VTE Prevention: From Filters to No Current Disclosures Fondaparinux - PDF document

6/1/2013 VTE Prevention: From Filters to No Current Disclosures Fondaparinux • Prior Support: Glaxo; Kendall; Rhone-Poulenc M. Margaret Knudson MD U. California, San Francisco CASE PRESENTATION • 21 year old chef stabbed in the Mission • Hypotensive on arrival with evisceration • Massive transfusion; thoracotomy • “tacos in the field”: stomach repair x 2 • Splenectomy; distal pancreatectomy • Extubated after just 24 hours • 3 days later: fever, tachycardia 1

6/1/2013 Case Presentation Continued • Full-dose anticoagulation with heparin • Lower GI bleed with drop in Hematocrit • Transfused; IVC Filter placed • Prophylatic doses of enoxaparin • Eventually transitioned to Coumadin Historical Perspectives Historical Perspectives “ A study of protocols of 9,882 postmortem exams • 124 trauma patients: venograms including death from injury…in the traumatic • Fracture patients: 35% venous thrombosis group embolisms were found in 61 cases(3.8%) • Thrombus found within 24 hours of injury and in the non-traumatic group in 222 cases (2.6%). Statistically, this appears to be a • Both injured/uninjured extremity significant difference.” • 2/3rds with DVT-asymptomatic Freeark et al, 1967 J.S. McCartney, 1934 2

6/1/2013 Incidence of Occult PE after INCIDENCE: OCCULT DVT Trauma • 349 injured patients: screening venography* • 90 consecutive patients; ISS> 9 • None receiving prophylaxis • Asymptomatic; no DVT • Proximal DVT rate: 18% • Chest CT: between 3-7 days • PE rate: 2% (43% mortality!!) • 22 had clot on CT; 4 were major! • 30% were receiving prophylaxis * Geerts et al, NEJM 1994 Schultz et al J Trauma 2004 METHODS THROMBOEMBOLISM AFTER TRAUMA AN ANALYSIS OF 1602 EPISODES FROM THE ACS NATIONAL • Data source: NTDB (1994-2001) TRAUMA DATA BANK Annals of Surgery 2004 • Data analysis: - Demographics M. Margaret Knudson MD Danagra G. Ikossi MD - Nature/severity of injuries Linda Khaw BA Diane Morabito RN, MPH - Complications/outcomes Larisa S. Speetzen BA • Survey: participating trauma centers The University of California, San Francisco - VTE risk factors/protocols 3

6/1/2013 RISK FACTOR ANALYSIS RESULTS • 450,375 patients included Risk Factor * Odds Ratio • 84% blunt injuries Shock on admission (BP < 90 mHg) 1.95 • 31% ISS>10 Age > 40 yrs. 2.29 • 998 pts: DVT (0.36%) Head injury (AIS > 3) 2.59 • 522 pts: PE (0.13%) • 82 pts: both DVT/PE Pelvic fracture 2.93 • PE mortality: 18.7% Lower extremity fracture 3.16 Spinal cord injury with paralysis 3.39 * Greenfield 1997, 2000; Knudson 1994, 1996 p < .0001 for all factors MULTIVARIATE ANALYSIS RISK FACTOR ANALYSIS (CONT’) Risk Factor Odds Ratio Risk Factor Odds Ratio Head injury (AIS  3) 1.24 Major surgical procedure 4.32 Major operative procedure 1.53 Lower extremity fracture (AIS  3) 1.92 Venous injury 7.93 Age  40 years 2.01 Ventilator days > 3 10.62 Venous injury 3.56 Ventilator days > 3 8.08 p < .0001 for all factors p  0.0125 for all factors 4

6/1/2013 PROPOSED ALGORITHM “APPEARANCES ARE DECEPTIVE”* Injured Patient High Risk Factor VERY High Risk Factor (OR for VTE = 4-10) (OR for VTE = 2-3) • Age ≥ 40 • Major operative procedure • Pelvic fx • Venous injury • Lower extremity fx • Ventilator days > 3 • Shock • 2 or more high risk factors • Spinal cord injury • Head trauma (AIS ≥ 3) Contraindication for heparin? No Yes Contraindication for heparin? Mechanical compression Yes No LMWH* and *Critical Evaluation of Vena Cava Plication: and serial CFD mechanical Bergen et al . Arch Surg 1964 OR temporary Mechanical LMWH* compression IVC filter compression *Prophylactic dose Historical Perspectives IVC Plication • IVC Ligation: post-op edema/ulceration • 1850 : Rudolph Virchow described PE • IVC Ligation: Sudden hypotension! • Recognized origin in femoral/pelvic veins • IVC Plication: absorbable sutures: • 1910 : Trendelberg ligated IVC for PE unpredictable • 1948 : Only 48 cases • 1964 : IVC Clip of IVC ligation 5

6/1/2013 “Filter Fever” IVC Filters: Indications • Recurrent VTE despite adequate anticoagulation • Documented VTE but with contraindications to anticoagulation • Complications while on anticoagulation Greenfield: Textbook of Surgery From Filter Fever to Filter Failure Prophylactic Vena Cava Filters? • Problems: • Technical - Recurrent PE: 3% • Timing - No protection against DVT • Truth - 10%: caval thrombosis • Trievable (as in Re) - permanence: leg edema • Tale - migration/IVC perforation - timing: 6% PE within 24 hours 6

6/1/2013 TIMING TRUTH Independent Risk Factors Odds Ratios • PE-occurs within 24 hours of injury: 6%* Head Injury (AIS>3) 1.24 • PE-seen on CT on day 1: 38%** Major Operation 1.53 • Early PE: highest in patients with fractures Lower Extremity Fx (AIS>3) 1.92 • For filter to be effective: placement in ED? Age > 40 years 2.01 Venous Injury 3.56 Ventilator Days >3 8.08 *Owens 1997 **Scalea 2007 Knudson et al: Analysis of 1602 Episodes of VTE; NTDB. Annals of Surgery, 2004 7

6/1/2013 TRUTH: PART II Retrievable Filters: “NOT” • May be retrieved within 5 days • 3,883/450,375: IVC FILTERS • May be left in place: 30 days? • 86%: PROPHYLACTICALLY • Solution for high risk patients? • Leads to 3-fold increase use • 410 PATIENTS: NO RISK FACTOR! • AAST study: >400 patients • Only 22% were retrieved! • $100,000/ PE prevented Antevil J Trauma 2006 Karmy-Jones J Trauma 2007 Hospital-Specific Risk Factors for Filter FICTION FEVER (AS IN “PULP”) Fever • 263 Northern California Hospitals • Frequency of VCF for VTE varied widely • Risk of getting a filter for acute VTE: -Admission to Rural Hospital -Admission to small hospital -Admission to private hospital -Not admitted to Kaiser JAMA 2013 8

6/1/2013 Fondaparinux Fondaparinux For The Prevention Of • Synthetic, non-heparin polysaccharide Venous Thromboembolism In High-risk • Long half life: once-daily dosing Trauma Patients • Excreted unchanged by kidney • Effective in orthopedics and general surgery • Previously untested in trauma J.P. Lu, MD and M. Margaret Knudson U. Of California, San Francisco Mechanism Of Action Study Objectives • To evaluate the efficacy and safety of • Binds to antithromin III, which inactivates factor fondaparinux for DVT prophylaxis in trauma Xa, preventing thrombin formation patients • To implement a VTE prevention protocol based on stratified risk factors • To measure Fondaparinux anti Xa activity in trauma patients 9

6/1/2013 Hypotheses Methods • Subjects: consecutive trauma admissions • VTE rate would be less than 5% in high-risk • Inclusion criteria: trauma patients with Fondaparinux – Age > 18 – Risk factor for VTE • Fondaparinux would NOT cause bleeding – Anticipated hospital stay > 5 days • Exclusion criteria: • Anti-Xa activity would be therapeutic – Prisoners – Pregnant women Proposed Algorithm Protocol Injured Patient High Risk Factor VERY High Risk Factor • Enrollment after (OR for VTE = 2-3) (OR for VTE = 4-10) consent • Age ≥ 40 • Major operative procedure • Ultrasound on • Pelvic fx • Venous injury • Lower extremity fx • Ventilator days > 3 admission and Q 5-7 • Shock • 2 or more high risk factors days • Spinal cord injury • Included both upper • Head trauma (AIS ≥ 3) Contraindication for heparin? and lower extremities • Fondaparinux within 36 No Yes Contraindication for heparin? Mechanical hours compression Yes No FND and and serial CFD mechanical OR temporary Mechanical FND: 2.5mg compression IVC filter compression 10

6/1/2013 Results: Enrollment Results: Risk Factors Enrolled Patient, n = 106 80 65% 70 No fondaparinux fondaparinux 60 n=17 n=89 Percentage 47% 50 40 5 1 5 76 25% 30 20% 19% 12 5 17% 20 2 7% 10 No 0 fondaparinux fondaparinux Major Age>40 LE Fx SBP<90 Mech Pelvic Fx Venous n=81 Operation Vent>72hr injury excluded n=6 excluded DVT risk factor n=2 n=12 excluded after late crossover n=5 Results: Incidence Of DVT Results: Incidence Of DVT 33.3% 33.3% 35 35 30 30 25 25 20 20 % % 15 15 10 10 2.5% 2.5% 5 5 0 0 fondaparinux No fondaparinux fondaparinux No fondaparinux 2/81 2/6 2/81 2/6 11

6/1/2013 Results Results: Anti Xa Activity • 2 DVTs in Fondaparinux: 1 with PIC line; 1 on 0.4 initial scan prior to receiving drug* 0.35 0.3 0.3 0.25 • No bleeding associated with Fondaparinux mg/L 0.2 0.15 • No thrombocytopenia 0.1 0.05 0.05 0 Trough Peak • No other major AEs identified *intent to treat Fondaparinux levels Summary • Fondaparinux has several advantages: – No risk of HIT – Once daily dosing: improves compliance – Cost effective • No major bleeding episodes or AEs 12