1. Optimal Strategies for DVT Prophylaxis: Translating Evidence into Practice Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School Samuel Z. Goldhaber, MD Cardiovascular Division Brigham and Women’s Hospital Professor of Medicine Harvard Medical School DVT-WRAP SlideCAST

2. The Challenge DVT/ PE are rampant but often preventable. ► Hospitalized patients are at risk, but prophylactic measures are often omitted. ► Behavior Modification and Quality Improvement strategies: - Electronic, Human alerts - 3-screen alert with default prophylaxis - Continuum of Care (ensure prophylaxis from admission to discharge, to SNF, and at home) DVT/ PE are rampant but often preventable. ► Hospitalized patients are at risk, but prophylactic measures are often omitted. ► Behavior Modification and Quality Improvement strategies: - Electronic, Human alerts - 3-screen alert with default prophylaxis - Continuum of Care (ensure prophylaxis from admission to discharge, to SNF, and at home)

5. Lung with PE

6. PE SXS/ Signs (PIOPED II) ► Dyspnea (79%) ► Tachypnea (57%) ► Pleuritic pain (47%) ► Leg edema, erythema, tenderness, palpable cord (47%) ► Cough/ hemoptysis (43%) ► Dyspnea (79%) ► Tachypnea (57%) ► Pleuritic pain (47%) ► Leg edema, erythema, tenderness, palpable cord (47%) ► Cough/ hemoptysis (43%) Stein PD. Am J Med 2007; 120: 871-879

7. Incidence 900,000 PEs/ DVTs in USA in 2002. Estimated 296,000 PE deaths: 7% treated, 34% sudden and fatal, and 59% undetected. Heit J. ASH Abstract 2005 ----------------------------------------- 762,000 PEs/ DVTs in EU in 2004. Thromb Haemostas 2007; 98: 756

8. ►The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed PE causing “sudden cardiac death” emphasize the need for improved preventive efforts. ►Failure to institute prophylaxis is a much bigger problem with Medical Service patients than Surgical Service patients. ►The high death rate from PE (exceeding acute MI!) and the high frequency of undiagnosed PE causing “sudden cardiac death” emphasize the need for improved preventive efforts. ►Failure to institute prophylaxis is a much bigger problem with Medical Service patients than Surgical Service patients.

9. Annual # At-Risk for VTE: US Hospitals ► 7.7 million Medical Service inpatients ► 3.4 million Surgical Service inpatients ► Based upon ACCP guidelines for VTE prophylaxis Anderson FA Jr, et al. Am J Hematol 2007; 82: 777-782 ► 7.7 million Medical Service inpatients ► 3.4 million Surgical Service inpatients ► Based upon ACCP guidelines for VTE prophylaxis Anderson FA Jr, et al. Am J Hematol 2007; 82: 777-782

10. Malignant Gliomas (N=9,489) and VTE ► California Cancer Registry ► 2-year VTE Incidence: 7.5% ► 16 VTE events per 100 person-years during 1 st 6 months ► Risk factors: older age, neurosurgery ► VTE: 30% increased risk of death ► California Cancer Registry ► 2-year VTE Incidence: 7.5% ► 16 VTE events per 100 person-years during 1 st 6 months ► Risk factors: older age, neurosurgery ► VTE: 30% increased risk of death J Neurosurg 2007; 106: 601-608

11. Outpatient and Inpatient VTE are Linked ► 74% of VTEs present in outpatients. ► 42% of outpatient VTE patients have had recent surgery or hospitalization. ► Only 40% had received VTE prophylaxis. ► 74% of VTEs present in outpatients. ► 42% of outpatient VTE patients have had recent surgery or hospitalization. ► Only 40% had received VTE prophylaxis. Spencer FA, et al. Arch Intern Med 2007; 167: 1471-1475

12. ICOPER Cumulative Mortality Mortality (%) Days From Diagnosis 17.5% 0 5 10 15 20 25 714306090 Lancet 1999; 353: 1386-1389

14. Progression of Chronic Venous Insufficiency From UpToDate 2006

15. Risk Factors Linking Venous and Arterial TE: Biologically Plausible 1.Activation of platelets and coagulation proteins 2.Increased fibrin turnover 3.Inflammation 4.Lipid profiles 1.Activation of platelets and coagulation proteins 2.Increased fibrin turnover 3.Inflammation 4.Lipid profiles

16. Dabish 20-Year Cohort: VTE, Subsequent CV Events ► Assessed risk of MI, Stroke ► 25,199 with DVT ► 16,925 with PE ► 163,566 population controls ► Assessed risk of MI, Stroke ► 25,199 with DVT ► 16,925 with PE ► 163,566 population controls Sorensen HT. Lancet 2007; 370: 1773-1779

17. RR CV Event in PE Patients CV Event 1 Year RR 2-20 Year RR Acute MI 2.61.3 Stroke2.91.3 Sorensen HT. Lancet 2007; 370: 1773-1779

18. Cardiovascular Risk Factors and VTE (N=63,552 meta-analysis) RFRR Obesity2.3 Hypertension1.5 Diabetes1.4 Cigarettes1.2 High Cholesterol1.2 RFRR Obesity2.3 Hypertension1.5 Diabetes1.4 Cigarettes1.2 High Cholesterol1.2 Ageno W. Circulation 2008; 117: 93-102

19. Risk Factors Meta-Analysis Implications 1.RFs for atherothrombosis are also associated with VTE 2.Cardiovascular RFs may be involved in pathogenesis of VTE 3.Atherosclerosis and VTE are not completely distinct entities. 1.RFs for atherothrombosis are also associated with VTE 2.Cardiovascular RFs may be involved in pathogenesis of VTE 3.Atherosclerosis and VTE are not completely distinct entities. Ageno W. Circulation 2008; 117: 93-102

21. Obesity and VTE: NHDS AGE RR (PE) RR (DVT) < 40 y 5.25.2 All Ages 2.22.5 Stein PD. Am J Med 2005; 118: 978-980

23. Steffen LM. Circulation 2007;115:188-195 Eat Veggies and Lower VTE Risk; Careful with Red Meat Adjusted Hazard Ratios (Quintiles) 2345p Fruits, veggie 0.730.570.47 0.59 0.03 Fish 0.580.600.55 0.70 0.30 Red Meat 1.241.211.09 2.01 0.02

24. Reversible Risk Factors 1.Nutrition: eat fruits, veggies, fish; less red meat 2.Quit cigarettes 3.Lose weight/ exercise 4.Prevent DM/ metabolic syndrome 5.Control hypertension 6.Lower cholesterol 1.Nutrition: eat fruits, veggies, fish; less red meat 2.Quit cigarettes 3.Lose weight/ exercise 4.Prevent DM/ metabolic syndrome 5.Control hypertension 6.Lower cholesterol

25. VTE Prophylaxis in 19,958 Medical Patients/ 9 Studies (Meta-Analysis) ► 62% reduction in fatal PE ► 57% reduction in fatal or nonfatal PE ► 53% reduction in DVT ► 62% reduction in fatal PE ► 57% reduction in fatal or nonfatal PE ► 53% reduction in DVT Dentali F, et al. Ann Intern Med 2007; 146: 278-288

26. Intermittent Pneumatic Compression Meta-Analysis in Postop Patients ► 2,270 patients in 15 randomized trials ► IPC devices reduced DVT risk by 60% (Relative Risk 0.40, 95% CI 0.29-0.56, p< 0.001) ► 2,270 patients in 15 randomized trials ► IPC devices reduced DVT risk by 60% (Relative Risk 0.40, 95% CI 0.29-0.56, p< 0.001) Urbankova J. Thromb Haemost 2005; 94: 1181-5

27. The Amin Report: Prophylaxis Rates in the US ► Studied 196,104 Medical Service discharges from 227 hospitals (Premier® database). ► VTE prophylaxis rate was 62%. ► ACCP-deemed appropriate prophylaxis rate was 34%. ► Studied 196,104 Medical Service discharges from 227 hospitals (Premier® database). ► VTE prophylaxis rate was 62%. ► ACCP-deemed appropriate prophylaxis rate was 34%. J Thromb Haemostas 2007; 5: 1610-6

28. Medical Patient Prophylaxis in Canada ► Studied 1,894 Medical Service discharges from 29 hospitals. ► VTE prophylaxis was indicated in 90% of patients. ► ACCP-deemed appropriate prophylaxis rate was 16%. ► Studied 1,894 Medical Service discharges from 29 hospitals. ► VTE prophylaxis was indicated in 90% of patients. ► ACCP-deemed appropriate prophylaxis rate was 16%. Thrombosis Research 2007; 119: 145-155

29. ENDORSE : WORLDWIDE (Lancet 2008; 371: 387-394) 68,183 patients; 32 countries; 358 sites First patient enrolled August 2, 2006;Last patient enrolled January 4, 2007

30. 42% at Risk for VTE Medical 40% receive ACCP Rec. Px 64% at Risk for VTE 59% receive ACCP Rec. Px Surgical Worldwide Prophylaxis Status for 68,183 Patients 52% at Risk for VTE (50% receive ACCP recommended prophy)

31. We have initiated trials to change MD behavior and improve implementation of VTE prophylaxis—not trials of specific types of prophylaxis—eAlert RCT, eAlert cohort, human Alert, 3-screen eAlert.

32. Quality Improvement Initiative to Improve Clinical Practice Randomized controlled trial to issue or withhold electronic alerts to MDs whose high-risk patients were not receiving DVT prophylaxis. Kucher N, et al. NEJM 2005;352:969-977

33. Definition of “High Risk” VTE risk score ≥ 4 points: ► Cancer3(ICD codes) ► Prior VTE3(ICD codes) ► Hypercoagulability3(Leiden, ACLA) ► Major surgery2(> 60 minutes) ► Bed rest1(“bed rest” order) ► Advanced age1(> 70 years) ► Obesity1(BMI > 29 kg/m 2 ) ► HRT/OC1(order entry) VTE risk score ≥ 4 points: ► Cancer3(ICD codes) ► Prior VTE3(ICD codes) ► Hypercoagulability3(Leiden, ACLA) ► Major surgery2(> 60 minutes) ► Bed rest1(“bed rest” order) ► Advanced age1(> 70 years) ► Obesity1(BMI > 29 kg/m 2 ) ► HRT/OC1(order entry)

34. Randomization VTE risk score > 4 No prophylaxis N = 2,506 INTERVENTION: Single alert N = 1,255 CONTROL No computer alert N = 1,251 Kucher N, et al. NEJM 2005;352:969-977

36. DVT Alert Screen

37. Rule Logic – Alert Details

38. Option A

40. Option B

42. Option C or “Done”

43. 90-Day Primary Endpoint Intervent. Control Hazard Ratio p Intervent. Control Hazard Ratio p N=1255 N=1251 (95% CI) N=1255 N=1251 (95% CI) Total VTE 61 (4.9) 103 (8.2) 0.59 (0.43-0.81) 0.001 Total VTE 61 (4.9) 103 (8.2) 0.59 (0.43-0.81) 0.001 Acute PE 14 (1.1) 35 (2.8) 0.40 (0.21-0.74) 0.004 Acute PE 14 (1.1) 35 (2.8) 0.40 (0.21-0.74) 0.004 Proximal DVT 10 (0.8) 23 (1.8) 0.47 (0.20-1.09) 0.08 Proximal DVT 10 (0.8) 23 (1.8) 0.47 (0.20-1.09) 0.08 Distal DVT 5 (0.4) 12 (1.0) 0.42 (0.15-1.18) 0.10 Distal DVT 5 (0.4) 12 (1.0) 0.42 (0.15-1.18) 0.10 UE DVT 32 (2.5) 33 (2.6) 0.97 (0.60-1.58) 0.90 UE DVT 32 (2.5) 33 (2.6) 0.97 (0.60-1.58) 0.90 Intervent. Control Hazard Ratio p Intervent. Control Hazard Ratio p N=1255 N=1251 (95% CI) N=1255 N=1251 (95% CI) Total VTE 61 (4.9) 103 (8.2) 0.59 (0.43-0.81) 0.001 Total VTE 61 (4.9) 103 (8.2) 0.59 (0.43-0.81) 0.001 Acute PE 14 (1.1) 35 (2.8) 0.40 (0.21-0.74) 0.004 Acute PE 14 (1.1) 35 (2.8) 0.40 (0.21-0.74) 0.004 Proximal DVT 10 (0.8) 23 (1.8) 0.47 (0.20-1.09) 0.08 Proximal DVT 10 (0.8) 23 (1.8) 0.47 (0.20-1.09) 0.08 Distal DVT 5 (0.4) 12 (1.0) 0.42 (0.15-1.18) 0.10 Distal DVT 5 (0.4) 12 (1.0) 0.42 (0.15-1.18) 0.10 UE DVT 32 (2.5) 33 (2.6) 0.97 (0.60-1.58) 0.90 UE DVT 32 (2.5) 33 (2.6) 0.97 (0.60-1.58) 0.90 Kucher N, et al. NEJM 2005;352:969-977

44. Primary End Point Intervention Control Number at risk 1255977900853 1251976893839 Intervention Control Time (days) 0306090 %Freedom from DVT/ PE 90 92 94 96 98 100 Kucher N, et al. NEJM 2005;352:969-977

45. Purpose: ► To evaluate use of the VTE risk score and eAlert system in “real world” setting ► To validate the efficacy of continued use of the eAlert after discontinuing randomization ► To determine whether VTE prophylaxis prescribing changed following NEJM publication Purpose: ► To evaluate use of the VTE risk score and eAlert system in “real world” setting ► To validate the efficacy of continued use of the eAlert after discontinuing randomization ► To determine whether VTE prophylaxis prescribing changed following NEJM publication J Thromb Thrombolysis 2008;25: 146-50 Electronic Alert Cohort

46. ► We identified 866 consecutive patients between January 2004 and July 2006 following completion of original study ► All patients met same inclusion/ exclusion NEJM eAlert criteria ► “Rules” for generating alerts remained identical to original VTE eAlert study ► We identified 866 consecutive patients between January 2004 and July 2006 following completion of original study ► All patients met same inclusion/ exclusion NEJM eAlert criteria ► “Rules” for generating alerts remained identical to original VTE eAlert study Baroletti S et al. J Thrombosis Thrombolysis 2008; 25: 146-50)

47. Cohort Study: Results P <0.001

48. Baroletti S et al. J Thrombosis Thrombolysis 2008; 25: 146-50 Prophylactic Measure in response to alert Cohort Alert Historical Alert p value Total 326 (37.7%)421 (33.6%) 0.052 Pharmacological234 (27.1%)296 (23.6%)0.73 UFH77 (8.9%)213 (17%)<0.001 LMWH108 (12.5%)55 (4.4%)<0.001 Warfarin49 (5.7%)28 (2.2%)<0.001 Mechanical 92 (10.6%)125 (10%)0.62 Stockings33 (3.8%)52 (4.1%)0.52 Pneumatic boots59 (6.8%)73 (5.8%)0.61 Cohort Study: Results

49. Cohort Summary (N=866) ► 18% high risk patients were not prophylaxed in the NEJM eAlert RCT ► After “turning off” randomization, 9% high risk patients were not prophylaxed in the cohort study ► 82% were Medical Service patients ► Symptomatic VTE at 90 days occurred in 5.1% ► 18% high risk patients were not prophylaxed in the NEJM eAlert RCT ► After “turning off” randomization, 9% high risk patients were not prophylaxed in the cohort study ► 82% were Medical Service patients ► Symptomatic VTE at 90 days occurred in 5.1% (Baroletti S et al. J Thrombosis Thrombolysis 2008; 25: 146-50)

50. VTE Prophylaxis: hALERT 1.We initiated a multicentered RCT of human alerts (hALERT) (N=2,500) 2.Objective: to recruit hospitals that differ from BWH re: IT, community vs. academic, urban vs. suburban/rural, location within USA. 3.Can a human alert be more effective than an electronic alert? 1.We initiated a multicentered RCT of human alerts (hALERT) (N=2,500) 2.Objective: to recruit hospitals that differ from BWH re: IT, community vs. academic, urban vs. suburban/rural, location within USA. 3.Can a human alert be more effective than an electronic alert?

51. 3-Screen eALERT ►Delves into MD reasoning for withholding VTE prophylaxis. ►Defaults to graduated compression stockings as an “opt out” measure ►Delves into MD reasoning for withholding VTE prophylaxis. ►Defaults to graduated compression stockings as an “opt out” measure

54. Default Options to Improve Healthcare ► Flu, pneumonia vaccines. ► Remove urinary catheters within 72h. ► Head of bed at 30-45  angle in ICU. ► Interrupt sedatives daily: vented pts. ► Prophylax against VTE. ► Flu, pneumonia vaccines. ► Remove urinary catheters within 72h. ► Head of bed at 30-45  angle in ICU. ► Interrupt sedatives daily: vented pts. ► Prophylax against VTE. Halpern SD et al. NEJM 2007; 357: 1340

55. Key Points 1.“Lump,” don’t “split”, venous and arterial TE risk factors. They are not separate silos. The risk factors and etiologic pathways are shared, similar. 2.VTE and Atherosclerosis [MI/ Stroke/ PVD] are linked: a) Worldwide problems b) VTE may herald arterial event 3.Lifestyle/ reversible risk factors provide foundation for prevention. 1.“Lump,” don’t “split”, venous and arterial TE risk factors. They are not separate silos. The risk factors and etiologic pathways are shared, similar. 2.VTE and Atherosclerosis [MI/ Stroke/ PVD] are linked: a) Worldwide problems b) VTE may herald arterial event 3.Lifestyle/ reversible risk factors provide foundation for prevention.

56. Summary 1.VTE causes CVI, pulmonary hypertension, disability, and death. 2.Prophylaxis is safe and effective. 3.Prophylaxis is underutilized. 4.Behavior modification strategies: a) electronic/ human alerts b) focus on discharge/ continuum of care, as well as admission 1.VTE causes CVI, pulmonary hypertension, disability, and death. 2.Prophylaxis is safe and effective. 3.Prophylaxis is underutilized. 4.Behavior modification strategies: a) electronic/ human alerts b) focus on discharge/ continuum of care, as well as admission