Thromboprophylaxis (DVT and PE, VTE in Orthopaedics) - Dushan Atkinson 16/03/2004

Incidence

Risks after orthopaedic procedures WITHOUT prophylaxis

Procedure

Any DVT (Radiological)

Proximal DVT (Radiological)

Clinical DVT

Nonfatal PE

Fatal PE

THR

32%

16%

1.9%

1.2%

0.3%

TKR

66%

16%

9%

1.9%

0.4%

Hip #

46%

19%

7%

8%

4%


Predisposing factors

General - Previous history of DVT

Aging

Use of general anaesthetic c/w spinal anaesthetic

Virchow's triad- stasis, hypercoagulability and intimal damage

Factors affecting venous stasis

Factors causing hypercoagulability

Factors causing intimal injury

Immobility Paralysis Pregnancy Varicose veins Obesity Congestive cardiac failure Recent MI Infection Inflammatory Bowel disease

Malignancy COCP I ncreased blood viscosity Smoking Clotting abnormalities, AT III def, Factor V Leiden, Homocysteinuria, Sickle cell, Polycythaemia, Thrombocythaemia

Trauma

Investigations

For DVT

  • Venography gold standard- 97% accurate (70% for iliac veins), expensive invasive
  • Doppler US, B mode, 90% accurate for thigh DVT.Not as useful in calf or pelvic thrombi. Sensitivity of 79%, specificity of 98%
  • Radiolabelled fibrinogen can cause false positives and is expensive and time consuming
  • Impedance plethysmography, noninvasive and allows monitoring, but needs to be followed up by venography or US.

For PE - CXR may show hyperlucency VQ scan Gold standard pulmonary angiography

A concept of categorising risk and treating prophylactically according to category has long been used. This example by Salzman and Hirsch (3) is a little ambiguous in its classification, but the general principal is a sound one.

Risk Calculation in Surgery:

DVT

Prox. Vein Thrombosis

Fatal Pulmonary Embolism

Low Risk Groups

< 10 %

< 1%

0.01%

Moderate Risk Groups

10-40 %

1-10 %

0.1-1 %

High Risk Groups

40-80 %

10-30 %

1-10 %

Group

Factors

Low

Minor Surgery (<30mins); no other risk factors other than age

Major Surgery (>30mins); 40 yrs; no other risk factors

Minor Trauma or medical illness

Moderate

Major Surgery; >40 yrs or other risk factors

Major medical illness eg Ca, Cardiac, Pulmonary

Major Trauma or Burns

Minor Surgery with past thrombo/embolic event

High

Fracture or Major Orthopaedic Surgery to Pelvis/Lower Limb

Major Pelvic or Abdominal Surgery for Ca

Major Surgery, Trauma or illness with past thrombo/embolic event

Reproduced from Salzman & Hirsch (1982) Prevention of thromboembolism.

  • Therefore Most Orthopaedic operations are HIGH RISK
  • The formation of a DVT in the lower limb is variable according to operation. The frequency of certain sites of DVT is dependent on procedure. In many studies a venogram is performed to identify the DVT. Many of the DVT's included in these studies are subclinical, therefore producing a higher incidence than recognized in clinical practice. This is reflected by Ciccone (Ciccone 1996) with their quoted incidence of 83% in TKR
  • The majority of DVT's in THR are in the Femoro-Popliteal region. The majority of DVT's in TKR however are in the calf. 17% of these will propagate to the Thigh.
  • Pelvic fractures are more proximal still, with 35-65% of patients forming DVT's, that are mainly Iliofemoral in nature.(8)
  • No data could be found regarding DVT site in # NOF reduction and fixation. The incidence figures quoted for PE's do not appear to take into account the different treatment modalities, such as Hemiarthroplasty, DHS and AO screws.
  • It is widely thought that the more proximal DVT's have a greater probability of forming a PE. There is NO evidence to support or condemn this theory. However, with both THR and TKR forming Femoro-Popliteal DVT's, the risk factors for both procedures are present.
  • In summary, most of the lower limb surgery performed is on a population that already has a higher incidental risk of forming DVT's. This coupled with major orthopaedic surgery, itself being a high risk factor, makes these patients of very high risk. This is a generally accepted and researched opinion.

Treatment
Location of DVT


  • DVT occurring in only the calf (below the knee) rarely embolize. Treatment consists of bedrest at home and anti-inflammatory medications. Anticoagulants are not needed unless the DVT continues to propagate into the proximal veins of the knee or thigh. Clot propagation occurs in 10 percent to 30 percent of DVTs below the calf
  • DVT - Compression stocking and analgesia
  • Heparin IV (needing monitoring), followed by warfarin for 3 mnths or LMWH Tinziparin (not needing monitoring) 175units/kg OD followed by warfarin
  • PE - Supportive Measures, Oxygen, analgesia
  • Heparin IV(needing monitoring), followed by warfarin for 3 mnths or LMWH Tinziparin (not needing monitoring) 175units/kg OD followed by warfarin. Rarely thrombolysis, vena cava interruption.

Long term sequelae in survivors

Post thrombotic limb- incidence of clinical morbidity is not known

PREVENTION OF THROMBOEMBOLISM IN ORTHOPAEDICS

MECHANICAL PROPHYLAXIS

1) Graduated Compression Stockings (TEDS):

  • 'Patients who had total hip replacement and wore below-knee stockings had a significantly higher rate of proximal or major calf DVT (p = 0.03). This pattern was reversed in patients with total knee replacement who developed a significantly lower rate of proximal or major calf DVT with below-knee stockings (p < 0.05).

  • With the exception of below-knee stockings in knee replacement patients, graded compression stockings were ineffective in preventing DVT after hip or knee replacement surgery.' Hui et al.; JBJS(Br), 1996

  • Reduce the incidence of DVT from 54% to 20% (in surgical patients). Ishak et al., Br J Surg, 1981:

2) Calf and foot pumps

Proven to have a similar effect to chemical prophylaxis

Tend only to be used during the inpatient period and some events happen after this.

Also some problems with compliance

CHEMICAL PROPHYLAXIS

  1. Unfractionated heparin UFH

  2. Low Molecular weight heparin LMWH

  3. Oral Anticoagulants

  4. Aspirin

Dose and frequency

Enoxeparin(Clexane)

2000 units O.D

Dalteparin (Fragmin)

5000 units O.D

Minihep

5000 units B.D

Heparins

Inhibit Factor Xa . Heparin- binds to & enhances the activity of Antithrombin III. -> inhibits thrombin, factors IXa & Xa. (reversed w/ Protamine))

- Current favourite in the UK.

- More effective than heparin in orthopaedic prevention of DVT and PE.

- Excess of bleeding complications smaller with LMWH than with heparin

- Longer halflife therefore able to give only once daily

- Does not need monitoring

Oral anticoagulants

- Warfarin as effective as heparins but requires monitoring

- Popular in U.S.A

- Affects factors 11, V11, 1X and X (Vitamin K dependent) so can take up to 48 hours to become effective

Antiplatelet drugs eg Aspirin

- Reduces platelet aggregation & inhibits cyclooxygenase.

Prevention of PE and DVT with low dose aspirin: Pulmonary Embolism Prevention (PEP) Lancet 2000, 355(9212):1295-302,

  • Material and methods, OZ, NZ, UK, SA, Sweden

- Recruitment of 13356 patients with # NOF

- 4088 for elective arthroplasty

- Randomly allocated to receive aspirin 160mg OD for 5 weeks starting preop

- Or matching placebo

- Additional prophylaxis already used by the surgeons was allowed to go ahead

- Clinical diagnosis with confirmation by routine investigations were used to determine PE and DVT

  • Results for aspirin

In # NOFs

% reduction c/w placebo

Thromboembolism

36% from 2.5% to 1.6%

Total PE

43%

Fatal PE

58% from 0.6% to 0.3%

DVT

29%

    • Bleeding was increased by 6 per 1000 people treated

    • No spinal haemorrhages in those with spinal or epidural anaesthesia

    • R eduction by about a third for both PE and DVT in arthroplasty group , but NOT SIGNIFICTANT difference when compared with placebo!!!!!

Thromboprophylaxis after replacement arthroplasty. BMJ 2001; 322:686-687.

    • Intermittent pneumatic compression in 500 patients reduced DVT to 5%, with a 1% incidence of PE. Hooker et al. efficacy of prophylaxis against thromboembolism with intermittent pneumatic compression. JBJS 1999. 81A:690-696.

    • No prophylaxis, 50% DVT

    • 7 small studies. 419 TJR pats given aspirin c/w controls. DVT 52% c/w 51%.

    • 20 trials. 3000 TJR pats. LMWH. Resulted in reduction of DVT to 15%. Clagett et al, prevention of venous thromboembolism. Chest 1998. 114:531-560.

    • Recommendations of Warfarin, heparin or LMWH for at least 10 days, or extended if patient bedridden. Salvati et al. recent advances in venous thromboembolic prophylaxis during and after TJR. JBJS 2000; 82A:517-528.

Meta-analysis of thromboembolic prophylaxis after TKR. Westrich et al. JBJS 2000. 82:795-800.

Systematic review of all propective studies of patients undergoing TKR; 23 studies. 6001 patients.

Patients undergoing TKR who take warfarin c/w aspirin LESS likely to get a symptomatic DVT. NNT 8

Patients taking LMWH c/w aspirin LESS likely to get symptomatic DVT. NNT 6

Patients getting pneumatic compression c/w aspirin LESS likely to get symptomatic DVT. NNT 4 or warfarin NNT 6

No clear difference between LMWH and pneumatic compression

Too few symptomatic PEs for statistical significance.

Risk of and prophylaxis for venous thromboembolism in hospital patients. Second thromboembolic risk factors (THRIFT) concensus group. Phlebology 1998. 13:87-97.

Review of published data 1991-1997. 981 studies. Only randomised were used.

TJR - LMWH and pneumatic compression both reduce radiog. DVT after THR and TKR. LMWH more effective than UFH and dextran . LMWH as effective as warfarin in THR, and more than warfarin in TKR. Despite LMWH or mech. prophylaxis, DVT risk remains high in TKR (25-45%)

HIP # - LMWH, UFH, warfarin and dextran reduce radiog. DVT in hip # LMWH causes no bleeding problem after THR LMWH and warfarin cause small increase in absolute risk of bleeding in TKR Pneumatic compression does not increase bleeding.

Up to 33% develop venographic DVT by day 28-35 after surgery. This is reduced by prolonging LMWH to day 28-35. Therefore recommendations to extend prophylaxis up till this time. Though less than 2% of patients need readmission for thromboembolism after THR. Question of benefits??

Thromboprophylaxis and death after total hip replacement, Murray, JBJS. 1996, 78(6):863-70.

A publication widely quoted regarding thromboprophylaxis. This is an accumulation of many previous studies, dating as far back as the '60's, on which a meta-analysis was performed.

A total of 130,000 patients were included in the analysis, all of which had received a total hip replacement. A large population study, but is it representative of general population?

Authors have advised caution in interpretation of results as they felt the studies included were very varied in content and quality.

1. DVT

CHEMICAL

MECHANICAL

NONE

Authors

Source

n

UFH

LMWH

Warfarin

Aspirin

TEDS

Foot Pump

Antiplatelet Trialists' Collaboration

BMJ 1994

8400

25

34

Anglen et al.

Am J Orthop 1998

124

4

Borris et al.

Thromb Res 1991

206

6

Dahl et al.

Thromb Haemost 1997

308

19.3

31

Saunders & Grant

J Natl Med Assoc 1998

56

0

3

Torholm

JBJS Br 1991

112

19

35

Huir et al.

JBJS Br 1996

177

22

27

Warwick et al.

JBJS Br 1995

156

15.4

32.1

Santori

JBJS Br 1994

122

32

13.4

Harris et al

J Am Med Assoc 1972

100

28

Stranks

JBJS Br 1992

82

0

23

Ciccone

Comp Orthop, 1998

25

Francis et al

JBJS Br 1989

21

Francis et al

AAOS, 1995

101

38

Fitzgerald

AAOS, 1995

25

45

Ishak

Br J Surg, 1981

20

54

Bradley et al.

J Arthroplasty, 1993

80

27

7

Wilson et al.

JBJS, 1992

50

69

30

15.96

32.25

14

21

14.88

38.14

2. Pulmonary Embolism

The fatal PE (FPE) rate for different types of prophylaxis in studies starting in the 1970s, 80s and 90s. Differences between groups do not quite reach statistical significance (p = 0.051). The death rate for different types of prophylaxis in studies starting in the 1970s, 80s and 90s. Differences between groups are not statistically significant (p = 0.2)

'To demonstrate a significant reduction in the incidence of fatal PE would require about 30 000 patients in each arm of a trial (Murray et al 1995; Warwick, Williams and Bannister 1995)'

3. COMPLICATIONS:

Warfarin Major bleeds = 1-3%, Minor = 2-5% [Paiemont, JBJS(A), 1996] less bleeding complications than LMWH (although warfarin less effective) [Fitzgerald, AAOS, 1995][Hull, NEJM, 1993]

LMWH bleeding 14.3% and wound haematoma 10%. [Warwick, 1998]

LMWH vs. UFH: LMWH had a higher benefit to risk ratio. [Leizorovicz, BMJ, 1992] No difference - Meta-analysis [Nurmohamed, Lancet, 1992]

LMWH vs. Foot Pump: THR: More soft-tissue side effects in the patients on enoxaparin than in those with foot pump: there was more bruising of the thigh and oozing of the wound (p 0.001), postoperative drainage (578 compared with 492 milliliters; p = 0.014), [Warwick, JBJS(A), 1998]

13.8% had excessive bleeding or wound haematomas, as against none in the impulse pump group [Santori, JBJS(Br), 1994]. TKR: No significant difference wrt wound complications. [Funk, 1999]

Foot Pumps: TKR- 2% intolerant, 12% Discomfort [Funk, 1999] THR - 3% intolerant, 17% Discomfort [Warwick, JBJS(A), 1998]

Pneumatic Calf Compression (Flowtrons) vs. LMWH: Less blood transfusion requirements, Operative field 'drier'. Stone et al., Int Orthop, 1996

4. COST:

1. Enoxaparin vs. warfarin:

M. E. Saunders and R. E. Grant, J Natl Med Assoc 1998

56 Patients. Total savings with enoxaparin averaged $1253 per patient, or $137,886 over the study period. The incidence of deep vein thrombosis or pulmonary embolism was 0% with enoxaparin and 3% with warfarin. These data indicate that enoxaparin is a more cost-effective and efficacious regimen for thromboprophylaxis following hip replacement surgery than warfarin.

2. Enoxaparin vs. UFH

Dunn & Goa, - Pharmacoeconomics 1996

UK cost comparison reported an overall cost saving of pounds 20 per patient (figures from 1989 to 1990) with enoxaparin 40mg once daily subcutaneously over subcutaneous UFH 5000IU 3 times daily

5. Spinal vs. General anaesthesia:

The overall incidence of deep vein thrombosis was 20%. Nine patients (13%) developed deep vein thrombosis in the spinal group and nineteen (27%) in the general anaesthetic group (p < 0.05). Davis et al, JBJS(Br), 1989

6. Cemented vs. Uncemented Prostheses:

No Significant Difference wrt DVT incidence. [Laupacis, JBJS(B), 1996]

7. How long?

Detectable thrombus formation after hip arthroplasty is noted at about 48 hours and peaks at 5 days (distal and proximal thrombi), and there is secondary peak distal thrombi formation at 10 days. [Paiemont, JBJS(A), 1996]

308 Patients undergoing THR. The incidence of symptomatic pulmonary embolism (PE) from day 7 to day 35 was 2.8% in the placebo-treated group compared with zero in the dalteparin-treated group. This study shows that prolonged thromboprophylaxis with dalteparin. 5000 IU, once daily for 35 days significantly reduces the frequency of DVT [Dahl, et al., Thromb Haemost, 1997]

DVT following discharge. 179 hip arthroplasty patients with a negative venogram at 14 days post-op to receive either a placebo or enoxaparin for another 21 days. A second venography was then performed and DVT was detected in 7.1% of the enoxaparin patients and 19.3% of the placebo patients. There were no deaths or symptomatic PE during the study period.

233 patients to a placebo (116 patients) or enoxaparin (117 patients) after the whole group had received enoxaparin for 9 days while in the hospital. Patients underwent a venography 21 days after randomization, and the DVT rate was 39% in the placebo group versus 18% in the treatment group. There were no deaths but 9% symptomatic DVT in the placebo group and 2% in the treatment group.

Three large clinical series have recently looked at the incidence of post-discharge clinical events after joint replacement. Overall fatal PE rate was 0.1%, and the symptomatic DVT rate after discharge was 2.0%.

ACCP Guidelines 2004 American College of Chest Physicians

1986 first concensus on antithrombotic therapy in the USA. Task force of physicians and surgeons. Decision based on balance between benefits, risks and costs

Grade 1A = Randomised controlled trials. Unbiased consistent results. Strong recommendation to most patients, most circumstances, without reservation. Grade 1B = RCTs with limitations, inconsistent results or flaws. Strong recommendation, likely to apply to most patients. Grade 1C+ = No RCTs, but overwhelming evidence from observational studies. Strong recommendation to most patients in most circumstances. Grade 1C = Observational studies. Intermediate strength recommendation, may change when data stronger

Grade 2A = RCTs without limitations. Intermediate strength, best action may differ depending on circumstances of patient. Grade 2B = RCTS with important limitations. Weak recommendation. Alternative approaches may be better for some patients Grade 2C = Observational studies. Very weak recommendation. Other alternatives may be equally reasonable.

Prophylactic anticoagulant therapy recommended for 10-14 days after surgery 1A or beyond this time for high-risk patients or major orthopaedic surgery 2A .

Do NOT recommend routine Duplex USS at discharge or OPD in asymptomatic patients having orthopaedic surgery or having received these regimes.

For Elective THR

LMWH started 12 h before surgery, or 12-24 op 1A Warfarin dose adjusted for INR 2.5 (range 2-3) started preop or post-op 1A or dose adjusted heparin therapy started pre-op 2A Adjuvant prophylaxis with TED stockings or Pneumatic Compression 2C DO NOT recommend solely aspirin, dextran, Pneu com, UFH

For Elective TKR

LMWH or adjusted dose warfarin (INR 2.5) 1A Alternative: use of IPC DO NOT recommend UFH 1C+

For # Surgery

LMWH or adjusted dose warfarin (INR 2.5) 1B Alternative UFH 2B DO NOT recommend sole therapy aspirin 2A

For Trauma with risk factor for PTE

LMWH as soon as considered safe 1A , if delayed because of bleeding concerns use TEDs, pneumatic compression or both 1C . If prophylaxis suboptimal then screen high-risk patients with Duplex USS 1C . If Proximal DVT demonstrated and anti-coag is contraindicated then IVC filter 1C+ .

Acute Spinal cord injury, recommend LMWH 1B , with or without TEDs/pneumo compression combination 2B . But not Solely TEDs/PC/UFH. Recommend LMWH or full warfarin therapy during rehabilitation.

Recommend Fondaparinux (ARIXTRA - SANOFI) the LMWH of choice. Selectively inhibits factor Xa. EPHESUS trial. May 2003 Lancet. Randomized 2309 patients 16 EU countries elective THR. By day 11 DVT rate was 4% c/w enoxaparin 9%.

Fondaparinux compared with enoxaparin for prevention of VTE after hip fracture surgery. Eriksson. NEJM. 345:1298-1304. 2002. Day 11 VTE rate was 8.3% c/w 19.1%. sig. But no differences in death rate or bleeding.

Scottish Intercollegiate Guidelines Network 2002.

TKR/THR

- Mechanical prophylaxis can be considered

- Aspirin 150mg can be considered and continue for 35 days

- UFH or LMWH can be considered for 7-15 days up to 5 weeks in high risk patients

- Oral anticoagulants can be considered in those already taking warfarin

- Summary ; Pats should receive thromboprophylaxis : Mechanical, Pharmacological or both

# NOFs

- Early surgery <24 hrs

- Mechanical prophylaxis. PCs or foot pumps but NO evidence for TEDs!

- Aspirin 150mg should be given to ALL and continue for 35 days

- Heparin reserved only for patients at high risk, due to multiple risk factors or contraindications to aspirin or other mechanical prophylaxis

Trauma

- Spinal cord injury, major lower limb trauma or multiple trauma can give LMWH prophylaxis (unless contraindicated eg. Intracranial bleed risk)

- PCs or foot pump if LMWH contraindicated

- If LMWH or mechanical contraindicated eg. In POP, then aspirin 150mg for 35 days.


New Oral Anticoagulants


XIMELAGATRAN

Well tolerated. Peak concentration at 2 hours post dose. Short half-life. Fixed dosing every 12 hours. No Blood levels needed!

EXPRESS trial. Randomised. Blinded, placebo-controlled. Examined efficacy c/w enoxaparin to prevent VTE in 2800 TKR pats. Ximelagatran had sig. fewer DVTs or PE than enoxaparin. No difference in clinical bleeding.

EXULT trial. Randomised. Blinded. Placebo-controlled. 2301 pats.Comparing it to warfarin found it to be significantly better in TKRs, with similar bleeding.

BUT-   WITHDRAWN because of liver toxicity



                RIVAROXABAN    and    DABIGATRAN

Phase 3 results with the new oral anticoagulants rivaroxaban (Johnson & Johnson/Bayer) and

dabigatran (Boehringer Ingelheim)



  • The first major phase 3 study of rivaroxaban

RECORD 3 , suggests superior efficacy in the prevention of venous thromboembolism, with similar bleeding rates compared with enoxaparin in TKR patients undergoing knee-replacement surgery


  • Two phase 3 trials with dabigatran in hip/knee-replacement surgery.

In the RE-NOVATE trial, dabigatran showed similar results to enoxaparin 40 mg ,

But the USA RE-MOBILIZE study, failed to show equivalence to a higher dose of enoxaparin (60 mg).


                FACTOR Xa INHIBITOR

Phase 2 results with oral factor Xa inhibitor (PRT054021, Portola Pharmaceuticals)

The EXPERT study of total-knee-replacement surgery, randomizing to one of two oral doses of PRT054021 (15 mg or 40 mg twice daily) or enoxaparin (30 mg twice daily by subcutaneous injection) for 10 to 14 days. The primary efficacy end point was the incidence of VTE through day 10 or 14 measured by venography. Similar, but possibly not as good as Enozaparin.



A phase 2 study with another oral factor Xa inhibitor, apixaban (Bristol-Myers Squibb/Pfizer) , looks at the treatment of acute symptomatic DVT.
Apixaban at three doses showed comparable safety and efficacy to a low-molecular-weight heparin or fondaparinux followed by a vitamin-K antagonist. Phase 3 trials are now under way.


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