Researching Venous Thromboembolism in

vulnerable adult populations

Professor DA FitzmauriceDepartment of Primary Care & General Practice

University of Birmingham

Conclusions 1• Risk factors for venous thromboembolism (VTE) are

common and widespread (and not just in hospital)• VTE is a common disease

• VTE is a major cause of death

• The majority of VTE-associated deaths are sudden PE or following undiagnosed and untreated VTE

• Therefore VTE must be managed by prevention

Conclusions 2• Many of these events and deaths are

preventable with available effective prophylaxis

• We know this is true for hospital in-patients, lack of research outside medical/surgical environments

VTE

• Comprises DVT and PE

• 3rd leading cause of cardiovascular mortality• 25-60,000 deaths per year in UK• 900,000 across Europe• 50% may be due to hospital stay • 1/20 lifetime incidence

THE SIZE OF THE VTE PROBLEM

• An estimated 60,000 deaths due to VTE in the UK• 2/3 due to hospital admission of which 25,000 are preventable

• Hospital acquired VTE causes more deaths than hospital -

acquired infection (MRSA & C difficile, peaked at 10,000)

• Autopsy data suggests reported incidences are markedly

underestimated. Baglin J Clin Path 1997; 50: 609-10

• Registered deaths in England in 2007 -19,000- but

underdiagnosed…(House of Commons Question summer 2009)

Hospital Preventive Strategies

"Making Health Care Safer: a Critical Analysis..."

A systematic review ranked 79 safety interventions

• Based on the strength of evidence

• The highest ranked safety practice was the "appropriate use of prophylaxis to prevent VTE.."

• Based on overwhelming evidence that thromboprophylaxis reduces adverse patient outcomes and decreasing overall costs

Shojania KG. Agency for Healthcare Research and Quality 2001; 20 July. Available at www.ahrq.gov/clinic/ptsafety.

VTE prevention in

SURGICAL patients

Heparin Reduces Total Mortality, Fatal PE and does not Increase Major Bleeding1

1. Collins R, et al. N Engl J Med 1988;318:1162–73

(1.7%) 109

7

191 (3.0%)

6

210223

PE Fatalbleeds

‘Other’ deaths

0

50

100

150

200

250

H C H C H C

Heparin n = 6366 Control n = 6426

Num

ber o

f sub

ject

s af

fect

ed

Non-fatal events

Fatal events

55 (0.9%)

(0.3%) 19

Total mortality

RRR 21%, p <0.02

VTE prevention in

MEDICAL patients

Anticoagulant prophylaxis to prevent symptomatic

VTE in hospitalized medical patients

RR [CI] Absolute risk reduction (%)

NNTB

Any PE 0.43 0.26 – 0.71 0.29 345

Fatal PE 0.38 0.21 – 0.69 0.25 400

Symptomatic DVT 0.47 0.22 – 1.00

Major bleeding 1.32 0.73 – 2.37

All cause mortality 0.97 0.79 – 1.19

Dentali F et al. Ann Intern Med. 2007; 146:278-288

• meta-analysis of 9 randomized trials comparing anticoagulant prophylaxis (UFH, LMWH, fondaparinux) with no treatment in hospitalized medical patients, n = 19,958

VTE prevention in

PRACTICE

ALIVE

DEAD

Coils of fresh thrombo-emboli straddled the pulmonary bifurcation and occluded branches of pulmonary arteries

Fresh thrombi in deep veins of both calves

Enlarged LV and evidence of hypertensive heart disease

Post mortem

Overview

• The problem

• Risk factors

• Prophylaxis in medical patients

• Therapeutic options

• New studies

Public / Media perception - travel

Travelling in cramped conditions

Other media perceptions: Game-

related / Office Workers?

VTE Hospital Trends

1. Alikhan R et al. J Clin Pathol 2004;57(12)1254-1257.2. Cohen AT, et al. Haemostasis. 1996;26:65-71.

71% reduction in fatal PE

Fata

l P

E (

%)

Surgical patients1,2

2.1%

0.6%

0

2

4

1966 2000

18% reduction in fatal PE

Medical patients1,2

Fata

l P

E (

%)

3.3%4.0%

0

2

4

1966 2000

Autopsy-detected Fatal PE inSurgical and Medical patients (21,515): 1966–2000

• Incidence of fatal PE

• Studies from Scandinavia, USA and UK

• 59% to 83%Nielsen et al. Acta Med Scand 1981;209:351-5Hauch et al. Acta Chir Scand 1990;156:747-9

Sperry et al. Hum Pathol 1990;21:159-65Cohen et al. Haemostasis 1996;26:65-71

Autopsy Proven Fatal PE

% in Medical Patients

60% of admissions

75% of PE deaths

Medical Inpatients

10% of consensus statements

Cohen et al. Haemostasis 1996;26:65-71

Epidemiology of VTE

• Mortality

Hypothesised Cause of Death of Jesus

Cause of Death Author’s background

Cardiac Rupture Cardiologist

Heart Failure General Physician

Hypovolaemic shock Forensic Pathologist

Syncope Surgeon

Acidosis Physician

Asphyxia Surgeon

Arrhythmia + Asphyxia Pathologist

Pulmonary Embolism Haematologist

Voluntary Surrender Life Physician

Didn’t actually Die Doctor of Theology

Clinical Suspicion of PE

Author Major

PE (n)

Autopsy

(n)

Death

(n)

SuspectedPE

Goldhaber

1973–1977

54 1,455 2,372 30%

Rubinstein

1980–1984

44 1,276 3,517 32%

Morgenthaler

1985–1989

92 2,427 5,358 32%

Pineda

1991–1996

67 778 6,023 45%

Pineda LA et al. Chest 2001;120:791–5

Overview

• The problem

• Risk factors

• Prophylaxis in medical patients

• New studies

Attributable Risk for DVT/PE

Risk factor AR (95% CI)

Hospitalization with surgery 23.8 (20.3–27.3)

Hospitalization without surgery 21.5 (17.3–25.6)

Malignant neoplasm 18.0 (13.4–22.6)

Congestive heart failure 9.5 (3.3–15.8)

Neurological disease with extremity paresis 6.9 (3.5–10.2)

Heit et al. Arch Intern Med 2002;162:1245-859 % Medical

Overview

• The problem

• Risk factors

• Prophylaxis in medical patients

• New studies

• Therapeutic options

Here is Darla being kissed by Chuck Ford, Senior Director of Clinical Operations for the Emergency Department of the IU Burn Center at Wishar

Heparins work

No trials of mechanical compression in general medical

patientsPassive Active

1980’s LMWH

MEDENOX1 63% Placebo

Enoxaparin

PREVENT2 49% Placebo

Dalteparin

ARTEMIS3 47% Placebo

Fondaparinux

14.9*

5.5

Study RRR Thromboprophylaxis Patients with VTE (%)

5.0*

2.8

10.5†

5.6

*VTE at day 14; †VTE at day 15.1Samama MM, Cohen AT et al. N Engl J Med. 1999;341:793-800.

2Leizorovicz A, Cohen AT et al. Circulation. 2004;110:874-9.3Cohen AT, Davidson B et al. BMJ 2006.

p < 0.001

p = 0.0015

p = 0.029

RRR = relative risk reduction

Medical thromboprophylaxis – consistent response

Major bleeding

MEDENOX 1. 1% 1.7%

PREVENT 0.2% 0.5%

ARTEMIS 0.2% 0.2%

Overview

• The problem

• Risk factors

• Prophylaxis in medical patients

• New studies

– based on ACCP recommendations

ACCP

American College of Chest Physicians recommendations

Are the gold standard

Are not just American but are written by experts from all over the globe

New Studies

VITAE – Epidemiology

PREVAIL Study – Stroke

ENDORSE study – Survey

EXCLAIM study – Medical

The Burden – VITAE Study

0

10000

20000

30000

40000

50000

60000

70000

VTE Breast cancer Road trafficaccidents

AIDS

VTE is a serious and preventable problem

(UK)More people die from VTE than the combined figure who die

from breast cancer, road traffic accidents and AIDS1-5

Num

ber

of d

eath

s pe

r ye

ar

1. House of Commons Health Committee Report. Second Session 2004-2005.2. Cohen AT,.VITAE, Thrombosis and Haemostasis 20073. Cancer Research UK Mortality Cancer Stats 2005. Available at www.cancerresearchuk.org4. Department of Transport, Road Casualties Great Britain, Main results 2006. Available at www.dft.gov.uk5. National Office of Statistics (NAO). HIV and AIDS. Available at www.statistics.gov.uk

VTE is a serious medical problem

VTE causes 60,000 deaths each year in the UK.;

37 times greater than the annual deaths from MRSA1,2

0

10000

20000

30000

40000

50000

60000

70000

VTE MRSA

Num

ber

of d

eath

s pe

r ye

ar

1. Cohen AT et al T&H 2007 2. National Office of Statistics (NAO). MRSA. Deaths Available at www.statistics.gov.uk

Total VTE events and mortality per year

extrapolated to 25 EU countries

*Cohen AT et al VITAE study, Thrombosis and Haemostasis Oct 2007.**Eurostat statistics on health and safety 2001. Available from: http://epp.eurostat.cec.eu.int.

Deaths due to VTE 543,454*

Exceed combined deaths due to– AIDS 5,860**

– breast cancer 86,831**

– prostate cancer 63,636**

– transport accidents 53,599**

Design and hospital characteristics

• Multinational, cross-sectional survey

• Hospitals randomly selected from authoritative national lists of all acute care hospitals

• Hospitals with greater than 50 beds for

– Acute medical illnesses

– Elective major surgery

All hospital wards were included in this

survey except• Psychiatric

• Pediatric

• Palliative care

• Maternity/obstetrics

• Neonatal

• Burn units

• Eye, ear, nose and throat units

• Dermatological/ophthalmologic wards

• Rehabilitation units/wards

• Emergency units

• Long-term care units

Objectives

• Primary

– To identify patients at risk for venous thromboembolism (VTE) hospitalized in representative hospitals throughout the world

– To determine the proportion of patients who receive effective VTE prophylaxis

• Secondary

– To define the above globally by acute illness (in medical and surgical populations)

32 countries -- 358 hospital32 countries -- 358 hospital

First pt in August 2006 - Last pt in January 2007Median of 8 days to enroll patients/hospital

Patients in medical & surgical wards

( N =68,183)

55%

45%

Surgical(N =30,827)

Medical(N =37,356)

Patients at risk for VTE and receiving ACCP

recommended prophylaxisPrimary objectives

52% at risk for VTE

50% received ACCPrecommended Px

Overall

( N= 68,163 )

42% at risk for VTE

48% received ACCPrecommended Px

Medical( n = 37,356 )

Secondary objectives

64% at risk for VTE

59% received ACCPrecommended Px

Surgical( n = 30,827 )

Cohen AT, Tapson VF, Bergmann J-F et al, Lancet 2008; 371:387-394

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 1011121314151617181920212223242526272829303132

Pe

rce

nt

Patients at risk for VTE by country

Mean=52%

N= 68,183

52% at risk for VTE

Alger

ia

Austra

lia

Bangl

ades

h

Brazil

Bulga

ria

Colom

bia

Czech

Rep

Egyp

t

Fran

ce

Germ

any

Greec

e

Hunga

ryIn

dia

Ireland

Kuwai

t

Mex

ico

Pakist

an

Poland

Portu

gal

Roman

ia

Russia

Saud

i Ara

bia

Slov

akia

Spain

Switz

erland

Thailand

Tuni

sia

Turk

eyUAE UK

USA

Venez

uela

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 1011121314151617181920212223242526272829303132

Pe

rce

nt

ACCP recommended prophylaxis

by country in patients at risk for VTE

Alger

ia

Austra

lia

Bangl

ades

h

Brazil

Bulga

ria

Colom

bia

Czech

Rep

Egyp

t

Fran

ce

Germ

any

Greec

e

Hunga

ryIn

dia

Ireland

Kuwai

t

Mex

ico

Pakist

an

Poland

Portu

gal

Roman

ia

Russia

Saud

i Ara

bia

Slov

akia

Spain

Switz

erland

Thailand

Tuni

sia

Turk

eyUAE UK

USA

Venez

uela

50% received VTE prophylaxis

Conclusions - ENDORSE

• First global view of VTE risk and prophylaxis practices

• Unprecedented scope: 32 Countries, 358 Hospitals, 68,183 Patients

• Risk for VTE is common (52%)– 64% of surgical patients– 42% of medical patients

• Prophylaxis is underutilized (50%)– Surgical patients: Omitted in 41%– Medically ill population: Omitted in 60%

Cohen AT, Tapson VF, Bergmann J-F et al, Lancet 2008; 371:387-394

These data reinforce the rationale to

• Urgently implement hospital-wide strategies

• Systematically assess patient risk for VTE

• Provide appropriate prophylaxis to prevent VTE

Cohen AT, Tapson VF, Bergmann J-F et al, Lancet 2008; 371:387-394

Thromboprophylaxis political momentum

NHS Operating Framework inclusion 2010/11

2004 2005 2006 2007 2008 2009 2010

Consistent investment and a coherent strategy leads to Department of

Health taking ownership for VTE prevention

Government documents on VTE prevention

March 2005 July 2005 April 2007 April 2007

The role of Primary Care

• Ensuring implementation of extended thromboprophylaxis

• Education of patients

• Risk Assessment?

• Commissioning of services?

Research?

• Residential homes

• Nursing homes

• Hospices

• Acutely unwell in own home

Issues

• Perception of importance

• “A good way to go”

• Measuring incidence/prevalence

• Use of chemical agents in the community

Proposed study

• Nursing home

• 1000 residents from 60 homes

• Baseline assessment of VTE risk taken, co-morbidity, medication, functional ability and VTE prevention strategies and then followed up 3 monthly for 1 year.

• Case records will be checked for any change in risk status from baseline.

Proposed study

• Outcomes: number of VTE events, associated hospital admissions, deaths and costs in relation to risk assessment and preventive strategies.

• Develop a pragmatic risk assessment tool for NH residents, building on the DH risk assessment tool for hospital in-patients

Conclusions 1• Risk factors for venous thromboembolism (VTE) are

common and widespread (and not just in hospital)• VTE is a common disease

• VTE is a major cause of death

• The majority of VTE-associated deaths are sudden PE or following undiagnosed and untreated VTE

• Therefore VTE must be managed by prevention

Conclusions 2• Many of these events and deaths are

preventable with available effective prophylaxis

• We know this is true for hospital in-patients, lack of research outside medical/surgical environments

Co-operation and balance are the keys to success