1. DVT Prophylaxis in Medical Patients Rog Kyle, MD MUSC 6/5/12

2. Review risks for developing DVT and bleeding from DVT prophylaxis Review current recommendations for inpatient DVT prophylaxis (AT9) Review different pharmacologic and mechanical methods for DVT prophylaxis Examine recent controversies in DVT prophylaxis

3. Risk for DVT Historical baseline – 0.8% DVT – 0.4% PE – Not used by ACCP 2012 Hospitalization in general associated with 8X VTE risk and 25% of all VTE 50-75% of all in hospital VTE events are on medical services

4. Risk for DVT Important to remember that most RCT’s looking at DVT prophylaxis used asymptomatic DVT detected by venography. – Start as calf DVT – Reduction in asymptomatic parallels reduction in symptomatic DVT – Does not mean that the relative effects of asymptomatic and symptomatic events will be similar (particularly PE) – Bleeding? - there are no published data addressing the relationship between wound or joint bleeding and either wound infection or long-term joint function Net benefit (non-fatal) – PE, DVT, GI bleed, periop bleed) – Prevention ≈ complication – Fatal events are rare

5. Risk for DVT AT9 Critically ill vs. non-critical In non-critical – RAM’s (risk assessment model) suffer from prospective validation, among other problems – ACCP 2012 guidelines utilize the “Padua Prediction Score”

7. Risk for DVT Critically ill vs. non-critical In non-critical – RAM’s (risk assessment model) suffer from prospective validation, among other problems – ACCP 2012 guidelines utilize the “Padua Prediction Score” – High Risk ≥ 4

8. Padua Prediction Score Journal of Thrombosis and Haemostasis 2010; 8: 2450– 2457 Prospective cohort study, 1180 pts. (medical) followed to 90 days after d/c Assessed – Whether pts could be assigned to high or low risk by a RAM – Whether prophylaxis worked (TID heparin, LMWH, fondaparinux) in either group Risk level was blinded to the treating MD Use of prophylaxis left up to the treating MD – Excluded bleeding, plts < 100K, CrCl < 30

9. Padua Prediction Score 40 % high risk, 60% low risk 40% of the high risk received DVT prophylaxis and 7.3% of the low risk Only investigated symptomatic pts for DVT/PE

11. Padua Prediction Score 40 % high risk, 60% low risk 40% of the high risk received DVT prophylaxis and 7.3% of the low risk Only investigated symptomatic pts for DVT/PE Highly significant (P < 0.001, HR 0.13) Of the 4 in the high risk/treated 3 occurred after d/c

12. Bleeding Risk from Prophylaxis ACCP 2012 choose 0.4% major bleeding risk – From the control arms of DVT prophylaxis trials – IMPROVE trial

13. Chest. 2011; 139(1):69-79

14. Bleeding Risk from Prophylaxis ACCP 2012 choose 0.4% major bleeding risk – From the control arms of DVT prophylaxis trials – IMPROVE trial – risk model “too complex” and “not validated”

15. AT9

16. 2.3. For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low molecular- weight heparin [LMWH], low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B).

17. AT9 2.4. For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B).

18. DVT Prophylaxis

19. LDUH vs. LMWH No difference in DVT, PE, overall mortality or HIT (one trial) No cost difference Minimally less major bleeds for LMWH (5/1000)

20. BID vs. TID LDUH The low quality evidence from these indirect comparisons provides no compelling evidence that LDUH TID dosing, compared with BID dosing, reduces VTE or causes more bleeding

21. Chest 2007;131;507-516 “BID heparin dosing causes fewer major bleeding episodes, while TID dosing appears to offer somewhat better efficacy in preventing clinically relevant VTE events”

22. Chest 2011;140;374-381 “Moderate-quality evidence suggests that subcutaneous UFH bid and UFH tid do not differ in effect on DVT, PE, major bleeding, and mortality”

23. GCS vs. IPC’s vs. VFP’s GCS – Conflicting data, thigh high probably better than knee high (CLOTS I, II trials) – Surgical, stroke pts – Most studies screened for asymptomatic DVT IPC/VFP – No studies in hospitalized medical pts – Less DVT (sx’c) but no mortality or PE benefit in surgical pts

24. GCS vs. IPC’s vs. VFP’s …the compelling evidence of a decrease in fatal PE that exists for anticoagulants and for aspirin does not exist for mechanical methods

25. Mechanical Compression vs. Heparin No studies in hospitalized medical pts Surgical pts – no difference in DVT, PE (except subgroup of LMWH vs. compression – less DVT); less bleeding with compression

26. Mechanical Compression + Heparinoids vs. Heparinoids Alone Surgical pts – IPC’s + pharm trended better than pharm alone – GCS + pharm better than pharm alone but more skin complications

27. But… Surgical studies looking at IPC functioning found them working or applied properly in only 20 - 50% of pts.

28. Extended Duration DVT Prophylaxis Approximately 70% of DVT’s in medical pts occur in the out patient setting Over half of these pts had been hospitalized within the past 3 months, and 2/3’s of these within 1 month MEDENOX RTC - N Engl J Med 1999;341: 793-800 – RTC – 40/20 lovenox vs. placebo – 3 mos f/u

31. Extended Duration DVT Prophylaxis Approximately 70% of DVT’s in medical pts occur in the out patient setting Over half of these pts had been hospitalized within the past 3 months, and 2/3’s of these within 1 month MEDENOX RTC - N Engl J Med 1999;341: 793-800 EXCLAIM - Ann Intern Med. 2010;153:8-18 – 40 lovenox for 28 days after initial therapy in hosp

32. EXCLAIM Only RTC of extended DVT prophylaxis (LMWH) in medical pts (in-hospital and 28 days post-d/c) – Reduced overall DVT (sym and asym) Level 1 mobility (bed rest) > 75 y.o. female – No difference fatal PE – No difference in overall mortality and 4 ICB’s (one fatal) in LMWH group (none in placebo) – Overall, 5/1000 fewer sx’c DVT’s, 4/1000 major bleeds AT9 – not recommended

33. ASA Studies in medical pts – 9 trials, 555 pts – all antiplatelet drugs Small number of events (DVT’s) Asymptomatic/symptomatic, proximal/distal US/fibrinogen labeling/venography Up to 8 wks of drug, bleeding events not reported

34. ASA Pooling 9 trials – 35% reduction in asymptomatic DVT – No effect on PE rate – Bleeding not reported

35. ASA PEP Trial - Lancet 2000; 355: 1295–302 – 13,000 + ortho pts (hip fx) – 160 mg ASA vs. placebo (+ “any other thromboprophylaxis thought necessary”) for 35 days – 35 days post hip fracture surg, THA, TKA Less DVT’s – sym and asym Less PE’s – fatal and non-fatal No overall mortality benefit No difference in fatal bleeding (some increase in surg site bleeds)

37. ASA PEP Trial - Lancet 2000; 355: 1295–302 – 13,000 + ortho pts (hip fx) – 160 mg ASA vs. placebo (+ “any other thromboprophylaxis thought necessary”) for 35 days – 35 days post hip fracture surg, THA, TKA Less DVT’s – sym and asym Less PE’s – fatal and non-fatal No overall mortality benefit No difference in fatal bleeding (some increase in surg site bleeds) “…there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism”

38. AT9 “Based on the low quality of available evidence…no recommendation could be made” There have been no studies of antiplatelet therapy compared with antithrombotic therapy (pharm or mech) to prevent VTE in acutely ill medical patients

39. Ann Intern Med. 2011;155:602-615

40. Large meta-analysis Randomized trials including medical patients or strokes Heparin, LMWH, mechanical prophylaxis 40 unique trials; 52,000 pts Medical and stroke pts, no surg/trauma/OB

41. Trials – Heparin vs no heparin (1) – LMWH vs no LMWH (2) – LMWH vs UFH (3) – Mechanical vs no mechanical (4) Outcomes – Death (primary); PE, major bleeding (secondary) (1, 2, 3) – Death (4)

42. Results – no significant effect of prophylaxis on mortality (there was a trend in favor of heparin prophylaxis (P=0.056) – Heparin vs no heparin 3 less PE’s, 9 more bleeds (4 major)/1000 pts – LMWH vs heparin No difference in outcomes – No improved outcomes with mechanical prophylaxis in stroke Conclusion – Reduced PE, no change total mortality, increased bleeding (heparin, LMWH) (stroke and medical pts) – Therefore, no net clinical benefit

43. Raised numerous questions – Which are the preferred outcomes (PE vs bleed) – Use of surrogate outcomes – asymptomatic DVT? Most PE not preceded by symptomatic DVT Asymptomatic PE’s? No studies screen with CT – Editorial comments JC’s recommendation for DVT proph only excludes children and pts hospitalized < 2 days

44. N Engl J Med 2011;365:2463-72

45. LMWH in Medical Patients Double blind, randomized, placebo controlled LMWH vs. placebo, all pts received elastic stockings with graduated compression – China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia 8300+ pts Primary outcome – death at 30 days Secondary outcomes – Death at 0-14 days, 0-90 days rate of cardiopulm death 14, 30, 90 days and sudden death or PE 14, 30, 90 days

47. Results

50. Conclusion – No reduction in the rate of death from any cause among hospitalized, acutely ill medical patients with the addition of lovenox Counterintuitive? – Pharm prophylaxis reduces DVT (including asympt DVT) in acutely ill medical pts by > 45% – Assumed that DVT’s in medical pts are the same as surgical – distal to proximal progression (we know that proximal DVT in medical pts has higher risk of PE than distal

51. References Kahn et al. Prevention of VTE in Nonsurgical Patients : Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141;e195S-e226S Kahn et al. Prevention of VTE in Nonsurgical Patients : Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141;e195S-e226S Barbar et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. Journal of Thrombosis and Haemostasis, 8: 2450–2457 Barbar et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. Journal of Thrombosis and Haemostasis, 8: 2450–2457 Decousus et al. Factors at Admission Associated With Bleeding Risk in Medical Patients. Chest. 2011; 139(1):69-79 King et al. Twice vs Three Times Daily Heparin Dosing for Thromboembolism Prophylaxis in the General Medical Population. Chest 2007;131;507-516 King et al. Twice vs Three Times Daily Heparin Dosing for Thromboembolism Prophylaxis in the General Medical Population. Chest 2007;131;507-516 Phung et al. Dosing Frequency of Unfractionated Heparin Thromboprophylaxis. Chest 2011;140;374-381 Phung et al. Dosing Frequency of Unfractionated Heparin Thromboprophylaxis. Chest 2011;140;374-381 CLOTS Trial Collaboration. Thigh-Length Versus Below-Knee Stockings for Deep Venous Thrombosis Prophylaxis After Stroke. Ann Intern Med. 2010;153:553-562. CLOTS Trial Collaboration. Thigh-Length Versus Below-Knee Stockings for Deep Venous Thrombosis Prophylaxis After Stroke. Ann Intern Med. 2010;153:553-562. Samama et al. A Comparison of Enoxaparin with Placebo for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients. N Engl J Med 1999;341:793-800. Samama et al. A Comparison of Enoxaparin with Placebo for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients. N Engl J Med 1999;341:793-800 Hull et al. Extended-Duration Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients With Recently Reduced Mobility. Ann Intern Med. 2010;153:8-18. Hull et al. Extended-Duration Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients With Recently Reduced Mobility. Ann Intern Med. 2010;153:8-18. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355: 1295–302 Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355: 1295–302 Lederle et al. Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients and Those With Stroke: A Background Review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2011;155:602-615 Lederle et al. Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients and Those With Stroke: A Background Review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2011;155:602-615 Kakkar et al. Low-Molecular-Weight Heparin and Mortality in Acutely Ill Medical Patients. N Engl J Med 2011;365:2463-72. Kakkar et al. Low-Molecular-Weight Heparin and Mortality in Acutely Ill Medical Patients. N Engl J Med 2011;365:2463-72.