Chapter 4. Prophylaxis of VTE in surgical cancer patients

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4.1. Bibliographic strategy results
4.2. Data extraction
4.3. Data analysis
4.4. Discussion
4.5. Recommendations – prophylaxis of VTE in surgical cancer patients


 

4.1. Bibliographic strategy results

For the comparison of LMWH or UFH with placebo or no treatment, one of the three metaanalyses focused on gynecologic patients [EINSTEIN2007] and the randomized controlled trial included few patients. The literature search was performed without including prophylaxis of VTE in cancer patients undergoing neurosurgery (see Chapter “specific cases”). When external compression devices were considered, the meta-analysis in neurosurgical cancer patients was included in the bibliographic search [COLLEN2008]. This meta-analysis is also discussed in the chapter on prophylaxis of VTE in cancer patients undergoing neurosurgery.

HTA Questions

Studies included

HTA 1: LMWH or UFH vs. placebo or no treatment

1 randomized controlled study

[SHUKLA2008]

3 meta-analyses

[MISMETTI2001] [EINSTEIN2007] [OATESWHITEHEAD2005[J1] ]

HTA 2: LMWH vs. UFH

3 randomized controlled trials

[ENOXACAN1997] [BAYKAL2001] [MCLEOD2001]

3 meta-analyses

[MISMETTI2001] [OATESWHITEHEAD2005] [AKL2008[J2] ]

HTA 3: Comparison of drugs

2 randomized controlled trials

Fondaparinux vs. dalteparin [AGNELLI2005]

Nadroparin vs. enoxaparin [SIMONNEAU2006]

HTA 4: Dose of LMWH

1 randomized controlled trial

Dalteparin 2500 IU vs. 5000 IU

[BERGQVIST1995 ]

HTA 5: Extended duration

4 randomized controlled trials

[LAUSEN1998] [RASMUSSEN2006] [BERGQVIST2002] [KAKKAR2010]

1 meta-analysis           

[AKL2008[J3] ]

HTA 6: External compression devices

3 randomized controlled trials

[TURPIE1989] [DICKINSON1998] [MAXWELL2001]

1 meta-analysis in neurosurgical patients [COLLEN2008]


 

4.2. Data extraction

4.2: data : Cliquez pour télécharger

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4.3. Data analysis

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LMWH or UFH compared to placebo or no treatment

Studies

3 meta-analyses

[MISMETTI2001] [EINSTEIN2007] (gynecologic patients), [OATESWHITEHEAD2005]

1 randomized controlled study (with few patients)

[SHUKLA2008]

Agreement

Yes

Quality of evidence

High (randomized trials, meta-analysis)

Results

In the RCT, there was no difference between LMWH and placebo in the rates of recurrence and bleeding In 2 of 3 meta-analyses [J1] [MISMETTI2001] [OATESWHITEHEAD2005], LMWH and UFH were superior to placebo or no prophylaxis in the prevention of postoperative VTE in cancer patients.

In 1 meta-analysis [MISMETTI 2001], the rate of any bleeding was higher with LMWH than with placebo or no treatment.

 

 

LMWH vs. UFH

Studies

3 randomized controlled trials

[ENOXACAN1997] [BAYKAL2001] [MCLEOD2001]

3 meta-analyses

[MISMETTI2001] [OATESWHITEHEAD2005] [AKL2008[J2] ]

Agreement

Yes

Quality of evidence

High

Results

In the clinical studies, LMWH and UFH showed the same efficacy with a trend towards less [J3] bleeding with LMWH.

In the meta-analyses, UFH given 3 times a day was as effective as LMWH [AKL2008[J4] ], but LMWH
once a day appear to be superior to UFH twice a day. The rate of bleeding was the same with UFH and LMWH.

 

Conclusion:
LMWH and UFH are superior to placebo or no prophylaxis in the prevention of postoperative VTE in cancer patients.

UFH x3/day is as effective as LMWH x1/day

LMWH x1/day seems superior to UFH x2/day.

There is no data to conclude on the superiority of one type of LMWH over another one.


 [J1]j’aurais dit les trois (?), pour DVT en tout cas

 [J2]2008D

 [J3]more – dans ENOXACAN et McLeod, c’est même significatif dans Mc Leod

 [J4]2008D

Comparison of drugs

Studies

2 randomized controlled trials

Fondaparinux vs. dalteparin [AGNELLI2005]

Nadroparin vs. enoxaparin [SIMONNEAU2006]

Agreement

Not applicable

Quality of evidence

Low (randomized, indirectness for one study, imprecision because of a non-inferiority study with a secondary endpoint)

Results

Nadroparin (2850 IU) is at least as effective as enoxaparin (4000 IU) with less major bleeding

In one study including two-thirds of cancer patients, fondaparinux compared to dalteparin is associated with less VTE recurrence and with a trend towards an increase in bleeding.

Conclusion
There is insufficient evidence to conclude on the superiority of fondaparinux over dalteparin
(1 study with two-thirds of cancer patients) or on the superiority of nadroparin over enoxaparin (1 study showing the same rate of venous thromboembolic events but with a difference in the rate of bleeding events).

 

Dose of LMWH

Studies

1 randomized controlled trial

Dalteparin 2500 IU vs. 5000 IU

[BERGQVIST1995 ]

Agreement

Not applicable

Quality of evidence

High (one randomized study but with a large effect size)

Results

For prophylaxis a high dose of LMWH is superior to a low dose

Conclusion
One study with a large effect size showed that a high dosage of LMWH is superior to a low dosage of LMWH in the prevention of VTE in surgical cancer patients.

 

Extended duration of prophylaxis

Studies

4 prospective randomized studies

[LAUSEN1998] [RASMUSSEN2006] [BERGQVIST2002] [KAKKAR2010]

1 meta-analysis           

[AKL2008[J1] ]

Agreement

No: 2 negative studies (but one was stopped before the calculated number of patients was achieved), 2 positive studies

Quality of evidence

Moderate (randomized trials, inconsistency, one study with limitations)

Results

There is little evidence for better efficacy of extended prophylaxis, but a trend towards a higher risk of bleeding was reported in one study [BERGQVIST2002] .

Conclusion
Four weeks of LMWH reduced the rate of postoperative VTE after major laparotomy surgery in cancer patients. The superiority of extended duration of LMWH (4 weeks) cannot be generalized to all cancer patients undergoing  major abdominal surgery for cancer, but may be considered in selected patients without a high risk of bleeding.

 


 [J1]2008E

External compression devices

Studies

3 randomized studies

[TURPIE1989] [DICKINSON1998] [MAXWELL2001]

1 meta-analysis in neurosurgical patients [COLLEN2008]

Agreement

Not applicable (different external compression devices were used)

Quality of evidence

Low (randomized but serious study limitations due to the differences in study design, study population and the external compression device used, inconsistency and imprecisions, so move down two grades)

Results

To prevent VTE in major abdominal or pelvic surgery for gynecologic malignancies, ECD and LMWH appeared equivalent

For prophylaxis after surgery for brain tumors:

  • GCS + IPC had the same efficacy as GCS alone, and both were superior to no prophylaxis.
  • In neurosurgical patients, LMWH were superior to ECD despite an increase of minor bleeding but with no increase in intracranial bleeding or in major bleeding.

Conclusion

External compression devices (ECD) are superior to no prophylaxis but inferior to LMWH. There are insufficient data to conclude on the superiority of one type of ECD or one ECD regimen over others.

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4.4. Discussion

Cancer patients undergoing surgery have an increased risk of VTE as compared to those
without cancer. Therefore, VTE prophylaxis after surgery is warranted in cancer patients. The risk is increased depending on the type of surgery. In general, it is commonly acknowledged that surgeries with a high risk of VTE are laparotomy, laparoscopy, thoracotomy and brain surgery lasting more than 30 minutes. Breast cancer surgery is considered to be associated with a lower risk of VTE, even in the case of breast reconstruction [PANUCCI2009].
Several methods of prophylaxis have been investigated in cancer patients undergoing surgery:
low-molecular-weight heparins (LMWH), unfractionnated heparin (UFH) and external
compression devices (ECD). Three meta-analyses have shown that LMWH and UFH are both superior to placebo or no prophylaxis in the prevention of VTE in cancer patients
[MISMETTI2001] [EINSTEIN2007] [OATESWHITEHEAD2005]. For VTE prophylaxis, both LMWH and UFH have overall the same efficacy. However, LMWH once daily seem to be superior to UFH twice daily. UFH three times daily is as effective as LMWH once daily. The use of LWMH and UFH as VTE prophylaxis in cancer patients is acceptable with respect to bleeding risk. In several studies in cancer patients undergoing major abdominal or pelvic surgery, the occurrence of bleeding did not differ significantly, in terms of major and minor bleeding, between LMWH and UFH [ENOXACAN1997] [BAYCAL2001] [MISMETTI2001]. The latter metaanalysis did not only concern abdominal surgery [MISMETTI2001]. Of note, significantly more bleeding events with LMWH vs. UFH were reported in one study [MCLEOD 2001].
Prophylaxis is started 12 to 2 hours before surgery and should be continued up to 7-10 days after surgery. However, the optimal duration of VTE prophylaxis in cancer patients after surgery remained to be determined. In patients undergoing major abdominal or pelvic surgery,extended prophylaxis reduced the incidence of VTE in certain studies [BERQVIST2002] [RASMUSSEN2006], but this finding was not confirmed in other studies [LAUSEN1998] [KAKKAR2010]. Therefore, an extended duration (>4 weeks) of prophylaxis should be considered in patients undergoing major abdominal surgery, especially those with a low bleeding risk and a high risk of VTE recurrence.

The administration of a high dose of LMWH before cancer surgery was associated with
significant reduction of VTE compared to the standard dose: 8.5% vs. 14.9%; p<0.001
[BERGQVIST1995]. The occurrence of bleeding in cancer patients did not differ between
the higher dose and the standard dose. As a consequence, we recommend the higher dose
of LMWH as VTE prophylaxis in cancer patients undergoing surgery.

As shown below several dosages of LMWH have been assessed in clinical trials.

LMWH Dalteparin 5000 IU/day for 8-9 daysDalteparin 2500 IU/day for 7 days

Nadroparin 2850 IU/day for 7-11 days

Enoxaparin 40 mg/day for 10±2 days

Enoxaparin 25 mg/day for 10±2 days

3 studies

1 study

1 study

3 studies

1 study

Anti-FXa Fondaparinux 2.5 mg/day for 5-9 days

1 study

LMWHextended use Tinzaparin 3500 IU/day for 3 weeks (after 7 days postoperatively)Enoxaparin 40 mg/day for 25-31 days (28 days)

Dalteparin 5000 IU/day for 21 days (after 7 days postoperatively)

Bemiparin sodium 3500 IU/day for 28 days

1 study

1 study

1 study

1 study

LMWH for braintumors during

hospitalization *

Nadroparin 7500 IU/dayDalteparin 2500 IU/day

Enoxaparin 40 mg/day

Enoxaparin 30 mg/day

Enoxaparin 20 mg/day

1 study

1 study

2 studies

1 study

1 study

* see Chapter “special cases : brain tumors”
The role of ECD (GCS + IPC) in VTE prophylaxis in cancer patients is unclear. There is poor and inadequate distinction in the literature between GCS and IPC. These prophylactic measures are often grouped together in studies, and there has been no head-to-head comparison. This may create confusion and inappropriate interpretation of the results. A few studies have addressed this problem. In a study of patients undergoing major abdominal or pelvic surgery for a known or suspected gynecologic malignancy, LMWH and ECD appear to have the same rates of recurrence and bleeding [MAXWELL2001]. Because only one study has compared heparins and ECD in abdominal and pelvic surgery, it is impossible to know their respective efficacy, and ECD alone are indicated as VTE prophylaxis whenever LMWH and UFH are contraindicated. Due to
the lack of data, no recommendation can be made regarding the type of device (GCS or IPC) used as VTE prophylaxis.
There is considerable uncertainty related to the thromboembolic risk after laparoscopic
procedures, especially in cancer patients. Some studies seem to indicate that the risk of VTE is lower with laparoscopic procedures than with comparable open procedures. In other studies, laparoscopic surgy could be associated with longer operation times than open surgery.
Nevertheless, the risk of VTE could be higher in cancer patients than in non-cancer patients, even in the case of laparoscopic procedures [GEERST2008]. For this reason, the experts recommend similar prophylaxis for laparoscopic surgery as for laparotomy in cancer patients.
Neurosurgery in cancer patients may be associated with an increased risk of intracranial
bleeding. As in patients without brain tumors, VTE prophylaxis after surgery for malignant brain tumors with LMWH, UFH and ECD has been shown to be superior to no prophylaxis.
Prophylaxis with LMWH or UFH in these patients is recommended to be started
postoperatively. The risk of minor bleeding is increased when LMWH is started
postoperatively. No increase in major bleeding was observed in published studies

[DICKINSON1998]. There were five cases of bleeding complications (four cases of intracerebral bleeding and one epidural hematoma) among the enoxaparin-treated patients, with no such complications for the SCD-treated group, this difference being not statistically significant [DICKINSON1998].
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4.5. Recommendations – prophylaxis of VTE in surgical cancer patients

R1. Use of LMWH once a day or low dose of UFH x3/day is recommended to prevent postoperative VTE in cancer patients. Pharmacological prophylaxis should be started 12 to 2 hours preoperatively and continued for at least 7 to 10 days. There are no data allowing conclusion on the superiority of one type of LMWH over another

Quality of evidence

High

Balance between desirable and undesirable effects

Overwhelming evidence of benefit

Values and preferences

LMWH once a day is more convenient

Costs (resource allocation)

Not considered

Level of recommendation

Strong

 

 

R2. There is no evidence to support fondaparinux as an alternative to LMWH for the prophylaxis of postoperative VTE in cancer patients

Quality of evidence

Low

Balance between desirable and undesirable effects

Undetermined

Values and preferences

Similar

Costs (resource allocation)

Not considered

Level of recommendation

Weak

 

 

R3. Use of the highest prophylactic dose of LMWH to prevent postoperative VTE in cancer patients is recommended

Quality of evidence

High

Balance between desirable and undesirable effects

Favorable

Values and preferences

Equal

Costs (resource allocation)

Not considered

Level of recommendation

Strong

 

R4. Extended prophylaxis (4 weeks) to prevent postoperative VTE after major laparotomy in cancer patients may be indicated in patients with a high VTE risk and low bleeding risk.

Quality of evidence

Moderate

Balance between desirable and undesirable effects

Increase of bleeding risk

Values and preferences

Longer duration of injection

Costs (resource allocation)

Not considered

Level of recommendation

Weak

 

 

R5. The use of LMWH for the prevention of VTE in cancer patients undergoing laparoscopic surgery may be recommended in the same way as for laparotomy.

Quality of evidence

Not applicable (No data)

Balance between desirable and undesirable effects

Increase of bleeding risk

Values and preferences

Daily injection

Costs (resource allocation)

In some countries the price of LMWH may influence the choice

Level of recommendation

Best practice

 

 

R6. Mechanical methods are not recommended as monotherapy except when pharmacological methods are contraindicated

Quality of evidence

Low

Balance between desirable and undesirable effects

Undetermined benefit

Values and preferences

No injection

Costs (resource allocation)

Not considered

Level of recommendation

Weak