© 2007 Schattauer GmbH, Stuttgart
`
`Blood Coagulation, Fibrinolysis and Cellular Haemostasis
`
`Venous thromboembolism (VTE) in Europe
`The number of VTE events and associated morbidity and mortality
`
`Alexander T. Cohen1, Giancarlo Agnelli2, Frederick A. Anderson3, Juan I. Arcelus4, David Bergqvist5, Josef G. Brecht6,
`Ian A. Greer7, John A. Heit8, Julia L. Hutchinson9, Ajay K. Kakkar10, Dominique Mottier11, Emmanuel Oger11,
`Meyer-Michel Samama12, Michael Spannagl13 for the VTE Impact Assessment Group in Europe (VITAE)
`1King’s College Hospital, London, UK; 2Division of Internal and Cardiovascular Medicine, University of Perugia, Perugia, Italy; 3Center for
`Outcomes Research, University of Massachusetts Medical School, Worcester, MA, USA; 4University of Granada Medical School and Hospital
`San Juan de Dios, Granada, Spain; 5Department of Surgical Sciences, University Hospital, Uppsala, Sweden; 6InForMed GmbH – Outcomes
`Research and Health Economics, Ingolstadt, Germany; 7Department of Obstetrics and Gynaecology, University of Glasgow, Glasgow Royal
`Infirmary, Glasgow, UK; 8Hematology Research, Mayo Clinic College of Medicine, Rochester, MN, USA; 9Fourth Hurdle Consulting, London,
`UK; 10Centre for Surgical Sciences, Barts and The London-Queen Mary School of Medicine, London, UK and Thrombosis Research Institute,
`London, UK; 11Groupe d’Etude de la Thrombose de Bretagne Occidentale (GETBO), Hôpital de la Cavale Blanche, Brest, France; 12Hôtel
`Dieu, Département d’Hématologie Biologique, Paris, France; 13Ludwig-Maximillians University Munich, Klinikum der Universität, Abteilung
`Haemostasiologe, Munich, Germany
`
`Summary
`Venous thromboembolism (VTE) is often asymptomatic, mis-
`diagnosed, and unrecognized at death, and there is a lack of rou-
`tine postmortem examinations.These factors are thought to re-
`sult in marked underestimates ofVTE incidence.The objective of
`our study was to estimate the total burden of VTE within the
`European Union (EU) per annum. An epidemiological model was
`constructed to estimate the number of community- and hospi-
`tal-acquired incidents and recurrent cases (attack rate) of non-
`fatal VTE and VTE-related deaths, as well as incident and preva-
`lent cases of post-thrombotic syndrome (PTS) and chronic
`thromboembolic pulmonary hypertension (PH) occurring in the
`EU per annum. Individual models were developed for six EU
`countries.The models were populated with data from published
`literature and, where necessary, expert opinions. The findings
`were tested using probabilistic sensitivity analyses. The esti-
`
`Keywords
`Deep-vein thrombosis, post-thrombotic syndrome, pulmonary
`embolism, pulmonary hypertension, venous thromboembolism,
`VTE prophylaxis
`
`mated total number of symptomaticVTE events (range based on
`probabilistic sensitivity analysis) per annum within the six EU
`countries was 465,715 (404,664–538,189) cases of deep-vein
`thrombosis, 295,982 (242,450–360,363) cases of pulmonary
`embolism (PE), and 370,012 (300,193–483,108) VTE-related
`deaths. Of these deaths, an estimated 27,473 (7%) were diag-
`nosed as being antemortem; 126,145 (34%) were sudden fatal
`PE, and 217,394 (59%) followed undiagnosed PE.Almost three-
`quarters of all VTE-related deaths were from hospital-acquired
`VTE.VTE is a major health problem in the EU,with over one mil-
`lionVTE events or deaths per annum in the six countries exam-
`ined. Given the availability of effective VTE prophylaxis, many of
`these events and deaths could have been prevented.These re-
`sults have important implications for the allocation of healthcare
`resources.
`
`Thromb Haemost 2007; 98: 756–764
`
`Introduction
`Venous thromboembolism (VTE), comprising deep-vein throm-
`bosis (DVT) and pulmonary embolism (PE), is associated with
`substantial morbidity and mortality. Detailed estimates of the an-
`nual number of VTE events are hard to obtain because VTE is
`
`difficult to diagnose. This is due to a number of factors; VTE is
`often clinically silent and, in many cases, the first sign of the dis-
`ease is a sudden fatal PE (1, 2). Despite modest increases in ante-
`mortem diagnosis of PE over the years, less than half of autopsy-
`detected PE cases are diagnosed antemortem (3). The lack of
`routinely performed postmortem examinations means that many
`
`Correspondence to:
`Alexander T. Cohen
`Vascular Medicine, Department of Surgery
`King’s College Hospital
`London, SE5 9RS, UK
`Tel.: +44 20 7346 3015, Fax: +44 20 7346 3927
`E-mail: alexander.cohen@kcl.ac.uk
`
`Received March 21, 2007
`Accepted after resubmission July 25, 2007
`
`Prepublished online September 10, 2007
`doi:10.1160/TH07–03–0212
`
`MYLAN EXHIBIT 1020
`
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`Cohen et al. Venous thromboembolism in Europe
`
`fatal pulmonary emboli remain unrecognized, leading to an
`underestimation of their incidence. Previous analyses have
`shown that, for every case of symptomatic non-fatal PE, there are
`2.5 cases of fatal autopsy-detected PE (4). Only 29% of patients
`who survive an initial embolic event are diagnosed with VTE (5).
`In 36% of patients diagnosed with PE, an initial diagnosis is
`made on the date of death or postmortem, with PE being the
`cause of death in 53% of these cases (2). Studies have also shown
`that asymptomatic DVT is strongly associated with the develop-
`ment of symptomatic VTE (6–8) and is also associated with an
`increased risk of death (9). Due to these factors, modeling is the
`only approach to achieve annual incidence figures and estimates
`of complications.
`The chronic nature of VTE and its recurrences and compli-
`cations requires considerable healthcare resources for its man-
`agement. Additionally, morbidity and healthcare costs are in-
`curred from associated complications of VTE, such as post-
`thrombotic syndrome (PTS), which affects at least one-third of
`
`DVT patients (10–17), and pulmonary hypertension (PH), which
`occurs in 4%–5% of patients following PE (18, 19). Data from
`the UK suggest that the total cost of VTE to the National Health
`Service in 1993 was £235–£257 million (e349–e382 million)
`(20), and estimates of the combined direct and indirect costs are
`now placed at approximately £640 million (e950 million) (21).
`The costs are further increased when long-term complications
`such as PTS are taken into consideration (22, 23). Therefore, it is
`important for healthcare decision-makers to have reliable esti-
`mates of the total annual number of incident and recurrent VTE
`events per year.
`To date, the most comprehensive epidemiological data have
`been generated from studies of specific populations. US popu-
`lation-based studies of defined geographical areas, which in-
`cluded patients with only incidentVTE at home or in hospital, re-
`vealed a VTE incidence of 71–117 per 100,000 person-years
`(24–26). One study also showed a thirty-day rate of VTE recur-
`rence of 4.8% (26). In Europe, studies in Western France (27)
`
`Table 1: Sources of data.
`
`Event estimated
`
`Source of data
`
`Probability (range) of event
`
`--
`
`-
`
`--
`
`--
`
`Oger 2000 (27)
`US Census Bureau International
`Data base (28)
`
`HES (29) and PMSI (30) databases
`
`Geerts et al. 2004 (31)
`Derived from Geerts et al. 2004 (31)
`
`Geerts et al. 2001 (32)
`Derived from Geerts et al. 2001 (32)
`
`Derived from
`Prandoni et al. 1996 (10)
`
`0.147 (0.074–0.221) first year,
`0.01 (0.005–0.015) in following years
`
`Community-acquired events
`Age and gender specific
`Country-specific population data
`
`Hospital-acquired events
`At-risk populations
`Surgical risk group
`DVT and PE without prophylaxis
`DVT and PE with prophylaxis
`Medical risk group
`DVT with and without prophylaxis
`PE with and without prophylaxis
`PTS
`Mild/moderate PTS in patient with DVT
`
`Severe PTS in patient with DVT (new)
`
`Prandoni et al. 1996 (10)
`
`PH
`
`Pengo et al. 2004 (18)
`
`DVT
`Symptomatic and diagnosed
`
`Death from DVT
`Medical DVT that has developed
`into PE
`PE
`Symptomatic and diagnosed
`Sudden death from PE
`Death from undiagnosed PE
`Death from diagnosed PE
`DVT recurrence
`
`PE recurrence
`
`Geerts et al. 2004 (31);
`Piovella et al. 2005 (35)
`Oster et al. 1987 (33)
`Oster et al. 1987 (33)
`
`Oster et al. 1987 (33)
`Oster et al. 1987 (33)
`Oster et al. 1987 (33)
`Oster et al. 1987 (33)
`Prandoni et al. 1996 (10);
`Heit et al. 2000 (34)
`
`Prandoni et al. 1996 (10);
`Heit et al. 2000 (34)
`
`0.026 (0.013–0.039) first year,
`0.017 (0.009–0.026) in following years
`0.31 (0.16–0.47) first year,
`0.38 (0.19–0.57) in following years
`
`0.10 (0.05–0.15)
`
`0.006 (0.003–0.009)
`0.115 (0.058–0.173)
`
`0.29 (0.15–0.44)
`0.11 (0.06–0.17)
`0.30 (0.15–0.45)
`0.08 (0.04–0.12)
`0.104 (0.052– 0.156) first year,
`0.02 (0.01–0.03) in following years
`
`0.025 (0.013–0.038) first year,
`0.005 (0.003–0.008) in following years
`
`DVT, deep-vein thrombosis; HES, Hospital Episodes Statistics; PE, pulmonary embolism; PH, pulmonary hypertension; PMSI, Le Programme de Médicalisation
`des Systèmes d’Information; PTS, post-thrombotic syndrome.
`
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`

`Cohen et al. Venous thromboembolism in Europe
`
`Figure 1: General model
`structure for estimating
`the number of country-
`specific, non-fatal sympto-
`matic venous thromboem-
`bolism (VTE) events and
`VTE-related deaths in a
`one-year period. *Treated
`deep-vein thrombosis (DVT)
`and pulmonary embolism (PE)
`(for the purpose of the model,
`we assume all diagnosed VTE is
`treated). PH, pulmonary hy-
`pertension; PTS, post-throm-
`botic syndrome.
`
`and Sweden (5), that included both incident and recurrent VTE
`events, reported an overall VTE incidence of 160–180 per
`100,000 person-years. Although these studies have contributed
`considerably to our understanding of the epidemiology of VTE,
`they underestimate the total burden of the disease on the health-
`care system because they do not include undiagnosed or mis-
`diagnosed clinical VTE events or unrecognized VTE-related
`deaths.
`In view of the potential impact of VTE to public health and
`the lack of comprehensive estimates on the number of sympto-
`matic VTE events and associated morbidity and mortality in Eu-
`rope, the VTE Impact Assessment Group in Europe (VITAE) de-
`signed a modified incidence-based model to estimate the total
`annual number of non-fatal incident and recurrent VTE events,
`associated complications (PTS and PH), and VTE-related deaths
`in six countries within the European Union (EU).
`
`Methods
`Data searches
`An extensive search of national databases was performed look-
`ing at published papers and grey literature. The search was con-
`ducted using MEDLINE and EMBASE databases between 1994
`to date. Seventy-five original papers were identified that de-
`scribed new epidemiological research. Only those giving infor-
`mation about the prevalence and incidence in Europe in defined
`geographical populations were used in the model. Key search
`terms were “venous thromboembolism”, “deep-vein thrombo-
`sis”, and “pulmonary embolism”. These terms were crossed with
`the terms “epidemiology”, “prevalence”, “incidence”, “risk fac-
`tors”, and “natural history”.
`
`Model structure
`A model was developed to estimate the number of country-spe-
`cific, non-fatal symptomatic VTE events and VTE-related
`deaths in a one-year period. Events estimated included incident
`and recurrent cases of non-fatal VTE, and incident and existing
`
`cases of PTS, PH, and VTE-related death. The base year for es-
`timating events was 2004.
`The core model structure, methodologies, and assumptions
`were validated by an advisory board consisting of VTE experts
`from across Europe and the USA. Individual models were devel-
`oped for six EU countries: France, Germany, Italy, Spain,
`Sweden, and the UK. Wherever possible, the parameter esti-
`mates for models were derived from data in the published litera-
`ture (Table 1) (10, 18, 27–35). Where data on model parameters
`were unavailable, the advisory board provided an expert opinion
`on the plausible ranges for sensitivity analyses. Published data
`were used as a source for all event rates, for the at-risk hospital
`population, and for the probabilities of events. Estimates of pro-
`phylaxis rates from experts in the individual countries were only
`used when published data were not available. Where there were
`any differences, or disagreements arose, experts were asked to
`reach a consensus.
`The model estimated the number of community-acquired
`VTE events and hospital-acquired VTE events. Hospital-ac-
`quired events were defined as events that occurred following ex-
`posure to hospital-related risk factors, surgical procedures, or
`admission to a medical ward, and which occurred within a hospi-
`tal setting or in the community within a 90-day period of admis-
`sion to hospital. Events not meeting these criteria were classified
`as community-acquired. The general model structure applies to
`both community- and hospital-acquired events (Fig. 1).
`
`Estimation of the number of community-acquired
`events
`Community-acquired events for each of the six EU countries
`were estimated on the basis of a large French epidemiological
`study (the Groupe d'Etude de la Thrombose de Bretagne Occi-
`dentale [EPI-GETBO] study) (27) with age- and gender-specific
`incidence rates applied to country-specific population data. The
`authors of the EPI-GETBO study (27) re-analyzed their study
`and provided additional data. They separated the events that took
`place in the community occurring within three months of hospi-
`
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`
`

`

`Table 2: At-risk hospital
`population estimates
`(baseline) extracted from
`or based on the Hospital
`Episodes Statistics (29)
`and Le Programme de
`Médicalisation des Systèm-
`es d’Information (30) data-
`bases 2004.
`
`Cohen et al. Venous thromboembolism in Europe
`
`General population
`At-risk population
`Surgical
`Moderate risk
`High risk
`Highest risk
`Medical
`Myocardial infarction*
`Stroke
`Other medical†
`
`France
`
`Germany
`
`Italy
`
`Spain
`
`Sweden
`
`UK
`
`60,424,000
`
`82,425,000
`
`58,058,000
`
`40,281,000
`
`8,986,000
`
`60,271,000
`
`577,362
`1,155,368
`365,212
`
`15,250
`67,499
`1,130,796
`
`751,436
`1,487,275
`474,948
`
`25,883
`106,691
`1,416,345
`
`532,200
`1,035,322
`339,129
`
`18,685
`79,025
`1,019,501
`
`385,328
`660,542
`216,299
`
`11,930
`50,464
`651,004
`
`84,178
`153,689
`50,576
`
`2,795
`11,876
`152,406
`
`599,355
`742,324
`250,162
`
`18,651
`74,678
`720,880
`
`†Cardiac, respiratory, and inflammatory diseases and severe infections. *The majority of patients with myocardial infarction receive anticoagulant therapy and
`are excluded.
`
`talization (16% of these events). As in the VITAE study these
`would not constitute a community-acquired event. The re-analy-
`sis of the EPI-GETBO study (27) also allowed the calculation of
`age-adjusted numbers of events for community-acquired VTE.
`
`Estimation of the number of hospital-acquired events
`Patients were included in the hospital-acquired events model if
`they were deemed to be at risk of developing VTE (the at-risk
`population), and met the aforementioned criteria. At-risk popu-
`lations were estimated on the basis of patient numbers derived
`from the Hospital Episodes Statistics (HES) database (29) in the
`UK and Le Programme de Médicalisation des Systèmes d’Infor-
`mation (PMSI) database (30) in France (Table 2). All HES and
`PMSI diagnostic and procedure codes relating to disease groups
`were carefully reviewed and those deemed to put a patient at risk
`of VTE according to current American College of Chest Phys-
`icians (ACCP) consensus guideline definitions (31) were in-
`cluded. At-risk patients from both public and private sectors
`were included. The hospital at-risk population was then divided
`into categories according to either type of surgery (moderate,
`high, and highest risk of VTE), or medical diagnosis on admis-
`sion (myocardial infarction, stroke, and other medical diagnoses
`associated with VTE risk, e.g. heart failure, respiratory failure,
`infectious and inflammatory diseases) (36). Cancer patients
`were not separately included in order to avoid double counting
`with cancer leading to surgery. This is because coding does not
`specify whether an admission for cancer leads to operation or
`whether an operation, such as colectomy, is for a benign or ma-
`lignant condition. We also did not include hematological cancers
`such as leukemia, and other cancers not known to be associated
`with VTE (e.g. skin cancers). Hence we took a conservative ap-
`proach. In addition, patients who were in hospital for day pro-
`cedures and minor surgery were excluded. Diagnoses requiring
`therapy with anticoagulants were also excluded.
`The at-risk populations for the UK and France were based on
`the HES (29) and PMSI (30) data, respectively. These databases
`are robust and readily accessible sources of patient-level data.
`Equivalent databases were either not available, or the method of
`data collection was inconsistent with HES and PMSI for the
`other countries. For these countries (Germany, Italy, Spain, and
`Sweden), a weighted average of the UK and French data was
`used to derive patient numbers. For each at-risk group, the age-
`
`Table 3: Probability of venous thromboembolism (VTE) events
`extracted or derived from Geerts et al. 2001 (32) and 2004
`(31).
`
`Probability ofVTE event
`
`Without prophylaxis
`DVT*
`PE†
`
`With prophylaxis
`DVT*
`PE†
`
`0.150
`0.300
`0.600
`
`0.240
`0.547
`0.160
`
`0.052
`0.103
`0.241
`
`0.025 (0.27)§
`0.057 (0.067)§
`0.017 (0.047)§
`
`0.041
`0.081
`0.162
`
`0.075
`0.235
`0.040
`
`0.027
`0.054
`0.126
`
`0.008
`0.024
`0.004
`
`At-risk population
`Surgical
`Moderate risk
`High risk
`Highest risk
`Medical
`Myocardial infarction
`Stroke
`Other medical‡
`
`*Objectively verified by venography (i.e. all deep-vein thrombosis [DVT] events – both symptomatic
`and asymptomatic). †In order to calculate mortality, the frequency of pulmonary embolism (PE) for
`surgical patients was inflated from the probability of diagnosed clinical PE to the probability of all PE
`(i.e. to include undiagnosed clinical PE) (37). For medical patients, the PE frequency was calculated
`by applying the Oster algorithm (33) to DVT frequencies. ‡Cardiac, respiratory, and inflammatory
`diseases and severe infections. §Figures based on clinical trials and inflated from the probability of
`diagnosed clinical PE to the probability of all PE.
`
`adjusted number ofVTE events was calculated on the basis of the
`weighted data and this was applied to age-specific breakdowns
`of the relevant country populations.
`Hospital-acquired events were estimated by applying spe-
`cific risk frequencies for developing VTE to the surgical and
`medical at-risk populations, according to whether or not they
`were receiving VTE prophylaxis. The probability of developing
`VTE with and without prophylaxis (Table 3) (31–33, 37) was
`combined with estimates of current prophylaxis use (Table 4) in
`order to calculate the number of incident clinical VTE events in
`each at-risk group. Prophylaxis use was estimated based on pub-
`lished data wherever possible and, if otherwise, on expert con-
`sensus.
`
`Estimation of the number of recurrentVTE events
`In order to fully capture the number of VTE events expected in a
`given year, we estimated the number of recurrent clinically evi-
`dent events alongside incident cases of clinical VTE. The major-
`ity of cases of recurrence occur within the first year of the index
`
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`Cohen et al. Venous thromboembolism in Europe
`
`At-risk population
`
`France
`
`Germany
`
`Spain
`
`Italy
`
`Sweden
`
`Surgical
`Moderate risk
`High risk
`Highest risk
`Medical
`Myocardial infarction
`Stroke
`Other medical*
`
`0.80
`0.90
`0.95
`
`0.85
`0.85
`0.60
`
`0.80
`0.85
`0.95
`
`0.55
`0.85
`0.62
`
`0.60
`0.80
`0.78
`
`0.60
`0.60
`0.62
`
`0.50
`0.70
`0.90
`
`0.30
`0.20
`0.25
`
`0.80
`0.80
`0.95
`
`0.20
`0.20
`0.20
`
`UK
`
`0.40
`0.90
`0.70
`
`0.48
`0.48
`0.30
`
`*Cardiac, respiratory, and inflammatory diseases and severe infections.
`
`Table 4: Probability (base-
`line estimate) of venous
`thromboembolism pro-
`phylaxis use in the at-risk
`population estimated from
`published data and clini-
`cian estimates, 2004.
`
`event; however, the cumulative frequency continues to increase
`as time from the index event elapses (34). Total recurrent events
`expected in a given year therefore comprised recurrences of inci-
`dent cases occurring in that year plus recurrences from incident
`events occurring in previous years. In order to incorporate this
`into the model, we assumed a constant incidence of index VTE
`over the previous five years and applied 1- to 5-year recurrence
`rates to these data (Table 5) (10, 18, 34).
`
`Estimation of the numbers of PTS and PH events
`A similar approach was taken to estimate the expected number of
`PTS cases. Total cases expected in a given year therefore com-
`prised PTS related to incident cases of VTE occurring in that
`year plus PTS related to incident cases of VTE occurring in the
`previous five years (10). However, given that PTS is a chronic
`disease, there is also an underlying level of disease existing in
`any given year that is equivalent to the sum of cases developed in
`previous years. In the model, PTS was further separated into
`mild/moderate disease and severe disease. This distinction was
`made because disease severity drives resource use. We assumed
`that once a patient has either severe or mild/moderate PTS, they
`will remain in this state (23). In reality, it is likely that patients
`will pass from one state to another over the course of the disease.
`The expected number of PH cases was estimated based on
`published incidence rates (18). Similar to PTS, expected cases of
`PH in any given year comprised PH related to incident cases of
`VTE occurring in that year plus PH related to incident cases of
`PE occurring in the previous two years. Rates of chronic PH ex-
`pected to result in surgical intervention were applied to the esti-
`mate of incident cases of PE in order to estimate the total number
`of PH cases in a given year.
`
`Estimation of the number ofVTE-related deaths
`Estimates of the number of VTE-related deaths included esti-
`mates of sudden death, death following diagnosed and treated
`disease, and death following undiagnosed, untreated disease.
`The number of deaths from recurrent cases was also estimated.
`The number of VTE-related deaths was estimated from
`numbers of treated VTE events on the basis of an algorithm de-
`veloped by Oster et al. (33). A simplified version of the algo-
`rithm is shown in Figure 2 (31, 33, 35). The key parameters de-
`fined by the algorithm are rates of diagnosed DVT, likelihood of
`progression from undiagnosed DVT (symptomatic and asympto-
`matic) to PE, and rates of death from diagnosed and undiagnosed
`VTE (symptomatic). For the purpose of the analysis, we as-
`sumed that diagnosed VTE was synonymous with treated VTE.
`We then applied the algorithm to the numbers of treated DVT and
`PE events in order to estimate the number of deaths related to
`diagnosed VTE in each of the six EU countries. This allowed us
`to estimate the number of expected deaths from cases of VTE
`that are not diagnosed as well as expected deaths from cases that
`are diagnosed. In order to assess whether the algorithm was ap-
`plicable and reflected current understanding of VTE, it was re-
`viewed by the advisory board. On the basis of this review, one
`parameter was adjusted. The likelihood of all DVT (initially
`asymptomatic and symptomatic) being detected and treated was
`adjusted from 16%, based on a report by Oster et al. (33), to 10%
`on the basis of more recent data (31, 35), which suggested that
`the original estimate overstates the current likelihood of clinical
`presentation and diagnosis.
`
`Probabilistic sensitivity analyses
`Probabilistic sensitivity analyses (PSAs) were conducted to as-
`sess the impact of uncertainty on the model results. One-way
`
`Recurrent event/outcome
`
`Year 1
`
`Year 2
`
`Year 3
`
`Year 4
`
`Year 5
`
`Cumulative
`
`Deep-vein thrombosis
`Pulmonary embolism
`Mild/moderate PTS
`Severe PTS
`Pulmonary hypertension
`
`PTS, post-thrombotic syndrome.
`
`0.104
`0.025
`0.147
`0.026
`0.014
`
`0.030
`0.007
`0.038
`0.017
`0.003
`
`0.017
`0.004
`0.001
`0.017
`-
`
`0.017
`0.004
`0.001
`0.017
`-
`
`0.017
`0.004
`0.001
`0.017
`-
`
`0.185
`0.044
`0.188
`0.094
`0.017
`
`Table 5: Probability of re-
`currence of venous throm-
`boembolism (10, 34) and
`associated outcomes (10,
`18) in the at-risk popu-
`lation.
`
`760
`
`

`

`Cohen et al. Venous thromboembolism in Europe
`
`Figure 2: Simplified ver-
`sion of the Oster et al. (33)
`algorithm showing poten-
`tial outcomes of hospital-
`acquired venous throm-
`boembolism. *The likelihood
`of a diagnosisof deep-vein
`thrombosis (DVT) was ad-
`justed from 16% as reported
`by Oster et al. (33) to 10% on
`the basis of more recent data
`(31, 35) estimating the current
`likelihood of diagnosis. PE, pul-
`monary embolism; P=Probabil-
`ity.
`
`sensitivity analyses were conducted according to the methodolo-
`gy of Sullivan et al. (38) with all inputs varied by ± 50%. All pa-
`rameters that had an impact >1% on the overall output of the
`model were included as inputs in PSAs. The distribution of the
`at-risk population and rates of VTE prophylaxis use were in-
`cluded a priori in the PSAs. Distribution and ranges of model in-
`puts were defined according to available information and recom-
`mended best practice as follows: clinician estimates were used
`for rates of VTE prophylaxis use; ACCP-specified ranges (31,
`32) were used for the rates of VTE with and without prophylax-
`is; published data were used for recurrence rates (34) and PTS
`rates (10); and methodology as outlined by Sullivan et al. (38)
`was used for the at-risk population, rates of death, and the prob-
`ability of symptomatic/diagnosed DVT and PE.
`
`Extrapolation of data
`To estimate the number of VTE events occurring per annum
`across the whole of the EU, the country-specific outputs from the
`six EU countries modeled were summed and then inflated by the
`ratio of population size in the six included countries (310.4 mil-
`lion) to the population size in all 25 member-state countries
`(454.4 million).
`
`Results
`Total number of non-fatalVTE events and associated
`complications
`In total, the model estimated that 761,697 non-fatal VTE events
`(465,715 cases of DVT and 295,982 cases of PE) and 399,808 as-
`sociated complications (395,673 patients with PTS and 4,135
`with PH) occurred across the six EU countries in 2004 (Table 6).
`
`Table 6: Total non-fatal ve-
`nous thromboembolism
`(VTE) events, VTE-related
`deaths, and associated
`outcomes across all six
`European Union countries
`modeled* in 2004.
`
`Event, n (95% CI)
`
`Community-acquired
`
`Hospital-acquired
`
`Total
`
`Non-fatalVTE event
`Deep-vein thrombosis
`
`Pulmonary embolism
`
`VTE-related deaths†
`
`TreatedVTE†
`
`UntreatedVTE
`
`Sudden death
`
`Associated outcome
`Post-thrombotic syndrome‡
`
`Pulmonary hypertension
`
`200,482
`(172,548–226,239)
`86,511
`(73,967–99,626)
`108,535
`(77,243–178,968)
`8,124
`(6,151–10,470)
`63,541
`(41,574–114,074)
`36,870
`(25,467–60,724)
`
`177,236
`(147,893–207,420)
`1,173
`(991–1,371)
`
`265,233
`(209,844–332,407)
`209,471
`(153,817–273,371)
`261,477
`(211,782–325,823)
`18,349
`(12,422–25,695)
`153,853
`(110,943–211,670)
`89,275
`(64,718–117,822)
`
`218,437
`(162,065–285,321)
`2,961
`(2,162–3,860)
`
`465,715
`(404,664–538,189)
`295,982
`(242,450–360,363)
`370,012
`(300,193–483,108)
`26,473
`(19,158–35,271)
`217,394
`(154,910–317,068)
`126,145
`(92,352–170,949)
`
`395,673
`(328,154–477,185)
`4,135
`(3,311–5,089)
`
`*Modeled countries were France, Germany, Italy, Spain, Sweden, and the UK. †Including deep-vein thrombosis- and pulmonary embolism-related deaths.
`‡Including all post-thrombotic syndrome (new cases plus those underlying from previous years). CI, confidence interval.
`
`761
`
`

`

`Cohen et al. Venous thromboembolism in Europe
`
`Hospital-acquired events represent 63% of all cases of VTE plus
`associated complications.
`Based on a total population estimate of 310.4 million inhab-
`itants and the number of non-fatal VTE events across the six EU
`countries included in our model, the estimated DVT attack rate
`(incidence of first lifetime and recurrent DVT) was 148 per
`100,000 person-years (65 per 100,000 for community-acquired
`DVT, and 83 per 100,000 for hospital-acquired DVT). Similarly,
`the estimated PE attack rate was 95 per 100,000 person-years
`(28 per 100,000 for community-acquired PE, and 67 per 100,000
`for hospital-acquired PE).
`
`Total number ofVTE-related deaths
`The total estimated number of VTE-related deaths for 2004
`across the six EU countries was 370,012 (Table 6). Of these, 7%
`(26,473) were expected to have resulted from diagnosed (and
`presumably treated) VTE, 34% (126,145) from sudden fatal PE,
`and 59% (217,394) from PE-related deaths following undiag-
`nosed (untreated) VTE. Deaths that occurred as a consequence
`of hospital-acquired VTE comprised 71% of the total number of
`VTE-related deaths in the six EU countries.
`
`Sensitivity analyses
`The results of the sensitivity analyses are reported as 95% con-
`fidence intervals in Table 6.
`
`Discussion
`This study describes the extent of the health burden attributed to
`VTE in the EU in terms of the total number of incident and recur-
`rent non-fatal DVT and PE clinical events, and VTE-related
`deaths per year in six EU countries. Our estimates indicate that
`VTE is a major public-health problem in these six countries, with
`a predicted total number of just under half a million DVT events
`and almost a third of a million PE events per annum. Fur-
`thermore, a third of a million deaths occur per year due to sudden
`PE or following undiagnosed and untreated VTE. Given the
`availability of effective VTE prophylaxis (31), many of these
`events and deaths could be prevented – particularly those that are
`hospital-acquired (39).
`The estimated total number of VTE events (DVT and PE: 148
`per 100,000 and 95 per 100,000, respectively) in the EU is higher
`than that reported for US communities (24–26), but is close to
`that reported in the EPI-GETBO study (27) in Western France
`(124 per 100,000 and 60 per 100,000, respectively). Only the
`community data from the EPI-GETBO study (27) were used in
`our analysis; the EPI-GETBO hospital data was not. Many of the
`other differences between estimates can be accounted for by the
`fact that the Worcester, MA (24) and Olmsted County, MN (25)
`studies excluded recurrent events, whereas the EPI-GETBO
`study (27) and our study included both incident and recurrent
`events; recurrent events accounted for 25% of events in the EPI-
`GETBO study (27) and 19% of events in this study. Our model
`conservatively assessed the contribution of asymptomatic hospi-
`tal events to symptomatic events (10% instead of 16% conver-
`sion rate). In addition, a comparison of the number of VTE
`events predicted by our model with data from the above epidemi-
`ological studies (24–27) is complicated by the fact that the latter
`
`only collected symptomatic, diagnosed VTE events, while our
`model also accounted for undiagnosed events leading to VTE
`mortality. The number of deaths in the 25 member states of the
`EU has been reported to be 4,432,177 per annum (40). Based on
`a population of 454.4 million, this gives an annual death rate of
`approximately 1%. The total number of deaths occurring in
`France, Germany, Italy, Spain, Sweden, and the UK has been re-
`ported to be 2,982,816 per annum (40). Our model estimates that
`370,012 (300,193–483,108) (12%) deaths per annum in these six
`EU countries are due to VTE, with the proportion varying from
`10% in the UK to 14% in Italy. While this figure may at first
`seem high, it is consistent with data from community- and hospi-
`tal-based postmortem examination studies, which have shown
`that approximately 10% of deaths in hospitals are due to PE
`(41–43). Furthermore, of the estimated 370,012 (300, 193–483,
`108) VTE-related deaths predicted per annum, 93% were a result
`of either sudden fatal PE or undiagnosed, untreated VTE. This
`means that only 7% of deaths followed diagnosed and treated
`VTE, and would have been recognized as VTE-related by the
`treating physician. Treating physicians may not be aware that
`VTE is responsible for more than 14 times as many deaths as
`those recognized as being VTE-related, reflecting the poor
`awareness that many physicians have of the potentially fatal out-
`comes of VTE and the importance of providing at-risk patients
`with VTE prophylaxis. In addition, at least 25% of VTE-related
`deaths were estimated to be “sudden” and, therefore only pre-
`ventable with appropriate prophylaxis as currently recom-
`mended (4, 31).
`The cost of treating VTE and related morbidity is substantial.
`Our data have important implications regarding VTE prophylax-
`is in both the surgical and medical settings. While some form of
`prophylaxis is given to most major-surgery patients, studies have
`shown that the type, duration, and intensity of prophylaxis are
`frequently inappropriate, usually leading to inadequate prophy-
`laxis (44). Furthermore, the use of recommended prophylaxis in
`medical patients, a sizeable proportion of whom will develop
`VTE if left unprotected, has been reported to be suboptimal (45,
`46).
`Estimates of the number of VTE events across the EU, based
`on extrapolation from the six modeled countries, were 684,019
`DVT events, 434,723 PE events, and 610,138 PTS events per
`annum. The number of VTE-related deaths was estimated at
`543,454 acro