Correspondence: Dr Anushka Patel, Asia-Pacific Cohort Studies Collaboration Secretariat, Institute for International Health, University of Sydney, PO Box 576, 144 Burren Street, Newtown NSW 2042, Australia. E-mail: apatel{at}iih.usyd.edu.au
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Abstract |
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Methods The Asia Pacific Cohort Studies Collaboration (APCSC) is an individual-participant data meta-analysis of prospective studies from the Asia-Pacific region. Cox models were applied to the combined data from 29 cohorts to estimate the region-, sex-, and age-specific hazard ratios of major cardiovascular diseases by the fifths of total cholesterol.
Results At baseline, the age/sex-adjusted mean value of total cholesterol was higher in Australia and New Zealand (ANZ) (5.52 ± 1.05 mmol/l) than in Asia (4.87 ± 1.05 mmol/l). During 2 million person-years of follow-up among 352 033 individuals, 4841 cardiovascular deaths were recorded. The association of total cholesterol with coronary heart disease and stroke was similar in Asian and ANZ cohorts. Overall, each 1-mmol/l higher level of total cholesterol was associated with 35% (95% CI: 2644%) increased risk of coronary death, 25% (95% CI: 1340%) increased risk of fatal or non-fatal ischaemic stroke, and 20% (95% CI: 830%) decreased risk of fatal haemorrhagic stroke.
Conclusions In both Asian and non-Asian populations in the Asia-Pacific region, total cholesterol is similarly strongly associated with the risk of CHD and ischaemic, but not haemorrhagic, stroke. Rising population-wide levels of cholesterol would be expected to contribute to a substantial increase in the overall burden of cardiovascular diseases in this region.
Accepted 17 January 2003
Data from observational studies16 and clinical trials of lipid-lowering therapy710 have provided reliable evidence regarding the importance of serum cholesterol level as a determinant of coronary heart disease (CHD) risk in mainly Caucasian populations from Europe, North America, Australia, or New Zealand. This has resulted in widespread efforts to reduce population levels of cholesterol, as well as to treat individuals at high risk of CHD with lipid-lowering drugs. The associations between cholesterol level and the risk of stroke are less clear; in particular, concerns remain regarding a possible inverse association between cholesterol levels and the risk of intracerebral haemorrhage.1113
The Asia-Pacific region currently accounts for approximately half the global burden of cardiovascular diseases, and future projections suggest this proportion will increase.14,15 Particularly in Eastern Asia, cholesterol levels and the incidence of CHD are lower than in most Caucasian populations, while the incidence of stroke is higher, and includes a greater proportion of haemorrhagic stroke.1619 However, there are data which indicate that population-wide levels of adverse risk factors, including cholesterol, are rising substantially in many countries in Asia.20,21 To date, predictions on future disease burden as a consequence of this have relied on knowledge of the associations between risk factors and atherothrombotic diseases in Western populations. Very few such data are available from Asia, and precise population-specific estimates of the nature and magnitude of the associations between risk factors and cardiovascular diseases in the region are lacking.
The Asia Pacific Cohort Studies Collaboration (APCSC) is an individual-participant data overview of prospective cohort studies conducted in a number of Asian countries, Australia, and New Zealand. With several thousand events recorded, the Collaboration provides a unique opportunity to produce reliable evidence regarding the nature and size of the associations between risk factors and cardiovascular diseases, and to compare these associations between Asian and non-Asian populations. In this report, we describe the results relating to total cholesterol, and estimate the likely effects of rising population-wide levels of cholesterol on the burden of CHD and stroke in this region.
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Methods |
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Measurement of baseline variables
Total cholesterol was measured at baseline in 25 of the 37 studies included in the APCSC database at the end of 2001. Of these studies, seven (five in Asia and two in ANZ) also obtained repeat cholesterol measurements on up to seven occasions. Cholesterol measurements were determined using serum samples, and these were obtained while fasting in approximately 93% of participants. As these studies were initiated over a long period of time (19661994), the methods and instruments used for measuring cholesterol varied. Information regarding method of cholesterol analysis was available from 15 studies comprising 68% of all participants; amongst these, 96% of cholesterol levels were determined using enzymatic methods. In each study, age, sex, and blood pressure at baseline were recorded. Wherever available, baseline body mass index (BMI), smoking status, alcohol consumption, and the presence or absence of diabetes were also recorded.
Outcomes
All studies reported deaths by underlying cause; a subset of studies also reported non-fatal cardiovascular disease events. Outcomes were classified according to the Ninth Revision of the International Classification of Diseases (ICD-9). The fatal outcomes considered in this analysis were: CHD (ICD-9: 410414); total stroke (430438); haemorrhagic stroke (431.0432.9); and ischaemic stroke (433.0434.9). Two composite outcomes were also considered: death due to CHD or non-fatal myocardial infarction (MI), and fatal or non-fatal stroke. Since most studies used record linkage with official sources, verification of strokes was not routinely reported. However, 9 of the 25 studies included in this analysis provided information on stroke verification; in these 9 studies, stroke sub-type was determined on the basis of imaging, lumbar puncture or autopsy in 515 of 606 cases (85%).
Statistical methods
All analyses used individual-participant data, and were restricted to individuals aged 20 years at the time of the baseline survey. To assess the association of usual cholesterol level with the outcomes of interest, baseline cholesterol measurements were adjusted to account for regression dilution bias.23,24 Repeat measurements of cholesterol were obtained from approximately 7% of participants between 1 and 18 years following the baseline measurement. These repeat measures were used to estimate regression dilution attenuation coefficients, using a linear mixed regression model that accounted for the heterogeneity of variance between studies, within-subject correlation, and the varying time intervals between measurements. The attenuation coefficients derived by this method were similar for men and women, and between age groups, but differed significantly between regions. Thus, region-specific attenuation coefficients24 were used for all separate analyses in Asian (2.30) and in ANZ (1.60) populations, while the overall population coefficient (1.70) was used for all other analyses.
For grouped analyses, individuals were classified according to approximately equal fifths of baseline cholesterol for the entire study population (4.1, 4.24.6, 4.75.1, 5.25.8, and
5.9 mmol/l). Trends in mean values of other major continuous cardiovascular risk factors across these fifths were assessed through simple linear regression, coding the groups in rank order. Trends in percentages for binary risk factors were assessed similarly using
2 tests for trend.25 Cox proportional hazards regression models were used to estimate hazard ratios (HR), with corresponding 95% CI calculated using the floating absolute risk method in order to provide a CI for the reference group.26 Log-linearity of cholesterol associations was explored through the analysis of fifths of cholesterol, and summarized through the HR and 95% CI for a 1-mmol/l increase in usual cholesterol.
All analyses reported here were stratified by study and sex, and adjusted for time-dependent age at risk, systolic blood pressure, and smoking status. For the subset of participants in whom baseline data on diabetes status, alcohol consumption, and BMI were available, further adjustment was made for these variables. However, these additional adjustments had very little effect and so are not reported here.
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Discussion |
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Aside from providing unique data involving Asian cohorts, the APCSC has many other advantages. The combination of data from numerous cohorts results in a large number of events, thus providing precise estimates of association. The use of individual-participant data and the availability of repeat cholesterol measures in a number of cohorts also provides the opportunity to limit systematic error due to regression dilution bias. We found that the use of population-specific attenuation factors to correct the effects of regression dilution bias had a substantial effect on our estimates of association, while adjustment for major confounding variables had relatively little effect. The calculated attenuation factor for Asia was higher than that for ANZ; this probably reflects greater variation in measurement error in determining cholesterol levels in Asia. Another important potential for bias resides in misclassification of events, particularly with respect to stroke subtype. Reliable verification of subtype requires imaging or autopsy data, and while it is likely that such information formed the basis of most reporting, this could not always be confirmed.
Numerous other observational studies, particularly in men, have demonstrated a strong, continuous, graded, and independent association between cholesterol and the risk of CHD.16 The current data clearly extend these findings to Asian populations with substantially lower average levels of cholesterol, and confirm that effects are similar in men and women.
Unlike CHD, the relationship between cholesterol level and the risk of stroke is complex. The APCSC data suggest that the lack of association between cholesterol and the overall risk of fatal stroke is due to a positive association between cholesterol and ischaemic stroke, partially counter-balanced by a weaker negative association between cholesterol and haemorrhagic stroke. The association with ischaemic stroke appears stronger and more conclusive; the lack of association for the endpoint of fatal stroke is likely explained by a higher case-fatality rate associated with haemorrhagic stroke,27 and thus disproportionate representation of this stroke sub-type among fatal outcomes. This is consistent with the finding of a positive association between cholesterol and total stroke risk when both fatal and non-fatal events are considered. Furthermore, the 1.5:1.0 ratio of non-fatal to fatal stroke observed in the current analysis (based only on those cohorts that reported both fatal and non-fatal outcomes) is somewhat lower than that expected from surveillance data.28 This is consistent with underreporting of non-fatal events (which are more likely to be ischaemic), and may have resulted in underestimation of the true association between cholesterol and total stroke. Again, we did not find any clear evidence of regional differences in any of these associations.
Other observational data have variably demonstrated a weak positive or a lack of any association between cholesterol levels and the risk of stroke.12,13,2936 However, most studies were conducted in Caucasian populations at relatively low risk of stroke, and thus with limited power to detect moderate yet meaningful associations, and many failed to examine associations with stroke sub-types. Some studies have reported clear evidence of a positive log-linear association between cholesterol and the risk of cerebral infarction,12 while others suggest that the excess risk is confined to those individuals with the highest cholesterol levels, generally within the top 5% of the distribution.3335 An association between lower cholesterol and an increased risk of haemorrhagic stroke has also been reported elsewhere,12,13,30,34,37,38 although not consistently so.39 While the current analysis provides some evidence in support of such an inverse association, the results indicate that the association is comparatively weak, and that the excess risk of haemorrhagic stroke appears mostly confined to individuals with the lowest cholesterol levels.
The difference in average baseline cholesterol level between ANZ and Asian cohorts in the APCSC was approximately 0.7 mmol/l. While it is important to recognize that these cohorts are not necessarily representative samples of the populations from which they were drawn, this average cholesterol difference is consistent with data from published cross-sectional surveys.4042 The current data suggest that a 0.7-mmol/l increase in average cholesterol levels in the Asian populations represented in APCSC could result in an approximate 2530% increase in the incidence of CHD, and a 1520% increase in the incidence of ischaemic stroke, which would not be counter-balanced by a possible 1015% decrease in the incidence of haemorrhagic stroke. Such predictions are based on changes in cholesterol levels only, and do not account for the influence of likely changes in the levels of other cardiovascular risk factors. Furthermore, as well as increasing the overall mortality due to CHD and stroke, rising population levels of cholesterol would be expected to result in a far greater burden of stroke-related disability. This is especially true since ischaemic stroke, which is expected to increase both in absolute numbers and relative to haemorrhagic stroke, has a comparatively lower case-fatality rate.
In summary, this study provides reliable data that indicate adverse changes in population-wide levels of cholesterol in many parts of Asia are likely to result in substantial increases in the incidence of atherothrombotic vascular diseases. The effects are likely to be similar to those observed during the epidemic of cardiovascular diseases observed in most Western countries several decades ago, with the potential to adversely influence the health of a large proportion of the global population. Action to arrest further increases, or preferably to reduce, cholesterol levels in the Asia-Pacific region is vital.
KEY MESSAGES
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References |
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