1. Researching Venous Thromboembolism in vulnerable adult populations Professor DA Fitzmaurice Department of Primary Care & General Practice University of Birmingham

2. 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

3. 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

4. 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

5. 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)

6. 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.

7. VTE prevention in SURGICAL patients

8. 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%) 109 7 191 (3.0%) 6 210 223 PE Fatal bleeds ‘Other’ deaths 0 50 100 150 200 250 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

9. VTE prevention in MEDICAL patients

10. Anticoagulant prophylaxis to prevent symptomatic VTE in hospitalized medical patients RR[CI]Absolute risk reduction (%) NNT B Any PE0.430.26 – 0.710.29345 Fatal PE0.380.21 – 0.690.25400 Symptomatic DVT0.470.22 – 1.00 Major bleeding1.320.73 – 2.37 All cause mortality0.970.79 – 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

11. VTE prevention in PRACTICE

14. ALIVE

15. DEAD

16. 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

17. Overview The problem Risk factors Prophylaxis in medical patients Therapeutic options New studies

19. Public / Media perception - travel

20. Travelling in cramped conditions

21. Other media perceptions: Game- related / Office Workers?

23. VTE Hospital Trends

24. 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 Fatal PE (%) Surgical patients 1,2 19662000 18% reduction in fatal PE Medical patients 1,2 Fatal PE (%) 19662000 Autopsy-detected Fatal PE in Surgical and Medical patients (21,515): 1966–2000

25. 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;21:159-65 Cohen et al. Haemostasis 1996;26:65-71 Autopsy Proven Fatal PE % in Medical Patients

26. 60% of admissions 75% of PE deaths Medical Inpatients 10% of consensus statements Cohen et al. Haemostasis 1996;26:65-71

27. Epidemiology of VTE Mortality

28. 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

29. Clinical Suspicion of PE AuthorMajor PE (n) Autopsy (n) Death (n) Suspected PE Goldhaber 1973–1977 541,4552,37230% Rubinstein 1980–1984 441,2763,51732% Morgenthaler 1985–1989 922,4275,35832% Pineda 1991–1996 67 7786,02345% Pineda LA et al. Chest 2001;120:791–5

30. Overview The problem Risk factors Prophylaxis in medical patients New studies

32. 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;162:1245-8 59 % Medical

33. Overview The problem Risk factors Prophylaxis in medical patients New studies Therapeutic options

34. 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

35. No trials of mechanical compression in general medical patients PassiveActive

36. 1980’s LMWH

37. MEDENOX 1 63%Placebo Enoxaparin PREVENT 2 49%Placebo Dalteparin ARTEMIS 3 47%Placebo Fondaparinux 14.9 * 5.5 StudyRRRThromboprophylaxisPatients with VTE (%) 5.0 * 2.8 10.5 † 5.6 * VTE at day 14; † VTE at day 15. 1 Samama MM, Cohen AT et al. N Engl J Med. 1999;341:793-800. 2 Leizorovicz A, Cohen AT et al. Circulation. 2004;110:874-9. 3 Cohen AT, Davidson B et al. BMJ 2006. p < 0.001 p = 0.0015 p = 0.029 RRR = relative risk reduction Medical thromboprophylaxis – consistent response

38. Major bleeding MEDENOX 1. 1% 1.7% PREVENT 0.2% 0.5% ARTEMIS 0.2% 0.2%

39. Overview The problem Risk factors Prophylaxis in medical patients New studies – based on ACCP recommendations

41. 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

42. New Studies VITAE – Epidemiology PREVAIL Study – Stroke ENDORSE study – Survey EXCLAIM study – Medical

43. The Burden – VITAE Study

44. 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 2004-2005. 2. Cohen AT,.VITAE, Thrombosis and Haemostasis 2007 3. Cancer Research UK Mortality Cancer Stats 2005. Available at www.cancerresearchuk.org 4. Department of Transport, Road Casualties Great Britain, Main results 2006. Available at www.dft.gov.uk 5. National Office of Statistics (NAO). HIV and AIDS. Available at www.statistics.gov.uk

45. 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 2007 2. National Office of Statistics (NAO). MRSA. Deaths Available at www.statistics.gov.uk

46. 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 **

48. 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

49. 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

50. 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)

51. 32 countries -- 358 hospital First pt in August 2006 - Last pt in January 2007 Median of 8 days to enroll patients/hospital

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

53. 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; 371:387-394

54. 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

55. 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

56. 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

57. 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

58. 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

59. Government documents on VTE prevention March 2005 July 2005 April 2007 April 2007

60. The role of Primary Care Ensuring implementation of extended thromboprophylaxis Education of patients Risk Assessment? Commissioning of services?

61. Research? Residential homes Nursing homes Hospices Acutely unwell in own home

62. Issues Perception of importance “A good way to go” Measuring incidence/prevalence Use of chemical agents in the community

63. 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.

64. 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

65. 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

66. 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

67. Co-operation and balance are the keys to success