Passive smoking and atherosclerosis - IESC/UFRJ

Intermediate Methods in Epidemiology
2008
Exercise No. 4 - Passive smoking and atherosclerosis
The purpose of this exercise is to allow students to recapitulate issues discussed
throughout the course which affect the inferential process aimed at establishing whether results
of observational studies are consistent with a cause-effect relationship.
Active cigarette smoking is an important risk factor for numerous unhealthy outcomes,
including lung cancer and cardiovascular diseases. In the 2006 report of the Surgeon General,
“Reducing the Health Consequences of Smoking”, it is estimated that smoking is responsible for
approximately 440,000 deaths each year, reflected in the 5,6 million years of life lost annually in
the U.S.
The importance of smoking as a hazardous exposure became widely recognized after
the publication of the 1964 Surgeon General’s Report based on a review of more than 7,000
scientific articles on smoking and health. As an interesting aside, the report was the first ever to
systematically apply the causality criteria that should be considered when assessing
observational data.
Environmental tobacco smoke (passive smoking) has also been explored in relation to
many different outcomes, including lung cancer, cardiovascular disease and reproductive
outcomes. Based on both case-control and cohort studies, the 2006 report of the Surgeon
General concluded that there is no threshold for the health effects of passive smoking, that is,
there are no “safe” exposure levels.
(1) Review Hill’s causality criteria. Based on the above Surgeon General’s
conclusion on passive smoking, state which criterion has been met.
This exercise will focus on the association of environmental tobacco smoke with the
process underlying many cardiovascular diseases, namely, atherosclerosis.
Atherosclerosis is a pathologic process involving the arterial intima and media, which
comprise the inner and middle layers of arteries, respectively. Atherosclerosis may start as
early as the second decade of life, and has a long natural history (Figure 1): It progresses from
benign lipid deposits in the intima (“fatty streaks”) to fully developed atherosclerotic plaques,
which are fibrous formations that may protrude into the arterial lumen and interfere with the
blood flow, thereby causing ischemia and its attending symptoms (e.g., angina pectoris). The
slowness and turbulence of the blood flow at the site of a narrowed arterial lumen facilitates the
formation of clots (thrombi) which may occlude the artery, leading to acute ischemia and its
attending severe clinical events (e.g., heart attack).
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Figure 1 – Natural History of Atherosclerosis
Lesion:
Fatty streaks
Fibrous
plaques
Raised lesions
Occlusion by
thrombus
Clinical
expression:
Decade of
life:
None None May cause symptoms
if lumen is narrowed,
e.g., intermittent
claudication, angina
pectoris
1 st / 2 nd / 3 rd 4 th / 5 th 6 th +
Heart attack,
stroke, etc.
(2) What is the relevance of the natural history of atherosclerotic disease in relation
to its primary prevention?
In addition to hypertension, high serum cholesterol levels and diabetes, active smoking
has been consistently identified as a strong determinant of atherosclerosis; it appears to be
particularly important in the more advanced stages of atherosclerosis (Sharrett et al, Am J
Epidemiol 1999;149:843-52.) . For example, active smoking cessation leads to the elimination
of virtually all excess risk of sudden coronary death in about one year after cessation.
.
(3) What does this fact tell you about the mechanism whereby active smoking
causes sudden coronary death? Is it appropriate to calculate rate per persontime
using a long follow-up interval to study the relationship of active smoking to
sudden coronary death?
Sudden coronary death is usually defined as an unexpected out-of-hospital death occurring
within 24 hours of the onset of symptoms (typically chest pain) and is caused by acute thrombosis leading
to massive myocardial ischemia.
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The concern that environmental tobacco exposure may be related to atherosclerosis
was a logical outgrowth of the role of active smoking, and has been explored in numerous
studies. Glantz & Parmley (Circulation 1991;83:1-12) showed that, of ten published studies
conducted both in the U.S. and abroad (Japan, Scotland, China), only one (by Lee et al) did not
yield a relative risk greater than 1.0 using clinical coronary heart disease death as an outcome
(Figure 2).
(4) Does the outcome used in these studies (mortality) allow firm conclusions on
whether the association of environmental tobacco smoke with coronary heart
disease risk is causal? Why?
(5) Which causality criterion is met by the demonstration that all but one study
showed a positive association between environmental tobacco smoke and death?
(6) When conducting a review of the literature such as that reported by Glantz and
Parmley, what possible bias may interfere with the interpretation of this causality
criterion? Are there situations when this criterion is not met, and yet the
association is still causal? What are these situations?
Wells (Environ Int 1988;14:249-65) estimated a pooled risk of coronary heart disease
death in persons exposed to environmental tobacco smoke relative to that in those not exposed
of 1.3 (95% confidence interval, 1.1-1.6) for men and 1.2 (95% confidence interval, 1.0 – 1.4) for
women. These estimates are consistent with those arrived at by Glantz & Palmer of 1.3 for both
genders (95% confidence interval 1.2 – 1.4), and have been confirmed by the 2006 report of the
Surgeon General.
(7) A relative risk close to one is often referred to as a “small effect”. Is that
statement always true? Why?
Using a relative risk estimate of 1.2 and an environmental tobacco smoke
prevalence of approximately 26% (Howard et al, Arch Intern Med
1994;154:1277-82), estimate the percentage of total clinical coronary deaths due
to environmental tobacco smoking in women.
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Recently, it has become possible to study not only clinical manifestations of
atherosclerosis, but also subclinical atherosclerosis on a community-wide basis. In the
Atherosclerosis Risk in Communities (ARIC) study, a cohort of approximately 15,800 people
aged 45-64 years at baseline recruited from four U.S. communities undergo periodic B-mode
ultrasound examinations of the carotid arteries in the neck for the purpose of measuring arterial
wall (intima plus media) thickness. An increased arterial thickness is a marker of subclinical
atherosclerosis.
ARIC’s baseline visit was conducted between 1987 and 1989, and included in addition to
ultrasound examination of the neck and risk factor measurements, questions about
environmental tobacco smoking. Information on exposure to environmental tobacco smoke was
obtained from non-active smokers by asking the following question: ”During the past year, about
how many hours per week, on the average, were you in close contact with people when they
were smoking? For example, in your home, in a car, at work, or other close quarters?”
Environmental tobacco smokers were defined as those who reported an exposure of 1 or more
hours per week to environmental smoke. Using this definition, approximately 26% of the ARIC
cohort participants were never active smokers exposed to environmental tobacco smoke, 33%
were past active smokers, 27% were current active smokers, and only 14% had never smoked
and were not exposed to environmental tobacco smoke.
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The unadjusted cross-sectional relationships between carotid wall thickness and
smoking in ARIC participants without clinically apparent atherosclerotic cardiovascular disease
are shown in table 1. Table 1 also shows the average increases in the mean, median and 90 th
percentile values of wall thickness associated with an average increase of one year of age in
never-active smokers not exposed to environmental tobacco smoke. (These values were based
on the cross-sectional relationships between age and wall thickness at the time of the baseline
examination of the cohort.)
Table 1. Unadjusted wall (intima + media) thickness of the carotid arteries by smoking status in
the Atherosclerosis Risk in Communities (ARIC) study at baseline (1987-89), excluding persons
with prevalent clinical cardiovascular disease¤
Category
Wall Thickness (mm)
Smoking Status
Never Active Smokers
Unexposed
to ETS
(n=1774)
Exposed
to ETS
(n=3358)
Former
Active smokers
(n=4081)
Current
Active
Smokers
(n=3366)
Estimated
Increase/Year of
Age (Standard
Error)§
Mean 0.693 0.705 0.756 0.761 0.0085 (0.0006)
25 th percentile 0.597 0.608 0.632 0.628
50 th percentile 0.671 0.681 0.719 0.717 0.0087 (0.0008)
75 th percentile 0.761 0.773 0.832 0.840
90 th percentile 0.869 0.881 0.978 1.010 0.0136 (0.0019)
¤ Myocardial infarction, angina pectoris, stroke, intermittent claudication
Environmental tobacco smoke (passive smoking)
§ In never active smokers not exposed to ETS
(Adapted from: Howard et al, Arch Intern Med 1994;154:1277-82)
(8) What biases may occur when examining the association between smoking and
wall thickness in the ARIC baseline visit, as shown in table 1? Are these biases
likely to occur when studying subclinical outcome only in persons without
evidence of clinical disease? Why?
(9) Why are different percentile values shown in the table, rather than just the mean
(or median) values?
(10) How would you describe the differences among smoking categories for the
values of the mean, median and 90 th percentile wall thickness vis-à-vis the
estimated increase/year of age?
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Stratification by age, adjusting for race and gender, is shown in Figure 3.
Figure 3. Race and gender-adjusted wall (intima + media)
thickness of the carotid arteries (IMT): Percentiles § by age
and smoking in the Atherosclerosis Risk in Communities (ARIC)
study at baseline (1987-89).
§ In the “box-whisker” plots, the bottom whisker provides the 10 th percentile; the bottom of the
box, the 25 th percentile; the horizontal line in the box, the 50 th percentile (median); the top of the
box, the 75 th percentile; and the top of the whisker, the 90 th percentile.
N=nonsmokers
E=exposed to environmental tobacco smoking
P=past smokers
C=current smokers
(11) What is the assumption underlying the presentation of data simultaneously
adjusted for race and gender? Are the findings in Figure 3 consistent with those
in table 1?
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Crude and adjusted estimates of the differences in mean carotid wall thickness in never
active smokers according to exposure to environmental tobacco smoke are shown in table 2.
Table 2. Differences in mean carotid wall thickness (mm) between never smokers exposed and
those unexposed to environmental tobacco smoke, unadjusted and adjusted for combinations of
selected factors in participants of the ARIC study baseline visit, excluding persons with
prevalent clinical cardiovascular disease¤
Difference in mean carotid
wall thickness (mm)
between never smokers
exposed and those
Adjusted for:
unexposed to ETS
(p-value)
No factors (crude) 0.012§
Age, race and gender
Age, race, gender plus life style factors (education, physical
activity, fat intake, alcohol intake, body mass index)
Age, race, gender, life style factors plus diabetes, hypertension
and low density lipoprotein cholesterol
¤ Myocardial infarction, angina pectoris, stroke, intermittent claudication
Environmental tobacco smoke
§ From table 1 (0.705 – 0.693 = 0.012)
0.019 (p0.001)
0.018 (p=0.003)
0.016 (p=0.001)
(12) Why is it important to examine the association between passive smoking and
carotid wall thickness adjusting for different combinations of risk factors (as
opposed to using a single model in which all potential confounders are
simultaneously adjusted)? What is the reason why the adjusted values are
larger than the unadjusted ones?
(13) What is the main shortcoming of assessing environmental tobacco smoke as a
dichotomous variable, as done in tables 1 and 2, and Figure 3?
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The relationship of reported number of hours of environmental tobacco smoking (ETS)
exposure to carotid wall thickness has been also assessed in ARIC. Using the authors’ own
words, the results (not shown in a table) were as follows: “For the 885 men with ETS exposure,
after controlling for age and race, there was an increase in IMT of 0.00792 mm per 10 hours of
weekly ETS exposure, a relationship that proved statistically significant. Despite a larger
sample of ETS women (n=2340), the increase in IMT per 10 hours of ETS exposure was only
0.0011 mm, a difference that proved statistically insignificant (p=0.43).”
(14) In the absence of any other data in the report, can you critically assess whether
there is indeed a linear dose-response relationship in men? Why?
(15) Assuming that these estimates of wall thickness increases are accurate and
precise, what term would you use to describe the gender difference? What are
some possible reasons for this difference?
In one of the four communities included in the ARIC study, Washington County,
Maryland (the Johns Hopkins site), the sampling frame used to select the ARIC cohort was
based on current Motor Vehicle Administration data, supplemented by a private census
conducted iun 1975 by the Johns Hopkins Training Center for Public Health Research.
About 2,884 of the 4,023 individuals who participated in the Washington County ARIC
baseline examination conducted in 1987-89 could be identified in the 1975 census, which
collected information on smoking in the household (Figure 4). Of these persons, data on both
smoking in 1975 and carotid wall thickness in 1987-89 were available for 2,073 (about 51% of
the total ARIC Washington County cohort). These 2,073 Washington County ARIC cohort
participants comprised the study group used by Diez-Roux et al to examine the relationship of
both active and passive smoking in 1975 to carotid wall thickness measured in the ARIC
baseline visit approximately 12 to 14 years later (Figure 5) (Preventive Medicine
1995;24:48-55).
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Figure 4. Schematic representation of the connection between the ARIC study Washington
County cohort at baseline (1987-89) and the Washington County census (1975)
ARIC BASELINE VISIT (1987-89)
Jackson, Miss
Minneapolis, MN
(n~3,600)
(n~4,000)
Wash Co, MD,
linked to 1975
census
(n~2,884)
Wash Co,
MD, not
linked to
1975 census
(n~1,139)
Forsythe Co, NC
(n~4,000)
WASHINGTON
COUNTY
CENSUS
(1975)
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Figure 5. Passive smoking collected in the 1975 Washington County Census carried out by the
Training Center for Public Health Research and carotid wall thickness measured in 1986-89 as
part of ARIC’s baseline visit (n=2,073).
Passive smoking (census) in
1975
Carotid Wall thickness (ARIC baseline visit)
in 1986-89
(16) What important causality criterion can be partly assessed in the study by Diez-
Roux, but not in Howard’s study? (The results of the latter are shown in tables 1
and 2 and Figure 3.) What are the major shortcomings of Diez-Roux’s design
which prevent a full assessment of the criterion?
When comparing the final study group with ARIC participants not linked to the 1975
census, some differences were noted, as shown in table 3:
Table 3. Characteristics of ARIC Participants Not Linked to the 1975 Census and the Study
Group in the Analysis by Diez-Roux et al
Characteristic (measured at the
time of the ARIC baseline visit)
ARIC Participants Not Linked
to the 1975 Census (n=1139)
Study Group (n=2073)
Mean Age in years (standard
deviation) 51.4 (5.7) 54.9 (5.5)
Percentage with High School
Education 72.4 70.5
LDL Cholesterol in mg/dl
(Standard Deviation) 138.3 (35.9) 139.6 (38.6)
Systolic Blood Pressure in
mmHg (Standard Deviation) 117.3 (16.7) 119.3 (17.6)
Percentage with Diabetes 9.1 8.7
Mean Carotid Wall Thickness in
0.746 (0.188) 0.758 (0.212)
mm (Standard Deviation)
The characteristics of the 811 ARIC Washington County cohort participants who were linked
to the 1975 census, but with missing information on passive smoking or wall thickness were
very similar to those of the study group.
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(17) Could these differences have affected the results pertaining to the relationship
between exposure to smoke in 1975 and wall thickness in 1987-89? Why or why
not?
The results of the analysis by Diez-Roux are shown in table 4.
Table 4. Crude and adjusted mean carotid wall thickness (mm) by exposure to tobacco smoke,
excluding persons with prevalent clinical cardiovascular disease¤, Washington County, 1975
and 1987-89
Exposure status
Never Active Smokers:
Sample
Size
Crude Mean
(mm)
Adjusted mean§ ± standard
error (mm) [p-value§§]
No ETS 189 0.681 0.696 ± 0.012
ETS 1975 only 65 0.711 0.722 ± 0.021 [0.29]
ETS 1987-89 only 250 0.732 0.733 ± 0.011 [0.02]
ETS 1975 and 1987-89 219 0.692 0.722 ± 0.012 [0.13]
Never Active Smokers Ever
Exposed to ETS
534 0.713 0.727 ± 0.007 [0.03]
Current active smoking in
both 1975 & 1987-89
362 0.776 0.785 ± 0.009 [0.0001]
¤ Myocardial infarction, angina pectoris, stroke, intermittent claudication
§ Adjusted for age, gender, systolic blood pressure, LDL cholesterol, presence of diabetes, fat
intake, physical activity scores, alcohol intake, education, body mass index
§§ P value vis-à-vis never active smokers not exposed to environmental tobacco smoke
Environmental tobacco smoke
(18) Do the results of the study by Diez-Roux et al confirm those of the study by
Howard et al? Are the results in table 4 entirely consistent with the hypothesis
that intensity of exposure is related to carotid wall thickness? How can the
consistency or lack thereof be explained?
(19) The results of the adjustment presented in table 4 were based on a multiple
linear regression model. Why?
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Matanoski et al compared the characteristics of about 2,500 non-active smoking women
whose husbands were smokers with those of approximately 1,400 non-active smoking women
whose husbands did not smoke. The study population was identified among women who had
participated in the first National Health and Nutrition Examination Survey (NHANES I) carried
out in 1971-75 and the NHANES I Epidemiologic Follow-up Study conducted in 1982-84 (Am J
Epidemiol 1995;142:149-57). The odds of having a smoking husband relative to that of having
a nonsmoking husband according to selected demographic and dietary characteristics are
shown in table 5.
Table 5. Odds ratios of having a smoking husband in women who were not active smokers
according to selected demographic and dietary variables: first National Health and Nutrition
Examination Survey (NHANES I) and NHANES I Epidemiologic Follow-up Study.
Characteristic/Food
Odds Ratio (95% confidence interval)
Age 60 years vs. < 40 1.29 (1.10-1.51)
White vs. Nonwhite 0.79 (0.65-0.95)
Urban vs. Rural residence 1.17 (1.01-1.36)
Education > 12 years vs. < 12 years 0.48 (0.40-0.57)
Raw vegetables 1 or more times daily vs. less than
once daily§
0.87 (0.75-1.02)
Eats poultry skin: Yes vs. No§ 1.19 (1.03-1.37)
Odds ratio = [Odds of exposure to factor with smoking spouse] [Odds of exposure to factor
with nonsmoking spouse]
§ Age-adjusted
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The relationship between education and atherosclerosis measured by average carotid
intima-media thickness using baseline data from the ARIC study is shown in table 6 (Am J
Epidemiol 1995;141:960-72).
Table 6. Age and gender-adjusted mean differences (mm) in intima-media carotid artery
average thickness by education and race.
Age and gender-adjusted mean differences (mm)
between each category and the reference category
Educational Level Blacks (n=3,318) Whites (n=9,140)
8 th grade or less 0.036 0.068
9 th – 11 th grade 0.033 0.058
12 th grade or GED 0.005 0.034
1-3 years of vocational school 0.003 0.028
1-4 years of college 0.000 0.018
Graduate or Professional school Reference Reference
General Education Development degree
(20) How do the results shown in tables 5 and 6 affect your inference that passive
smoking is a risk factor for atherosclerosis in general?
(21) Do you believe that passive smoking causes atherosclerosis? Why?
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