1. DVT Prophylaxis in Orthopedic Patients Rogers Kyle, MD Medical University of South Carolina 11/27/12

2. Objectives Review the newest ACCP recommendations on DVT prophylaxis in orthopedic patients. Recognize the limitations of historical studies attempting to address the risk/benefit of DVT prophylaxis in orthopedic patients. Multiple therapeutic modalities are avilable and now include aspirin. Examine the potential role for new anticoagulants for DVT prophylaxis in orthopedic patients.

3. Key Messages The new ACCP guidelines for prevention of VTE in orthopedic surgery patients were published in 2012 and contain many new options ASA is now included as one of the acceptable pharmacologic agents for initial prophylaxis (1B) as are SCD’s (1C) LMWH is still the preferred alternative (2C/2B) SCD’s should be used in combination with all pharmacologic therapies (2C) Prophylaxis should be extended to 35 days (2B) With increased bleeding risk used SCD’s or no prophylaxis (2C) If patient refuses injection use apixaban or dabigatran

4. Key Messages

7. ACCP 9 (2012) Symptomatic DVT/PE vs. increased major bleeding – “the trade-off” – Patient Values and Preferences

8. Historical Points Trials before 2000 used asymptomatic DVT on screening as primary end point. No general agreement on “bleeding” – ‘major and minor’ in older studies – ‘clinically relevant non-major’ in recent studies – NOT included in current update

9. Major Bleeding Definitions – any fatal bleeding – bleeding into a critical organ (eg, retroperitoneal, intracranial, intraocular, or intraspinal) – clinically overt (eg, GI) bleeding associated with a 2 g/dL drop in hemoglobin level or requiring 2 units of blood transfused – bleeding leading to reoperation

10. Bleeding Risk

11. Baseline Risk of DVT/PE Changes over time – LOS for HFS in 60’s – 35 days. Now 3.2 days. – Pre-1980 – 15 to 30% without prophylaxis – Many changes in the interim Surgical technique Early ambulation Earlier discharge – Post prophylaxis dropped to 1-2% by 2001

12. Baseline Risk of DVT/PE A Randomized Controlled Trial of a Low- Molecular-Weight Heparin (Enoxaparin) to Prevent Deep-Vein Thrombosis in Patients Undergoing Elective Hip Surgery (NEJM 1986) – LMWH vs. placebo – 100 pts., elective THA – Venography (impedance pleth/fibrinogen) in 76 – 10.8% in LMWH vs. 51.3% in placebo – asymptomatic

13. Baseline Risk of DVT/PE Since 2003 rate of symptomatic DVT/PE on LMWH prophylaxis is 1.15% (0.8% DVT, 0.35% for PE) Symptomatic VTE rate off prophylaxis – 1.8% DVT, 1% PE. Assume that the risk reduction for DVT and PE on LMWH for symptomatic and asymptomatic – 50-60% DVT, 2/3’s PE Cumulative – 7, 14, 35 days – Includes TKA, THA, HFS

14. Baseline Risk of DVT/PE

16. Baseline Risk of Bleeding ‘difficult to estimate’ – Better op techniques Mostly from placebo (or GCS) arm of LMWH trials and the PEP trial

17. PEP Trial Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial (Lancet 2000) – Not in US – 17,000+ pts – THA or HFS 160 mg ASA + “any other thromboprophylaxis thought necessary vs. placebo – reductions in pulmonary embolism of 43% (95% CI 18–60; p=0·002) and in symptomatic deep-vein thrombosis of 29% (3–48; p=0·03) - including patients receiving subcutaneous heparin

18. Baseline Risk of Bleeding ‘difficult to estimate’ – Better op techniques Mostly from placebo (or GCS) arm of LMWH trials and the PEP trial Median rate – 1.5% Can we estimate the bleeding risk pre-op?

19. Baseline Risk of Bleeding ‘difficult to estimate’ – Better op techniques Mostly from placebo (or GCS) arm of LMWH trials and the PEP trial Median rate – 1.5% Can we estimate the bleeding risk pre-op? – “did not find any bleeding risk assessments that have been sufficiently validated in the orthopedic surgery population”

20. Recommendations THA, TKA, HFS – 10-14 days Low molecular weight heparin (LMWH) Fondaparinux Apixaban Dabigatran Rivaroxaban Low dose heparin (LDUH) Adjusted dose coumadin ASA (“One panel member believed strongly that aspirin alone should not be included as an option”) Intermittent pneumatic compression devices (IPCD)

21. Lovenox THA – 30 mg SQ Q12H starting 12-24 hrs post-op OR – 40 mg SQ QD starting 12 ± 3 hrs post-op – 7-14 days; up to 35 days (40 mg QD) TKA – 30 mg SQ BID – 7-14 days

22. Lovenox Benefit 13 fewer VTE/1000 with 7-14 days No increased major bleeding Symptomatic DVT reduced by ½ with extended treatment (9 fewer VTE/1000) No mortality benefit

23. Fondaparinux Fondaparinux vs. enoxaparin; THA (Lancet 2002) – 10 days 2.5 mg fondaparinux vs. 30 mg BID enoxaparin – Non-inferior Fondaparinux 6-8 days followed by placebo vs. fondaparinux for total 19-23 days; HFS (Arch Int Med 2003) – 12 fewer VTE/1000 – 12 more major bleeds/1000

24. Coumadin Few trials (8 RCT’s/700 pts); few events – 55% reduction DVT; 80% reduction PE INR 2-3 Begin post-op day of surgery – 18 fewer VTE/1000 – 7 more major bleeds/1000

25. Low Dose Unfractionated Heparin 5,000 Units SQ BID vs. TID – Chest 2011 – no difference in medical pts (vs. Chest 2007) – AHRQ Guidelines – “Not recommended” 13 fewer VTE/1000 4 more major bleeds/1000

26. ASA Pulmonary Embolism Prevention (PEP) trial – 160 mg, 35 days – HFS (13,000+ pts), THA (4,000+ pts) 7 fewer VTE/1000 3 more major bleeds/1000 2 more non-fatal MI’s

27. Intermittent Pneumatic Compression Devices (IPCD) Not GCS (CLOTS trial Lancet 2009) Number of IPCD studies, one venous foot pump study (TKA; 60 pts, less extensive clot; 1992) – 16 fewer VTE/1000 – Compliance is problematic; newer battery powered might be better

28. Apixaban Approved in Europe, Canada ADVANCE 1, 2, and 3 trials – ADVANCE 1 (NEJM 2009) TKA 2.5 mg BID apixaban vs. 30 mg BID enoxaparin x 10-14 days Symptomatic and asymptomatic DVT, PE, death – ‘Total venous thromboembolism and all-cause mortality’ No difference but did not meet prespecified criteria for non-inferiority; less ‘clinically relevant’ bleeding but not major

29. Apixaban – ADVANCE 2 (Lancet 2010) TKA 2.5 mg BID apixaban vs. 40 mg QD enoxaparin x 10-14 days Also a non-inferiority trial but demonstrated superiority in preventing DVT (mostly asymptomatic); not PE, mortality Same bleeding ?? difference in enoxaparin (30 mg BID vs. 40 md QD)

31. Apixaban – ADVANCE 3 (NEJM 2010) THA Apixaban 2.5 mg BID vs. enoxaparin 40 mg QD x 35 days Also a non-inferiority trial but demonstrated superiority in preventing DVT (mostly asymptomatic); not PE, mortality Same bleeding

32. Dabigatran In Europe and Canada RENOVATE (Lancet 2007) – THA – Dabigatran 220 mg or 150 mg QD vs. enoxaparin 40 mg QD – 30 days – ‘Total venous thromboembolism and all-cause mortality’ – Non-inferior

33. Dabigatran RE-NOVATE II (Thrombosis Haemostasis 2010) – THA – Dabigatran 220 mg QD vs. enoxaparin 40 mg QD – 28-35 days – Primary endpoint - DVT (sym and asym)/PE, mortality – ‘Total venous thromboembolism and all-cause mortality’ – Non-inferiority Non-inferior for primary endpoint (mostly asym) Superior for major VTE/VTE related death but only because of asym proximal DVT

35. Rivaroxaban FDA approved for DVT prophylaxis in THA, TKA RECORD 1 (NEJM 2008), and 2 (THA); 3 and 4 (TKA) – 10 mg rivaroxaban QD vs 40 mg enoxaparin QD – extended prophylaxis - 35 days – THA – Primary endpoint - any DVT, nonfatal pulmonary embolism, or death from any cause. – Non-inferiority/superiority – Rivaroxaban superior efficacy; similar bleeding risk

36. Rivaroxaban

38. LMWH vs. LDUH ACCP9 – – 20% relative risk reduction of primarily asymptomatic DVT in favor of LMWH (RR, 0.80; 95% CI, 0.73-0.88), with similar effects seen in the subgroups of THA, TKA, and HFS – LMWH may reduce symptomatic VTE from 16 per 1,000 with LDUH to 13 per 1,000 without an increase in major bleeding – Q8H vs Q12H LDUH?

39. LMWH vs. Coumadin – initial vs. extended prophylaxis ACCP9 – Initial - LMWH → less asymptomatic DVT, no diff PE; increased bleeding (initial prophylaxis) – Extended – Coumadin → less PE, same DVT, more more bleeds

40. LMWH vs. ASA - initial vs. extended prophylaxis ACCP 9 – 2 small trials (one is an abstract). One trial was SCD’s + LMWH vs. SCD’s + ASA – Initial and extended – ASA more asymptomatic DVT, few PE’s, no bleeding difference ‘evidence from a head-to head comparison of LMWH compared with aspirin is sparse and of low quality’

41. LMWH vs. Fondaparinux - initial vs. extended prophylaxis ACCP 9 – pooled results failed to demonstrate or exclude a beneficial or detrimental effect of fondaparinux on symptomatic DVT and PE despite a substantial reduction in asymptomatic DVT – may increase major bleeding events by nine per 1,000 (fondaparinux)

42. LMWH vs. Rivaroxaban - initial vs. extended prophylaxis ACCP 9 – Rivaroxaban reduced symptomatic DVT by > 50% – There may be more bleeds – Therefore – LMWH more appealing than rivaroxaban for initial prophylaxis; extended unknown

43. LMWH vs. Dabigatran - initial vs. extended prophylaxis ACCP 9 – Dabigatran similar to enoxaparin (note – many of the studies used a 150 mg dose of dabigatran)

44. LMWH vs Apixaban - initial vs. extended prophylaxis ACCP 9 – Apixaban reduced symptomatic DVT 60% vs. LMWH (very small numbers) – No major differences in bleeding – Still favor LMWH (longer experience)

45. IPCD + ASA vs LMWH ACCP 9 There are 2 articles that are interesting and make the choice of prophylaxis in THA/TKA difficult These articles are both reviewed in ACCP 9. They are considered ‘low-quality evidence’ with ‘significant methodologic limitations’ However, these studies either demonstrated a similar or reduced rate of DVT/PE along with a reduced risk of bleeding (remember definition of bleeding)

46. IPCD + ASA vs LMWH Deep Vein Thrombosis Prevention in Joint Arthroplasties (Journal of Arthroplasty 2006) – 136 patients (no fractures) – SCD’s (mobile) + 100 mg ASA vs. enoxaparin 40 mg – Venograms 5-8 days and clinical evaluation at 30 days – Primary – DVT; secondary – bleeding – Results DVT 28.3% LMWH, 6.6% SCD’s/ASA; more prox DVT and contralateral DVT in LMWH Very few bleeds in either group (no difference) Cost - $2600+/pt less with SCD/ASA – Total savings/1000 pts - $2,628,557

47. IPCD + ASA vs LMWH Thrombosis Prevention After Total Hip Arthroplasty (J Bone Joint Surg 2010) – 400+ pts – SCD’s (mobile) +/- ASA 81 mg vs enoxaparin 30 mg BID → 40 mg QD at discharge – U/S – Primary – bleeding; secondary – DVT/PE – Results Less bleeding (esp major) 0% vs 6% No difference in DVT/PE

49. Summary TKA, THA, HFS – LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH, adjusted-dose VKA, aspirin or an IPCD - all are recommended vs no prophylaxis – LMWH recommended over all alternatives – LMWH 12 hr before or after surgery (not 4 hrs post op) – Extended duration up to 35 days recommended – Dual prophylaxis recommended – IPCD + ‘antithrombotic agent’

50. Summary If not LMWH (HIT) – Apixaban, dabigatran, rivaroxaban, VKA, fondaparinux, IPCD, IPCD + ASA More bleeding with fondaparinux, rivaroxaban, VKA Compliance – mechanicals, VKA, injection as outpt Apixaban 2.5 mg BID, Dabigatran 220 mg QD

51. Summary Increased bleeding risk – TKA, THA, HFS – IPCD or no prophylaxis – Remember that ACCP 9 defines bleeding risk as “major”. Surgeons do not.

52. Summary Increased bleeding risk – TKA, THA, HFS – IPCD or no prophylaxis – If the risk factor is an antiplatelet agent consider pharmacologic prophylaxis – Don’t use IVC filter as primary prevention – Don’t use IVC filter even if increased bleeding risk/contraindication to pharmacologic and mechanical prophylaxis

53. References 1.Falck-Ytter et al. Prevention of VTE in Orthopedic Surgery Patients : Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141;e278S-e325SFalck-Ytter et al. Prevention of VTE in Orthopedic Surgery Patients : Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141;e278S-e325S 2. Colwell et al. Thrombosis Prevention After Total Hip Arthroplasty. J Bone Joint Surg Am. 2010;92:527-35Colwell et al. Thrombosis Prevention After Total Hip Arthroplasty. J Bone Joint Surg Am. 2010;92:527-35 3.Lassen et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807–15Lassen et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807–15 4.Eriksson et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). Thromb Haemost 2011; 105: 721–729Eriksson et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). Thromb Haemost 2011; 105: 721–729 5.Eriksson et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty. N Engl J Med 2008;358:2765-75Eriksson et al. Rivaroxaban versus Enoxaparin for Thromboprophylaxis after Hip Arthroplasty. N Engl J Med 2008;358:2765-75 6.PREPIC Study Group. Eight-Year Follow-Up of Patients With Permanent Vena Cava Filters in the Prevention of Pulmonary Embolism. Circulation. 2005;112:416-422PREPIC Study Group. Eight-Year Follow-Up of Patients With Permanent Vena Cava Filters in the Prevention of Pulmonary Embolism. Circulation. 2005;112:416-422 7.Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trialPulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial 8.Turpie et al. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip replacement surgery: a randomised double- blind trial. Lancet 2002; 359: 1721–26Turpie et al. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip replacement surgery: a randomised double- blind trial. Lancet 2002; 359: 1721–26