Non-coronary heart disease mortality and risk of fatal cancer in patients with treated heterozygous familial hypercholesterolaemia: a prospective registry study
Introduction
Familial hypercholesterolaemia is an autosomal co-dominant disorder with an estimated frequency of 1 in 500 of the population. Most cases are caused by mutations of the low-density lipoprotein-receptor, more than 800 of which have been reported [1]. These result in accumulation of low-density lipoprotein (LDL) cholesterol in the plasma from birth [2] and subsequent development of tendon xanthoma, xanthelasma and atheroma [2], [3], [4]. In the heterozygous condition, the cumulative risk of a coronary event by the age of 60 years without effective treatment is at least 50% in men and about 30% in women [5], [6] with coronary disease occurring earlier in men than women [3], [4], [5], [6], [7]. The prognosis has, however, improved substantially since the introduction and widespread use of both HMG Co-A reductase inhibitors (statins) [4]. It has also been suggested that mortality from causes other than cardiovascular disease is lower amongst statin-treated familial hypercholesterolaemic patients than for the general population [8], although this was based on too few person-years observation to achieve statistical significance.
We report the risk of all-cause, non-coronary and cancer mortality in a large cohort of 2871 patients with heterozygous familial hypercholesterolaemia given lifestyle advice, and treated with lipid-lowering drug therapy followed prospectively for up to 18 years.
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Patients and methods
The methods [3] and diagnostic criteria [4] have been described previously. Patients were registered by 21 participating clinics with the Simon Broome Hyperlipidaemia Register and were flagged by the National Health Service Central Register. A diagnosis of definite FH was made if (a) total cholesterol concentration (either pre-treatment or highest on treatment) in adults over 16 years was above 7.5 mmol/l or the LDL-cholesterol concentration was above 4.9 mmol/l, plus (b) either tendon xanthomas
Registration and follow-up
The demographic and clinical characteristics of patients were recorded on a standard registration form [3]. A fasting venous blood specimen was taken at the registration visit and serum total cholesterol, triglycerides and high-density lipoprotein were measured by the laboratories routinely used by the participating clinics and low-density lipoprotein concentrations were calculated using the Friedewald formula [10]. The names of registered patients were flagged by the National Health Service
Statistical methods
The expected number of deaths from coronary heart disease (CHD) (ICD codes 4100–4149); stroke (4300–4389); non-coronary causes (10-4099 and 415-9999); cancers (1400–2089); accidents and violence (8000–9999); and total mortality was calculated by applying 5-year age and calendar-period specific mortality rates for men and women in the general population of England and Wales to the person-years accumulated by men and women in the cohort. Subjects were censored on embarkation or on reaching 80
Results
After excluding 22 (0.8%) patients whose vital status was unknown, the cohort consisted of 1569 patients with definite and 1302 patients with possible familial hypercholesterolaemia registered between 1 January 1980 and 31 December1998 [11]. Five of these subjects were subsequently censored on embarkation. The cohort was followed up for 22,992 person-years with a median duration of follow-up of 7.9 years (inter-quartile range 4.9, 12.0). Table 1 shows the clinical characteristics of patients at
Discussion
The principal finding of this long-term prospective cohort study of patients with familial hypercholesterolaemia was that, although coronary mortality remained elevated with statin treatment, all-cause mortality after 1991 did not differ from that of the general population. This was due mainly to an unanticipated 50% decrease in the risk of fatal cancer. The reduction in cancer mortality can reasonably be interpreted as being attributable to the effects of giving lifestyle advice as part of
Acknowledgements
The Simon Broome FH register is currently supported by an unrestricted educational grant from Astra Zeneca, and has also received support previously from Pfizer Ltd. and Schering-Plough Ltd. HAWN and SEH would like to acknowledge Grants RG93008 and PG2000015 from the British Heart Foundation. The sponsors had no involvement in any aspect of the study or publication.
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Members of Scientific Steering Committee: D.J. Betteridge, N.E. Capps (Chairman), P.N. Durrington, S.E. Humphries, J.I. Mann, R.P Naoumova, H.A.W. Neil, M. Seed (Honorary Secretary). Participating physicians and clinics: K. Arnsten, S. Flemming (Royal Cornwall Hospital, Truro), D.J. Betteridge (University College Hospital, London), P.N. Durrington (Manchester Royal Infirmary), R.S. Elkeles (St. Mary's Hospital, London), R.M. Finnie (St. John's Hospital, Livingston), D.J. Galton (St Bartholomew's Hospital, London), R. Hillson (Hillingdon Hospital, Uxbridge and Mount Vernon Hospital, Northwood), E.A. Hughes (Sandwell District Hospital, West Bromwich), M.F. Laker (Royal Victoria Infirmary, Newcastle-Upon-Tyne), B. Lewis, A.S. Wierzbicki (St. Thomas's Hospital, London), R. Lorimer (Glasgow Royal Infirmary), J.I. Mann (John Radcliffe Hospital, Oxford), D.R. Matthews, H.A.W. Neil (Radcliffe Infirmary, Oxford), J.P. Miller (University Hospital of South Manchester), J.P.D. Reckless (Royal United Hospital, Bath), L.N. Sandle (Trafford General Hospital, Manchester), M.Seed (Charing Cross Hospital, London, and King Edward VII Hospital), K.G. Taylor (City Hospital, Birmingham), G.R. Thompson, R.P. Naoumova (Hammersmith Hospital, London), R. West (St. George's Hospital, London).