The epidemiology of venous thromboembolism

Venous thromboembolism (VTE) is categorized by the U.S. Surgeon General as a major public health problem. VTE is relatively common and associated with reduced survival and substantial health-care costs, and recurs frequently. VTE is a complex (multifactorial) disease, involving interactions between acquired or inherited predispositions to thrombosis and VTE risk factors, including increasing patient age and obesity, hospitalization for surgery or acute illness, nursing-home confinement, active cancer, trauma or fracture, immobility or leg paresis, superficial vein thrombosis, and, in women, pregnancy and puerperium, oral contraception, and hormone therapy. Although independent VTE risk factors and predictors of VTE recurrence have been identified, and effective primary and secondary prophylaxis is available, the occurrence of VTE seems to be relatively constant, or even increasing.


Introduction
Thrombosis can affect virtually any venous circulation. This chapter focuses on the epidemiology of venous thromboembolism (VTE), including deep vein thrombosis (DVT) of the leg or pelvis, and its complication, pulmonary embolism (PE). Thrombosis affecting the superficial leg (e.g. saphenous) veins and other venous circulations (e.g. arm, cerebral, mesenteric, renal, hepatic, portal veins) is beyond the scope of this chapter. VTE is a complex (multifactorial) disease, involving interaction between acquired or inherited predispositions to thrombosis (i.e. thrombophilia) and environmental exposures (i.e. clinical risk factors) [1][2][3][4][5]. Moreover, the type of VTE event (PE vs. DVT) may also be partly heritable [6,7]. Most studies of VTE epidemiology addressed populations of predominantly European origin, and the data discussed in this chapter mainly relate to these populations. Where available, data from populations originating from other continents are presented.

Methods
This chapter focuses on population-based studies and addresses nine questions regarding the epidemiology of VTE (Table 1). Questions were developed by consensus from the authors. The literature addressing the above questions was reviewed by searching electronic databases (PubMed, Medline), including the references of all identified papers and the author's personal libraries. Since this review is informational only and does not address diagnosis, treatment or management of VTE, there are no associated guidance statements. The post thrombotic syndrome and the epidemiology of inherited and acquired & John A. Heit heit.john@mayo.edu thrombophilia are reviewed in Chapters 9 and 10, respectively.

Questions
(1) What is the incidence of VTE, PE with or without (±) DVT and leg DVT alone, both overall, and by age, sex and race, and by idiopathic versus secondary VTE?
VTE is predominantly a disease of older age; VTE is rare prior to late adolescence [8, 10-15, 18]. Incidence rates increase markedly with age for both men and women ( Fig. 1) and for both DVT and PE (Fig. 2) [10, 14, 15]. The overall age-adjusted incidence rate is higher for men (130 per 100,000) then women (110 per 100,000; male:female sex ratio is 1.2:1) [10,15]. Incidence rates are somewhat higher in women during childbearing years, while incidence rates after age 45 years are generally higher in men. PE accounts for an increasing proportion of VTE with increasing age for both sexes [10]. The percentage of incident VTE events that are idiopathic ranges from 25 to 40 % [26,28,29]. In one study, 19 % of events among Asian/Pacific Islanders were idiopathic [26].
(2) What are the trends in incidence over time of overall VTE, leg DVT alone and PE ± DVT, and of idiopathic versus secondary VTE? How are these trends (1) What is the incidence of VTE, PE with or without (±) DVT and leg DVT alone, both overall, and by age, sex and race, and by idiopathic versus secondary VTE?
(2) What are the trends in incidence over time of overall VTE, leg DVT alone and PE ± DVT, and of idiopathic versus secondary VTE? How are these trends affected by changes in diagnostic test utilization, imaging resolution and autopsy rates over time?
(3) What is the cumulative incidence of VTE recurrence, both overall and by leg DVT alone versus PE ± DVT?
(4) What baseline and time-dependent characteristics are independent predictors of VTE recurrence after adjustment for primary treatment and secondary prophylaxis? Within the major predictors of VTE recurrence, can the individual patient be further stratified into high and low risk? How well do available VTE recurrence risk-prediction scores operate in predicting recurrence? affected by changes in diagnostic test utilization, imaging resolution and autopsy rates over time?
Data on trends in VTE incidence are limited; overall VTE incidence rates as well as incidence rates for PE ± DVT and DVT alone either remained relatively constant or increased for the period, 1981-2000, with a significant increase in the overall VTE incidence rate from 2001 to 2009, mostly due to an increasing incidence of PE ± DVT (Fig. 3) [10, 14, 18, 30]. The incidence rates of incident cancer-associated VTE, secondary non cancerassociated VTE and idiopathic VTE, 1999-2009, appear to be relatively constant [29]. The observed increase in overall VTE and PE ± DVT incidence rates over the most recent time period may, in part, reflect increased utilization of objective imaging and improved image resolution, particularly computed tomography, pulmonary angiography, and magnetic resonance imaging [18].
(3) What is the cumulative incidence of VTE recurrence, both overall and by leg DVT alone vs. PE ± DVT?
VTE recurs frequently; about 30 % of patients develop recurrence within the next 10 years (Fig. 4)     . Several VTE recurrence prediction scores have been derived for stratifying recurrence risk among patients with incident idiopathic or cancer-associated VTE. In the ''Men continue and HERDOO2 00 score, there were no predictors of a reduced risk of recurrence among men with incident idiopathic VTE. In contrast, women with idiopathic VTE who had B1 of the following risk factors had a significantly lower risk of VTE recurrence: (1) older age (C 65 years), (2) obesity (BMI C 30 kg/m 2 ), (3) an increased D-dimer prior to stopping warfarin therapy and (4) signs of post thrombotic syndrome [93]. In the Vienna prediction model, male sex, incident VTE site (PE and proximal DVT vs. isolated calf DVT) and increasing D-dimer level were predictors of recurrence after idiopathic incident VTE [94]. In the DASH prediction score, a persistently increased D-dimer after stopping anticoagulation therapy, age \50 years, male sex and VTE unrelated to hormonal therapy (in women) predicted an increased risk of recurrence after an ''idiopathic'' incident VTE [95]. Thus, the only inconsistent risk factor in these models is the effect of patient age, with older and younger age being associated with a higher recurrence risk among women in the HER-DOO2 model and among men and women in the DASH model, respectively [ There are few data on the total number of VTE events (incident and recurrent) occurring in the USA per year, and available estimates vary widely. Using age-and sexspecific incidence rates for the five-year time period, 1991-95, projected to the 2000 United States white population, at least 260,000 first-lifetime cases of VTE occur among whites in the United States annually [13]. If incidence rates among African-Americans are similar, then 27,000 additional incident cases occur among African-Americans in the United States annually. In an incidencebased modeling study that included both hospital-and community-acquired, incident and recurrent VTE events, an estimated 600,000 non-fatal VTE events ( In population-based studies, the adjusted mean predicted costs were 2.5-fold higher for patients with VTE related to current or recent hospitalization for acute medical illness ($62,838) compared to hospitalized controls matched on active cancer status ($24,464; p \ 0.001) from the VTE event date (or index date for controls) to 5 years post index; cost differences between cases and controls were greatest within the first 3 months (mean difference = $16,897) [101]. Similarly, the adjusted mean predicted costs were 1.5-fold higher for patients with VTE related to current or recent hospitalization for major surgery ($55,956) compared to hospitalized controls matched to cases on type of surgery and active cancer status ($32,718; p \ 0.001) from the VTE event date (or index date for controls) to 5 years post index [102]. Cost differences between cases and controls were also greatest within the first 3 months after index (mean difference = $12,381). Costs were significantly higher for cases than controls (mean difference = $10,797) from 3 months to up to 5 years post-index and together accounted for about half of the overall cost difference. Finally, the adjusted mean predicted costs were over 2-fold higher for patients with VTE related to active cancer ($52,422) compared to active cancer controls matched on the duration of active cancer ($23,951; p \ 0.001) from the VTE event date (or index date for controls) to 5 years post index [103]. Cost differences between cases and controls were greatest within the first 3 months (mean difference = $16,488) but remained significantly higher for up to 4 years after index.
(7) What is the survival after VTE overall, and after leg DVT alone vs. PE ± DVT. What are the independent predictors of survival? What are the trends in survival over time after PE ± DVT?
Overall, survival after VTE is worse than expected, and survival after PE is much worse than after DVT alone ( While risk assessment models for predicting VTE among hospitalized non-surgical patients have been   143], thalidomide [144] or lenalidomide [145], or tamoxifen [146]. Routine screening for occult cancer is controversial and likely not warranted. However, if clinical features suggest a possible occult cancer (i.e. idiopathic VTE, especially among patients with abdominal vein or bilateral leg vein thrombosis [147] or in whom VTE recurs [148]) then the only imaging study shown to be useful is a CT scan of the abdomen and pelvis [148]. Among cancer patients, the risk of chemotherapy-associated VTE is increased in patients with pancreatic or gastric cancer, platelet count C350 9 10 9 /L, hemoglobin \100 g/L or use of red cell growth factors, leukocyte count C11 9 10 9 /L, or body mass index C35 kg/m 2 [149]; biomarkers (plasma soluble P-selectin and D-dimer) add further predictive value [150].
A central venous catheter or transvenous pacemaker accounts for 9 % of all incident VTE occurring in the community [28]. Central venous access via femoral vein catheters is associated with a higher incidence of VTE compared to subclavian vein catheterization [151]. Prior superficial vein thrombosis is an independent risk factor for subsequent DVT or PE remote from the episode of superficial thrombophlebitis [112,152]. The risk of DVT imparted by varicose veins is uncertain and appears to vary by patient age [112, 153,154]. Long haul ([4-6 h) air travel is associated with a slightly increased risk for VTE (*1 per 4656 flights [155][156][157]) that is preventable with elastic stockings [158]. HMG-Coenzyme A reductase inhibitor (statin) therapy may provide a 20-50 % risk reduction for VTE [159][160][161]. Hypertriglyceridemia doubles the risk of VTE in postmenopausal women [162]. However, the risk associated with atherosclerosis, or other risk factors for atherosclerosis, remains uncertain [118, [163][164][165][166][167] 172,176], and therapy with the selective estrogen receptor modulator, raloxifene [177]. First and third generation oral contraceptives convey higher risk than second generation oral contraceptives [173]. Injectable depot-medroxyprogesterone acetate for contraception is associated with a three-fold increased risk for venous thromboembolism, while a levonorgestrel intrauterine device imparts no risk [178]. Hormone therapy is associated with a 2-to fourfold increased risk of VTE [117,174], but the risk may vary by type of estrogen [179] and there may be no risk with transdermal estrogen therapy [180]. The overall incidence of pregnancy-associated VTE is about 200 per 100,000 woman-years; compared to nonpregnant women of childbearing age, the relative risk is increased about fourfold [176,181]. The risk during the postpartum period is about fivefold higher than the risk during pregnancy [176]. Prior superficial vein thrombosis is an independent risk factor for VTE during pregnancy or postpartum [182,183].
conflicts of interest. Only recent outside payments from UpToDate for a chapter on Aspirin in Primary Prevention of Cardiovascular Disease and Malignancy (\2 K). Potential intellectual conflicts of interest are prior NIH grants for study of venous thromboembolism epidemiology.
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