ArticlesBlood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths
Introduction
The effects of other vascular risk factors—–particularly blood pressure—on the epidemiological associations of cholesterol with ischaemic heart disease (IHD) and stroke remain uncertain. Although blood levels of total cholesterol are used widely to predict IHD, the relative risk per unit change in cholesterol decreases with age1, 2 and, perhaps, blood pressure,3, 4 and it is unclear whether an importantly positive association persists into old age. Furthermore, total cholesterol consists largely of the cholesterol in low-density lipoprotein particles (LDL cholesterol) plus the cholesterol in high-density lipoprotein particles (HDL cholesterol), which have opposite associations with IHD risk. Results from randomised trials have shown that treatment with a statin, which lowers LDL cholesterol, substantially reduces the incidence of IHD.5 These trials have also shown a substantial reduction in the incidence of ischaemic stroke (without any apparent increase in haemorrhagic stroke).5 The definite reduction in total stroke in the statin trials contrasts strongly with the weakness of the epidemiological association between blood cholesterol and stroke,1, 6, 7, 8, 9, 10, 11, 12, 13 and that epidemiological association needs further exploration.
The results from retrospective epidemiological studies of IHD or stroke can be distorted by reverse causality (since vascular disease can itself directly or indirectly affect both blood cholesterol and blood pressure). In people with no previous history of vascular disease, however, prospective epidemiological studies have to be very large to assess reliably the extent to which one risk factor affects the relevance of another. The Prospective Studies Collaboration (PSC) has brought together evidence from many individual prospective studies of vascular mortality that recorded both blood pressure and total cholesterol at baseline, to undertake collaborative meta-analyses of the joint relevance of these two risk factors.
The present collaboration differs from previous meta-analyses in several ways that increase its reliability and precision: it is large, involving 55 262 vascular deaths in 892 337 apparently healthy adults in 61 cohorts (and, additionally, provides parallel analyses of the Multiple Risk Factor Intervention Trial [MRFIT] observational study that involve a further 34 242 vascular deaths); HDL cholesterol measurements at baseline are available for 153 798 of these participants, in whom there were 4966 vascular deaths (but, HDL cholesterol was not measured at baseline in MRFIT); and individual records are available for every participant in every study (except MRFIT), allowing detailed analyses of cause-specific mortality with respect to age, sex, blood pressure, and some other factors. Moreover, repeat measurements of HDL cholesterol in 40 313 participants allow quantitative correction for the regression dilution bias.14 Results for blood pressure have already been published,15 and the present report characterises, with greater precision and better control of some biases than has previously been possible, the age-specific relevance of total and HDL cholesterol to vascular mortality, and the extent to which this relation is modified by sex, blood pressure, and other risk factors.
Section snippets
Study design
Details of study selection, data collection, and statistical methods have all been described previously,15, 16 and are available in full in the webappendix (which includes webtables 1–6 and webfigures 1–11).
Cause-specific mortality was sought in the greatest detail available, using a three-digit International Classification of Diseases coding (ICD-6 to ICD-10), with vascular causes categorised as before15 (webtable 1). In most studies the cause of death was initially obtained from the death
Results
Individual records for all 892 337 eligible participants (without previous vascular disease recorded) in 61 studies were included in this meta-analysis: 70% from Europe, 20% from the USA or Australia, and 10% from Japan or China (webtable 5). During 11·6 million person-years at risk between the ages of 40 and 89 years (mean follow-up 13 [SD 6] years; mean time to death in those who died was 12 [7] years), there were 33 744 deaths attributed to IHD, 11 663 to stroke, and 9855 to other vascular
Discussion
This collaborative meta-analysis of almost 900 000 individuals in 61 prospective observational studies, with 55 000 vascular deaths during nearly 12 million person-years of follow-up, has characterised reliably the age-specific associations of total cholesterol with IHD, stroke, and other vascular mortality, and has assessed the quantitative and qualitative relevance of other risk factors to these associations. For IHD mortality, age and blood pressure substantially affected the strength of the
References (25)
- et al.
High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study
Lancet
(2001) - et al.
Low-density lipoprotein particle size, triglycerides, and high-density lipoprotein cholesterol as risk factors for coronary heart disease in older Japanese-American men
Am J Cardiol
(2000) - et al.
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial
Lancet
(2003) Cholesterol, coronary heart disease and stroke in the Asia Pacific region
Int J Epidemiol
(2003)- et al.
By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?
BMJ
(1994) Joint effects of systolic blood pressure and serum cholesterol on cardiovascular disease in the Asia Pacific region
Circulation
(2005)- et al.
Combined effects of systolic blood pressure and total cholesterol on cardiovascular disease risk
Circulation
(2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins
Lancet
(2005)Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in 450 000 people in 45 prospective cohorts
Lancet
(1995)- et al.
Lipids are risk factors for ischaemic stroke: overview and review
Cerebrovasc Dis
(1992)
Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial
N Engl J Med
Assessing possible hazards of reducing serum cholesterol
BMJ
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Collaborators listed in full at end of paper