DVT Prophylaxis in Medical Patients

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 symptomaticpts 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. AT9 • 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. Chest2011;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 + orthopts (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 + orthopts (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 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