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
• 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, 2008]. 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, 2008].
• 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].
• 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 Follow up in 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, 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].