Venous Thromboembolism
`A Public Health Concern
`
`Michele G. Beckman, MPH, W. Craig Hooper, PhD, Sara E. Critchley, MS,
`Thomas L. Ortel, MD, PhD
`
`Abstract: Venous thromboembolism (VTE), defıned as deep vein thrombosis, pulmonary embo-
`lism, or both, affects an estimated 300,000–600,000 individuals in the U.S. each year, causing
`considerable morbidity and mortality. It is a disorder that can occur in all races and ethnicities, all age
`groups, and both genders. With many of the known risk factors—advanced age, immobility, surgery,
`obesity—increasing in society, VTE is an important and growing public health problem.
`Recently, a marked increase has occurred in federal and national efforts to raise awareness and
`acknowledge the need for VTE prevention. Yet, many basic public health functions—surveillance,
`research, and awareness—are still needed. Learning and understanding more about the burden and
`causes of VTE, and raising awareness among the public and healthcare providers through a compre-
`hensive public health approach, has enormous potential to prevent and reduce death and morbidity
`from deep vein thrombosis and pulmonary embolism throughout the U.S.
`(Am J Prev Med 2010;38(4S):S495–S501) Published by Elsevier Inc. on behalf of American Journal of Preventive
`Medicine
`
`IntroductionV enous thromboembolism (VTE) is a condition
`
`in which the blood clots inappropriately, caus-
`ing considerable morbidity and mortality. The
`term VTE encompasses a continuum that includes both
`deep vein thrombosis (DVT), clots in the deep veins of
`the body; and pulmonary embolism (PE), which occurs
`when a clot breaks free and enters the arteries of the lungs.
`All races and ethnicities are affected by VTE, as are both
`genders and all age groups. With many of the known risk
`factors—advanced age, immobility, surgery, obesity—
`increasing in society, it is an important and growing
`public health problem. Yet, until recently, this condition
`has received little attention from the public health com-
`munity. Fortunately, in many cases, VTE is preventable;
`thus, the importance of research and prevention of VTE
`is being increasingly recognized. However, critical and
`essential public health pieces are still missing. The cur-
`rent paper provides an overview of the epidemiology of
`VTE; discusses some recent, key public health activities;
`
`From the Division of Blood Disorders (Beckman, Hooper, Critchley), Na-
`tional Center on Birth Defects and Developmental Disabilities, CDC, At-
`lanta, Georgia; and Duke University Medical Center (Ortel), Durham,
`North Carolina
`Address correspondence and reprint requests to: Michele G. Beckman,
`MPH, Division of Blood Disorders, National Center on Birth Defects and
`Developmental Disabilities, CDC, 1600 Clifton Road, MS-E64, Atlanta GA
`30333. E-mail: mbeckman@cdc.gov.
`0749-3797/00/$17.00
`doi: 10.1016/j.amepre.2009.12.017
`
`and identifıes gaps in essential functions that are needed
`to prevent and reduce morbidity and mortality.
`
`Epidemiology
`Clinically, patients with VTE can be defıned as pre-
`senting with DVT, PE, or both. About two thirds of
`patients with VTE present for care with DVT, and the
`remaining one third present with PE, which is the
`primary cause of mortality associated with VTE, often
`resulting in sudden death. It is also the leading cause of
`preventable hospital death and a leading cause of ma-
`ternal mortality in the U.S.1,2
`
`Incidence
`Currently, there is no national surveillance for VTE, so
`the precise number of people affected by VTE is un-
`known. Based on analyses of clinical administrative data-
`bases and hospital- and community-based studies, the
`overall annual incidence of VTE in the U.S. is estimated
`to be between 1 and 2 per 1000 of the population, or
`300,000–600,000 cases.3–5 However,
`these incidence
`rates differ by age, race, and gender (Table 1). The inci-
`dence ranges from 1 per 100,000 in the young and in-
`creases to about 1 per 100 in people aged ⱖ80 years. The
`overall rate is higher among blacks and whites than
`among other races and ethnicities. Men have a slightly
`higher overall incidence rate than women, but women
`have a slight increase during the reproductive years.5,9 –11
`However, because of the diffıculty in documenting DVT
`
`Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine
`
`Am J Prev Med 2010;38(4S)S495–S501 S495
`MYLAN EXHIBIT 1019
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`Beckman et al / Am J Prev Med 2010;38(4S):S495–S501
`S496
`clots, which also decreases quality of life and places them
`Table 1. Estimated incidence of venous
`thromboembolism by age, race, and gender
`at an increased risk for adverse bleeding episodes.
`
`Characteristics
`
`Race/ethnicity
`
`Annual incidence per 1000
`
`White
`
`Black
`
`Asian
`
`Hispanic
`
`Age (years)
`
`⬍15
`
`15–44
`
`45–79
`
`ⱖ80
`
`Gender
`
`Male
`
`Female
`
`Overall
`
`1.173
`
`0.776–1.415
`
`0.297
`
`0.617
`
`⬍0.53,8
`
`1.493
`
`1.929
`
`5–63,4,8,9
`
`1.33
`
`1.13
`
`1–23–5
`
`and PE, the limitations of administrative databases, and
`the regional and racial specifıcity of community-based
`studies, VTE may be vastly under-reported.12,13
`
`Morbidity and Mortality
`Venous thromboembolism is often fatal. Depending on
`case ascertainment and the use of autopsy data, studies
`estimate that 10%–30% of all patients suffer mortality
`within 30 days; the majority of deaths occur among those
`with PE, as an estimated 20%–25% of all PE cases present
`as sudden death.6,8 –10 Other serious complications of
`DVT and PE include increased risks of recurrent throm-
`boembolism and chronic morbidity (e.g., venous insuffı-
`ciency, pulmonary hypertension). Following a standard
`course of anticoagulant therapy, about one third of all
`VTE patients experience a recurrence within 10 years of the
`initial event, with the highest risk occurring within the fırst
`year, yet they remain at risk throughout their lives.6,14 One
`third to one half of lower-extremity DVT patients develop
`post-thrombotic syndrome and chronic venous insuffı-
`ciency, lifelong conditions characterized by pain, swelling,
`skin necrosis, and ulceration.6,15
`Quality of life has been reported to be adversely af-
`fected up to 4 months after DVT, and for those with
`post-thrombotic syndrome, quality of life actually de-
`clines further during this period, with changes similar to
`those seen in individuals with chronic heart, lung, or
`arthritic disease.15 In addition, subsets of VTE patients
`require long-term anticoagulation to prevent additional
`
`Economic Burden
`Venous thromboembolism is complex and presents in
`both inpatient and outpatient settings, and although many
`cases have been attributed to hospitalization, about two
`thirds of cases occur in outpatients.16 Although data are
`lacking on the exact cost attributed to VTE, a recent analysis
`of healthcare claims estimated that the total annual health-
`care cost for VTE ranges from $7594 to $16,644 per pa-
`tient.17 With estimates of 300,000–600,000 incident cases
`per year, this cost equates to a total annual cost of $2 billion
`to $10 billion attributable to VTE.
`
`Etiology and Risk Factors
`The etiology of VTE is not fully understood. It is a multi-
`factorial condition involving genetic and both constant
`and transient acquired risk factors (Table 2). A threshold
`seems to exist, as the presence of one risk factor does not
`always result in disease status; however, an interactive
`effect of multiple triggers and events can lead to clot
`formation. Yet, in about 50% of cases there is no acquired
`risk factor identifıed (idiopathic), and in 10%–20% there is
`no acquired or genetic risk identifıed, signifying the effect of
`still unknown genetic and/or acquired risk factors.12,13,18
`Known acquired risks include chronic disease, can-
`cer, obesity, antiphospholipid antibodies, and advanced
`age.6,9,11,19 –21 Other acquired risks can be thought of as
`transient states, which include surgery, trauma, immobi-
`lization, infection, and hospitalization.6,8,19 –21 Women
`also have increased risk during pregnancy and the post-
`partum period and while taking hormonal contraceptives
`and hormone replacement therapy.11,22–25 Hospitaliza-
`tion is an especially important risk factor as it provides a
`unique period in which multiple risk factors may be
`
`Table 2. Identified risk factors for venous
`thromboembolism
`
`Genetic
`
`Acquired
`
`Transient acquired
`
`Family history
`
`Advanced age
`
`Pregnancy
`
`Factor V Leiden
`
`Prothrombin
`G20210A
`
`Antiphospholipid
`antibodies
`
`Oral contraceptives
`
`Cancer
`
`Hormone therapy
`
`Protein C deficiency Chronic disease Hospitalization
`
`Protein S deficiency Obesity
`
`Antithrombin
`deficiency
`
`Sickle cell trait
`
`—
`
`—
`
`Surgery
`
`Trauma
`
`Immobilization
`
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`

`Beckman et al / Am J Prev Med 2010;38(4S):S495–S501
`S497
`increase risk. For example, reports have shown even
`present (surgery, trauma, intravenous catheters and ac-
`greater increased risk among women with factor V Lei-
`cess devices, immobilization, pregnancy, chronic condi-
`den or sickle cell trait, while they are taking oral contra-
`tions); it has been estimated that as many as half of out-
`ceptives. Among women with the factor V Leiden, taking
`patient VTE occurrences can be linked directly to a prior
`hospitalization up to 3 months postdischarge.16 This
`oral contraceptives increased their risk fıvefold.31 Screen-
`fınding indicates that the hospitalization period provides
`ing for factor V Leiden prior to prescription of oral con-
`a unique intervention and prevention point.
`traceptives is not recommended in asymptomatic indi-
`viduals, however, because the absolute risk is still low.32
`Family history of VTE is associated with DVT and
`Among those with sickle cell trait, the risk was three times
`PE occurrence,19,26 indicating that genetics also plays
`higher, much greater than the multiplicative effect of the
`an important etiologic role. Several genetic risk fac-
`two exposures.33 Genetic risk also exacerbates the risk of
`tors, also known as inherited thrombophilias, have
`VTE during pregnancy, with estimates of 20%–50% of
`been identifıed and include factor V Leiden; prothrom-
`pregnancy-related VTE associated with the presence of at
`bin G20210A mutation; and defıciency of the natural
`least one thrombophilia.23,34,35 As expected, individuals
`anticoagulants protein C, protein S, and antithrombin.
`with more than one thrombophilia also have a greater
`The prevalence of these mutations in the general popula-
`risk than individuals having a single inherited risk
`tion varies from ⬍1%–5% and implies a three- to ten-fold
`factor.18,28,36
`increased risk of VTE in their heterozygous states.27,28
`Defıciencies of the natural anticoagulants confer the most
`risk, but these disorders are also less common in the
`population. Presence of one of these mutations does not
`always lead to the development of VTE, but it has been
`estimated that approximately 25%–35% of individuals
`with a fırst VTE express at least one of these fıve muta-
`tions
`in either
`the heterozygous or homozygous
`state.18,28,29 Some of these genetic risk factors are much
`less common in non-white populations (e.g., factor V
`Leiden, prothrombin G20210A), and research into ge-
`netic risk factors among other races and ethnicities is
`needed. Recently, the Genetic Attributes and Throm-
`bosis Epidemiology (GATE) study identifıed sickle cell
`trait to be associated with VTE.30
`Interactions between risk factors in the form of both
`gene–gene and gene–environment interactions further
`
`Public Health Activities and Gaps
`Recently, there has been a marked increase in federal and
`national efforts to raise awareness about VTE and ac-
`knowledge it as a growing and important public health
`problem (Figure 1). In 2001, the Agency for Healthcare
`Research and Quality (AHRQ) identifıed prevention of
`VTE through appropriate thromboprophylaxis as the
`number-one safety practice for hospitals.37 In 2003,
`the American Public Health Association (APHA) and the
`Centers for Disease Control and Prevention (CDC) held a
`Leadership Conference on Deep Vein Thrombosis to
`stress the need for increased awareness of VTE.38 In
`March 2005, the U.S. Senate, in honor of journalist Da-
`vid Bloom, passed a resolution declaring March as
`DVT Awareness Month.39
`From 2006 through 2008,
`in recognition of the high
`attributable risk of hospi-
`talization and the fact
`that PE is the most pre-
`ventable cause of hospi-
`tal death, the National
`Quality Forum, the Joint
`Commission, and the Cen-
`ters for Medicare and Med-
`icaid Services all instituted
`policiesandmeasurestore-
`duceVTEandpromoteap-
`propriate prophylaxis to at-
`risk patients in the hospital
`setting.12,40,41
`time,
`same
`At
`the
`CDC and the National
`Institutes of Health (NIH)
`
`Figure 1. Timeline of recent public health activities and initiatives related to venous
`thromboembolism
`AHRQ, Agency for Healthcare Research and Quality; APHA, American Public Health
`Association; ASH, American Society of Hematology; CMS, Centers for Medicare and
`Medicaid Services; DVT, deep vein thrombosis; NATT, National Alliance for Thrombosis
`and Thrombophilia; NQF, National Quality Forum
`
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`

`Beckman et al / Am J Prev Med 2010;38(4S):S495–S501
`S498
`Thrombosis and Pulmonary Embolism,12 urging a coordi-
`have increased their activities in public health and clinical
`nated, multifaceted plan to reduce the numbers of cases
`research of VTE. In 2001, CDC began a Thrombosis and
`of DVT and PE nationwide, through the following:
`Hemostasis Centers pilot sites program to provide
`health-related services and conduct research directed to-
`● Increased public and provider awareness;
`ward the reduction or prevention of complications of
`● Use of evidence-based practices for screening, prevent-
`thrombosis and thrombophilia.42 Based on the initial
`ing, diagnosing, and treating DVT and PE;
`work of these pilot sites, in July 2007, CDC implemented
`● More research on the causes, prevention, and treat-
`the Thrombosis and Hemostasis Centers Research and
`ment of DVT.
`Prevention Network to foster collaborative epidemio-
`logic research to identify risks (both genetic and ac-
`These important and much-needed activities have
`quired) among a U.S. population and ultimately improve
`placed the spotlight on VTE as a serious and important
`diagnosis and treatment.43 In 2008, NIH funded grantees
`public health problem and further emphasized the need
`to conduct research with the goal of improved diagnosis,
`for a public health response. Yet, there are still areas in all
`therapy, and prevention of VTE.44 The CDC and NIH are
`three of the core essential services of public health (assess-
`working together to encourage collaboration and interac-
`ment, policy development, and assurance) in which more
`tion among grantees to further foster and improve clini-
`knowledge and activities are needed.
`cal and public health research.
`In 2007, CDC began supporting education and out-
`reach activities to provide health promotion and wellness
`programs for people at risk for or affected by clotting
`disorders at both the community and national level.
`Working with the National Alliance for Thrombosis and
`Thrombophilia (NATT), CDC funded a health promo-
`tion and wellness initiative called “Stop the Clot” that
`develops and disseminates health information for people
`who have been affected by VTE.33 The program conducts
`community education forums on clotting, sponsors a
`website with resources and information for the public,
`and has established support groups for people who have
`experienced VTE. Additionally, CDC and NATT have
`developed an online training program on the basics of
`VTE for nonphysician healthcare providers. This year,
`CDC will continue its work with NATT and has ex-
`panded its health promotion program to work with the
`Venous Disease Coalition (a coalition of healthcare pro-
`fessionals and organizations) to develop a program spe-
`cifıcally for women who may be at risk for VTE.
`To address the dramatic increased risk of VTE among
`the elderly, the American Society of Hematology (ASH)
`conducted a Thrombosis in the Elderly workshop in May
`2006. Participants stressed the need for further research
`on mechanisms and risk factors for VTE and its compli-
`cations among the elderly, as well as further development
`of safe and effective treatment strategies.45 In June 2008,
`in recognition that the true burden of VTE is unknown,
`ASH, on behalf of the CDC, convened an expert panel for
`a National Workshop on Thrombosis Surveillance. The
`panel’s recommendations included the need for strength-
`ened national surveillance of DVT and PE and increased
`public awareness.13
`Most recently, in September 2008, the U.S. Surgeon
`General released a Call to Action to Prevent Deep Vein
`
`Public Health Surveillance
`Presently, there is no national surveillance of VTE, and
`current prevalence and incidence estimates are likely un-
`derestimates. Because prevalence studies have focused
`mainly on whites, the risks—and more importantly, the
`true burden—of VTE for minority populations is un-
`known and unaccounted for in current estimates. Fur-
`ther, PE often presents as sudden death. Given that the
`number of autopsies performed in the U.S. is low, and
`that PE may be misdiagnosed as heart failure, current
`estimates of the number of PE events are probably low.
`Similarly, because DVT has many presentations and is
`diagnosed and cared for by multiple providers and in
`multiple settings (inpatient and outpatient), the overall
`burden of DVT is likely to be underestimated as well.
`The purpose of public health surveillance is to assess
`public health status, defıne public health priorities, eval-
`uate programs, and stimulate research.46 Surveillance for
`DVT and PE must be the fırst step toward preventing
`morbidity and mortality and reducing burden from VTE.
`Without the important knowledge of why, where, and
`among whom VTE occurs, it is diffıcult to understand
`where to focus research and target prevention measures.
`Surveillance data will also provide a much-needed base-
`line upon which to assess the effectiveness of prevention
`efforts. The objectives that a strengthened surveillance
`system should meet include the ability to:
`● Establish population-based estimates of VTE inci-
`dence, prevalence, and mortality;
`● Facilitate longitudinal epidemiologic research of
`VTE to evaluate morbidity and mortality and further
`identify and quantify risks factors for VTE and its
`complications;
`
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`

`Beckman et al / Am J Prev Med 2010;38(4S):S495–S501
`S499
`Early and accurate diagnosis of VTE is important for
`● Translate surveillance fındings into targeted awareness
`and prevention messages and into hypotheses for pub-
`preventing deaths and having favorable long-term out-
`lic health epidemiologic research.
`comes. Because these events can be silent, it is vital that all
`healthcare providers be aware of situations that put pa-
`tients at risk, and provide appropriate tests, prophylaxis,
`and treatment. According to the call to action, much is
`known about effective prevention and treatment of VTE,
`yet this evidence is not applied consistently and system-
`atically in healthcare settings.12 Part of the diffıculty lies
`in the complexity of VTE itself, as it occurs in many
`healthcare settings and, therefore, is diagnosed and man-
`aged by many providers (e.g., hematologists, surgeons,
`obstetricians, emergency physicians, primary care physi-
`cians). Yet, there is no national consensus by practitio-
`ners and hospitals on the best way to approach this con-
`dition. The most adhered-to guidelines have been
`published by the American College of Chest Physicians
`(ACCP); however, these guidelines are not accepted and
`followed by all specialties as evidenced by the differences
`between the ACCP guidelines and those of the American
`Academy of Orthopedic Surgeons for VTE prophylaxis
`for patients undergoing hip or knee surgery.12,51–54
`Moreover, with the increased focus on prevention of
`VTE, a risk of unnecessary treatment and bleeding from
`use of anticoagulant prophylaxis, screening, and testing
`arises. Development of consensus standards for screen-
`ing, testing, managing, and preventing VTE is needed,
`with the ultimate goal of prevention and optimal health.
`
`Research
`Further research into the causes, both acquired and ge-
`netic, and the complications of VTE is essential to pre-
`venting morbidity and mortality and reducing health dis-
`parities. More than 50% of VTE cases are spontaneous or
`unprovoked, indicating that many acquired risk factors
`have yet to be elucidated. The proportion of blacks who
`suffer from VTE is equal to or greater than that of whites;
`yet, some studies suggest that blacks may be more likely to
`present with PE and may have higher mortality rates from
`VTE, even though traditional (inherited and non-inher-
`ited) risk factors may not be as prevalent among
`blacks.7,19,47–50 The strong association of family history
`of VTE with occurrence of VTE in whites and blacks
`suggests a genetic component, but few genetic markers
`have been found among non-white populations.19,47–50
`Knowledge of genetic risk factors historically has been of
`great interest because it could be used to predict which
`individuals are at risk for developing VTE. Such informa-
`tion could be used in conjunction with environmental
`factors to develop a risk profıle that could be used for
`intervention and prevention strategies, particularly dur-
`ing high-risk situations such as surgery, pregnancy, or
`immobilization.
`These genetic risks also warrant further investigation
`as they may be involved in other disorders such as adverse
`pregnancy outcomes. In addition, the long-term out-
`comes and complications of VTE,
`including post-
`thrombotic syndrome and recurrent VTE, need to be
`better understood in order to prevent long-term morbid-
`ity and improve the quality of life of those affected.
`
`Summary and Conclusion
`Venous thromboembolism is a major public health prob-
`lem that affects an estimated 300,000–600,000 individu-
`als in the U.S. each year. With many of the known ac-
`quired risks increasing in the U.S. population, we can
`expect to see growing numbers of people affected by VTE.
`Increasing surveillance, research, and awareness of VTE
`must be a priority. By employing a comprehensive public
`health approach to learning about the burden and causes
`of VTE and raising awareness among the public and
`healthcare providers, enormous potential exists to pre-
`vent and reduce death and morbidity from DVT and PE
`throughout the U.S.
`
`The fındings and conclusions in this paper are those of the
`authors and do not necessarily represent the views of the
`Centers for Disease Control and Prevention.
`TLO has received research grants from Eisai and
`GlaxoSmithKline, and consults for Sanofı-Aventis.
`No other fınancial disclosures were reported by the
`authors of this paper.
`
`Awareness
`As noted at the APHA–CDC leadership conference and
`in the Surgeon General’s call to action, there is a lack of
`awareness among patients, providers, and the general
`public about VTE signs and symptoms.12,38 To learn
`more about the public’s knowledge of DVT and identify
`its symptoms and risk factors, the CDC submitted DVT-
`related questions to the 2007 HealthStyles survey. Results
`showed that despite a low frequency of personal experi-
`ence of DVT (14%), most respondents identifıed pain and
`swelling as symptoms (68% and 64%, respectively), and
`most knew that medical care should be sought for these
`symptoms (89%). However, only 38% of respondents
`knew that a DVT was a blood clot in a vein, and most
`could not identify common risk factors for DVT, such as
`aging or surgery (SEC, unpublished observations, 2009).
`
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`S500
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