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Lifetime Risk of Venous Thromboembolism in Two Cohort Studies

Published:November 17, 2015DOI:https://doi.org/10.1016/j.amjmed.2015.10.014

      Abstract

      Background

      Greater public awareness of venous thromboembolism may be an important next step for optimizing venous thromboembolism prevention and treatment. “Lifetime risk” is an easily interpretable way of presenting risk information. Therefore, we sought to calculate the lifetime risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study.

      Methods

      We followed participants aged 45-64 years in ARIC (n = 14,185) and ≥65 in CHS (n = 5414) at baseline visits (1987-1989 in ARIC, 1989-1990 and 1992-1993 in CHS) for incident venous thromboembolism (n = 728 in ARIC through 2011 and n = 172 in CHS through 2001). We estimated lifetime risks and 95% confidence intervals of incident venous thromboembolism using a modified Kaplan-Meier method, accounting for the competing risk of death from other causes.

      Results

      At age 45 years, the remaining lifetime risk of venous thromboembolism in ARIC was 8.1% (95% confidence interval, 7.1-8.7). High-risk groups were African Americans (11.5% lifetime risk), those with obesity (10.9%), heterozygous for the factor V Leiden (17.1%), or with sickle cell trait or disease (18.2%). Lifetime risk estimates differed by cohort; these differences were explained by differences in time period of venous thromboembolism ascertainment.

      Conclusions

      At least 1 in 12 middle-aged adults will develop venous thromboembolism in their remaining lifetime. This estimate of lifetime risk may be useful to promote awareness of venous thromboembolism and guide decisions at both clinical and policy levels.

      Keywords

      Clinical Significance
      • At least 1 in 12 middle-aged adults will develop venous thromboembolism (VTE) in their remaining lifetime.
      • This estimate of lifetime risk may be useful to promote awareness of VTE and guide decisions at both clinical and policy levels.
      A recent Surgeon General's Call to Action
      Office of the Surgeon General (US)
      The Surgeon General's Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism.
      aimed to “raise consumer awareness about DVT/PE [deep vein thrombosis/pulmonary embolism] and the magnitude of the burden caused by these conditions.” Indeed, there is a case for raising awareness of deep vein thrombosis and pulmonary embolism, collectively termed venous thromboembolism, as awareness in the general population is very low. One telephone survey found that only a quarter of respondents had heard of deep vein thrombosis, fewer than 1 in 10 had any knowledge of its symptoms or risk factors, and only 1 in 17 knew that deep vein thrombosis could be prevented.

      American Public Health Association. Deep-Vein Thrombosis: Advancing Awareness to Protect Patient Lives. Public Health Leadership Conference on Deep-Vein Thrombosis. White Paper. Available at: http://www.leepbook.com/eventdownloads/4168_APHAWhitePaperonDeep-VeinThrombosis.pdf. Accessed December 21, 2015.

      In other words, only about 6% of Americans know what deep vein thrombosis is and that it can be prevented. Compare this with the 93% who had heard of diabetes and allergies, and 91% who had heard of stroke. Even colitis was better known than deep vein thrombosis, with 42% of the survey population having heard of it. The Surgeon General's Call to Action also aimed to raise policymakers' awareness of deep vein thrombosis/pulmonary embolism, in hopes that they will in turn support public awareness campaigns; venous thromboembolism education for health care professionals, including the dissemination of evidence-based guidelines; and the development of tools that facilitate implementation of knowledge (such as hospital-based prevention of venous thromboembolism) into clinical practice. Venous thromboembolism is a substantial source of morbidity and mortality, so prevention is imperative.
      ISTH Steering Committee for World Thrombosis Day
      Thrombosis: a major contributor to global disease burden.
      Promoting awareness of venous thromboembolism may be an important next step for venous thromboembolism prevention and treatment.
      Lifetime risk estimates of venous thromboembolism – defined as the cumulative incidence of venous thromboembolism between an index age and death – could help in promoting awareness of venous thromboembolism. Studies show that the general public finds lifetime risk of disease more easily interpretable than some other formats of risk information (eg, an annual incidence rate).
      • Sasieni P.D.
      • Adams J.
      Standardized lifetime risk.
      • Fortin J.M.
      • Hirota L.K.
      • Bond B.E.
      • O'Connor A.M.
      • Col N.F.
      Identifying patient preferences for communicating risk estimates: a descriptive pilot study.
      Interpretability is essential for a public awareness campaign. The most widely cited lifetime risk is for breast cancer—1 in 8—and was effective at promoting awareness, prevention, and treatment of breast cancer. In addition, lifetime risk estimates allow for easy comparison of burden between diseases, and hence can be an important tool to guide decisions at both clinical and policy levels.
      To our knowledge, no estimates of the lifetime risk of venous thromboembolism exist. Therefore, we calculated the lifetime risk of venous thromboembolism using data from 2 large, prospective community-based cohort studies: the Cardiovascular Health Study (CHS)
      • Tell G.S.
      • Fried L.P.
      • Hermanson B.
      • Manolio T.A.
      • Newman A.B.
      • Borhani N.O.
      Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study.
      and the Atherosclerosis Risk in Communities (ARIC)
      The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators.
      study, which have similar protocols.

      Methods

      Study Population

      Between 1987 and 1989, ARIC recruited and examined 15,792 participants aged 45-64 years living in 4 US communities: Forsyth County, NC; Jackson, MS (African Americans only); suburban Minneapolis, MN; and Washington County, MD.
      The Atherosclerosis Risk in Communities (ARIC) Study: design and objectives. The ARIC investigators.
      Response rates for the baseline examination were 46% in Jackson and 65%-67% at other clinic sites; differences between respondents and nonrespondents have been described.
      • Jackson R.
      • Chambless L.E.
      • Yang K.
      • et al.
      Differences between respondents and nonrespondents in a multicenter community-based study vary by gender ethnicity. The Atherosclerosis Risk in Communities (ARIC) Study Investigators.
      CHS sampled from Medicare lists, recruited, and examined 5888 community-dwelling participants aged ≥65 years living in 4 US communities (Pittsburgh [Allegheny County], PA; Forsyth County, NC; Sacramento County, CA; and Washington County, MD) from 1989-1990 and 1992-1993 (African Americans only).
      • Tell G.S.
      • Fried L.P.
      • Hermanson B.
      • Manolio T.A.
      • Newman A.B.
      • Borhani N.O.
      Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study.
      The response rate for the baseline examination was 61% of those eligible; differences between respondents and nonrespondents have been described.
      • Tell G.S.
      • Fried L.P.
      • Hermanson B.
      • Manolio T.A.
      • Newman A.B.
      • Borhani N.O.
      Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study.
      We excluded individuals from all analyses if they had a history of venous thromboembolism or anticoagulant use at baseline (n = 347 in ARIC, 419 in CHS); were of a race other than African American or White (due to small numbers) (n = 48 in ARIC, 38 in CHS); in ARIC, were African American from Washington County or Minneapolis suburbs (due to small numbers) (n = 55); or had missing data on any variable included in the main analysis (n excluded in ARIC = 1157: 25 missing body mass index [BMI] measurements, 547 missing factor V Leiden status, 340 missing prothrombin G20210A status, 238 missing blood group measurements, and 7 missing sickle cell trait measurements; n excluded in CHS = 17 missing BMI measurements). Our final sample size for statistical analyses was 14,185 in ARIC and 5414 in CHS. The Institutional Review Boards of the collaborating institutions approved both studies. The investigators obtained informed consents from all participants before inclusion in the studies.

      Venous Thromboembolism Ascertainment

      Incident venous thromboembolism was defined as the first occurrence of a validated deep vein thrombosis or pulmonary embolism from baseline through the end of follow-up: December 31, 2011 for the ARIC Study and December 31, 2001 for CHS.
      Hospitalizations were identified through participant report in both studies, through Medicare records in CHS, and through surveillance of community hospitals' discharge lists in ARIC.
      • Cushman M.
      • Tsai A.W.
      • White R.H.
      • et al.
      Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.
      International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) discharge codes from all identified hospitalizations were recorded to identify possible cases of venous thromboembolism. Records with ICD-9-CM discharge codes (where x can take any value) 38.7 (procedure code), 415.1, 415.1X, 451, 451.1, 451.1X, 451.2, 451.8, 451.8X, 451.9, 453, 453.X, 453.XX, 996.7, 996.7X, 997.2, or 999.2 were considered to indicate possible venous thromboembolism. The records were copied and independently reviewed by 2 physicians using standardized criteria, with differences resolved by discussion.
      • Cushman M.
      • Tsai A.W.
      • White R.H.
      • et al.
      Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.
      Definite deep vein thrombosis was defined as a positive venogram, duplex ultrasound, or autopsy. Probable deep vein thrombosis was defined as a positive Doppler examination or impedance plethysmography. Definite pulmonary embolism was defined as a positive pulmonary angiogram, ventilation/perfusion scans indicating “high probability” of pulmonary embolism or at least 2 segmental perfusion defects without ventilation defects, computed tomography, or autopsy.
      • Cushman M.
      • Tsai A.W.
      • White R.H.
      • et al.
      Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology.
      Repeat classification has shown excellent repeatability.

      Baseline Measurements

      Age, race, sex, and history of venous thromboembolism were self-reported in both studies. BMI was calculated as weight (kg) divided by height (m)2; obesity was defined as BMI ≥30 kg/m2. In ARIC only, factor V Leiden,
      • De Ronde H.
      • Bertina R.M.
      Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria.
      prothrombin G20210A,
      • Poort S.R.
      • Rosendaal F.R.
      • Reitsma P.H.
      • Bertina R.M.
      A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.
      ABO blood group,
      • Ohira T.
      • Cushman M.
      • Tsai M.Y.
      • et al.
      ABO blood group, other risk factors and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE).
      and hemoglobin S genotype
      • Folsom A.R.
      • Tang W.
      • Roetker N.S.
      • et al.
      Prospective study of sickle cell trait and venous thromboembolism incidence.
      were measured as previously described.

      Statistical Analyses

      Analyses were performed using SAS (version 9.2, SAS Institute, Cary, NC). Because age-specific incidence rates (IRs) differed by cohort, all analyses were stratified by cohort. We computed person-years of follow-up from the date of the baseline examination to whichever came first: venous thromboembolism event, death, loss to follow-up, or the end of follow-up. Person-years of follow-up were allocated to 5-year age-specific groups. Age-specific venous thromboembolism IRs per 1000 person-years were calculated by dividing the age-specific number of incident venous thromboembolism events by age-specific person-years of follow-up, and multiplying this number by 1000.
      Lifetime risk was approximated as the cumulative incidence
      • Rychetnik L.
      • Hawe P.
      • Waters E.
      • Barratt A.
      • Frommer M.
      A glossary for evidence based public health.
      of venous thromboembolism through age 85 years, because many ARIC participants were not older than 85 at the end of follow-up. We used the Practical Incidence Estimators SAS Macro
      • Beiser A.
      • D'Agostino R.B.
      • Seshadri S.
      • Sullivan L.M.
      • Wolf P.A.
      Computing estimates of incidence, including lifetime risk: Alzheimer's disease in the Framingham Study. The Practical Incidence Estimators (PIE) macro.
      to estimate the remaining lifetime risk of incident venous thromboembolism conditional on survival (alive and free of venous thromboembolism) to selected index ages, and then repeated the estimation stratified by subgroups: sex, race, obesity status at baseline, factor V Leiden, prothrombin G20210A, blood group, and sickle cell trait. These variables were chosen because they are common risk factors for venous thromboembolism in the general population, and most are static across time. As tends to be the case in prospective cohort studies with a long period of follow-up, not all individuals in ARIC and CHS were followed for the entire duration. To account for this, we used a modified Kaplan-Meier approach to approximate cumulative incidence
      • Beiser A.
      • D'Agostino R.B.
      • Seshadri S.
      • Sullivan L.M.
      • Wolf P.A.
      Computing estimates of incidence, including lifetime risk: Alzheimer's disease in the Framingham Study. The Practical Incidence Estimators (PIE) macro.
      (ie, lifetime risk and its confidence interval). We adjusted lifetime risk estimates for the competing risk of death.
      • Beiser A.
      • D'Agostino R.B.
      • Seshadri S.
      • Sullivan L.M.
      • Wolf P.A.
      Computing estimates of incidence, including lifetime risk: Alzheimer's disease in the Framingham Study. The Practical Incidence Estimators (PIE) macro.
      • Pintilie M.
      Analysing and interpreting competing risk data.
      Thus, each participant was classified as either a venous thromboembolism event, censored (loss to follow-up or the end of follow-up), or a nonvenous thromboembolism-related death, whichever came first.
      Because age-specific venous thromboembolism IRs varied by cohort, we conducted sensitivity analyses to explore these differences. We restricted ARIC's follow-up to 2001 to match CHS' and calculated IRs. We also investigated the effect of cohort and time period of venous thromboembolism ascertainment on IRs by plotting cohort- and age-specific IRs by time period.

      Results

      At baseline, the mean age of ARIC participants was 54 years, approximately 50% were female, one-quarter were African American, and one-quarter were obese. In comparison, the CHS cohort at baseline was older (mean age of 73 years), had a similar sex distribution, a lower proportion of African Americans, and a lower proportion of participants who were obese (Table 1).
      Table 1Baseline Characteristics of ARIC and CHS Participants
      Characteristics (Means or Prevalences)ARIC (n = 14,185)CHS (n = 5414)
      Age, y (SD)54.1 (5.8)72.8 (5.6)
      Male, %44.742.8
      African American, %26.115.7
      Obese
      Obesity is defined as a body mass index of ≥30.
      , %
      27.219.3
      Factor V Leiden, % AA or AG
      AA = homozygous mutant, AG = heterozygous mutant.
      4.5N/A
      Prothrombin G20210A, % AA or AG
      AA = homozygous mutant, AG = heterozygous mutant.
      2.2N/A
      Non-O group blood type, %57.5N/A
      HbS genotype among African Americans, % AS (sickle cell trait) or SS (sickle cell disease)
      AS = heterozygosity for hemoglobin S, SS = homozygosity for hemoglobin S. HbS genotype was measured in ARIC African Americans only (n = 3704).
      6.9N/A
      Baseline ARIC Study: 1987-1989.
      Baseline CHS: 1989-1990 and 1992-1993.
      ARIC = Atherosclerosis Risk in Communities study; CHS = Cardiovascular Health Study; HbS = hemoglobin S; SD = standard deviation.
      Obesity is defined as a body mass index of ≥30.
      AA = homozygous mutant, AG = heterozygous mutant.
      AS = heterozygosity for hemoglobin S, SS = homozygosity for hemoglobin S. HbS genotype was measured in ARIC African Americans only (n = 3704).
      After the index age of 45 years, ARIC participants developed 728 venous thromboembolism events over 288,535 person-years of follow-up. After the index age of 65 years, CHS participants developed 172 venous thromboembolism events over 54,207 person-years of follow-up. As evidenced by sparse person-years (Table 2), few ARIC participants were followed past age 85, and few CHS participants survived past age 95 years. Incidence rates of venous thromboembolism increased exponentially across increasing age groups. Notably, the age-specific rates in ARIC were higher than for CHS.
      Table 2Age-specific Incidence Rates of Venous Thromboembolism per 1000 Person-years, ARIC and CHS
      Age Group, yARIC (n = 14,185)CHS (n = 5414)
      # of Venous ThromboembolismsPerson-yearsIncidence Rates of Venous Thromboembolism# of Venous ThromboembolismsPerson-yearsIncidence Rates of Venous Thromboembolism
      45-49611,5170.5---
      50-541530,1270.5---
      55-594546,5621.0---
      60-6410660,0751.8---
      65-6916860,6642.8448190.8
      70-7416543,3013.83814,1452.7
      75-7913224,6225.44717,3532.7
      80-848010,1217.94311,3203.8
      85-891115487.13149866.2
      90-94010.0813585.9
      95-99---12054.9
      100-104---0220.0
      Baseline through end of follow-up in the ARIC Study = 1987-1989 through 2011.
      Baseline through end of follow-up in CHS = 1989-1990 through 2001.
      ARIC = Atherosclerosis Risk in Communities study; CHS = Cardiovascular Health Study; HbS = hemoglobin S.
      Conditional on survival (alive and free of venous thromboembolism) to age 45 years, the remaining lifetime risk of venous thromboembolism in ARIC was 8.1% (95% confidence interval, 7.1-8.7) (Table 3). There was little difference in lifetime risk of venous thromboembolism by sex. Particularly high-risk groups were African Americans, with a lifetime risk (95% confidence interval) of 11.5% (8.8-13.1), participants who were obese at baseline (10.9% [8.7-12.3]), participants with factor V Leiden (17.1% [11.4-21.4]), and participants with sickle cell trait or disease (18.2% [3.8-25.1]). As expected, remaining lifetime risk of venous thromboembolism decreased across increasing index ages, reflecting the shorter life expectancy and period at risk of older participants (Supplementary Figure, Panels A-E; Appendix, available online).
      Table 3Lifetime Risk (95% CI) of Venous Thromboembolism, ARIC
      Lifetime Risk of Venous Thromboembolism
      % (95% CI)
      Total8.1 (7.1-8.7)
      Sex
       Male7.7 (6.3-8.6)
       Female8.4 (7.0-9.3)
      Race
       White6.9 (5.9-7.7)
       African American11.5 (8.8-13.1)
      Obesity status at baseline
      Obesity is defined as a body mass index ≥30.
       Obese10.9 (8.7-12.3)
       Not obese7.0 (5.9-7.7)
      Factor V Leiden
      AA = homozygous mutant, AG = heterozygous mutant, GG = wild type.
       AA or AG17.1 (11.4-21.4)
       GG7.6 (6.6-8.3)
      Prothrombin G20210A
      AA = homozygous mutant, AG = heterozygous mutant, GG = wild type.
       AA or AG6.3 (1.6-9.7)
       GG8.1 (7.1-8.8)
      Blood type
       Non-O group blood type8.9 (7.5-9.8)
       O group blood type7.0 (5.5-7.9)
      HbS Genotype among African Americans
      HbS genotype was measured in ARIC African Americans only (n = 3,704). AS = heterozygosity for hemoglobin S, SS = homozygosity for hemoglobin S, No S = wild type.
       AS (sickle cell trait) or SS (sickle cell disease)18.2 (3.8-25.1)
       No S11.0 (8.3-12.5)
      Lifetime risk is to age 85 years, conditional on survival free of venous thromboembolism to age 45 years, with death free of venous thromboembolism considered a competing event.
      Baseline through end of follow-up in the ARIC Study = 1987-1989 through 2011.
      ARIC = Atherosclerosis Risk in Communities study; CI = confidence interval; HbS = hemoglobin S.
      Obesity is defined as a body mass index ≥30.
      AA = homozygous mutant, AG = heterozygous mutant, GG = wild type.
      HbS genotype was measured in ARIC African Americans only (n = 3,704). AS = heterozygosity for hemoglobin S, SS = homozygosity for hemoglobin S, No S = wild type.
      When comparing lifetime risk estimates between the cohorts, those for CHS were about half those for ARIC (Lifetime risk at index age 65 years: ARIC – 7.1%, CHS – 3.9%; lifetime risk at index age 75 years: ARIC – 5.2%, CHS – 2.6%) (Supplementary Figure, Panel A; Appendix, available online). At least part of this difference by cohort may relate to ARIC, but not CHS, having follow-up for 2002-2011. When the follow-up for ARIC was restricted to 2001 to match that for CHS, the IRs were more similar (Supplementary Table; Appendix, available online). Additionally, when we compared cohort- and age-specific IRs by time period of venous thromboembolism ascertainment, the IRs per 1000 person-years were similar by study (≤1995, 65-74 years: ARIC = 2.1, CHS = 1.8; 1996-2001, 65-74 years: ARIC = 2.9, CHS = 3.2; 1996-2001, 75-84 years: ARIC = 3.9, CHS = 3.6), and age-specific IRs of venous thromboembolism increased across increasing time periods of venous thromboembolism ascertainment (Figure).
      Figure thumbnail gr1
      FigureCohort- and age- specific venous thromboembolism incidence rates by time period of venous thromboembolism ascertainment. ARIC = Atherosclerosis Risk in Communities study; CHS = Cardiovascular Health Study.

      Discussion

      The lifetime risk of venous thromboembolism in ARIC was one in 12. High-risk groups were African Americans (1 in 9), those with obesity (1 in 9), those with factor V Leiden (1 in 6), and those with sickle cell trait or disease (1 in 5). The lifetime risk of venous thromboembolism decreased with age, as expected, but still remained relatively high at older ages. IRs and lifetime risk estimates differed between ARIC and CHS; these differences were largely explained by differences in time period of venous thromboembolism ascertainment, with IRs of venous thromboembolism being higher in recent years.
      The lifetime risk of venous thromboembolism is substantial, although lower than for other major cardiovascular diseases. At age 40 years, the lifetime risk estimates of coronary heart disease are 1 in 2 for males and 1 in 3 for females
      • Lloyd-Jones D.M.
      • Larson M.G.
      • Beiser A.
      • Levy D.
      Lifetime risk of developing coronary heart disease.
      ; atrial fibrillation, 1 in 4
      • Lloyd-Jones D.M.
      • Wang T.J.
      • Leip E.P.
      • et al.
      Lifetime risk for development of atrial fibrillation: the Framingham Heart Study.
      ; and congestive heart failure, at least 1 in 5.
      • Lloyd-Jones D.M.
      • Larson M.G.
      • Leip E.P.
      • et al.
      Lifetime risk for developing congestive heart failure: the Framingham Heart Study.
      • Huffman M.D.
      • Berry J.D.
      • Ning H.
      • et al.
      Lifetime risk for heart failure among white and black Americans: cardiovascular lifetime risk pooling project.
      At age 55, the lifetime risk estimates of stroke are 1 in 6 for males and 1 in 5 for females.
      • Seshadri S.
      • Beiser A.
      • Kelly-Hayes M.
      • et al.
      The lifetime risk of stroke: estimates from the Framingham Study.
      At age 40 years, the lifetime risk of breast cancer is 1 in 8 for females.
      • Feuer E.J.
      • Wun L.M.
      • Boring C.C.
      • Flanders W.D.
      • Timmel M.J.
      • Tong T.
      The lifetime risk of developing breast cancer.
      To reiterate, these estimates of lifetime risk may be useful to promote awareness of venous thromboembolism and guide decisions at policy levels. In addition, the lifetime risk estimates could plausibly be used to counsel patients. For instance, screening for sickle cell disease in newborns is now mandated in the US, so the lifetime risk estimate of venous thromboembolism in those with sickle cell trait may be useful in counseling families of identified sickle cell trait newborns. Additionally, factor V Leiden was associated with a high lifetime risk; this estimate might be useful in counseling individuals with factor V Leiden. However, testing for the factor V Leiden mutation in clinical practice is controversial, as it is unknown whether testing improves outcomes in those with venous thromboembolism or in family members of those with a mutation. If testing was paired with education, it could result in awareness of symptoms and risk factors for venous thromboembolism.
      • Segal J.B.
      • Brotman D.J.
      • Necochea A.J.
      • et al.
      Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review.
      Our estimates of lifetime risk of venous thromboembolism are generalizable only to US populations similar to ARIC. Participants in this study were exclusively African American or White, so results may not generalize to other race groups. Asians and Hispanics in the US have lower incidence rates of venous thromboembolism than Whites. African Americans may have higher rates
      • White R.H.
      • Zhou H.
      • Murin S.
      • Harvey D.
      Effect of ethnicity and gender on the incidence of venous thromboembolism in a diverse population in California in 1996.
      • White R.H.
      • Zhou H.
      • Romano P.S.
      Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California.
      than Whites, although a recent paper calls this into question.
      • Zakai N.A.
      • McClure L.A.
      • Judd S.E.
      • et al.
      Racial and regional differences in venous thromboembolism in the United States in 3 cohorts.
      It is important to remember the lifetime risk estimates represent population averages; an individual's estimated risk of venous thromboembolism will vary depending on the presence or absence of various factors.
      Differences in IRs and lifetime risk estimates between ARIC and CHS may be explained by changes over time in how venous thromboembolism was ascertained. Computed tomographic pulmonary angiography (CTPA)—a highly sensitive imaging technique to detect pulmonary embolism—was introduced in 1998; CTPA largely and rapidly replaced other tests for pulmonary embolism.
      • Wittram C.
      • Meehan M.J.
      • Halpern E.F.
      • Shepard J.O.
      • McLoud T.C.
      • Thrall J.H.
      Trends in thoracic radiology over a decade at a large academic medical center.
      Thought to be in large part a result of the introduction of CTPA, pulmonary embolism incidence in the US increased substantially after 1998.
      • Wiener R.S.
      • Schwartz L.M.
      • Woloshin S.
      Time trends in pulmonary embolism in the United States: evidence of overdiagnosis.
      In concordance, our data show a sharp increase in IRs during the time period that CTPA was adopted (Figure). Of course, if venous thromboembolism IRs truly increase over time, or the detection of venous thromboembolism becomes more sensitive, estimates of lifetime risk will increase correspondingly.
      Other possible explanations for the observed differences between ARIC and CHS exist. CHS participants were aged 65 years or older at recruitment. Baseline exclusions and self-selection could have made the CHS cohort healthier in old age than ARIC, for whom exclusions at recruitment occurred when participants were 20 years younger (recruited at ages 45-64) and thus included more unhealthy people by age 65 plus. Also, ARIC had a higher proportion of African Americans (26% vs 15%) and participants with obesity (27% vs 19%) compared with CHS. However, race- and obesity-specific IRs did not explain the discrepancies between cohorts (data not shown).
      It is likely that we underestimated the incidence of venous thromboembolism, and thus lifetime risk, in these cohorts. As in most studies, fatal and undiagnosed venous thromboembolisms would have been under-ascertained. Further, cases of venous thromboembolism treated solely in outpatient settings were not captured. An ARIC pilot study estimated that 40% of venous thromboembolisms (based just on ICD code) were outpatients for 1991-2009. However, this is an overestimate, because these potential venous thromboembolism events are not validated. Data from REasons for Geographic and Racial Differences in Stroke (REGARDS), a nationally representative cohort study, estimates a lower proportion of outpatient venous thromboembolisms: between 2003 and 2007, only 10.3% of validated venous thromboembolisms (39 of 379) were treated in an outpatient setting. And although most venous thromboembolisms occur later in life, we missed venous thromboembolisms before the age of 45, including most venous thromboembolisms related to pregnancy and oral contraceptive use. And finally, approximating lifetime risk estimates as the cumulative incidence of venous thromboembolism through age 85 years assumed that nobody developed venous thromboembolism after age 85, further supporting that our estimates are underestimates.
      Strengths of this study include a prospective design; 2 large, population-based biracial samples with a wide geographic distribution in the US; venous thromboembolism validation; and a long period of follow-up. Drawbacks of this study warrant discussion as well. Participants were exclusively African American or White, so results may not generalize to other race groups. IRs and lifetime risk estimates were unadjusted for other variables, raising the possibility that differences in these metrics between risk subgroups were due to differences in the distribution of other variables. We potentially misclassified obesity, as BMI is not necessarily static across time. However, the lifetime risk estimates in the “obese at baseline” strata are interpretable: in ARIC, it is the lifetime risk of venous thromboembolism if obese in middle age; in CHS, it is the lifetime risk of venous thromboembolism if obese in older age. And, as discussed above, we likely underestimated lifetime risk.
      In conclusion, at least 1 in 12 middle-aged adults develop venous thromboembolism in their lifetime. The fact that 8% of individuals will develop venous thromboembolism during their life highlights the high morbidity of this condition. Considering that fewer than 1 in 10 Americans have any knowledge of deep vein thrombosis,

      American Public Health Association. Deep-Vein Thrombosis: Advancing Awareness to Protect Patient Lives. Public Health Leadership Conference on Deep-Vein Thrombosis. White Paper. Available at: http://www.leepbook.com/eventdownloads/4168_APHAWhitePaperonDeep-VeinThrombosis.pdf. Accessed December 21, 2015.

      these findings reiterate the need for venous thromboembolism awareness. This estimate of lifetime risk may be useful to promote awareness of venous thromboembolism and guide decisions at both clinical and policy levels.

      Acknowledgment

      The authors thank the staff and participants of the ARIC and CHS studies for their important contributions.

      Appendix

      Figure thumbnail fx1
      Supplementary FigureCumulative risk of VTE at selected index ages (A) by cohort and, in ARIC, for race- and sex-specific groups (B-E), with death considered a competing event. Lifetime risk for a given index age is cumulative risk through 85 years of age. ARIC = Atherosclerosis Risk in Communities study; CHS = Cardiovascular Health Study; VTE = venous thromboembolism.
      Supplementary TableARIC Follow-up Restricted to 2001: Incidence Rates of VTE per 1000 Person-years, ARIC and CHS
      Age Group, yARIC (n = 14,185)CHS (n = 5414)
      # of VTE CasesPerson-yearsIncidence Rates of VTE# of VTE CasesPerson-yearsIncidence Rates of VTE
      45-49611,5170.5---
      50-541530,1270.5---
      55-594345,2291.0---
      60-646245,6701.4---
      65-697132,7512.2448190.8
      70-744915,7553.13814,1452.7
      75-79729202.44717,3532.7
      80-84020.04311,3203.8
      85-89---3149866.2
      90-94---813585.9
      95-99---12054.9
      100-104---0220.0
      Baseline (1987-1989) through 2001 in the ARIC Study.
      Baseline (1989-1990) through end of follow-up (2001) in CHS.
      ARIC = Atherosclerosis Risk in Communities study; CHS = Cardiovascular Health Study; VTE = venous thromboembolism.

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