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Hypercholesterolaemia - familial - Management
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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

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

These recommendations are in line with a guideline published by the National Institute for Health and Clinical 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].

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):
    • 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):
  • 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

These recommendations are in line with a guideline published by the National Institute for Health and Clinical 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, 2008].

Statin monotherapy

  • Statins compared to placebo
  • 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, 2008], 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, 2008].
    • 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

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, 2008].

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, 2008].
  • 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].

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

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

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

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

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

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

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 interventions 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

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 Clinical Excellence (NICE) guideline, Identification and management of familial hypercholesterolaemia [NICE, 2008]:

Dietary interventions

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.
Basis for recommendation

These recommendations are in line with a guideline published by the National Institute for Health and Clinical 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.

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

These recommendations are in line with a guideline published by the National Institute for Health and Clinical 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.

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