Chapter 7. Prophylaxis of catheter-related thrombosis

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7.1. Bibliographic strategy results
7.2. Data extraction
7.3. Data analysis
7.4. Discussion
7.5.Recommendations –Prophylaxis of catheter-related thrombosis


 

7.1. Bibliographic strategy results

 

HTA Questions

Studies included

HTA 1: VKA

5 randomized controlled trials

[BERN1990] [COUBAN2005] [HEATON2002] [RUUD2006] [YOUNG2009]

6 meta-analyses

[CARRIER2007] [AKL2007] [RAWSON2007] [KIRKPATRICK2007] [CHAUKIYAL2008] [AKL2008[J1] ]

HTA 2: UFH

1 randomized study

[ABDELKEFI2004]

HTA 3: LMWH

6 randomized trials

[MONREAL1996] [MISMETTI2003] [VERSO2005] [KARTHAUS2006] [NIERS2007] [DECICCO2009]

5 meta-analyses

[CARRIER2007] [AKL2007] [RAWSON2007] [J2] [KIRKPATRICK2007] [CHAUKIYAL2008]

HTA 4: Thrombolytics

1 non-randomized prospective study

[KALMANTI2002]

1 randomized double-blind study

[VANROODEN2008]

HTA 4: Type of CVC and insertion techniques

1 meta-analysis

[SABER2010]

3 randomized trials

[BIFFI2001] [CARLO2004] [BIFFI2009]

4 prospective non-randomized trials [LABOUREY2004] [LEE2006] [LUCIANI2001] [NIGHTINGALE1997]

6 retrospective studies

[EASTRIDGE1995] [CRAFT1996 [CADMAN2004] [CAERS2005] [MORAZIN2005] [MCLEAN2005]



 [J1]lequel ? dans la liste des références, je ne vois pas de titre évoquant CRT parmi les AKL2008. Dans PubMed j’ai trouvé cette ref, mais de 2011 :

 

Akl EA, Vasireddi SR, Gunukula S, Yosuico VE, Barba M, Sperati F, Cook D, Schünemann H. Anticoagulation for patients with cancer and central venous catheters. Cochrane Database Syst Rev. 2011 Apr 13;(4):CD006468. Review.

 

 [J2]Je ne vois pas de comparaison impliquant LMWH, ni table 33, ni dans le titre de l’article, ni dasn l’abstract que j’ai consulté sur PubMed (?)
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7.2. Data extraction

7.2: Data extraction: Cliquez pour télécharger

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7.3. Data analysis

 

VKA

Studies

5 randomized controlled trials

[BERN1990] [COUBAN2005] [HEATON2002] [RUUD2006] [YOUNG2009]

5 meta-analyses

[CARRIER2007] [AKL2007] [RAWSON2007] [KIRKPATRICK2007] [CHAUKIYAL2008][J1]

Agreement

Yes

4 randomized trials in agreement

4 meta-analyses in agreement

Quality of evidence

High

Results

VKA low dose:

In the most recent studies: similar CRT rate with and without VKA prevention (5% symptomatic CRT)

One meta-analysis showed a decrease of CRT, but no effect on PE in all CRT (few symptomatic and asymptomatic events) [KIRKPATRICK2007]

One positive study on asymptomatic CRT with VKA started before CVC insertion [DECICCO 2009[J2] ]

Low intensity VKA (INR 1-5 to 2):

One randomized study (1570 patients included and evaluated) showing a decrease of symptomatic CRT with an increased risk of bleeding [YOUNG 2009].

 

UFH

Studies

1 randomized study

[ABDELKEFI2004]

Agreement

Not applicable

Quality of evidence

Moderate (randomized, serious study limitation)

Results

Continuous intravenous infusion of UFH may decrease the incidence of symptomatic and asymptomatic CRT as diagnosed by Doppler US in bone marrow transplant recipients (adults and children)

 

LMWH

Studies

6 randomized trials

[MONREAL1996] [MISMETTI2003] [KARTHAUS2006] [VERSO2005] [NIERS2007] [DECICCO2009]

5 meta-analyses

[CARRIER2007] [AKL2007] [RAWSON2007] [KIRKPATRICK2007] [CHAUKIYAL2008]

Agreement

Yes

Quality of evidence

High

Results

The randomized trials showed no excess in major bleeding, but no benefit in preventing symptomatic VTE in the superior vena cava

Meta-analyses indicated a trend towards reduction of asymptomatic CRT or all CRT (asymptomatic and symptomatic) using different comparisons (VKA vs. no treatment[J3] , VKA + LMWH vs. no treatment)

 

Thrombolytics

Studies

1 non-randomized prospective study

[KALMANTI2002]

1 randomized double-blind study

[VANROODEN2008]

Agreement

Yes

Quality of evidence

Low (only one randomized study, but limitations as one study included few patients and one study evaluated CRT as a secondary endpoint, inconsistency)

Results

Neither study supported the use of fibrinolysis to prevent CRT in cancer patients.

 


 [J1]il y en a 6 au chapitre 7.1 Ici il manque le AKL2008 (existe-t-il ?)

 [J2]n’aurait-il pas fallu mettre cettte étude dans la liste des randomized controlled trials examinés pour VKA ? (car elle compare bien VKA à no treatment)

 

 [J3]pourquoi ici, dans la case LMWH ?

Conclusions
For the prevention of  CRT, when compared to no prophylaxis, there is no evidence to support:

  • the routine use of low dose of VKA (warfarin 1 mg )
  • the routine use of VKA to maintain an INR between 1.5 and 2
  • the use of continuous IV UFH or fibrinolytics
  • the routine use of LMWH

 

 

Type of CVC and insertion techniques

Studies

1 meta-analysis

[SABER2010]

3 randomized trials

[BIFFI2001] [CARLO2004] [BIFFI2009]

4 prospective non-randomized trials [LABOUREY2004] [LEE2006] [LUCIANI2001] [NIGHTINGALE1997]

6 retrospective studies

[EASTRIDGE1995] [CRAFT1996] [CADMAN2004] [CAERS2005] [MORAZIN2005] [MCLEAN2005]

Agreement

Yes

Quality of evidence

High (meta-analysis + consistency)

Results

Independent risk factors for CRT include:

–  Catheter tip location: SVC-RA junction or RA

–  Insertion site: jugular vein better than subclavian, right side better than left side

–  Type of catheter: valved tips = open-ended tips, implanted ports better than external
catheter

–  Past medical history of CVC

–  Doppler US guidance: no data

Conclusion
The catheter should be located:

  • at the SVC-RA junction
  • in the jugular vein rather than the subclavian vein

Implanted ports are better than a SC catheter

There is no evidence to support the use of Doppler US guidance to prevent CRT.
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7.4. Discussion

Central venous catheter thrombosis is an important cause of morbidity in cancer patients [LEE2007; AKL2008A]. Consequently, many investigators have attempted to identify an effective CVC-DVT prophylaxis regimen. An open, randomized study by Bern and colleagues suggested that low-dose warfarin (1 mg daily) could significantly reduce the incidence of CVC-DVT in cancer patients (37.5% vs. 9.5%) [BERN1999]. However, several subsequent RCTs failed to demonstrate any protective effect with fixed low-dose warfarin [HEATON2002] [COUBAN2005] [RUUD2006] [YOUNG2009]. In the WARP study, a large multicenter open-label study comparing no warfarin, fixed dose warfarin (1 mg daily) and adjusted-dose warfarin (INR 1.5 to 2.0), Young and colleagues demonstrated that adjusted-dose warfarin was associated with a significant reduction in CRT (13/473, 2.7% vs. 34/471, 7.2%; OR=0.38; 95%CI:
[0.20-0.71]; p=0.002), but also with a trend towards more major bleeding events (16/473, 3.4%vs. 7/471, 1.5%; p=0.04) when compared with fixed-dose VKA [YOUNG2009]. Randomized, controlled trials of LMWH showed a similar findings. A small, open RCT conducted by Monreal et al. demonstrated that dalteparin 2500 IU once daily significantly reduced CVC-DVT compared with no treatment (1/16, 6.2% vs. 8/13, 61.5%; p=0.002) [MONREAL1996].
However, subsequent larger RCTs employing prophylactic regimens of dalteparin, nadroparin and enoxaparin were unable to demonstrate reductions in CVC-DVT [VERSO2005] [KARTHAUS2006] [NIERS2007] [DECICCO2009]. A small, open-label trial of continuous infusion UFH (100 IU/kg/day) performed in adult and pediatric bone marrow transplant patients noted a significant reduction in CVC-DVT (1/65 1.5% vs. 8/63 12.6%; p=0.03) [ABDELKEFI2004].
However, this regimen has not been replicated perhaps because it is rather cumbersome and labor-intensive to administer.
Two studies tested thrombolytic agents in the prevention of CVC-DVT [KALMANTI2002] [VANROODEN2008]. In a small study in 30 pediatric oncology patients, Kalmanti et al found that 10000 units of urokinase administered once weekly reduced the rate of CVC thrombosis from 81% (9/11) to 43% (7/15) [KALMANTI2002]. No bleeding was noted. In contrast, Van Rooden et al found no difference in symptomatic CRT, catheter-related and non-catheterassociated infections and premature catheter removal with 5000 units of urokinase administered three times weekly compared with placebo [VANROODEN2008].
Six meta-analyses of anticoagulant CVC thromboprophylaxis have been performed [CARRIER2007] [RAWSON2007] [KIRKPATRICK2007] [AKL2007] [CHAUKIYAL2008] [AKL2008].
Carrier et al. and Kirkpatrick et al. did not note any reduction in symptomatic CVC-associated DVT, while Akl et al. found a 44% relative risk reduction in symptomatic CVC-DVT episodes when the results of all anticoagulant modalities were combined [AKL2007]. Kirkpatrick et al.
reported that VKA and LMWH were associated with a 63% and 28% relative risk reduction, respectively, in all CVC-DVT (asymptomatic plus symptomatic) [KIRKPATRICK2007], whereas Chaukiyal et al. did not, likely due to differences in study inclusion criteria [CHAUKIYAL2008].
No study demonstrated the superiority of any anti-thrombotic regimen (e.g., VKA vs. LMWH).
No differences in major bleeding or mortality between control patients and patients receiving anticoagulants were noted.
Retrospective and prospective observational studies, as well as randomized controlled trials [BIFFI2001] [CARLO2004] and one meta-analysis [SABER2011], suggest that catheter insertion site (left>right, femoral>subclavian>jugular) and catheter tip location (SVC>RA) can influence the risk of CVC-DVT. A history of a previous CVC and more than one insertion attempt were found to be risk factors for CVC-DVT in one study [LEE2006]. Implanted ports may have a lower risk than PICC catheters or external CVC [MCLEAN2005]. In contrast, ultrasound-guided
placement has not been shown to decrease CVC-DVT [BIFFI2009].
In summary, the existing literature does not support the use of thromboprophylaxis for CVC in cancer patients. The results of the WARP trial [YOUNG2009] suggest that more intensive anticoagulant regimens such as dose-adjusted warfarin may be promising, but more research is warranted to identify convenient, effective and safe regimens for CVC thromboprophylaxis.
Catheter location can influence the risk of CVC-DVT, so low-risk locations should be preferentially utilized.

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7.5. Recommendations: prophylaxis of catheter-related thrombosis

 

R1. Use of anticoagulation for routine prophylaxis of CRT is not recommended

Quality of evidence

High

Balance between desirable and undesirable effects

Unfavorable for anticoagulation

Values and preferences

Bleeding risk with anticoagulants

Costs (resource allocation)

Not considered

Level of recommendation

Strong

 

R2. Catheters should be inserted in the right side, in the jugular vein, and distal extremity of the central catheter should be located at the junction of the superior vena cava and the right atrium

Quality of evidence High
Balance between desirable and undesirable effects Favorable
Values and preferences Not considered
Costs (resource allocation) Not considered
Level of recommendation Strong