Scholarly article on topic 'Thrombosis: A major contributor to global disease burden'

Thrombosis: A major contributor to global disease burden Academic research paper on "Health sciences"

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Abstract Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE). The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden due to VTE in low, middle and high income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between 2 and 7 per 1,000 among those 70years of age or more. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted-life-years (DALYs) lost in low and middle income countries, and second in high income countries, responsible for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low, middle, and high income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate if improved utilization of preventive measures will reduce the burden.

Academic research paper on topic "Thrombosis: A major contributor to global disease burden"

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Review Article

Thrombosis: A major contributor to global disease burden^

ISTH Steering Committee for World Thrombosis Day The members of the ISTH Steering Committee for World Thrombosis Day: G.E. Raskob a* P. Angchaisuksirib, A.N. Blancoc, H. Buller d, A. Gallus e, B.J. Huntf, E.M. Hylek g, A. Kakkar h, S.V. Konstantinides', M. McCumber a, Y. Ozakij, A. Wendelboe a, J.I. Weitz k

a College of Public Health, University of Oklahoma Health Sciences Center, 801 NE 13th Street Oklahoma City, OK 73104 United States b Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Rama V! Rd. Bangkok 10400 Thailand c Division Hemostasia, Academia Nacional de Medicina, Av. Scalabrini Ortiz 2894 Buenos Aires Argentina d Academic Medical Center, Department of Vascular Medicine, Meibergdreef 9 Amsterdam 1105 Netherlands e SA Pathology - Department of Hematology, Flinders Medical Center, Flinders Drive, Bedford Park South Australia, 5042 Australia f Thrombosis & Thrombophilia Centre, Guy's & St Thomas', NHS Foundation Trust, London England g Boston University School of Medicine, 801 Massachusetts Ave. Boston 02118 United States h Thrombosis Research Institute, Manresa Road London sw3 6LR England

i Center for Thrombosis and Hemostasis, Johannes Gutenberg University, Langenbeckstr. 1 Mainz, 55131 Germany

j Department of Laboratory Medicine, University ofYamanashi, 1110 Shimokato, Chuo Yamanashi, 409-3898Japan

k McMaster University and the Thrombosis and Atherosclerosis Research Institute, 237 Barton Street E Hamilton, Ontario, L8L 2X2 Canada

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ARTICLE INFO

ABSTRACT

Article history: Received 13 August 2014 Accepted 19 August 2014 Available online 10 October 2014

Thrombosis is a common pathology underlying ischemic heart disease, ischemic stroke, and venous thromboembolism (VTE).The Global Burden of Disease Study 2010 (GBD 2010) documented that ischemic heart disease and stroke collectively caused one in four deaths worldwide. GBD 2010 did not report data for VTE as a cause of death and disability. We performed a systematic review of the literature on the global disease burden due to VTE in low, middle and high income countries. Studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent results with annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population. The incidence increased to between 2 and 7 per 1,000 among those 70 years of age or more. Although the incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging. VTE associated with hospitalization was the leading cause of disability-adjusted-life-years (DALYs) lost in low and middle income countries, and second in high income countries, responsible for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events. VTE causes a major burden of disease across low, middle, and high income countries. More detailed data on the global burden of VTE should be obtained to inform policy and resource allocation in health systems, and to evaluate if improved utilization of preventive measures will reduce the burden.

© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license

(http://creativecommons.org/licenses/by-nc-nd/3.0/).

Contents

Introduction................................................................................................................................932

Methods..................................................................................................................................932

Literature Search and Review............................................................................................................932

Results....................................................................................................................................934

Literature Search........................................................................................................................934

Incidence of VTE........................................................................................................................934

Prevalence of VTE......................................................................................................................934

Disability Adjusted Life Years (DALYs)....................................................................................................934

☆ Reprinted with permission of the International Society on Thrombosis and Haemostatis. For citation purposes, please use the original publication details: ISTH Steering Committee for World Thrombosis (2014). Thrombosis: A major contributor to global disease burden. J Thromb Haemost 2014; http://dx.doi.org/10.1111/jth.12698; 12:1580-1590. * Corresponding author. Fax: +1 405 271 3039. E-mail address: Gary-Raskob@ouhsc.edu (G.E. Raskob).

http://dx.doi.org/10.1016/j.thromres.2014.08.014

0049-3848/© 2014 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Discussion..................................................................................................................................935

Conflict of Interest Statement................................................................................................................936

Acknowledgements..........................................................................................................................936

References..................................................................................................................................936

Introduction

A doubling of life expectancy and quadrupling of the world population during the 20th century have been associated with a transition from infectious to non-communicable diseases as the major cause of death and disability worldwide [1-3]. Cardiovascular disease is a leading contributor to the burden caused by non-communicable diseases. Thrombosis is the most common underlying pathology of the three major cardiovascular disorders: ischemic heart disease (acute coronary syndrome), stroke, and venous thromboembolism (VTE).

The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD Study), which was initiated by the World Health Organization and the World Bank, is a systematic scientific investigation aimed at quantifying the comparative magnitude of health loss due to diseases, injuries and risk factors by age, sex and geographic region throughout the world [3-5]. The most recent version of this effort, GBD 2010, documents the number of deaths from 235 causes from 1990 through 2010, using data from 187 countries and 21 regions; these regions are grouped further into 7 super-regions [4,5]. The study also provides estimates of the years of life lost due to premature mortality (YLL), the years lived with disability (YLD) and the disability-adjusted life years (DALYs) [4,5]. DALYs estimate how many years of healthy life are lost because of premature death or non-fatal illness or disability, and are calculated as the sum of YLL and YLD [6].

GBD 2010 documented 52.8 million deaths globally in 2010 [3]. Non-communicable disease accounted for 34.5 million deaths, or two out of every three deaths [3]. Ischemic heart disease (7.0 million deaths) and stroke (5.9 million deaths) collectively caused one in four deaths worldwide [3]. The 7.0 million deaths from ischemic heart disease represent a 35% increase since 1990. About half of all stroke deaths were from ischemic stroke, which is caused by thrombosis. The 2.8 million deaths from ischemic stroke represent a 25% increase since 1990. Although there is substantial regional variation, ischemic heart disease ranks as the number one or two causes of YLL in 13 of the 21 regions, and ranks in the top five causes of death in 17 regions [3]. Stroke ranks as the first or second cause of YLL in 8 regions, and is in the top five causes in 14 regions [3]. Ischemic heart disease was the leading cause of DALYs lost worldwide in 2010 (up from fourth rank in 1990, an increase of 29%), and stroke was the third leading cause (up from fifth rank in 1990, an increase of 19%) [6]. More than 60% of new strokes, and 45% of deaths from stroke occur in individuals less than 75 years of age [7].

GBD 2010 clearly documents the major impact of arterial thrombosis on global disease burden because it is the pathological mechanism underlying most cases of ischemic heart disease and ischemic stroke. However, the study does not report data for VTE as a specific cause of death and disability. A cursory review of the literature from Western Europe and North America suggests that VTE is a major contributor to the burden from non-communicable diseases. For example, Cohen and colleagues used an incidence-based epidemiology model to estimate the number of non-fatal symptomatic VTE events, which includes both deep-vein thrombosis (DVT) and pulmonary embolism (PE), and the number of VTE - related deaths across the European Union in 2004 (population 454.4 million) [8]. The results yielded estimates of 684,019 DVT events; 434,723 PE events; and a total of 543,454 VTE - related deaths [8]. In the United States, investigators from the Centers for Disease Control and Prevention

used data from the National Hospital Discharge Survey to estimate there were an average of 547,596 adult hospitalizations with a diagnosis of VTE each year during 2007 to 2009 among the population of 301 to 307 million [9]. If VTE causes a proportionate burden of disease across the other global regions, it would be highly ranked in the causes of death and DALYs worldwide. Given that much of the mortality and morbidity from VTE is potentially preventable [10-13], data on the disease burden are important for health systems and policy makers for planning resource allocation, both for health care delivery and for setting research priorities.

We therefore performed a systematic review of the literature on the global burden of disease due to VTE. The objective was to review the evidence for disease burden in each of the geographic regions specified in the GBD Study 2010, using the variables of annual incidence rate (number of new cases each year per 1,000 population at risk), prevalence (proportion of the population with the condition at a point in time), annual number of deaths, and DALYs.

Methods

Literature Search and Review

A computer search of the literature was performed using OVID Medline, OVID Medline In-Process and Other Non-Indexed Citations, and EMBASE, from inception of these databases to May 2014. We used the disease-related key words venous thromboembolism, deep-vein thrombosis, venous thrombosis, vein thrombosis, thrombophlebitis, pulmonary embolism, and lung embolism, together with the additional key words incidence, prevalence, mortality, case fatality, morbidity, surveillance and epidemiology, years lived with disability (YLD), and disability -adjusted life years (DALY), to search the titles and abstracts of articles in these databases. We also reviewed the bibliographies of published articles. We excluded non-human studies, case reports and clinical trials, as well as non-relevant publication types, including reports of clinical conferences and editorials. We also excluded articles published in languages other than English; and the current report is confined to the literature published in English. The identified citations from each database were exported to an ENDNOTE library where the citations were de-duplicated. The merged list of citations was exported to a Word document that included citation number, title, list of authors, the full abstract, and the journal citation.

The abstracts were reviewed independently by two reviewers (A.W., G.R) who categorized them according to the level of evidence as either level A, level B, or other; disagreements were resolved through discussion and consensus. Level A evidence was defined as population-based estimates of the parameters of the disease burden (incidence, prevalence, number of deaths, DALYs) in the general population (age 18 years or older) derived from either population-based cohort studies, or from analysis of national health system databases or private health insurance claims data within a defined population, or derived using a combination of the former methods with appropriate epidemiologic modeling methods. Level B evidence was defined as estimates of the burden in specific sub-populations such as the elderly, pregnancy, etc. using the same methods described for level A. The category of "Other" evidence included all other study designs without a defined population to derive the disease burden parameters, such as single hospital base cohort studies or record review, and autopsy studies. Population-based mortality studies based on hospital discharge or other databases, or

Table 1

Studies comprising Level A evidence for burden of disease from Venous Thromboembolism (VTE): incidence per 1,000 population per year.

Author and Year Study Design Global Super Region Global Region Country VTE Incidence DVT Incidence PE Incidence

Haldet al. 2013 [14] Population-based cohort combined with hospital based discharge diagnosis, High Income Western Europe Norway 1.48 NR NR

autopsy and procedure registries

Holst et al. 2010 [15] Population-based cohort combined with national cause of death registry High Income Western Europe Denmark 2.69 NR NR

and national patient registry

Morettietal. 2010 [16] Population -based hospital discharge database High Income Western Europe Italy NR NR 0.189

Severinsen et al. 2010 [17] Population based cohort in men and women age 50 to 64 combined with High Income Western Europe Denmark 1.15 0.65 0.51

the National patient registry

Cohen et al. 2007 [8] Incidence -based epidemiologic model of country-specific non-fatal VTE High Income Western Europe France, Germany, NR 1.48 0.95

events and VTE -related deaths Italy, Spain,

Sweden, UK

Heurtaetal. 2007 [18] Prospective population -based cohort identified using the General Practice High income Western Europe UK 0.745 0.403 0.342

database. Nested case-control analysis also done

Naessetal. 2007 [19] Population-based cohort identified by electronic hospital registries and High Income Western Europe Norway 1.43 0.93 0.50

case-finding search of tertiary care center for discharge diagnoses of VTE 0.036* 0.15*

Guijarro et al. 2005 [20] Hospital discharge database of the Andalusian health care service for 1998 to 2001 High Income Western Europe Spain NR

Ogeret al. 2000 [21] Population -based cohort study of both hospitalized and outpatient cases High Income Western Europe France 1.83 1.24 0.60

within a defined populations in 1998 and 1999 using standardized

prospective data collection

Nordstrom et al. 1992 [22] Population-based cohort of hospital based venography cases in 1987 High Income Western Europe Sweden NR 1.55 male NR

1.62 female

Kierkegarrd 1980 [23] Population-based cohort of hospital based venography cases High Income Western Europe Sweden NR 0.85 male NR

0.68 female

Tagalakis et al. 2013 [24] Provincial healthcare databases linking hospital discharges and healthcare High Income North America Canada 1.22 0.78 0.45

claims data 2000 through 2009 (Quebec)

Yusufetal. 2012 [9] Search of the National Hospital Discharge database 2007 - 2009 High Income North America USA 2.39 1.52 1.15

Weineret al. 2011 [25] HCUP Nationwide inpatient sample of hospital discharges and national High Income North America USA NR NR 1.12

cause of death file databases 1998- 2006

Cushman et al 2004 [26] Population-based cohort with prospective follow-up of patients combined High Income North America USA 1.61 1.17 0.45

with search of hospital discharge and Medicare records 1.30** 1.04** 0.36**

Stein etal. 2004 [27] Search of the National Hospital Discharge database High Income North America USA

Janke et al. 2000 [28] Vital statistics data obtained from the Minnesota State Department of Health High Income North America USA NR NR 0.60 to 0.90 male

and hospital discharge data from a State uniform billing claims database 1980 to 1994 0.19*** 0.60 female

Klatsky et al. 2000 [29] Population-based cohort of a California pre-paid health plan for 1978 High Income North America USA NR NR

through 1985 combined with hospital record review

Silverstein et al. 1998 [30] Population-based cohort with medical record review and search of High Income North America USA 1.17 0.48 0.69

computerized databases of diagnoses and procedures, billing data, death

certificates and autopsy records 0.230****

White etal. 1998 [31] Database analysis of the linked California patient discharge data set High Income North America USA NR NR

Anderson et al. 1991 [32] Population-based cohort of hospital cases with hospital record review High Income North America USA 1.07 0.48 0.23

Shiraevetal. 2013 [33] National databases on hospitalization and deaths 2009 to 2010 High Income Australasia Australia NR NR 0.53

Ho et al. 2008[34] Population-based cohort study with cases identified prospectively and also High Income Australasia Australia 0.83 0.52 0.31

retrospectively through Western Australian Department of Health database

Vazquez et al. 2013 [35] Population-based cohort within a health maintenance organization High Income Southern Latin Argentina 1.65 1.30 0.64

America

Janget al. 2010 [36] National Health Insurance database in 2008 High Income High Income Korea 0.138 0.0531 0.0701

Asia Pacific

Lee et al 2010 [37] National health Insurance claims database for Taiwan Southeast Asia, East Asia Taiwan 0.159 NR NR

East Asia, Oceania

Cheuket al. 2004 [38] Database of Hong Kong Hospital Authority of all hospitalizations, diagnoses, Southeast Asia, East Asia Hong Kong NR 0.171 0.039

procedures and outcomes 2000 to 2001 East Asia, Oceania

Woo et al. 1988 [39] National vital statistics analysis combined with hospital record review Southeast Asia, East Asia Hong Kong 0.079 NR NR

(rate is for 1985) East Asia, Oceania

* This study evaluated cases where VTE or PE was the primary reason for hospital admission.

** The rates are for the Caucasian population. Corresponding incidence rates for African Americans were VTE 1.38, DVT 107, PE 0.40, and for Asian/Pacific Islanders were VTE 0.26, DVT 0.22, and PE 0.07. *** The rate is for overall population. Corresponding incidence rates by race were Caucasian 0.21, African American 0.22, Asian 0.02, and Hispanic 0.09.

**** The rate is for a first idiopathic DVT in Caucasian population. Corresponding incidence rates by race were African American 0,293, Hispanic 0.139, and Asian/Pacific Islander 0.060.

health department death certificate data, were also assigned to the category of "Other." This article focuses on the Level A evidence for overall disease burden according to global region. Selected Level B evidence on the relationship between age and disease burden were also included where relevant. The evidence categorized as "Other" was not systematically reviewed.

To simplify comparison of incidence results across studies and between global regions, all incidence rates were converted to a rate per 1,000 individuals per year.

Results

Literature Search

The computerized literature search identified a total of 9,603 citations. Of these citations, 8,817 (92%) were in the English language. After the de-duplication check, a total of 8,702 citations remained for review.

The two independent reviewers were in agreement on the classified level of evidence for 8,671 (99 %) of the 8,702 reviewed citations; the remaining 31 citations were classified after discussion and consensus between the reviewers. The final classification designated 29 citations as level A evidence [14-42], 29 as level B evidence [43-71 ], and the remainder as other. Most of the level A studies evaluated the incidence ofVTE or its components, DVT and/or PE [14-40]; two studies evaluated the prevalence ofVTE [41,42].

Incidence ofVTE

The results of the studies classified as level A evidence of incidence are summarized in Table 1.

This evidence comes from only two of the 7 global super regions designated by GBD 2010; those designated "High Income", and "Southeast Asia, East Asia, and Oceania". Within the High Income super region, 11 level A studies were from the region of Western Europe [8,14-23], 10 were from North America, 2 were from Australasia (both from Australia) [33,34], one was from the Southern Latin America region (Argentina) [35], and one was from the Asia Pacific region (Korea) [36]. The three level A studies from the super region of "Southeast Asia, East Asia, and Oceania" all came from the region of East Asia [37-39] (two studies from Hong Kong and one from Taiwan).

The relationship between increasing age and the incidence ofVTE was evaluated in several of the level A studies [9,19,21,22,24,30,32, 35-38,40]. The results of these studies are summarized in Table 2.

The level B studies evaluated the incidence ofVTE in various subpopulations, such as during pregnancy or the post-partum period [43-54], males or females of selected age categories [55-64], subgroups with or without selected risk factors or comorbidities [65-70], or special categories of thrombosis [71]. All but one of the level B studies came from the super region designated High Income; the exception was from Sub-Saharan Africa (South Africa) [51]. Within the High Income super region, 14 of the level B studies were from the region of Western Europe [43,44,46,49,54,55,57-59,61-63,65,69], 11 were from North America [45,47,50,52,56,60,64,67,68,70,71], two were from Australasia (both from Australia) [48,53], and one was from the high income Asia Pacific region (Japan) [66].

Prevalence of VTE

Two studies were identified that evaluated the prevalence ofVTE; both were done in the United States by the same investigators [41,42]. The national prevalence ofVTE was determined during the five year period from 2002 through 2006 using a health insurance claims database of 12.7 million enrollees that included both private insurance claims and Medicare claims. The prevalence ofVTE was 3.2 per 1,000 enrollees in 2002, and 4.2 per 1,000 enrollees in 2006 [41]. Among patients 65 years of age or older, the prevalence in 2006 was 13.8 per 1,000 enrollees, compared with 2.3 per 1,000 enrollees in those less than 65 years of age [41]. The authors used the 2006 data to project the US national prevalence as 0.95 million cases, and to project the future prevalence in 2050 to be 1.82 million cases [41]. The second study found that the prevalence ofVTE was highest in African - American males, followed by Caucasian males, Caucasian females, and African -American females [42]. Hispanic individuals of both sexes had lower prevalence [42].

Disability Adjusted Life Years (DALYs)

Our search identified two studies that evaluated disease burden in terms of DALYs [72,73]. The methodologically strongest was the study byJha and colleagues, as part of the World Health Organization's Patient Safety Program [72]. This study used analytic modeling to estimate the incidence rates ofVTE, annual number of cases, and DALYs from VTE

Table 2

Incidence rates per 1,000 population per year according to age category: studies comprising level A evidence.

Author and Year Global Region Country Age 40 to 49 Age 50 to 59 Age 60 to 69 Age 70 to 79 Age 80 or more

Kroger et al. 2010 [40] Western Europe Germany 0.30 male* 1.24 male 3.45 male

0.28 female 0.94 female 3.72 female

Naess et al. 2007 [19] Western Europe Norway 0.20 maleA, ** 0.72 male 1.14 male 1.85 male 3.73 male

0.17 female 0.72 female 0.93 female 1.45 female 3.84 female

Ogeret al. 2000 [21] Western Europe France 1.52 male ~ 5.33 male 10.81 male

1.05 female 4.53 female 12.04 female

Nordstrom et al. 1992 [22] Western Europe Sweden 0.69 male ** 2.85 male 3.27 male 5.64 male 7.65 male

0.97 female 1.03 female 2.17 female 4.29 female 8.22 female

Tagalakis et al. 2013 [24] North America Canada (Quebec) 0.83 1.42 2.57 4.41 6.85

Yusufet al. 2012 [9] North America USA 1.43 2.00 3.91 7.27 11.34

Silverstein et al. 1998 [30] North America USA 0.90 maleA 0.76 male 1.63 male 6.46 male 9.84 male

0.45 femaleA 0.83 female 1.69 female 3.22 female 8.49 female

Anderson et al. 1991 [32] North America USA 0.17** 0.43 1.19 2.32 2.91

Lee et al. 2010 [37] East Asia Taiwan NR*** NR*** NR*** NR*** 8.31 male

11.82 female

Cheuk et al. 2004 [38] East Asia Hong Kong 0.096AA -N-R--*-*-*- -N-R--*-*-*-- 0.81AA

Vazquez etal. 2013 [35] Southern Latin America Argentina (2006 -2012) NR*** NR*** 5.93

Janget al. 2011 [36] High Income Asia Pacific Korea(2008) 0.099 male 0.173 male 0.381 male 0.765 male 1.088 male

0.097 female 0.131 female 0.412 female 1.042 female 1.092 female

Footnotes NR = Not reported.

* Age categories shown are 30 to 49,50 to 69, and 70 to 90, ** Incidences are for DVT (all VTE not reported). ~ Age categories shown are 40 to 59,60 to 74, and 75 or more.

A Age categories shown are 40 to 44,50 to 54,60 to 64, 70 to 74, and 80 to 84,AA Age categories shown are 45 to 64, and 65 or more. *** Rates are shown in graphical form; actual numerical values not provided.

associated with hospitalization in high, middle and low income countries [72]. The data for the modeling were generated from two sources; an extensive literature review, and epidemiologic studies commissioned by the WHO, which were conducted in 26 hospitals across eight low and middle income countries in the Eastern Mediterranean and North Africa regions (Egypt, Jordan, Kenya, Morocco, South Africa, Sudan, Tunisia, Yemen) [74], and in 35 hospitals across five countries in Latin America (Argentina, Colombia, Costa Rica, Mexico, and Peru) [75]. This approach enabled the authors to estimate the number of VTE events associated with hospitalization during 2009 for 117.8 million hospitalizations among 1.1 billion citizens of high income countries, and for 203.1 million hospitalizations among 5.5 billion citizens of low and middle income countries [72,74,75].

The study reported incidences ofVTE per 100 hospitalizations of 3.3 (95% confidence interval [CI] 1.9 to 4.8) in high income countries, and 3.0 (95% CI 1.0 to 4.8) in low and middle income countries [72]. The estimated annual number of cases ofVTE was 3.9 million (95% CI 1.9 to 6.3) for the high income countries, and 6.0 million (95% CI 1.2 to 12.8) for the low and middle income countries. VTE was the leading cause of hospital-related DALYs lost overall, being responsible for a full one-third (7,681) of the total of 22,644 DALYs, and VTE accounted for more DALYs lost than nosocomial pneumonia, catheter-related blood stream infections, and adverse drug events [72]. VTE was the leading cause of DALYs lost in the low and middle income countries, and ranked second in the high income countries [72]. Premature death was the source of 64% of the DALYs lost in high income countries and for 66% of the DALYs lost in low and middle income countries [72].

The second study was conducted by the Australia and New Zealand Working Party on the Management and Prevention of Venous Thromboembolism [73]. This group used incidence data from Western Australia, together with mortality estimates and disability weighting derived from the literature, much ofwhich comes from other countries, to estimate the DALYs associated with VTE in Australia for the year 2008. The estimated overall loss for Australia in 2008 was 78,408 DALYs [73]. The premature mortality (YLL) was 99.7% of the estimated total burden of disease [73].

Discussion

The results of our systematic review of the literature suggest several inferences. First, there is substantial evidence that VTE is associated with a major global burden of disease. Second, most of the level A evidence of this burden comes from the super region "High Income" defined by GBD 2010, although some evidence also comes from the super region of "Southeast Asia, East Asia and Oceania" (Table 1). Third, the evidence of disease burden is primarily based on the incidence ofVTE events, and to a lesser extent on the estimated number of deaths for a region or country. Our review identified only one rigorous study estimating the DALYs associated with VTE [72]. Fourth, there is consistent and strong evidence that the global incidence of VTE increases with increasing age, and is especially pronounced in the elderly (Table 2). This finding has major implications for global health because life expectancy continues to improve in low and middle income countries, and these countries continue the transition from infectious diseases to non-communicable diseases as the major cause of death and disability. Finally, the evidence and the above inferences lead us to recommend that VTE be measured as a specific cause of death in future efforts of the GBD project. We expand further on these themes in the paragraphs below.

Regarding the annual incidence of VTE, the studies from Western Europe, North America, Australia, and Southern Latin America (Argentina) yielded consistent findings. These studies reported overall annual incidences ranging from 0.75 to 2.69 per 1,000 individuals in the population, with the incidence in most of the studies ranging between 1.07 and 1.83 (Table 1). The study by Oger and colleagues [21] reported that the incidence ofVTE was similar to that of myocardial

infarction in the same country during a similar time frame. Further, the study byJha and colleagues [72] estimated 3.9 million cases of hospital-associated VTE during one year among 1.1 billion citizens of high income countries (3.5 per 1,000 population), and 6.0 million cases among 5.5 billion citizens of low and middle income countries (1.1 per 1,000 population) [72]. Thus, the aggregate evidence from the literature indicates that VTE is a common condition globally across the spectrum of high, middle and low income regions.

There was a strong and consistent association of increasing incidence of VTE with increasing age. The annual incidence increased to between 2 and 7 per 1,000 population among those 70 years of age or more in most of the studies, and to between 3 and 12 per 1,000 population among those 80 years of age or older (Table 2). This finding has major implications for healthcare systems and for the care of the elderly. For example, a study of the incidence ofVTE among nursing home residents in Kansas reported an incidence of 13 per 1,000 residents per year [70]. Reardon and colleagues analyzed nursing home records from 19 states in the United States, and found that 1 in 25 admissions had a diagnosis ofVTE [56]. It is likely that the high incidence ofVTE in the elderly reflects the high prevalence of co-morbid acquired risk factors in these patients, especially malignancy, heart failure, and immobility associated with surgery or hospitalization for medical illness, which account for the majority of the population attributable risk ofVTE in older individuals. In contrast, genetic factors account for only 7 to 22 per cent of the population attributable risk in the elderly [76].

The significant burden ofVTE is not confined to the elderly, and VTE should not be considered a disease of old age. The annual incidence among individuals in their 40s, 50s, and 60s ranged from 0.2 to 5.3 per 1,000 population (Table 2), with the incidence in the very contemporary studies ranging from 0.8 to 3.9 [9,24].

The level A studies from Taiwan, Hong Kong, and Korea reported lower annual incidences ofVTE or DVT (ranging from 0.079 to 0.171 per 1000 population, Table 1 [37-39]). These results are consistent with the findings of studies in the United States, which reported lower annual incidences ofVTE in Asian- Americans than in Caucasians and African Americans [31 ]. There was also a strong association between increasing age and increased incidence in the studies from Hong Kong, Taiwan, and Korea [36-38] (Table 2). So, although the overall incidence is lower in individuals of Chinese and Korean ethnicity, their disease burden is not low because of population aging and increased life expectancy. Recent studies undertaken in Asian countries have demonstrated rates ofVTE after major surgery and in hospitalized medical patients approaching those observed in Western populations [77].

The literature review identified limited information on the number of deaths due to VTE. The strongest evidence comes from the study by Cohen and colleagues, who used an incidence-based model in six European countries to estimate that there were 534,454 deaths related to VTE across the European Union in 2004 [8]. A similar approach applied to the data from the United States suggested approximately 300,000 deaths from VTE each year [78,79]. The direct ascertainment of deaths due to VTE is difficult because of the low rate of autopsy in most countries, and because autopsy studies have consistently demonstrated that pulmonary embolism is often not diagnosed ante-mortem and that deaths due to pulmonary embolism are frequently mis-classified as cardiac deaths. Further, pulmonary embolism may be the primary cause of death, such as in patients with unprovoked VTE, or a secondary (contributing) cause of death, for example, in the cancer patient or the patient with multiple medical conditions. Secondary causes may not always be documented or measured in studies of causes of death. For these reasons, estimates of the number of deaths from VTE based on death certificates or hospital discharge data will underestimate the death burden.

Our review found limited information on the DALYs associated with VTE. The study byJha and colleagues [72] provides evidence that VTE causes a major burden of disease across low, middle, and high income countries. VTE was the highest ranked cause of DALYs overall among

the seven causes of hospital-associated adverse events. However, because the study only evaluated DALYs related to inpatient adverse events, it underestimates the total contribution ofVTE, since a substantial proportion ofVTE events occur out of hospital [78]. Premature death accounts for approximately two-thirds of the DALYs lost due to VTE [72]. Thus, even in patients with underlying chronic or terminal illness (eg. advanced heart failure or cancer), VTE causes earlier death for many of these patients.

Disability was responsible for 34% of the DALYs associated with VTE [72], indicating that VTE causes significant YLD because of the non-fatal consequences of DVT and PE. Despite treatment, about 10% to 20% of patients with DVT develop severe post-thrombotic syndrome, a chronic disorder that decreases quality of life and reduces the capacity to walk and to work [80,81]. In the most severe cases, patients with post-thrombotic syndrome can develop venous ulcers, which are slow to heal and costly for the healthcare system [80,81]. Heit and colleagues reported an incidence of venous ulcers of 1.8 per 1,000 population per year [82]. PE is associated with chronic thromboembolic pulmonary hypertension in up to 4% of patients [83]. Patients with this disorder have varying degrees of respiratory and cardiac impairment. Therefore, the long-term consequences ofVTE are associated with considerable disability, and are likely to produce significant YLD. Consequently, the disease burden ofVTE occurs through both YLL and YLD. More recently, the long-term psychological consequences of PE have been documented to include emotional distress, worry and anxiety due to uncertainty about whether or when a recurrence might occur, and in some cases, symptoms characteristic of post-traumatic stress disorder [84]. Therefore, in addition to the physical burden, there is also an emotional burden associated with VTE.

VTE may affect more people than those who suffer from it. First, current prevention strategies must be applied to large numbers of patients at risk. Most of these patients receive anticoagulant thromboprophylaxis, which is associated with major bleeding in 0.2% to 1.1% of patients [85-87]. Patients with thrombosis, particularly if they have a positive family history, are often tested for hereditary or acquired thrombophilic conditions. If abnormalities are found, this testing is sometimes extended to family members, which may lead to medical interventions, and have psychological consequences. The perceived risk of thrombosis affects many more people than those actually afflicted by it.

VTE was not assessed as a cause of death at the disaggregated level in GBD 2010 [3,5,6]. GBD 2010 used three criteria for including causes of death at the disaggregated level: potentially large burden, substantial health policy interest, and the feasibility of measurement [5]. We believe that VTE meets all of these criteria. The feasibility of evaluating VTE across the global regions is established by the results of the WHO Patient Safety Program [72,74,75]. The WHO is commended for including VTE among the adverse outcomes assessed in the Patient Safety Program. Future efforts of the GBD study should include evaluation ofVTE as a cause of death and the associated DALYs, both for hospital- associated events, which account for up to 60% of all VTE [78], and also for events that occur outside the hospital setting, such as unprovoked VTE.

Prevention is the key to reducing death and disability from VTE. This includes thromboprophylaxis in patients at risk (primary prevention), such as those undergoing surgery or those hospitalized with medical illnesses [10-12], and prevention of recurrent thromboembolic events in patients with established DVT or PE [88] (secondary prevention). Effective primary prevention is available for most high risk patient groups [10-12]. However, a global audit of utilization of primary thromboprophylaxis documented widespread underuse in eligible patients [89]. There is evidence that a concerted effort by a health system to include VTE risk assessment at the time of hospital admission and the provision of appropriate primary thromboprophylaxis is effective for reducing VTE-related death and readmission with nonfatal VTE [90,91]. The increased implementation of proven, evidence-based primary prevention against VTE should be a global health priority. The safety and simplicity of extended anticoagulant therapy has improved significantly

in recent years [88], and this approach to secondary prevention has the potential to markedly reduce the burden from recurrent venous throm-boembolic events if appropriately implemented on a global scale. Future research may further refine our ability to optimize the benefit-to-risk profile of anticoagulant treatment at the individual patient level, and minimize the side-effects of prevention. Strengthening the global effort to prevent VTE is consistent with the World Health Assembly's goal of significantly reducing the global burden from non-communicable diseases by 2025 [92].

In conclusion, this literature review found substantial evidence of a major global disease burden from VTE. Although this burden has been less extensively evaluated than the burden from arterial thrombosis, which includes ischemic heart disease and ischemic stroke, the available evidence indicates a major burden of disease across low, middle, and high income countries. Because many of these events are potentially preventable, more detailed data on the burden due to VTE should be obtained to inform public health policy and resource allocation in health systems, especially in regions where evidence is now limited or lacking, and to evaluate whether the broader and improved implementation of preventive measures will reduce the disease burden.

Conflict of Interest Statement

Acknowledgements

The authors accepted no direct funding from government or corporate sources for the preparation of this article.

References

[1 ] Hunter DJ, Fineberg HV. Convergence to common purpose in global health. N Engl J Med 2014;370:1753-5.

[2] Jamison DT, Summers LH, Alleyne G, Arrow KJ, Berkley S, Binagwaho A, et al. Global health 2035: a world converging within a generation. Lancet 2013;382:1898-955.

[3] Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380:2095-128.

[4] Horton R. GBD 2010: understanding disease, injury, and risk. Lancet 2012;380: 2053-4.

[5] Murray CJ, Ezzati M, Flaxman AD, Lim S, Lozano R, Michaud C, et al. GBD 2010: design, definitions, and metrics. Lancet 2012;380:2063-6.

[6] Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life years (DALYs) for 291 diseases and 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2197-223.

[7] Feigin V, Forouzanfar M, Krishnamurthi R, Mensah GA, Connor M, Bennett DA, et al. Global and regional burden of stroke during 1990-2010: findings from the Global Burden of Disease Study 2010. Lancet 2014;383:245-55.

[8] Cohen AT, Agnelli G, Anderson FA, Arcelus JI, Bergqvist D, Brecht JG, et al. Venous thromboembolism (VTE) in Europe. The number ofVTE events and associated morbidity and mortality. Thromb Haemost 2007;98:756-64.

[9] Yusuf HR, Tsai J, Atrash HK, Boulet S, Grosse SD. Venous thromboembolism in adult hospitalizations-United States, 2007-2009. MMWR Morb Mortal Wkly Rep 2012; 61:401-4.

[10] Kahn S, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al. Prevention ofVTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012;141 (2 Suppl.):e195S-226S.

[11] Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012;141 (2 Suppl.):e227S-77S.

[12] Falck-Yitter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-based Clinical Practice Guidelines. Chest 2012;141 (2 Suppl):e278S-325S.

[13] Nicolaides AN, Fareed J, Kakkar AK, Comerota AJ, Goldhaber SZ, Hull R, et al. Prevention and treatment of venous thromboembolism-international consensus statement. Int Angiol 2013;32:111-260.

[14] Hald EM, Enga KF, Lochen ML, Mathiesen EB, Njolstad I, Wilsgaard T, et al. Venous thromboembolism increases the risk of atrial fibrillation: the Tromso study. J Am Heart Assoc 2014;3:e000483.

[15] Holst AG, Jensen G, Prescott E. Risk factors for venous thromboembolism: results from the Copenhagen City Heart Study. Circulation 2010;121:1896-903.

[16 ] Moretti AM, Tafuri S, Parisi D, Germinario C. Epidemiology of pulmonary embolism in Apulia from analysis of current data. Monaldi Arch Chest Dis 2010;73:18-24.

[17 ] Severinsen MT, Johnsen SP, Tjonneland A, Overvad K, Dethlefsen C, Kristensen SR. Body height and sex-related differences in incidence of venous thromboembolism: a Danish follow-up study. Eur J Intern Med 2010;21:268-72.

[18] Huerta C, Johansson S, Wallander MA, Garcia Rodriguez LA. Risk factors and short-term mortality of venous thromboembolism diagnosed in the primary care setting in the United Kingdom. Arch Intern Med 2007;167:935-43.

[19] Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrom J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007;5:692-9.

[20] Guijarro R, San Roman CM, Perello JI, Nuno E, Efficiency Group of the Internal Medicine Services of Andalusia, Strategic Plan of SADeMi (Andalusia Society of Internal Medicine). A study of hospital discharges for venous thromboembolism in the south of Spain. An analysis of 19,170 cases from a regional database from 1998 to 2001. Eur J Intern Med 2005;16:279-86.

[21 ] Oger E. Incidence of venous thromboembolism: a community-based study in Western France. EPI-GETBP Study Group. Groupe d'Etude de la Thrombose de Bretagne Occidentale. Thromb Haemost 2000;83:657-60.

[22] Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992;232:155-60.

[23] Kierkegaard A. Incidence of acute deep vein thrombosis in two districts: a phlebographic study. Acta Chir Scand 1980;146:267-9.

[24] Tagalakis V, Patenaude V, Kahn SR, Suissa S. Incidence of and mortality from venous thromboembolism in a real-world population: the Q-VTE Study Cohort. Am J Med 2013;126:832.e13-21.

[25] Wiener RS, Schwartz LM, Woloshin S. Time trends in pulmonary embolism in the United States: evidence of overdiagnosis. Arch Intern Med 2011;171:831-7.

[26] Cushman M, Tsai AW, White RH, Heckbert SR, Rosamond WD, Enright P, et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. AmJ Med 2004;117:19-25.

[27] Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asians/ Pacific Islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med 2004; 116:435-42.

[28] Janke RM, McGovern PG, Folsom AR. Mortality, hospital discharges, and case fatality for pulmonary embolism in the Twin Cities: 1980-1995. J Clin Epidemiol 2000;53: 103-9.

[29] Klatsky AL, Armstrong MA, Poggi J. Risk of pulmonary embolism and/or deep venous thrombosis in Asian-Americans. Am J Cardiol 2000;85:1334-7.

[30] Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton 3rd LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-93.

[31] White RH, Zhou H, Romano PS. Incidence of idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 1998 May;128:737-40.

[32] Anderson Jr FA, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism. The Worcester DVT Study. Arch Intern Med 1991;151:933-8.

[33] Shiraev TP, Omari A, Rushworth RL. Trends in pulmonary embolism morbidity and mortality in Australia. Thromb Res 2013;132:19-25.

[34] Ho WK, Hankey GJ, Eikelboom JW. The incidence of venous thromboembolism: a prospective, community-based study in Perth, Western Australia. Med J Aust 2008;189:144-7.

[35] Vazquez FJ, Posadas-Martinez ML, Vicens J, Gonzalez Bernaldo de Quiros F, Giunta DH. Incidence rate of symptomatic venous thromboembolic disease in patients from a medical care program in Buenos Aires, Argentina: a prospective cohort. ThrombJ 2013;11:16.

[36] Jang MJ, Bang SM, Oh D. Incidence of venous thromboembolism in Korea: from the Health Insurance Review and Assessment Service database. J Thromb Haemost 2011;9:85-91.

[37] Lee CH, Lin LJ, Cheng DL, Kao Yang YH, Chen JY, Tsai LM. Incidence and cumulative recurrence rates of venous thromboembolism in the Taiwanese population. J Thromb Haemost 2010;8:1515-23.

[38] Cheuk BL, Cheung GC, Cheng SW. Epidemiology of venous thromboembolism in a Chinese population. Br J Surg 2004;91:424-8.

[39] Woo KS, Tse LK, Tse CY, Metreweli C, Vallance-Owen J. The prevalence and pattern of pulmonary thromboembolism in the Chinese in Hong Kong. IntJ Cardiol 1988;20: 373-80.

[40] Kroger K, Moerchel C, Moysidis T, Santosa F. Incidence rate of pulmonary embolism in Germany: data from the federal statistical office. J Thromb Thrombolysis 2010;29: 349-53.

[41 ] Deitelzweig SB, Johnson BH, Lin J, Schulman KL. Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol 2011;86:217-20.

[42] Deitelzweig SB, Lin J, Johnson BH, Schulman KL. Venous thromboembolism in the US: does race matter? J Thromb Thrombolysis 2011;31:133-8.

[43] Abdul Sultan A, Tata LJ, Grainge MJ, West J. The incidence of first venous thrombo-embolism in and around pregnancy using linked primary and secondary care data: a population based cohort study from England and comparative meta-analysis. PLoS One 2013;8:e70310.

[44] Kane EV, Calderwood C, Dobbie R, Morris C, Roman E, Greer IA. A population-based study of venous thrombosis in pregnancy in Scotland 1980-2005. Eur J Obstet Gynecol Reprod Biol 2013;169:223-9.

[45] Heyl PS, Sappenfield WM, Burch D, Hernandez LE, Kavanaugh VM, Hill WC. Pregnancy-related deaths due to pulmonary embolism: findings from two state-based mortality reviews. Matern Child Health J 2013;17:1230-5.

[46] Virkus RA, Lokkegaard EC, Bergholt T, Mogensen U, Langhoff-Roos J, Lidegaard O. Venous thromboembolism in pregnant and puerperal women in Denmark 19952005. A national cohort study. Thromb Haemost 2011;106:304-9.

[47] Berg CJ, Callaghan WM, Syverson C, Henderson Z. Pregnancy-related mortality in the United States, 1998 to 2005. Obstet Gynecol 2010;116:1302-9.

[48] Sharma S, Monga D. Venous thromboembolism during pregnancy and the post-partum period: incidence and risk factors in a large Victorian health service. Aust N Z J Obstet Gynaecol 2008;48:44-9.

[49] Samuelsson E, Hellgren M, Hogberg U. Pregnancy-related deaths due to pulmonary embolism in Sweden. Acta Obstet Gynecol Scand 2007;86:435-43.

[50] Wen SW, Huang L, Liston R, Heaman M, Baskett T, Rusen ID, et al. Severe maternal morbidity in Canada, 1991-2001. CMAJ 2005;173:759-64.

[51] Fawcus SR, van Coeverden de Groot HA, Isaacs S. A 50-year audit of maternal mortality in the Peninsula Maternal and Neonatal Service, Cape Town (1953-2002). BJOG 2005; 112:1257-63.

[52] Heit JA, Kobbervig CE, James AH, Petterson TM, Bailey KR, Melton 3rd LJ. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697-706.

[53] Sullivan EA, Ford JB, Chambers G, Slaytor EK. Maternal mortality in Australia, 19731996. Aust N Z J Obstet Gynaecol 2004;44:452-7 [discussion 377].

[54] Lindqvist P, Dahlback B, Marsal K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999;94:595-9.

[55] Santosa F, Moysidis T, Moerchel C, Kroger K, Bufe A. Pulmonary embolism in young people. Trends in Germany from 2005 to 2011. Hamostaseologie 2014;34:88-92.

[56] Reardon G, Pandya N, Nutescu EA, Lamori J, Damaraju CV, Schein J, et al. Incidence of venous thromboembolism in nursing home residents. J Am Med Dir Assoc 2013;14: 578-84.

[57] Schmidt M, Johannesdottir SA, Lemeshow S, Lash TL, Ulrichsen SP, Botker HE, et al. Obesity in young men, and individual and combined risks of type 2 diabetes, cardiovascular morbidity and death before 55 years of age: a Danish 33-year follow-up study. BMJ Open 2013;3:e002698.

[58] Sweetland S, Beral V, Balkwill A, Liu B, Benson VS, Canonico M, et al. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J Thromb Haemost 2012;10:2277-86.

[59] Moysidis T, Kroger K, Moerchel C, Santosa F, Grochenig E. Pulmonary embolism in young males and females in Germany: data from the Federal Statistical Office. Blood Coagul Fibrinolysis 2010;21:511-5.

[60] Lutsey PL, Virnig BA, Durham SB, Steffen LM, Hirsch AT, Jacobs Jr DR, et al. Correlates and consequences of venous thromboembolism: The Iowa Women's Health Study. Am J Public Health 2010;100:1506-13.

[61 ] Spannagl M, Heinemann LA, Dominh T, Assmann A, Schramm W, Schurmann R Comparison of incidence/risk of venous thromboembolism (VTE) among selected clinical and hereditary risk markers: a community-based cohort study. Thromb J 2005;3:8.

[62] Samuelsson E, Hagg S. Incidence of venous thromboembolism in young Swedish women and possibly preventable cases among combined oral contraceptive users. Acta Obstet Gynecol Scand 2004;83:674-81.

[63] Mellemkjaer L, Sorensen HT, Dreyer L, Olsen J, Olsen JH. Admission for and mortality from primary venous thromboembolism in women of fertile age in Denmark, 1977-95. BMJ 1999;319:820-1.

[64] Kniffin Jr WD, Baron JA, Barrett J, Birkmeyer JD, Anderson Jr FA. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994;154:861-6.

[65] Gaborit FS, Overvad K, Norgaard M, Kristensen SR, Tjonneland A, Severinsen MT. Alcohol intake and risk of venous thromboembolism. A Danish follow-up study. Thromb Haemost 2013;110:39-45.

[66] Kunisawa S, Ikai H, Imanaka Y. Incidence and prevention of postoperative venous thromboembolism: are they meaningful quality indicators in Japanese health care settings? World J Surg 2012;36:280-6 [Erratum in World J Surg 2012; 36: 278 -9].

[67] White RH, Dager WE, Zhou H, Murin S. Racial and gender differences in the incidence of recurrent venous thromboembolism. Thromb Haemost 2006;96:267-73.

[68] Beemath A, Skaf E, Stein PD. Pulmonary embolism as a cause of death in adults who died with heart failure. AmJ Cardiol 2006;98:1073-5.

[69] Petrauskiene V, Falk M, Waernbaum I, Norberg M, Eriksson JW. The risk of venous thromboembolism is markedly elevated in patients with diabetes. Diabetologia 2005;48:1017-21.

[70] Gomes JP, Shaheen WH, Truong SV, Brown EF, Beasley BW, Gajewski BJ. Incidence of venous thromboembolic events among nursing home residents. J Gen Intern Med 2003;18:934-6.

[71] Stein PD, Matta F, Yaekoub AY. Incidence of vena cava thrombosis in the United States. Am J Cardiol 2008;102:927-9.

[72] Jha AK, Larizgoitia I, Audera-Lopez C, Prasopa-Plaizier N, Waters H, Bates DW. The global burden of unsafe medical care: analytic modelling of observational studies. BMJ Qual Saf 2013;22:809-15.

[73] Access Economics Pty Limited. The burden ofvenous thromboembolism in Australia. The Australia and New Zealand Working Party on the Management and Prevention of Venous Thromboembolism; 2008 May [49 pp.].

[74] Wilson RM, Michel P, Olsen S, Gibberd RW, Vincent C, El-Assady R, et al. Patient safety in developing countries: retrospective estimation of scale and nature of harm to patients in hospital. BMJ 2012;344:e832.

[75] Aranaz-Andres JM, Aibar-Remon C, Limon-Ramirez R, Amarilla A, Restrepo FR, Urroz O, et al. Prevalence of adverse events in the hospitals of five Latin American

countries: results of the 'Iberoamerican Study of Adverse Events' (IBEAS). BMJ Qual Saf 2011;20:1043-51.

[76] Engers MJ, van Hylckama Vlieg A, Rosendaal FR. Venous thrombosis in the elderly: incidence, risk factors and risk groups. J Thromb Haemost 2010;8:2105-12.

[77] Angchaisuksiri P. Venous thromboembolism in Asia - an unrecognized and under-treated problem? Thromb Haemost 2011;106:585-90.

[78] Heit JA. The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 2008;28:370-2.

[79] Heit J, Cohen AT, Anderson FJ. Estimated annual number of incident and recurrent, fatal and non-fatal venous thromboembolism (VTE) events in the US. Blood 2005; 106:267A.

[80] Kahn SR, Hirsch A, Shrier I. Effect of postthrombotic syndrome on health-related quality of life after deep venous thrombosis. Arch Intern Med 2002;162: 1144-8.

[81] Kachroo S, Boyd D, Bookhart BK, LaMori J, Schein JR, Rosenberg DJ, et al. Quality of life and economic costs associated with postthrombotic syndrome. Am J Health Syst Pharm 2012;69:567-72.

[82] Heit JA, Rooke TW, Silverstein MD, Mohr DN, Lohse CM, Petterson TM, et al. Trends in the incidence of venous stasis syndrome and venous ulcer: a 25-year population-based study. J Vasc Surg 2001;33:1022-7.

[83] Pengo V, Lensing AW, Prins MH, Marchiori A, Davidson BL, Tiozzo F, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350:2257-64.

[84] Noble S, Lewis R, Whithers J, Lewis S, Bennett P. Long-term psychological consequences of symptomatic pulmonary embolism: a qualitative study. BMJ Open 2014;4:e004561.

[85] Cohen AT, Spiro TE, Buller H, HR, Haskell L, Hu D, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368:513-23.

[86] Goldhaber sZ, Leizorovicz A, Kakkar AK, Haas SK, Merli G, Knabb RM, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011;365:2167-77.

[87] Raskob GE, Gallus AS, Pineo GF, Chen D, Ramirez LM, Wright RT, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: Pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br 2012;94:257-64.

[88] Wells PS, Forgie MA, Rodger MA. Treatment of venous thromboembolism. JAMA 2014;311:717-28.

[89] Cohen AT, Tapson VF, Bergmann JF, Goldhaber SZ, Kakkar AK, Deslandes B, et al. ENDORSE Investigators. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study. Lancet 2008;371:387-94 [Erratum in: Lancet 2008; 371:1914].

[90] Lester W, Freemantle N, Begaj I, Ray D, Wood J, Pagano D. Fatal venous thromboem-bolism associated with hospital admission: a cohort study to assess the impact of a national risk assessment target. Heart 2013;99:1734-9.

[91] Catterick D, Hunt BJ. Impact of the national venous thromboembolism risk assessment tool in secondary care in England: retrospective population-based database study. Blood Coagul Fibrinolysis 2014;25:571-6.

[92] Sixty-sixth World Health Assembly. Follow-up to the political declaration of the high-level meeting of the General Assembly on the prevention and control of non-communicable diseases. http://apps.who.int/gb/ebwha/pdf_files/WHA66/A66_R10-en.pdf; May 27, 2013.