Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management
Introduction
Heterozygous familial hypercholesterolaemia is an autosomal dominant disorder of lipoprotein metabolism characterised by mutations of the low density lipoprotein receptor resulting in an accumulation of low density lipoprotein cholesterol in the plasma and a substantial excess mortality from coronary heart disease [1]. Although the heterozygous condition affects about 1 in 500 of the UK population [1], there are few published data about the risks of coronary heart disease in treated heterozygous patients and it would no longer be ethical to conduct placebo controlled trials to obtain more information. Clinical management, therefore, is largely based on evidence from a small number of observational studies and extrapolation from the results of clinical trials of lipid-lowering conducted in patients with polygenic hypercholesterolaemia.
In a preliminary analysis of the mortality experience of a cohort of treated heterozygous patients, we found the relative risk of fatal coronary heart disease to be increased nearly 100-fold in young adults aged 20–39 years, although patients who survived through middle age appeared no longer to be at a substantially increased relative risk [2]. This early report was, however, based on only three fatal coronary events in patients aged 20–39 years and needs to be confirmed. Since our initial analysis in 1990, drug treatment of familial hypercholesterolaemia has changed substantially with the introduction of the HMG CoA (hydroxymethylglutaryl co-enzyme A) reductase inhibitors or statins. These have been shown to reduce mortality in clinical trials of both primary and secondary prevention of coronary heart disease [3], [4], and would be expected to have improved the prognosis in familial hypercholesteroloaemia. There remains, however, some concern that lipid-lowering drug therapy may increase non-coronary mortality [5].
Clinical guidelines for the management of hyperlipidaemia have also changed since 1990 and the importance of information about the absolute benefits and risks of treatments for clinical decision taking is being increasingly emphasised [6]. Nevertheless, recently published tables to identify patients at sufficiently high coronary risk to benefit by treatment with a statin specifically exclude patients with genetically determined lipid disorders [7] because the prediction equations on which these tables are based have not been shown to be valid for familial hypercholesterolaemia [8]. In this paper we report the absolute and relative mortality from all causes, non-coronary causes and coronary heart disease in our enlarged cohort of 1185 men and women with treated heterozygous familial hypercholesterolaemia now followed prospectively for up to 16 years. We also examine the mortality before and after the widespread use of statins and consider the implications for management.
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Patients and methods
The methods have been described in detail previously [2]. Recruitment of patients to the Simon Broome Familial Hyperlipidaemia Register began in 1980 and continues. The 21 participating clinics registered patients referred to them by either general practitioners or hospital specialists. This report is restricted to 1185 patients meeting the diagnostic criteria of the register for definite familial hypercholesterolaemia. This was defined as a total cholesterol concentration, either before
Registration and follow-up
The demographic and clinical characteristics of patients, including the presence of tendon xanthomas, were recorded on a standard registration form. A fasting venous blood sample was taken at the registration visit and total cholesterol, serum triglycerides, and high density lipoprotein cholesterol were measured by the laboratories routinely used by the participating clinics. Serum low density lipoprotein concentrations were calculated using the Friedewald formula [9]. The names of registered
Statistical methods
The analysis was undertaken using a computer programme for cohort studies [10] that applies standard methods [11]. Person-years at risk were accumulated within 5-year age groups and 5-year calendar periods to estimate the expected numbers of deaths from specified causes. Seven subjects were censored on reaching the age of 80 years, and five patients who had emigrated were censored at the date of embarkation. The expected number of deaths from coronary heart disease (ICD codes 410-414);
Results
A total of 1190 patients with definite familial hypercholesterolaemia were registered between 1 January 1980 and 31 December 1995. Five patients whose vital status was unknown were excluded from the analysis. The resulting cohort of 1185 patients (605 men) has been followed for 8770 person years with a median duration of follow-up of 7.8 years for men and 6.9 years for women. At registration the median age was 40.3 years for men and 43.9 years for women. At their most recent clinic visit,
Discussion
Our results are based on the largest published cohort of patients with heterozygous familial hypercholesterolaemia. They extend and confirm our earlier preliminary report [2] of a nearly 100-fold increase in relative risk for fatal coronary heart disease in young adults aged 20–39 years, although patients who survived through middle age were no longer at a substantially increased relative risk. These observations are now derived from a four-fold greater period of exposure and a three-fold
Implications for clinical management
The results have a number of implications for the management of adults with heterozygous familial hypercholesterolaemia. There was an appreciable excess coronary mortality despite treatment and, unlike polygenic hypercholesterolaemia, the high absolute risk was not restricted to older patients. Consequently the cumulative risk of a coronary event by the age of 60 years without effective treatment is at least 50% in men and ∼30% in women [31], [32], with a marked increase occurring
Acknowledgements
Funding: British Heart Foundation grant RG 93008, British Hyperlipidaemia Association, Simon Broome Heart Research Trust, and Parke Davis and Company. Conflicts of interest: none. Members of the Scientific Steering Committee of the Simon Broome Register Group: D.J. Betteridge, K. Broome, P.N. Durrington, M.M. Hawkins, S.E. Humphries, J.I. Mann, J.P. Miller, H.A.W. Neil, G.R. Thompson, M. Thorogood. Writing Committee: H.A.W. Neil, M.M. Hawkins, M. Potok, F. Mathews. Participating physicians and
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