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Cardiovascular Risk Factors and Venous Thromboembolism Incidence
The Longitudinal Investigation of Thromboembolism Etiology
Albert W. Tsai, PhD;
Mary Cushman, MD;
Wayne D. Rosamond, PhD;
Susan R. Heckbert, MD, PhD;
Joseph F. Polak, MD, MPH;
Aaron R. Folsom, MD
Arch Intern Med. 2002;162:1182-1189.
ABSTRACT
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Background The association between traditional cardiovascular risk factors and
risk of venous thromboembolism (VTE) has not been extensively examined in
prospective studies.
Methods To determine whether atherosclerotic risk factors are also associated
with increased incidence of VTE, we conducted a prospective study of 19 293
men and women without previous VTE in 6 US communities between 1987 and 1998.
Results There were 215 validated VTE events (1.45 per 1000 person-years) during
a median of 8 years of follow-up. The age-adjusted hazard ratio was 1.4 (95%
confidence interval [CI], 1.1-1.9) for men vs women, 1.6 (95% CI, 1.2-2.2)
for blacks vs whites, and 1.7 (95% CI, 1.5-2.0) per decade of age. Cigarette
smoking, hypertension, dyslipidemia, physical inactivity, and alcohol consumption
were not associated with risk of VTE. Age-, race-, and sex-adjusted hazard
ratios for body mass index categories (calculated as the weight in kilograms
divided by the height in meters squared) of less than 25, 25 to less than
30, 30 to less than 35, 35 to less than 40, and 40 or more were 1.0, 1.5,
2.2, 1.5, and 2.7, respectively (P<.001 for the
trend). Diabetes was also associated with an increased risk of VTE (adjusted
hazard ratio, 1.5 [95% CI, 1.0-2.1]).
Conclusions Our data showing no relationship of some arterial risk factors with
VTE corroborate the view that the etiology of VTE differs from atherosclerotic
cardiovascular disease. In addition, the findings suggest a hypothesis that
avoidance of obesity and diabetes or vigilance in prophylaxis in patients
with those conditions may prevent some venous thromboses.
INTRODUCTION
DEEP VEIN thrombosis (DVT) and pulmonary embolus (PE), collectively
referred to as venous thromboembolism (VTE), are major sources of morbidity
and mortality. Several risk factors for VTE are well established, including
hereditary predisposition, immobilization, surgery, and cancer.1
However, it remains unclear whether arterial disease risk factors are also
important to VTE because few population-based prospective epidemiologic studies
of VTE have been done.2-4
None has examined whether physical inactivity or abstaining from alcohol may
increase risk of VTE.
Risk factors might contribute to the development and propagation of
a venous thrombus by enhancing coagulability, endothelial injury, or venous
stasis. For example, cigarette smoking is associated with elevated levels
of plasma fibrinogen and may activate the intrinsic coagulation pathway through
endothelial wall damage or anoxia.5-6
Physical inactivity, obesity, and diabetes are associated with enhanced coagulation
and reduced fibrinolytic potential and may contribute to venous stasis.6 Lipids, particularly elevated lipoprotein(a) ([Lp(a)])
or triglycerides, interact with the coagulation and fibrinolytic cascades.6 In contrast, alcohol use is associated with enhanced
fibrinolysis and reduced fibrinogen levels.5-6
The Longitudinal Investigation of Thromboembolism Etiology combines
information from 2 prospective cohort studies, the Atherosclerosis Risk In
Communities (ARIC) study7 and the Cardiovascular
Health Study (CHS),8-9 to investigate
multiple risk factors for VTE. This analysis explores the associations between
arterial disease risk factors and incidence of VTE.
SUBJECTS AND METHODS
STUDY POPULATION
The ARIC study is a prospective epidemiologic study that investigates
the etiology of atherosclerosis and its clinical sequelae in 4 US communities.7 These communities include Forsyth County, North Carolina;
Jackson, Miss; suburbs of Minneapolis, Minn; and Washington County, Maryland.
The study population consisted of 15 792 men and women, aged 45 to 64
years at recruitment in 1987 through 1989. Three samples represent the ethnic
mix of their communities; the Jackson sample is composed exclusively of black
subjects. A home interview, which included items on cardiovascular risk factors,
socioeconomic factors, and family medical history, was administered to each
cohort member. A subsequent clinic visit included physical measures, including
sitting blood pressure, anthropometry, venipuncture, and medical history.
Participants underwent reexamination in 1990 through 1992 (93% return rate),
1993 through 1995 (86%), and 1996 through 1998 (80%). A telephone questionnaire
was administered annually to update information on cardiovascular events and
hospitalizations.
The CHS is a population-based longitudinal study of coronary heart disease
and stroke in adults 65 years and older.8-9
A total of 5201 men and women sampled from Medicare eligibility lists were
recruited from 4 communities in 1989 through 1990. These communities were
Forsyth County, North Carolina; Sacramento County, Calif; Washington County,
Maryland; and Pittsburgh, Pa. An additional 687 black subjects were recruited
in 1992 and 1993. Extensive physical and laboratory evaluations were performed
to identify the presence and severity of cardiovascular disease risk factors.
Follow-up included semiannual contacts, alternating between telephone calls
and surveillance clinic visits through 1999. The participation rate (for clinic,
phone, or proxy contact) in 1998-1999 was 95%. Both studies were approved
by institutional review committees, and the subjects gave written informed
consent at the baseline interviews.
RISK FACTOR MEASUREMENTS
The 2 studies had very similar protocols for many baseline risk factor
measurements, allowing us to pool data to increase statistical power. In both
studies, weight in pounds, standing height, and waist and hip circumference
in centimeters were measured at the clinic examination by standard protocols.
Level of overweight was measured by body mass index (BMI). Both studies asked
questions on number of cigarettes smoked per day and duration of smoking;
responses to these questions provided the foundation for the definitions of
smoking status and pack-years of smoking. Average alcohol intake (grams per
week) was calculated in both studies based on the weekly number of glasses
of wine, number of bottles and/or cans of beer, and number of drinks of liquor.
Blood pressure was measured in both studies using the same protocol.
Three measurements were taken with a random-zero sphygmomanometer, and the
mean of the last 2 of 3 measurements was used. Hypertension was defined as
systolic blood pressure of 140 mm Hg or higher or diastolic blood pressure
of 90 mm Hg or higher or current treatment with blood pressure medications.
Pooling of some variables was not possible between the ARIC and CHS
studies. The ARIC study used the Baecke questionnaire10
for physical activity, expressed as a sport index or a leisure-time index
ranging from 0 (low) to 5 (high). In the CHS, a modified Health Interview
Survey questionnaire11 was administered, yielding
an estimate of total kilocalories expended per week, including total leisure
activity and household kilocalories.
LABORATORY METHODS
Blood collection, sample preparation, and laboratory quality assurance
methods in the CHS were patterned after the ARIC study.12-15
Diabetes mellitus was defined at baseline as fasting glucose levels of 126
mg/dL (7 mmol/L) or higher,16 nonfasting glucose
levels of 200 mg/dL (11.1 mmol/L) or higher, or a history of or treatment
for diabetes. Impaired fasting glucose level was defined as 110 mg/dL (6.1
mmol/L) or higher but lower than 126 mg/dL (7 mmol/L). Plasma total cholesterol
(milligrams per deciliter) and triglyceride levels (milligrams per deciliter)
were measured by enzymatic methods in both studies using Centers for Disease
Control and Prevention–standardized laboratories, and low-density lipoprotein
(LDL) cholesterol (milligrams per deciliter) was calculated indirectly using
the Friedewald equation.17 High-density lipoprotein
(HDL) cholesterol was measured after precipitation of the other lipoprotein
fractions by dextran sulfate.18 In the ARIC
study, Lp(a) (milligrams per deciliter) was measured as its total apolipoprotein
by using a double-antibody enzyme-linked immunosorbent assay technique for
apolipoprotein(a) detection.19 In the CHS,
Lp(a) was measured as its total apolipoprotein using a double-antibody enzyme-linked
immunosorbent assay that detects the various isoforms of Lp(a) using in-house
reagents, with monoclonal antibodies and calibrator provided by Wei Lee Wong,
PhD, at Genentech Inc, South San Francisco, Calif.20
CASE ASCERTAINMENT
The ARIC study cohort was contacted annually by telephone and seen at
a clinic visit every 3 years through 1998. Hospitalizations were identified
by participant report and surveillance of local hospital discharge lists for
cohort members. For each hospitalization identified, International
Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge codes were recorded. In the CHS, follow-up
involved alternating telephone calls and clinic visits every 6 months. Hospitalizations
were identified primarily by self-report of the participant or proxy, and
additionally by search of Health Care Financing Administration records. For
every hospitalization, hospital discharge summaries and ICD-9-CM discharge codes were obtained. From each study's discharge
code database, cases of possible VTE were identified by each study's coordinating
center using the following ICD-9-CM codes: 415.1x,
451, 451.1x, 451.2, 451.8x, 451.9, 453.0, 453.1, 453.2, 453.8, 453.9, 996.7x,
997.2, and 999.2, and procedure code 38.7.
Hospital records were obtained at each field center and photocopies
made of discharge summaries, physician and consultant reports, vascular and
radiological studies, and records of hospitalizations within 3 months of the
index hospitalization. Information retrieved from the hospital records was
assigned a VTE classification separately by 2 physicians (M.C. and A.R.F.).
Differences between the 2 physicians were adjudicated by discussion.
CASE CLASSIFICATION
Deep vein thrombosis was classified as definite, probable, or absent.
Definite DVT was defined by a positive duplex ultrasound or venogram finding
or occasionally by other means such as computed tomography. Probable DVT required
a positive Doppler ultrasound or impedance plethysmography finding. A clinical
diagnosis in the absence of objective tests was not considered to be a DVT.
Deep vein thrombosis was further categorized as right or left lower extremity,
upper extremity, or other site, and if in the lower extremity, as proximal,
distal, or unknown. Pulmonary embolus was classified as definite or absent
based on high-probability lung scintigraphy findings classified according
to the PIOPED criteria,21 angiogram results,
or autopsy findings. Classification as definite PE required ventilation perfusion
scanning that showed multiple segmental or subsegmental mismatched perfusion
defects, a positive pulmonary angiogram, or occasionally another positive
test finding (eg, computed tomography). Indeterminate scans without angiograms,
positive findings of perfusion scans in the absence of ventilation scans,
and clinical diagnosis in the absence of objective testing were considered
nondiagnostic.
At the time of adjudication, each event was classified as an idiopathic
or secondary VTE. All events that occurred within 12 months of a cancer diagnosis
or within 90 days of acute medical conditions (eg, major trauma, surgery,
or marked immobility) were classified as secondary.
SUBJECTS
Participants with self-reported prevalent VTE at baseline (n = 630),
those taking anticoagulant medication (n = 185), and those having a history
of cancer at baseline (n = 1714) were excluded from the analysis. Prevalent
VTE was defined in the CHS by participants' positive response to either of
the following baseline questions: "Has a doctor ever told you that you had
deep vein thrombosis or blood clots in your legs?" or "Has a doctor ever told
you that you had pulmonary embolus or blood clots in your lungs?" In the ARIC
study, prevalent VTE at baseline was determined retrospectively at the visit-4
examination by participants' positive response to either of the following
questions: "Has a doctor ever told you that you had a blood clot in the leg
(deep vein thrombosis)?" or "Has a doctor ever told you that you had a blood
clot in your lungs (pulmonary embolus)?" In the ARIC study, prevalent VTE
information was missing on participants who did not attend the visit-4 exam;
these people and those who reported their VTE history as unknown (total, 4269)
were included as at risk for incident VTE. Participants with a history of
cancer were excluded.
STATISTICAL ANALYSIS
The dependent variable was occurrence of first validated VTE (definite
or probable DVT or definite PE) from baseline (1989-1990) through June 30,
1997, in the CHS and baseline (1987-1990) through December 31, 1996, in the
ARIC study. All independent variables were measured at the baseline examination.
Incidence rates and 95% confidence intervals (CIs) were calculated using
Poisson regression models. Cox proportional hazards regression models were
used to estimate the hazard ratios (HRs) of VTE by level of each risk factor.
A test for interaction of each risk factor with time showed that the proportional
hazards assumption was not violated. Independence of variables was determined
by statistical significance of the Wald  2 values for main
effect terms after adding covariates to the models. Potential interactions
of all risk factors with age, race, or sex were tested by using cross-product
terms in the proportional hazards models. Trends in HRs were examined by fitting
a linear model to the median values within increasing categories of each risk
factor. We explored the possibility that those at the extreme values of some
of these risk factors might be at increased risk of VTE by computing the HRs
in the upper decile compared with the lowest tertile of LDL cholesterol, HDL
cholesterol, total cholesterol, triglyceride, and Lp(a) levels, and the lowest
decile of alcohol consumption and physical activity vs the highest tertile.
Etiologic fractions (EF) were calculated using a standard formula: EF = p(RR -
1)/(1 + p [RR-1]), where p is the proportion of population exposed to
the risk factor, and RR is the estimate for relative risk (HR) for the disease
for those above vs below a standard cutoff point of that risk factor.
RESULTS
The mean age of the 19 293 participants at baseline was 59 years,
with 55% of the sample being women, 26% black, and 92% having a high school
education or less. After exclusions, there were 215 validated incident VTE
events (93 idiopathic, 122 secondary) during 148 054 person-years of
follow-up (median, 7.8 years) for an overall crude incidence rate of VTE of
1.45 per 1000 person-years (95% CI, 1.27-1.66). Of the 215 events, 130 occurred
within the ARIC study sample while 85 occurred in the CHS (Table 1). The crude incidence rate was higher in the older CHS cohort
(2.80 per 1000 person-years) than in the ARIC study cohort (1.10 per 1000
person-years). The event rate was higher in men (1.70 per 1000 person-years)
than in women (1.24 per 1000 person-years). In addition, the rate in blacks
was higher than in whites (1.68 vs 1.38 per 1000 person-years).
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Table 1. Number of Incident Venous Thrombosis or Pulmonary Embolic
(VTE) Events and Crude VTE Incidence Rates*
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Table 2 summarizes age-adjusted
incidence rates of VTE and HRs adjusted for age, race, and sex by various
levels of cardiovascular risk factors under consideration. Compared with subjects
younger than 55 years at baseline, the incidence of VTE was 2 to 7 times higher
in older age groups. Incidence increased 74% (95% CI, 53%-98%) per decade
of age when modeled as a continuous variable. Men were at substantially increased
risk compared with women (HR, 1.44; 95% CI, 1.10-1.89), as were blacks compared
with whites (HR, 1.64; 95% CI, 1.21-2.22). We found no association between
education level and the incidence of VTE.
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Table 2. Age-Adjusted Incidence Rates of Venous Thrombosis or Pulmonary
Embolic (VTE) Events per 1000 Person-Years by Risk Factor Status and Age-,
Race-, and Sex-Adjusted Hazard Ratios of VTE*
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Many of the traditional atherosclerotic risk factors, including cigarette
smoking (status and pack-years), hypertension, low alcohol consumption, physical
inactivity, and dyslipidemia were not associated with elevated risk of VTE
(Table 2). Tests for trends in
HRs were not statistically significant for any of those risk factors. Those
in the extreme categories of each of these risk factors were not at significantly
higher risk of VTE. The ARIC study, but not the CHS, had data on number of
cigarettes smoked currently; current heavy smokers ( 25 cigarettes per
day) were at nonsignificantly higher risk than never smokers (HR, 1.68; 95%
CI, 0.91-3.1). Nonsteroidal anti-inflammatory medication use was associated
with a 1.44-fold increase in risk (95% CI, 1.03-2.02), but this association
became null after further adjustment for BMI and diabetes. Other variables,
including aspirin use, elevated hematocrit, elevated hemoglobin level, and
elevated platelet count were also not associated with increased risk of VTE
(Table 2).
In contrast, obesity and diabetes were each associated with significantly
increased risks of VTE in the age-, race-, and sex-adjusted models (Table 2). The incidence of VTE in the upper
tertile of BMI (calculated as the weight in kilograms divided by height in
meters squared) was 2.42 times that in those in the lowest BMI tertile. The
incidence of VTE in obese individuals (BMI 30) was 2.01 (95% CI, 1.60-2.52)
per 1000 person-years, compared with 0.83 (95% CI, 0.62-1.11) in those with
BMI lower than 25. Those with diabetes at baseline had a 1.70-fold greater
risk (95% CI, 1.20-2.40) than those with normal fasting glucose levels, although
those with impaired fasting glucose levels were not at increased risk.
Table 3 shows the multivariate-adjusted
HRs for VTE. Increasing age conveyed greater risk of VTE, with those 85 years
or older having a 15-fold higher risk than those aged 45 to 54 years. The
age association was greater for secondary than for idiopathic VTE (Figure 1). The HR for any VTE was 1.40 (95%
CI, 1.02 -1.93) for blacks vs whites, slightly larger for secondary than for
idiopathic (Figure 1). Men were
at higher risk than women, and this HR was only significant for secondary
VTE (HR, 1.65; 95% CI, 1.14-2.40) (Figure
1).
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Table 3. Multivariate Hazard Ratios for Venous Thrombosis or Pulmonary
Embolic (VTE) Events by Risk Factor Level*
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Multivariate hazard ratios with confidence intervals for idiopathic
and secondary venous thrombosis or pulmonary embolic (VTE) events by risk
factor level. Body mass index (BMI) is calculated as weight in kilograms divided
by height in meters squared.
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In the multivariate model, BMI (5 categories) remained positively associated
with VTE incidence (P<.001 for the trend), although
the HRs did not increase in a monotonic manner (Table 3). Those subjects in the highest category of BMI (40)
were at nearly 3 times greater risk of VTE than those with BMIs lower than
25. In a separate model (not shown) with BMI as a dichotomous variable (cutoff
BMI, 30), the etiologic fraction of VTE due to obesity was calculated to be
15%, based on a prevalence of 26% of the sample with a BMI of 30 or higher
and an HR of 1.71 (1.27-2.29) for a BMI of 30 or higher vs lower than 30.
The association of BMI and VTE was greater for idiopathic VTE than secondary
VTE, as shown in Figure 1. After
adjustment for BMI, the HR for VTE for diabetes vs no diabetes was attenuated
to 1.46 (95% CI, 1.03-2.05). Compared with those subjects with no diabetes,
those with diabetes had a greater risk for secondary VTE (HR, 1.62; 95% CI,
1.03-2.54) than for idiopathic VTE (HR, 1.27; 95% CI, 0.75-2.16).
There was a statistically significant age-by-race interaction (P = .02), with older blacks at highest risk of VTE. However,
a stratified analysis suggested that the HR differences between the race groups
with increasing age were minimal, and there were relatively few VTE events
among blacks. In the absence of a main effect, an age-by-hypertension interaction
was statistically significant (P = .02), with those
of older age with hypertension at highest risk. No other interactions between
any of the remaining risk factors and age, race, or sex were observed.
COMMENT
We found that VTE incidence was associated with older age, male sex,
black ethnicity, BMI, and diabetes. Venous thromboembolism was not associated
with educational attainment, smoking, alcohol consumption, physical inactivity,
hypertension, or lipid or Lp(a) levels.
There are few epidemiologic reports on the association between coronary
heart disease risk factors and VTE. To our knowledge, no data have been reported
on the association of VTE with alcohol consumption or physical activity. While
we hypothesized that low consumption of alcohol might increase risk of venous
thrombosis, we found no such association. Similarly, very low physical activity
might be associated with venous stasis, but there was no increase in risk
of VTE with low physical activity levels, as measured at baseline.
Results vary across studies of the association of VTE incidence and
dyslipidemia, cigarette smoking, and hypertension. In the Framingham Study,2 higher total serum cholesterol levels in women (but
not men) predicted increased PE death. A Japanese case-control study showed
that hyperlipidemia was more prevalent in patients with DVT than in controls.22 However, a study of Swedish men found no association
between serum cholesterol or triglyceride levels and VTE.23
Likewise, the Nurses' Health Study3 found no
association between high serum cholesterol levels and primary PE. In a study
of children, no difference in plasma levels of cholesterol, triglycerides,
HDL cholesterol, or LDL cholesterol was found between those with venous thrombosis
and controls, but an increased Lp(a) level (>30 mg/dL) was a risk factor (odds
ratio, 7.2; 95% CI, 3.7-14.5).24 Elevated Lp(a)
levels, as a potential antifibrinolytic factor, may also increase risk of
VTE. In a case-control study, von Depka et al25
found that VTE was associated with elevated Lp(a) levels. We found no association,
however, between lipid levels and risk of VTE. The only suggested association
was between Lp(a) levels and VTE in blacks, but this was hampered by a limited
sample size.
Despite a reasonable biological basis for hypothesizing a relationship
between smoking and VTE, we found no association. A number of case-control
studies26-28 and
1 prospective study29 also found no association
between cigarette smoking and risk of VTE. The Framingham Study2
reported a borderline association of PE death with cigarette use in men but
not in women. However, the Nurses' Health Study found that heavy cigarette
smoking predicted PE (HR, 3.3; 95% CI, 1.7-6.5),3
and a study of Swedish men found that smoking 15 cigarettes per day or more
carried an HR of 2.82 (95% CI, 1.30-6.13).23
There is conflicting evidence from past studies about the association
of hypertension with VTE. The Nurses' Health Study found that self-reported
hypertension was associated with PE incidence (HR, 1.9; 95% CI, 1.2-2.8).
However, no association was found between blood pressure and risk of death
from PE in the Framingham cohort2 or incidence
of VTE in Swedish men.23 There was no evidence
for an association of hypertension with VTE in the Longitudinal Investigation
of Thromboembolism Etiology.
We found that VTE incidence increases with age, consistent with previous
studies.4, 30 Age is a very significant
risk factor for VTE, since the HRs are dramatically increased in the later
decades of life. Men were at higher risk for VTE than women in this study,
which agrees with other reports of middle-aged to older subjects.1, 30-32 In
contrast, studies of younger subjects have reported VTE incidence higher in
women than in men.31 Blacks had a higher incidence
of VTE than whites. Other researchers have reported higher mortality33-34 and incidence35
of VTE in blacks.
Obesity is another important cardiovascular risk factor whose role in
venous disease has not been extensively studied. Our findings of a significant
positive and independent association between BMI and risk of VTE are consistent
with several previous studies.2-3,23, 27, 36-37
In addition, higher BMI was associated with a somewhat greater risk of idiopathic
than secondary VTE. Obesity is associated with venous stasis and with higher
levels of prothrombotic factors such as fibrinogen, plasminogen activator
inhibitor 1, and factor VII,38-39
which may partly explain the relationship. On the other hand, it is possible
that obese individuals were more likely to be hospitalized (and thus subject
to precipitating factors such as surgery and immobilization) during the follow-up
period. In any case, we found that a considerable amount of VTE (etiologic
fraction, 15%) might be due to obesity in the population.
There is little information about the association of diabetes mellitus
with the risk of VTE. Diabetes was not related to idiopathic PE (HR, 0.7;
95% CI, 0.3-1.9) in the Nurses' Health Study.3
In addition, neither the Framingham Study2
nor the study of Swedish men23 found any relationship
between glucose level and VTE end points. In contrast, our results suggest
that diabetes is associated with a 60% increase in the risk of VTE. Diabetes
is associated with a hypercoagulable state and vascular damage,40
which may play a causal role in VTE. Because the association was attenuated
after accounting for BMI, it is likely that some of the association with diabetes
mellitus is related to a higher prevalence of obesity among people with diabetes.
Since few established arterial disease risk factors are associated with
the risk of VTE, it is reasonable to conclude that venous disease has a different
etiology from arterial disease. Although thrombosis following atherosclerotic
plaque rupture is important, risk factors such as cigarette smoking and hypertension
may contribute more to atherosclerosis, endothelial dysfunction, and plaque
instability than to thrombosis per se. Levels of prothombotic or fibrinolytic
factors may play a larger role in venous disease than do atherosclerosis risk
factors.
The present study has many strengths. It is one of the largest epidemiologic
studies to investigate risk factors for VTE. The cohorts studied are typical
of general US adult populations, including a wide age range. Validation of
VTE events was standardized and thorough, and risk factors were accurately
measured. The main limitation was that the ARIC and CHS studies had somewhat
different methods for measuring a few risk factors, but the fact that there
were no important interactions with age suggests that pooling the results
probably did not create a biased result. Another limitation was that statistical
power was insufficient for detailed analysis of VTE risk factors by race or
sex.
In summary, among traditional risk factors for atherosclerotic cardiovascular
disease, only age, male sex, black ethnicity, obesity, and diabetes were independently
associated with VTE incidence in these pooled cohorts. The fact that smoking,
high blood pressure, and dyslipidemia were not associated with VTE corroborates
that venous disease likely has a different etiology from that of atherosclerotic
cardiovascular disease. However, our data suggest a hypothesis that avoidance
of obesity and diabetes, or vigilance in prophylaxis of patients with these
conditions, might be able to prevent some venous thromboses.
AUTHOR INFORMATION
Accepted for publication September 27, 2001.
The ARIC study was funded by contracts N01-HC-55015, N01-HC-55016, N01-HC-55018,
N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022, and the CHS was
funded by contracts N01-HC-85079 through N01-HC-85086 from the National Heart,
Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
We thank the staff and participants in the CHS and ARIC study for their
important contributions over many years.
Corresponding author and reprints: Aaron R. Folsom, MD, Division
of Epidemiology, School of Public Health, University of Minnesota, 1300 S
Second St, Suite 300, Minneapolis, MN 55454 (e-mail: folsom{at}epi.umn.edu).
From the Division of Epidemiology, School of Public Health, University
of Minnesota, Minneapolis (Drs Tsai and Folsom); Department of Medicine, Division
of Hematology/Oncology, University of Vermont, Burlington (Dr Cushman); Department
of Epidemiology, School of Public Health, University of North Carolina at
Chapel Hill (Dr Rosamond); Department of Epidemiology, Cardiovascular Health
Research Unit, University of Washington, Seattle (Dr Heckbert); and Department
of Radiology, Brigham and Women's Hospital, Harvard University, Boston, Mass
(Dr Polak).
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