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DVT Prophylaxis in Orthopedic Patients

DVT Prophylaxis in Orthopedic Patients. Rogers Kyle, MD Medical University of South Carolina 11/27/12. Objectives . Review the newest ACCP recommendations on DVT prophylaxis in orthopedic patients.

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DVT Prophylaxis in Orthopedic Patients

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  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

  5. Key Messages

  6. 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

  15. 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 medicalpts (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 enoxaparinx 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)

  30. 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

  31. 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

  32. 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

  33. 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

  34. Rivaroxaban

  35. Rivaroxaban

  36. 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?

  37. 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

  38. 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’

  39. 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)

  40. 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

  41. 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)

  42. 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)

  43. 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)

  44. 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

  45. 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

  46. 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’

  47. 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

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