Researching Venous Thromboembolism in vulnerable adult populations Professor DA Fitzmaurice Department 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 3 rd 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: Registered deaths in England in ,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

VTE prevention in SURGICAL patients

Heparin Reduces Total Mortality, Fatal PE and does not Increase Major Bleeding 1 1. Collins R, et al. N Engl J Med 1988;318:1162–73 (1.7%) (3.0%) PE Fatal bleeds ‘Other’ deaths HCHCHC Heparin n = 6366 Control n = 6426 Number of subjects affected 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 (%) NNT B Any PE – Fatal PE – Symptomatic DVT – 1.00 Major bleeding – 2.37 All cause mortality – 1.19 Dentali F et al. Ann Intern Med. 2007; 146: 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) Cohen AT, et al. Haemostasis. 1996;26: % reduction in fatal PE Fatal PE (%) Surgical patients 1, % reduction in fatal PE Medical patients 1,2 Fatal PE (%) Autopsy-detected Fatal PE in Surgical 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;209:351-5 Hauch et al. Acta Chir Scand 1990;156:747-9 Sperry et al. Hum Pathol 1990;21: Cohen 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 DeathAuthor’s background Cardiac RuptureCardiologist Heart FailureGeneral Physician Hypovolaemic shockForensic Pathologist SyncopeSurgeon AcidosisPhysician AsphyxiaSurgeon Arrhythmia + AsphyxiaPathologist Pulmonary EmbolismHaematologist Voluntary Surrender LifePhysician Didn’t actually DieDoctor of Theology

Clinical Suspicion of PE AuthorMajor PE (n) Autopsy (n) Death (n) Suspected PE Goldhaber 1973– ,4552,37230% Rubinstein 1980– ,2763,51732% Morgenthaler 1985– ,4275,35832% Pineda 1991– ,02345% 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 surgery23.8 (20.3–27.3) Hospitalization without surgery21.5 (17.3–25.6) Malignant neoplasm18.0 (13.4–22.6) Congestive heart failure9.5 (3.3–15.8) Neurological disease with extremity paresis6.9 (3.5–10.2) Heit et al. Arch Intern Med 2002;162: % 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 Heparins work

No trials of mechanical compression in general medical patients PassiveActive

1980’s LMWH

MEDENOX 1 63%Placebo Enoxaparin PREVENT 2 49%Placebo Dalteparin ARTEMIS 3 47%Placebo Fondaparinux 14.9 * 5.5 StudyRRRThromboprophylaxisPatients with VTE (%) 5.0 * † 5.6 * VTE at day 14; † VTE at day Samama MM, Cohen AT et al. N Engl J Med. 1999;341: Leizorovicz A, Cohen AT et al. Circulation. 2004;110: Cohen AT, Davidson B et al. BMJ p < p = p = 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

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 AIDS 1-5 Number of deaths per year 1. House of Commons Health Committee Report. Second Session Cohen AT,.VITAE, Thrombosis and Haemostasis Cancer Research UK Mortality Cancer Stats Available at 4. Department of Transport, Road Casualties Great Britain, Main results Available at 5. National Office of Statistics (NAO). HIV and AIDS. Available at

VTE is a serious medical problem VTE causes 60,000 deaths each year in the UK.; 37 times greater than the annual deaths from MRSA 1,2 Number of deaths per year 1. Cohen AT et al T&H National Office of Statistics (NAO). MRSA. Deaths Available at

Total VTE events and mortality per year extrapolated to 25 EU countries * Cohen AT et al VITAE study, Thrombosis and Haemostasis Oct ** Eurostat statistics on health and safety Available from: 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 hospital First pt in August Last pt in January 2007 Median of 8 days to enroll patients/hospital

Patients in medical & surgical wards ( N =68,183) Surgical (N =30,827) Medical (N =37,356)

Patients at risk for VTE and receiving ACCP recommended prophylaxis Primary objectives 52% at risk for VTE 50% received ACCP recommended Px Overall ( N= 68,163 ) 42% at risk for VTE 48% received ACCP recommended Px Medical ( n = 37,356 ) Secondary objectives 64% at risk for VTE 59% received ACCP recommended Px Surgical ( n = 30,827 ) Cohen AT, Tapson VF, Bergmann J-F et al, Lancet 2008; 371:

Patients at risk for VTE by country Mean=52 % N= 68,183 52% at risk for VTE Algeria Australia Bangladesh Brazil Bulgaria Colombia Czech Rep Egypt France Germany Greece Hungary India Ireland Kuwait Mexico Pakistan Poland Portugal Romania Russia Saudi Arabia Slovakia Spain Switzerland Thailand Tunisia Turkey UAE UK USA Venezuela

ACCP recommended prophylaxis by country in patients at risk for VTE Algeria Australia Bangladesh Brazil Bulgaria Colombia Czech Rep Egypt France Germany Greece Hungary India Ireland Kuwait Mexico Pakistan Poland Portugal Romania Russia Saudi Arabia Slovakia Spain Switzerland Thailand Tunisia Turkey UAE UK USA Venezuela 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:

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:

Thromboprophylaxis political momentum NHS Operating Framework inclusion 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