Abstract

Introduction

Familial hypercholesterolaemia is an autosomal dominant condition caused mainly by mutations of the low density lipoprotein receptor gene which result in substantially raised serum cholesterol concentrations.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 110000 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. When a mutation is known within a family an unequivocal diagnosis can be made by DNA testing at any age.¹² A mutation is detected in only half of clinically identified cases, probably because of technical insensitivity, clinical misdiagnosis, or causes of familial hypercholesterolaemia not related to the low density lipoprotein gene.¹³

One report on the cost effectiveness of screening for familial hypercholesterolaemia was published in 1993¹⁴ and updated in 1997.¹⁵ This reported US data and did not present costs and effectiveness separately so it is not possible to adapt the findings to the United Kingdom. We carried out a modelling exercise to determine the costs and benefits of different screening strategies in the United Kingdom.

Methods

We identified potential screening strategies in a systematic literature review¹⁶: 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. With the exception of screening 16 year olds, outcomes were modelled for each sex within 10 year age bands from 16 to 54 years because there are no clinical endpoint data to support the effectiveness of statin treatment at later ages.

We developed a hypothetical care pathway (figure). 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.¹⁷ 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 calculated the life years gained that were attributable to the use of statins by patients with familial hypercholesterolaemia as the life expectancy (expected age at death) with statin treatment minus the life expectancy in the absence of treatment for each age and sex group. 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. From 1992 treatment was mostly with statins; before 1992 treatment was with bile acid sequestrants.⁵ This cohort study was the only published report of the effect of statins on mortality in familial hyperlipidaemia that we identified. We used population mortality in the life tables for ages 60 years and over because the cohort in this age range was small.

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 (table ​(table1).1).

We calculated screening cost per case diagnosed as the screening cost per person invited multiplied by the number needed to screen. We calculated the cost per life year gained (C/LYG) as the screening cost per patient diagnosed (ScreenCost) plus the additional drug costs arising from the new diagnoses (StatinCost_Screen–StatinCost_NoScreen) plus the cost savings due to reduced incidence of coronary events (EventCost_Screen–EventCost_NoScreen) divided by the life years gained (LY_Screen–LY_NoScreen): C/LYG=(ScreenCost+ (StatinCost_Screen–StatinCost_NoScreen)+(EventCost_Screen–EventCost_NoScreen))/(LY_Screen–LY_NoScreen).

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 £1544.²⁵ 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% in accordance with Treasury and Department of Health guidelines.²⁶ We carried out sensitivity analyses by altering parameters in five areas to check the robustness of the model. Marks et al give further details of the modelling procedures and assumptions.¹⁶ The full HTA report can be found at www.hta.nhsweb.nhs.uk/fullmono/mon429.pdf.

Results

Cost effectiveness ratios

Table ​Table44 shows cost effectiveness of the screening strategies with clinical or genetic confirmation of diagnosis together with undiscounted rates and results for cost and effectiveness data discounted at 3% for comparison. 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). In addition, identification of relatives is the most cost effective for all age groups (£3097 to £4914 per life year gained).

Table 4

Comparison of overall cost per life year gained of different screening strategies using clinical or genetic confirmation of diagnosis

Strategy	Main results		Results with alternative discount rates
	Baseline discount rates (effectiveness 1%; costs 6%)		Undiscounted effectiveness	Costs and effectiveness discounted at 3%
Clinical
Universal (16 year olds)	£2777		£1798	£7 244
Universal	£13 029		£10 269	£21 289
Opportunistic (GP)*	£11 310		£8909	£18 578
Opportunistic (MI)†	£9281		£7513	£15 738
Family tracing	£3097		£2420	£6 084
Genetic
Universal (16 year olds)	£14 842		£9610	£33 882
Universal	£78 060		£61 661	£120 841
Opportunistic (GP)*	£70 009		£55 283	£108 578
Opportunistic (MI)†	£21 106		£17 116	£32 833
Family tracing	£4914‡		£3856	£8 865

Open in a separate window

^*Patients attending general practitioner. 

^†Patients hospitalised for myocardial infarction. 

^‡Including cost of finding mutation in proband. 

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 (table ​(table5).5). If the genetic mutation was known within the family then the cost per life year gained was only slightly increased by genetic diagnostic confirmation (table ​(table5).5).

Table 5

Life years gained and cost per life year gained for men and women at different ages using family tracing strategy with clinical or genetic confirmation of diagnosis

Age-sex group	Life years gained discounted at 1%	Cost per life year gained
Clinical confirmation (family tracing age 16-54 years)
Men:
16-24	5.0	£870
25-34	2.8	£1468
35-44	0.4	£8278
45-54	0.2	£11 344
Women:
16-24	5.9	£796
25-34	5.6	£766
35-44	5.5	£637
45-54	2.8	£838
All	3.5	£3097
Genetic confirmation (family tracing age 16-54 years, including cost of testing proband)
Men:
16-24	5.0	£1216
25-34	2.8	£2093
35-44	0.4	£12 298
45-54	0.2	£19 591
Women:
16-24	5.9	£1090
25-34	5.6	£1075
35-44	5.5	£953
45-54	2.8	£1470
All	3.5	£4914

Open in a separate window

Sensitivity analysis

In the analyses we altered the number of first degree relatives of the proband (which affects the cost effectiveness of a family tracing strategy—cascade screening); the proportion of identifiable mutations (which affects the cost of genetic confirmation of the diagnosis); drug costs (which are likely to decrease after the expiry of patents for some statins); attendance rates; discount rates for cost and effectiveness data; cost of a coronary event; and life years gained

The ranking of cost effectiveness between or within the strategies was not affected by any of the sensitivity analyses (table ​(table6).6). 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. This was particularly true of the family tracing strategy.

Table 6

Effect on estimates of cost effectiveness of changing paramaters used in model (sensitivity analysis)

	Universal (at 16 years old)	Universal	Opportunistic (GP)*	Opportunistic (MI)†	Case finding
Baseline cost per life year gained	£2777	£13 029	£11 310	£9281	£3097
Changed assumptions:
1.31 relatives per proband	No change	No change	No change	No change	£3113
5.75 relatives per proband	No change	No change	No change	No change	£3092
37% reduction in drug cost	£2451	£11 972	£10 352	£6344	£2040
73% reduction in drug cost	£2134	£10 944	£9419	£3787	£1011
80% attendance	£2651	£12 461	£10 919	£9338	£3102
50% attendance	£3499	£17 043	£14 441	£9683	£3128
CHD event cost reduced by 50%	£2797	£13 059	£11 338	£9321	£3126
CHD event cost increased by 50%	£2757	£13 000	£11 282	£9242	£3067
Life years gained decreased by 50%	£5555	£26 058	£22 621	£18 563	£6194
Life years gained increased by 50%	£1852	£8686	£7540	£6188	£2065
Genetic
Baseline cost per life year gained	£14 842	£78 060	£70 009	£21 106	£4914‡
30% identified mutations	£24 142	£128 128	£114 894	£29 670	£5990‡
70% identified mutations	£10 856	£56 602	£50 772	£17 448	£4453‡
50% reduction in cost of genetic testing	£9753	£50 580	£44 975	£15 682	£4065‡

Open in a separate window

CHD=coronary heart disease. 

^*Patients attending general practitioners. 

^†Patients hospitalised for myocardial infarction. 

^‡Including cost of testing proband. 

Discussion

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.²⁷ 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,²⁸ and the success of a programme based on genetic testing in the Netherlands has recently been reported.²⁹ 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 interventions³⁰ and suggests that pilot evaluation programmes should be conducted.

Screening of patients admitted to hospital with premature myocardial infarction may be worth considering but costs three times more per life year gained compared with family tracing though it ensures complete coverage. Universal screening restricted to 16 year olds and with clinical methods of diagnosis was even more cost effective than family tracing. However, we assumed that 55% of 16 year olds would attend screening and that most of those diagnosed would adhere to statin treatment over many years. Neither of these assumptions can be currently validated and the ethical acceptability of such a strategy is unclear. Such a strategy would also, by definition, exclude the possibility of diagnosis for all those aged over 16 years and hence its full benefits in reducing population mortality from familial hypercholesterolaemia would not be seen for many years.

Supplementary Material

Footnotes

References