Vascular Medicine
Racial and Regional Differences in Venous
Thromboembolism in the United States in 3 Cohorts
Neil A. Zakai, MD, MSc; Leslie A. McClure, PhD; Suzanne E. Judd, PhD;
Monika M. Safford, MD; Aaron R. Folsom, MD; Pamela L. Lutsey, PhD; Mary Cushman, MD, MSc
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
Background—Blacks are thought to have a higher risk of venous thromboembolism (VTE) than whites. However, prior
studies are limited to administrative databases that lack specific information on VTE risk factors or have limited
geographic scope.
Methods and Results—We ascertained VTE from 3 prospective studies: the Atherosclerosis Risk in Communities Study
(ARIC), the Cardiovascular Health Study (CHS), and the Reasons for Geographic and Racial Differences in Stroke study
(REGARDS). We tested the association of race with VTE using Cox proportional hazard models adjusted for VTE risk
factors. Over 438 090 person-years, 916 incident VTE events (302 in blacks) occurred in 51 149 individuals (17 318
blacks) who were followed up. In risk factor–adjusted models, blacks had a higher rate of VTE than whites in the CHS
(hazard ratio, 1.81; 95% confidence interval, 1.20–2.73) but not ARIC (hazard ratio, 1.21; 95% confidence interval,
0.96–1.54). In REGARDS, there was a significant region-by-race interaction (P=0.01): Blacks in the Southeast had a
significantly higher rate of VTE than blacks in the rest of the United States (hazard ratio, 1.63; 95% confidence interval,
1.08–2.48) that was not seen in whites (hazard ratio, 0.83; 95% confidence interval, 0.61–1.14).
Conclusions—The association of race with VTE differed in each cohort, which may reflect the different time periods of the
studies or different regional rates of VTE. Further studies of environmental and genetic risk factors for VTE are needed to
determine which underlie racial and perhaps regional differences in VTE. (Circulation. 2014;129:1502-1509.)
Key Words: continental population groups ◼ epidemiology ◼ venous thrombosis
V
enous thromboembolism (VTE), consisting of pulmonary embolism (PE) and deep venous thrombosis (DVT),
is a common cardiovascular disease, affecting >300 000 individuals annually in the United States with 100 000 fatalities
per year.1 Many studies suggest that black Americans have
higher rates of VTE than white Americans.2 Reasons for these
potential racial differences are unclear, with risk factors such
as obesity,3 diabetes mellitus,4 and elevated factor VIII5 being
more common in blacks and genetic polymorphisms such as
factor V Leiden and the prothrombin gene 20210A mutation
more common in whites.2
any observed differences, we assessed VTE incidence in blacks
and whites in 3 large cohorts: the Cardiovascular Health Study
(CHS), the Atherosclerosis Risk in Communities Study (ARIC),
and the Reasons for Geographic and Racial Differences in
Stroke study (REGARDS).10–13 Together, these studies have
followed up 51 149 individuals over 439 090 person-­years and
include 17 318 blacks. They offer a unique opportunity to study
the association of race with VTE and, in the case of REGARDS,
to evaluate the association of region of residence with VTE in
the United States. Our goal was to study the association of race
with VTE risk in these 3 cohorts and whether common VTE
risk factors affected any race association.
Editorial see p 1463
Clinical Perspective on p 1509
Methods
Prior studies on race and VTE in the United States have been
limited in that they examined administrative databases without
validation of VTE events,6–8 had limited numbers of blacks, were
from discrete geographic areas, or excluded outpatient-treated
DVTs.9 Furthermore, many studies were not able to evaluate
whether differences in VTE risk factors explained any race association.6–8 To determine the association of race with VTE and to
evaluate whether conventional VTE risk factors might mediate
Cohorts
VTE events were ascertained in 3 longitudinal cohorts designed to
study the causes and consequences of vascular disease (Table 1 and
Table I in the online-only Data Supplement). ARIC12 recruited 15 792
individuals (4266 blacks) 45 to 64 years old in 1987 to 89 from 4
field centers: Forsyth County, North Carolina; Washington County,
Maryland; suburban Minneapolis, MN; and Jackson, MS. CHS13
recruited 5201 individuals ≥65 years of age in 1989 to 90 and an
Received September 24, 2013; accepted January 13, 2014.
From the University of Vermont, Burlington (N.A.Z., M.C.); University of Alabama at Birmingham, Birmingham (L.A.M., S.E.J.., M.M.S.); and
University of Minnesota, Minneapolis (A.R.F.., P.L.L.).
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.
113.006472/-/DC1.
Correspondence to Neil A. Zakai, MD, MSc, University of Vermont College of Medicine, Colchester Research Facility, 208 S Park Dr, Colchester, VT
05446. E-mail [email protected]
© 2014 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.113.006472
1502
Zakai et al Region, Race, and Venous Thrombosis in the US 1503
Table 1. Cohort Characteristics by Race
ARIC
Participants, n
CHS
Blacks
Whites
Blacks
Whites
Blacks
Whites
4266
11 478
924
4925
12 128
17 428
Mean (SD) follow-up, y
15.1 (4.4)
15.8 (3.7)
Person-years of follow-up
65 263
181 829
Mean age (SD), y
53.6 (5.8)
54.4 (5.7)
Minimum, maximum age, y
REGARDS
44, 66
44, 66
7.9 (2.8)
7336
72.9 (5.7)
9.7 (3.4)
4.6 (1.7)
4.7 (1.6)
47 720
55 254
82 689
72.8 (5.6)
64.1 (9.3)
65.4 (9.5)
64, 93
63, 100
45, 96
45, 98
Male, n (%)
1631 (38)
5428 (47)
343 (37)
2,135 (43)
4578 (38)
8687 (50)
BMI (SD), kg/m2
29.6 (6.2)
27.0 (4.9)
28.5 (5.6)
26.3 (4.5)
30.8 (6.7)
28.3 (5.6)
16 (2)
81 (2)
111 (0.9)
199 (1)
Obesity, n (%)
Underweight (BMI <18.5 kg/m2)
Normal (BMI 18.5–24.9 kg/m )
45 (1)
97 (0.8)
887 (21)
4162 (36)
226 (25)
1934 (39)
2074 (17)
4873 (28)
Overweight (BMI 25–29.9 kg/m2)
1589 (37)
4597 (40)
381 (41)
2036 (42)
4016 (33)
6814 (39)
Obese (BMI ≥30 kg/m2)
1730 (41)
2612 (23)
297 (32)
860 (18)
5823 (48)
5447 (31)
821 (20)
1046 (9)
230 (26)
715 (15)
3588 (31)
2672 (16)
2374 (56)
3121 (27)
713 (77)
3138 (64)
8641 (71)
8821 (51)
103 (18)
93 (13)
80 (23)
67 (17)
90 (26)
82 (21)
eGFR ≥ 60 mL·min−1·1.73 m−2
4024 (98)
11 284 (98)
719 (82)
3083 (63)
10 195 (89)
14 834 (88)
eGFR 30–59 mL·min ·1.73 m
77 (2)
143 (16)
1753 (36)
1059 (9)
eGFR 15–29 mL·min−1·1.73 m−2
10 (0.2)
2 (0.02)
8 (0.9)
53 (1)
117 (1)
eGFR 0–14 mL·min−1·1.73 m−2
0 (0)
0 (0.0)
6 (0.7)
2
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Diabetes mellitus, n (%)
Hypertension, n (%)
Mean (SD) eGFR, mL·min−1·1.73 m−2
Kidney disease (n, %)
−1
−2
117 (2)
6 (0.1)
94 (0.8)
1899 (11)
96 (0.6)
18 (0.1)
Income, n (%)
Refused
430 (10)
494 (4)
57 (6)
318 (7)
1531 (13)
2114 (12)
≤20th percentile
1571 (37)
763 (7)
453 (49)
1003 (20)
3229 (27)
2075 (12)
21st –50th percentile
1153 (27)
2176 (19)
239 (26)
1679 (34)
3194 (36)
3941 (23)
51st –75th percentile
843 (20)
4664 (41)
138 (15)
1253 (25)
3088 (26)
5701 (33)
>75th percentile
269 (6)
3381 (30)
37 (4)
672 (14)
1086 (9)
3597 (21)
Less than high school
1777 (42)
1977 (17)
416 (45)
1306 (27)
2399 (20)
1273 (7)
High school graduate
912 (21)
4165 (35)
196 (21)
1416 (29)
3374 (28)
4257 (24)
More than high school
Education, n (%)
1565 (37)
5322 (47)
307 (33)
2192 (45)
6341 (52)
11 889 (68)
Baseline VTE, n (%)
80 (3)
156 (2)
56 (6)
297 (6)
681 (6)
1068 (6)
Baseline warfarin, n (%)
20 (0.5)
20 (2)
77 (2)
301 (3)
787 (5)
67 (0.6)
ARIC indicates Atherosclerosis Risk in Communities; BMI, body mass index; CHS, Cardiovascular Health Study; eGFR, estimated glomerular filtration
rate; REGARDS, Reasons for Geographical and Racial Differences in Stroke; and VTE, venous thromboembolism.
additional 687 black men and women in 1991 to 92 from 4 field centers: Forsyth County, North Carolina; Sacramento County, California;
Washington County, Maryland; and Pittsburgh, PA (924 blacks).
The study of VTE in CHS and ARIC is called the Longitudinal
Investigation of Thromboembolism Etiology (LITE) study. The
methods for the LITE study, including VTE case ascertainment, have
been described in detail elsewhere.10
REGARDS recruited 30 239 black and white individuals ≥45 years
of age between 2003 and 2007 in the contiguous United States, oversampling blacks and individuals living in the Southeast (Alabama,
Arkansas, Georgia, Louisiana, Mississippi, North Carolina, South
Carolina, and Tennessee).11 Exclusion criteria included self-reported
race other than white or black, inability to converse in English,
cognitive impairment as judged by the telephone interviewer, residence in or on the waiting list for a nursing home, or active cancer
or current treatment for cancer. After enrollment, medical history
(including self-reports of prior VTE events) and risk factors were
assessed via computer-assisted telephone interview followed by an
in-home visit, which included anthropomorphic and blood pressure
measures, medication ascertainment, and phlebotomy (Examination
Management Systems Inc, Irving, TX).
Participants in ARIC, CHS, and REGARDS gave written informed
consent. This study was approved by the Institutional Review boards
of all participating institutions.
Event Ascertainment
In CHS and ARIC, VTE (consisting of DVT and PE) events were captured by review of hospital discharge codes and verified by 2 physicians
(A.R.F. and M.C.). Briefly, participants in ARIC were followed up by
clinic visits every 3 years and annual telephone calls. Further hospitalizations not captured by other methods were obtained from surveillance
of community hospitals. In CHS, participants were followed up by alternating telephone calls and clinic visits every 6 months. Hospitalizations
were also identified through Medicare records. For all hospitalizations,
hospital discharge codes were used to identify possible cases of thrombosis. By design, hospital record review was similar to that reported
in REGARDS below. A detailed description of event ascertainment
1504 Circulation April 8, 2014
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has previously been published.10 VTE events were captured through
December 31, 2001, in CHS and December 31, 2005, in ARIC.
REGARDS participants were contacted by telephone every 6
months, and deaths were ascertained by proxy report and through
periodic searches of the National Death Index.14 VTE events were
captured in 4 ways. First, at each telephone call, participants or their
proxies were asked for an update on the participant’s medical status and for the reasons for any hospitalizations. A research nurse
reviewed the text recorded for each reported hospitalization through
February 2010. Any report of a blood clot in the legs, arms, or lungs
was considered a potential case for physician review. Second, a telephone interview was developed and administered between February
2010 and February 2011 to ascertain participant-reported VTE events
back to baseline. Similar questionnaires in epidemiological studies
have 98% specificity and >70% sensitivity for ascertaining VTE.15
Third, the reasons for all deaths were reviewed by the use of any
available data (National Death Index determination of death, exit
interview with proxy/next of kin, or records from last hospital stay).
Fourth, VTE events discovered from a review of other events (stroke
and coronary heart disease) were abstracted. On the basis of all available information, we retrieved medical records up to 1 year before
and 1 year after potential events. Retrieved records were used to help
guide further record retrieval if they did not contain the primary VTE
event. Primary inpatient and outpatient records, including history and
physical examinations, discharge summaries, imaging reports, and
outpatient notes, were retrieved using up to 3 attempts. If after review
by a research nurse and confirmation by a physician (N.A.Z.) it was
ascertained that no VTE occurred and no workup for VTE occurred,
the record was closed as a nonevent. If separate events were judged
by the research nurse and the physician to be 1 event (ie, a DVT and
PE that occurred on the same day) or events were captured via >1
mechanism (ie, through reviewing reasons for hospitalizations and
through the telephone interview), the events were consolidated. Each
potential event was reviewed by 2 of 3 physicians (N.A.Z. reviewed
all events; M.C. and A.R.F. each reviewed 60% of events). Major disagreements, defined as a disagreement in the level of evidence of a
VTE event or whether the event was provoked or unprovoked, were
adjudicated by blind review by the third reviewer. Telephone conferences were used in cases when all 3 reviewers disagreed. Minor
disagreements (such as date of a VTE event) were resolved by a physician (N.A.Z.) and the research nurse.
Definitions
Consistent definitions were used in REGARDS and LITE to define
VTE events. PE was considered thrombus in the pulmonary arteries, and DVT was considered thrombus of the deep veins of the
legs or arms (including distal veins). Provoked VTE was defined as
a VTE event preceded within 90 days by major trauma, surgery, or
marked immobility or associated with active cancer or chemotherapy.
All other events were considered unprovoked. Definite VTE events
required an autopsy, unambiguous imaging, or a healthcare provider’s
description of positive imaging. Probable VTE events required a high
clinical suspicion but without a record of definitive radiology evidence of VTE. Baseline VTE was defined as a self-reported history of
PE or DVT before enrollment.
Body mass index was defined as weight in kilograms divided
by the square of height in meters. Estimated glomerular filtration
rate was defined with the Chronic Kidney Disease Collaboration
equation.16 Diabetes mellitus was defined as fasting glucose
≥126 mg/dL, nonfasting glucose ≥200 mg/dL, or participant
report of diabetes mellitus or the use of hypoglycemic medication. Hypertension was defined as blood pressure >140/90 mm Hg
or self-report of current treatment for hypertension. Because of
the differing years of recruitment and because participants only
selected ranges for income, income was divided into cohort-specific percentiles by cohort with a category for refused (≤20th,
21st–50th, 51st–75th, and >75th percentile). Race was defined
from participant self-report.
Statistical Analysis
As a result of differences in methodology, follow-up, and start date,
analyses were stratified by cohort. Differences between blacks and
whites were tested by the use of t tests, Wilcoxon rank-sum tests, and
χ2 tests of associations as appropriate. After the exclusion of participants with self-reported baseline VTE, Poisson regression was used
to estimate VTE incidence rates accounting for age, sex, and race.
Cox proportional hazard models tested the association of race with
VTE, excluding individuals with baseline VTE (Table 1). Interaction
terms of race with age, sex, and region (in REGARDS) were assessed,
and values of P<0.10 were considered significant. Because of a significant region-by-race interaction, analyses in REGARDS were presented stratified by race or region. Sensitivity analyses were done by
determining the probability that nonretrieved records in REGARDS
represented VTE events and including the probabilities in analyses.
The probability that a nonretrieved record would be a VTE was calculated on the basis of the percent of retrieved records that were VTE
(stratified by region and race). Follow-up time for the probable events
was determined from a random uniform distribution, the distribution most closely representing the temporal distribution of validated
VTE events in REGARDS (Tables II and III in the online-only Data
Supplement). Analyses were performed with SAS version 9.3 (SAS
Institute Inc, Cary, NC).
Results
The cohort characteristics by race are reported in Table 1 and
Table I in the online-only Data Supplement. Briefly, ARIC had
the lowest mean age (54 years), CHS had the highest mean age
(73 years), and REGARDS had an intermediate mean age (65
years). The prevalence of obesity was lowest in CHS (20%)
and highest in REGARDS (38%), with the highest prevalence
of diabetes mellitus in REGARDS. In all cohorts, blacks had
a higher body mass index than whites, had greater prevalences
of diabetes mellitus and hypertension, were less likely to be
in the top 25th percentile of income, and were more likely to
have lower levels of education (Table 1).
VTE event ascertainment has previously been reported in
detail for ARIC and CHS.10 In REGARDS, 936 potential VTE
events were identified (Figure). Among the 785 events for
which records were requested (after consolidation of duplicate
events), 624 records (79.5%) were successfully retrieved, and
471 (75.5%) were reviewed by physicians. Among blacks, 231
of 321 records (72%) were retrieved, and among whites, 393
of 464 records (85%) were retrieved. Among the 471 records
reviewed, there were 379 VTE events in 332 individuals; 268
were first-time VTE events in those not reporting VTE at
baseline (123 in blacks). Retrieval rates by race and region in
REGARDS and the percent of retrieved records that became
cases are presented in Tables II and III in the online-only Data
Supplement. Blacks had lower record retrieval than whites,
although there were no differences by region. In CHS, there
were 172 validated incident VTE events (37 in blacks), and in
ARIC, there were 476 validated incident VTE events (163 in
blacks; Table 2). In all cohorts, blacks had a higher percentage
of VTEs that were DVTs than whites but a similar percentage
of VTEs that were PEs, except in ARIC in which blacks had
a lower percent of PEs than whites (26% versus 41%). The
percent of VTEs that were provoked was similar in blacks and
whites in each cohort (Table 2).
Table 3 presents VTE rates for ARIC, CHS, and REGARDS
in blacks and whites normalizing to the mean age and sex
distribution of each cohort. Overall, blacks had a higher
Zakai et al Region, Race, and Venous Thrombosis in the US 1505
489 Reported Events
309 Hospitalizations
51 Discovered Events
87 Death Events
151 Duplicate Events
785 Potential VTE Events
161 Potential Events with No Records Retrieved (55 with
baseline VTE or separately validated VTE event)
624 Potential VTE Events
153 No Event on Prescreening Chart
92 No Event after Physician Review (ARF, NAZ, MC)
379 VTE Events
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
47 Recurrent VTE on Study
64 VTE in Participants with Baseline VTE
268 First-Time VTE Events
129 Reported Events + 79 Hospitalizations + 44 Discovered Events + 16 Death Events
Figure. Venous thromboembolism event (VTE) tracking in the Reasons for Geographic and Racial Differences in Stroke study.
incidence of VTE than whites in ARIC, in CHS, and in the
Southeast in REGARDS but not in REGARDS outside the
Southeast. These differences were statistically significant in
CHS and ARIC but not in REGARDS. These patterns were
similar for DVT. In contrast, PE incidence was not higher in
blacks than whites in ARIC, CHS, or REGARDS. The rate of
provoked VTE was higher in blacks than whites in CHS but
not in ARIC or REGARDS.
Table 4 presents a series of sequentially adjusted Cox
proportional hazard models demonstrating the association of black versus white race with incident VTE in each
of the cohorts. In a model adjusted for age and sex, blacks
had a greater risk of VTE than whites in ARIC and CHS. In
REGARDS, blacks had a nonsignificantly increased hazard
of VTE compared with whites in the Southeast (hazard ratio
[HR], 1.33; 95% confidence interval [CI], 0.94–1.87) and a
nonsignificantly decreased hazard of VTE than whites in the
rest of the nation (HR, 0.78; 95% CI, 0.54–1.12; P for interaction=0.03). Adjusting for body mass index reduced the HR for
race by >10% in ARIC, in CHS, and in participants living in
the Southeast in REGARDS. Adjusting for body mass index,
hypertension, diabetes mellitus, kidney disease, and baseline
warfarin use decreased the association of race with VTE in
ARIC (HR from 1.61 to 1.25) but had little effect on the HR in
CHS (HR from 1.82 to 1.72) or REGARDS in the Southeast
(HR from 1.33–1.34). Adjustment for socioeconomic factors had little effect on the association of race with VTE in
CHS but decreased the black versus white HR in ARIC and in
participants in the Southeast in REGARDS. In a final model
including all risk factors, the association of race with VTE was
Table 2. Number and Distribution of Incident Venous Thrombosis Events by Cohort
ARIC
All
VTE, n
DVT, n (%)*
Black
CHS
White
All
Black
REGARDS
White
All
Black
White
476
163
313
172
37
135
268
102
166
373 (78)
140 (88)
233 (74)
144 (84)
34 (92)
110 (81)
187 (70)
75 (74)
112 (67)
PE, n (%)†
171 (36)
43 (26
128 (41)
53 (31)
11 (30)
42 (31)
123 (46)
47 (46)
76 (46)
Unprovoked VTE, n (%)
174 (37)
58 (36)
116 (37)
62 (36)
11 (30)
51 (38)
126 (47)
49 (48)
77 (46)
Provoked VTE, n (%)
302 (63)
105 (64)
197 (63)
110 (64)
26 (70)
84 (62)
142 (53)
53 (52)
89 (54)
ARIC indicates Atherosclerosis Risk in Communities; CHS, Cardiovascular Health Study; DVT, deep venous thrombosis; PE, pulmonary embolism;
REGARDS, Reasons for Geographical and Racial Differences in Stroke; and VTE, venous thrombosis.
*DVT=DVT±PE.
†PE=PE±DVT.
1506 Circulation April 8, 2014
Table 3. VTE Event Rates per 1000 Person-Years (95% Confidence Intervals) by Cohort*
REGARDS
ARIC
Blacks
CHS
Whites
Rest of Nation
Black
Whites
Blacks
Southeast
Whites
Blacks
Whites
VTE events, n
163
313
37
135
47
80
55
86
Person-years
65 263
181 829
7336
47 720
26 778
32 716
25 442
45 122
VTE
2.59
(2.21–3.03)
1.66
(1.48–1.86)
7.46
(4.68–11.90)
4.39
(3.13–6.16)
1.43
(1.02–2.00)
2.05
(1.58–2.66)
2.24
(1.72–2.92)
1.62
(1.26–2.07)
DVT†
2.21
(1.86–2.62)
1.23
(1.07–1.41)
7.03
(4.27–11.59)
3.89
(2.22–4.88)
1.00
(0.67–1.51)
1.36
(0.99–1.88)
1.66
(1.22–2.26)
1.13
(0.84–1.52)
PE‡
0.69
(0.51–0.93)
0.68
(0.57–0.82)
1.71
(0.68–4.29)
1.75
(1.03–2.97)
0.70
(0.43–1.14)
0.95
(0.64–1.39)
0.97
(0.65–1.47)
0.74
(0.52–1.07)
Unprovoked
0.89
(0.68–1.17)
0.60
(0.50–0.74)
3.82
(1.79–8.16)
1.82
(1.05–3.17)
0.70
(0.43–1.13)
1.01
(0.69–1.47)
1.10
(0.75–1.60)
0.63
(0.42–0.93)
Provoked
1.68
(1.39–2.04)
1.05
(0.91–1.22)
3.90
(2.16–7.07)
2.58
(1.68–3.97)
0.73
(0.45–1.18)
1.03
(0.72–1.48)
1.12
(0.77–1.64)
0.98
(0.72–1.34)
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
ARIC indicates Atherosclerosis Risk in Communities; CHS, Cardiovascular Health Study; DVT, deep venous thrombosis; PE, pulmonary embolism;
REGARDS, Reasons for Geographical and Racial Differences in Stroke; and VTE, venous thrombosis.
*Normalized for mean age and sex distribution of each cohort.
†DVT=DVT±PE.
‡PE=PE±DVT.
no longer significant in ARIC (HR, 1.21; 95% CI, 0.96–1.54)
and was little changed in CHS (HR, 1.81; 95% CI, 1.20–2.73)
and REGARDS (outside the Southeast: HR, 0.68; 95% CI,
0.46–1.02; in the Southeast: HR, 1.34; 95% CI, 0.93–1.94).
In REGARDS, a significant regional difference in the association of race with VTE was found in all models (all P for interactions ≤0.03). Among blacks in REGARDS, the HR of VTE
for living in the Southeast versus elsewhere was 1.63 (95% CI,
1.08–2.48), but among whites, living in the Southeast was not
associated with increased risk (Table 5).
Tables 5 and 6 break down the results by VTE type (PE
or DVT, unprovoked or provoked). In fully adjusted models, blacks had a higher risk of DVT than whites in ARIC,
in CHS, and in the Southeast in REGARDS but not outside
the Southeast in REGARDS. After full multivariable adjustment, there was little evidence of an increased risk of PE for
blacks versus whites in ARIC, CHS, or REGARDS. There
was no association of black race with provoked or unprovoked VTE in ARIC, but the HR for blacks versus whites
remained elevated in CHS for both unprovoked and provoked
Table 4. Sequentially Adjusted Hazard Ratios (95% Confidence Intervals) for Venous Thromboembolism of
Black Versus White Race
REGARDS
ARIC
CHS
Rest of Country
Southeast
P Value*
1.61 (1.33–1.95)
1.82 (1.25–2.65)
0.78 (0.54–1.12)
1.33 (0.94–1.87)
0.03
Body mass index
1.38 (1.13–1.68)
1.57 (1.07–2.31)
0.72 (0.51–1.01)
1.06 (0.77–1.46)
0.03
Hypertension
1.43 (1.17–1.74)
1.87 (1.28–2.72)
0.77 (0.55–1.07)
1.18 (0.86–1.62)
0.03
Diabetes mellitus
1.52 (1.25–1.85)
1.82 (1.25–2.65)
0.79 (0.57–1.11)
1.19 (0.87–1.63)
0.03
Kidney disease
1.55 (1.28–1.88)
1.99 (1.36–2.92)
0.78 (0.56–1.08)
1.18 (0.87–1.61)
0.03
Warfarin use
1.62 (1.34–1.96)
1.83 (1.26–2.67)
0.76 (0.53–1.10)
1.34 (0.95–1.87)
0.03
All conditions listed
1.25 (1.02–1.54)
1.72 (1.16–2.56)
0.68 (0.46–1.00)
1.34 (0.93–1.92)
0.01
Education
1.60 (1.31–1.95)
1.81 (1.24–2.65)
0.83 (0.59–1.17)
1.16 (0.85–1.60)
0.02
Income
1,40 (1,12–1.75)
1.90 (1.29–2.80)
0.80 (0.57–1.12)
1.15 (0.84–1.58)
0.03
Education and income
1.44 (1.14–1.81)
1.86 (1.25–2.76)
0.78 (0.54–1.12)
1.35 (0.95–1.92)
0.03
Model 4: final model
1.21 (0.96–1.54)
1.81 (1.20–2.73)
0.68 (0.46–1.02)
1.34 (0.93–1.94)
0.01
Model 1†
Model 2: medical conditions
Model 3: socioeconomic
ARIC indicates Atherosclerosis Risk in Communities; CHS, Cardiovascular Health Study; and REGARDS, Reasons for Geographical and
Racial Differences in Stroke.
*P for interaction between region of residence and race.
†Model 1: adjusted for age, sex, and race; model 2: adjusted for age, sex, race, plus each medical condition individually, and then all
medical conditions; model 3: adjusted for age, sex, race, plus education or income (modeled as dummy variables as outlined in Table 1);
and model 4: adjusted for age, sex, race, plus all variables in the table.
Zakai et al Region, Race, and Venous Thrombosis in the US 1507
Table 5. Hazard Ratios (95% Confidence Intervals) of VTE for Black Versus White Race*
REGARDS
ARIC
CHS
Rest of Country
Southeast
P†
DVT
1.39 (1.07–1.81)
2.10 (1.37–3.23)
0.84 (0.55–1.29)
1.44 (0.97–2.14)
0.03
PE
0.88 (0.57–1.35)
1.52 (0.69–3.35)
0.82 (0.49–1.38)
1.16 (0.70–1.93)
0.26
Unprovoked VTE
1.24 (0.84–1.84)
1.86 (0.92–3.77)
0.79 (0.47–1.34)
1.44 (0.89–2.34)
0.05
Provoked VTE
1.20 (0.89–1.62)
1.79 (1.08–2.97)
0.72 (0.44–1.19)
1.08 (0.67–1.73)
0.18
ARIC indicates Atherosclerosis Risk in Communities; CHS, Cardiovascular Health Study; DVT, deep venous thrombosis; PE, pulmonary
embolism; REGARDS, Reasons for Geographical and Racial Differences in Stroke; and VTE, venous thrombosis.
*Adjusted for age, sex, race, body mass index, hypertension, diabetes mellitus, kidney disease, baseline warfarin use, education,
and income (modeled as dummy variables as outlined in Table 1). In REGARDS, additionally adjusted for living in the Southeast and a
race–by–living in the Southeast interaction term.
†P for interaction between race and region (REGARDS).
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
VTE. In REGARDS, again, there was evidence of a regional
interaction, with blacks in the Southeast having a higher rate
of both DVT and PE than whites in the Southeast but not
outside the Southeast.
Sensitivity analyses excluding those on baseline warfarin
or including only VTE events ascertained by the computer-­
assisted telephone interview in REGARDS did not materially
affect the conclusions (data not shown). Table IV in the onlineonly Data Supplement presents one scenario of the potential
effect that differential record retrieval by race or region may
have had in REGARDS, which assumes that had all records
been obtained, the percent validated as VTEs would have been
the same for the percent actually validated among received
records. From this analysis, we estimated that we missed
≈70 VTE events (44 in blacks) because of incomplete record
retrieval. The region and race differences in REGARDS
were preserved in a sensitivity analysis accounting for these
potentially missing events, and the nearly significant inverse
association of black race (versus white) with VTE outside the
Southeast disappeared.
Discussion
In 3 large US cohort studies including 51 149 individuals and
916 VTE events, we found at most a modest association of
race with risk of VTE, particularly once comorbid conditions
and socioeconomic status were accounted for. The studied
Table 6. Hazard Ratios (95% Confidence Intervals) of VTE
for Living in the Southeast Versus Elsewhere in REGARDS in
Blacks and Whites*
Blacks
Whites
P for Interaction
VTE
1.63 (1.08–2.48)
0.83 (0.61–1.14)
0.01
DVT
1.71 (1.05–2.78)
0.88 (0.60–1.30)
0.04
PE
1.41 (0.77–2.58)
0.83 (0.52–1.34)
0.18
Unprovoked VTE
1.81 (1.00–3.29)
0.63 (0.40–1.01)
0.006
Provoked VTE
1.49 (0.84–2.66)
1.06 (0.68–1.64)
0.36
DVT indicates deep venous thrombosis; PE, pulmonary embolism; REGARDS,
Reasons for Geographical and Racial Differences in Stroke; and VTE, venous
thrombosis.
*Adjusted for age, sex, race, living in the southeast, body mass index,
hypertension, diabetes mellitus, kidney disease, baseline warfarin use,
education, income (modeled as dummy variables as outlined in Table 1), and a
race–by–living in the Southeast interaction term.
cohorts were recruited with different methods spanning 20
years (from 1987 through 2007) and revealed different results
for the association of race with VTE. In ARIC, blacks had a
higher risk of VTE that was attenuated by VTE risk factors;
in CHS, blacks had a higher risk of VTE that was not attenuated by risk factors; and in REGARDS, there was a significant
region-by-race interaction whereby blacks in the Southeast
were at significantly higher risk of VTE relative to blacks outside the Southeast, whereas in the rest of the country, there
was no evidence that risk of VTE varied by race. Furthermore,
no study demonstrated a racial association with PE alone.
Race in the United States is as much a social construct as a
marker of continental origin, with self-identified blacks having on average 20% European ancestry but with great variation
both within populations and between different locations in the
United States.17 There are few studies in the United States in
which the risk of VTE can be directly compared between blacks
and whites. In hospital discharge registries from California7,18
and the National Hospital Discharge Survey,8 blacks had a
higher risk of VTE compared with whites (relative risk, 1.37
and 1.18, respectively). These analyses, although powerful, have limitations, including potential misclassification of
events and race, with reliance on discharge codes for events
and on census data to classify the racial characteristics of the
population. International Classification of Diseases, Ninth
Revision coding of VTE is challenging; in 1 report, >20% of
hospitalized International Classification of Diseases, Ninth
Revision–reported VTEs were miscoded.19 The assumption
with administrative databases is that miscoding is consistent
by race and region, which may not be the case.20 Blacks also
have a 50% greater risk of death resulting from PE compared
with whites in the United States, but whether this results from
an increased rate of VTE or a higher case fatality rate is not
known.21–24 Apart from an earlier report from the LITE,9 no
other national cohorts with physician-validated VTE events
have reported racial differences in VTE in the United States.
Further discussion of the differences between ARIC, CHS,
and REGARDS is warranted. Our original intent was to perform a pooled analysis; however, these cohorts had different
recruitment ages, geographic scopes, and enrollment years,
decreasing the scientific appropriateness of a pooled analysis.
Differences in the race association between CHS and ARIC
could be due to age differences; however, REGARDS encompassed the entire age spectrum of ARIC and CHS. In terms of
1508 Circulation April 8, 2014
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geographic scope, REGARDS is the only study to include a
substantial number of blacks outside the Southeast. The majority of blacks in ARIC resided in Jackson, MS, and Forsyth
County, North Carolina; the majority of blacks in CHS resided
in Forsyth County, North Carolina, and to a lesser extent in
Pittsburgh, PA. No ARIC whites came from Jackson. In ARIC
and CHS, there were only 2 and 21 VTE events, respectively,
in blacks outside the Southeast, precluding an analysis by
region in these cohorts. Although individual-level national data
on VTE in the United States do not exist, the effect of race
seems modest at best in an analysis from the National Hospital
Discharge Survey, with blacks having an 18% higher risk than
whites.8 Further data from the Centers for Disease Control
show that blacks were at greater risk of PE death relative to
whites in the Northeast, Midwest, and South, but not the West
(see Table V in the online-only Data Supplement).25 Reasons
for these differences are unclear but may be due to true biological differences and differences in the prevalence of comorbidities that may lead to VTE, result in complications among VTE
patients that predispose to death, or may relate to access to
medical care, quality of medical care, and quality of medical
reporting. Further confounding the observations in the current
studies, differences in VTE event rates among the studies may
be due to secular trends in the evaluation of suspected VTE.
The diagnosis of VTE has shifted from relying on ventilation-­
perfusion scans for PE to computed tomography angiography
and from inpatient to outpatient treatment of DVT.26 If these
changes in medical care differed by age, race, or region, this
could have contributed to the different patterns observed here.
Possible limitations of our study include self-identification
of race, lack of generalizability of the cohorts to the population
of the United States, although the national reach of REGARDS
mitigates this somewhat, and issues of underascertainment or
biased ascertainment for VTE. In each cohort, race was self-­
defined and thus represents both a social and a genetic construct. Other phenotypes such as coronary artery calcium vary
by genetic origin even within racial groups, and by using self-­
identified race, we may have missed these associations.17 LITE
did not capture out-of-hospital VTE deaths (there are likely
few) and outpatient treatment of VTE. During the time period
of LITE, the proportion of DVT events treated in the outpatient setting was small because evidence for the safety of this
practice did not emerge until the late 1990s.27 In REGARDS,
there were no discrete field centers or local hospitals to search
for discharges, and case ascertainment relied predominantly
on participant report. Therefore, cases were missed, but VTE
events treated in the outpatient setting were sought. Despite
efforts, record retrieval was not 100%, and fewer records of
blacks than whites were obtained. However, although record
retrieval differed by race in REGARDS, it did not differ by
region. When we accounted for potential cases resulting from
missing records, blacks in the Southeast remained at greater
risk than whites, whereas for the rest of the country, there was
no evidence of a relation (Tables II–IV in the online-only Data
Supplement). Furthermore, as shown in in the Centers for
Disease Control data, there are clear regional and racial differences in PE mortality in the United States, demonstrating the
need to define geography and race when studying racial differences in VTE (Table V in the online-only Data Supplement).25
Conclusions
We present the most detailed examination yet of the association of race with VTE in the United States. In contrast to
prior studies, we were able to study the association of race
with VTE using validated VTE events and individual-level
data over a long time period. The differences seen by cohort
may represent secular trends in the diagnosis or incidence of
VTE, may reflect an unrecognized race-by-region interaction
in which blacks in the Southeast have higher rates of VTE than
whites and blacks outside the Southeast, or may be an artifact
of bias. Whether differences in VTE by race are compared on
a regional, national, or global scale will greatly influence associations of race on VTE. Study limitations necessitate caution
in the interpretation of the results, but these results highlight
the need for further studies of VTE in the United States in
diverse geographic and racial populations.
Acknowledgments
We thank the staff and participants of ARIC, CHS, and REGARDS
for their important contributions. The Executive Committee or
Publications Committee of ARIC, CHS, and REGARDS reviewed
and approved this manuscript for publication.
Sources of Funding
The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts
(HHSN268201100005C, HHSN268201100006C, HHSN2682011
00007C, HHSN268201100008C, HHSN268201100009C, HHSN
268201100010C, HHSN268201100011C, and HHSN2682011
00012C). CHS was supported by contracts HHSN268201200036C,
HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080,
N01HC85081, N01HC85082, N01HC85083, and N01HC85086
and grant HL080295 from the National Heart, Lung, and Blood
Institute, with additional contribution from the National Institute
of Neurological Disorders and Stroke. Additional support was provided by AG023629 from the National Institute on Aging. LITE was
funded by grant R01-HL59367 from the National Heart, Lung, and
Blood Institute. REGARDS was funded by cooperative agreement
NS 041588 from the National Institute of Neurological Disorders
and Stroke, with additional funding from the American Recovery
and Reinvestment Act grant RC1HL099460 from the National Heart,
Lung, and Blood Institute.
Disclosures
None.
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Clinical Perspective
Venous thromboembolism (VTE) is the third-leading cause vascular disease in the United States with >100 000 deaths annually. Prior studies have suggested that blacks have higher rates of VTE than whites in the United States, but these studies are
limited in geographic or racial scope or rely on administrative databases. We studied the association of race (black versus
white) with VTE in 3 large cohort studies to assess whether race and geography are associated with VTE in the United States.
In the Cardiovascular Health Study (individuals ≥65 years of age recruited between 1989 and 1991 from 4 field centers),
blacks had an increased risk of VTE not explained by conventional risk factors. In the Atherosclerosis Risk in Communities
Study (individuals 45–64 years of age recruited between 1989 and 1991 from 4 field centers), blacks had a higher risk of
VTE explained by conventional risk factors. In the Reasons for Geographic and Racial Differences in Stroke study (individuals ≥45 years of age recruited between 2003 and 2007 from throughout the contiguous United States), overall there was no
association of race with VTE; however, blacks in the Southeast had a higher risk of VTE than blacks in the rest of the nation
that was not explained by VTE risk factors, with no geographic differences apparent in whites. These data highlight that
there are no unquestioned differences in VTE risk in blacks compared with whites and that geographic differences may be
as important as race.
Racial and Regional Differences in Venous Thromboembolism in the United States in 3
Cohorts
Neil A. Zakai, Leslie A. McClure, Suzanne E. Judd, Monika M. Safford, Aaron R. Folsom,
Pamela L. Lutsey and Mary Cushman
Downloaded from http://circ.ahajournals.org/ by guest on June 14, 2017
Circulation. 2014;129:1502-1509; originally published online February 7, 2014;
doi: 10.1161/CIRCULATIONAHA.113.006472
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2014 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://circ.ahajournals.org/content/129/14/1502
Data Supplement (unedited) at:
http://circ.ahajournals.org/content/suppl/2014/02/07/CIRCULATIONAHA.113.006472.DC1
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Supplemental Material
1
Supplemental Table 1: Characteristics of the Cardiovascular Health Study, the Atherosclerosis Risk in Communities study,
and the REasons for Geographic and Racial Differences in Stroke Study
Primary Objectives
Atherosclerosis Risk in
Communities
1. Investigate the etiology and
natural history of
atherosclerosis
2. Investigate the etiology of
clinical atherosclerotic
diseases
3. Measure variation in
cardiovascular risk factors,
medical care, and disease by
race, sex, place, and time
Recruitment Years
1987-89
VTE Follow-up Date
Number of Participants
12/31/2005
15,792
Cardiovascular Health Study
REasons for Geographic and
Racial Differences in Stroke
1. To quantify associations of
1. To provide national data on
conventional and
stroke incidence and case
hypothesized risk factors with
fatality and assess geographic
CHD and stroke
variations and racial
2. To assess the association of
differences in these measures
indicators of subclinical
2. To provide national data on
disease, identified by
prevalence and levels of
noninvasive measures such as
stroke risk factors and assess
carotid ultrasonography and
geographic and racial
echocardiography, with the
variation in these prevalences
incidence of CHD and stroke 3. To assess the degree to which
3. To quantify the association of
geographic and racial
conventional and
variations in stroke incidence,
hypothesized risk factors with
case fatality and mortality are
subclinical disease
attributable to variations in
4. To characterize the natural
risk factor prevalence
history of CHD and stroke,
4. To assess geographic and
and identify factors
racial variations in the
associated with clinical
magnitude of the impact of
course
prevalent stroke risk factors
5. To describe the prevalence
5. To assess the impact of
and distributions of risk
migration on stroke
factors, subclinical disease,
incidence, case fatality and
and clinically diagnosed CHD
mortality
and stroke
6. To create a blood, urine and
DNA repository as a resource
for future studies
1989-90, 1991-92 (minority
2003-07
cohort)
12/31/2001
2/1/2010
5,888
30,239
2
Number of Blacks
Recruitment Age
Geographic Location
Exclusion Criteria
Active Cancer
Resident / waiting list for
nursing home or hospice
Wheelchair bound at Baseline
Cognitive Impairment
Unable to get to field center
4,266
45-64
Forsyth County, North Carolina
924
≥65
Forsyth County, North Carolina
Washington County, Maryland
Washington County, Maryland
Suburban Minneapolis, Minnesota
Sacramento County, California
Jackson, Mississippi
Pittsburgh, Pennsylvania
Not Excluded
Not Excluded
Excluded
Excluded
Excluded
Excluded
Not Excluded
Not Excluded
Excluded
Excluded
Not Excluded
Excluded
Not Excluded
Excluded
NA
3
12,128
≥45
Contiguous 48 United States
Half of individuals from the
following states:
Alabama, Arkansas,
Georgia, Louisiana,
Mississippi, North
Carolina, South Carolina,
Tennessee.
Supplemental Table 2: Record Retrieval by Race and Region in REGARDS in those without
Baseline VTE
Whites
Blacks
Outside of the Southeast
85% (106/124)
69% (72/105)
4
Southeast
88% (175/198)
72% (88/123)
Supplemental Table 3: Percent of Retrieved Records Resulting in a Confirmed VTE in those
without Baseline VTE in REGARDS
Whites
Blacks
Outside of the Southeast
74% (78/106)
65% (47/72)
5
Southeast
50% (87/175)
65% (56/88)
Supplemental Table 4: Association of Race or Region with VTE in REGARDS adjusting
for record non-retrieval*
HR (95% CI)
Whites (n = 192)
0.86 (0.66, 1.13)
Southeast vs. Rest of Country
Blacks (n = 146)
1.48 (1.10, 1.99)
Blacks vs. Whites
Southeast (n = 181)
1.33 (0.98, 1.81)
*
Rest of Country (n = 157)
0.94 (0.67, 1.30)
Adjusted for age, sex, race, body mass index, hypertension, diabetes, kidney disease, baseline
warfarin, education, income and race or living in the southeast as appropriate. The probability
of being a case was calculated by race and region in the 106 potential events where no records
were obtained. These potential “cases” were weighted by the probability of being a case and the
timing of the VTE was randomly assigned using a uniform distribution for the duration of
follow-up.
6
Supplemental Table 5: Age-Adjusted Rate of Pulmonary Embolism Mortality per 10,000
population in Blacks and Whites in the United States*
Deaths
Rate
Black
White
Black
White
Northeast
1,124
7,635
0.8 (0.7, 0.8)
0.5 (0.5, 0.5)
Midwest
1,761
12,089
1.2 (1.2, 1.3)
0.7 (0.6, 0.7)
South
5,235
17,491
1.2 (1.2, 1.2)
0.7 (0.7, 0.7)
West
401
6,281
0.5 (0.4, 0.5)
0.5 (0.5, 0.5)
Total
8,521
43,496
1.1 (1.1, 1.1)
0.6 (0.6, 0.6)
*
Including black and white individuals 45 years and over and excluding residents of Hawaii and
Alaska. Standardized to population in 2000.
7