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(Circulation. 2005;112:3384-3390.)
© 2005 American Heart Association, Inc.
Epidemiology |
Correspondence to Dr Anthony Rodgers MBChB, PhD, FAFPHM, Clinical Trials Research Unit, Private Bag 92019, Auckland, New Zealand. E-mail a.rodgers{at}ctru.auckland.ac.nz
Received January 20, 2005; revision received July 31, 2005; accepted August 8, 2005.
| Abstract |
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Methods and Results This analysis included 29 cohorts from Asia (78% of the total 380 216 participants) and 7 from Australia and New Zealand, with a total of 2 547 447 person-years of observation. Stratified time-dependent Cox proportional-hazards analyses were used to regress time until first event against baseline systolic blood pressure (SBP) and total cholesterol levels. A total of 3079 CHD and 4247 stroke events occurred; stroke subtypes were confirmed by CT, MRI, or necropsy in 1471 (35%) stroke events. Usual values of SBP were strongly linearly associated with ischemic stroke, hemorrhagic stroke, and CHD. The slope of the association with SBP became steeper with decreasing levels of cholesterol for ischemic stroke (P=0.007) and CHD (P
0.0001). For example, for the cholesterol groups of <4.75, 4.75 to 5.49, 5.50 to 6.24, and
6.25 mmol/L, each 10mm Hghigher systolic pressure was associated with 34% (95% CI, 30% to 37%), 28% (95% CI, 21% to 35%), 25% (95% CI, 18% to 32%), and 21% (95% CI, 13% to 27%) higher CHD risk, respectively. Adjustments for other leading cardiovascular risk factors made no appreciable differences in these results.
Conclusions In Asia-Pacific populations, there are hazards of increasing SBP at all cholesterol levels and hazards of increasing cholesterol at all levels of SBP, but the associations of SBP with CHD risk and ischemic stroke risk are slightly steeper among those with low cholesterol levels. The joint effects of SBP and total cholesterol on cardiovascular disease seem consistent across various Western and Asian populations.
Key Words: blood pressure epidemiology cholesterol hypertension cardiovascular diseases
| Introduction |
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Editorial p 3373
| Methods |
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Primary outcomes included in this report were total (fatal and nonfatal) CHD events and total (fatal and nonfatal) ischemic stroke. Secondary outcomes were nonfatal and fatal CHD events and stroke and total hemorrhagic stroke (primary intracerebral hemorrhage and subarachnoid hemorrhage). Nonfatal events were defined as those that did not result in death within 28 days. Because most studies used record linkage with official sources, verification of strokes was not routinely reported. However, 12 of the 36 studies included in this analysis provided information on stroke verification, and in 6 studies (n=193 959), a pathological subtype of stroke was determined by CT, MRI scan, or brain autopsy in >75% of stroke cases (n=1471). All data provided to the secretariat were checked for completeness and consistency and recoded when necessary to maximize comparability across cohorts. Summary reports were referred back to principal investigators of each collaborating study for review and confirmation.
Statistical Methods
Stratified time-dependent Cox proportional-hazards analyses19 were used to regress time until first event against baseline SBP and total cholesterol levels using individual participant data collected on all cohorts. Lowest levels of both SBP and cholesterol were used as the reference group. All analyses were stratified by sex and cohort, and the assumption of (log) linear relationships of blood pressure and cholesterol levels with risk of CVD was confirmed. Hazard ratios were plotted against corresponding categories: <130, 130 to 144, 145 to 159, and
160 mm Hg for SBP and <4.75, 4.75 to 5.49, 5.50 to 6.24, and
6.25 mmol/L for total serum cholesterol levels. These cut points were chosen on the basis of approximately equal numbers of events occurring in each category. Effect estimates were both adjusted and unadjusted for potential confounding (baseline body mass index and smoking habit), always including correction for regression dilution bias.12,20 Simultaneous adjustment for regression dilution bias was performed by a method described previously.21 Age at the time of the event was treated as an external time-dependent covariate to assess change in hazard ratios as age increases, given that the cohorts had different start and follow-up times.22 For each exposure group, 95% CIs were estimated. The methods followed those for assessing the associations with blood pressure, cholesterol, and CHD separately.23,24 These analyses reported direct positive associations across age, sex, and region subgroups. Tests for interactions and whether the group of linear blood pressure and categorical cholesterol effects differed in those >70 and <70 years of age were evaluated by means of a likelihood ratio test.
The primary hypothesis was that the effects of SBP and cholesterol on the predefined cardiovascular outcomes were multiplicative (ie, the absence of a statistical interaction between the 2 effects). This was tested in 2 ways. First, the continuous slope of SBP was fitted within each of the 4 categories of cholesterol. Regression dilution correction for SBP alone was conducted in this analysis. Second, a categorical analysis was performed with both variables defined into 4 groups. In this latter analysis, regression dilution correction was performed on both variables simultaneously to calculate the correct displacement of SBP and cholesterol groups.21 Likelihood ratio tests were used to assess the statistical significance of an interaction between SBP and cholesterol in both analyses.
Sensitivity analyses were conducted with the results adjusted for regression dilution simultaneously and individually and to assess the impact of different combinations of other covariates. Correlation analyses were performed to assess the degree of clustering within individuals in SBP and total cholesterol exposure levels. Subgroup analyses were also examined for all the analyses above on the basis of age, sex, and region. Finally, an additional sensitivity analysis was made on total ischemic stroke outcome after restricting the data to only those studies that provided information on stroke verification on at least 70% of participants.
| Results |
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Low levels of both SBP (<130 mm Hg) and cholesterol (<4.75 mmol/L) were present at baseline in 29% of the subjects; high levels of both SBP (
160 mm Hg) and cholesterol (
6.25 mmol/L) were observed in 1.4% of the subjects (Table 2). There was correlation between cholesterol and SBP levels (r=0.20, P<0.0001).
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Joint Effects of Blood Pressure and Cholesterol on Stroke
Figures 1 and 2
show the combined effects of SBP and total cholesterol on the risk of ischemic stroke (Figure 1) and hemorrhagic stroke (Figure 2). The hazard ratio for total ischemic stroke increased substantially with increasing levels of both SBP and cholesterol. There was a clear trend (P<0.007 for the likelihood ratio test of linear interactions) toward steeper associations of SBP in those with low values of cholesterol (and vice versa) (Figure 3). For example, with regard to risk of total ischemic stroke, a 10mm Hghigher SBP was associated with hazard ratios of 40% (95% CI, 36 to 43), 39% (95% CI, 33 to 45), 37% (95% CI, 29 to 43), and 29% (95% CI, 21 to 37) in cholesterol groups of <4.75, 4.75 to 5.49, 5.50 to 6.24, and
6.25 mmol/L, respectively. Sensitivity analyses restricted to cohorts with CT/MRI-documented ischemic strokes demonstrated similar findings. With regard to risk of hemorrhagic stroke, there was no association with cholesterol levels analyzed independently of SBP values, and there was no clear effect of cholesterol in modifying the steepness of the slope with SBP. For example, a 10mm Hghigher SBP was associated with 48% (95% CI, 45 to 51), 52% (95% CI, 47 to 57), 49% (95% CI, 42 to 55), and 45% (95% CI, 37 to 52) higher risks of hemorrhagic stroke in cholesterol groups of <4.75, 4.75 to 5.49, 5.50 to 6.24, and
6.25 mmol/L, respectively. Similar patterns (shape) of associations were found for adjusted analyses, fatal and nonfatal strokes, men and women, young (<70 years of age) and older (
70 years of age) age groups (Figure 3), and Asian and Australasian regions, but the strength of the associations was less strong in those >70 years of age.
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Joint Effects of Blood Pressure and Cholesterol on CHD
Combined effects of SBP and total cholesterol on the risk of CHD are shown in Figure 4. The risk of CHD increased with increasing levels of both SBP and total cholesterol, but these associations were attenuated with age. As with ischemic stroke, the associations of SBP with CHD risk were steeper in those with lower cholesterol levels (and vice versa) (P<0.001 for the likelihood ratio test of linear interactions) (Figure 3). For example, a 10mm Hghigher SBP was associated with 34% (95% CI, 30 to 37), 28% (95% CI, 21 to 35), 25% (95% CI, 18 to 32), and 21% (95% CI, 13 to 27) higher risk of total CHD in <4.75, 4.75 to 5.49, 5.50 to 6.24, and
6.25 mmol/L cholesterol groups, respectively. Similar patterns (shape) of associations were seen in men and women, younger and older age groups, and Asian and Australasian regions, but the strength of the associations was less strong in those >70 years of age (Figure 3).
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| Discussion |
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Major strengths and limitations of the study have been described elsewhere.23,24 There were 2 major limitations of this study: (1) variations in measurement error in determining cholesterol levels in Asia and (2) possible misclassification of events, particularly with respect to stroke subtype. Reliable verification of stroke subtype requires imaging or autopsy data, and although it is likely that such information formed the basis of most reporting, this could not always be confirmed. A particular methodological strength of this report was the simultaneous adjustment of effect estimates for regression dilution biases of both blood pressure and cholesterol measurements (including simultaneous correction for measurement errors in the same model) and for other conventional confounders such as body mass index and smoking. These analyses involved adjustment of effect estimates for regression dilution biases of both blood pressure and cholesterol simultaneously. Interestingly, these simultaneous adjustments did not differ substantially from the simpler analysis involving independent corrections for SBP and cholesterol. We also analyzed ischemic stroke separately from hemorrhagic strokes, thus improving clinical homogeneity of the study. However, restricting cohort studies to only those that reported ischemic strokes separately from hemorrhagic strokes led to a reduction of studies eligible for the present analyses, thus diminishing the precision of the effect estimates. The relatively high proportion of fatal stroke and CHD events can be explained by sampling bias resulting from selective reporting of fatal events only by some centers. The relatively low proportion of ischemic strokes is likely to be related to the overall low rate of imaging (CT/MRI) examination of the head.
Our findings confirm and extend those from previous cohort studies912 by showing that in the Asia-Pacific populations, there are hazards of increasing SBP at all cholesterol levels and hazards of increasing cholesterol at all levels of SBP, but the associations of SBP with CHD risk and ischemic stroke risk are slightly steeper among those with low cholesterol levels. The consistency of these findings with those observed previously in North American and Western European cohorts912 suggests that the joint associations of blood pressure and cholesterol are likely to be generalizable, although this would ideally be tested with direct data from other populations. This study found no evidence of a particular increase in hemorrhagic stroke with the combination of low cholesterol and high SBP, suggesting that if there is an association, it is smaller than indicated in other cohorts.25,,26
Findings of this study have important clinical and public health implications relating to the long-term effects of dual strategies to control both SBP and total cholesterol on the risk of stroke and CHD. They indicate that the clinical benefits of the joint control of blood pressure and total cholesterol seen in studies of mostly Western populations for CHD mortality are likely to be at least as great in Asian Pacific populations and include CHD morbidity and stroke morbidity and mortality. Our results also provide a way to estimate the size of the potential benefits from joint blood pressure and cholesterol-lowering strategies. These data provide a further rationale for simultaneous lowering of risk factors, because the effects of a given reduction in blood pressure may be greater if cholesterol has been lowered (and vice versa).
In summary, this project clearly demonstrates the substantial potential benefits from joint reductions of blood pressure and total cholesterol on CVD morbidity and mortality, which are consistent across various Western and Asian populations. These data form part of the rationale for such joint interventions playing an increasing role in initiatives to reduce the burden of CVD worldwide.
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| Acknowledgments |
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| Footnotes |
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| References |
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