Serum Cholesterol and Mortality from Coronary Heart Disease in Young, Middle-aged, and Older Men and Women from Three Chicago Epidemiologic Studies Alan R. Dyer, PhD, Jeremiah
Stamler,
MD, and Richard B. Shekelle,
PhD
The association of total serum cholesterol with mortality from coronary heart disease wus examined in 12 IO white men aged 42 to 60 in 1959 to 1963 and 1008 white men aged 45 to 64 in 1959 to Z969, followed up to 25 years from the Chicago Peoples Gus Company Study; in 1903 white men aged 41 to 57 in 1959, followed up to 24 years from the Chicago Western Electric Company Study; and in 17,880 white men aged 25 to 74 and 8327 white women aged 40 to 74 in 1967 to 1973, followed up to 18 years fTom the Chicago Heart Association Detection Project in Industry. In these studies total cholesterol level was related positively to coronary mortality in young men and in middle-aged and older men and women. Relative tisks of mortality were generally higher in young and mid&-aged persons compared to older persons, whereas absolute excess risks were generally greater in older than in younger persons. Ann Epidemiol 1992;2:51-57. Serum cholesterol, coronary heart disease, mortality,
KEY WORDS:
older persons.
INTRODUCTION This
report
coronary
examines
heart disease
the association (CHD)
of total
in middle-aged
serum
cholesterol
with
mortality
and older men from the Chicago
from
Western
Electric Company Study (WE) and the Chicago Peoples Gas Company Study (PG), and in young men and in middle-aged and older men and women from the Chicago Heart Association Detection Project in Industry (CHA). Because this report was initially prepared for a National Heart, Lung, and Blood Institute (NHLBI) workshop on cholesterol and heart disease focusing on older persons and women, follow-up in the middle-aged cohorts from these three studies was divided into follow-up prior to age 65 and that from age 65 on.
POPULATIONS
AND
METHODS
Populations The
studies
providing
data
for these
analyses
have
been
described
at Length
else-
where-WE (1, 2), PG (2-4), and CHA (5). Briefly, participants in the WE study were randomly selected from a population of 5397 men, aged 40 to 55 years, who had worked at the company’s Hawthorne Works near Chicago for 2 years or more as of 1957. Between 1958, 2107 men were assessed. On the 25th anniversary
October 1957 and December of the first examination, the
From the Department of Community Health and Preventive Medicine, Northwestern University Medical School, Chicago, IL (A.R.D., J.S.), and the School of Public Health, University of Texas Health Science Center at Houston, Houston, TX (R.B.S.). Address reprint requests to: Alan R. Dyer, PhD, Department of Community Health and Preventive Medicine, Northwestern University Medical School, 680 N. Lake Shore Drive, Suite 1102, Chicago, IL 60611-4402. Received November 28, 1990; revised April 4, 1991. 0 1992 Elsevier Science Publishing
Co., Inc.
1047.2797/92/$03.50
52
Dyer et al. CHOLESTEROL
AND CORONARY
MORTALITY
AEP Vol. 2. No. l/2 January/March 1992: 5 I-57
IN CHICAGO
vital status of all 2107 participants was known. Participants
in the PG study were male
employees who were 40 to 59 years old on January 2, 1958. Between January and December 1958, 1465 men in that age range were examined. Vital status on all men was known as of July 31, 1988. Participants in the CHA study were men and women employed at 84 cooperating companies and institutions in the Chicago area. Between November
1967 and January 1973,
women were screened.
39,572
young, middle-aged,
to 15 years. In the PG and WE studies, total cholesterol Abell-Kendall
and older men and
These men and women have been followed an average of 14 was measured in venous serum by the
method (6)) and in the CHA cohort it was measured from venous serum
by auto-analyzer using the method of Levine and Zak (7). For the WE group, the serum cholesterol measured at the first anniversary examination in 1959 was used in these analyses. For the PG study, the first measurement
between
1959 and 1963 was
used in analyses for men followed to age 65, while the last measurement between 1959 and 1969 was used in analyses for follow-up from age 65. For the CHA cohort, the baseline measurement
was used in all analyses. In the CHA
and WE studies, death
certificates were coded according to the eighth revision of the International tion of Diseases (ICD) CHA
studies,
and in PG according to the seventh revision.
deaths from CHD
were those
assigned to ICD
codes 410-412
410-413, and in the study, PG to codes 420-422. In the CHA study, men and women with electrocardiographic myocardial infarction
Classifica-
In the WE and
evidence
or of a
(MI) were excluded, while in the WE and PG studies, men with
any history of CHD were excluded. Due to small numbers of blacks and/or deaths among blacks in the three study groups, these analyses were restricted to whites. Because a major focus of the NHLBI workshop was on the association of serum cholesterol with heart disease in older persons, for this report follow-up was divided into that prior to age 65, and that from age 65 to age 79, with analyses then done separately for each follow-up period. Analyses based on full follow-up were also done for WE men and CHA men and women. In PG, cohorts with measurements examinations Table
from different sets of
were used for follow-up to age 65 and follow-up from age 65.
1 lists the study subgroups included in these analyses. The table lists the
total sample size, the mean cholesterol,
the number of deaths from CHD,
and the
average length of follow-up. For WE men and middle-aged CHA men and women, information is provided for full foll ow-up, follow-up to age 65, and follow-up beginning at age 65. For example, in WE men, among the 310 who died from CHD, 155 were less than 65 at death, and 151 were between 65 and 79 at death. Among these subgroups, mean cholesterol levels varied from 5.0 mmol/L in men aged 25 to 39 from the CHA cohort to 6.1 mmol/L in WE men. For CHA and WE men, 50 to 60% of those who died from CHD were younger than 65, while for CHA women only 34% who died from CHD were younger than 65. Follow-up to age 65 averaged about 11 years in the PG and CHA cohorts and about 15 years in the WE cohort. For the six older cohorts included in these analyses, only for men and women aged 64 to 74 from the CHA study did follow-up actually begin at the time of the cholesterol measurement. In the other groups, the interval between measurement and start of follow-up averaged 15 years in the WE, 9 years in the CHA, and 5 years in the PG groups.
Statistical
Methods
For each of the 14 groups listed in Table 1, rates of CHD death per 10,000 personyears for cholesterol subgroups were computed based on the National Cholesterol Education Program (NCEP) cutpoints (8) for classifications of high (> 6.2 mmol/L)
AEP Vol. 2. No. J/2
TABLE
53
Dyer et al. CHOLESTEROL AND CORONARY MORTALITY IN CHICAGO
January IMarch 1992: 5 l-57
1
Subnrouus examined Mean cholesterol level (mmol/L)
CHD deaths
1903 1903 1567 1210
6.1 6.1 6.1 5.8
310 155 151 92
20.8 14.9 7.1 11.8
Sample size
Study and subgroup
Average follow-up (Y)
MEN Western Electric: ages 41-57 Follow-up to age 65 Follow-up from age 65 Peoples Gas: ages 42-60 Follow-up to age 65 Peoples Gas: ages 45-64 Follow-up from age 65 Chicago Heart: ages 25-39 Chicago Heart: ages 40-63 Follow-up to age 65 Follow-up from age 65” Chicago Heart: ages 64-74
1008
5.8
168
10.1
7873 9506 9506 4652 501
5.0 5.5 5.5 5.5 5.4
55 572 329 242 91
14.8 14.1 11.2 6.0 11.7
Chicago Heart: ages 40-63 Follow-up to age 65 Follow-up from age 65 Chicago Heart: ages 64-74
7887 7887 4539 440
5.7 5.7 5.9 6.1
172 58 114 42
14.5 11.1 5.9 13.3
WOMEN
* Because
follow-up
from
age 65 was truncated
at age 79,
the numbers
of deaths
in the two periods
do not necessarily
add up to the total.
and borderline
high (5.2
to 6.2 mmol/L).
Age-adjusted
relative risks for men with
high or borderline high levels compared to men with normal levels by NCEP were obtained
from the Cox proportional
hazards model was also used for multivariate analyses in which cholesterol as a continuous
criteria
hazards model (9). The Cox proportional was entered
variable along with age, systolic blood pressure, cigarettes smoked per
day, and body mass index.
RESULTS Tables 2 and 3 present the CHD death rates per 10,000
person-years
within NCEP
cholesterol categories for each of the 14 cohorts listed in Table 1. Table 2 gives the results for the nine CHA cohorts, while Table 3 gives the results for the five cohorts from the WE and PG studies. Each table also contains the results of the multivariate Cox regression analyses for each group. Relative risks and 95% confidence intervals associated with a difference
in total cholesterol
of 1.0 mmol/L (40 mg/dL) are given.
In the youngest men from the CHA study (see Table 2)) mortality from CHD rose markedly with increasing cholesterol levels. For men with high levels by NCEP criteria, the age-adjusted relative risk of CHD death was 5.1. For full follow-up among CHA men aged 40 to 63, CHD mortality increased progressively with increasing total cholesterol levels. For men with high levels by NCEP criteria, the relative risk was 2.0, and for men with borderline high levels it was 1.4. Prior to age 65, mortality rose more sharply with increasing cholesterol levels than from age 65 on. Prior to age 65, the relative risk for those with high levels by NCEP criteria was 2.5, with an absolute excess risk of 32.6 deaths per 10,000 person-
54
Dyer et al. CHOLESTEROL
AND CORONARY
MORTALITY
AEP Vol. 2. No. 112 January/March 1992: 51-57
IN CHICAGO
TABLE 2 Total serum cholesterol and CHD mortality: White men and women from the Chicago Heart Association Detection Project in Industry Total cholesterol (mmol/L)
White women
White men Person-years
Deaths
Rate“
RRb
AGES 25-39 5
5.1
5.2-6.2 > 4.2 Cox RR’
68,239 36,581 12,055
14 26 15 1.90 (1.51,
49,243 55,931 28.746
149 246 177 1.33 (1.24, AGES 40-63
5 5.1 5.2-6.2 > 6.2 Cox RR‘
39,444 43,756 22,821
5.1 5.2-6.2 > 6.2 Cm RR’
9785 12,160 5920
5 5.1 5.2-6.2 > 6.2 Cox RR’
2185 2666 1014
79 130 120 1.39 (1.29, AGES 40-63
5
70 116 56 1.16 (1.00,
1.00 3.09 5.06
Rate”
RRb
-
-
-
2.40) IN 1967-73, 30.3 44.0 61.6
FULL FOLLOW-UP 1.00 1.38 1.99
34,736 46,061 33,633
1.43) IN 1967-73,
FOLLOW-UP 1.00 1.43 2.50
20.0 29.7 52.6
IN 1967-73,
FOLLOW-UP
71.5 95.4 94.6
1.00 1.33 1.37
29,492 34,984 22,922
1.51)
10.1 11.1 25.6
1.00 .a3 1.57
5.4 5.1 10.5
1.00 .86 1.58
36.3 29.8 57.9
1.00 .81 1.57
54.1 61.9 88.7
1.00 1.14 1.64
1.43)
16 18 24 1.30 (1.04,
1.62)
FROM AGE 65 5239 11,067 10,700
1.34)
146.5 142.5 207.1
35 51 86 1.25 (1.10,
TO AGE 65
1.50)
AGES 64-74 32 38 21 1.19 (.93,
Deaths
IN 1967-73
2.1 7.1 12.4
AGES 40-63 5 5.1 5.2-6.2 > 6.2 Cox RR’
Person-years
19 33 62 1.24 (1.05,
1.46)
IN 1967-73 1.00 1.02 1.49
1109 2260 2480
6 14 22 1.15 (.87,
1.51)
n Rate per 10,000 person-years. b Age-adjusted relative risk. c Relative risk and 95% confidence tntetval associated with a difference in seturn cholesterol of 1.0 mmol/L from Cox regression, wrth adjustment for age, systolic blood pressure, cigarettes smoked per day, and body mass index.
years. For men with borderline
high levels, the relative risk was 1.4. For follow-up
from age 65, relative risks were 1.3 and 1.4 for men with borderline
high and high
levels, respectively. For CHA men aged 64 to 74 at baseline, mortality from CHD was higher only for men with high cholesterol levels by NCEP criteria, with a relative risk of 1.5. For CHA women aged 40 to 63 who were classified as borderline high, the ageadjusted relative risks of death from CHD were similar for full follow-up, follow-up to age 65, and follow-up from age 65. Relative risks were all less than 1, indicating a slightly lower mortality for women with borderline high levels compared to women with normal levels. Similarly, for women with high levels by NCEP criteria, the relative risk was 1.6 for full follow-up, follow-up to age 65, and follow-up from age 65 and above. For CHA women aged 64 to 74 at baseline, CHD mortality rose with increasing cholesterol levels. The relative risk was 1.1 for those with borderline high levels and 1.6 for those with high levels by NCEP criteria.
AEP Vol. 2. No. 1I2 JanwnylMarch 1992: 51-57
CHOLESTEROL AND CORONARY
TABLE 3 Total serum cholesterol and CHD mortality: Company and Chicago Peoples Gas Company studies Total cholesterol (mmol/L)
Person-years
Deaths
7989 15,362 16,181
Rate”
34 102 174
Electric
Peoples Gas
TOTAL 5 5.1 5.2-6.2 > 6.2
White men from the Chicago Western
Western Electric
55
Dyer et al. IN CHICAGO
MORTALITY
42.6 66.4 107.5
RRb
Person-years
Deaths
-
-
Rate’
RRb
FOLLOW-UP 1.00 1.48 2.41
-
-
1.27 (1.17, 1.38)
Cox RR’
FOLLOW-UP TO AGE 65 5 5.1 5.2-6.2 > 6.2 Cox RR’
5784 10,958 11,608
15 25.9 47 42.9 93 80.1 1.24 (1.10, 1.40)
5 5.1 5.2-6.2 > 6.2 Cox RR’
2196 4389 4560
19 86.5 53 120.8 79 173.2 1.28 (1.14, 1.45)
1.00 1.62 3.04
4018 5599 4666
21 40 31 1.07 (.88, 1.30)
52.3 71.4 66.4
1.00 1.34 1.26
2550 4263 3328
32 125.5 65 152.5 71 213.3 1.18 (1.01, 1.36)
1.00 1.21 1.69
FOLLOW-UP FROM AGE 65 1.00 1.31 1.86
E Rate per 10,ooOperson-years. b Ageadjustedrelativerisk. ’ Relativerisk and 95% confidenceintervalassociatedwith a differencein serumcholesterolof 1.0 m&/L adjustmentfor age, systolicblood pressure,cigarettessmokedper day, and body mass index.
from Cox regression,with
The results of the Cox regression analyses in Table 2 indicated that total cholesterol level was significantly related to CHD mortality in young men, middle-aged men and women followed to age 65, middle-aged
men and women followed from age 65, but
not in men and women initially aged 64 to 74 at baseline. Comparison of the relative risks from the Cox regressions or the relative risks for those high by NCEP criteria in relation to those normal by NCEP criteria generally indicated a decline in relative risk with age, but an increase in absolute excess risk with age. For example,
for men aged
25 to 39 the relative risk for those with high levels by NCEP criteria was 5.1 and the absolute excess risk was 10.3 deaths per 10,000 person-years. In contrast, for middleaged men followed from age 65 or men aged 64 to 74, relative risks were 1.4 and 1.5, while absolute excess risks were 23.1 and 60.6 deaths per 10,000 person-years, respectively. For women with high cholesterol levels by NCEP criteria, relative risks were similar for women followed to age 65, women followed from age 65, and women aged 64 to 74. However, absolute excess risk was only 5.1 deaths per 10,000 personyears in the women followed to age 65, compared to 21.6 and 33.6 deaths in the two older groups. Table 3 gives the results for the three WE cohorts and the two cohorts from PG. For full follow-up in WE men, CHD mortality increased progressively with increasing cholesterol levels, with relative risks of 1.5 and 2.4 for men with borderline high and high levels by NCEP criteria, respectively. Relative risks during follow-up at middle age were generally larger than those during follow-up at older ages. Prior to age 65 relative risks were 1.6 and 3.0 for men classified as having borderline high and high levels, respectively. For follow-up from age 65, relative risks were 1.3 and 1.9 for men in these two categories. However, while relative risks were lower at follow-up at older compared to middle ages, absolute excess risks were greater during follow-up at older
56
Dyer et al. CHOLESTEROL
AND CORONARY
MORTALITY
AEP Vol. 2. No. 112 January/March 1992: 51-57
IN CHICAGO
ages, that is 86.7 and 34.3 deaths per 10,000 person-years for men with high and borderline high levels during follow-up at older ages compared to 54.2 and 17.0 deaths per 10,000
person-years
during follow-up at middle age.
In WE men, the results of the Cox regression analyses indicated associations of total cholesterol with CHD mortality in all analyses.
significant
For the PG cohort followed to age 65, mortality was modestly higher with increasing cholesterol, but associations were weaker than those seen in the WE and CHA cohorts. Nonetheless, for men with cholesterol levels of 5.2 mmol/L or higher, mortality was still about 30% higher than for men with values below this level. For the older PG cohort, the association with CHD mortality was stronger than that in the middleaged cohort. For men with high levels by NCEP criteria, the relative risk was 1.7. Further,
the absolute excess risk was 87.8 CHD deaths per 10,000
person-years.
For the PG men, the Cox regression analyses indicated a significant of total cholesterol aged cohort.
with CHD mortality
in the older cohort,
association
but not in the middle-
CONCLUSIONS In these three studies, total serum cholesterol to mortality from CHD in young men, Further,
relative
persons
compared
in older
than
risks
of mortality
to older persons,
in younger
with elevated cholesterol
level was strongly and positively related
and in middle-aged
were wheress
generally
higher
absolute
excess
and older
men and women.
in young
and middle-aged
risks were generally
greater
associated levels may decline with age, which might be construed by
persons.
Hence,
some to suggest that the importance
while
the
relative
of serum cholesterol
risk of CHD
as a risk factor for CHD
declines with age, the increase in absolute excess risk with age clearly indicates that such a conclusion
is incorrect.
The increase in absolute excess risk of CHD death with
age clearly indicates that elevated serum cholesterol is a public health problem for men and women of all ages and provides strong support for the application of the NCEP guidelines
to reduce
morbidity
and mortality
from CHD in men and women throughout
the life span. This research was supported by the Chicago Heart Association, American Heart Association, Illinois Heart Association, Illinois Regional Medical Program, and by grant HL21010 from the National Heart, Lung, and Blood Institute and grant CA38326 from the National Cancer Institute. The authors thank the Chicago companies and organizations, their officers, staffs, and employees, whose volunteer efforts made the Chicago Heart Association Detection Project in Industry possible. The authors also thank the staff and volunteers of the Chicago Heart Association who served the Project and the volunteer members of its Heart Disease Committee. The authors thank the officers, executive leaderships, and medical departments of both the Peoples Gas Company and Western Electric Company, whose cooperation and support since the late 1950s made these two studies possible. Thanks are also extended to the research staff of the Peoples Gas Company Study and the physicians who were active in the Western Electric Company Study, particularly the founder of the study, Dr. Oglesby Paul.
REFERENCES 1.
Paul 0,
Circulation. 2.
Lepper MJ, Phelan WH, et al. A longitudinal
study of coronary heart disease,
1963;28:20-31.
Pooling
Project
Research
Group.
Relationship
of blood pressure,
serum cholesterol,
smoking habit,
relative
weight and ECG abnormalities
Final report of the pooling project, 3.
Stamler
pathogenesis
J, Berkson
4.
DM,
of the atherosclerotic
of Atherosclerosis.
Baltimore;
Dyer AR, Stamler
J Chronic Lindberg
to incidence
of major coronary
events:
Dis. 1978;31:201-306. HA.
Risk factors:
Their
role in the etiology
and
diseases. In: Wissler RW and Geer JC, eds. The Pathogenesis
Williams
J, Berkson
body mass index to 14-year mortality Dis.
57
Dyer et al. CHOLESTEROL AND CORONARY MORTALITY IN CHICAGO
AEP Vol. 2. No. 1I2 January/March 1992: 5 I-57
&I Wilkins;
1972:41-l
19.
DM, Lindberg HA. Relationship in the Chicago
of relative
Peoples Gas Company
weight and
Study, J Chronic
1975;28:109-23. 5.
Stamler
J, Rhomberg
ship of seven variables Project
in Industry,
6. 7.
1967-1972,
J Chronic
Abel1 L, Levy B, Brodie B, Kendall
cholesterol Acta.
P, Schoenberger
in serum and the demonstration Levine JB,
JA, et al. Multivariate
to blood pressure: Findings of the Chicago
Zak B. Automated
Dis.
analysis of the relation-
Heart Association
Detection
1975;28:527-48.
FE. A simplified method for the measurement of its specificity,
determination
J Biol Chem.
of
1952;195:357-66.
of serum total cholesterol,
Clin
Chim
1964;10:381-4. 8.
The Expert Panel. Report of the National
on detection,
evaluation,
and treatment
Cholesterol
Education
of high blood cholesterol
Program Expert Panel
in adults, Arch Intern
Med.
1988;148:36-9. 9.
Cox DR. Regression
models and life tables, J R Stat Sot Ser (B).
1972;34:187-202.
Stamler,
MD, and Richard B. Shekelle,
PhD
The association of total serum cholesterol with mortality from coronary heart disease wus examined in 12 IO white men aged 42 to 60 in 1959 to 1963 and 1008 white men aged 45 to 64 in 1959 to Z969, followed up to 25 years from the Chicago Peoples Gus Company Study; in 1903 white men aged 41 to 57 in 1959, followed up to 24 years from the Chicago Western Electric Company Study; and in 17,880 white men aged 25 to 74 and 8327 white women aged 40 to 74 in 1967 to 1973, followed up to 18 years fTom the Chicago Heart Association Detection Project in Industry. In these studies total cholesterol level was related positively to coronary mortality in young men and in middle-aged and older men and women. Relative tisks of mortality were generally higher in young and mid&-aged persons compared to older persons, whereas absolute excess risks were generally greater in older than in younger persons. Ann Epidemiol 1992;2:51-57. Serum cholesterol, coronary heart disease, mortality,
KEY WORDS:
older persons.
INTRODUCTION This
report
coronary
examines
heart disease
the association (CHD)
of total
in middle-aged
serum
cholesterol
with
mortality
and older men from the Chicago
from
Western
Electric Company Study (WE) and the Chicago Peoples Gas Company Study (PG), and in young men and in middle-aged and older men and women from the Chicago Heart Association Detection Project in Industry (CHA). Because this report was initially prepared for a National Heart, Lung, and Blood Institute (NHLBI) workshop on cholesterol and heart disease focusing on older persons and women, follow-up in the middle-aged cohorts from these three studies was divided into follow-up prior to age 65 and that from age 65 on.
POPULATIONS
AND
METHODS
Populations The
studies
providing
data
for these
analyses
have
been
described
at Length
else-
where-WE (1, 2), PG (2-4), and CHA (5). Briefly, participants in the WE study were randomly selected from a population of 5397 men, aged 40 to 55 years, who had worked at the company’s Hawthorne Works near Chicago for 2 years or more as of 1957. Between 1958, 2107 men were assessed. On the 25th anniversary
October 1957 and December of the first examination, the
From the Department of Community Health and Preventive Medicine, Northwestern University Medical School, Chicago, IL (A.R.D., J.S.), and the School of Public Health, University of Texas Health Science Center at Houston, Houston, TX (R.B.S.). Address reprint requests to: Alan R. Dyer, PhD, Department of Community Health and Preventive Medicine, Northwestern University Medical School, 680 N. Lake Shore Drive, Suite 1102, Chicago, IL 60611-4402. Received November 28, 1990; revised April 4, 1991. 0 1992 Elsevier Science Publishing
Co., Inc.
1047.2797/92/$03.50
52
Dyer et al. CHOLESTEROL
AND CORONARY
MORTALITY
AEP Vol. 2. No. l/2 January/March 1992: 5 I-57
IN CHICAGO
vital status of all 2107 participants was known. Participants
in the PG study were male
employees who were 40 to 59 years old on January 2, 1958. Between January and December 1958, 1465 men in that age range were examined. Vital status on all men was known as of July 31, 1988. Participants in the CHA study were men and women employed at 84 cooperating companies and institutions in the Chicago area. Between November
1967 and January 1973,
women were screened.
39,572
young, middle-aged,
to 15 years. In the PG and WE studies, total cholesterol Abell-Kendall
and older men and
These men and women have been followed an average of 14 was measured in venous serum by the
method (6)) and in the CHA cohort it was measured from venous serum
by auto-analyzer using the method of Levine and Zak (7). For the WE group, the serum cholesterol measured at the first anniversary examination in 1959 was used in these analyses. For the PG study, the first measurement
between
1959 and 1963 was
used in analyses for men followed to age 65, while the last measurement between 1959 and 1969 was used in analyses for follow-up from age 65. For the CHA cohort, the baseline measurement
was used in all analyses. In the CHA
and WE studies, death
certificates were coded according to the eighth revision of the International tion of Diseases (ICD) CHA
studies,
and in PG according to the seventh revision.
deaths from CHD
were those
assigned to ICD
codes 410-412
410-413, and in the study, PG to codes 420-422. In the CHA study, men and women with electrocardiographic myocardial infarction
Classifica-
In the WE and
evidence
or of a
(MI) were excluded, while in the WE and PG studies, men with
any history of CHD were excluded. Due to small numbers of blacks and/or deaths among blacks in the three study groups, these analyses were restricted to whites. Because a major focus of the NHLBI workshop was on the association of serum cholesterol with heart disease in older persons, for this report follow-up was divided into that prior to age 65, and that from age 65 to age 79, with analyses then done separately for each follow-up period. Analyses based on full follow-up were also done for WE men and CHA men and women. In PG, cohorts with measurements examinations Table
from different sets of
were used for follow-up to age 65 and follow-up from age 65.
1 lists the study subgroups included in these analyses. The table lists the
total sample size, the mean cholesterol,
the number of deaths from CHD,
and the
average length of follow-up. For WE men and middle-aged CHA men and women, information is provided for full foll ow-up, follow-up to age 65, and follow-up beginning at age 65. For example, in WE men, among the 310 who died from CHD, 155 were less than 65 at death, and 151 were between 65 and 79 at death. Among these subgroups, mean cholesterol levels varied from 5.0 mmol/L in men aged 25 to 39 from the CHA cohort to 6.1 mmol/L in WE men. For CHA and WE men, 50 to 60% of those who died from CHD were younger than 65, while for CHA women only 34% who died from CHD were younger than 65. Follow-up to age 65 averaged about 11 years in the PG and CHA cohorts and about 15 years in the WE cohort. For the six older cohorts included in these analyses, only for men and women aged 64 to 74 from the CHA study did follow-up actually begin at the time of the cholesterol measurement. In the other groups, the interval between measurement and start of follow-up averaged 15 years in the WE, 9 years in the CHA, and 5 years in the PG groups.
Statistical
Methods
For each of the 14 groups listed in Table 1, rates of CHD death per 10,000 personyears for cholesterol subgroups were computed based on the National Cholesterol Education Program (NCEP) cutpoints (8) for classifications of high (> 6.2 mmol/L)
AEP Vol. 2. No. J/2
TABLE
53
Dyer et al. CHOLESTEROL AND CORONARY MORTALITY IN CHICAGO
January IMarch 1992: 5 l-57
1
Subnrouus examined Mean cholesterol level (mmol/L)
CHD deaths
1903 1903 1567 1210
6.1 6.1 6.1 5.8
310 155 151 92
20.8 14.9 7.1 11.8
Sample size
Study and subgroup
Average follow-up (Y)
MEN Western Electric: ages 41-57 Follow-up to age 65 Follow-up from age 65 Peoples Gas: ages 42-60 Follow-up to age 65 Peoples Gas: ages 45-64 Follow-up from age 65 Chicago Heart: ages 25-39 Chicago Heart: ages 40-63 Follow-up to age 65 Follow-up from age 65” Chicago Heart: ages 64-74
1008
5.8
168
10.1
7873 9506 9506 4652 501
5.0 5.5 5.5 5.5 5.4
55 572 329 242 91
14.8 14.1 11.2 6.0 11.7
Chicago Heart: ages 40-63 Follow-up to age 65 Follow-up from age 65 Chicago Heart: ages 64-74
7887 7887 4539 440
5.7 5.7 5.9 6.1
172 58 114 42
14.5 11.1 5.9 13.3
WOMEN
* Because
follow-up
from
age 65 was truncated
at age 79,
the numbers
of deaths
in the two periods
do not necessarily
add up to the total.
and borderline
high (5.2
to 6.2 mmol/L).
Age-adjusted
relative risks for men with
high or borderline high levels compared to men with normal levels by NCEP were obtained
from the Cox proportional
hazards model was also used for multivariate analyses in which cholesterol as a continuous
criteria
hazards model (9). The Cox proportional was entered
variable along with age, systolic blood pressure, cigarettes smoked per
day, and body mass index.
RESULTS Tables 2 and 3 present the CHD death rates per 10,000
person-years
within NCEP
cholesterol categories for each of the 14 cohorts listed in Table 1. Table 2 gives the results for the nine CHA cohorts, while Table 3 gives the results for the five cohorts from the WE and PG studies. Each table also contains the results of the multivariate Cox regression analyses for each group. Relative risks and 95% confidence intervals associated with a difference
in total cholesterol
of 1.0 mmol/L (40 mg/dL) are given.
In the youngest men from the CHA study (see Table 2)) mortality from CHD rose markedly with increasing cholesterol levels. For men with high levels by NCEP criteria, the age-adjusted relative risk of CHD death was 5.1. For full follow-up among CHA men aged 40 to 63, CHD mortality increased progressively with increasing total cholesterol levels. For men with high levels by NCEP criteria, the relative risk was 2.0, and for men with borderline high levels it was 1.4. Prior to age 65, mortality rose more sharply with increasing cholesterol levels than from age 65 on. Prior to age 65, the relative risk for those with high levels by NCEP criteria was 2.5, with an absolute excess risk of 32.6 deaths per 10,000 person-
54
Dyer et al. CHOLESTEROL
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MORTALITY
AEP Vol. 2. No. 112 January/March 1992: 51-57
IN CHICAGO
TABLE 2 Total serum cholesterol and CHD mortality: White men and women from the Chicago Heart Association Detection Project in Industry Total cholesterol (mmol/L)
White women
White men Person-years
Deaths
Rate“
RRb
AGES 25-39 5
5.1
5.2-6.2 > 4.2 Cox RR’
68,239 36,581 12,055
14 26 15 1.90 (1.51,
49,243 55,931 28.746
149 246 177 1.33 (1.24, AGES 40-63
5 5.1 5.2-6.2 > 6.2 Cox RR‘
39,444 43,756 22,821
5.1 5.2-6.2 > 6.2 Cm RR’
9785 12,160 5920
5 5.1 5.2-6.2 > 6.2 Cox RR’
2185 2666 1014
79 130 120 1.39 (1.29, AGES 40-63
5
70 116 56 1.16 (1.00,
1.00 3.09 5.06
Rate”
RRb
-
-
-
2.40) IN 1967-73, 30.3 44.0 61.6
FULL FOLLOW-UP 1.00 1.38 1.99
34,736 46,061 33,633
1.43) IN 1967-73,
FOLLOW-UP 1.00 1.43 2.50
20.0 29.7 52.6
IN 1967-73,
FOLLOW-UP
71.5 95.4 94.6
1.00 1.33 1.37
29,492 34,984 22,922
1.51)
10.1 11.1 25.6
1.00 .a3 1.57
5.4 5.1 10.5
1.00 .86 1.58
36.3 29.8 57.9
1.00 .81 1.57
54.1 61.9 88.7
1.00 1.14 1.64
1.43)
16 18 24 1.30 (1.04,
1.62)
FROM AGE 65 5239 11,067 10,700
1.34)
146.5 142.5 207.1
35 51 86 1.25 (1.10,
TO AGE 65
1.50)
AGES 64-74 32 38 21 1.19 (.93,
Deaths
IN 1967-73
2.1 7.1 12.4
AGES 40-63 5 5.1 5.2-6.2 > 6.2 Cox RR’
Person-years
19 33 62 1.24 (1.05,
1.46)
IN 1967-73 1.00 1.02 1.49
1109 2260 2480
6 14 22 1.15 (.87,
1.51)
n Rate per 10,000 person-years. b Age-adjusted relative risk. c Relative risk and 95% confidence tntetval associated with a difference in seturn cholesterol of 1.0 mmol/L from Cox regression, wrth adjustment for age, systolic blood pressure, cigarettes smoked per day, and body mass index.
years. For men with borderline
high levels, the relative risk was 1.4. For follow-up
from age 65, relative risks were 1.3 and 1.4 for men with borderline
high and high
levels, respectively. For CHA men aged 64 to 74 at baseline, mortality from CHD was higher only for men with high cholesterol levels by NCEP criteria, with a relative risk of 1.5. For CHA women aged 40 to 63 who were classified as borderline high, the ageadjusted relative risks of death from CHD were similar for full follow-up, follow-up to age 65, and follow-up from age 65. Relative risks were all less than 1, indicating a slightly lower mortality for women with borderline high levels compared to women with normal levels. Similarly, for women with high levels by NCEP criteria, the relative risk was 1.6 for full follow-up, follow-up to age 65, and follow-up from age 65 and above. For CHA women aged 64 to 74 at baseline, CHD mortality rose with increasing cholesterol levels. The relative risk was 1.1 for those with borderline high levels and 1.6 for those with high levels by NCEP criteria.
AEP Vol. 2. No. 1I2 JanwnylMarch 1992: 51-57
CHOLESTEROL AND CORONARY
TABLE 3 Total serum cholesterol and CHD mortality: Company and Chicago Peoples Gas Company studies Total cholesterol (mmol/L)
Person-years
Deaths
7989 15,362 16,181
Rate”
34 102 174
Electric
Peoples Gas
TOTAL 5 5.1 5.2-6.2 > 6.2
White men from the Chicago Western
Western Electric
55
Dyer et al. IN CHICAGO
MORTALITY
42.6 66.4 107.5
RRb
Person-years
Deaths
-
-
Rate’
RRb
FOLLOW-UP 1.00 1.48 2.41
-
-
1.27 (1.17, 1.38)
Cox RR’
FOLLOW-UP TO AGE 65 5 5.1 5.2-6.2 > 6.2 Cox RR’
5784 10,958 11,608
15 25.9 47 42.9 93 80.1 1.24 (1.10, 1.40)
5 5.1 5.2-6.2 > 6.2 Cox RR’
2196 4389 4560
19 86.5 53 120.8 79 173.2 1.28 (1.14, 1.45)
1.00 1.62 3.04
4018 5599 4666
21 40 31 1.07 (.88, 1.30)
52.3 71.4 66.4
1.00 1.34 1.26
2550 4263 3328
32 125.5 65 152.5 71 213.3 1.18 (1.01, 1.36)
1.00 1.21 1.69
FOLLOW-UP FROM AGE 65 1.00 1.31 1.86
E Rate per 10,ooOperson-years. b Ageadjustedrelativerisk. ’ Relativerisk and 95% confidenceintervalassociatedwith a differencein serumcholesterolof 1.0 m&/L adjustmentfor age, systolicblood pressure,cigarettessmokedper day, and body mass index.
from Cox regression,with
The results of the Cox regression analyses in Table 2 indicated that total cholesterol level was significantly related to CHD mortality in young men, middle-aged men and women followed to age 65, middle-aged
men and women followed from age 65, but
not in men and women initially aged 64 to 74 at baseline. Comparison of the relative risks from the Cox regressions or the relative risks for those high by NCEP criteria in relation to those normal by NCEP criteria generally indicated a decline in relative risk with age, but an increase in absolute excess risk with age. For example,
for men aged
25 to 39 the relative risk for those with high levels by NCEP criteria was 5.1 and the absolute excess risk was 10.3 deaths per 10,000 person-years. In contrast, for middleaged men followed from age 65 or men aged 64 to 74, relative risks were 1.4 and 1.5, while absolute excess risks were 23.1 and 60.6 deaths per 10,000 person-years, respectively. For women with high cholesterol levels by NCEP criteria, relative risks were similar for women followed to age 65, women followed from age 65, and women aged 64 to 74. However, absolute excess risk was only 5.1 deaths per 10,000 personyears in the women followed to age 65, compared to 21.6 and 33.6 deaths in the two older groups. Table 3 gives the results for the three WE cohorts and the two cohorts from PG. For full follow-up in WE men, CHD mortality increased progressively with increasing cholesterol levels, with relative risks of 1.5 and 2.4 for men with borderline high and high levels by NCEP criteria, respectively. Relative risks during follow-up at middle age were generally larger than those during follow-up at older ages. Prior to age 65 relative risks were 1.6 and 3.0 for men classified as having borderline high and high levels, respectively. For follow-up from age 65, relative risks were 1.3 and 1.9 for men in these two categories. However, while relative risks were lower at follow-up at older compared to middle ages, absolute excess risks were greater during follow-up at older
56
Dyer et al. CHOLESTEROL
AND CORONARY
MORTALITY
AEP Vol. 2. No. 112 January/March 1992: 51-57
IN CHICAGO
ages, that is 86.7 and 34.3 deaths per 10,000 person-years for men with high and borderline high levels during follow-up at older ages compared to 54.2 and 17.0 deaths per 10,000
person-years
during follow-up at middle age.
In WE men, the results of the Cox regression analyses indicated associations of total cholesterol with CHD mortality in all analyses.
significant
For the PG cohort followed to age 65, mortality was modestly higher with increasing cholesterol, but associations were weaker than those seen in the WE and CHA cohorts. Nonetheless, for men with cholesterol levels of 5.2 mmol/L or higher, mortality was still about 30% higher than for men with values below this level. For the older PG cohort, the association with CHD mortality was stronger than that in the middleaged cohort. For men with high levels by NCEP criteria, the relative risk was 1.7. Further,
the absolute excess risk was 87.8 CHD deaths per 10,000
person-years.
For the PG men, the Cox regression analyses indicated a significant of total cholesterol aged cohort.
with CHD mortality
in the older cohort,
association
but not in the middle-
CONCLUSIONS In these three studies, total serum cholesterol to mortality from CHD in young men, Further,
relative
persons
compared
in older
than
risks
of mortality
to older persons,
in younger
with elevated cholesterol
level was strongly and positively related
and in middle-aged
were wheress
generally
higher
absolute
excess
and older
men and women.
in young
and middle-aged
risks were generally
greater
associated levels may decline with age, which might be construed by
persons.
Hence,
some to suggest that the importance
while
the
relative
of serum cholesterol
risk of CHD
as a risk factor for CHD
declines with age, the increase in absolute excess risk with age clearly indicates that such a conclusion
is incorrect.
The increase in absolute excess risk of CHD death with
age clearly indicates that elevated serum cholesterol is a public health problem for men and women of all ages and provides strong support for the application of the NCEP guidelines
to reduce
morbidity
and mortality
from CHD in men and women throughout
the life span. This research was supported by the Chicago Heart Association, American Heart Association, Illinois Heart Association, Illinois Regional Medical Program, and by grant HL21010 from the National Heart, Lung, and Blood Institute and grant CA38326 from the National Cancer Institute. The authors thank the Chicago companies and organizations, their officers, staffs, and employees, whose volunteer efforts made the Chicago Heart Association Detection Project in Industry possible. The authors also thank the staff and volunteers of the Chicago Heart Association who served the Project and the volunteer members of its Heart Disease Committee. The authors thank the officers, executive leaderships, and medical departments of both the Peoples Gas Company and Western Electric Company, whose cooperation and support since the late 1950s made these two studies possible. Thanks are also extended to the research staff of the Peoples Gas Company Study and the physicians who were active in the Western Electric Company Study, particularly the founder of the study, Dr. Oglesby Paul.
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