Anticoagulation for people with cancer and central venous catheters Edited (no change to conclusions)

Abstract

Abstract 

Background 

Central venous catheter (CVC) placement increases the risk of thrombosis in people with cancer. Thrombosis often necessitates the removal of the CVC, resulting in treatment delays and thrombosis‐related morbidity and mortality. This is an update of the Cochrane Review published in 2014.

Objectives 

To evaluate the efficacy and safety of anticoagulation for thromboprophylaxis in people with cancer with a CVC.

Search methods 

We conducted a comprehensive literature search in May 2018 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; searching for ongoing studies; and using the 'related citation' feature in PubMed. This update of the systematic review was based on the findings of a literature search conducted on 14 May 2018.

Selection criteria 

Randomized controlled trials (RCTs) assessing the benefits and harms of unfractionated heparin (UFH), low‐molecular‐weight heparin (LMWH), vitamin K antagonists (VKA), or fondaparinux or comparing the effects of two of these anticoagulants in people with cancer and a CVC.

Data collection and analysis 

Using a standardized form, we extracted data and assessed risk of bias. Outcomes included all‐cause mortality, symptomatic catheter‐related venous thromboembolism (VTE), pulmonary embolism (PE), major bleeding, minor bleeding, catheter‐related infection, thrombocytopenia, and health‐related quality of life (HRQoL). We assessed the certainty of evidence for each outcome using the GRADE approach (Balshem 2011).

Main results 

Thirteen RCTs (23 papers) fulfilled the inclusion criteria. These trials enrolled 3420 participants. Seven RCTs compared LMWH to no LMWH (six in adults and one in children), six RCTs compared VKA to no VKA (five in adults and one in children), and three RCTs compared LMWH to VKA in adults.

LMWH versus no LMWH 
 Six RCTs (1537 participants) compared LMWH to no LMWH in adults. The meta‐analyses showed that LMWH probably decreased the incidence of symptomatic catheter‐related VTE up to three months of follow‐up compared to no LMWH (risk ratio (RR) 0.43, 95% confidence interval (CI) 0.22 to 0.81; risk difference (RD) 38 fewer per 1000, 95% CI 13 fewer to 52 fewer; moderate‐certainty evidence). However, the analysis did not confirm or exclude a beneficial or detrimental effect of LMWH on mortality at three months of follow‐up (RR 0.82, 95% CI 0.53 to 1.26; RD 14 fewer per 1000, 95% CI 36 fewer to 20 more; low‐certainty evidence), major bleeding (RR 1.49, 95% CI 0.06 to 36.28; RD 0 more per 1000, 95% CI 1 fewer to 35 more; very low‐certainty evidence), minor bleeding (RR 1.35, 95% CI 0.62 to 2.92; RD 14 more per 1000, 95% CI 16 fewer to 79 more; low‐certainty evidence), and thrombocytopenia (RR 1.03, 95% CI 0.80 to 1.33; RD 5 more per 1000, 95% CI 35 fewer to 58 more; low‐certainty evidence).

VKA versus no VKA 
 Five RCTs (1599 participants) compared low‐dose VKA to no VKA in adults. The meta‐analyses did not confirm or exclude a beneficial or detrimental effect of low‐dose VKA compared to no VKA on mortality (RR 0.99, 95% CI 0.64 to 1.55; RD 1 fewer per 1000, 95% CI 34 fewer to 52 more; low‐certainty evidence), symptomatic catheter‐related VTE (RR 0.61, 95% CI 0.23 to 1.64; RD 31 fewer per 1000, 95% CI 62 fewer to 51 more; low‐certainty evidence), major bleeding (RR 7.14, 95% CI 0.88 to 57.78; RD 12 more per 1000, 95% CI 0 fewer to 110 more; low‐certainty evidence), minor bleeding (RR 0.69, 95% CI 0.38 to 1.26; RD 15 fewer per 1000, 95% CI 30 fewer to 13 more; low‐certainty evidence), premature catheter removal (RR 0.82, 95% CI 0.30 to 2.24; RD 29 fewer per 1000, 95% CI 114 fewer to 202 more; low‐certainty evidence), and catheter‐related infection (RR 1.17, 95% CI 0.74 to 1.85; RD 71 more per 1000, 95% CI 109 fewer to 356; low‐certainty evidence).

LMWH versus VKA 
 Three RCTs (641 participants) compared LMWH to VKA in adults. The available evidence did not confirm or exclude a beneficial or detrimental effect of LMWH relative to VKA on mortality (RR 0.94, 95% CI 0.56 to 1.59; RD 6 fewer per 1000, 95% CI 41 fewer to 56 more; low‐certainty evidence), symptomatic catheter‐related VTE (RR 1.83, 95% CI 0.44 to 7.61; RD 15 more per 1000, 95% CI 10 fewer to 122 more; very low‐certainty evidence), PE (RR 1.70, 95% CI 0.74 to 3.92; RD 35 more per 1000, 95% CI 13 fewer to 144 more; low‐certainty evidence), major bleeding (RR 3.11, 95% CI 0.13 to 73.11; RD 2 more per 1000, 95% CI 1 fewer to 72 more; very low‐certainty evidence), or minor bleeding (RR 0.95, 95% CI 0.20 to 4.61; RD 1 fewer per 1000, 95% CI 21 fewer to 95 more; very low‐certainty evidence). The meta‐analyses showed that LMWH probably increased the risk of thrombocytopenia compared to VKA at three months of follow‐up (RR 1.69, 95% CI 1.20 to 2.39; RD 149 more per 1000, 95% CI 43 fewer to 300 more; moderate‐certainty evidence).

Authors' conclusions 

The evidence was not conclusive for the effect of LMWH on mortality, the effect of VKA on mortality and catheter‐related VTE, and the effect of LMWH compared to VKA on mortality and catheter‐related VTE. We found moderate‐certainty evidence that LMWH reduces catheter‐related VTE compared to no LMWH. People with cancer with CVCs considering anticoagulation should balance the possible benefit of reduced thromboembolic complications with the possible harms and burden of anticoagulants.

Author(s)

Lara A Kahale, Ibrahim G Tsolakian, Maram B Hakoum, Charbel F Matar, Maddalena Barba, Victor ED Yosuico, Irene Terrenato, Francesca Sperati, Holger Schünemann, Elie A Akl

Abstract

Plain language summary 

Blood thinners to prevent blood clots in people with cancer and central venous catheters 

Background 
 A central venous catheter (CVC) is a tube that is inserted into a large vein to give fluids or medicines. CVC placement increases the risk of blood clots in people with cancer. This review evaluated the effectiveness and safety of blood thinning agents (anticoagulants) in people with cancer and a CVC.

Study characteristics 
 We searched the scientific literature for studies of anticoagulants in people with cancer and a CVC. The evidence is current to 14 May 2018.

Key results 
 We included 13 trials enrolling 3420 people with cancer and a CVC. Most trials included people with various types and stages of cancer. Seven studies compared injectable blood thinners to no anticoagulation, six studies compared blood thinner pills to no anticoagulation, and three studies compared injectable blood thinners to blood thinner pills. When considering people with cancer and a CVC, injectable blood thinners probably reduced the risk of CVC‐related blood clots compared to no anticoagulation and probably increased the risk of thrombocytopenia (low levels of platelets in the blood, which causes bleeding into the tissues) compared to blood thinner pills.

Certainty of the evidence 
 When comparing injectable blood thinners to no anticoagulation, we judged the certainty of the evidence to be moderate for blood clot at the catheter site, low for mortality, infection at the catheter site and minor bleeding, and very low for major bleeding.

When comparing blood thinner pills to no anticoagulation, we judged the certainty of the evidence to be low for mortality major and minor bleeding, premature catheter removal and catheter‐related infection low, and very low for blood clot at the catheter site.

When comparing injectable blood thinners to blood thinner pills, we judged the certainty of the evidence to be low for mortality and blood clots in the limbs and very low for blood clot at the catheter site, major and minor bleeding.

Author(s)

Lara A Kahale, Ibrahim G Tsolakian, Maram B Hakoum, Charbel F Matar, Maddalena Barba, Victor ED Yosuico, Irene Terrenato, Francesca Sperati, Holger Schünemann, Elie A Akl

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

People with cancer with central venous catheters (CVCs) considering anticoagulation should balance the possible benefit of reduced incidence of thromboembolic complications with the harms and burden of taking anticoagulants. People may opt against prophylactic anticoagulation because they are bleeding averse, because anticoagulants (e.g. daily subcutaneous injections) would be a burden for them, or they are uncomfortable with the uncertainty of benefit. Other people may opt for prophylactic anticoagulation because they have low aversion to bleeding, because they do not consider anticoagulation as a burden, and they have a high preference for avoidance of thrombosis (and the associated increased risk of a pulmonary embolism, premature CVC removal, and the need to start a relatively long therapeutic anticoagulation).

Implications for research 

More data from randomized controlled trials (RCT) are needed to answer the question about the role of anticoagulants for thromboprophylaxis in people with cancer and CVC confidently. Studies should adhere to high methodologic quality and be adequately powered to assess participant‐important outcomes such as mortality, premature CVC removal, symptomatic thrombosis, and bleeding. Studies should also aim to use standardized definitions for major and minor bleeding and for catheter‐related infections. Research should demonstrate a definite benefit of anticoagulation before conducting additional studies comparing the effects of different anticoagulants. Researchers should consider making the raw data of RCTs available for individual participant data meta‐analysis. In addition, as recognized by Cochrane, addressing all important outcomes including harm is of great importance in making evidence‐based healthcare decisions.

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