Abstract
Introduction
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 three 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) followed. In risk factor-adjusted models, blacks had a higher rate of VTE than whites in CHS (HR 1.81; 95% CI 1.20, 2.73) but not ARIC (HR 1.21; 95% CI 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 US (HR 1.63; 95% CI 1.08, 2.48) which was not seen in whites (HR 0.83; 95% CI 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 and/or different regional rates of VTE. Further study of environmental and genetic risk factors for VTE are needed to determine which underlie racial and perhaps regional differences in VTE.
Keywords: Venous Thrombosis, Epidemiology, Race
Venous thromboembolism (VTE) consisting of pulmonary embolism (PE) and deep venous thrombosis (DVT) is a common cardiovascular disease affecting over 300,000 individuals annually in the United States with 100,000 fatalities per year1. Many studies suggest African-Americans (blacks) have higher rates of VTE than Caucasian-Americans (whites)2. Reasons for these potential racial differences are unclear, with risk factors such as obesity3, diabetes4 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 whites2.
Prior studies on race and VTE in the United States have been limited in that they examined administrative databases without validation of VTE events6–8, had limited numbers of blacks, or were from discrete geographic areas, and excluded outpatient-treated DVTs9. Further, many studies were not able to evaluate whether differences in VTE risk factors explained any race association6–8. In order to determine the association of race and VTE and evaluate whether conventional VTE risk factors might mediate any observed differences, we assessed VTE incidence in blacks and whites in three large cohorts: the Cardiovascular Health Study (CHS), the Atherosclerosis Risk in Communities Study (ARIC), and the REasons for Geographic and Racial Differences in Stroke (REGARDS) study10–13. Together, these studies have followed 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 three cohorts and whether common VTE risk factors affected any race association.
Methods
Cohorts
VTE events were ascertained in 3 longitudinal cohorts designed to study the causes and consequences of vascular disease (Table 1, eTable 1 see supplement). ARIC12 recruited 15,792 individuals (4,266 blacks) 45 to 64 years old in 1987–89 from 4 field centers; Forsyth County, North Carolina; Washington County, Maryland; suburban Minneapolis, Minnesota; and Jackson, Mississippi. CHS13 recruited 5,201 individuals ≥65 years in 1989–90 and an additional 687 black men and women in 1991–92 from 4 field centers: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; Pittsburgh, Pennsylvania (924 blacks). The study of VTE in CHS and ARIC is called the Longitudinal Investigation of Thromboembolism Etiology (LITE) study, whose methods including VTE case ascertainment have been described in detail elsewhere10.
Table 1.
Cohort Characteristics by Race*
| ARIC | CHS | REGARDS | ||||
|---|---|---|---|---|---|---|
| Blacks | Whites | Blacks | Whites | Blacks | Whites | |
| Participants (n) | 4,266 | 11,478 | 924 | 4,925 | 12,128 | 17,428 |
| Mean Follow-up (Years, SD) | 15.1 (4.4) | 15.8 (3.7) | 7.9 (2.8) | 9.7 (3.4) | 4.6 (1.7) | 4.7 (1.6) |
| Person-years of follow-up | 65,263 | 181,829 | 7,336 | 47,720 | 55,254 | 82,689 |
| Age (Mean, SD) | 53.6 (5.8) | 54.4 (5.7) | 72.9 (5.7) | 72.8 (5.6) | 64.1 (9.3) | 65.4 (9.5) |
| Age (Minimum, Maximum) | 44, 66 | 44, 66 | 64, 93 | 63, 100 | 45, 96 | 45, 98 |
| Male (n, %) | 1,631 (38) | 5,428 (47%) | 343 (37%) | 2,135 (43%) | 4,578 (38%) | 8,687 (50%) |
| Body Mass Index (kg/m2, SD) | 29.6 (6.2) | 27.0 (4.9) | 28.5 (5.6) | 26.3 (4.5) | 30.8 (6.7) | 28.3 (5.6) |
| Obesity (n, %) | ||||||
| Underweight (BMI <18.5) | 45 (1) | 97 (0.8%) | 16 (2%) | 81 (2%) | 111 (0.9%) | 199 (1%) |
| Normal (BMI 18.5–24.9) | 887 (21%) | 4,162 (36%) | 226 (25%) | 1.934 (39%) | 2,074 (17%) | 4,873 (28%) |
| Overweight (BMI 25–29.9) | 1,589 (37%) | 4,597 (40%) | 381 (41%) | 2,036 (42%) | 4,016 (33%) | 6,814 (39%) |
| Obese (BMI ≥30) | 1,730 (41%) | 2,612 (23%) | 297 (32%) | 860 (18%) | 5,823 (48%) | 5,447 (31%) |
| Diabetes (n, %) | 821 (20%) | 1,046 (9%) | 230 (26%) | 715 (15%) | 3,588 (31%) | 2,672 (16%) |
| Hypertension (n, %) | 2,374 (56%) | 3,121 (27%) | 713 (77%) | 3,138 (64%) | 8.641 (71%) | 8,821 (51%) |
| Estimated GFR (mean, SD)† | 103 (18) | 93 (13) | 80 (23) | 67 (17) | 90 (26) | 82 (21) |
| Kidney Disease (n, %)† | ||||||
| eGFR ≥ 60 | 4,024 (98%) | 11,284 (98%) | 719 (82%) | 3,083 (63%) | 10.195 (89%) | 14,834 (88%) |
| eGFR 30–59 | 77 (2%) | 117 (2%) | 143 (16%) | 1.753 (36%) | 1,059 (9%) | 1,899 (11%) |
| eGFR 15–29 | 10 (0.2%) | 2 (0.02%) | 8 (0.9%) | 53 (1%) | 117 (1%) | 96 (0.6%) |
| eGFR 0–14 | 0 (0%) | 0 (0.0%) | 6 (0.7%) | 6 (0.1%) | 94 (0.8%) | 18 (0.1%) |
| Income (n, %) | ||||||
| Refused | 430 (10%) | 494 (4%) | 57 (6%) | 318 (7%) | 1,531 (13%) | 2,114 (12%) |
| ≤ 20th Percentile | 1,571 (37%) | 763 (7%) | 453 (49%) | 1,003 (20%) | 3.229 (27%) | 2,075 (12%) |
| 21st – 50th Percentile | 1,153 (27%) | 2,176 (19%) | 239 (26%) | 1,679 (34%) | 3,194 (36%) | 3,941 (23%) |
| 51st – 75th Percentile | 843 (20%) | 4,664 (41%) | 138 (15%) | 1,253 (25%) | 3,088 (26%) | 5,701 (33%) |
| >75th Percentile | 269 (6%) | 3,381 (30%) | 37 (4%) | 672 (14%) | 1,086 (9%) | 3,597 (21%) |
| Education (n, %) | ||||||
| < High School | 1,777 (42%) | 1,977 (17%) | 416 (45%) | 1,306 (27%) | 2,399 (20%) | 1,273 (7%) |
| High School Graduate | 912 (21%) | 4,165 (35%) | 196 (21%) | 1.416 (29%) | 3,374 (28%) | 4.257 (24%) |
| > High School | 1,565 (37%) | 5,322 (47%) | 307 (33%) | 2,192 (45%) | 6,341 (52%) | 11,889 (68%) |
| Baseline VTE (n, %) | 80 (3%) | 156 (2%) | 56 (6%) | 297 (6%) | 681 (6%) | 1,068 (6%) |
| Baseline Warfarin (n, %) | 20 (0.5%) | 67 (0.6%) | 20 (2%) | 77 (2%) | 301 (3%) | 787 (5%) |
Abbreviations: ARIC: Atherosclerosis Risk in Communities. CHS: Cardiovascular Health Study. REGARDS: REasons for Geographical and Racial Differences in Stroke
Units = mL / (min × 1.73m2)
REGARDS recruited 30,239 black and white individuals aged ≥45 years between 2003–07 in the contiguous United States, oversampling blacks and individuals living in the southeast (Alabama, Arkansas, Georgia, Louisiana, Mississippi, North Carolina, South Carolina, 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 (Exam Management Systems Incorporated, Irving, Texas).
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 two physicians (ARF and MC). Briefly, participants in ARIC were followed 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 using alternating telephone calls and clinic visits every 6 months. Hospitalizations were also identified using 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 has been previously published10. VTE events were captured through December 31, 2001 in CHS and December 31, 2005 in ARIC.
REGARDS participants were contacted by telephone every six months and deaths were ascertained by proxy report and through periodic searches of the National Death Index14. VTE events were captured in four 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 epidemiologic studies have 98% specificity and over 70% sensitivity for ascertaining VTE15. Third, the reasons for all deaths were reviewed using any available data (National Death Index determination of death, exit interview with proxy/next of kin, records from last hospital stay). Fourth, VTE events discovered from review of other events (stroke and coronary heart disease) were abstracted. Based on all available information, we retrieved medical records up to one year prior and one 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 exams, discharge summaries, imaging reports, and outpatient notes were retrieved using up to three attempts. If after review by a research nurse and confirmed by NAZ that no VTE occurred and no work-up for VTE occurred, the record was closed as a non-event. If separate events were judged by the research nurse and NAZ to be one event (i.e. a DVT and PE which occurred on the same day), or events were captured via more than one mechanism (i.e. through reviewing reasons for hospitalizations and through the telephone interview) the events were consolidated. Each potential event was reviewed by 2 of 3 physicians (NAZ, MC, ARF). NAZ reviewed all events and ARF and MC 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 where all three reviewers disagreed. Minor disagreements (such as date of a VTE event) were resolved by NAZ and the research nurse.
Definitions
Consistent definitions were used in REGARDS and LITE to define VTE events. Pulmonary embolism (PE) was considered as thrombus in the pulmonary arteries and DVT as 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, 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 health care 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 (BMI) was defined as weight in kilograms divided by the square of height in meters. Estimated glomerular filtration rate (GFR) was defined using the Chronic Kidney Disease Collaboration equation16. Diabetes mellitus was defined as fasting glucose ≥126mg/dL, nonfasting glucose ≥200mg/dL, or participant report of diabetes or taking hypoglycemic medication. Hypertension was defined as blood pressure >140/90 mm Hg or self-report of current treatment for hypertension. Due to the differing years of recruitment and participants only selecting ranges for income, income was divided into cohort-specific percentiles by cohort with a category for refused (≤20th percentile, 21st – 50th percentile, 51st–75th percentile, and >75th percentile). Race was defined from participant self-report.
Statistical Analysis
Due to differences in methodology, follow-up, and the start date, analyses were stratified by cohort. Differences between blacks and whites were tested using t-tests, Wilcoxon Rank Sum tests, and χ2 tests of associations as appropriate. After excluding participants with self-reported baseline VTE, Poisson regression was used to estimate VTE incidence rates accounting for age, sex, and race. Cox proportional hazards 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 p<0.10 considered significant. Due to 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 non-retrieved records in REGARDS represented VTE events, and including the probabilities in analyses. The probability that a non-retrieved record would be a VTE was calculated based on the percent of retrieved records that were VTE (stratified by region and race). Follow-up time for the probable events was determined using a random uniform distribution, the distribution most closely representing the temporal distribution of validated VTE events in REGARDS (eTables 2 and 3). Analyses were performed using SAS 9.3 (SAS Inc., Cary, NC).
Results
The cohort characteristics by race are reported in Table 1 and eTable 1 (see supplement). Briefly, ARIC had the lowest mean age (54 years), CHS the highest (73 years), and REGARDS 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 in REGARDS. In all cohorts, blacks had a higher body mass index than whites, had greater prevalences of diabetes 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).
Venous thromboembolism event ascertainment has been reported in detail in ARIC and CHS previously10. In REGARDS, 936 potential VTE events were identified (Figure 1). Among the 785 events where records were requested (after consolidating duplicate events), 624 records (79.5%) were successfully retrieved and 471 (75.5%) were reviewed by physicians. Record retrieval among blacks was 231 of 321 (72%) and among whites was 393 of 464 records (85%). 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, as well as the percent of retrieved records that became cases, are presented in eTable 2 and eTable 3 (see supplement); blacks had lower record retrieval than whites, though 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 did whites but a similar percentage of VTEs that were PEs, except in ARIC where blacks had a lower percent of PEs than whites (26% vs. 41%). The percent of VTEs that were provoked was similar in blacks and whites in each cohort (Table 2).
Figure 1.
Venous Thromboembolism Event Tracking in the REasons for Geographic and Racial Differences in Stroke
Table 2.
Number and Distribution of Incident Venous Thrombosis Events by Cohort*
| ARIC | CHS | REGARDS | |||||||
|---|---|---|---|---|---|---|---|---|---|
| All | Black | White | All | Black | White | All | Black | White | |
| VTE (n) | 476 | 163 | 313 | 172 | 37 | 135 | 268 | 102 | 166 |
| DVT (n, %)† | 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%) |
Abbreviations: ARIC: Atherosclerosis Risk in Communities. CHS: Cardiovascular Health Study. REGARDS: REasons for Geographical and Racial Differences in Stroke. VTE: Venous Thrombosis. DVT: deep venous thrombosis. PE: Pulmonary Embolism.
DVT = DVT ± PE
PE = PE ± DVT
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 incidence of VTE than did whites in ARIC, CHS, and in the southeast in REGARDS, but not in REGARDS outside of the southeast. These differences were statistically significant in CHS and ARIC but not in REGARDS. These patterns were similar for DVT. By 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 3.
VTE Event Rates per 1000 person-years and 95 % Confidence Intervals by Cohorta
| ARIC | CHS | REGARDS | ||||||
|---|---|---|---|---|---|---|---|---|
| Rest of Nation | Southeast | |||||||
| Blacks | Whites | Black | Whites | Blacks | Whites | Blacks | Whites | |
| VTE Events (n) | 163 | 313 | 37 | 135 | 47 | 80 | 55 | 86 |
| Person-Years | 65,263 | 181,829 | 7,336 | 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) |
Normalized for mean age and sex distribution of each cohort.
DVT = DVT ± PE
PE = PE ± DVT
Table 4 presents a series of sequentially adjusted Cox proportional hazard models demonstrating the association of black vs. white race with incident VTE in each of the cohorts. In a model adjusting for age and sex, blacks had a greater risk of VTE than whites in ARIC and CHS. In REGARDS, blacks had a non-significantly increased hazard of VTE than whites in the southeast (HR 1.33; 95% CI 0.94, 1.87) and a non-significantly decreased hazard of VTE than whites in the rest of the nation (HR 0.78; 95% CI 0.54, 1.12), p-interaction 0.03. Adjusting for body mass index reduced the HR for race by more than 10% in ARIC, CHS, and in participants living in the southeast in REGARDS. Adjusting for body mass index, hypertension, diabetes, 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 to 1.34). Adjustment for socio-economic factors had little effect on the association of race with VTE in CHS but decreased the black vs. 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 no longer significant in ARIC (HR 1.21; 95% CI 0.96, 1.54), was little changed in CHS (HR 1.81; 95% CI 1.20, 2.73) and little changed in REGARDS (HR 0.68; 95% CI 0.46, 1.02 outside of the southeast, HR 1.34; 95% CI 0.93 1.94 in the southeast). In REGARDS, a significant regional difference in the association of race with VTE was found in all models (all p-interactions ≤0.03). Among REGARDS blacks, the HR of VTE for living in the southeast vs. 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).
Table 4.
Sequentially Adjusted Hazard Ratios and 95% Confidence Intervals for Venous Thromboembolism of Black vs. White Race
| ARIC | CHS | REGARDS | |||
|---|---|---|---|---|---|
| Rest of Country | Southeast | p* | |||
| Model 1† | 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 |
| Model 2 – Medical Conditions | |||||
| 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 | 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 |
| Model 3 – Socioeconomic | |||||
| 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 |
P-interaction between region of residence and race.
Models:
Model 1: Adjusted for age, sex, and race
Model 2: Adjusted for age, sex, race, plus each medical condition individually then all medical conditions
Model 3: Adjusted for age, sex, race plus education or income (modeled as dummy variables as outlined in Table 1).
Model 4: Adjusted for age, sex, race plus all variables in table.
Table 5.
Hazard Ratios (95% CIs) of VTE for Black vs. White Race*
| ARIC | CHS | REGARDS | |||
|---|---|---|---|---|---|
| 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 |
Adjusted for age, sex, race, body mass index, hypertension, diabetes, kidney disease, baseline warfarin, 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-interaction between race and region (REGARDS)
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, CHS, and in the southeast in REGARDS, but not outside of the southeast in REGARDS. After full multivariable adjustment, there was little evidence of an increased risk of PE for blacks vs. 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 vs. whites remained elevated in CHS for both unprovoked and provoked 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.
Table 6.
Hazard Ratios (95% CIs) of VTE for Living in the Southeast vs. Elsewhere in REGARDS in Blacks and Whites*
| Blacks | Whites | p-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 |
Adjusted for age, sex, race, living in the southeast, body mass index, hypertension, diabetes, kidney disease, baseline warfarin, education, and income (modeled as dummy variables as outlined in Table 1), and a race by living in the southeast interaction term
Sensitivity analyses excluding those on baseline warfarin or including only VTE events ascertained by the CATI in REGARDS did not materially affect the conclusions (data not shown). eTable 4 (see supplement) presents one scenario of the potential effect of 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. Based on this analysis, we estimated that we missed approximately 70 VTE events (44 in blacks) due to incomplete record retrieval. The region and race differences in REGARDS were preserved in a sensitivity analysis accounting for these potentially missing events, and the near-significant inverse association of black race (vs. white) with VTE outside the southeast disappeared.
Discussion
In three 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 accounting for comorbid conditions and socioeconomic status. The studied cohorts were recruited using 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 which was attenuated by VTE risk factors; in CHS, blacks had a higher risk of VTE which 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, while in the rest of the country there was no evidence that risk of VTE varied by race. Further, 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 States17. There are few studies in the US where the risk of VTE can be directly compared between blacks and whites. In hospital discharge registries from California7, 18 and the National Hospital Discharge Survey8, blacks had a higher risk of VTE compared to whites (respective relative risks 1.37 and 1.18). These analyses, though 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. ICD-9 coding of VTE is challenging; in one report over 20% of hospitalized ICD-9 reported VTEs were miscoded19. The assumption with administrative databases is that miscoding is consistent by race and region, which may not be the case20. Blacks also have a 50% greater risk of death from PE compared to whites in the United States, but whether this results from an increased rate of VTE or a higher case-fatality rate is not known21–24. Apart from an earlier report from the LITE9, no other national cohorts with physician validated VTE events have reported on racial differences in VTE in the United States.
Further discussion of the differences between ARIC, CHS, and REGARDS is warranted. Our original intent had been 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 geographic scope, REGARDS is the only study to include a substantial number of blacks outside of the southeast. The majority of blacks in ARIC resided in Jackson, Mississippi and Forsyth County, North Carolina and in CHS in Forsyth County, North Carolina and to a lesser extent Pittsburgh, Pennsylvania. No ARIC whites came from Jackson, Mississippi. In ARIC and CHS, there were only 2 and 21 VTE events respectively in blacks outside of the southeast precluding an analysis by region in these cohorts. While 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 whites8. Further data from the Centers for Disease Control show blacks were at greater risk of PE death relative to whites in the Northeast, Midwest, and South, but not the West (see eTable 5 in supplement)25. Reasons for these differences are unclear, but may be due to true biologic differences, differences in the prevalence of comorbidities which may lead to VTE or result in complications among VTE patients which predispose to death, or may relate to access to medical care, quality of medical care, and/or quality of medical reporting. Further confounding the current studies observations, 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 CT angiography, and from inpatient to outpatient treatment of DVT26. 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, though the national reach of REGARDS mitigates this somewhat, and issues of under-ascertainment or biased ascertainment for VTE. In each cohort, race was self-defined and thus represents both a social and 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 associations17. LITE did not capture VTE deaths out of the hospital (there are likely few) and outpatient treatment of VTE. During the time period of LITE the proportion of DVT events treated as outpatient was small, as evidence for the safety of this practice did not emerge until the late 1990’s27. In REGARDS, there were no discrete field centers or local hospitals to search for discharges and case ascertainment relied predominately on participant report. Therefore, cases were missed, but VTE events treated as an outpatient were sought. Despite efforts, record retrieval was not 100% and fewer records of blacks were obtained than whites; however while record retrieval differed by race in REGARDS, it did not differ by region. When we accounted for potential cases due to missing records, in the southeast blacks remained at greater risk than whites, while for the rest of the country there was no evidence of a relation (eTables 2–4). Further, 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 as well as race when studying racial differences in VTE (see eTable 5 in the supplement)25.
In summary, we present the most detailed examination yet of the association of race with VTE in the United States. In contrast to prior studies, we are 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 and/or incidence of VTE, an unrecognized race by region interaction where blacks in the southeast have higher rates of VTE than whites and blacks outside of 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 when interpreting the results, but these results highlight the need for further studies of VTE in the United States in diverse geographic and racial populations.
Supplementary Material
Acknowledgements
The authors thank the staff and participants of ARIC, CHS, and REGARDS for their important contributions. ARIC, CHS, and REGARDS Executive Committees or Publications Committees have each reviewed and approved this manuscript for publication.
Funding Sources
The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C).. CHS was supported by contracts HHSN268201200036C, HHSN268200800007C, N01 HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, 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. The Longitudinal Investigation of Thromboembolism Etiology 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.
Footnotes
Disclosures: None
References
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