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Rationale for Thromboprophylasis. High Prevalence of VTEAdverse Consequences of VTEEfficacy and effectiveness of thromboprophylaxisHighly efficacious in prevention of DVTHighly efficacious in prevention of symptomatic VTE and fatal PEDVT prevention prevents PECost effectiveness has been demonstrated.
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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 RCTs with consistent results
Grade B RCTs 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 RCTs 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 RCTs
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