VTE Prevention

1. VTE Prevention Roxie M. Albrecht, MD, FACS Associate Professor of Surgery University of Oklahoma

2. Most hospital patients have one or more risk factors for VTE. Risk factors are cumulative. Most hospital patients have one or more risk factors for VTE. Risk factors are cumulative.

3. Incidence 10-40% in medical or general surgery patients 40-60% following major orthopaedic surgery 10% hospital deaths attributed to PE

4. Absolute Risk of DVT in Hospitalized Patients

5. Consequences of Unprevented VTE Symptomatic DVT and PE Fatal PE Costs of investigating symptomatic patients Risks and costs of treating unprevented VTE Increased future risk of recurrent VTE Chronic post-thrombotic syndrome Massive PE usually occurs without warning and there is often no potential to resuscitate patients with this complication. Prevention of symptomatic DVT and PE are improtant objectives because of the acute morbidity substantial consumption of resources and longterm sequelae of the clinical and economic significance. Chronic post phlebitic syndrome – chronic leg swelling, discomfort, dermatitis, leg ulcers, Prophylaxis is most appropriate to reduce sequela, better than screening strategies and reliance on symptoms or signs of early DVTMassive PE usually occurs without warning and there is often no potential to resuscitate patients with this complication. Prevention of symptomatic DVT and PE are improtant objectives because of the acute morbidity substantial consumption of resources and longterm sequelae of the clinical and economic significance. Chronic post phlebitic syndrome – chronic leg swelling, discomfort, dermatitis, leg ulcers, Prophylaxis is most appropriate to reduce sequela, better than screening strategies and reliance on symptoms or signs of early DVT

6. Thromboprophylaxis reduces VTE events PE is the most common preventable cause of hospital death Highest ranked safety practice - Appropriate use of VTE prophylaxis Overwhelming evidence that thromboprophylaxis reduces adverse patien outcomes while decreasing overall cost. Risks – bleeding – no good evidence that appropriately used thromboprophylaxis has a desirable risk/benefit ration and is cost effective.Overwhelming evidence that thromboprophylaxis reduces adverse patien outcomes while decreasing overall cost. Risks – bleeding – no good evidence that appropriately used thromboprophylaxis has a desirable risk/benefit ration and is cost effective.

7. Risk Factors for VTE Surgery Trauma Immobility, paresis Malignancy Cancer therapy Previous VTE Increasing age Pregnancy and postpartum Estrogen-containing oral contraception or HRT Selective estrogen receptor modulators Acute medical illness Heart or respiratory failure Inflammatory bowel disease Nephrotic syndrome Myeloproliferative disorders Paroxysmal nocturnal hemoglobinuria Obesity Smoking Varicose veins Central venous catheterization Inherited or acquired thrombophilia

8. Risk Factor Stratification Individual Approach Individual predisposing factors and risk associated with current illness or procedure Group-specific prophylaxis Individual Approach drawbacks – Unable to confidently identify individual patients who do not require prophylaxis, it has not been subjected to rigorous clinical evaluation, and is logistically complex and likely associated with suboptimal compliance. Group specific prophylaxis – for most patient groups, sufficient numbers of randomized clinical trials are available to allow strong recommendations in regard to benefits and risks Individual Approach drawbacks – Unable to confidently identify individual patients who do not require prophylaxis, it has not been subjected to rigorous clinical evaluation, and is logistically complex and likely associated with suboptimal compliance. Group specific prophylaxis – for most patient groups, sufficient numbers of randomized clinical trials are available to allow strong recommendations in regard to benefits and risks

9. Guidelines for Prophylaxis American College of Chest Physicians Chest 2004 Grade I – Recommendations are strong and indicate that the benefits do or do not out weigh risks, burden and costs Grade 2 – Recommendations are less certain. Suggest feasibility, acceptability and cost related to implementation strategies.  Grade A – RCT’s with consistent results Grade B – RCT’s with inconsistent results or method weaknesses Grade C – Observational studies or generalizations from one group of patients in a RCT. A + is given if the generalizations are secure or overwhelming.

10. Methods of Prophylaxis Mechanical Methods Graduated Compression Stockings Intermittent pneumatic compression device Venous foot pump Studies Not blinded High rate of false negative scans Compliance in true practice – poor Acceptable option High risk for bleeding (Grade 1C+) Adjunct to anticoagulant prophylaxis (Grade 2A) Improves efficacy when used in combination with anticoagulant prophylaxis Attraction of mechanical methods – lack of bleeding potential, but less efficacious than anticoagulant based options. No mechanical based option hs shown to reduce the risk of death or PE. Trials are not blinded Poor compliance with all mechanical options Use with caution in patients with arterial insufficiency. When used must be of correct size, properly applied and removed only short periods of the day.Attraction of mechanical methods – lack of bleeding potential, but less efficacious than anticoagulant based options. No mechanical based option hs shown to reduce the risk of death or PE. Trials are not blinded Poor compliance with all mechanical options Use with caution in patients with arterial insufficiency. When used must be of correct size, properly applied and removed only short periods of the day.

11. Methods of Prophylaxis Aspirin Poor study methods Acceptable DVT screening – 38% ASA alone in only 1/3 of trials No significant benefit Small increased risk of major bleeding Poor results v. LMWH Not recommended alone for VTE in any patient group (Group 1A) ASA v ardeparin, LMWH and danaparoid ASA was inferior Hip fracture surgery – ASA v Danaparoid VTE detected in 44 % v 28 % of patients Hip or knee surgery – ASA v LMWH – risk reduction of VTE was 63% with LMWHASA v ardeparin, LMWH and danaparoid ASA was inferior Hip fracture surgery – ASA v Danaparoid VTE detected in 44 % v 28 % of patients Hip or knee surgery – ASA v LMWH – risk reduction of VTE was 63% with LMWH

12. Unfractionated Heparin &Low Molecular Weight Heparin Most widely used and studied prophylaxis Low molecular weight heparin have more predictable pharmacokinetic and pharmacodynamic properties due to consistent binding sites Dosing LMWH more cumbersome – Anti – Xa monitoring UFH – needs site specific validation of aPTT therapeutic range due to variability of reagents LMWH – ? Limited uses in renal failure and obesity – dose adjustments possible

13. Low Molecular Weight Heparin Reduced anti-factor IIa relative to anti-factor Xa activity More favorable benefit/risk ratio in animal studies Superior pharmacokinetic properties SC bioavailability near 100% More predicable dose response peak at 3-5 hr Monitoring Renal failure (CrCl < 30mL/Kg) & obesity Four hours post dose - anti-factor Xa level Enoxaparin 1.0 IU/mL, Tinzaparin 0.85 IU/mL, Nadroparin 1.3 IU/mL, Dalteparin 1.05 IU/mL Only the last is of clear clinical improtanceOnly the last is of clear clinical improtance

14. Reversal LMWH Protamine Neutralizes approx. 60% 1mg per 100 anti-factor Xa units LMWH 1 mg enoxaparin = 100 anti-factor Xa units ? Activated factor VIIa

15. General Surgery 46 RTC Low Dose Unfractionated Heparin v. placebo or no proph. Reduced DVT 22 to 9% Symptomatic PE 2 to 1.3% Fatal PE .8 to 3% Meta-analysis 5000 Units TID more efficacious than BID No increase in wound hematoma or bleeding

16. General Surgery LMWH Meta-analysis (Douketis Arch Intern Med 2002) 70 % reduction DVT v. no prophylaxis Nine meta-analysis and systematic reviews No difference in DVT LMWH and UFH Some trial fewer hematomas and bleeding complications with LMWH No difference in total mortality, fatal PE between LDUH 5000 units TID and LMWH

17. General Surgery Low Risk Minor Surgery < 40 years of age No additional risk factors Risk DVT Calf – 2% Proximal – 0.4% PE Clinical – 0.2% Fatal - <0.01% Prevention Strategies No specific prophylaxis; early mobilization Grade 1C+ Low risk surgery – hernia repair, outpatient surgeryLow risk surgery – hernia repair, outpatient surgery

18. General Surgery Moderate Risk Minor Surgery with additional risk factors Age 40-60 with no risk factors Major surgery, < 40 with no risk factors Risk DVT Calf - 10-20% Proximal - 2-4% PE Clinical - 1-2% Fatal - 0.1-0.4 % Prevention Strategies LDUH (5,000 units q 12 hours, start 1-2 hrs pre-op)* LMWH ( < 3,400 U daily)* (Grade 1A) Graduated compression stockings Intermittent Pneumatic Compression devices 46 RTC in general surgery compared LDH with no prophylaxis or placebo rate of DVT reduction was reduced from 22 to 9% LDUH and LMWH have similar efficacy and bleeding rates. Meta analysis BJSurg 1997 – 36 RCT extracted out general surgery studies LMWH and UFH can be assumed to be equivalent with respect to efficacy odds ration 0.99, fewer WHs were observed with LMWH in the gen surgery subgroup. No difference in general surgery of high v. low dose LMWH, except more wound hematomas in the high dose group. Clinical advantage of LMWH over LDUH include the once-daily administration and the lower risk of HIT Disadvantage is the cost of the LMWH A systematic review observed a significant 52% reduction in DVT rate with the use of GCS compared to no prophylaxis which is equivalent to a pooled OR of 0.3. GCS enhances the protective effect of LDUH Limitations of GCS include lack of standardization of the quality of the stockings, dificulty with fitting patients with unusual limb sizes or shapes and poor compliance with their use by both health care providers and patients.46 RTC in general surgery compared LDH with no prophylaxis or placebo rate of DVT reduction was reduced from 22 to 9% LDUH and LMWH have similar efficacy and bleeding rates. Meta analysis BJSurg 1997 – 36 RCT extracted out general surgery studies LMWH and UFH can be assumed to be equivalent with respect to efficacy odds ration 0.99, fewer WHs were observed with LMWH in the gen surgery subgroup. No difference in general surgery of high v. low dose LMWH, except more wound hematomas in the high dose group. Clinical advantage of LMWH over LDUH include the once-daily administration and the lower risk of HIT Disadvantage is the cost of the LMWH A systematic review observed a significant 52% reduction in DVT rate with the use of GCS compared to no prophylaxis which is equivalent to a pooled OR of 0.3. GCS enhances the protective effect of LDUH Limitations of GCS include lack of standardization of the quality of the stockings, dificulty with fitting patients with unusual limb sizes or shapes and poor compliance with their use by both health care providers and patients.

19. General Surgery High Risk Non-major surgery in age > 60 yr. or have additional risk factors Major Surgery > 40 or have additional risk factors Risks DVT Calf – 20-40% Proximal – 4-8% PE Clinical – 2-4 % Fatal – 0.4-1.0% Prevention Strategies LDUH (5,000 U q 8 hours) LMWH ( > 3,400 U daily) Grade 1A

20. General Surgery Highest Risk Surgery in patients with multiple risk factors Risk DVT Calf – 40-80% Proximal – 10-20% PE Clinical – 4-10% Fatal - 0.2 - 5% Prevention Strategies LDUH ( 5,000 q 8 hours) or LMWH ( > 3,400 U daily) with GCS and/or IPCGrade 1C+ Higher doses of LMWH provide greater protection than lower doses.Higher doses of LMWH provide greater protection than lower doses.

21. General Surgery Special Considerations High Risk of bleeding Properly fitted GCS and/or IPC (Grade 1A) Major Cancer Surgery Post hospital discharge prophylaxis with LMWH for 2-3 weeks (Grade 2A) Three clinical trial addressed the use of extended prophylaxis beyond the period of hospitalization following general surgery. One study 118 patients abdominal and thoracic surgery patients 4 weeks tinzaparin – no reductions in DVT compared to 1 week. 233 patients major abdominal surgery dalteparin 1 or 4 weeks. 16% v 6% DVT with duplex. A subgroup in these patients with malignancy had a significant risk reduction with Final – 332 abdominal and pelvic cancer surgery patients – enoxaparin 40 q day for 9 or 28 days venogram at 25 and 31 days showed significant decrease DVT with prolonged prophylaxia 12 to 5 %.Three clinical trial addressed the use of extended prophylaxis beyond the period of hospitalization following general surgery. One study 118 patients abdominal and thoracic surgery patients 4 weeks tinzaparin – no reductions in DVT compared to 1 week. 233 patients major abdominal surgery dalteparin 1 or 4 weeks. 16% v 6% DVT with duplex. A subgroup in these patients with malignancy had a significant risk reduction with Final – 332 abdominal and pelvic cancer surgery patients – enoxaparin 40 q day for 9 or 28 days venogram at 25 and 31 days showed significant decrease DVT with prolonged prophylaxia 12 to 5 %.

22. Vascular Surgery Risk Aortic Surgery - DVT – 0.9 - 12 % No prophylaxis – 41% Femorodistal – DVT – 0.7 – 9% No prophylaxis – 18% RPCT – 4 – Heparin during the procedure in all 1 - 49 patients – ABF – Belch Thromb Haemost 1979 LDUH 5000 U BID 4% DVT v placebo 24% DVT Stopped early due to significantly greater clinical bleeding 2 – 43 patients – Spebar Am J Surg 1981 No Benefit LDUH v no prophylaxis 3 - 100 patients – Aortic Surgery –Killewich Arch Surg 1997 LDUH plus GCS v no prophylaxis - No difference in DVT 4 – 233 patients – Aorta/Infraing. – Farkas Eur J Vas Surg 1993 LDUH 7500 Units BID v enoxaparin 40 mg daily for < 2 days No difference in DVT, major bleeding 2% in both groups Prevention Strategies No routine prophylaxis in patients without risk factors (Grade 2B) LDUH or LMWH in patients with risk factors (Grade 1C+)

23. Laparoscopic Surgery Laparoscopic Cholecystectomy J Soc Laparosc Surg 2001 587 patients 3% received thromboprophylaxis No DVT or PE Surg Laparosc Endosc 1997 153,832 patients Various thromboprophylaxis techniques Clinical DVT – 0.03% PE - 0.06% Fatal PE – 0.02% GI laparoscopy Surg Laparosc Endosc Precutan Tech 1999 2,384 patients LMWH DVT – 0.3% PE - None

24. Prospective Trials DVT following Laparoscopy 313 and 320 are the only randomized clinical trials of thromboprophylaxis in laparoscopic surgery patients.313 and 320 are the only randomized clinical trials of thromboprophylaxis in laparoscopic surgery patients.

25. Recommendations in Laparoscopy European Association for Endoscopic Surgery Intraoperative IPC for all prolonged laparoscopic procedures SAGES Same thromboprophylaxis options with laparoscopic procedures as for the equivalent open surgical procedures ACCP No risk factors – aggressive early mobilization (G1A) With risk factors – LDUH, LMWH, IPC or GCS (G1C+)

26. Major Trauma Highest Risk of all Hospitalized Patients Risk – without Rx exceeds 50% DVT Calf – 40-80% Proximal – 10-20% PE Clinical – 4-10% Fatal - 0.2 - 5% Risk with routine thromboprophylaxis DVT Calf – 27% Proximal – 7% Increased Risk Factors Spinal Cord injury, lower extremity or pelvic Fx, need for surgery, increasing age, femoral venous line insertion or major venous repair, prolonged immobility, prolonged ventilatory support and longer duration of hospital stay, +/- ISS PE is the 3rd leading cause of death in those who survive the first day.PE is the 3rd leading cause of death in those who survive the first day.

27. Trauma Prophylaxis Trials

28. Compression Devicesin Trauma Patients Meta-analysis IPC No RRR with IPC v. no prophylaxis Problems with use 1/3 unable to use Fractures, casts, dressing, poor compliance Foot Pumps RCT – DVT was 3x higher that with IPC Cohort Study – DVT rate 57%

29. LDUH v. LWMH in Trauma Patients Double blind, RCT (Geerts NEJM 1996) 344 major trauma without ICH 1st dose within 36 hours of injury No mechanical prophylaxis 5000 U LDUH v. 30 mg enoxaparin BID RRR DVT 30% and pDVT 58% for LMWH No significant difference in bleeding, transfusions or hematocrit changes Cost effective analyses favors LMWH (Shorr, CCM 2001)

30. Trauma Recommendations All patients with at least one risk factor receive thromboprophylaxis (G1A) LMWH as soon as considered ‘safe’ (G1A) If LMWH delayed – IPC (G1B) Continued thromboprophylaxis until mobility adequate with LMSH or VKA (G2C) Duplex ultrasound screening – high risk and suboptimal prophylaxis or no prophylaxis (G1C)

31. OUMC Trauma Protocol Trauma DVT Prophylaxix – Enoxaparin Criteria Enoxaparin 30 mg sq q12h - start between 24-36 hours after admission after HCT stable for patients requiring DVT prophylaxis if pt. Is immobile or projected to be immobile for > 24 hrs - femur, tibia, fibula fractures - any pelvic fracture - facial or abdominal or chest trauma on a ventilator - vascular repair - spinal cord injuries Hold drug for: - subdural hematoma - epidural hematoma - focal intracranial hemorrhage - intraventricular hemorrhage - subarachnoid hemorrhage - ocular hemorrhage - systemic coagulopathy - PTT > 40 sec or INR > 1.5 - Platelets < 70,000 - or a platelet decrease by 50% or platelets < 70,000 after enoxaparin started - unexplained drop in HCT > 5% - signs of active hemorrhage - hypersensitivity reaction to medication - serum creatinine of > 3 - if pt is going to OR hold morning dose - resume 12 hrs post operative Discontinue enoxaparin: - If pt is fully ambulatory

32. Spinal Cord Injury Highest Risk Risk DVT Calf – 40-80% Proximal – 10-20% PE Clinical – 4-10% Fatal - 0.2 - 5% Prevention Strategies Small RCT’s – LDUH and IPC – ineffective Multicenter trial (Spinal Cord Injury Thromboprophylaxis Investigators J Trauma 2003) 107 patients acute phase, 72 hours of injury, no diff UFH v. LMWH 476 patients in rehab, C2- T12 LDUH 5000 U TID/IPC v. enoxaparin 30mg BID Major VTE 16% v. 12%, no fatal PE and equal bleeding rates Uncontrolled studies Oral VKA – reduces symptomatic VTE IVC Filter placement Use has not been proven to decrease VTE/PE

33. DVT after Spinal Cord Injury

34. Acute Spinal Cord Injury VTE prophylaxis recommendations Recommend against the use of LDUH, GCS or IPC as single agents (G1A) GCS and/or IPC when anticoagulation is contraindicated early after injury (G1C+) Prophylaxis with LMWH once primary hemostasis is evident (G1B) Combined use of IPC and LDUH (G2B) or LMWH (G2C) as alternative to above Continuation of LMWH or oral VKA during rehabilitation phase (G1C)

35. Neurosurgery Risk Factors Intracranial surgery, active malignancy, length of procedure, presence of leg weakness and advance age. Highest risk - Malignant Brain Tumors 31% symptomatic DVT IPC with or without GCS - Most common Concern for intracranial/spinal bleeding 68% relative risk reduction – lowering DVT from 22 to 7% Heparin One RCT - LDUH v. no Rx – RRR of 82% 2 Studies – GCS v. GCS/LMWH postop Control DVT/pDVT – 26/12% Rx 19/7% Control DVT/pDVT – 33/13% Rx 17/5%

36. Craniotomy RCT – 100 patients - preop IPC + LDUH 5000 BID or IPC + dalteparin 2500 daily Intracranial bleed equal 1/49 v 2/51 DVT rate equal – 0/49 v. 2 asymptomatic/51 Pooled Data Intracranial hemorrhage in RCT’s 2.1% for postoperative LMWH 1.1% for mechanical or no prophylaxis Intracranial hemorrhage in meta-analysis Bleeding with post operative LMWH – 6.1% Bleeding with mechanical prophylaxis – 3.0%

37. Traumatic Brain Injury Norwood Arch Surg 2002 150 patients with Blunt TBI LMWH 24 hours after admission Marshall CT grade progression of ICH 23% had CT progression – 19% before LMWH and 6% after All with progression survived, none to OR DVT rate 2%

38. Neurosurgery Recommendations Major Elective Neurosurgery/Intracranial Surgery IPC, with or without GCS (Grade 1A) IPC, w or w/o GCS + LDUH (Grade 2B) IPC, w or w/o GCS + postoperative LMWH (G2A) High Risk Neurosurgery Patients Mechanical + LDUH or LMWH (G2B)

39. Critical Care Critical Ill patients have multiple risk factors for VTE, some predate admission ICU entry 990 patients with DUS at admit DVT rate 5.5%

40. DVT in Critical Care

41. DVT in Critical Care Patients 11,000 patients in a 28 center randomized clinical trial comparing LDUH and enoxaparin 324patients were included11,000 patients in a 28 center randomized clinical trial comparing LDUH and enoxaparin 324patients were included

42. Recommendations: Critical Care Assess all patients risk for VTE at admit (G1A) Moderate VTE risk – LDUH or LMWH (G1A) Medically ill or postoperative High VTE risk – LMWH (G1A) Major trauma, orthopaedic surgery High bleeding risk patients Mechanical Prophylaxis (G1C+)

43. New Antithrombotic Agents Ximelagatran Oral direct thrombin inhibitor Rapid absorption and conversion to melagatran predictable pharmacokinetics, no food interactions Hip and knee replacement (Lancet 2002, phase II trial) Melagatran 3mg BID/ximelagatran 24mg/d v dalteparin 5000 IU BID DVT 15.1 v 28.2% Fondaparinux synthetic pentasaccharides with selective inhibitor of activated factor X (NEJM 2001, Lancet 2002) RRR 56.4%/59.5% v. enoxaparin q day hip surgery RRR 22.6% v enoxaparin BID RRR 12.5% in Knee sugery higher bleedingBoth have better efficacy that LMWH for prophylaxis however cost effectiveness has not yet been proven

44. Conclusion Most strategies include LMWH Exception – high bleeding risk – GCS and IPS best option Renal failure – monitor Obesity - monitor Further research Laparoscopy Vascular Duration Safety of LMWH Neurosurgery New antithrombotic agents in nonorthopedic groups

46. Weight Based Heparin Dosing Unfractionated Heparin Treatment of Venous Thromboembolism Bolus – 80 Units/Kg Infusion – 18 Units/Kg/hour Monitoring Measure 6 hours after bolus Goal – Plasma heparin concentration of 0.3 IU/mL (by factor Xa inhibition – anti factor-Xa units) aPTT levels vary due to reagents and methods of clot detection and are inaccurate measures of heparin levels CAP and ACCP recommendation Therapeutic aPTT range calibrated with heparin levels equivalent to 0.3 – 0.7 IU/mL by factor Xa inhibition

47. Vitamin K antagonists Initiation of Oral Dose 5-10 mg for first 1-2 days – most patients < 5 mg for first days – elderly/elevated bleeding risk/liver disease/CHF/malnutrition Goal INR 2.0-3.0 Monitoring Initiation – daily, 2-3 X/wk for 1-2 weeks, when stable 1X/4 weeks Reversal Elevated INR Hold dose v. Oral Vitamin K (1 – 2.5 mg) Elective Surgery Hold for 4 days Hold for 4 days and initiate UFH or LMWH Serious/Life threatening Bleeding Vitamin K – IV, FFP, protamine, recombinant Factor VIIa Initiation of dose Reduce if age >60, The 2-3 INR goal is acceptable for most indicationsInitiation of dose Reduce if age >60, The 2-3 INR goal is acceptable for most indications

48. Hip or Knee Arthroplasty Highest Risk Risk DVT Calf – 40-80% Proximal – 10-20% PE Clinical – 4-10% Fatal - 0.2 - 5% Prevention Strategies LMWH ( >3,400 U daily) start before or within 24 hours of surgery Oral VKA (INR 2-3) preoperative or evening after surgery