The Surgeon General’s Call to Action
`to Prevent Deep Vein Thrombosis
`and Pulmonary Embolism
`
`2008
`
`
`
`MYLAN EXHIBIT 1018
`U.S. Department of Health and Human Services
`
`MYLAN EXHIBIT 1018
`
`

`

`

`

`The Surgeon General’s Call to Action
`to Prevent Deep Vein Thrombosis
`and Pulmonary Embolism
`2008
`
`

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`

`

`Table of Contents
`
`Message from the Secretary, U.S. Department of Health and
`Human Services…………………………..........................................1
`
`Foreword from the Acting Surgeon General, U.S. Department of
`Health and Human Services……………....................………………3
`
`Message from the Director, National Heart, Lung, and Blood
`Institute……….................................................……………………..5
`
`Introduction: Definitions of Deep Vein Thrombosis and Pulmonary
`Embolism……................................................................................7
`
`Section I: Deep Vein Thrombosis and Pulmonary Embolism as
`Major Public Health Problems........................................................9
`
`Section II: Reducing the Risk for DVT/PE …………………….…..19
`.
`Section III: Gaps in Application and Awareness of Evidence-based
`Interventions.................................................................................22
`
`Section IV: A Call to Action: A Public Health Response to
`Reducing DVT and PE..................................................................26
`
`Section V: A Catalyst for Action…………………...............………33
`
`Conclusion: A Vision for the Future…………………...............…..35
`References………………………………………………..........……..36
`Acknowledgements……………………………………..........………41
`
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`Message from the Secretary
`U.S. Department of Health and Human Services
`
`Additionally, as in any area of medicine, gaps
`still remain in our knowledge about how best
`to care for certain patient subpopulations, and
`further research is needed.
`
`This Surgeon General’s Call to Action represents
`an opportunity for multiple stakeholders to
`come together in a coordinated effort to reverse
`the projected trends and to dramatically reduce
`the pain and suffering caused by DVT and PE
`in this nation through specific steps in com-
`munication, action, research and evaluation.
`With the involvement of individuals, families,
`communities, all aspects of research and health
`care systems, organizations, governments, and
`the media, we can bring better health to this
`country. I urge everyone with an interest in
`improving health to work with the Surgeon
`General to achieve this Call to Action’s ambi-
`tious and essential vision.
`
`Michael O. Leavitt
`Secretary of Health & Human Services
`United States Public Health Service
`
`Over the last several decades we have seen dra-
`matic drops in the mortality rates from cardio-
`vascular disease, the leading cause of death in
`this country. Yet challenges remain, and certain
`areas of medicine have not seen improvements.
`One of the biggest challenges relates to blood
`clots in the legs (a disease know as deep vein
`thrombosis or DVT), which can not only cause
`pain, swelling, and other discomfort, but also
`frequently travel to the lungs, causing a poten-
`tially fatal pulmonary embolism (PE).
`
`The best estimates indicate that 350,000 to
`600,000 Americans each year suffer from DVT
`and PE, and that at least 100,000 deaths may
`be directly or indirectly related to these diseases.
`This is far too many, since many of these deaths
`can be avoided. Because the disease dispropor-
`tionately affects older Americans, we can expect
`more suffering and more deaths in the future
`as our population ages–unless we do something
`about it.
`
`The Institute of Medicine has classified the
`failure to provide appropriate screening and
`preventive treatment to hospitalized, at-risk
`patients as a medical error, and the Agency for
`Healthcare Research and Quality has ranked
`the provision of such preventive treatment as
`one of the most important things that can be
`done to improve patient safety. Proven, effective
`measures are available to prevent and treat DVT
`and PE in high-risk individuals. Yet today the
`majority of individuals who could benefit from
`such proven services do not receive them. Too
`few Americans know what DVT or PE is, how
`to recognize the symptoms, or how to talk with
`their clinicians about prevention, diagnosis, and
`treatment. Too few health care professionals
`are aware of the evidence-based practices for
`identifying high-risk patients and providing
`preventive, diagnostic, or therapeutic services.
`
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`Foreword from the Acting Surgeon General
`U.S. Department of Health and Human Services
`
`As the acting Surgeon General, my primary
`role is to provide the American people with
`the information they need to improve their
`health and reduce the risk of injury and illness.
`This first “Call to Action to Prevent Deep Vein
`Thrombosis (DVT) and Pulmonary Embolism
`(PE),” provides vital information on critical
`health problems that cause enormous health
`consequences and numerous deaths in our
`country. Estimates suggest that at least 350,000,
`and as many as 600,000, Americans each year
`contract DVT/PE, and at least 100,000 deaths
`are thought to be related to these diseases each
`year. Many of those who survive have complica-
`tions that have a serious and negative impact
`on the quality of their lives. Without the joint
`efforts of all stakeholders, including clinicians
`and families, the problem will only worsen as
`the population ages.
`
`This Call to Action came out of a Surgeon
`General’s Workshop on DVT/PE held in May
`2006. The message from that workshop was
`clear—there is great hope and optimism about
`prevention, diagnosis and treatment of these
`diseases. The presentations and discussion that
`took place during those two days demonstrated
`that we have made progress in our knowledge
`of how to prevent, diagnose and treat DVT/
`PE. It is also clear that we are not applying that
`knowledge on a systematic basis. The workshop
`highlighted the tremendous gap in understand-
`ing and knowledge that exists about these
`diseases. In order to address that gap, we must
`disseminate information more widely about the
`availability of effective interventions to prevent
`and treat DVT/PE. We must also continue to
`invest in basic scientific, clinical and epidemio-
`logical research related to DVT/PE. In addition,
`our investment in translational research is essen-
`tial in order to ensure that the public and the
`medical community can put the latest evidence
`
`into practice quickly and easily. To make this
`vision a reality, the Surgeon General’s Call to
`Action is intended to serve as a stimulus for the
`development of a coordinated plan to reverse
`the current trend and dramatically reduce the
`morbidity and mortality caused by DVT/PE.
`The kinds of activities that are part of this plan
`are outlined in this document. The critical step
`for all stakeholders is to come together and
`address this important health problem. We seek
`to engage all levels of government as well as
`individuals and private sector institutions and
`organizations in a coordinated, multifaceted
`effort to prevent and reduce the incidence of
`deep vein thrombosis and pulmonary embolism.
`
`I am encouraged by the participation of so many
`people and organizations in the May 2006
`workshop and the development of this Call to
`Action. I would like to thank them for their
`willingness to assist us in gathering the best
`scientific evidence as a catalyst for improvement.
`Efforts to reduce the incidence of DVT/PE will
`demand the full attention and committed efforts
`of all stakeholders. I am confident that working
`together we can take real steps to reduce the
`burden of these diseases. The reward for this
`effort will be to prove the forecasters wrong.
`Instead of ever-increasing numbers of individu-
`als developing and suffering from DVT/PE, we
`will see dramatic reductions in the incidence and
`prevalence of these conditions.
`
`Steven K. Galson, M.D., M.P.H.
`RADM, U.S. Public Health Service
`Acting Surgeon General
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`Message from the Director of the National, Heart,
`Lung, and Blood Institute, National Institutes of Health
`
`Thousands of Americans suffer from deep
`vein thrombosis (DVT) in the United States
`today, and many will die from its complication,
`pulmonary embolism (PE). The tragedy of these
`diseases is that their diagnosis is easy to over-
`look because the signs and symptoms are often
`diffuse and difficult to recognize. In many cases,
`there are no clinically apparent signs at all.
`Perhaps as many as 50 percent of the cases of
`DVT are “silent.” Very often the first symptom
`of DVT is a fatal PE.
`
`There are few public health problems as
`serious as DVT/PE, yet these diseases receive
`so little attention. Some estimates suggest that
`these conditions cause more deaths each year
`than breast cancer, AIDS, or motor vehicle
`incidents—illnesses or injuries that are well
`understood by most Americans. Up until now,
`levels of public awareness and knowledge about
`the risks of these diseases have been extremely
`low. The “Surgeon General’s Call to Action
`to Prevent Deep Vein Thrombosis and Pulmo-
`nary Embolism” finds the status quo
`unacceptable.
`
`The National Heart, Lung, and Blood Institute
`(NHLBI) is the primary agency within the
`National Institutes of Health that is responsible
`for promoting research leading to improved
`diagnosis and treatment of DVT/PE. The NHLBI
`has a long and distinguished record of support-
`ing and guiding seminal advances in thrombosis
`research that have yielded unprecedented
`improvements in the nation’s health. It has
`supported basic research in venous biology for
`the development of improved treatment for
`venous diseases and their complications; indeed,
`much of the science contained in this Call to
`Action is a result of NHLBI-funded research.
`Despite these accomplishments, there are many
`factors that impede progress in research and
`
`treatment, including a limited understanding of
`venous biology and coagulation proteins, and
`the lack of a critical mass of investigators and
`providers devoted to this research. Without
`technological innovation, training opportuni-
`ties, and committed investigators, progress will
`continue to be slow.
`
`It is NHLBI’s hope that this Call to Action will
`stimulate innovative research by investigators
`who are committed to finding new ways to
`prevent and treat these conditions. As the
`Surgeon General stated at his workshop on
`DVT in May of 2006, there are many differ-
`ences in how health professionals deal with the
`issue, and there is no consensus nationally by
`practitioners and hospitals on the best way to
`approach this problem. There is also an urgent
`need to develop a consensus on science-based
`standards of care, especially for high-risk
`groups. It is critical that we identify new areas
`of research related to venous biology, DVT/ PE,
`their complications, and clinical interventions.
`This kind of basic and clinical science is needed
`to provide a foundation for the development of
`evidence-based guidelines.
`
`This Call to Action concludes that in order to
`impact the incidence and burden of DVT/PE,
`stakeholders need to come together to increase
`public awareness, support the development
`of evidence-based practices, and carry out the
`scientific research that can address the gaps in
`knowledge. I urge all of us to work together
`to achieve this ambitious and essential vision.
`This is a vision that the NHLBI wholeheartedly
`supports.
`
`Elizabeth G. Nabel, M.D.
`Director, National Heart, Lung,
`and Blood Institute
`National Institutes of Health
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`INTRODUCTION
`Definitions of Deep Vein Thrombosis
`and Pulmonary Embolism
`
`Deep vein thrombosis (DVT) refers to the for-
`mation of one or more blood clots (a blood clot
`is also known as a “thrombus,” while multiple
`clots are called “thrombi”) in one of the body’s
`large veins, most commonly in the lower limbs
`(e.g., lower leg or calf) 1. The clot(s) can cause
`partial or complete blocking of circulation in
`the vein, which in some patients leads to pain,
`swelling, tenderness, discoloration, or redness of
`the affected area, and skin that is warm to the
`touch. However, approximately half of all DVT
`episodes produce few, if any, symptoms 2. For
`some patients, DVT is an “acute” episode (that
`is, the symptoms go away once the disease is
`successfully treated), but roughly 30 percent of
`patients suffer additional symptoms, including
`leg pain and swelling, recurrent skin breakdown,
`and painful ulcers 3-5. In addition, individuals
`experiencing their first DVT remain at increased
`risk of subsequent episodes throughout the
`remainder of their lives 4, 6.
`
`The most serious complication that can arise
`from DVT is a pulmonary embolism (PE) which
`occurs in over one-third of DVT patients 7.
`A PE occurs when a portion of the blood clot
`
`breaks loose and travels in the bloodstream,
`first to the heart and then to the lungs, where it
`can partially or completely block a pulmonary
`artery or one of its branches. A PE is a serious,
`life-threatening complication with signs and
`symptoms that include: shortness of breath,
`rapid heartbeat, sweating, and/or sharp chest
`pain (especially during deep breathing). Some
`patients may cough up blood, while others
`may develop dangerously low blood pressure
`and pass out. Pulmonary embolism frequently
`causes sudden death 6, particularly when one or
`more of the vessels that supply the lungs with
`blood are completely blocked by the clot. Those
`who survive generally do not have any lasting
`effects because the body’s natural mechanisms
`tend to resorb (or “lyse”) blood clots. However,
`in some instances, the blood clot in the lung
`fails to completely dissolve, leading to a chronic
`serious complication that can cause chronic
`shortness of breath and heart failure. DVT and
`PE are commonly grouped together and some-
`times referred to as “venous thromboembolism”
`(VTE).
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`SECTION I
`Deep Vein Thrombosis and Pulmonary
`Embolism as Major Public Health
`Problems
`
`Deep Vein Thrombosis and Pulmonary Embo-
`lism (DVT/PE) represent a major public health
`problem, exacting a significant human and
`economic toll on the Nation. These common
`conditions affect hundreds of thousands of
`Americans each year. A 25-year population-
`based study published in 1998 found that the
`overall age- and sex-adjusted annual incidence
`of VTE was 1.17 per 1,000 (.48 per 1,000 for
`DVT and .69 per 1,000 for PE) 8. Applying
`these figures to today’s population of approxi-
`mately 300 million Americans suggests that
`more than 350,000 individuals are affected by
`DVT/PE each year 9. A 1991 study that extrapo-
`lated findings from 16 short-stay hospitals in
`Worcester, Massachusetts is fairly consistent
`with these estimates. This study found that
`approximately 270,000 individuals were hospi-
`talized for DVT/PE in 1991, including 170,000
`new cases and 99,000 recurrent ones 10.
`
`But there is reason to believe that the true
`incidence rate (and total number of cases) could
`be significantly higher, as several studies suggest
`that these diseases are often undiagnosed. The
`Worcester study cited above also concluded that
`more than half of the cases that actually occur
`are never diagnosed, and therefore as many as
`600,000 cases may occur each year 10. Another
`study found that the diagnosis of PE is often
`missed; this study of nursing home patients
`found that the condition was correctly diagnosed
`before death in only 39 to 50 percent of patients
`where it was confirmed in an autopsy 11, 12. While
`the precise incidence and prevalence remain
`“elusive” 10 and a matter of some debate, one
`thing is undeniably clear—DVT/ PE are major
`national health problems that have a dramatic,
`negative impact on the lives of hundreds of
`thousands of Americans each year.
`
`There is reason to believe that the magnitude of
`the problem will increase. Several studies have
`found that the incidence has remained relatively
`stable over time 8, 13, although one study found
`an increased incidence of DVT in hospitalized
`patients between 1979 and 1999 14. Assuming
`that the overall incidence remains the same,
`one would expect the total number of DVT/PE
`cases to grow at the same rate as overall popu-
`lation growth. However, the incidence of DVT/
`PE increases markedly with age. Thus, as the
`United States population increases in average
`age, it is quite possible that, in the absence of
`other influences such as better prevention, the
`growth in the total number of DVT/PE cases
`will outpace population growth. Given that
`DVT/PE are already common and devastating
`conditions, it is imperative that all stakeholders
`come together to halt, and hopefully reverse,
`the growth in the number of cases.
`
`What Are the Consequences of DVT and PE?
`
`Mortality
`DVT and PE together may be responsible for
`more than 100,000 deaths each year. DVT
`alone does not frequently result in death; the
`National Center for Health Statistics reports
`that it is an underlying or contributing cause
`of death in over 10,000 cases per year 15. PE
`is responsible for many more deaths, although
`estimates of the exact toll are also elusive 10
`and vary widely, ranging from just below
`30,000 to over 80,000. The most conservative
`estimates come from studies that review death
`certificate data. A 20-year review of data from
`1979-1998 found that the age-adjusted death
`rate for PE was 94 per 1,000,000 individuals 16.
`Extrapolating to today’s population suggests
`that an estimated 28,200 people die each year
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`The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism
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`from this disease. But as noted previously, PE
`is often undiagnosed, and thus the true death
`rate is almost certainly substantially higher. In
`fact, community-based epidemiological studies
`suggest that roughly one in five individuals die
`almost immediately from PE, while 40 percent
`die within 3 months 17, 18. Applying this 40
`percent figure to the 207,000 recognized annual
`PE cases cited earlier suggests an annual death
`rate of 82,800.
`
`Another way to estimate the death toll is to
`look at statistics related to both diseases. An
`estimated 30 percent of patients die within 3
`months 6. Applying this 30 percent figure to the
`previously cited estimates of between 350,000
`and 600,000 cases each year suggests that at
`least 100,000, and perhaps as many as 180,000,
`individuals die directly or indirectly as a result
`of DVT/PE each year.
`
`Morbidity
`Many of those who survive will be affected for
`the rest of their lives. At a minimum, those who
`have had DVT or PE will remain at increased
`risk for another episode. (See figure 1). Roughly
`30 percent of those who have a DVT in a given
`year will suffer from a recurrent episode some-
`time in the next 10 years, with the risk being
`greatest in the first two years 5, 6, 19, 20. Recur-
`rence is also more likely if the initial episode
`was “spontaneous”—that is, not provoked by
`transient (often one-time) events such as trauma,
`surgery, or hormonal changes due to pregnancy,
`oral contraceptives, or hormone replacement 4, 5.
`Patients with symptomatic PE tend to have a
`higher risk of recurrent VTE than those present-
`ing with DVT symptoms alone. The recurrence
`in those who initially presented with PE is more
`likely to be another embolism (as opposed to
`DVT alone) 21. For reasons that remain unclear,
`the risk of recurrent VTE is higher among men
`than women. (See figure 2). 22. To minimize the
`
`risk of recurrence, anyone who has had either
`disease must remain vigilant about avoiding
`and/or managing the potential impact of other
`risk factors such as prolonged air travel, surgery,
`or trauma.
`
`Along with the potential for recurrence, indi-
`viduals who suffer an initial episode may also
`experience chronic venous insufficiency (CVI),
`which is also referred to as postthrombotic
`syndrome or PTS, with 30 percent suffering
`from CVI either immediately or within 10-20
`years of the initial episode 3, 19, 23. In one cohort
`of VTE patients followed for 10 years, more
`than half showed signs of CVI, while six percent
`developed severe disease 20. CVI occurs when
`the blood clot injures or destroys one or more
`of the venous valves that are located in the deep
`veins of the leg. When functioning properly,
`these valves work against gravity to help pump
`blood back to the heart when an individual is
`sitting or standing. When these valves are either
`damaged or destroyed, individuals may feel
`leg pain and experience swelling when stand-
`ing. They may also develop other unpleasant
`symptoms, including mild or extensive varicose
`veins (which are cosmetically unappealing and
`can cause additional chronic pain and burn-
`ing), skin breakdown, ulcers, and brownish
`skin pigmentation changes, which tend to be
`permanent and irreversible. The most severely
`affected patients may find that the skin inside
`their ankles becomes thickened, darkened, and
`prone to recurrent skin breakdown and painful
`ulcers (known as venous stasis ulcers) that often
`do not easily heal. CVI has been found to cause
`a significant reduction in the quality of life,
`similar to the impact caused by chronic heart,
`lung, or arthritic disease 24, 25.
`
`10
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`Figure 1:
`The Cumulative Incidence of Recurrent Venous Thromboembolism in
`Patients with a First Episode of Symptomatic Deep Venous Thrombosis.
`
`30
`
`25
`
`20
`
`15
`
`10
`
`5 0
`
`Cumulative
`Incidence (%)
`
`0
`
`1
`
`2
`
`4
`Year
`Prandoni et al, Ann Intern Med 1996;125:1–7
`
`3
`
`5
`
`6
`
`7
`
`8
`
`Figure 2:
`Kaplan-Meier Estimates of the Likelihood of Recurrent Venous
`Thromboembolism According to Sex.22
`
`p<0.001
`
`826 idiopathic VTE patients
`followed for 3 years
`
`Men
`
`Women
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`Cumulative Probability of Recurrence (%)
`
`0
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Years after Withdrawal of Oral Anticoagulants
`
`No. at Risk
`Men
`Women
`
`373
`453
`
`263
`342
`
`183
`248
`
`133
`193
`
`95
`142
`
`65
`103
`
`42
`72
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`What Factors Raise the Risk for DVT and PE?
`
`Age, Gender, and Race-Specific Incidence
`
`There are differential effects by gender, race, and
`age on individuals with DVT/PE. These diseases
`also disproportionately effect certain groups of
`individuals, such as those who:
`
`• have experienced recent trauma
`• have undergone major surgery
`• are obese
`• have cancer
`• are pregnant
`• use hormone therapy
`• smoke
`
`
`Like many diseases, DVT/ PE disproportionately
`affect the elderly. (See figure 3). The incidence
`among children (under the age of 14) is quite
`low, at less than 1 per 100,000 measured in
`person-years. Incidence rates rise relatively
`slowly until the age of 50, then accelerate
`dramatically, reaching 1,000 per 100,000
`person-years by the age of 85 8.
`
`
`Women have a higher incidence of DVT during
`their child-bearing years although this risk is
`still relatively low compared to risk levels for
`older men and women. However, after the age
`of 50 8, men are at greater risk than women.
`
`Figure 3:
`Annual Incidence of all Venous Thromboembolism, Deep Vein Thrombosis (DVT) Alone,
`and Pulmonary Embolism (PE) With or Without Deep Vein Thrombosis (PE+/-DVT)
`Among Residents of Olmstead County Minnesota from 1966 to 1990 by Age
`
`1200
`
`1000
`
`800
`
`600
`
`400
`
`200
`
`0
`
`Annual inciidence/1000,000
`
`0–14
`
`80–84
`70–74
`60–64
`50–54
`40–44
`30–34
`20–24
`0–14
`20–24
`30–34
`40–44
`50–54
`60–64
`70–74
`80–84
`
`Age group (yr)
`
`All DVT or PE
`PE ± DVT
`DVT alone
`
`Silverstein. M.D. et al Arch Intern Med 1998; 158:585–593
`
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`For reasons that are not completely understood,
`African Americans and Caucasians tend to have
`a greater risk for these conditions than those
`whose ethnic background is either Asian or
`Native American. African Americans have a 30
`percent higher risk than do Caucasians, while
`Asian and Native Americans have a 70 percent
`lower risk 26, 27.
`
`
`Genetic Factors That Raise Risk
`
`Thrombophilia is an inherited blood clotting
`disorder caused by one or more genetic risk
`factors or mutations that make a person suscep-
`tible to DVT/ PE. These factors include deficien-
`cies in the anticoagulation factors protein C,
`protein S, and antithrombin, and mutations
`in the factor V and prothrombin genes which
`result in Factor V Leiden and prothrombin
`G20210A 28 respectively. Over one-third (35
`percent) of DVT patients have at least one of
`these five factors 29, 30. An individual with such
`a genetic mutation will not necessarily develop
`these conditions, and fewer than 10 percent of
`those who carry the most common mutations
`will develop a detectable blood clot each year
`31. But the risks are much greater for those
`individuals with thrombophilia compared to the
`population at large, particularly for those who
`also have another risk, such as surgery, hospital-
`ization, or a prolonged bed stay.
`
`
`
`• Factor V Leiden: Factor V Leiden is a
` relatively common mutation in the gene
` for clotting factor V that leads to an increased
` risk of DVT/PE. An estimated 15 to 20
` percent of DVT/PE patients have this
` abnormality 29, 30. This defect is most
` commonly found among Caucasians (with
` roughly five percent carrying it) 32, with
` Asians and Africans rarely carrying the
` mutation.
`• Prothrombin 20210: Roughly two to three
` percent of Caucasians have a mutation in
` the gene that produces prothrombin, which
` is called clotting factor II 33. Approxi-
` mately six percent of all DVT/PE patients
` have this mutation, which leads to a three-
` fold increase in the risk of thrombosis (34)
`• Antithrombin, Protein C, and Protein S
` Deficiency: Mutations in the genes
` that produce protein C and its cofactor
` protein S are found in less than one percent
` of the population, while deficiencies in the
` gene that produces antithrombin are found
` in roughly 1 in 5,000 individuals 35, 36.
` Deficiencies in the natural anticoagulants
` protein C, protein S, and antithrombin lead
` to a tenfold increase in risk of thrombosis in
` an individual who inherits the gene mutation
` from one parent, with the highest risk in
` those with antithrombin deficiency 37.
`
`
`
`Acquired Factors That Raise Risk
`
`In almost all cases, the presence of an inherited
`blood clotting disorder in an individual indi-
`cates that at least one of the parents also has the
`disorder, and there is a 50 percent chance that
`any sibling or child of that individual will have
`it as well. Other blood relatives, including aunts,
`uncles, and cousins, may also have the mutation.
`
`Following is a brief description of the most
`common genetic mutations:
`
`Exposure to steroid hormones—especially
`estrogen—can raise the risk of developing a
`blood clot. Thus, women using oral contracep-
`tives in their child-bearing years and postmeno-
`pausal women who use hormone therapy (HT)
`are at increased risk. Oral contraceptives that
`contain both estrogen and progestin increase
`the risk of a blood clot by two- to eight-fold 38-43.
`(The risk may even be greater with patches that
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`The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism
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`

`contain transdermal contraceptives, since the
`amount of estrogen absorbed can be 60 percent
`higher 44). An alternative to consider may be
`contraceptives that use only progestin as these
`do not appear to increase the risk of DVT or PE
`45-47. However, it is important to keep in mind
`that the absolute risk for women of fertile age
`who use oral contraceptives is fairly low—
`2 to 8 per 10,000 person-years, which is still
`
`A Case Study
`
`This is the story of a college-age girl with
`a genetic susceptibility to blood clots who
`experienced an unusual manifestation of
`venous thrombosis that ultimately claimed
`her life. Like many young women, she was
`very self-conscious about her complexion.
`Her gynecologist explained that one of the
`beneficial side effects of hormone-based
`contraceptives is to help clear one’s complex-
`ion. So she began taking oral contraceptives
`and later switched to a patch. While the patch
`cleared her complexion, she and her parents
`did not know that she was one of 7,000,000
`women in the U.S. with Factor V Leiden, a
`genetic abnormality that made her much more
`likely to develop DVT/PE 28. The combination
`of a genetic predisposition and the use of oral
`contraceptives proved to be a deadly one, as
`she developed blood clots in the portal and
`hepatic veins of her abdomen. (The presence
`of clots in these locations is not technically
`classified as DVT, but it is considered a form
`of venous thrombosis, thus highlighting the
`fact that VTE can occur anywhere in the body.)
`After months of suffering from fatigue, nausea,
`and, ultimately, a markedly swollen abdomen,
`she died in May 2003 at the age of 21.
`
`substantially less than the risk faced by older
`women and men 48, 49.
`
`Pregnancy increases the risk of DVT fivefold
`compared to nonpregnancy, with the risk being
`even greater postpartum 50. DVT can be life-
`threatening in pregnancy, as pulmonary embo-
`lism is the most common cause of maternal
`death in developed countries 51. Comorbiditites
`such as obesity and diabetes magnify the
`existing risk.
`
`Post-menopausal women undergoing HT also
`have a higher risk of DVT/PE, with recent large
`studies suggesting a two- to four-fold increase
`in risk, with even larger increases in risk for
`those on high doses of estrogen (greater than
`1.25 mg/day) 52-55. Women with thrombophilia
`who also are exposed to oral contraceptives,
`pregnancy, or HT will face a significantly
`greater risk than the above statistics suggest 28.
`
`Individuals who develop tumors have a greater
`tendency to develop blood clots, thus creating
`increased risk. About 10 percent of patients
`who present with DVT/PE will have an occult
`cancer diagnosed within two years of the
`thrombotic episode 56.
`
`Although all patients with active cancer have
`an increased risk of DVT/PE, the risk appears
`to be higher for those with pancreatic cancer,
`lymphoma, malignant brain tumors, cancer of
`the liver, leukemia, and colorectal and other
`digestive cancers. The risk is especially high
`for patients whose cancer has spread to other
`parts of the body 57-60. Cancer patients receiving
`chemotherapy are at even higher risk 57, 61-65.
`Cancer patients with VTE face much worse
`outcomes than those with cancer alone. The
`probability of death within 183 days of initial
`hospital admission is over 94 percent for those
`with VTE and malignant disease, compared to
`
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`The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism
`
`

`

`Figure 4:
`Concurrent VTE and Cancer Increases the Risk of Death
`Probability of Death within 183 days of intial hospital admission
`
`DVT/PE and
`malignant disease
`
`Malignant
`disease alone
`
`1.0
`
`0.80
`
`0.60
`
`0.40
`
`0.20
`
`0.00
`
`Probabilty of Death
`
`0 40 80 120 180
`Number of Days
`
`adapted from Levitan et al Medicine 1999
`
`less than 40 percent for those with cancer alone.
`(See figure 4) 66.
`
`The incidence of DVT/PE is substantially higher
`for cancer patients than for non-cancer patients
`across all types of major surgery, including
`neurosurgery, head and neck, vascular, urologic,
`gastrointestinal, and orthopedic surgeries 67.
`In the