4 Research recommendations

The Guideline Development Group has made the following recommendations for research, based on its review of evidence, to improve NICE guidance and patient care in the future. The Guideline Development Group's full set of research recommendations is detailed in the full guideline (see section 5).

4.1 Identification using clinical registers

What is the clinical and cost effectiveness of identifying a person with FH (defined by DNA testing) from GP registers and from secondary care registers?

Why this is important

Research is needed to compare the utility of strategies other than cascade screening to identify new index cases, because currently recommended strategies are likely to lead to the identification of less than 50% of the expected number of people with FH in the UK.

These additional strategies should evaluate note searching in general practice and from secondary care coronary heart disease registers (for example, MINAP), using a 'reference standard' of known FH-causing mutations. This will require the development of different algorithms for patient identification in primary and secondary care. These algorithms should be based on the UK FH diagnostic criteria and a combination of different cut-off points for untreated raised total or LDL-C concentration, age of onset of heart disease in the index case, age of onset of heart disease in first-degree relatives, and other factors.

4.2 Lipid-modifying drug therapy in children

What is the clinical effectiveness and safety of differing doses of lipid-modifying therapy in children with FH?

Why this is important

There have been no published studies to establish target serum LDL-C concentration in treated children with FH receiving lipid-modifying drug therapy. Treatment is recommended from 10 years onwards, however this lack of data prevents a recommendation regarding the aim of pharmacological treatment on serum LDL-C concentrations.

Research (both cross-sectional and longitudinal) should assess the evidence of end-organ involvement (for example, carotid intima medial thickness [IMT]) to determine at which age abnormalities can first be seen in children. The aim would be to identify a threshold effect, with an LDL-C concentration below which carotid IMT is normal and where thickening is absent, and above which it is abnormal and where thickening is observed. Outcomes should include fasting serum total and LDL-C concentration, carotid artery IMT, and growth and pubertal development.

4.3 LDL apheresis for people with heterozygous FH

What are the appropriate indications, effectiveness and safety of LDL apheresis in people with heterozygous FH?

Why this is important

There is limited evidence to inform specific indications for LDL apheresis in people with heterozygous FH. In addition, there is limited published evidence on the cardiovascular outcome of such patients treated with LDL apheresis.

Evidence on the value of investigations (various measures of vascular status, considered to reflect the extent or activity of atherosclerotic vascular disease of the coronary arteries) in predicting outcome from LDL apheresis should ideally be based on evidence from randomised controlled trials with clinical outcomes. It is difficult to identify a suitable alternative treatment because LDL apheresis is generally only considered in people for whom no other treatment is available. One comparator may be novel therapies with antisense oligonucleotides (ApoB).

A national register should be established for all people with FH who are referred for and/or are undergoing LDL apheresis. Data should be collected on the natural history of FH and the temporal relationship of clinical and vascular features in relation to treatments and other parameters.

4.4 Pregnancy in women with FH

What are the implications of FH for the safety of a mother during pregnancy and what are the risks of fetal malformations attributable to pharmacological therapies?

Why this is important

There is little information on the outcomes of pregnancy in women with FH. A small number of conflicting studies have suggested a small increase in fetal abnormalities if the mother has taken statins during the first trimester, but there are not sufficient data to provide an accurate estimate of the level of risk. There is also limited information on the risk of pregnancy (including cardiac death) in a woman with FH.

Data on the incidence of cardiac problems in pregnancy and incidence of fetal malformation would inform future recommendations. This could reduce uncertainty for women, and help to identify risks during the pregnancy that could be better managed. The only feasible research method to address these questions is an observational longitudinal study following women with FH and other women (not diagnosed with FH) using statins through their pregnancies using a national register.

4.5 Cardiovascular evaluation for people with FH

What is the utility of routine cardiovascular evaluation for asymptomatic people with FH?

Why this is important

Because of their inherent high risk of developing premature coronary heart disease, a low threshold of suspicion for coronary disease is recommended for people with FH. Routine monitoring to detect sub-clinical atherosclerosis should be non-invasive, sensitive, specific and cost effective. Research to assess the prevalence of both asymptomatic coronary and non-coronary atherosclerosis in people with definite heterozygous FH is required.

As well as exercise ECG testing followed by stress echocardiography before possible angiography in people with an abnormal exercise test and ankle brachial pressure measures, research should include magnetic resonance imaging (MRI) in addition to other modalities such as carotid IMT and coronary calcification. Outcomes should include changes in exercise ECG/ankle brachial pressure testing/IMT/calcification over time.

Consideration should also be given to the feasibility of conducting a long-term randomised trial to compare the differences in morbidity or mortality attributable to early diagnosis using routine monitoring or symptom-based investigation.

  • National Institute for Health and Care Excellence (NICE)