Welcome DVT Prophylaxis in Orthopaedic Surgery Symposium, American

Welcome DVT Prophylaxis in Orthopaedic Surgery Symposium, American

Welcome DVT Prophylaxis in Orthopaedic Surgery Symposium, American Academy of Orthopedic Surgeons, Annual Meeting, San Diego, California February 14, 2007 Program Faculty Javad Parvizi, MD, FRCS Associate Professor Department of Orthopedics Thomas Jefferson University Rothman Institute Philadelphia, PA Eugene R Viscusi, MD Director, Acute Pain Management

Associate Professor Department of Anesthesiology Thomas Jefferson University Philadelphia, PA Peter B. Hanson, MD Medical Director of Orthopedics Chief of Staff Grossmont Hospital La Mesa, CA Paul F. Lachiewicz, MD Department of Orthopaedics University of North Carolina School of Medicine Chapel Hill, NC Russell Hull, MBBS, MSc Professor of Medicine

Director, Thrombosis Research Unit University of Calgary Calgary, Alberta Canada Financial Disclosures Javad Parvizi, MD, FRCS Grant/Research Support: NIH, OREF, DOD, Aircast, GSK, Ortho McNeill, Pfizer, Smith and Nephew, Stryker Consultant: Stryker Orthopaedics Speakers Bureau: Endo Peter B. Hanson, MD Speakers Bureau: Eisai, sanofiaventis, Bristol-Myers Squibb Russell Hull, MBBS, MSc Grant/Research Support: sanofiaventis, Bayer Consultant: sanofi-aventis, Wyeth, GSK, Leo Pharmaceuticals, Pfizer, Bayer

Eugene R Viscusi, MD Research Support: Ortho-McNeil Pharmaceutical, Inc., Endo Pharmaceuticals, SkyePharma, Pfizer Inc, Xsira Pharmaceuticals, Baxter Pharmaceutical Products, Inc., and Progenics Pharmaceuticals, Inc. Consultant: Ortho-McNeil Pharmaceutical, Inc., Adolor Corporation, Endo and SkyePharma Speakers Bureau: Endo Paul F. Lachiewicz, MD Consultant: Zimmer, Endo Research Grant: Aircast 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. Educational Objectives 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. DVT Prophylaxis After TJA Importance Catastrophic cardiopulmonary problem Death DVT Prophylaxis After TJA Importance Orthopedic

procedures are high risk DVT Prophylaxis After TJA Objectives Learn current guidelines (ACCP, AAOS) Stratify orthopedic surgery patients How to apply various modalities

DVT Prophylaxis After TJA Objectives Pharmacologic agents Unfractionated heparin LMWH Coumadin Aspirin Mechanical Multimodal DVT Prophylaxis After TJA

Objectives Select pharmacologic agents based on efficacy, safety, pharmacoeconomic parameters Issues related to coadministration of anesthesia and DVT prophylaxis DVT Prophylaxis After TJA Format Four 20 minutes talk

Discussion DVT Prophylaxis After TJA First Talk Russell Hull MBBS, MSc Professor of Medicine, Director, Thrombosis Research Unit, University of Calgary Current guidelines (ACCP) Risk stratification DVT Prophylaxis After TJA Second Talk

Peter Hanson, MD Medical Director of Orthopedics, Chief of Staff Grossmont Hospital, La Mesa, CA Current Agent controversies selection Duration of prophylaxis DVT Prophylaxis After TJA Third Talk

Paul Lachiewicz MD Professor of Orthopedic Surgery, University of North Carolina School of Medicine, Chapel Hill, NC Multimodal Evidence Clinical approach based implications of prophylaxis DVT Prophylaxis After TJA Final Talk Eugene Viscusi MD Director of Acute Pain,

Department of Anesthesia Thomas Jefferson University, Philadelphia, PA Challenges of coadministration of DVT prophylaxis and anesthesia Applying The Science of DVT Prophylaxis to Orthopedic Surgery Javad Parvizi MD, FRCS Rothman Institute of Orthopedics, Thomas Jefferson University Philadelphia, PA DVT Prophylaxis After THA Literature Pubmed;

MesH heading DVT and THA 29,714 articles DVT Prophylaxis After THA Importance Fatal P.E. Historic 1 - 2% Current 0.1 - 0.2% DVT Prophylaxis After THA Importance In

many cases the complication is preventable We (not the internists) are responsible for choosing and administering prophylaxis DVT Prophylaxis After THA Introduction What agent? How long

Screening DVT Prophylaxis After THA Introduction 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 THA Prophylaxis: 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%

DVT Prophylaxis After THA Prophylaxis: Yes Effective prophylaxis is necessary in these patients [THA, TKA] . . . NIH consensus panel, 1986 European consensus conference 1992 DVT Prophylaxis After THA In 2007 in North America we are obligated to do something

King obtains $1.5M settlement for husband and children in pulmonary embolism death September 14, 2004 | Massachusetts Lawyers Weekly: Verdicts & Settlements DVT Prophylaxis After THA Agents Available Unfractionated heparin LMWH Aspirin Mechanical prophylaxis DVT Prophylaxis After THA LMWH

Advantages: Predictable dose response Proven efficacy Disadvantages: Bleeding complications Injection required DVT Prophylaxis After THA LMWH: Results LMWH 194 THA

DVT 8 BID rate 5% major bleeding episodes Colwell et al, JBJS Am, 1994 DVT Prophylaxis After THA Warfarin 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 DVT Prophylaxis After THA LMWH 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 DVT Prophylaxis After THA LMWH Bottom Line: Effective 2nd most commonly used agent in N. America Probably increased bleed risk esp. if given too early DVT Prophylaxis After THA Results: Summary 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 THA Preventative Measures Expeditious surgery Minimize time vessels kinked in surgery

Mobilize promptly Calf exercises in bed Elastic stockings (?) Epidural anesthesia Lemos, Clin. Orth. 1992 DVT Prophylaxis After THA

Prophylaxis Options What is the best agent for prophylaxis? OREF Survey 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 DVT Prophylaxis After THA Which 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 DVT Prophylaxis After THA Summary Proven efficacy Works for you DVT Prophylaxis After THA Duration of Prophylaxis

How long should prophylaxis be continued after THA? DVT Prophylaxis After THA Duration of Prophylaxis LMWH Conflicting data Warfarin Amstutz: 15 days Colwell: 7 days DVT Prophylaxis After THA

LMWH 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 DVT Prophylaxis After THA Duration 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 DVT Prophylaxis After THA Duration of Prophylaxis Patients with no specific risk factors (1-3 weeks) Patients with specific risk factor (6 weeks) (like previous DVT) DVT Prophylaxis After THA Screening

Do patients need routine screening for DVT after THA? DVT Prophylaxis After THA Screening Advantages: Identify and treat clots Disadvantages:

Accuracy of tests varies Problem of treating asymptomatic clots Unproven advantage Cost DVT Prophylaxis After THA Screening A large prospective randomized trial comparing discharge ultrasound with sham ultrasound showed NO advantage to screening Robinson, Robinson, KS KS et et al.

al. Ann Ann Intern Intern Med Med.. 1997 1997 Sep Sep 15;127(6):439-45 15;127(6):439-45 Good judgment comes from experience and experience comes from bad judgment Winston Churchill Current Guidelines for Deep Vein Thrombosis Prophylaxis in Orthopedic Surgery: ACCP Guidance

and Risk Stratification Strategies Matching Intensity of Therapy with Patient Subgroups Russell D. Hull Professor of Medicine,Thrombosis Research Unit University of Calgary Diagnosis Of Fatal Pulmonary Embolism In North America Is Problematic Due To The Low Autopsy Rate Evidence-Based Guidelines Recommendations Two Components: Methodological Quality of a Recommendation Grade A

Grade B Or Grade C Benefit/Risk Grade 1 Or Grade 2 The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 179S-187S. Methodologic Quality Grade A Consistent findings by randomized trials Grade B Randomized clinical trials with inconsistent results

Grade C Observational studies Chest 2004; 126: 179S-187S. Benefit/Risk Grade 1 If we are very certain that the benefits do, or do not, outweigh the risks, burdens, and cost, we make a strong recommendation (in our formulation, Grade 1) Grade 2 If we are less certain of the magnitude of the benefits and the risks, burdens, and costs, and thus of their relative impact, we make a weaker Grade 2 recommendations

Chest 2004; 126: 179S-187S. Thromboprophylaxis Regimens Mechanical Graduated Compression Stockings (GCS) Intermittent Pneumatic Compression (IPC) Anticoagulants Low-Dose Unfractionated Heparin (LDUH) Low-Molecular-Weight Heparin (LMWH/fondaparinux) Vitamin-K-Antagonists (VKA) Chest 2004; 126: 179S-187S.

ASA We recommend against the use of ASA alone as prophylaxis against VTE for any patient group (Grade 1A) Chest 2004; 126: 179S-187S. X Antiplatelets: -ASA Screening for DVT We recommend against the routine use of DUS screening at the time of

hospital discharge in asymptomatic patients following major orthopedic surgery (Grade 1A) Chest 2004; 126: 338S-400S. Levels of Thromboembolism Risk in Surgical Patients Without Prophylaxis Risk Stratification Patients are stratified as: Low Risk Moderate Risk

High Risk Highest Risk Chest 2004; 126: 338S-400S. High Risk DVT, % Surgery in patients with multiple risk factors (age >40 yr, cancer prior VTE) Calf

40-80 Proximal 10-20 PE, % Clinical Fatal 4-10 0.2-5 Hip or knee arthroplasty, HFS Major trauma; SCI Successful Prevention Strategies: LMWH (>3,400 U daily), fondaparinux, oral VKAs (INR, 2-3), or IPC/GCS + LDUH/LMWH Chest 2004; 126: 338S-400S.

Orthopaedic Surgery Elective Hip Surgery Highest risk Elective Hip Arthroplasty For patients undergoing elective THR, we recommend the routine use of one of the following three anticoagulants: LMWH (at a usual high-risk dose, started 12 h before surgery or 12 to 24 h after surgery, or 4 to 6 h after surgery at half the usual high-risk dose and then increasing to the usual high-risk dose the following day)

fondaparinux, (2.5 mg started 6 to 8h after surgery) Adjusted-dose VKA started preoperatively or the evening after surgery (INR target, 2.5; INR range, 2.0 to 3.0) [all Grade 1A] Chest 2004; 126: 338S-400S. Elective Hip Arthroplasty We recommend against the use of:

ASA Dextran Low-dose unfractionated heparin Graduated compression stockings Intermittent pneumatic compression Venous foot pump As the only method of thromboprophylaxis in these patients (Grade 1A) Chest 2004; 126: 338S-400S. Elective Hip Arthroplasty Underlying values and preferences We have not recommended the use of: fondaparinux over LMWH and VKA

Or the use of LMWH over VKA Because we place a relatively low value on the prevention of venographic thrombosis and a relatively high value on minimizing bleeding complications Chest 2004; 126: 338S-400S. Elective Knee Surgery Highest risk Elective Knee Arthroplasty For patients undergoing elective TKA, we recommend routine thromboprophylaxis using: LMWH (at the usual high-risk dose)

Fondaparinux Adjusted-dose VKA (target INR, 2.5; INR range, 2.0 to 3.0) all Grade 1A Chest 2004; 126: 338S-400S. Elective Knee Arthroplasty The optimal use of IPC is an alternative option to anticoagulant prophylaxis (Grade 1B)

We recommend against the use of any of the following as sole methods of thromboprophylaxis: ASA (Grade 1A) LDUH (Grade 1A) Or venous foot pump (Grade 1B) Chest 2004; 126: 338S-400S. Elective Knee Arthroplasty Underlying values and preferences We have not recommended: fondaparinux over LMWH and VKA Or LMWH over VKA Because we place a relatively low value on the prevention of venographic thrombosis and a relatively high value on minimizing bleeding complications

Chest 2004; 126: 338S-400S. Hip Fracture Surgery Highest risk Hip Fracture Surgery For patients undergoing hip fracture surgery, we recommend the routine use of: fondaparinux (Grade 1A) LMWH at the usual high-risk dose (Grade 1C)

Adjusted-dose VKA (target INR, 2.5; INR range, 2.0 to 3.0) (Grade 2B) Or LDUH (Grade 1B) Chest 2004; 126: 338S-400S. Hip Fracture Surgery We recommend against the use of ASA alone (Grade 1A) If surgery will likely be delayed, we recommend that prophylaxis with either

LDUH or LMWH be initiated during the time between hospital admission and surgery (Grade 1C+) We recommend mechanical prophylaxis if anticoagulant prophylaxis is contraindicated because of a high risk of bleeding (Grade 1C) Chest 2004; 126: 338S-400S. Distal Fracture of the Lower Extremity Isolated Lower Extremity Injuries We suggest that clinicians not use thromboprophylaxis routinely in patients with isolated lower extremity injuries (Grade 2A)

Chest 2004; 126: 338S-400S. Special Considerations Timing of Thromboprophylaxis Knee arthroscopy Thrombocytopenia Timing of Thromboprophylaxis

North American Dalteparin Trial (NAFT) We performed a randomized, double-blind trial Patients received either: Just-in-time subcutaneous dalteparin sodium once daily (initiated immediately pre-operatively or early post-operatively) Or warfarin during the acute hospital stay Hull et al. Arch Intern Med 2000; 160: 2199-2207. Hull et al. Arch Intern Med 2000; 160: 2208-2215. NAFT Multicentre: 28 centres in the United States and Canada Randomized Double-blind Hull et al. Arch Intern Med 2000; 160: 2199-2207. Hull et al. Arch Intern Med 2000; 160: 2208-2215.

NAFT Overall Study Design Phase I Day 0 (surgery) Phase II Day 62 Day 72 Day 352 Pre-op Dalteparin (2,500 IU) Dalteparin (5,000 IU) Post-op Dalteparin (2,500 IU)

Dalteparin (5,000 IU) Warfarin Placebo for Warfarin Venography Hull et al. Arch Intern Med 2000; 160: 2199-2207. Hull et al. Arch Intern Med 2000; 160: 2208-2215. Venography Frequency Frequency of of DVT: DVT: Acute

Acute Hospital Hospital Phase Phase DVT Rate (%) 25 Pre-operative dalteparin Post-operative dalteparin Combined pre- and postoperative dalteparin Warfarin 20 15 10 5 0

All DVT Proximal DVT Relative Risk Reductions Pre-op dalteparin vs warfarin: All DVT 55% (p<0.001); Proximal DVT 72% (p=0.035) Post-op dalteparin vs warfarin: All DVT 45% (p<0.001); Proximal DVT 72% (p=0.033) Combined pre- and post-op dalteparin vs warfarin: All DVT 50% (p<0.001); Proximal DVT 72% (p=0.009) Hull et al. Arch Intern Med 2000; 160: 2199-2207. Hull et al. Arch Intern Med 2000; 160: 2208-2215. Low-Molecular-Weight Heparin Prophylaxis Using Dalteparin in Close Proximity to Surgery Vs Warfarin

in Hip Arthroplasty Patients A modified dalteparin regimen in close proximity to surgery resulted in substantive risk reductions for all and proximal deep vein thrombosis, compared with warfarin therapy Such findings have not been observed with low-molecular-weight heparin therapy commenced 12 hours preoperatively or 12 to 24 hours postoperatively vs oral anticoagulants Hull et al. Arch Intern Med 2000; 160: 2199-2207. Low-Molecular-Weight Heparin Prophylaxis Using Dalteparin in Close Proximity to Surgery

Vs Warfarin in Hip Arthroplasty Patients Increased major but not serious bleeding occurred in patients receiving preoperative dalteparin Dalteparin therapy initiated postoperatively provided superior efficacy vs warfarin without significantly increased overt bleeding Hull et al. Arch Intern Med 2000; 160: 2199-2207. Odds Ratio Quadratic Fit For Study Odds Ratio For DVT Vs Number Of Hours From Surgery For The First

Dose Of LMW Heparin Hours from Surgery Upper and lower dashed lines indicate the 95% confidence interval for the true odds ratio Hull et al. Arch Intern Med 2001; 161: 1952-60 in Patients Undergoing Elective Hip Surgery Study Time of Initiation (hrs) Expt n/N (%) Ctrl n/N (%)

Relative Risk Relative p (95% CI*) Risk Value Hull (1993) Post:18-24 69/332 (20.8) 79/340 (23.2) 0.89 0.444 Hamulyak Pre:12 27/195 (13.8) 27/196 (13.8)

1.01 0.984 Francis 28/192 (14.6) 49/190 (25.8) 0.57 0.008 80/673 (11.8) 81/338 (24.0)

0.50 <0.001 Pre: 2 2 Hull (2000) Pre: Post:4-6 0.01 0.10 Favours LMWH * CI Fixed Hull et al. Arch Intern Med 2001; 161: 1952-60 1.00 10.0 100.0 Favours Oral Anticoagulants in Patients Undergoing Elective Hip

Surgery Time of Initiation (hrs) Expt n/N (%) Ctrl n/N (%) Relative Risk Relative p (95% CI*) Risk Value Hull (1993) Post:18-24 16/332 (4.8) 13/340 (3.8)

1.26 0.526 Hamulyak Pre:12 12/195 (6.2) 9/196 (4.6) 1.34 0.495 Francis 10/192 (5.2) 16/190 (8.4) 0.62

0.218 6/712 (0.8) 11/363 (3.0) 0.28 0.011 Study Pre: 2 Hull (2000) Pre: 2 Post:4-6 0.01 0.10 1.00 10.0 100.0

Favours LMWH * CI Fixed Hull et al. Arch Intern Med 2001; 161: 1952-60 Favours Oral Anticoagulants Timing of Initial Administration of Low-Molecular-Weight Heparin Prophylaxis Against Deep Vein Thrombosis in Patients Following Elective Hip Arthroplasty The timing of initiating LMWH significantly influences antithrombotic effectiveness The practice of delayed initiation of LMWH prophylaxis results in suboptimal

antithrombotic effectiveness without a substantive safety advantage Hull et al. Arch Intern Med 2001; 161: 1952-60 Timing of Prophylaxis For major orthopedic surgical procedures, we recommend that a decision about the timing of the initiation of pharmacologic prophylaxis be based on the efficacy-to-bleeding tradeoffs for that particular agent (Grade 1A) For LMWH, there are only small differences between starting preoperatively or postoperatively, and both options are acceptable (Grade 1A)

Chest 2004; 126: 338S-400S. Dosing Options for Patients Undergoing Hip Replacement Surgery Dose of Dalteparin to be Given Subcutaneously Timing of First Dose of 10-14 hr Dalteparin Pre-op Post-op start --Pre-op start-day of --surgery Pre-op start-evening 5000 IU before surgery4 1 2

3 4 Within 2 hr 4-8 hr Post-op Pre-op Post-op1 Period2 --2500 IU3 5000 IU qd 2500 IU 2500 IU3 5000 IU qd --- 5000 IU

5000 IU qd Or later, if hemostasis has not been achieved. Up to 14 days of treatment was well tolerated in controlled clinical trials, where the usual duration of treatment was 5 to 10 days postoperatively. Allow a minimum of 6 hours between this dose and the dose to be given on Postoperative Day 1. Adjust the timing of the dose on Postoperative Day 1 accordingly. Allow approximately 24 hours between doses. www.fda.gov/medwatch/SAFETY/2003/03Feb_PI/Fragmin_pdf Knee Arthroscopy Knee Arthroscopy We suggest clinicians do not use routine thromboprophylaxis in these

patients, other than early mobilization (Grade 2B) Chest 2004; 126: 338S-400S. Knee Arthroscopy For patients undergoing arthroscopic knee surgery who are at a higher than usual risk based on: Pre existing VTE risk factors Or following a prolonged or complicated procedure We suggest thromboprophylaxis with LMWH (Grade 2B)

Chest 2004; 126: 338S-400S. Thrombocytopenia The Harbinger of Doom for Unfractionated Heparin Risk for Heparin-Induced Thrombocytopenia with Unfractionated and Low Molecular-Weight Heparin Thromboprophylaxis: A Meta-Analysis Heparin-induced thrombocytopenia (HIT) is an uncommon but potentially devastating complication of anticoagulation with unfractionated heparin (UFH) or low-molecularweight heparin (LMWH) The inverse varianceweighted average that determined the absolute risk for HIT with LMWH

was 0.2%, and with UFH the risk was 2.6%. Most studies were of patients after orthopedic surgery Martel et al. Blood 2005; 106:2710-15 How Frequently is VTE in Heparin-Treated Patients Associated with Heparin-Induced Thrombocytopenia (HIT) VTE is associated with HIT infrequently (<1%) in LMWH-treated patients, yet often (approximately one in eight cases) in unfractionated heparintreated patients. Physicians should suspect the possibility of HIT if VTE develops during or soon after unfractionated heparin use; if

thrombocytopenia is present, alternative anticoagulation should be used until HIT is excluded. Levine et al. CHEST 2006; 130(3): 681-687. Electronic Medical Alerts So Simple, So Complex One of the most consistent findings in health research is the gap between evidence and practice. Durieux. N Engl J Med 2005: 352: 1034-1036 Appendix Obesity

The Safety of Dosing Dalteparin Based on Actual Body Weight for the Treatment of Acute Venous Thromboembolism in Obese Patients Our study suggests that it is safe to administer dalteparin at or near full dose based on actual body weight for the treatment of acute venous thromboembolism without an increased risk of major hemorrhage Limiting the dose of dalteparin to 18 000 IU could lead to an increased risk of recurrence of venous thromboembolism Al-Yaseen et al. J Thromb Haemost 2005; 3: 100-102. Dosing in Heavy-Weight/Obese Patients with the LMWH, Tinzaparin: A Pharmacodynamic Study

Subcutaneous tinzaparin dosing in heavy or obese patients is appropriate based on body weight alone; the dose need not be capped at a maximal absolute dose Hainer J et al. J Thromb Haemost 2002; 87: 817-823. Renal Impairment Is Impaired Renal Function a Contraindication to the Use of Low-Molecular-Weight Heparin? The use of a 30-mL/min (0.50-mL/s) cutoff is not justified, on the basis of currently available evidence, to select individuals at increased risk of accumulation when LMW heparin is used

The pharmacokinetic response to impaired renal function may differ among low-molecularweight heparin preparations Nagge et al. Arch Intern Med 2002; 162: 2605-2609. Evidence-Based Guidelines Recommendations Two Components: Methodological Quality of a Recommendation Grade A Grade B or Grade C Benefit/Risk

Grade A or Grade B The 7th ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 179S-187S. Venous Thromboembolism: Recognizing and Treating the Patient at Risk Peter Hanson, MD Medical Director of Orthopaedics Chief of Staff Grossmont Hospital, La Mesa, CA What Are We Trying To Prevent? Asymptomatic DVT?

Symptomatic DVT? All PEs? Fatal PEs? Post-phlebitic Syndrome? Dear Surgeon..

?? Virchows Triad Thrombosis Risk in Orthopedic Surgery Vascular Injury Venous Stasis Tourniquet Immobilization and bed rest

Surgical manipulation of the limb Very High Risk Endothelial injury Medium/High Risk Low/Medium Risk Hypercoagulability Increase in thromboplastin agents

DVT Prevention in Knee Replacement (Total DVT by venography) 80% 70% IPC LMWHs LD heparin Warfarin Stockings Untreated Aspirin DVT Rate (%) 60% 50%

40% 30% 20% 10% 0% Preventive Method Preventing DVT in TKR With Aspirin Aspirin Alone Is Not Effective Prophylaxis After TKR DVT Prophylaxis in Total Knee Replacement (TKR) LMWH vs Warfarin Proximal DVT 12 P<0.001

Total DVT 50 10 % Incidence 45.4 40 8 30 6

25.4 20 4 2 P0.001 11.4 1.7 10 0 Enoxaparin 30 mg sc

twice daily (n=173) Warfarin dose-adjusted INR 2-3 (n=176) Spiro et al. Blood. 1994;84(suppl 1):246a. 0 Enoxaparin 30 mg sc twice daily (n=173) Warfarin

dose-adjusted INR 2-3 (n=176) Bleeding in Total Knee Replacement (TKR) LMWH vs Warfarin P=0.04 40 33.5 30 23.3 20

% Incidence 10 2.3 5.2 3.4 6.4 0 Major Bleeding Wound Complications

(clinically significant) Warfarin dose-adjusted INR 2-3 Spiro et al. Blood. 1994;84(suppl 1):246a. Overall Bleeding Enoxaparin 30 mg sc bid Enoxaparin vs Warfarin in Total Knee Replacement Leclerc JR et al. Ann Intern Med. 1996, 124.619-626. Fondaparinux Targeted

Mechanism of Action Intrinsic pathway 1 Antithrombin 2 ATIII Extrinsic pathway 3 ATIII Fondaparinux ATIII Xa

Xa II IIa Fibrinogen ATIII = antithrombin III Adapted with permission from Turpie AGG, et al. N Engl J Med. 2001;344:619-625. Fibrin clot TKR Efficacy Results: Primary Endpoint Patients (%) 32

Incidence of patients with VTE up to day 11 28 24 RRR = 55% P = 0.0000003 27.8 12.5 n = 101 20 16 12 8 4

0 n = 45 Fondaparinux 2.5 mg QD (n=361) 95% CI Pentamaks 9.2; 16.3 Enoxaparin 30 mg BID(n=363) 23.3; 32.7 TKR Efficacy Results: Secondary Endpoint 30 Incidence of patients with VTE up to day 11

27.1 Patients (%) 25 Fondaparinux Enoxaparin 21.3 20 15 12.5 9.4 10

5.4 5 0 2.4 Any DVT P < 0.0001 Pentamaks Proximal DVT Distal DVT only P = 0.056 P = 0.000009 TKR Safety: Bleeding From 1st injection to day 11 all treated patients Fondaparinux 2.5 mg QD

Enoxaparin P 30 mg BID value Fatal bleeding, n 0 0 NS Nonfatal bleeding in critical organ, n 0 0

NS Bleeding leading to reoperation, n (%) 2 (0.4) 1 (0.2) NS Bleeding with transfusion 2 units and/or hg decrease 2 g/ dL, n (%) 9 (1.7) 0 (0.0)

<0.05 Other bleeding (minor), n (%) 15 (2.9) 21 (4.0) NS Pentamaks NS = no statistically significant difference Thromboprophylaxis for Knee Replacement Dalteparin vs Warfarin: Post-Hoc Analysis 40

Post-hoc analysis of patients (n=155) who received the 1st dose of dalteparin >7.5 hours postoperatively 30.0 30 Incidence of VTE 20 (%) 25.7 19.7 10 0 >7.5 and 9 hrs (n=61)

>9 and 12 hrs (n=74) >13 hrs (n=20) Time to first dalteparin dose VTE, venous thromboembolism Ayers DC et al. Poster presented at: American Academy of Orthopaedic Surgeons 2006 Annual Meeting; March 22, 2006; Chicago, IL. Rationale for Extended Prophylaxis After THR/TKR Cumulative Risk of Thromboembolic Events During First 3 Months Postoperatively All VTE 3

% Incidence PE Primary Knee Primary Hip 3 2 2 1 1

0 0 14 28 42 56 Days 70 84 Primary Knee

Primary Hip 14 28 42 56 Days The incidence of thromboembolic events does not stabilize until approximately 10 weeks after THR White et al. Arch Intern Med. 1998;158:1525-1531. 70 84

Rationale for Extended Prophylaxis % of patients with PE Incidence of PE within 3 months post-surgery 1.1% 1.0 0.8% 0.5 0 Total Hip Arthroplasty n = 19,000

White et al. Arch Intern Med. 1998;158:1525-1531. Total Knee Arthroplasty n = 24,000 Rationale for Extended Prophylaxis 80 76 % DVT Diagnosis 60 Made Post-Discharge 47 40

20 0 Total Hip Replacement Total Knee Replacement n=19,000 n=24,000 White et al. Arch Intern Med. 1998;158:1525-1531. Rationale for Extended Prophylaxis Median Time of DVT Diagnosis After Surgery (Days) Total Hip Arthroplasty

17 Days n=19,000 Total Knee Arthroplasty 7 Days n=24,000 0 5 White et al. Arch Intern Med. 1998;158:1525-1531. 10

15 20 NAFT Study Design Acute Phase Day 0 (surgery) Extended Phase Day 6 Day 7 Dalteparin (pre-op) Dalteparin Dalteparin (post-op)

Dalteparin Warfarin Switched to Placebo Screening visit Venography Day 35 Venography NAFT Results Extended Outpatient Phase (Day 35 2) (Patients with negative bilateral venograms at day 62)

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)

*RR=combined risk reduction vs. warfarin/placebo group P=0.023 P<0.001 P=0.007 P=0.003 Hull RD, et al. Arch Intern Med. 2000;160:2199-2207. 36.7 NAFT Results Extended Outpatient Phase (Day 35 2) (Patients with negative bilateral venograms at day 62) Treatment Group

Major 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 Hull RD, et al. Arch Intern Med. 2000;160:2199-2207. Enoxaparin: Extended Prophylaxis Comp et al 2001 JBJS:

Enoxaparin 7-10 days vs 4 wks, TKAs and THAs Extended dosing in THAs significantly decreased DVTs, no difference in TKAs No added bleeding risk Recent Studies: Extended Prophylaxis Eikelboom et al 2001 Lancet:

Meta-analysis of 3999 patients, THA and TKA, extended prophylaxis vs placebo/no tx Decreased Sxic DVT in hips (not knees) Decreased Asxic DVT in hips (not knees) 20 sxic DVT/1000 pts, 1death/1000 pts prevented $4-7 / day in UK, $24-28 / day in US No warfarin studies available Extended Prophylaxis: PENTasaccharide in HipFRActure Surgery (PENTHIFRA Plus) Results Incidence (%) of Events Placebo Fondaparinux RRR %

VTE* 35 1.4 95.9 DVT* 33.9 1.4 95.8 Proximal DVT*

15.8 0.9 94.3 Major Bleeding 0.6 2.4 Minor Bleeding 0.6 1.5 * p < 0.001

no significant difference between treatment groups Eriksson BI et al. Arch Intern Med. 2003;163:1337-1342. Extended Prophylaxis with Fondaparinux: Hip Fracture Repair 35.0% Patients (%) 35 30 25 RRR = 96% 20

n = 77 15 10 5 0 1.4% n=3 Fondaparinux (n=208) Eriksson BI et al. Arch Intern Med. 2003;163:1337-1342. Placebo (n=220) 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 Definition of Practice Guidelines Practice guidelines are systematically developed statements to assist practitioner and patient decisions about appropriate health care for specific clinical circumstances. Seventh ACCP Recommendations Seventh ACCP Recommendations

Seventh ACCP Recommendations 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 Multimodal Approach to VTED Prophylaxis for THA and TKA ACCP Orthopaedists

Paul F. Lachiewicz, M.D. Department of Orthopaedics University of North Carolina - Chapel Hill 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 These major changes in THA techniques suggest that our older ideas about chemoprophylaxis should be reconsidered in 2007 Multimodal Prophylaxis Preoperative Intraoperative Postoperative

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 Preoperative Autologous Donation

Retrospective study: 2043 patients Donation 1037; not 1006 DVT (venogram) P.E. (clinical) Bae et al. JBJS (B) 2001 Donation

Not Donation Not 9.0% 13.5% (p=0.003) 0.3% (ns) 0.7% Thromboembolism THR Anesthesia

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 Mechanical Prophylaxis THA Intraoperative use does not interfere with positioning, exposure, placement of implants Mechanical Prophylaxis THA 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 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 Venous Hemodynamics After THA 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 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 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 Materials & Methods Anesthesia Regional 95% 5%

General only Intraoperative mechanical bilateral, thigh-high sterile sleeve-operative limb single manufacturer Recovery room + until discharge Duplex ultrasound prior to discharge (day 3-8) Results - Mortality 30 day mortality 3 of 1032 (0.3%) 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. 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 Mechanical Prophylaxis with Aspirin 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 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% 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 Orthopaedists Concerns Prevention of

Fatal PE Symptomatic PE Symptomatic DVT Knee bleeding How important is it to prevent asymptomatic venogram or Duplex scan-detected thrombi? Orthopaedists 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 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? Increase in verious velocity (%) Venous Hemodynamics After TKA DPF A-V impulse system PlexiPulse

foot Foot Westrich et al. JBJS (B) 1998 PlexiPulse foot-calf Foot calf VenaFlow Flowtron DVT SCD system Calf Calf-thigh Jobst athrombic pump

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?

Two Mechanical Devices for Prophylaxis of Thromboembolism After TKA Prospective, randomized study Lachiewicz et al. JBJS (B), Nov 2004. University of North Carolina-Chapel Hill Patient Population 423 patients, 472 knees Mean age 66.8 yrs (23-94) Mean wt 87.3 kg (45-148)

Diagnosis DJD RA 25 Rev. 64 Other 27 307 Results Asymmetrical Compression Circumferential Compression

206 232 0 217 240 1 (.46%) 0 1 (.46%) Patients Knees Mortality Pulm. Embolism Thrombi Calf

Proximal 16 (6.9%) 15 1 36 (15%) p = .007 30 6 Thromboembolism Knee Procedure Asymmetrical Compression Circumferential Compression Unilateral, primary

Knees Thrombi 155 158 13 (8.4%) 26 (15.8%) p = 0.03 Patients (knees) 25 (50) 22 (44) Patients-thrombi Limbs-thrombi

1 (4%) 2 (4%) Bilateral, primary 5 (22.7%) 7 (15.9%) p = 0.09 p = 0.05 Personal TKA Series Calf IPC Plus Aspirin 1991 - present 856 TKAs Mortality (MI)

1 (0.12%) Symptomatic PE 3 (0.35%) DVT (Duplex) 66 (7.7%) (56 pts) Multimodal Prophylaxis TKA Venaflow + LMWH vs. Venaflow + Aspirin

Prospective, randomized 275 unilateral TKAs Duplex scan 3-5 days; 4-6 weeks DVT 14.1% vs 17.8% No difference between groups!

Westrich et al. J. Arthroplasty 2006 (p = 0.27) VTED Prophylaxis TKA What 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 Anticoagulation and the Orthopedic Patient: the Anesthesiologists Perspective Eugene R Viscusi, MD Director, Acute Pain Management Associate Professor Department of Anesthesiology Thomas Jefferson University, Philadelphia, PA 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 Overview 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 noncompressible 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. The Challenge 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 dont 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) 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 against epidural catheter Warfarin; target INR for TJA is 2.5 If achieved would preclude epidural catheters Chest. Sept 2004, supp 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 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

Authors calculated risk for females undergoing TKA 1:3,600! (female, age, spinal canal pathology, duration of catheter, thromboprophylaxis) Onethird of all spinal hematomas occurred in patients receiving thromboprophylaxis in accordance with current guidelines Moen V, et al. Anesthesiology. 2004;101:950-959 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 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. Can Epidural Anesthesia and Warfarin 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) Can Epidural Anesthesia and Warfarin be Coadministered?1 If the INR is elevated, should anticoagulation be reversed? Pulmonary embolism is a serious risk FFP is not without risk in itself Decision should be taken case by case and the thought process fully

documented! 1. Parvizi J, Viscusi ER. CORR, 2007( in press) 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 Standard Heparin and Regional 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 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 hasnt been written) ASRA consensus guidelines LMWH 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 DSousa G, Viscusi ER. ASA 2006 (abstract) 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 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 Fondaparinux

Factor Xa inhibitor with half-life of 21 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 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 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 Analgesic Techniques: Knee

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 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

Recently Viewed Presentations