Introduction

Top Abstract Introduction Methods Results Discussion References

Familial hypercholesterolaemia is an autosomal dominant condition caused mainly by mutations of the low density lipoprotein receptor gene.¹ Men with this condition have over a 50% risk of coronary heart disease by the age of 50 years. For women the risk is at least 30% at 60 years. ^{2 3} About 110 000 people in the United Kingdom are thought to be affected, and at least 75% of them are undiagnosed.⁴ Treatment with hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is effective ^{5 6} and delays or prevents the onset of coronary heart disease.^7-10 Effective primary prevention, however, requires early diagnosis.

A diagnosis of familial hypercholesterolaemia is made on the basis of the plasma total and low density lipoprotein cholesterol concentrations combined with either a clinical examination and family history¹¹ or a genetic test.

We carried out a modelling exercise to determine the costs and benefits of different screening strategies in the United Kingdom.

	Methods

Top Abstract Introduction Methods Results Discussion References

We identified potential screening strategies in a systematic literature review¹²: universal population screening; opportunistic screening of patients consulting for unrelated reasons in primary care; opportunistic screening of patients admitted to hospital with premature myocardial infarction; and systematic screening of first degree relatives of people with diagnosed familial hypercholesterolaemia. We added to these the option of screening all young people aged 16 years.

We developed a hypothetical care pathway. In the universal and opportunistic strategies, people with a non-fasting total cholesterol concentration above the population 95th centile are invited for a fasting blood test. Those with a confirmed fasting total cholesterol concentration above 7.5 mmol/l and low density lipoprotein cholesterol above 4.9 mmol/l are referred for diagnostic confirmation by clinical examination with a lipid clinic consultant or by genetic testing on blood or buccal cells. For the family tracing strategy, a lipid clinic nurse approaches existing patients, collects family histories, and asks permission to approach relatives.¹³ For each strategy we used a combination of decision analysis and life table analysis to estimate life years gained per case diagnosed as a result of screening and subsequent treatment with statins; number needed to screen, defined as the number of people who must be invited for screening for one case to be identified; cost of screening per case diagnosed; and cost effectiveness in terms of the cost per life year gained.

We constructed life expectancy tables using mortality data from a UK cohort of 1185 patients with heterozygous familial hypercholesterolaemia who have been followed prospectively since 1980. We used population mortality in the life tables for ages 60 years and over.

We calculated the number needed to screen and the screening cost per person invited using a decision analytic model. Unit cost data (including laboratory costs, staff time, letters, and overheads) and probabilities (including attendance rates and prevalence of familial hypercholesterolaemia) were taken from published sources where available.

We estimated the annual cost of treatment to be £411 (672, $594) with a treatment regimen of statin therapy (70% simvastatin 40 mg daily and 30% atorvastatin 20 mg daily, based on data from a specialist lipid clinic) and an annual general practitioner appointment until the age of 60 years. We calculated drug costs after allowing for an 18% rate of non-adherence to treatment. The cost of a coronary event was taken as £1544.¹⁴ We calculated the lifetime cost of drug and event treatment using the life tables.

We discounted life expectancy and life years gained at 1% and costs at 6%.¹⁵ We carried out sensitivity analyses by altering parameters in five areas to check the robustness of the model. Further details are given on bmj.com and in the full health technology report¹² (see also www.hta.nhsweb.nhs.uk/fullmono/mon429.pdf).

	Results

Top Abstract Introduction Methods Results Discussion References

Increase in life expectancy
The gain in life years was highest when treatment was started earliest (7.0 years in men and 9.1 years in women aged 16-24 years) and decreased with increasing age (0.3 and 3.4 years at age 45-54 years) (table 1).

Number needed to screen
The number needed to be invited for screening to result in the identification of one person with familial hypercholesterolaemia is determined by the prevalence of familial hypercholesterolaemia, the attendance rate in the care pathway, and by whether a clinical or genetic confirmation of diagnosis is made (table 2). A genetic confirmation of diagnosis requires greater numbers because currently a mutation is detected in only half of clinically diagnosed cases.¹⁶ The number varied from 2292 people in the general population (confirmed by genetic screening) to 2.6 people in first degree relatives of identified cases (with clinical confirmation).

Cost per case detected
More targeted strategies are more expensive but fewer people need be invited to find one case. Costs per case detected ranged from £133 for a clinically diagnosed relative (family tracing) to £9645 in a population wide strategy (clinically confirmed) (table 2).

Cost effectiveness ratios
The earlier a diagnosis of familial hypercholesterolaemia is made the more cost effective the screening strategy becomes (£2777 per life year gained for 16 year olds) (table 3). In addition, identification of relatives is the most cost effective for all age groups (£3097 to £4914 per life year gained).

Screening women was more cost effective than screening men because women gained more life years after treatment. Within each strategy it was more cost effective to screen younger men and women, although this trend was less pronounced in women. There was a 10-fold increase in the cost per life year gained between the oldest and the youngest age group in the family tracing strategy. If the genetic mutation was known within the family then the cost per life year gained was only slightly increased by genetic diagnostic confirmation.

Sensitivity analysis
The ranking of cost effectiveness between or within the strategies was not affected by any of the sensitivity analyses (see bmj.com). When we modelled lower drug costs the cost effectiveness ratio improved most in those strategies where the drug costs were a larger proportion of the overall costs.

	Discussion

Top Abstract Introduction Methods Results Discussion References

This modelling exercise identified screening of relatives of people with familial hypercholesterolaemia as the most cost effective way of detecting cases across the whole population. Familial hypercholesterolaemia fulfils the World Health Organization criteria for screening programmes.¹⁷ Clinical endpoint trials of lipid lowering drug treatment with statins have shown their effectiveness in the primary and secondary prevention of coronary heart disease risk,^7-10 especially in the groups at highest risk, although there are no trials specifically in patients with familial hypercholesterolaemia. Family tracing in a pilot study in the United Kingdom was acceptable and feasible,¹⁸ and the success of a programme based on genetic testing in the Netherlands has recently been reported.¹⁹ We estimated the cost effectiveness of family tracing to be £3097 per life year gained (or £4914 with genetic confirmation). This represents good value for money compared with common medical interventions²⁰ and suggests that pilot evaluation programmes should be conducted.

Accuracy of estimates
The estimates of life expectancy of people with familial hypercholesterolaemia were based on a UK familial hypercholesterolaemia register. ^{5 11} This may underestimate the true benefit of statins, which have been widely available for just over 10 years. Earlier identification and longer treatment are likely to give greater benefit. On the other hand, the register data may overestimate the gain in life expectancy because our model used mortality data before and after the introduction and widespread use of statins to estimate life years gained but did not take account of the underlying population trend of decreasing mortality. In addition, it is possible that clinics contributing to the register provided closer medical supervision and more aggressive statin treatment than elsewhere. As people with familial hypercholesterolaemia aged over 60 years in the Simon Broome cohort had a similar mortality and longevity to the general population neither the costs nor benefits of treatment were estimated beyond that age.⁵ Nevertheless, we advocate continuing treatment at this age.

Awareness by general practitioners, accident and emergency staff, cardiology teams, and the general public of the signs of familial hypercholesterolaemia and the benefits of early treatment is important, and extra training would be needed. All screening strategies will become cheaper (and therefore more cost effective) as drug costs fall, which can be expected as the patents for some statins expire. The generic equivalent of a preparation can be between one third to two thirds of the cost of the proprietary product. As the technology improves (especially DNA diagnostic techniques) the cost effectiveness of all strategies will benefit.