Chapter 2. Early maintenance (10 days to 3 months) and LT treatment (> 3 months) of established VTE

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2.1. Bibliographic strategy resultss
2.2. Data extraction
2.3. Data analysis
2.4. Discussion
2.5. Recommendations – early maintenance treatment (10 days to 3 months) and long-term treatment (beyond 3 months) of established VTE


 

2.1. Bibliographic strategy results

As only one specific study on the duration of anticoagulation [SIRAGUSA2010] was identified, we included the four non-specific clinical trials on the treatment of VTE in cancer patients [MEYER2002] [LEE2003] [DEITCHER2006] [HULL2006].
The early maintenance treatment period corresponds to time beyond the tenth day up to the third month of anticoagulation and the long-term treatment of VTE corresponds to treatment indicated beyond the third month of anticoagulation.

HTA Questions

Studies included

HTA 1: Early maintenance and long-term use of LMWH

1 prospective study

[MONREAL2004]

6 randomized controlled trials

[LOPEZ-BERET2001] [MEYER2002] [LEE2003] [DEITCHER2006] [HULL2006] [ROMERA2009]

6 meta-analyses

[IORO2003] [FERRETTI2006] [LOUZADA2008[J1] ] [AKL2008A[J2] ] [AKL2008B[J3] ] [NOBLE2008]

HTA 2: Idraparinux

1 analysis of a subgroup of patients included in a randomized trial performed
in the general population (VANGOGH trial)

[VANDOORMAAL2010]

HTA 3: Duration of treatment

4 non-specific randomized controlled trials

[MEYER2002] [LEE2003] [DEITCHER2006] [HULL2006]

1 specific randomized controlled trial

[SIRAGUSA2010]

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2.2. Data extraction

Data extraction: cliquez pour télécharger

 

2.3. Data analysis

Early maintenance treatment (10 days to 3 months) and long-term treatment by use of LMWH

Studies

1 prospective study

[MONREAL2004]

6 randomized controlled trials

[LOPEZ-BERET2001] [MEYER2002] [LEE2003] [DEITCHER2006] [HULL2006] [ROMERA 2009]

6 meta-analyses

[IORO2003] [FERRETTI2006] [LOUZADA2008] [AKL2008A] [AKL2008B[J1] ] [NOBLE2008]

Agreement

Yes, except studies with low number of patients [DEITCHER 2006] [ROMERA2009]

Coherent data for cancer patients (3/5 good-quality trials and meta-analyses)

Quality of evidence

High (randomized, meta-analysis, consistency)

Results

Early maintenance treatment (10 days to 3 months) and long-term treatment by LMWH alone (beyond 3 months) vs. heparins (UFH/LMWH) with early VKA in cancer patients with VTE decreases the recurrence rate by 50% with no increase in bleeding risk or any effect on the mortality rate.

Conclusion
LMWH at therapeutic dose for 3 to 6 months is superior to VKA in the treatment of VTE
in cancer patients.

 

Long-term use of idraparinux

Studies

1 randomized trial non-specific to cancer patients

[VANDOORMAAL 2010]

Agreement

Not applicable

Quality of evidence

Low (randomized, inconsistency, indirectness, idraparinux not available, so move down 2 grades)

Results

For early maintenance treatment (10 days to 3 months) and long-term treatment (beyond
3 months) of VTE in cancer patients, idraparinux is as effective as VKA with the same rate
of bleeding.

Conclusion
There are not enough data to evaluate the efficacy of idraparinux, which has now been withdrawn form the market.

 

Duration of anticoagulation

Studies

4 randomized controlled trials not specifically designed to evaluate the duration
of anticoagulation
[MEYER2002] [LEE2003] [DEITCHER2006] [HULL2006]

1 specific randomized controlled trial

[SIRAGUSA2010]

Agreement

Impossible to determine because of only one specific study

Quality of evidence

Low (a randomized trial but serious indirectness; 4 non-specific studies)

Results

Early maintenance treatment (10 days to 3 months) and long-term treatment by LMWH alone (beyond 3 months) are validated in cancer patients.

There is no study comparing 3 vs. 6 months of LMWH, but two specific positive studies used
a 6-month regimen. It is important to distinguish between the duration of anticoagulation and
the duration of LMWH treatment.

In patients with DVT, after 6 months of anticoagulation, the use of:

  • Doppler US is not reliable and remains debated at this stage
  • Use of D-dimer assay to determine the need for further anticoagulation is not well documented

 


 [J1]B et C

Conclusion
Among studies conducted in a cancer patient population, two used LMWH for six months
[LEE2003, DEITCHER2006], the two others for three months [MEYER2002, HULL2006].
No specific study assessed the optimal duration of anticoagulation in cancer patients.
The use of D-dimer assay and the presence of residual thrombosis on Doppler US cannot
be recommended to determine the duration of anticoagulation.

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2.4. Discussion

The benefit of long-term use of LMWH over VKA is well documented with 3 positive
randomized trials. These results consistently showed that in cancer patients with VTE,
compared with short-term heparin followed by VKA, early maintenance treatment (10 days to 3 months) and long-term treatment by LMWH (3 to 6 months) significantly reduced the risk of VTE recurrence by approximately 50% without increasing the bleeding risk; this treatment had  no effect on mortality. In all the selected trials, the safety in terms of bleeding risk, in patients receiving long-term LMWH, was at least as good as in patients with cancer treated with shortterm  heparin followed by VKA. Several meta-analysis focused on the treatment of VTE in cancer patients confirmed the importance of the pivotal trials.
Whenever possible, it is better to prescribe the same LMWH at the same dosage and the same duration as those noted in the studies. When these LMWH are not available on the market, it is best to treat patients with another LMWH than with VKA. The following table indicates the different drugs used in these studies.

Drug Dosage and duration Study
Dalteparin
200 IU/kg/day for 1 month150 IU/kg/day for 5 months
CLOT[LEE2003]
Tinzaparin 175 IU/kg/day for 3 months LITE[HULL2006]
Enoxaparin 1.5 mg/kg/day for 3 months CANTHANOX[MEYER2002]
Idraparinux

2.5 mg/week first dose, then 2.5 mg/week or 1.5 mg/week
if creatinine clearance <30 mL/min

For 3 or 6 months

VANGOGH subgroup[VANDOORMAAL2010]

For early maintenance treatment and long-term treatment periods, there is only one study comparing idraparinux and VKA, which corresponds to the analysis of cancer patients included in the VANGOGH trial. Therefore, the data for cancer patients are drawn from a subgroup analysis and should be interpreted with caution. Thus it is not possible to exactly evaluate  the efficacy of idraparinux, which is no longer available. In the VANGOGH trial, idraparinux was not biotinylated and no antidote is available for this drug in the event of major bleeding.

Cancer DACUS is the only study evaluating an individual marker for assessing the duration of anticoagulation in an active cancer population [SIRAGUSA2010]. The absence of residual venous thrombosis (RVT) of the lower limbs could be of help to identify patients at low risk for recurrent VTE, who could safely stop LMWH after 6 months [SIRAGUSA2010].
However, no clinical trial has compared 3 months of LMWH vs. 6 months or more in cancer patients. The value of RVT is not well documented in either the general population or in cancer patients and the screening of RVT is not useful in patients without confirmed DVT of the lower limbs [DOUKETIS2010]. Therefore, in patients with DVT, after 6 months of anticoagulation, the use of Doppler US is not reliable and remains debated at this stage, especially in cancer patients who are at high risk of recurrence. Similarly, the value of D-dimer assay has been tested in the general population, but is not documented to be of help to determine the need for further anticoagulation in cancer patients. For all these reasons, the duration of LMWH recommended by the working group is at least three months. It is important to distinguish between the duration of LMWH treatment and the duration of anticoagulation, since many patients, especially those with active cancer or those treated with chemotherapy or anti-angiogenic therapy, are still at high risk of VTE after six months of anticoagulant therapy.

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2.5. Recommendations – early maintenance treatment (10 days to 3 months) and long-term treatment (beyond 3 months) of established VTE

R1. LMWH are preferred over VKA for the early maintenance treatment (ten days to third month) and long-term treatment (beyond 3 months) of VTE in cancer patients

Quality of evidence

High

Balance between desirable and undesirable effects

Favorable

Values and preferences

Daily subcutaneous injection, no variability, no uncertainty

Costs (resource allocation)

Not considered

Level of recommendation

Strong

 

 

R2. Idraparinux is not recommended for the early maintenance treatment (10 days to 3 months) and long-term treatment (beyond 3 months) of VTE in cancer patients. Idraparinux is currently not available on the market.

Quality of evidence

Low

Balance between desirable and undesirable effects

Uncertain

Values and preferences

Easier to use

Costs (resource allocation)

Not considered

Level of recommendation

Weak

R3. LMWH should be used for a minimum of three months to treat established VTE in cancer patients. However, in this setting the largest study treated patients for six months.

Quality of evidence

High

Balance between desirable and undesirable effects

Favorable

Values and preferences

Daily injection, no variability, no uncertainty

Costs (resource allocation)

Not considered

Level of recommendation

Strong

 

 

 

R4. After 3 to 6 months, termination or continuation of anticoagulation (LMWH or VKA) should be based on individual evaluation of the benefit-risk ratio, tolerability, patients’ preference and cancer activity

Quality of evidence

Not applicable (no data)

Balance between desirable and undesirable effects

Depending on the benefit-risk ratio

Values and preferences

Daily injection, no variability, no uncertainty

Costs (resource allocation)

Not considered

Level of recommendation

Best practice

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