DVT Prophylaxis in Orthopaedic Surgery

Slide 2:DVT Prophylaxis in Orthopaedic Surgery

Symposium, American Academy of Orthopedic Surgeons, Annual Meeting, San Diego, California February 14, 2007

Slide 5:Educational Objectives

Learn how to explain current guidelines issued by national professional organizations and colleges, such as the AAOS, ACCP, and ASA, mandating risk-directed prophylaxis against DVT in low-to-high risk patients undergoing orthopedic surgery. Learn how to identify factors to risk stratify orthopedic surgery patients undergoing THA, TKA, fracture repair, to assess their likelihood for incurring DVT. Learn how to describe pharmacologic and/or intermittent compression devices as part of a multimodal prophylaxis strategy aimed at the incidence of DVT in the OS patient population. Learn how to specify pharmacologic agents used for DVT prophylaxis based on an analysis of efficacy, safety, and pharmacoeconomic parameters.

Slide 6: Learn to discuss the special anesthesiological needs of OS patients at risk for DVT, with a focus on timing of prophylaxis, transitioning agents, and duration of prophylaxis based on the surgical procedure. Describe how to risk stratify patients undergoing orthopedic surgery, and implement ACCP-mandated pharmacologic and non-pharmacologic measures aimed at DVT prophylaxis. Learn how to apply landmark clinical trials focusing on DVT prevention in OS patients.

Educational Objectives

Slide 7:DVT Prophylaxis After TJAImportance

Catastrophic cardiopulmonary problem Death

Slide 8:Orthopedic procedures are high risk

DVT Prophylaxis After TJAImportance

Slide 9:Learn current guidelines(ACCP, AAOS) Stratify orthopedic surgery patients How to apply various modalities

DVT Prophylaxis After TJAObjectives

Slide 10:Pharmacologic agents Unfractionated heparin LMWH Coumadin Aspirin Mechanical Multimodal

DVT Prophylaxis After TJAObjectives

Slide 11:Select pharmacologic agents based on efficacy, safety, pharmacoeconomic parameters Issues related to coadministration of anesthesia and DVT prophylaxis

DVT Prophylaxis After TJAObjectives

Slide 12:Four 20 minutes talk Discussion

DVT Prophylaxis After TJAFormat

Slide 13:Russell Hull MBBS, MSc Professor of Medicine, Director,Thrombosis Research Unit,University of Calgary Current guidelines (ACCP) Risk stratification

DVT Prophylaxis After TJAFirst Talk

Slide 14:Peter Hanson, MD Medical Director of Orthopedics, Chief of Staff Grossmont Hospital, La Mesa, CA Current controversies Agent selection Duration of prophylaxis

DVT Prophylaxis After TJASecond Talk

Slide 15:Paul Lachiewicz MD Professor of Orthopedic Surgery,University of North Carolina School of Medicine, Chapel Hill, NC Multimodal approach Evidence based Clinical implications of prophylaxis

DVT Prophylaxis After TJAThird Talk

Slide 16:Eugene Viscusi MD Director of Acute Pain,Department of AnesthesiaThomas Jefferson University,Philadelphia, PA

Challenges of coadministration of DVT prophylaxis and anesthesia DVT Prophylaxis After TJAFinal Talk

Slide 17:Applying The Science of DVT Prophylaxis to Orthopedic Surgery

Javad Parvizi MD, FRCS Rothman Institute of Orthopedics, Thomas Jefferson University Philadelphia, PA

Slide 18:Pubmed; MesH heading ‘DVT’ and ‘THA’ 29,714 articles

DVT Prophylaxis After THALiterature

Slide 19:Historic 1 - 2% Current 0.1 - 0.2%

Fatal P.E. DVT Prophylaxis After THAImportance

Slide 20:In many cases the complication is preventable We (not the internists) are responsible for choosing and administering prophylaxis

DVT Prophylaxis After THAImportance

Slide 21:DVT Prophylaxis After THAIntroduction

Slide 22:Data Difficult to Interpret: Different methods of diagnosis clinical - ultrasound venography - scans Different endpoints death - DVT proximal vs distal clinical PE or DVT Different definitions of complications bleeding: major, minor post phlebitic syndrome

DVT Prophylaxis After THAIntroduction

Slide 23:DVT Prophylaxis After THAProphylaxis: No

Warwick, JBJS, Br, 1995 1162 THA No chemical prophylaxis Fatal PE 0.34% Murray et al, JBJS Br, 1996 Meta-analysis 130,000 THA Reported fatal PE 0.1 - 0.2%

Slide 24:“Effective prophylaxis is necessary in these patients [THA, TKA] . . .” NIH consensus panel, 1986 European consensus conference 1992

DVT Prophylaxis After THAProphylaxis: Yes

Slide 25:In 2007 in North America we are obligated to do something

DVT Prophylaxis After THA

Slide 26:DVT Prophylaxis After THAAgents Available

Unfractionated heparin LMWH Aspirin Mechanical prophylaxis

Slide 27:DVT Prophylaxis After THALMWH

Advantages: Predictable dose response Proven efficacy Disadvantages: Bleeding complications Injection required

Slide 28:DVT Prophylaxis After THALMWH: Results

LMWH BID 194 THA DVT rate 5% 8 major bleeding episodes Colwell et al, JBJS Am, 1994

Slide 29:DVT Prophylaxis After THAWarfarin vs. LMWH

Prospective, randomized Venography endpoint LMWH started 2 hrs postop Proximal DVT 5% (LMWH) vs 8% (Warfarin), p = 0.19 More bleeding in LMWH group (p=0.001) Francis, et al: JBJS (A), 1995

Slide 30:DVT Prophylaxis After THALMWH

Randomized, double blind 1472 THA Dalteparin before or early after vs warfarin Venogram detected DVT Symptomatic thrombi less frequent in preop dalteparin group (p<0.02) Increased bleeding at surgical site for preop dalteparin group Modified regimen (postoperative) Hull R et al: Arch Intern Med. 2000

Slide 31:Bottom Line: Effective 2nd most commonly used agent in N. America Probably increased bleed risk esp. if given too early

DVT Prophylaxis After THALMWH

Slide 32:Coumadin and LMWH equally effective at preventing DVT after THA A slightly higher bleeding rate with LMWH Coumadin is harder to use (outpatient monitoring)

DVT Prophylaxis After THAResults: Summary

Slide 33:DVT Prophylaxis After THAPreventative Measures

Expeditious surgery Minimize time vessels kinked in surgery Mobilize promptly Calf exercises in bed Elastic stockings (?) Epidural anesthesia Lemos, Clin. Orth. 1992

Slide 34:DVT Prophylaxis After THAProphylaxis Options

What is the best agent for prophylaxis?

Slide 35:434 surgeons representing 48 states and three countries (Canada, Egypt, Pakistan) Surgeons have been in practice an average of 19 years >96% prophylax for DVT in their THA and TKA patients

OREF Survey

Slide 36:OREF Survey

Slide 37:DVT Prophylaxis After THAWhich LMWH

Certoparin (18 mg), dalteparin 30 mg, enoxaparin (24 mg) 188 patients undergoing TJA, or spine sx Changes in venous flow pre and postop doppler DVT= 1.1% Bleeding = 11.2% (13 in certoparin, 4 in each) No difference in APTT, TCT, blood count All as efficacious Janni W, et al.Zentralbl Chir. 2001

Slide 38:DVT Prophylaxis After THASummary

Proven efficacy Works for you

Slide 39:DVT Prophylaxis After THADuration of Prophylaxis

How long should prophylaxis becontinued after THA?

Slide 40:LMWH Conflicting data Warfarin Amstutz: 15 days Colwell: 7 days

DVT Prophylaxis After THADuration of Prophylaxis

Slide 41:DVT Prophylaxis After THALMWH

Randomized, double blind 569 THA dalteparin vs warfarin in hospital and placebo out of hospital (35 days) Venogram preop and postop Proximal DVT significantly higher in warfarin/placebo group No major bleeding Hull R et al: Arch Intern Med. 2000

Slide 42:DVT Prophylaxis After THADuration of Prophylaxis

Markov-based decision analysis Outcome measures: PE prevented, hemorrhages induced, overall cost, overall cost for each PE prevented Agents: LMWH, warfarin, ASA, nothing Extending to 4 weeks was safe for all agents LMWH-most effective ASA-most cost effective Conclusion: Safe to extend the prophylaxis to 4 but NOT 6 weeks Sarasin FP, Bounameaux H.Thromb Haemost 2002

Slide 43:Patients with no specific risk factors (1-3 weeks) Patients with specific risk factor (6 weeks) (like previous DVT)

DVT Prophylaxis After THADuration of Prophylaxis

Slide 44:DVT Prophylaxis After THAScreening

Do patients need routine screening for DVT after THA?

Slide 45:Advantages: Identify and treat clots Disadvantages: Accuracy of tests varies Problem of treating asymptomatic clots Unproven advantage Cost

DVT Prophylaxis After THAScreening

Slide 46:A large prospective randomized trial comparing discharge ultrasound with sham ultrasound showed NO advantage to screening

DVT Prophylaxis After THAScreening Robinson, KS et al. Ann Intern Med. 1997 Sep 15;127(6):439-45

Slide 47:“Good judgment comes from experience and experience comes from bad judgment” Winston Churchill

Slide 103:What Are We Trying To Prevent?

Asymptomatic DVT? Symptomatic DVT? All PE’s? Fatal PE’s? Post-phlebitic Syndrome?

Slide 104:Dear Surgeon………..

Slide 105:Venogram showing a proximal thrombus This slide shows a free-floating thrombus within the right superficial femoral vein extending up to the common femoral vein. Untreated proximal (popliteal, femoral, or iliac veins) venous thrombi like this are associated with a 10% risk of fatal PE and a 50% risk of PE or recurrent venous thrombosis.3 Extensive proximal venous thrombosis is also associated with the postphlebitic syndrome, which carries its own long-term morbidity. References 3. Hull RD, Pineo GF. Prophylaxis of deep venous thrombosis and pulmonary embolism: current recommendations. Med Clin North Am. 1998;82:477–493.Venogram showing a proximal thrombus This slide shows a free-floating thrombus within the right superficial femoral vein extending up to the common femoral vein. Untreated proximal (popliteal, femoral, or iliac veins) venous thrombi like this are associated with a 10% risk of fatal PE and a 50% risk of PE or recurrent venous thrombosis.3 Extensive proximal venous thrombosis is also associated with the postphlebitic syndrome, which carries its own long-term morbidity. References 3. Hull RD, Pineo GF. Prophylaxis of deep venous thrombosis and pulmonary embolism: current recommendations. Med Clin North Am. 1998;82:477–493.

Slide 106:Spiral CT scan showing PE What we are attempting to prevent is demonstrated on this and the next slide. This shows free thrombus in the right main pulmonary artery extending into the right lower lobe pulmonary artery, with also a small amount in a left segmental pulmonary artery. The use of contrast material-enhanced spiral computed tomography (CT) scanning has increased in importance of the last few years and is often used as a primary screening technique for pulmonary embolism. With improved techniques, it shows slightly lower sensitivity but higher specificity compared with ventilation-perfusion scanning and is also useful in being able to make alternative diagnoses for those examinations that do not show a PE.6 It is reasonably accurate down to the fifth order of segmental pulmonary arteries. References 6. Garg K, Welsh CH, Feyerabend AJ, et al. Pulmonary embolism: diagnosis with spiral CT and ventilation-perfusion scanning. Correlation with pulmonary angiographic results or clinical outcome. Radiology. 1998;208:201–208. Spiral CT scan showing PE What we are attempting to prevent is demonstrated on this and the next slide. This shows free thrombus in the right main pulmonary artery extending into the right lower lobe pulmonary artery, with also a small amount in a left segmental pulmonary artery. The use of contrast material-enhanced spiral computed tomography (CT) scanning has increased in importance of the last few years and is often used as a primary screening technique for pulmonary embolism. With improved techniques, it shows slightly lower sensitivity but higher specificity compared with ventilation-perfusion scanning and is also useful in being able to make alternative diagnoses for those examinations that do not show a PE.6 It is reasonably accurate down to the fifth order of segmental pulmonary arteries. References 6. Garg K, Welsh CH, Feyerabend AJ, et al. Pulmonary embolism: diagnosis with spiral CT and ventilation-perfusion scanning. Correlation with pulmonary angiographic results or clinical outcome. Radiology. 1998;208:201–208.

Slide 107:Virchow’s TriadThrombosis Risk in Orthopedic Surgery

Core The contribution of identified risk factors to the pathogenesis of DVT have been described in terms of Virchow’s Triad, named for the pioneering anatomical work of Rudolph Virchow in 1856. Changes in the properties of the blood, changes in blood flow, and abnormalities of the vessel wall are the main contributors to DVT The specific risk factors of Virchow’s Triad in orthopedic surgery encompass — Venous stasis: immobilization, bed rest, and tourniquet use and surgical limb positioning — Vascular injury: surgical manipulation of the limb and large vessels, and endothelial injury — Hypercoagulability: increase in thromboplastin agents and reaming of the femoral canal The overall risk of developing DVT increases in direct proportion to the number of risk factorsCore The contribution of identified risk factors to the pathogenesis of DVT have been described in terms of Virchow’s Triad, named for the pioneering anatomical work of Rudolph Virchow in 1856. Changes in the properties of the blood, changes in blood flow, and abnormalities of the vessel wall are the main contributors to DVT The specific risk factors of Virchow’s Triad in orthopedic surgery encompass — Venous stasis: immobilization, bed rest, and tourniquet use and surgical limb positioning — Vascular injury: surgical manipulation of the limb and large vessels, and endothelial injury — Hypercoagulability: increase in thromboplastin agents and reaming of the femoral canal The overall risk of developing DVT increases in direct proportion to the number of risk factors

Slide 108:DVT Prevention in Knee Replacement(Total DVT by venography)

DVT prevention in knee replacement This slide demonstrates weighted-pooled total (proximal and distal) DVT prevalence rates for different prophylactic regimens as determined by clinical trials involving mandatory postoperative venography. DVT rates after TKR remain high compared with THR despite what regimen is used. Although IPC shows the greatest pooled risk reduction (82%), these results are based on low numbers of trials compared with LMWH or warfarin therapy.1 LMWH is the most efficacious pharmacologic agent in TKR, but the venographic prevalence of DVT remains substantial at 25% to 45%. Despite their use, aspirin, low-dose UFH, and elastic stockings are less effective. References 1. Clagett GP, Anderson FA, Geerts W, et al. Prevention of venous thromboembolism. Chest. 1998;114(5):531S–560S. 29. Levine MN, Gent M, Hirsh J, Weitz J, Turpie AG, Powers P, et al. Ardeparin (low-molecular-weight heparin) vs graduated compression stockings for the prevention of venous thromboembolism: a randomized trial in patients undergoing knee surgery. Arch Intern Med. 1996;156:851–856.DVT prevention in knee replacement This slide demonstrates weighted-pooled total (proximal and distal) DVT prevalence rates for different prophylactic regimens as determined by clinical trials involving mandatory postoperative venography. DVT rates after TKR remain high compared with THR despite what regimen is used. Although IPC shows the greatest pooled risk reduction (82%), these results are based on low numbers of trials compared with LMWH or warfarin therapy.1 LMWH is the most efficacious pharmacologic agent in TKR, but the venographic prevalence of DVT remains substantial at 25% to 45%. Despite their use, aspirin, low-dose UFH, and elastic stockings are less effective. References 1. Clagett GP, Anderson FA, Geerts W, et al. Prevention of venous thromboembolism. Chest. 1998;114(5):531S–560S. 29. Levine MN, Gent M, Hirsh J, Weitz J, Turpie AG, Powers P, et al. Ardeparin (low-molecular-weight heparin) vs graduated compression stockings for the prevention of venous thromboembolism: a randomized trial in patients undergoing knee surgery. Arch Intern Med. 1996;156:851–856.

Slide 109:Preventing DVT in TKR With AspirinAspirin Alone Is Not Effective Prophylaxis After TKR

Notes: This slide shows the venous thromboembolism (VTE) event rates in studies from 1984 through 1996 in which aspirin was the only method of prophylaxis used after total knee replacement (TKR)1-4 These results show plainly that aspirin alone is not effective prophylaxis after TKR1-4 References: 1. Lotke PA, Ecker ML, Alavi A, Berkowitz H. Indications for the treatment of deep venous thrombosis following total knee replacement. J Bone Joint Surg Am. 1984;66:202-208. 2. Haas SB, Insall JN, Scuderi GR, Windsor RE, Ghelman B. Pneumatic sequential-compression boots compared with aspirin prophylaxis of deep-vein thrombosis after total knee arthroplasty. J Bone Joint Surg Am. 1990;72:27-31. 3. Haas SB, Tribus CB, Insall JN, Becker MW, Windsor RE. The significance of calf thrombi after total knee arthroplasty. J Bone Joint Surg Br. 1992;74:799-802. 4. Westrich GH, Sculco TP. Prophylaxis against deep venous thrombosis after total knee arthroplasty. Pneumatic plantar compression and aspirin compared with aspirin alone. J Bone Joint Surg Am. 1996;78:826-834. Notes: This slide shows the venous thromboembolism (VTE) event rates in studies from 1984 through 1996 in which aspirin was the only method of prophylaxis used after total knee replacement (TKR)1-4 These results show plainly that aspirin alone is not effective prophylaxis after TKR1-4 References: 1. Lotke PA, Ecker ML, Alavi A, Berkowitz H. Indications for the treatment of deep venous thrombosis following total knee replacement. J Bone Joint Surg Am. 1984;66:202-208. 2. Haas SB, Insall JN, Scuderi GR, Windsor RE, Ghelman B. Pneumatic sequential-compression boots compared with aspirin prophylaxis of deep-vein thrombosis after total knee arthroplasty. J Bone Joint Surg Am. 1990;72:27-31. 3. Haas SB, Tribus CB, Insall JN, Becker MW, Windsor RE. The significance of calf thrombi after total knee arthroplasty. J Bone Joint Surg Br. 1992;74:799-802. 4. Westrich GH, Sculco TP. Prophylaxis against deep venous thrombosis after total knee arthroplasty. Pneumatic plantar compression and aspirin compared with aspirin alone. J Bone Joint Surg Am. 1996;78:826-834.

Slide 110:DVT Prophylaxis in Total Knee Replacement (TKR) LMWH vs Warfarin

Spiro et al. Blood. 1994;84(suppl 1):246a. Enoxaparin 30 mg sc twice daily(n=173) Warfarin dose-adjusted INR 2-3 (n=176) Total DVT 25.4 45.4 0 10 20 30 40 50 P<0.001 P<0.001 Proximal DVT Core The efficacy and safety of enoxaparin for thromboprophylaxis in patients undergoing total knee replacement (TKR) were compared with warfarin in a randomized, parallel-group study in 349 patients Enoxaparin (30 mg sc twice daily) and warfarin (once daily, dose-adjusted to INR) were both initiated postoperatively As assessed by venography, the rate of all DVT was 45.4% for the warfarin group and 25.4% for the enoxaparin group (P<0.001) The incidence of proximal DVT was 1.7% with enoxaparin and 11.4% with warfarin (P<0.001) Although the overall incidence of hemorrhagic complications was significantly higher in the enoxaparin group (P=0.04), there were no significant between-group differences in incidences of major bleeding episodes and hemorrhagic wound complications Another later trial by Leclerc et al in 670 patients undergoing TKR also found enoxaparin 30 mg sc twice daily (initiated postoperatively) to be significantly more effective than warfarin (all DVT enoxaparin 36.9%; warfarin 51.7%; P=0.003) The incidence of major bleeding was comparable in both groups (enoxaparin 2.1%; warfarin 1.8%; P>0.2) Spiro et al. Blood. 1994;84(suppl 1):246a. Leclerc et al. Ann Intern Med. 1996;124(7):619-626.Core The efficacy and safety of enoxaparin for thromboprophylaxis in patients undergoing total knee replacement (TKR) were compared with warfarin in a randomized, parallel-group study in 349 patients Enoxaparin (30 mg sc twice daily) and warfarin (once daily, dose-adjusted to INR) were both initiated postoperatively As assessed by venography, the rate of all DVT was 45.4% for the warfarin group and 25.4% for the enoxaparin group (P<0.001) The incidence of proximal DVT was 1.7% with enoxaparin and 11.4% with warfarin (P<0.001) Although the overall incidence of hemorrhagic complications was significantly higher in the enoxaparin group (P=0.04), there were no significant between-group differences in incidences of major bleeding episodes and hemorrhagic wound complications Another later trial by Leclerc et al in 670 patients undergoing TKR also found enoxaparin 30 mg sc twice daily (initiated postoperatively) to be significantly more effective than warfarin (all DVT enoxaparin 36.9%; warfarin 51.7%; P=0.003) The incidence of major bleeding was comparable in both groups (enoxaparin 2.1%; warfarin 1.8%; P>0.2) Spiro et al. Blood. 1994;84(suppl 1):246a. Leclerc et al. Ann Intern Med. 1996;124(7):619-626.

Slide 111:Bleeding in Total Knee Replacement (TKR) LMWH vs Warfarin

Warfarindose-adjustedINR 2-3 Enoxaparin30 mg sc bid P=0.04 Spiro et al. Blood. 1994;84(suppl 1):246a. Core In the trial by Spiro et al noted earlier, the efficacy and safety of enoxaparin for thromboprophylaxis in patients undergoing total knee replacement (TKR) were compared with warfarin in a randomized, parallel-group study in 349 patients Enoxaparin (30 mg sc twice daily) and warfarin (once daily, INR dose-adjusted) were both initiated postoperatively Although the overall incidence of hemorrhagic complications was significantly higher in the enoxaparin group, there were no significant between-group differences in incidences of major bleeding episodes and hemorrhagic wound complications Another later trial by Leclerc et al in 670 patients undergoing TKR found the incidence of major bleeding comparable in both groups (enoxaparin 2.1%; warfarin 1.8%; P>0.2) Spiro et al. Blood. 1994;84(suppl 1);246a.Core In the trial by Spiro et al noted earlier, the efficacy and safety of enoxaparin for thromboprophylaxis in patients undergoing total knee replacement (TKR) were compared with warfarin in a randomized, parallel-group study in 349 patients Enoxaparin (30 mg sc twice daily) and warfarin (once daily, INR dose-adjusted) were both initiated postoperatively Although the overall incidence of hemorrhagic complications was significantly higher in the enoxaparin group, there were no significant between-group differences in incidences of major bleeding episodes and hemorrhagic wound complications Another later trial by Leclerc et al in 670 patients undergoing TKR found the incidence of major bleeding comparable in both groups (enoxaparin 2.1%; warfarin 1.8%; P>0.2) Spiro et al. Blood. 1994;84(suppl 1);246a.

Slide 112:Enoxaparin vs Warfarin inTotal Knee Replacement

Leclerc JR et al. Ann Intern Med. 1996, 124.619-626. Notes: Enoxaparin was significantly more effective than warfarin in reducing the prevalence of deep vein thrombosis (DVT) in patients undergoing total knee replacement 1 Only 76 (36.9%) of the 206 patients treated with enoxaparin had any type of DVT, compared with 109(51.7%) of the 211 patients treated with warfarin, a statistically significant difference (P<0.003)1 Proximal DVT occurred in 24 (11.7%) of the patients receiving enoxaparin versus 22 (10.4%) of the patients receiving warfarin; that difference did not attain significance1 The incidence of major bleeding was statistically equivalent, occurring in 7 of the 336 intention-to-treat population receiving enoxaparin and 6 of the 334 intention-to-treat population receiving warfarin1 References: Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of venous thromboembolism after knee arthroplasty. A randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med. 1996;124:619-626. Notes: Enoxaparin was significantly more effective than warfarin in reducing the prevalence of deep vein thrombosis (DVT) in patients undergoing total knee replacement 1 Only 76 (36.9%) of the 206 patients treated with enoxaparin had any type of DVT, compared with 109(51.7%) of the 211 patients treated with warfarin, a statistically significant difference (P<0.003)1 Proximal DVT occurred in 24 (11.7%) of the patients receiving enoxaparin versus 22 (10.4%) of the patients receiving warfarin; that difference did not attain significance1 The incidence of major bleeding was statistically equivalent, occurring in 7 of the 336 intention-to-treat population receiving enoxaparin and 6 of the 334 intention-to-treat population receiving warfarin1 References: Leclerc JR, Geerts WH, Desjardins L, et al. Prevention of venous thromboembolism after knee arthroplasty. A randomized, double-blind trial comparing enoxaparin with warfarin. Ann Intern Med. 1996;124:619-626.

Slide 113:Fondaparinux Targeted Mechanism of Action

IIa II Fibrinogen Fibrin clot Extrinsic pathway Intrinsic pathway 3 ATIII Xa 1 ATIII ATIII 2 Fondaparinux Xa ATIII = antithrombin III Antithrombin Adapted with permission from Turpie AGG, et al. N Engl J Med. 2001;344:619-625. KEY POINT: Fondaparinux acts exclusively by inhibiting factor Xa through the strong activation of ATIII, leading to potent and targeted physiologic control.1–3 1. Binding of fondaparinux to ATIII2,3 Fondaparinux approaches the fondaparinux binding site on ATIII. Fondaparinux binds to ATIII with high affinity. 2. Fondaparinux binding induces a conformational change in ATIII1–3 The binding of fondaparinux produces a conformational change in ATIII, exposing a loop that binds factor Xa. Exposure of the arginine-containing loop greatly increases the affinity of ATIII for factor Xa. 3. Fondaparinux is released from the ATIII/factor Xa complex1,3 Once ATIII binds factor Xa, a further conformational change releases fondaparinux from its binding site. While the binding of ATIII to factor Xa is irreversible, once fondaparinux is released, it can go on to bind further ATIII molecules. References 1. Turpie AGG, Gallus AS, Hoek JA, for the Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med. 2001;344:619-625. 2. Olson ST, Björk I, Sheffer R, Craig PA, Shore JD, Choay J. Role of the antithrombin- binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions. J Biol Chem. 1992;267:12528-12538. 3. van Boeckel CAA, Petitou M. The unique antithrombin III binding domain of heparin: a lead to new synthetic antithrombotics. Angew Chem Int Ed Engl. 1993;32:1671-1690. KEY POINT: Fondaparinux acts exclusively by inhibiting factor Xa through the strong activation of ATIII, leading to potent and targeted physiologic control.1–3 1. Binding of fondaparinux to ATIII2,3 Fondaparinux approaches the fondaparinux binding site on ATIII. Fondaparinux binds to ATIII with high affinity. 2. Fondaparinux binding induces a conformational change in ATIII1–3 The binding of fondaparinux produces a conformational change in ATIII, exposing a loop that binds factor Xa. Exposure of the arginine-containing loop greatly increases the affinity of ATIII for factor Xa. 3. Fondaparinux is released from the ATIII/factor Xa complex1,3 Once ATIII binds factor Xa, a further conformational change releases fondaparinux from its binding site. While the binding of ATIII to factor Xa is irreversible, once fondaparinux is released, it can go on to bind further ATIII molecules. References 1. Turpie AGG, Gallus AS, Hoek JA, for the Pentasaccharide Investigators. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med. 2001;344:619-625. 2. Olson ST, Björk I, Sheffer R, Craig PA, Shore JD, Choay J. Role of the antithrombin- binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions. J Biol Chem. 1992;267:12528-12538. 3. van Boeckel CAA, Petitou M. The unique antithrombin III binding domain of heparin: a lead to new synthetic antithrombotics. Angew Chem Int Ed Engl. 1993;32:1671-1690.

Slide 114:TKR Efficacy Results: Primary Endpoint

Pentamaks

Slide 115:TKR Efficacy Results:Secondary Endpoint

Incidence of patients with VTE up to day 11 Pentamaks

Slide 116:TKR Safety: Bleeding

P value NS NS NS <0.05 NS From 1st injection to day 11 – all treated patients 0 0 2 (0.4) 9 (1.7) 15 (2.9) 0 0 1 (0.2) 0 (0.0) 21 (4.0)

Slide 117:Thromboprophylaxis for Knee ReplacementDalteparin vs Warfarin: Post-Hoc Analysis

Post-hoc analysis of patients (n=155) who received the 1st dose of dalteparin >7.5 hours postoperatively Ayers DC et al. Poster presented at: American Academy of Orthopaedic Surgeons 2006 Annual Meeting; March 22, 2006; Chicago, IL.

Slide 118:Rationale for Extended Prophylaxis After THR/TKR

Cumulative Risk of Thromboembolic Events DuringFirst 3 Months Postoperatively All VTE PE The incidence of thromboembolic events does not stabilize untilapproximately 10 weeks after THR White et al. Arch Intern Med. 1998;158:1525-1531. Supplemental It appears that the incidence of thromboembolic events does not stabilize until about 10 weeks postoperatively The cumulative incidence of DVT and/or PE within 3 months of surgery was 2.8% after THR and 2.1% after TKR These statistics point to the need for early and continued prophylaxis after THR and TKR White et al. Arch Intern Med. 1998;158:1525-1531.Supplemental It appears that the incidence of thromboembolic events does not stabilize until about 10 weeks postoperatively The cumulative incidence of DVT and/or PE within 3 months of surgery was 2.8% after THR and 2.1% after TKR These statistics point to the need for early and continued prophylaxis after THR and TKR White et al. Arch Intern Med. 1998;158:1525-1531.

Slide 119:Rationale for Extended Prophylaxis

White et al. Arch Intern Med. 1998;158:1525-1531. 1.1% 0.8% 0 0.5 1.0 Total Hip Arthroplasty n = 19,000 Total Knee Arthroplasty n = 24,000 % of patients with PE Incidence of PE within 3 months post-surgery

Slide 120:Rationale for Extended Prophylaxis

White et al. Arch Intern Med. 1998;158:1525-1531. Core Although routine prophylaxis in patients undergoing THR and TKR has become a widely accepted practice over the past decade, DVT remains an important problem While the majority of patients receive prophylaxis in the hospital, 50% to 75% of thromboembolic events are diagnosed after discharge White and colleagues performed an analysis of the incidence and time course of objectively diagnosed DVT events following 19,587 primary unilateral THR and 24,059 unilateral TKR procedures performed in California during a 2-year period (1991-1993) The diagnosis of DVT was made after hospital discharge in 76% of THR patients and in 47% of TKR patients (P<0.001) 95% of patients had received thromboprophylaxis, mainly with warfarin or UFH, with or without IPC. Approximately 32% received warfarin after hospital discharge for an average duration of 4 weeks The authors concluded that earlier, more intense prophylaxis may be needed in TKR and more extended prophylaxis may be required after The following 3 slides will help you reinforce the data from this study White et al. Arch Intern Med. 1998;158:1525-1531.Core Although routine prophylaxis in patients undergoing THR and TKR has become a widely accepted practice over the past decade, DVT remains an important problem While the majority of patients receive prophylaxis in the hospital, 50% to 75% of thromboembolic events are diagnosed after discharge White and colleagues performed an analysis of the incidence and time course of objectively diagnosed DVT events following 19,587 primary unilateral THR and 24,059 unilateral TKR procedures performed in California during a 2-year period (1991-1993) The diagnosis of DVT was made after hospital discharge in 76% of THR patients and in 47% of TKR patients (P<0.001) 95% of patients had received thromboprophylaxis, mainly with warfarin or UFH, with or without IPC. Approximately 32% received warfarin after hospital discharge for an average duration of 4 weeks The authors concluded that earlier, more intense prophylaxis may be needed in TKR and more extended prophylaxis may be required after The following 3 slides will help you reinforce the data from this study White et al. Arch Intern Med. 1998;158:1525-1531.

Slide 121:Rationale for Extended Prophylaxis

White et al. Arch Intern Med. 1998;158:1525-1531. Core The median time for postsurgical diagnosis of DVT was 17 days in THR patients and 7 days in TKR patients (P<0.001) This diagnosis may often occur after discharge — At 17 days for THR — At 7 days for TKR White et al. Arch Intern Med. 1998;158:1525-1531.Core The median time for postsurgical diagnosis of DVT was 17 days in THR patients and 7 days in TKR patients (P<0.001) This diagnosis may often occur after discharge — At 17 days for THR — At 7 days for TKR White et al. Arch Intern Med. 1998;158:1525-1531.

Slide 122:NAFT Study Design

visit Screening Day 35 Dalteparin (post-op) Dalteparin Dalteparin (pre-op) Dalteparin Warfarin Venography Switched to Placebo Acute Phase Extended Phase Day 0 (surgery) Day 6 Day 7 Venography Extended Phase Included the continuation of dalteparin 5000 units qd Warfarin was changed to placebo Venography was done 35 days out Moderator Note: Patients with negative venograms at the end of the in-hospital phase were entered in the extended, out-of-hospital phase of the trial; patients who had received dalteparin continued on dalteparin, and those on warfarin continued with placebo injections During the extended, outpatient phase, patients received either dalteparin 5,000 IU sc once daily or matching placebo On day 35 (±2 days), bilateral venography was again performed Bilateral venography was performed in 170, 159, and 154 patients in the preoperative dalteparin, postoperative dalteparin, and warfarin/placebo groups, respectively, on day 35±2. Patent lumen adequacy rates were 91.2%, 90.6%, and 90.9%, respectively Extended Phase Included the continuation of dalteparin 5000 units qd Warfarin was changed to placebo Venography was done 35 days out Moderator Note: Patients with negative venograms at the end of the in-hospital phase were entered in the extended, out-of-hospital phase of the trial; patients who had received dalteparin continued on dalteparin, and those on warfarin continued with placebo injections During the extended, outpatient phase, patients received either dalteparin 5,000 IU sc once daily or matching placebo On day 35 (±2 days), bilateral venography was again performed Bilateral venography was performed in 170, 159, and 154 patients in the preoperative dalteparin, postoperative dalteparin, and warfarin/placebo groups, respectively, on day 35±2. Patent lumen adequacy rates were 91.2%, 90.6%, and 90.9%, respectively

Slide 123:NAFT Results

Treatment Group Proximal DVT RR* Total DVT RR* (%) (%) (%) (%) Pre-op dalteparin 3.1 67† 17.2 55‡ Post-op dalteparin 2.0 79§ 22.2 41¥ Warfarin/placebo 9.2 (5 de novo) 36.7 Extended Outpatient Phase (Day 35 ± 2) (Patients with negative bilateral venograms at day 6±2) Hull RD, et al. Arch Intern Med. 2000;160:2199-2207. Core Bilateral venography was performed in 170, 159, and 154 patients in the preoperative dalteparin, postoperative dalteparin, and warfarin/placebo groups on day 35±2. Adequacy rates were 91.2%, 90.6%, and 90.9%, respectively Rates of proximal DVT during the entire study interval were 3.1%, 2.0%, and 9.2% for the preoperative dalteparin, postoperative dalteparin, and warfarin/placebo groups, respectively Risk reduction in proximal DVT for preoperative dalteparin vs placebo was 67% (P=0.024) and 79% (P=0.007) for postoperative dalteparin vs warfarin/placebo Total DVT rates for the entire study interval (day 0 to 35) were 17.2%, 22.2%, and 36.7% in the preoperative dalteparin, postoperative dalteparin, and warfarin/placebo groups, respectively Risk reductions for the preoperative dalteparin vs placebo and the postoperative dalteparin vs placebo groups were 55% (P<0.001) and 41% (P=0.003), respectively Hull et al. Arch Intern Med. 2001. In press.Core Bilateral venography was performed in 170, 159, and 154 patients in the preoperative dalteparin, postoperative dalteparin, and warfarin/placebo groups on day 35±2. Adequacy rates were 91.2%, 90.6%, and 90.9%, respectively Rates of proximal DVT during the entire study interval were 3.1%, 2.0%, and 9.2% for the preoperative dalteparin, postoperative dalteparin, and warfarin/placebo groups, respectively Risk reduction in proximal DVT for preoperative dalteparin vs placebo was 67% (P=0.024) and 79% (P=0.007) for postoperative dalteparin vs warfarin/placebo Total DVT rates for the entire study interval (day 0 to 35) were 17.2%, 22.2%, and 36.7% in the preoperative dalteparin, postoperative dalteparin, and warfarin/placebo groups, respectively Risk reductions for the preoperative dalteparin vs placebo and the postoperative dalteparin vs placebo groups were 55% (P<0.001) and 41% (P=0.003), respectively Hull et al. Arch Intern Med. 2001. In press.

Slide 124: MajorTreatment Group Bleeding (%) Wound Hematoma (%) Complicated Uncomplicated Pre-op dalteparin 0 0.5 2.5 Post-op dalteparin 0 0.5 2.1 Warfarin 0 1.1 2.8

NAFT Results Extended Outpatient Phase (Day 35 ± 2) (Patients with negative bilateral venograms at day 6±2) Hull RD, et al. Arch Intern Med. 2000;160:2199-2207. Core No major bleeding was reported in extended outpatient phase Minor bleeding and wound hematomas were similar in the 3 groups during the out-of-hospital phase Bleeding was investigator observed and considered major if it was clinically overt, associated with a decrease in hemoglobin of ³20 g/L, or required transfusion of ³2 units of blood; if it was intracranial, intraocular, intraspinal, or retroperitoneal; or if it occurred in a prosthetic joint Hull et al. Arch Intern Med. 2000. In press.Core No major bleeding was reported in extended outpatient phase Minor bleeding and wound hematomas were similar in the 3 groups during the out-of-hospital phase Bleeding was investigator observed and considered major if it was clinically overt, associated with a decrease in hemoglobin of ³20 g/L, or required transfusion of ³2 units of blood; if it was intracranial, intraocular, intraspinal, or retroperitoneal; or if it occurred in a prosthetic joint Hull et al. Arch Intern Med. 2000. In press.

Slide 125:Enoxaparin: Extended Prophylaxis

Comp et al 2001 JBJS: Enoxaparin 7-10 days vs 4 wks, TKA’s and THA’s Extended dosing in THA’s significantly decreased DVT’s, no difference in TKA’s No added bleeding risk

Slide 126:Recent Studies: Extended Prophylaxis

Eikelboom et al 2001 Lancet: Meta-analysis of 3999 patients, THA and TKA, extended prophylaxis vs placebo/no tx Decreased Sx’ic DVT in hips (not knees) Decreased Asx’ic DVT in hips(not knees) 20 sx’ic DVT/1000 pts, 1death/1000 pts prevented $4-7 / day in UK, $24-28 / day in US No warfarin studies available

Slide 127:Extended Prophylaxis: PENTasaccharide in Hip-FRActure Surgery (PENTHIFRA Plus) Results

Eriksson BI et al. Arch Intern Med. 2003;163:1337-1342. * p < 0.001†no significant difference between treatment groups

Slide 128:Extended Prophylaxis with Fondaparinux: Hip Fracture Repair

35.0% 1.4% 0 5 10 15 20 25 30 35 Fondaparinux (n=208) Placebo (n=220) n = 3 n = 77 RRR = 96% Patients (%) Eriksson BI et al. Arch Intern Med. 2003;163:1337-1342.

Slide 129:Guidelines for Prevention of VTE:Are They Relevant?

Current Findings: Applications for Thromboprophylaxis in Orthopaedic Surgery The Four Seasons Hotel, San Francisco March 10, 2004

Slide 130:Definition of Practice Guidelines

Practice guidelines are systematically developedstatements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances.

Slide 131:Seventh ACCP Recommendations

Notes: The most recent evidence-based guidelines of the American College of Chest Physicians (ACCP) on prevention of venous thromboembolism (VTE) present specific recommendations regarding extended prophylaxis for patients undergoing total knee replacement (TKR) that are the same as those for patients undergoing total hip replacement1 The guidelines state that patients undergoing TKR receive thromboprophylaxis with low-molecular-weight heparin (LMWH) (using a high-risk dose), fondaparinux (2.5 mg daily), or a vitamin K antagonist (target international normalized ratio [INR] 2.5; INR range 2 to 3) for at least 10 days1 These recommendations are graded 1A, the highest possible grading, indicating that the ACCP has judged the evidence supporting these recommendations to be strong and that the benefits of following these recommendations outweigh the risks, burden, and costs The ACCP does not recommend the use of low-dose unfractionated heparin, aspirin, or a venous foot pump as sole agents to prevent VTE1 The guidelines do not recommend the use of fondaparinux over LMWH, such as enoxaparin, because the minimization of bleeding complications is considered to be a primary goal1 References: Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):338S-400S. Notes: The most recent evidence-based guidelines of the American College of Chest Physicians (ACCP) on prevention of venous thromboembolism (VTE) present specific recommendations regarding extended prophylaxis for patients undergoing total knee replacement (TKR) that are the same as those for patients undergoing total hip replacement1 The guidelines state that patients undergoing TKR receive thromboprophylaxis with low-molecular-weight heparin (LMWH) (using a high-risk dose), fondaparinux (2.5 mg daily), or a vitamin K antagonist (target international normalized ratio [INR] 2.5; INR range 2 to 3) for at least 10 days1 These recommendations are graded 1A, the highest possible grading, indicating that the ACCP has judged the evidence supporting these recommendations to be strong and that the benefits of following these recommendations outweigh the risks, burden, and costs The ACCP does not recommend the use of low-dose unfractionated heparin, aspirin, or a venous foot pump as sole agents to prevent VTE1 The guidelines do not recommend the use of fondaparinux over LMWH, such as enoxaparin, because the minimization of bleeding complications is considered to be a primary goal1 References: Geerts WH, Pineo GF, Heit JA et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):338S-400S.

Slide 132:Seventh ACCP Recommendations

Notes: This slide presents the most recent evidence-based recommendations of the American College of Chest Physicians (ACCP) regarding thromboprophylaxis with low-molecular-weight heparin (LMWH) and unfractionated heparin during total hip replacement1 It is recommended that LMWH at a usual high-risk dose be started 12 hours before surgery, or 12 to 24 hours after surgery, or 4 to 6 hours after surgery at half the usual high risk dose1 Adjusted dose vitamin K antagonist (VKA) is recommended preoperatively or the evening after surgery1 The ACCP recommends against the use of aspirin, dextran, LDUH, GCS, IPC or VFP as the only method of thromboprophylaxis The recommendations state that fondaparinux is not specifically recommended over LMWH and VKA, nor is LMWH recommended over VKA for thromboprophylaxis. It is noted that minimizing bleeding complications is to take priority1 These recommendations are Grade 1A, the highest possible grading, indicating that the ACCP has judged these recommendations to be strong and that the benefits of following these recommendations outweigh the risks, burden, and costs1 References: 1. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):338S-400S. Notes: This slide presents the most recent evidence-based recommendations of the American College of Chest Physicians (ACCP) regarding thromboprophylaxis with low-molecular-weight heparin (LMWH) and unfractionated heparin during total hip replacement1 It is recommended that LMWH at a usual high-risk dose be started 12 hours before surgery, or 12 to 24 hours after surgery, or 4 to 6 hours after surgery at half the usual high risk dose1 Adjusted dose vitamin K antagonist (VKA) is recommended preoperatively or the evening after surgery1 The ACCP recommends against the use of aspirin, dextran, LDUH, GCS, IPC or VFP as the only method of thromboprophylaxis The recommendations state that fondaparinux is not specifically recommended over LMWH and VKA, nor is LMWH recommended over VKA for thromboprophylaxis. It is noted that minimizing bleeding complications is to take priority1 These recommendations are Grade 1A, the highest possible grading, indicating that the ACCP has judged these recommendations to be strong and that the benefits of following these recommendations outweigh the risks, burden, and costs1 References: 1. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):338S-400S.

Slide 133:Seventh ACCP Recommendations

Notes: The most recent evidence-based guidelines of the American College of Chest Physicians (ACCP) on prevention of venous thromboembolism (VTE) present specific recommendations regarding extended prophylaxis in total hip replacement (THR) surgery1 The guidelines state that patients undergoing THR or total knee replacement receive thromboprophylaxis with low-molecular-weight heparin (using a high-risk dose), fondaparinux (2.5 mg daily), or a vitamin K antagonist (target international normalized ratio [INR] 2.5; INR range 2-3) for at least 10 days1 The guidelines also recommend that patients undergoing THR be given extended prophylaxis for up to 28 to 35 days after surgery1 These recommendations are Grade 1A, the highest possible grading, indicating that the ACCP has judged these recommendations to be strong and that the benefits of following these recommendations outweigh the risks, burden, and costs1 References: Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):338S-400S. Notes: The most recent evidence-based guidelines of the American College of Chest Physicians (ACCP) on prevention of venous thromboembolism (VTE) present specific recommendations regarding extended prophylaxis in total hip replacement (THR) surgery1 The guidelines state that patients undergoing THR or total knee replacement receive thromboprophylaxis with low-molecular-weight heparin (using a high-risk dose), fondaparinux (2.5 mg daily), or a vitamin K antagonist (target international normalized ratio [INR] 2.5; INR range 2-3) for at least 10 days1 The guidelines also recommend that patients undergoing THR be given extended prophylaxis for up to 28 to 35 days after surgery1 These recommendations are Grade 1A, the highest possible grading, indicating that the ACCP has judged these recommendations to be strong and that the benefits of following these recommendations outweigh the risks, burden, and costs1 References: Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 Suppl):338S-400S.

Slide 134:Duration Of Treatment (ACCP)

Optimal duration of prophylaxis after THR or TKR - at least 7-10 days Extended prophylaxis with LMWH recommended at least for “high risk” patients

Slide 135:Multimodal Approach to VTED Prophylaxis for THA and TKA

Paul F. Lachiewicz, M.D. Department of Orthopaedics University of North Carolina - Chapel Hill ACCP Orthopaedists

Slide 136:THA Techniques

Then Now Bed rest =1 week <1 day Hospital stay 2-3 weeks 2-4 days EBL (mean) 1650 ml 300-600 ml Blood Homologous Autologous Transfusion (mean) 1144 ml 0-500 ml Anesthesia General Regional

Slide 137:These major changes in THA techniques suggest that our older ideas about chemoprophylaxis should be reconsidered in 2007

Slide 138:Preoperative Intraoperative Postoperative

Multimodal Prophylaxis

Slide 139:Preoperative Risk Factors VTED

Genetic predisposition Hypercoaguable states Prior history PE Oral contraceptives (?) Classic risk factors have not correlated with VTED in elective THA patients

Slide 140:PreoperativeAutologous Donation

Retrospective study: 2043 patients Donation 1037; not 1006 DVT Donation 9.0% (p=0.003) (venogram) Not 13.5% P.E. Donation 0.3% (ns) (clinical) Not 0.7% Bae et al. JBJS (B) 2001

Slide 141:Thromboembolism THRAnesthesia

Spinal or epidural anesthesia reduces risk by 40-50% Regional anesthesia increased blood flow in lower extremities during and after the procedure Lower blood loss, ? quicker surgery

Slide 142:Mechanical Prophylaxis THA

Intraoperative use does not interfere with positioning, exposure, placement of implants

Slide 143:Intraop and postop IPC is specific localized prophylaxis: Decreased venous stasis increase venous velocity increase venous volume Inhibits coagulation cascade ? tissue factor pathway inhibitor ? factor VIIa ? NO and endogenous NO synthase

Mechanical Prophylaxis THA

Slide 144:Wide variety of devices foot pump calf thigh-calf Each device has its own mechanics with resultant change in peak venous velocity and venous volume For THA, optimal characteristics of pneumatic compression are not known

Mechanical Prophylaxis THA

Slide 145:Venous Hemodynamics After THA

Devices with rapid inflation time Produced the greatest increase in peak venous velocity Devices that compress calfand thigh Produced the greatest increase in venous volume

Slide 146:Multimodal Prophylaxis

June 1991 – May 2005 Single surgeon 1042 consecutive THA (388 in previous study) 10 exclusions (5 hemophilia, 5 other) Lachiewicz, Soileau. Clin Orthop 2006

Slide 147:Study Group

1032 hip procedures 422 male, 610 female Mean age 64 (22-95) Primary 680 Revision 352 *Patients with prior history of TED or on warfarin for cardiac conditions not excluded

Slide 148:Materials & Methods

Anesthesia Regional 95% General only 5% Intraoperative mechanical bilateral, thigh-high sterile sleeve-operative limb single manufacturer Recovery room + until discharge Duplex ultrasound prior to discharge (day 3-8)

Slide 149:Results - Mortality

1 fatal pulmonary embolism (0.09%) 24 days postop-autopsy patient in long-leg brace minimal ambulation 1 cerebrovascular accident 1 unknown; abdominal pain & cardiac arrest ? M.I. vs P.E. 30 day mortality 3 of 1032 (0.3%)

Slide 150:Pulmonary Embolism

Symptomatic 7 (0.7%) 4 early (POD #4-7) 3 late POD # 23 24 (fatal) 37 Only 1 of 7 also had DVT or ? Duplex

Slide 151:Mechanical Prophylaxis withAspirin vs Aspirin Alone

Prospective, randomized 100 hips - MR venography Rapid inflation device (Venaflow®) applied in recovery room epidural hypotensive anesthesia aspirin 325 mg BID Mechanical + aspirin 8% prox. DVT aspirin alone 22% prox. DVT (p<.05) Ryan et al. JBJS 2002

Slide 152:Multimodal Prophylaxis THA

Calf-thigh compression begun intraoperatively is effective and acceptable for 99% THA patients 1032 hips Fatal PE 0.09% Total DVT-PE 4.6% Pulmonary embolism 0.7%

Slide 153:VTED After TKA Orthopaedic Perspective

Different “disease” than after THA Most thrombi occur in calf only Extension to proximal veins occurs infrequently Pulmonary embolism rare

Slide 154:Orthopaedist’s Concerns

Prevention of Fatal PE Symptomatic PE Symptomatic DVT Knee bleeding How important is it to prevent asymptomatic venogram or Duplex scan-detected thrombi?

Slide 155:Orthopaedist’s Concerns Anticoagulation TKA

Increased risk of major bleeding into knee and wound complications (0.9 – 5.2%) True risk of bleeding and outcome not established for all TKA patients Bleeding into TKA associated with hematomas, drainage, infection and poorer outcomes

Slide 156:Mechanical Prophylaxis TKA

Wide variety of devices thigh-calf calf only foot pump Each device has its own mechanics with different changes in peak venous velocity and volume Optimal characteristics for devices?

Slide 157:Venous Hemodynamics After TKA

Westrich et al. JBJS (B) 1998

Slide 158:Mechanical Prophylaxis TKA

Devices with rapid inflation time produced the greatest increase in peak venous velocity Devices that compress calf and thigh produced the greatest increase in venous volume What matters most – velocity or volume?

Slide 159:Two Mechanical Devices for Prophylaxis of Thromboembolism After TKA

Lachiewicz et al. JBJS (B), Nov 2004. University of North Carolina-Chapel Hill Prospective, randomized study

Slide 160:Patient Population

423 patients, 472 knees Mean age 66.8 yrs (23-94) Mean wt 87.3 kg (45-148) Diagnosis DJD 307 RA 25 Rev. 64 Other 27

Slide 161:Results

Asymmetrical Circumferential Compression Compression   Patients 206 217 Knees 232 240 Mortality 0 1 (.46%) Pulm. Embolism 0 1 (.46%) Thrombi 16 (6.9%) 36 (15%) p = .007   Calf 15 30 Proximal 1 6

Slide 162:ThromboembolismKnee Procedure

Asymmetrical Circumferential Compression Compression  Unilateral, primary   Knees 155 158   Thrombi 13 (8.4%) 26 (15.8%) p = 0.03   Bilateral, primary Patients (knees) 25 (50) 22 (44)   Patients-thrombi 1 (4%) 5 (22.7%) p = 0.09   Limbs-thrombi 2 (4%) 7 (15.9%) p = 0.05

Slide 163: Personal TKA Series Calf IPC Plus Aspirin

856 TKAs Mortality (MI) 1 (0.12%) Symptomatic PE 3 (0.35%) DVT (Duplex) 66 (7.7%) (56 pts) 1991 - present

Slide 164:Multimodal Prophylaxis TKAVenaflow® + LMWH vs. Venaflow® + Aspirin

Prospective, randomized 275 unilateral TKAs Duplex scan 3-5 days; 4-6 weeks DVT 14.1% vs 17.8% (p = 0.27) No difference between groups! Westrich et al. J. Arthroplasty 2006

Slide 165:VTED Prophylaxis TKAWhat is Acceptable in 2007

Mechanical prophylaxis plus aspirin is safe and effective for most TKA patients Recommend rapid-inflation, asymmetric calf compression device Anticoagulation for patients allergic to aspirin or with heritable coagulopathy Multimodal prophylaxis is an acceptable alternative to ACCP Guidelines

Slide 166:Anticoagulation andthe Orthopedic Patient:the Anesthesiologist’s Perspective

Eugene R Viscusi, MD Director, Acute Pain Management Associate Professor Department of Anesthesiology Thomas Jefferson University, Philadelphia, PA

Slide 167:Overview

Venous thromboembolism (VTE), DVT and PE are real and significant threats to the orthopedic patient The anesthesia and analgesia plan must accommodate treatment of VTE Anesthesia and pain management can be challenging and pose risks to the patient in the absence of communication and cooperation between care teams

Slide 168:The 2004 ACCP recommendations further increased the level and duration of thromboprophylasis. Despite the reduction of asymptomatic thromboembolic events, an actual reduction of clinically relevant events has been difficult to demonstrate 1,2 These changes create new challenges for managing neuraxial and invasive non-compressible peripheral blockade

1. Murray DW, et al. J Bone Joint Surg. 1996;78:863-870. 2. Mantilla CB, et al. Anesthesiology. 2002;96:1140-1146. Overview

Slide 169:The ACCP guidelines and the ASRA consensus statement on neuraxial techniques often leave the clinician in the zone of discomfort: Both statements provide important clinical information but don’t address all situations ASRA guidelines are based on knowledge of the agents and past adverse events rather than large studies. (Difficult to provide the denominator)

The Challenge

Slide 170:2004 ACCP Recommendations

Unfractionated heparin every 8 hours No data documenting safety of neuraxial catheters; complicates catheter removal Fondaparinux following major orthopedic surgery ASRA recommends againstepidural catheter Warfarin; target INR for TJA is 2.5 If achieved would precludeepidural catheters Chest. Sept 2004, supp

Slide 171:2004 ACCP Recommendations

Dosing of LMWH early in the postoperative period was associated with an increased risk of neuraxial bleeding Anticoagulate a minimum of 10 days; 28-35 for total hip Interaction of prolonged thromboprophylaxis, neuraxial instrumentation, difficult or traumatic needle insertion is UNKNOWN

Slide 172:1,260,000 spinals; 450,000 epidurals

33 spinal hematomas 24 in females, 25 with epidural Coagulopathy in 11 Time of occurrence: 24 hours (6H-14D) 5 of 33 recovered (delay in treatment) 4 patients with indwelling epidural catheters received 5,000 U heparin during surgery Moen V, et al. Anesthesiology. 2004;101:950-959

Slide 173:Authors calculated risk for females undergoing TKA 1:3,600! (female, age, spinal canal pathology, duration of catheter, thromboprophylaxis) One–third of all spinal hematomas occurred in patients receiving thromboprophylaxis in accordance with current guidelines

Moen V, et al. Anesthesiology. 2004;101:950-959

Slide 174:Spinal Hematoma

May occur in the absence of identifiable risk factors Neurological monitoring is critical for early intervention Early recognition and treatment is key to improved outcome (laminectomy within 8 hours) 1 Focus not only on prevention but also improving neurological outcome Vandermeulen ER, et al. Anesth Analg 1994:79:1165-77

Slide 175:Warfarin

INR of less than 1.5 is recommended for removal of epidural catheters1 Check INR: Every day with an indwelling epidural catheter Prior to needle insertion if given more than 36 hours prior 1. 2nd ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation. Reg Anesth Pain Med. 2003;28:172-197.

Slide 176:Can Epidural Anesthesia andWarfarin be Coadministered?1

Prudence must be exercised when enforcing these guidelines, both in the upper INR limit as well as potential reversal of anticoagulation1 11,235 patients: no detectable hematomas 1030 randomly reviewed charts: 398 patients had INR greater than 1.5 (1.54 mean, range 0.93-4.25) 1. Parvizi J, Viscusi ER. CORR, 2007( in press)

Slide 177:If the INR is “elevated”, should anticoagulation be reversed? Pulmonary embolism is aserious risk FFP is not without risk in itself Decision should be taken case by case and the thought process fully documented!

Can Epidural Anesthesia andWarfarin be Coadministered?1 1. Parvizi J, Viscusi ER. CORR, 2007( in press)

Slide 178:Standard (Unfractionated) Heparin

BID dosing is theoretically safe if catheter removal is timed with trough levels TID dosing: no data exists but PTT (anecdotally) may remain elevated Heparin induced thrombocytopena (HIT) is a real concern Platelet count is indicated after 5 days of unfractionated heparin

Slide 179:Standard Heparin andRegional Anesthesia

No contraindication following subcutaneous injection prior to spinal/epidural needle insertion Delay administration for one hour following needle placement Remove indwelling catheter at trough level or one hour prior to next dose Prolonged therapy is linked to increase in spinal hematoma Traumatic needle insertion may increase risk of spinal hematoma ASRA consensus guidelines

Slide 180:LMWH

Restrict to once daily dosing regimen with epidural catheter LMWH dosing minimum of 2 hours after catheter removal Spinal hematomas have been reported with this regimen; (The last chapter hasn’t been written) ASRA consensus guidelines

Slide 181:Consider the risk/benefit ratio of thromboembolic event vs. spinal hematoma Timing: With once daily dosing, time epidural catheter removal in a safe window before next dose Minimize delay of next dose Renal function affects metabolism of LMWH (and other drugs). Elderly at particular risk. Dose accordingly 1

D’Sousa G, Viscusi ER. ASA 2006 (abstract) LMWH

Slide 182:Antiplatelet Medications

Uncommon as primary agents for thromboprophylaxis but may be used chronically by orthopedic patients1 A number of large studies demonstrated relative safety However, if this is combined with heparin there may be increased (but unquantified) risk Horlocker T, Wedel D. Anesth Analg 1995;80:303-309

Slide 183:Platelet Aggregation Inhibitors

Interfere with platelet-fibrinogen binding and platelet-platelet interaction Ticlopidine: stop 14 days Clopidogrel: stop 7 days Platelet glycoprotein IIb/IIIa receptor antagonists 48 hours: abciximab 8 hours eptifibatide, tirofiban ASRA consensus guidelines

Slide 184:Fondaparinux

Factor Xa inhibitor with half-life of21 hours1 Clinical trials: Atraumatic epidural needle placement Epidural catheter removed 2 hours prior to dosing Avoid indwelling epidural catheters with this drug Turpie AG et al.[Letter]NEJM. 2001; 345:292

Slide 185:Recommendations for Safety with Neuraxial Techniques

Know the ASRA guidelines Employ single agent anticoagulation Understand risks of each individual agent Follow developments with peripheral nerve blocks Careful monitoring of dose timing, coagulation studies and neurologic function are critical Atraumatic needle placement if possible

Slide 186:Analgesic Techniques: Hip

Intrathecal Morphine Lumbar Plexus Block Single injection or continuous catheter Epidural Analgesia Single injection, standard morphine Extended-release Epidural Morphine Indwelling epidural catheter

Slide 187:Femoral Block Single injection or catheter Lumbar plexus (posterior approach) Single injection or continuous catheter Epidural analgesia Indwelling continuous catheter Extended-release Epidural Morphine Single injection standard morphine

Analgesic Techniques: Knee

Slide 188:Summary

Safe and effective anesthesia and pain management for the orthopedic patient can be achieved in the presence of VTE prophylaxis when the entire care team (orthopedics, anesthesiology, nursing) understands the limitations, risks and works together