medication are extrapolated from the guideline published by NICE, Hypertension: management of hypertension in adults in primary care (partial update of NICE clinical guideline 18), in which treatment with blood pressure lowering medication is recommended in 'patients at raised cardiovascular risk (10-year risk of CVD of 20% or more, or existing cardiovascular disease or target organ damage) with persistent blood pressure of more than 140/90 mmHg' [NICE, 2006]. This assumes that all people with FH are at raised cardiovascular risk.

The recommendation to consider a higher threshold and a lower target in some cases is based on other evidence:

Two other UK guidelines on the prevention of cardiovascular disease recommend that, for people with FH who are 40 years of age or younger, blood pressure lowering medication should only be started if blood pressure is consistently greater than 160/100 mmHg. Both guidelines also recommend that the target for all people being treated is a blood pressure less than 140/85 mmHg [British Cardiac Society et al, 2005; SIGN, 2007].

Two recent, large cohort studies found that statins nearly normalize the coronary heart disease risk in people with FH [Neil et al, 2008; Versmissen et al, 2008].

Aspirin

Recommendations regarding the use of aspirin are based on expert opinion expressed in two guidelines on the prevention of cardiovascular disease issued by the Joint British Societies (JBS) [British Cardiac Society et al, 2005] and the Scottish Intercollegiate Guidelines Network (SIGN) [SIGN, 2007]:

Aspirin is recommended for adults with FH who are 40 years of age or more (by SIGN), but for those who are 50 years of age or more (by JBS). The lower age was selected by CKS on the basis that, untreated, people with FH are at very high risk of premature coronary heart disease [Marks et al, 2003].

Recommendations to bring forward or delay the use of aspirin depending on statin use are based on comments from CKS external expert reviewers and the findings of two recent, large cohort studies that statins nearly normalize the coronary heart disease risk in people with FH [Neil et al, 2008; Versmissen et al, 2008] — see Statins versus placebo in adults. Furthermore, two recent randomized, controlled trials (not in people with FH) did not find that aspirin reduced the risk of most cardiovascular outcomes in some groups:

The Women's Health Study, a primary prevention study involving 39,876 women 45 years of age or older (90% of whom were less than 65 years of age), found that aspirin 100 mg had no significant effect on the risk of fatal or non-fatal myocardial infarction compared with placebo (relative risk 1.02, 95% CI 0.84 to 1.25, p = 0.83), although aspirin significantly lowered the risk of stroke [Ridker et al, 2005].

The prevention of progression of arterial disease and diabetes (POPADAD) trial found no statistically significant differences in the risk of any cardiovascular outcome between aspirin 100 mg and placebo in 1276 adults who were 40 years of age or more with type 1 or type 2 diabetes and asymptomatic peripheral arterial disease [Belch et al, 2008].

The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) trial found that, compared with placebo, aspirin 81 mg or 100 mg did not reduce atherosclerotic events in 2539 Japanese adults with type 2 diabetes (hazard ratio 0.80, 95% CI 0.58 to 1.10, p = 0.16) [Ogawa et al, 2008].

Cholesterol lowering in adults with heterozygous FH

How do I specifically manage high cholesterol in an adult with heterozygous familial hypercholesterolaemia?

Do not use cardiovascular disease risk assessment tools to guide management, because people with familial hypercholesterolaemia (FH) are already at a high risk of premature coronary heart disease.

Adults with confirmed heterozygous FH at particularly high risk of a coronary event should be managed by a specialist with expertise in FH.

Prescribe a high intensity statin to achieve a target reduction in low-density lipoprotein cholesterol (LDL-C) concentration of greater than 50% from baseline:

Start simvastatin 40 mg, atorvastatin 20 mg, or rosuvastatin 10 mg once daily (each preferably to be taken at night, especially simvastatin):

For information on monitoring before and after initiation of statins, see Monitoring: LFTs and CK in the CKS topic on Lipid modification - CVD prevention.

Recheck serum lipids at 4–12 weeks. If the target has not been reached:

If taking simvastatin 40 mg, either increase to simvastatin 80 mg daily or, if there are particular concerns about the risk of myopathy with simvastatin 80 mg, change to atorvastatin 40 mg or rosuvastatin 20 mg daily.

If simvastatin 80 mg fails to achieve the target, change to atorvastatin 80 mg or rosuvastatin 40 mg daily.

If taking atorvastatin 20 mg or rosuvastatin 10 mg, titrate up to the maximum licensed or tolerated dose to achieve the target.

See also Special considerations in women and girls.

If statins are not tolerated due to new-onset muscle pain (often associated with increased levels of muscle enzymes such as creatine kinase), significant gastrointestinal disturbance, or alterations in liver function tests (LFTs):

Consider stopping the statin — see Adverse effects of statins in the CKS topic on Lipid modification - CVD prevention.

If statins are contraindicated or not tolerated:

Refer to a specialist with expertise in FH.

Provided creatine kinase and LFTs have returned to normal, consider prescribing ezetimibe 10 mg once daily instead of a statin whilst the person is waiting to be seen by the specialist.

If statin monotherapy fails to achieve the target:

Prescribe ezetimibe 10 mg once daily in addition to a statin.

If ezetimibe is contraindicated or not tolerated, refer to a specialist with expertise in FH (for consideration for treatment with a bile acid sequestrant [resin], nicotinic acid, or a fibrate).

If combined treatment with a statin and ezetimibe fails to achieve the target:

Refer to a specialist with expertise in FH.

Basis for recommendation

Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008], and a summary of NICE guidance published in the British Medical Journal, which helps to define the role of primary care [Wierzbicki et al, 2008].

Target reduction of low-density lipoprotein cholesterol (LDL-C) more than 50% from baseline

The recommendation by NICE for this target is based on the findings of the ASAP study, a randomized, double-blind trial in adults (n = 325) comparing atorvastatin 80 mg and simvastatin 40 mg [Smilde et al, 2001]:

The primary outcome was change in carotid intima media thickness (IMT).

In the atorvastatin group IMT reduced, whereas in the simvastatin group it increased (p = 0.0001 for the difference); mean reduction in LDL-C was 50.5% in the atorvastatin group, compared with 41.2% in the simvastatin group (p = 0.0001 for the difference).

NICE concluded that the therapeutic response was associated with lack of progression of atherosclerosis [National Collaborating Centre for Primary Care, 2008b].

Statin monotherapy

Statins compared to placebo

There is limited evidence, from four small controlled trials and two large cohort studies, of the efficacy of statins for adults with FH. It is now considered unethical to carry out placebo-controlled trials in adults with FH [National Collaborating Centre for Primary Care, 2008b]. Consequently, in their recommendation to prescribe a statin as first-line treatment for adults with FH, NICE extrapolated evidence of the efficacy, tolerability, and safety of statins for the secondary prevention of cardiovascular disease [Cooper et al, 2007; National Collaborating Centre for Primary Care, 2008a].

High intensity compared to lower intensity statins

NICE recommends the use of a 'high intensity' statin in adults with FH on the basis of limited evidence from a systematic review and a health economic analysis (both commissioned by NICE) [National Collaborating Centre for Primary Care, 2008b], as well as evidence from studies in people without FH.

NICE specify only that a 'high intensity' statin is one that produces greater LDL-C reductions than simvastatin 40 mg (for example, simvastatin 80 mg and appropriate doses of atorvastatin and rosuvastatin) [NICE, 2008]. CKS has interpreted this statement with reference to a meta-analysis of 164 short-term randomized controlled trials (RCTs) which calculated absolute and percentage reductions of total cholesterol and LDL-C with different doses and different statins [Law et al, 2003; National Collaborating Centre for Primary Care, 2008a].

For further details, see Table 1 in Lipid lowering effects in the CKS topic on Lipid modification - CVD prevention.

Expert reviewers expressed concerns over the use of simvastatin 80 mg: two RCTs have found an increased risk of myopathy associated with the use of simvastatin at the dose of 80 mg daily compared with lower doses.

Higher intensity statin therapy with simvastatin 80 mg daily was associated with a small increase in rhabdomyolysis (0.13%) compared with simvastatin 20 mg daily (0%) [de Lemos et al, 2004].

The results of a subsequent RCT using simvastatin 80 mg daily, the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial [SEARCH Collaborative Group, 2010] also found a small increased risk of myopathy with simvastatin 80 mg (0.9%) compared with simvastatin 20 mg (0.02%); number needed to harm 118 over 6.7 years [NPC, 2010].

The Medicines and Healthcare products Regulatory Agency (MHRA) has recently reviewed these data and advised that simvastatin 80 mg should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks [MHRA, 2010].

In trials involving atorvastatin 80 mg or rosuvastatin 40 mg, no increased risk of myopathy was found [Smilde et al, 2001; Cannon et al, 2004; LaRosa et al, 2005; Pedersen et al, 2005; Crouse et al, 2007], although this may be due to differences in definitions and methods of detection of myopathy.

Repeat lipid monitoring

This recommendation is extrapolated from the CKS recommendations for lipid monitoring for secondary prevention of cardiovascular disease — see the CKS topic on Lipid modification - CVD prevention.

Ezetimibe monotherapy

The recommendation to consider ezetimibe (if statins are contraindicated or not tolerated) whilst awaiting specialist referral, is in line with a Health Technology Appraisal (HTA) and a guideline, both published by NICE [NICE, 2007; NICE, 2008]. In the absence of any RCTs of ezetimibe monotherapy that included only adults with FH, recommendations by NICE are extrapolated from evidence from trials in adults with primary (heterozygous-familial and non-familial) hypercholesterolaemia [NICE, 2007]. NICE found that ezetimibe was superior to placebo in reducing LDL-C concentrations in adults with primary hypercholesterolaemia in whom statins were considered inappropriate or had not been tolerated. There were no serious adverse events, and there was no difference in adverse event rates between ezetimibe and placebo groups. Although the effects of ezetimibe on cardiovascular mortality or morbidity are unknown, NICE selected reduction of LDL-C concentration as the primary target of drug treatment in people with FH [National Collaborating Centre for Primary Care, 2008b].

Statin plus ezetimibe

The recommendation to combine ezetimibe with a statin to reach the treatment target is based on evidence from just one RCT (n = 720) in adults with heterozygous FH [Kastelein et al, 2008], as well as evidence extrapolated from two systematic reviews (n = 3610; n = 1800) of RCTs in adults with heterozygous FH and adults with non-familial hypercholesterolaemia [Ara et al, 2008]. (The RCT was published after the search date of the systematic review.)

None of the studies included clinical outcomes, such as cardiovascular morbidity or mortality, although NICE states that the primary target of drug therapy is reduction of LDL-C concentration [National Collaborating Centre for Primary Care, 2008b].

Although a systematic review showed an overall safety profile for the combination similar to that of a statin alone [Ara et al, 2008], one subsequent trial has found an increased risk of cancer in people taking ezetimibe together with a statin [Rossebo et al, 2008], a finding not confirmed in a meta-analysis [Peto et al, 2008].

Referral

Referral to a specialist with expertise in FH is required for adults who cannot take a statin or ezetimibe (where indicated), or where the target reduction in LDL-C has not been achieved, so that consideration can be given to using bile acid sequestrants (resins), nicotinic acid, or fibrates [NICE, 2008].

Management of homozygous FH

How do I manage people with confirmed homozygous familial hypercholesterolaemia?

Refer people with suspected or confirmed homozygous familial hypercholesterolaemia (FH) to a specialist with expertise in FH.

Additional information

Additional information

Specialist treatments for people with homozygous FH

Bile acid sequestrants (resins), nicotinic acid, and/or fibrates (usually in addition to statins and/or ezetimibe).

Low-density lipoprotein (LDL) apheresis:

Involves removal of blood (usually via an arterio-venous fistula) for treatment to clear low-density lipoprotein-cholesterol.

Takes 3–4 hours and is required every 7–14 days.

Should be considered for people with homozygous FH and, in exceptional circumstances, those with heterozygous FH.

Angiotensin-converting enzyme (ACE) inhibitors are contraindicated and should be substituted with angiotensin-II receptor blockers.

Warfarin should be discontinued 4 days prior to LDL apheresis and substituted with low molecular weight heparin.

Liver transplant:

May be considered for people with homozygous FH.

[Thompsen and Thompson, 2006; NICE, 2008]

Basis for recommendation

Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

Management of children and young people

How do I manage a child or young person?

All children and young people (up to 15 years of age) with suspected or confirmed familial hypercholesterolaemia (FH) should be managed by a specialist.

Ideally, referral will be to a specialist with particular expertise in FH in children and young people. If unavailable locally, refer to a specialist with expertise in FH (usually at a lipid or metabolic clinic).

Additional information

Additional information

Specialist treatment for children and young people with FH

Lipid-modifying drug treatment should usually be considered by 10 years of age, although the decision to treat with drugs should be based on individualized risk assessment.

Initial treatment should be with a statin.

Bile acid sequestrants (resins), fibrates, or ezetimibe may considered for children and young people who are unable to tolerate statins.

Routine monitoring of growth and pubertal development is recommended.

[NICE, 2008]

Basis for recommendation

Basis for recommendation

This recommendation is in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

Advice

What advice should I give to someone with familial hypercholesterolaemia?

Offer lifestyle advice, in particular on diet, smoking, and exercise, in addition to lipid-lowering medication.

See Advice on lifestyle in the CKS topic on CVD risk assessment and management, which applies to people with familial hypercholesterolaemia (FH), except:

Do not advise against the consumption of food products containing stanols and sterols. If people with FH wish to consume them, advise them that such products cannot be prescribed, and they need to be taken consistently to be effective.

Offer individualized nutritional advice from a healthcare professional with specific expertise in nutrition.

Inform people with FH about HEART UK (www.heartuk.org.uk, telephone 0845 450 5988) which provides information and advice on preventing premature deaths caused by high cholesterol.

Basis for recommendation

Basis for recommendation

These recommendations, and the linked recommendations in the CKS topic on CVD risk assessment and management, are in line with the National Institute for Health and Care Excellence (NICE) guideline, Identification and management of familial hypercholesterolaemia [NICE, 2008]:

Dietary interventions

There is very limited evidence of the efficacy of dietary interventions for people with familial hypercholesterolaemia (FH). Recommendations by NICE for people with FH [NICE, 2008] are extrapolated from three systematic reviews of dietary interventions in the general population [Howell et al, 1997; Hooper et al, 2000; Brunner et al, 2007] which suggest that dietary treatment can lead to a maximum lipid lowering of 5–10% [National Collaborating Centre for Primary Care, 2008b].

There is also very limited evidence from a systematic review [Moruisi et al, 2006] and one subsequent, small, short-term study [Jakulj et al, 2006] that foods containing plant sterols and stanols can reduce low-density lipoprotein cholesterol concentrations in people with heterozygous FH.

Special considerations in women and girls

What special considerations are there for women and girls?

Pregnancy and breastfeeding

Although there is no reason to advise against pregnancy or breastfeeding, inform all women and girls of childbearing age with familial hypercholesterolaemia (FH) that:

Because lipid-lowering medication may increase the risk of fetal malformation if taken during the first trimester:

They should stop lipid-lowering medication 3 months before attempting to conceive.

In the event of an unplanned pregnancy, they should immediately stop lipid-lowering medication and seek medical advice.

If the woman is considering pregnancy or is pregnant, refer her for pre-pregnancy planning and antenatal care by an obstetrician and, if she is not already under their care, a specialist with expertise in FH and a cardiologist.

In the event of an unplanned pregnancy in a woman taking lipid-lowering medication:

Refer urgently (to be seen within 14 days) to an obstetrician for fetal assessment.

Avoid lipid-lowering medication, except bile acid sequestrants (resins), during lactation.

Contraception

Although combined oral contraceptives (COCs) are not contraindicated, other methods of contraception should be considered because of the potential increased risk of cardiovascular events with COC use.

Due to potential interactions between statins and the hormones within COCs, consult the British National Formulary and the summaries of product characteristics (SPCs) of the COC and the relevant lipid-lowering medication (see www.medicines.org.uk).

See the section on Multiple risk factors for cardiovascular disease in the CKS topic on Contraception - assessment.

Basis for recommendation

Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

Although evidence is inconclusive, there may be a small increase in the rate of fetal malformations if statins have been taken in the first trimester. However, most pregnancies have a normal outcome [National Collaborating Centre for Primary Care, 2008b].

The risk of a maternal cardiovascular event during pregnancy, either on or off medication, is not known, but it is possible that pregnancy increases the risk of an event in women and girls with familial hypercholesterolaemia (FH) [National Collaborating Centre for Primary Care, 2008b].

FH appears to increase the risk of aortic stenosis or atheroma involving the aortic valve, although these findings are mainly in people with homozygous FH, or people with heterozygous FH who have prolonged, severe hypercholesterolaemia [Rallidis et al, 1998].

Although NICE recommend that prescribers should refer to summaries of product characteristics for individual drugs regarding potential interactions, they identified one small study of concomitant use of rosuvastatin and a third generation COC which showed no decrease in contraceptive efficacy or cholesterol-lowering efficacy [National Collaborating Centre for Primary Care, 2008b].

NICE identified observational studies that did not demonstrate a significant increase in the risk of myocardial infarction in women taking a third generation COC [National Collaborating Centre for Primary Care, 2008b]. NICE also reported (then unpublished) results from a cohort study, that found no 'significant increase' in the risk of coronary heart disease in women of reproductive age taking statins. The study has now been published: there was one death in 4107 person-years of observation in women likely to have been on statins who were 20–39 years of age [Neil et al, 2008]. It is unsurprising that no statistical significance was found given such low frequencies, but this mortality rate represents a standardized mortality ratio (SMR) of 3333.

Follow up

What follow up is required?

For people with familial hypercholesterolaemia (FH) who have been discharged from specialist care:

Offer a regular structured review that is carried out at least annually.

Ask about symptoms of coronary heart disease (CHD).

In adults, consider a baseline electrocardiogram (ECG) if this was not carried out at diagnosis.

A low threshold for referral is recommended for evaluation for possible CHD symptoms.

Check medication adherence and ask about possible adverse effects.

Assess smoking status: offer smoking cessation advice and referral to a smoking cessation clinic, if necessary. See the CKS topic on Smoking cessation.

Check blood pressure.

Check fasting lipids and any other tests relevant to drug monitoring. See the section on Prescribing information in the CKS topic on Lipid modification - CVD prevention.

Consider checking blood glucose and renal function.

Consider whether any of the following are needed (see Management of adults with heterozygous FH):

Additional lifestyle measures.

Changes to cholesterol or blood pressure lowering medication.

Aspirin.

Referral to a specialist with expertise in FH.

Discuss any plans for pregnancy and needs for contraception. See Special considerations in women and girls.

Inquire about the progress of family cascade testing, and advise that untested relatives should seek medical advice.

Basis for recommendation

Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Care Excellence (NICE), Identification and management of familial hypercholesterolaemia [NICE, 2008].

The recommendation to consider checking blood glucose and renal function is extrapolated from guidelines for people with non-familial dyslipidaemia, including a NICE guideline, Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease [National Collaborating Centre for Primary Care, 2008a]; the Scottish Intercollegiate Guidelines Network (SIGN) guideline Risk estimation and the prevention of cardiovascular disease [SIGN, 2007]; and the Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice [British Cardiac Society et al, 2005].

The identification of additional risk factors for coronary heart disease will guide the management (in particular, referral) of adults with familial hypercholesterolaemia.

Evidence

Evidence

Supporting evidence

Dietary interventions

Evidence on dietary interventions

There is very limited evidence of the efficacy of dietary interventions in people with familial hypercholesterolaemia (FH). Recommendations by the National Institute for Health and Care Excellence (NICE) for people with FH [NICE, 2008] are extrapolated from three systematic reviews of dietary interventions in the general population [Howell et al, 1997; Hooper et al, 2000; Brunner et al, 2007] which suggest that cholesterol lowering diets can lead to a maximum lipid lowering of 5–10% [National Collaborating Centre for Primary Care, 2008b]. There is also very limited evidence from a systematic review [Moruisi et al, 2006] and one subsequent, small, short-term study [Jakulj et al, 2006] that foods containing plant sterols and stanols can reduce low-density lipoprotein cholesterol (LDL-C) concentrations in people with heterozygous FH.

Dietary interventions in people with FH

All dietary treatments:

In a Cochrane review of dietary treatment for FH (most recent search date: 2003), seven small, crossover, randomized controlled trials (RCTs) were included (n = 135) [Poustie and Rutherford, 2001]. The studies were too small, of too short duration (1–3 months), or lacked appropriate analysis for any conclusions to be made about the efficacy of dietary treatments for FH.

Plant stanols and sterols:

A systematic review of the efficacy of phytosterols/stanols in lowering total cholesterol and LDL-C concentration in FH subjects reported on the findings of six RCTs (n = 150), four of which were included in the meta-analysis (n = 123), two being excluded because of inappropriately high concentrations of plant sterols used [Moruisi et al, 2006].

Studies lasted between 4 weeks and 3 months.

In the meta-analysis of four studies, fat spreads containing phytosterols/stanols reduced total cholesterol and LDL-C by 0.65 mmol/L (95% CI 0.42 to 0.88, p < 0.001) and 0.64 mmol/L (95% CI 0.43 to 0.86, p < 0.001) respectively over an average of 6.5 weeks, compared with control treatment.

There were either no, or minor, gastrointestinal adverse effects reported.

The results were statistically homogeneous but no sensitivity analysis was done to assess the effect of excluding the two studies from the meta-analysis.

A crossover RCT, published subsequently, compared a plant stanol-containing yoghurt with a yoghurt without plant stanol in 41 pre-pubescent children with FH [Jakulj et al, 2006]:

LDL-C decreased with treatment by a mean of –0.48 mmol/L (9.2%) compared with placebo, but the authors report the 95% CI for the difference as –0.69 to +0.27 and the p-value for the difference as < 0.001; the p-value and 95% CI are inconsistent.

Dietary interventions in the general population

Three systematic reviews of dietary interventions have been published [Howell et al, 1997; Hooper et al, 2000; Brunner et al, 2007]. Meta-analyses were carried out of trials with mixed populations and diets. Only one review reported clinical outcomes [Hooper et al, 2000]. Based on the findings of the reviews, NICE concluded that cholesterol lowering diets can lead to a maximum lipid lowering of 5–10% [National Collaborating Centre for Primary Care, 2008b].

In a Cochrane review of primary prevention of cardiovascular disease with reduced or modified dietary fat, 27 trials (30,901 person-years) lasting at least 6 months were included [Hooper et al, 2000]:

There was no significant effect on total mortality or cardiovascular mortality (relative risk [RR] 0.91, 95% CI 0.77 to 1.07), but a significant reduction in cardiovascular events (RR 0.84, 95% CI 0.72 to 0.99) was found.

When a large study that included fish oils in the intervention was excluded, statistical significance was lost.

The average reduction in total serum cholesterol was 0.64 mmol/L (11.1%; confidence interval and p-value not reported).

In an earlier review of 224 dietary intervention studies, including those of low quality (internal validity), meta-analysis suggested that, in people with baseline LDL-C concentrations greater than 4.14 mmol/L, reductions in intake of saturated and polyunsaturated fatty acids lead to average reductions in LDL-C of 4.5–7.7%, depending on the intensity of the diet [Howell et al, 1997].

In another Cochrane review of dietary advice for cardiovascular risk, meta-analysis was performed on 38 RCTs in adults (n = 17,871) [Brunner et al, 2007]. Study inclusion criteria were a drop-out rate of less than 20% and a study duration of at least 3 months. Benefits of dietary advice were statistically significant but small: dietary advice reduced total serum cholesterol by 0.16 mmol/L (95% CI 0.06 to 0.25) and reduced LDL-C by 0.18 mmol/L (95% CI 0.1 to 0.27) after 3–24 months.

Statin monotherapy in adults

Evidence on statin monotherapy in adults

Statins versus placebo in adults

Evidence on statins versus placebo in adults

There is limited evidence, from four small controlled trials and two large cohort studies, of the efficacy of statins for adults with familial hypercholesterolaemia (FH). It is now considered unethical to carry out placebo-controlled trials in adults with FH [National Collaborating Centre for Primary Care, 2008b]. Consequently, in their recommendation to prescribe a statin as first-line treatment for adults with FH, the National Institute for Health and Care Excellence (NICE) extrapolated evidence from trials of the efficacy, tolerability, and safety of statins for the secondary prevention of cardiovascular disease in people without FH [Cooper et al, 2007; National Collaborating Centre for Primary Care, 2008a].

See the sections on Statins for secondary prevention and Adverse effects of statins in the CKS topic on Lipid modification - CVD prevention.

Efficacy of statins compared to placebo in adults with FH

Two systematic reviews, one carried out for the NICE guideline on FH, failed to identify any good quality RCTs of statin monotherapy in adults with FH [Marks et al, 2003; National Collaborating Centre for Primary Care, 2008b].

NICE reported the results of four small, controlled studies of statins in adults with FH which found, in the most part, statistically significant reductions in low-density lipoprotein cholesterol (LDL-C) concentrations compared with placebo [National Collaborating Centre for Primary Care, 2008b].

One observational study compared mortality from coronary heart disease (CHD) in adults with FH treated in UK lipid clinics before (1980 to 1991) and after (1992 to 1995) the introduction of statins [Scientific Steering Committee on behalf of the Simon Broome Register Group, 1999]:

In a cohort 20–59 years of age (with or without CHD; 6241 person-years of observation), the relative risk reduced from 8.0 (95% CI 4.8 to 12.6) before statins to 3.7 (95% CI 1.6 to 7.2), but this did not reach statistical significance (p = 0.081).

The follow-up rate was high (more than 95%).

The Simon Broome Register Group recently updated these analyses and reported that, in 2582 people with heterozygous FH, followed between 1980 and 2006, primary prevention resulted in a 48% reduction in the standardized mortality ratio (SMR) for CHD after 1991 when statins were prescribed routinely [Neil et al, 2008]:

It is not clear whether this reduction was statistically significant as confidence intervals are not presented for this result (although they are presented for other results).

All-cause mortality was 33% (95% CI 21 to 50) lower in the statin-treated cohort than in the general population; this was mainly due to a 37% lower risk of fatal cancer, probably attributable to advice not to smoke.

For the purposes of determining the SMR, the expected number of CHD deaths was calculated by applying the age- and calendar-specific death rates for men and women in the general population of England and Wales to the person-years accumulated by men and women in the cohorts.

Another observational study compared the risk of coronary heart disease in people with FH without established CHD treated with statins with those 'untreated' (where there was a delay in starting statin treatment) [Versmissen et al, 2008]:

A Cox hazard regression model was used to analyse statin treatment as a time-dependent variable (that is, taking into account the time that statins were used). The model also adjusted appropriately for measurable risk factors and baseline characteristics.

Out of 1707 people included, 196 (9%) were were lost to follow up or excluded because of missing data.

People treated with statins had an overall 82% risk reduction (hazard ratio 0.18, 95% CI 0.13 to 0.25, p < 0.001) compared with those 'untreated', after adjustment.

Confounding by dietary and other lifestyle factors cannot be excluded.

High intensity versus lower intensity statins in adults

Evidence on high intensity versus lower intensity statins in adults

NICE recommends the use of a 'high intensity' statin in adults with familial hypercholesterolaemia (FH) on the basis of limited evidence from a systematic review and a health economic analysis (both commissioned by NICE), as well as evidence from studies in adults without known FH (see the section on the efficacy of higher versus lower intensity statin treatment for secondary prevention, and the section on Higher intensity statin therapy in the CKS topic on Lipid modification - CVD prevention).

The Medicines and Healthcare products Regulatory Agency (MHRA) has advised that simvastatin 80 mg should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.

A systematic review of studies comparing high and lower dose statins and studies comparing different statins identified mainly small, older, or short-term randomized controlled trials (RCTs) [National Collaborating Centre for Primary Care, 2008b]:

In each study comparing high and lower dose statins in people with FH, there was either a trend towards or a statistically significant reduction in low-density lipoprotein cholesterol (LDL-C) concentration with higher dose compared with lower dose.

Most of the studies that compared different statins in people with FH were limited by poor study design (small sample size or crossover), absence of clinical outcomes (lipid measurements only), or by the lack of generalizability (the use of unlicensed doses or statins unavailable in the UK).

One double-blind RCT found significant reductions in carotid intimal thickness (considered by NICE to reflect a lack of progression of atherosclerosis) in people randomized to receive atorvastatin 80 mg compared with simvastatin 40 mg (p = 0.0001) [Smilde et al, 2001].

The health economic analysis modelled the cost effectiveness of high intensity statins compared with low intensity statins in the management of FH [National Collaborating Centre for Primary Care, 2008b].

Simvastatin 80 mg, atorvastatin 80 mg, and rosuvastatin 40 mg were each found to be cost-effective when compared with simvastatin 40 mg.

Expert reviewers expressed concerns over the use of simvastatin 80 mg: two RCTs have found an increased risk of myopathy associated with the use of simvastatin at the dose of 80 mg daily compared with lower doses [de Lemos et al, 2004; SEARCH Collaborative Group, 2010]. In trials involving atorvastatin 80 mg or rosuvastatin 40 mg, no increased risk of myopathy was found [Smilde et al, 2001; Cannon et al, 2004; LaRosa et al, 2005; Pedersen et al, 2005; Crouse et al, 2007], although this may be due to differences in definitions and methods of detection of myopathy.

The Medicines and Healthcare products Regulatory Agency (MHRA) has recently reviewed these data and advised that simvastatin 80 mg should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks [MHRA, 2010].

Ezetimibe monotherapy in adults

Evidence on ezetimibe monotherapy in adults

In the absence of any randomized, placebo-controlled trials (RCTs) of ezetimibe monotherapy that included only adults with familial hypercholesterolaemia (FH), recommendations by the National Institute for Health and Care Excellence (NICE) regarding ezetimibe monotherapy for adults with FH are extrapolated from evidence from trials in adults with primary (heterozygous-familial and non-familial) hypercholesterolaemia [NICE, 2007]. NICE found that ezetimibe was superior to placebo in reducing low-density lipoprotein cholesterol (LDL-C) concentrations in adults with primary hypercholesterolaemia in whom statins were considered inappropriate or had not been tolerated. There were no serious adverse events, and there was no difference in adverse event rates between ezetimibe and placebo.

Although the effects of ezetimibe on cardiovascular mortality or morbidity are unknown, reduction of LDL-C concentration was selected by NICE as the primary target of drug treatment in people with FH [National Collaborating Centre for Primary Care, 2008b].

Efficacy of ezetimibe monotherapy

In a meta-analysis (commissioned by NICE) of seven RCTs (n = 2577) comparing ezetimibe monotherapy with placebo in people with primary (heterozygous-familial or non-familial) hypercholesterolaemia in whom statins were considered inappropriate or were not tolerated [NICE, 2007; Ara et al, 2008]:

Ezetimibe was associated with a statistically significant mean reduction in total cholesterol concentrations (13.4%, 95% CI 12.6 to 14.2) and LDL-C concentrations (18.6%, 95% CI 17.4 to 19.7) compared with placebo.

Subgroup analysis was carried out for four studies of the effect of ezetimibe therapy in people with or without heterozygous FH:

Although greater reductions in LDL-C and total cholesterol concentrations were found in the heterozygous FH group, they were not found to be statistically significant.

The following limitations of the studies were noted:

All of the studies were short term, each lasting just 12 weeks.

None reported any clinical endpoints such as cardiovascular morbidity and mortality.

They included mixed populations of people with and without a history of cardiovascular disease.

Safety and tolerability of ezetimibe monotherapy

In the systematic reviews, adverse event profiles were similar in both ezetimibe and placebo groups [Ara et al, 2008]:

Adverse events occurred in 61% of subjects in the placebo group and 63% in the ezetimibe group, but there were no significant between-group differences in laboratory or clinical parameters.

The most commonly reported adverse events, regardless of relationship to study drug, were musculoskeletal disorders (2–5%) and upper respiratory infections (7–11%).

Other common adverse events included headache, back pain, and gastrointestinal adverse events.

Creatine kinase and liver enzymes were not influenced by treatments.

Serious adverse events occurred rarely (up to 1.4%) and all trials reported no serious treatment-related adverse events.

A death which occurred in the ezetimibe arm was considered by investigators not to be related to study treatment.

Statin and ezetimibe combination in adults

Evidence on statin and ezetimibe combination in adults

There is limited evidence from one randomized, controlled trial (RCT) in adults with heterozygous familial hypercholesterolaemia (FH) that ezetimibe plus statin is superior to statin alone in reducing LDL-cholesterol (LDL-C) concentration [Kastelein et al, 2008]. Evidence of efficacy and safety of the combination is also extrapolated from two systematic reviews (n = 3610, n = 1800) of RCTs including both adults with heterozygous FH and adults with non-familial hypercholesterolaemia [Ara et al, 2008]. (The RCT was published after the search date of the systematic review.)

None of the studies included clinical outcomes, such as cardiovascular morbidity or mortality, although the National Institute for Health and Care Excellence (NICE) state that the primary target of drug therapy is reduction of low-density lipoprotein cholesterol (LDL-C) concentration [National Collaborating Centre for Primary Care, 2008b].

Although a systematic review showed an overall safety profile for the combination similar to that of a statin alone [Ara et al, 2008], one subsequent trial has found an increased risk of cancer in people taking ezetimibe together with a statin [Rossebo et al, 2008], a finding not confirmed in a meta-analysis [Peto et al, 2008].

Efficacy of ezetimibe plus statin versus statin alone

Only one double-blind RCT has been published comparing ezetimibe plus simvastatin with placebo plus simvastatin in adults with heterozygous FH (that is, excluding non-familial hypercholesterolaemia) [Kastelein et al, 2008]:

After a single-blind placebo run-in period of 6 weeks, 720 men and women aged 30–75 years were randomized to receive simvastatin 80 mg with either placebo or ezetimibe 10 mg, for 2 years.

The study was powered to detect an important difference in carotid artery wall thickness, not a difference in cholesterol concentrations.

The trial was sponsored by Merck and Schering–Plough.

The between-group difference in the reduction of LDL-C concentrations was 16.5% in favour of ezetimibe plus statin (p < 0.01). However:

Confidence intervals are not reported.

The statistical test used was analysis of variance (ANOVA) but it is not clear if the p-value was adjusted for multiple statistical testing.

There was no statistical difference in the mean change in the carotid-artery intima-media thickness (primary outcome) between the two groups (p = 0.29).

In a systematic review of fixed-dose studies of ezetimibe plus statin versus statin alone (commissioned by NICE) for people with primary hypercholesterolaemia not adequately controlled with a statin alone, six studies (n = 3610) were identified as suitable for inclusion [Ara et al, 2008]:

All of the trials included people with both heterozygous-familial and non-familial hypercholesterolaemia.

Meta-analysis found that, compared with statin alone, the combination of ezetimibe and statin treatment was associated with statistically significant incremental reductions of 13.94% (95% CI 12.98 to 14.90, p < 0.00001) in LDL-C and 10.36% (95% CI 9.63 to 11.09, p < 0.00001) in total cholesterol.

There was low statistical heterogeneity.

In a systematic review of titrated-dose studies of ezetimibe plus statin versus statin alone (commissioned by NICE) for people with primary hypercholesterolaemia not adequately controlled with a statin alone, four studies (n = 1800) were identified as suitable for inclusion [Ara et al, 2008]:

Meta-analysis was not performed owing to heterogeneity.

Two studies demonstrated that co-administered ezetimibe and atorvastatin reduces LDL-C significantly more than atorvastatin alone (between-treatment mean difference 9.8% [p < 0.05] and 12.9% [p < 0.05], respectively).

Another study found that ezetimibe plus simvastatin reduced LDL-C by 59.4% versus 52.5% with atorvastatin alone (difference of 6.9%, p < 0.05).

One further study looked at a combination of ezetimibe and simvastatin versus simvastatin alone and found the between-treatment mean difference to be 27% (p < 0.05) in favour of combination treatment.

Safety and tolerability of ezetimibe plus statin versus statin alone

An RCT comparing ezetimibe plus simvastatin with placebo plus simvastatin in adults with heterozygous FH did not detect a significant difference in adverse events between ezetimibe plus simvastatin (34.2%) and simvastatin alone (29.5%, p = 0.18 for the difference) [Kastelein et al, 2008].

Rates of discontinuation owing to adverse events were also similar: 9.4% in the simvastatin-only group and 8.1% in the combined-treatment group (p = 0.56), mostly owing to increases in liver enzymes (2.2% and 2.8%) or creatine kinase (2.2% and 1.1%). There was one case of myopathy and one case of possible hepatitis in the simvastatin-only group.

Systematic reviews of adults with both heterozygous-familial and non-familial hypercholesterolaemia found similar rates of treatment-related adverse events (17.5% of people in the pooled statin arm and 18.5% in the ezetimibe plus statin arm) and rates of discontinuation owing to adverse events (4.9% and 5.9% respectively) [Ara et al, 2008].

Meta-analysis was not performed.

The total incidence of musculoskeletal adverse events was similar in both combination and monotherapy groups (9% and 10%, respectively). No cases of rhabdomyolysis were reported.

Elevations in liver enzymes (alanine aminotransferase [ALT] and aspartate aminotransferase [AST]) more than three times the upper limit of normal were uncommon and similar in each group.

The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial, an RCT (n = 1873) of simvastatin 40 mg combined with ezetimibe 10 mg or placebo in people with mild-to-moderate asymptomatic aortic stenosis, found a statistically significant increase in incidence of cancer in the group receiving ezetimibe (11.1% versus 7.5%, p = 0.02) [Rossebo et al, 2008]. This finding was not confirmed in a meta-analysis of three trials (including the SEAS trial and two ongoing trials which were prematurely unblinded) [Peto et al, 2008], but controversy persists regarding the safety of ezetimibe when added to a statin [Nissen, 2009]. For further information, see the section on Risk of cancer in the CKS topic on Lipid modification - CVD prevention.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of familial hypercholesterolaemia, with additional searches in the following areas:

the underlying causes of secondary hypercholesterolaemia

managing other cardiovascular risk factors in people with familial hypercholesterolaemia

cohort studies of statins for treatment of familial hypercholesterolaemia

Search dates

General search for FH: 1950 – November 2008

Underlying causes search: January 1998 – November 2008

Statins search: January 1998 – December 2008

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline and these were adapted for other databases. Further details are available on request.

familial hyperlipid?emia.ti,ab., Hypercholesterolemia, Familial/, familial hypercholesterol?emia.ti,ab., essential hypercholesterol?emia.ti,ab., heterozygous fh.ti,ab., homozygous fh.ti,ab., monogenic hyperlipid?emia.ti,ab., familial apolipoprotein c-II defici$.ti,ab., familial defective apolipoprotein B.ti,ab., exp Hyperlipoproteinemia Type II/

Hypercholesterolemia/et [Etiology]

exp Cardiovascular Diseases/, exp Risk Factors/, cardiovascular risk factor$.tw., cv risk.tw.

exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/

Table 1 . Key to search terms.
Search commands Explanation
/ indicates a MeSh subject heading with all subheadings selected
.tw indicates a search for a term in the title or abstract
exp indicates that the MeSH subject heading was exploded to include the narrower, more specific terms beneath it in the MeSH tree
$ indicates that the search term was truncated (e.g. wart$ searches for wart and warts)
Topic specific literature search sources

British Heart Foundation

American Heart Association

European Society of Cardiology

MEDPED

Heart UK

Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

Medline (with guideline filter)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

BMJ Clinical Evidence

DynaMed

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

References

Ara, R., Tumur, I., Pandor, A. et al. (2008) Ezetimibe for the treatment of hypercholesterolaemia: a systematic review and economic evaluation. Health Technology Assessment 12(21), 1-212. [Abstract] [Free Full-text]

Aronson, J.K. (Ed.) (2006) Meyler's side effects of drugs. The international encyclopedia of adverse drug reactions and interactions. 15th edn. Oxford: Elsevier.

Belch, J., MacCuish, A., Campbell, I. et al. (2008) The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 337(), a1840. [Abstract] [Free Full-text]

Bhatnagar, D., Soran, H. and Durrington, P.N. (2008) Hypercholesterolaemia and its management. BMJ 337(), a993.

British Cardiac Society, British Hypertension Society, Diabetes UK et al. (2005) JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart 91(Suppl 5), v1-v52. [Free Full-text]

Brunner, E.J., Thorogood, M., Rees, K. and Hewitt, G. (2007) Dietary advice for reducing cardiovascular risk (Cochrane Review). The Cochrane Library. Issue 4. John Wiley & Sons Ltd. www.thecochranelibrary.com [Free Full-text]

Cannon, C.P., Braunwald, E., McCabe, C.H. et al. (2004) Intensive versus moderate lipid lowering with statins after acute coronary syndromes. New England Journal of Medicine 350(15), 1495-1504. [Abstract] [Free Full-text]

Clinical Trial Service Unit (2008) Results from the world’s largest trial of the benefits of more intensive cholesterol lowering and of the safety of folic acid supplementation. Clinical Trial Service Unit. .Oxford: . www.ctsu.ox.ac.uk [Free Full-text]

Cooper, A., Skinner, J., Nherera, L. et al. (2007) Clinical guidelines and evidence review for post myocardial infarction: secondary prevention in primary care and secondary care for patients following a myocardial infarction (full NICE guideline) [Replaced by CG172]. . Clinical guideline 48. National Collaborating Centre for Primary Care and Royal College of General Practitioners. www.nice.org.uk [Free Full-text]

Crouse, J.R., Raichlen, J.S., Riley, W.A. et al. (2007) Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. Journal of the American Medical Association 297(12), 1344-1353. [Abstract] [Free Full-text]

de Lemos, J.A., Blazing, M.A., Wiviott, S.D. et al. (2004) Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. Journal of the American Medical Association 292(11), 1307-1316. [Abstract] [Free Full-text]

Hooper, L., Summerbell, C.D., Higgins, J.P. et al. (2000) Reduced or modified dietary fat for preventing cardiovascular disease (Cochrane Review). The Cochrane Library. Issue 2. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Howell, W.H., McNamara, D.J., Tosca, M.A. et al. (1997) Plasma lipid and lipoprotein responses to dietary fat and cholesterol: a meta-analysis. American Journal of Clinical Nutrition 65(6), 1747-1764. [Abstract] [Free Full-text]

Jakulj, L., Vissers, M.N., Rodenburg, J. et al. (2006) Plant stanols do not restore endothelial function in pre-pubertal children with familial hypercholesterolemia despite reduction of low-density lipoprotein cholesterol levels. Journal of Pediatrics 148(4), 495-500. [Abstract]

Kastelein, J.J.P., Akdim, F., Stroes, E.S.G. et al. (2008) Simvastatin with or without ezetimibe in familial hypercholesterolemia. New England Journal of Medicine 358(14), 1431-1443. [Abstract] [Free Full-text]

Kumar, P. and Clark, M. (Eds.) (1994) Clinical medicine. A textbook for medical students and doctors. 3rd edn. London: Bailliere Tindall.

LaRosa, J.C., Grundy, S.M., Waters, D.D. et al. (2005) Intensive lipid lowering with atorvastatin in patients with stable coronary disease. New England Journal of Medicine 352(14), 1425-1435. [Abstract] [Free Full-text]

Law, M.R., Wald, N.J. and Rudnicka, A.R. (2003) Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. British Medical Journal 326(7404), 1423-1429. [Abstract] [Free Full-text]

Marks, D., Thorogood, M., Neil, H.A. and Humphries, S.E. (2003) A review on the diagnosis, natural history, and treatment of familial hypercholesterolaemia. Atherosclerosis 168(1), 1-14. [Abstract]

MHRA (2009) Aspirin: not licensed for primary prevention of thrombotic vascular disease. Drug Safety Update 3(3), 10-11. [Free Full-text]

MHRA (2010) Simvastatin: increased risk of myopathy at high dose (80 mg). Drug Safety Update 3(10), 7-8. [Free Full-text]

Moruisi, K.G., Oosthuizen, W. and Opperman, A.M. (2006) Phytosterols/stanols lower cholesterol concentrations in familial hypercholesterolemic subjects: a systematic review with meta-analysis. Journal of the American College of Nutrition 25(1), 41-48. [Abstract]

National Collaborating Centre for Primary Care (2008a) Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease (full NICE guideline). . Clinical guideline 67. Royal College of General Practitioners. www.nice.org.uk [Free Full-text]

National Collaborating Centre for Primary Care (2008b) Identification and management of familial hypercholesterolaemia (FH) (full NICE guideline). . Clinical guideline 71. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

Neil, A., Cooper, J., Betteridge, J. et al. (2008) Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. European Heart Journal 29(21), 2625-2633. [Abstract] [Free Full-text]

NICE (2004) Hypertension: management of hypertension in adults in primary care (NICE guideline) [Replaced by clinical guideline 34]. . Clinical guideline 18. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2006) Hypertension: management of hypertension in adults in primary care (partial update of NICE clinical guideline 18) [Replaced by clinical guideline 127]. . Clinical guideline 34. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

NICE (2007) Ezetimibe for the treatment of primary (heterozygous-familial and non-familial) hypercholesterolaemia (NICE technology appraisal 132). National Institute for Health and Clinical Evidence. www.nice.org.uk [Free Full-text]

NICE (2008) Identification and management of familial hypercholesterolaemia. . NICE clinical guideline 71. National Institute for Health and Care Excellence. www.nice.org.uk [Free Full-text]

Nissen, S.E. (2009) Letter: analyses of cancer data from three ezetimibe trials. New England Journal of Medicine 360(1), 86-87.

NPC (2010) SEARCH finds simvastatin black triangle 80mg vs 20mg does not reduce vascular events. MeReC Rapid ReviewNational Prescribing Centre. www.npci.org.uk [Free Full-text]

Ogawa, H., Nakayama, M. and Morimoto, T. (2008) Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 300(18), 2134-2141. [Abstract] [Free Full-text]

Pedersen, T.R., Faergeman, O., Kastelein, J.J. et al. (2005) High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. Journal of the American Medical Association 294(19), 2437-2445. [Abstract] [Free Full-text]

Peto, R., Emberson, J., Landray, M. et al. (2008) Analyses of cancer data from three ezetimibe trials. New England Journal of Medicine 359(13), 1357-1366. [Abstract] [Free Full-text]

Poustie, V.J. and Rutherford, P. (2001) Dietary treatment for familial hypercholesterolaemia (Cochrane Review). The Cochrane Library. Issue 2. . www.thecochranelibrary.com [Free Full-text]

Rallidis, L., Naoumova, R.P., Thompson, G.R. and Nihoyannopoulos, P. (1998) Extent and severity of atherosclerotic involvement of the aortic valve and root in familial hypercholesterolaemia. Heart 80(6), 583-590. [Abstract] [Free Full-text]

Ridker, P.M., Cook, N.R., Lee, I.M. et al. (2005) A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. New England Journal of Medicine 352(13), 1293-1304. [Abstract] [Free Full-text]

Rossebo, A.B., Pedersen, T.R., Boman, K. et al. (2008) Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. New England Journal of Medicine 359(13), 1343-1356. [Abstract] [Free Full-text]

Scientific Steering Committee on behalf of the Simon Broome Register Group (1999) Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Atherosclerosis 142(1), 105-112. [Abstract]

SEARCH Collaborative Group (2010) Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin daily in 12 064 survivors of myocardial infarction: a double-blind randomised trial. Lancet 376(9753), 1658-1669. [Abstract] [Free Full-text]

SIGN (2007) Risk estimation and the prevention of cardiovascular disease: a national clinical guideline. Scottish Intercollegiate Guidelines Network. www.sign.ac.uk [Free Full-text]

Smilde, T.J., van Wissen, S., Wollersheim, H. et al. (2001) Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 357(9256), 577-581. [Abstract]

Thompsen, J. and Thompson, P.D. (2006) A systematic review of LDL apheresis in the treatment of cardiovascular disease. Atherosclerosis 189(1), 31-38. [Abstract]

Versmissen, J., Oosterveer, D.M., Yazdanpanah, M. et al. (2008) Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 337(), a2432. [Abstract] [Free Full-text]

Warrell, D.A., Cox, T.M. and Firth, J.D. (Eds.) (2003) Oxford textbook of medicine. Volume 2. 4th edn. New York: Oxford University Press.

WHO (1998) Familial hypercholesterolaemia (FH). Report of a second WHO consultation. World Health Organization. www.who.int

Wierzbicki, A., Humphries, S.E. and Minhas, R. (2008) Familial hypercholesterolaemia: summary of NICE guidance. BMJ 337(), a1304.

Winder, A.F, Jolleys, J.C., Day, L.B. and Butowski, P.F. (1998) Corneal arcus, case finding and definition of individual clinical risk in heterozygous familial hypercholesterolaemia. Clinical Genetics 54(6), 497-502. [Abstract]