Abstract

Background

The choice of the appropriate perioperative thromboprophylaxis for people with cancer depends on the relative benefits and harms of different anticoagulants.

Objectives

To systematically review the evidence for the relative efficacy and safety of anticoagulants for perioperative thromboprophylaxis in people with cancer.

Search methods

This update of the systematic review was based on the findings of a comprehensive literature search conducted on 14 June 2018 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL, 2018, Issue 6), 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.

Selection criteria

Randomized controlled trials (RCTs) that enrolled people with cancer undergoing a surgical intervention and assessed the effects of low‐molecular weight heparin (LMWH) to unfractionated heparin (UFH) or to fondaparinux on mortality, deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding outcomes, and thrombocytopenia.

Data collection and analysis

Using a standardized form, we extracted data in duplicate on study design, participants, interventions outcomes of interest, and risk of bias. Outcomes of interest included all‐cause mortality, PE, symptomatic venous thromboembolism (VTE), asymptomatic DVT, major bleeding, minor bleeding, postphlebitic syndrome, health related quality of life, and thrombocytopenia. We assessed the certainty of evidence for each outcome using the GRADE approach (GRADE Handbook).

Main results

Of 7670 identified unique citations, we included 20 RCTs with 9771 randomized people with cancer receiving preoperative prophylactic anticoagulation. We identified seven reports for seven new RCTs for this update.

The meta‐analyses did not conclusively rule out either a beneficial or harmful effect of LMWH compared with UFH for the following outcomes: mortality (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.63 to 1.07; risk difference (RD) 9 fewer per 1000, 95% CI 19 fewer to 4 more; moderate‐certainty evidence), PE (RR 0.49, 95% CI 0.17 to 1.47; RD 3 fewer per 1000, 95% CI 5 fewer to 3 more; moderate‐certainty evidence), symptomatic DVT (RR 0.67, 95% CI 0.27 to 1.69; RD 3 fewer per 1000, 95% CI 7 fewer to 7 more; moderate‐certainty evidence), asymptomatic DVT (RR 0.86, 95% CI 0.71 to 1.05; RD 11 fewer per 1000, 95% CI 23 fewer to 4 more; low‐certainty evidence), major bleeding (RR 1.01, 95% CI 0.69 to 1.48; RD 0 fewer per 1000, 95% CI 10 fewer to 15 more; moderate‐certainty evidence), minor bleeding (RR 1.01, 95% CI 0.76 to 1.33; RD 1 more per 1000, 95% CI 34 fewer to 47 more; moderate‐certainty evidence), reoperation for bleeding (RR 0.93, 95% CI 0.57 to 1.50; RD 4 fewer per 1000, 95% CI 22 fewer to 26 more; moderate‐certainty evidence), intraoperative transfusion (mean difference (MD) ‐35.36 mL, 95% CI ‐253.19 to 182.47; low‐certainty evidence), postoperative transfusion (MD 190.03 mL, 95% CI ‐23.65 to 403.72; low‐certainty evidence), and thrombocytopenia (RR 3.07, 95% CI 0.32 to 29.33; RD 6 more per 1000, 95% CI 2 fewer to 82 more; moderate‐certainty evidence). LMWH was associated with lower incidence of wound hematoma (RR 0.70, 95% CI 0.54 to 0.92; RD 26 fewer per 1000, 95% CI 39 fewer to 7 fewer; moderate‐certainty evidence). The meta‐analyses found the following additional results: outcomes intraoperative blood loss (MD ‐6.75 mL, 95% CI ‐85.49 to 71.99; moderate‐certainty evidence); and postoperative drain volume (MD 30.18 mL, 95% CI ‐36.26 to 96.62; moderate‐certainty evidence).

In addition, the meta‐analyses did not conclusively rule out either a beneficial or harmful effect of LMWH compared with Fondaparinux for the following outcomes: any VTE (DVT or PE, or both; RR 2.51, 95% CI 0.89 to 7.03; RD 57 more per 1000, 95% CI 4 fewer to 228 more; low‐certainty evidence), major bleeding (RR 0.74, 95% CI 0.45 to 1.23; RD 8 fewer per 1000, 95% CI 16 fewer to 7 more; low‐certainty evidence), minor bleeding (RR 0.83, 95% CI 0.34 to 2.05; RD 8fewer per 1000, 95% CI 33 fewer to 52 more; low‐certainty evidence), thrombocytopenia (RR 0.35, 95% CI 0.04 to 3.30; RD 14 fewer per 1000, 95% CI 20 fewer to 48 more; low‐certainty evidence), any PE (RR 3.13, 95% CI 0.13 to 74.64; RD 2 more per 1000, 95% CI 1 fewer to 78 more; low‐certainty evidence) and postoperative drain volume (MD ‐20.00 mL, 95% CI ‐114.34 to 74.34; low‐certainty evidence)

Authors' conclusions

We found no difference between perioperative thromboprophylaxis with LMWH versus UFH and LMWH compared with fondaparinux in their effects on mortality, thromboembolic outcomes, major bleeding, or minor bleeding in people with cancer. There was a lower incidence of wound hematoma with LMWH compared to UFH.

Author(s)

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

Abstract

Plain language summary

Blood thinners for the prevention of blood clots in people with cancer undergoing surgery

Background
 People with cancer undergoing surgery are at an increased risk of blood clots. Blood thinners (anticoagulants) administered to prevent these clots include unfractionated heparin (UFH) infused intravenously (into a vein), low‐molecular weight heparin (LMWH) injected subcutaneously (under the skin) once or twice per day, and fondaparinux. These blood thinners may have different effectiveness and safety profiles.

Study characteristics
 We searched scientific databases for clinical trials looking at the effects of blood thinners on death, pulmonary embolism (blood clot in the lungs), deep vein thrombosis (blood clot in the veins of the legs), bruising, bleeding, and need for blood transfusion in people with cancer having operations. We included trials of adults and children of any age or sex with either solid tumors or blood cancer irrespective of the type of cancer treatment. The evidence is current to 14 June 2018.

Key results
 We found 20 studies that included 9771 people with cancer. The evidence did not identify any difference between the effects of LMWH and UFH on death, getting a blood clot, or bleeding. There was less bruising around the wound following the operation with LMWH compared with UFH. Fondaparinux may have reduced the risk of getting a blood clot.

Reliability of evidence
 The reliability of evidence varied from low to moderate across the outcomes of interest.

Author(s)

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

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Given the lack of clear evidence of superiority of one medicine over the other as a result of this imprecision, clinicians should base their choice on cost and patient preferences using an individualized decision‐making process. The American College of Chest Physicians (ACCP) 9th iteration of the antithrombotic guidelines does not recommend using either of the two anticoagulants of interest over the other in people with cancer undergoing surgical interventions (Gould 2012).

Implications for research 

Despite the large number of participants enrolled in these trials, there is still some lack of precision for several critical outcomes. This is partly because several trials assessed surrogate outcome (asymptomatic deep venous thrombosis (DVT)) instead of patient‐important outcomes such as DVT and pulmonary embolism. Researchers can use these results to plan additional randomized controlled trials to either exclude or confirm a superiority of one of the two drugs over the other on patient‐important outcomes.

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