Published online before print November 21, 2005, doi: 10.1161/CIRCULATIONAHA.105.537472
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(Circulation. 2005;112:3384-3390.)
© 2005 American Heart Association, Inc.
Epidemiology |
Joint Effects of Systolic Blood Pressure and Serum Cholesterol on Cardiovascular Disease in the Asia Pacific Region
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.
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Abstract |
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Background— Although interest in multifactorial interventions for cardiovascular disease is increasing, data on the strength and shape of the joint effects of blood pressure and cholesterol levels on the risk of cardiovascular disease are scarce, confined primarily to coronary heart disease (CHD) mortality in early middle-aged Western populations.
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 10–mm Hg–higher 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
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Introduction |
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Interest in multifactorial interventions for cardiovascular disease (CVD) is increasing,1,2 and several international guidelines on blood pressure and cholesterol management have recommended an integrated approach to the management of these cardiovascular risk factors.3–5 In particular, recent data show that most cardiovascular disease is attributable to nonoptimal levels of blood pressure and cholesterol,1,6 that almost all individuals with coronary disease have these or other major risk factors,7 and that substantial numbers of individuals have elevated levels of both blood pressure and cholesterol.8 However, data on the strength and shape of the joint effects of blood pressure and cholesterol levels on the risk of CVD are scarce. In 4 large cohort studies,9–12 the combination of high levels of total cholesterol and blood pressure had multiplicative effects on risk; ie, the proportional associations of 1 risk factor were approximately consistent across levels of the other. However, these studies were confined mainly to coronary heart disease (CHD) mortality in early middle-aged Western populations. Clearly, further information is needed on the joint effects of blood pressure and serum cholesterol levels to guide expectations of preventive interventions in different age, sex, and region groups. In this report, we describe the combined effects of serum cholesterol and blood pressure levels on cardiovascular risk in several studies from the Asia-Pacific region.
Editorial p 3373
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Methods |
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Identification of Studies and Collection of Data
The Asia Pacific Cohort Studies Collaboration is an individual participant data overview conducted by the principal investigators of cohort studies in the region. Methods of study identification and characteristics of the studies included have been reported elsewhere.13 In brief, studies were eligible for inclusion in the project if they satisfied the following criteria: (1) a study population from the Asia Pacific region; (2) a prospective study design; (3) at least 5000 person-years of follow-up recorded; (4) date of birth (or age), sex, and blood pressure recorded at baseline; and (5) date of death (or age at death) recorded during follow-up. For this report, only studies that reported data on both blood pressure and total serum cholesterol were included. Because most of the studies have demonstrated that the association between systolic blood pressure (SBP) and CVD is stronger than that of other blood pressure indexes in most age and gender groups,14–18 we analyze data on SBP in this report. In addition to SBP and total cholesterol, data were sought on date of baseline survey, history of CVD, diabetes, height, weight, and smoking habit. Data were also requested on any repeated measures of risk factors. To analyze regional differences, the study region was dichotomized into Asia and Australia and New Zealand (ANZ), largely representing a split by ethnicity into Asians and whites.
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.
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Results |
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Study Population Characteristics
Individual participant data from 36 cohorts representing 9 countries (84% of all studies included in the APCSC) have been included in this report (Table 1). There were 29 cohorts from Asia (11 from Japan, 12 from mainland China, 2 from Singapore, 1 from South Korea, 1 from Hong Kong, 1 from Thailand, and 1 from Taiwan;) and 7 from the ANZ region (6 from Australia and 1 from New Zealand). Most studies were initiated in the 1980s. Of the total 380 216 participants, the majority (78%) were from Asia; women constituted 42%; and the average age was 47 years. The mean follow-up period in the ANZ cohorts (9.8 years; median, 8.4 years) was longer than in the Asian cohorts (5.9 years; median, 4 years), but participants in the Asian cohorts were on average 5 years younger than in the ANZ cohorts. In total, there were 2 547 447 person-years of follow-up (mean follow-up, 6.7 years; median follow-up, 4 years). Participants from Asian cohorts had lower baseline levels of SBP, total cholesterol, and body mass index. Asian cohorts contributed 3178 (75%) and 1063 (35%) of total stroke and CHD events, respectively (Table 1). Of the 4247 total stroke events, 2156 (51%) were fatal (52% in the Asian cohorts and 48% in the ANZ cohorts). Of the 2522 stroke events with reported stroke subtype, 1476 (59%) were classified as ischemic (58% in the Asian cohorts and 63% in the ANZ cohorts) and 1046 (41%) as hemorrhagic (42% in the Asian cohorts and 37% in the ANZ cohorts). Of the total 3079 CHD events, 2235 (73%) were fatal (64% in the Asian cohorts and 77% in the ANZ cohorts).
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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 10–mm Hg–higher 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 10–mm Hg–higher 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 10–mm Hg–higher 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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This project is the first large-scale, individual participant data overview of joint effects of SBP and total serum cholesterol on stroke and CHD morbidity and mortality. The major findings of this study are 2-fold. First and most important, there was clear evidence in the Asia Pacific region of hazards of increasing SBP at all cholesterol levels and hazards of increasing cholesterol at all levels of SBP. The similarities of the joint SBP-cholesterol effects across the Asia Pacific region occurred despite substantial differences in background levels of other risk factors, different times at which the studies were carried out, and different ethnic groups involved. The second main finding was that the associations of SBP with CHD risk and ischemic stroke risk were slightly steeper among those with low cholesterol levels; conversely, the associations with cholesterol and these outcomes were slightly steeper at low SBP levels. In addition, for hemorrhagic stroke, our results showed no independent association with cholesterol levels and no modification of the SBP associations by cholesterol levels, although this may be due to small numbers.
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 studies9–12 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 cohorts9–12 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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This project has received grants from the Health Research Council of New Zealand, the National Institute on Aging (grant PO1-AG17625), the National Health and Medical Research Council of Australia, and an unrestricted educational grant from Pfizer Inc. The sponsors had no influence on design, analysis, or interpretation of results.
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Footnotes |
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Writing Committee and members are listed in the Appendix, which is available at http://circ.ahajournals.org/cgi/content/full/ CIRCULATIONAHA.105.537472/DC1.
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