Abstract

Abstract Background

Oral anticoagulants may improve the survival of people with cancer through both an antitumor effect and antithrombotic effect, yet increase the risk of bleeding.

To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, hormonal therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.

We conducted a comprehensive literature search in February 2016 that included a major electronic search of Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE (Ovid) and Embase (Ovid); handsearching of conference proceedings; checking of references of included studies; a search for ongoing studies; and using the 'related citation' feature in PubMed. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified. This update of the systematic review is based on the findings of a literature search conducted on 14 December 2017.

Randomized controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC) in ambulatory people with cancer. These participants are typically undergoing systemic anticancer therapy, possibly including chemotherapy, target therapy, immunotherapy or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.

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

Of 8545 identified citations, including 7668 unique citations, 16 papers reporting on 7 RCTs fulfilled the inclusion criteria. These trials enrolled 1486 participants. The oral anticoagulant was warfarin in six of these RCTs and apixaban in the seventh RCT. The comparator was either placebo or no intervention. The meta‐analysis of the studies comparing VKA to no VKA did not rule out a clinically significant increase or decrease in mortality at one year (risk ratio (RR) 0.95, 95% confidence interval (CI) 0.87 to 1.03; risk difference (RD) 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate certainty evidence). One study assessed the effect of VKA on thrombotic outcomes. The study did not rule out a clinically significant increase or decrease in PE when comparing VKA to no VKA (RR 1.05, 95% CI 0.07 to 16.58; RD 0 fewer per 1000, 95% CI 6 fewer to 98 more; very low certainty evidence), but found that VKA compared to no VKA likely decreases the incidence of DVT (RR 0.08, 95% CI 0.00 to 1.42; RD 35 fewer per 1000, 95% CI 38 fewer to 16 more; low certainty evidence). VKA increased both major bleeding (RR 2.93, 95% CI 1.86 to 4.62; RD 107 more per 1000, 95% CI 48 more to 201 more; moderate certainty evidence) and minor bleeding (RR 3.14, 95% CI 1.85 to 5.32; RD 167 more per 1000, 95% CI 66 more to 337 more; moderate certainty evidence).

The study assessing the effect of DOAC compared to no DOAC did not rule out a clinically significant increase or decrease in mortality at three months (RR 0.24, 95% CI 0.02 to 2.56; RD 51 fewer per 1000, 95% CI 65 fewer to 104 more; low certainty evidence), PE (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence), symptomatic DVT (RR 0.07, 95% CI 0.00 to 1.32; RD 93 fewer per 1000, 95% CI 100 fewer to 32 more; low certainty evidence), major bleeding (RR 0.16, 95% CI 0.01 to 3.91; RD 28 fewer per 1000, 95% CI 33 fewer to 97 more; low certainty evidence); and minor bleeding (RR 4.43, 95% CI 0.25 to 79.68; RD 0 fewer per 1000, 95% CI 0 fewer to 8 more; low certainty evidence).

The existing evidence does not show a mortality benefit from oral anticoagulation in people with cancer but suggests an increased risk for bleeding.

Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence, as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Author(s)

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

Abstract

Plain language summary

Oral blood thinners in people with cancer 

Background 
Research evidence suggests that blood thinners (called anticoagulants) may not only prevent life‐threatening blood clots, but also have a direct anticancer effect. However, blood thinners can also increase the risk of serious and fatal bleeding. Therefore, it is important to understand the pros and cons of treatment to allow people and their doctors to be aware of the balance of risks and benefits.

Study characteristics 
We searched the scientific literature for studies of anticoagulants in people with cancer. The evidence is current to December 2017.

Key results 
We included seven trials including 1486 participants with cancer. Most trials included participants with various types of cancer especially lung and pancreatic cancer. We found six studies using warfarin and one study using apixaban. When considering people with cancer in general, warfarin had no effect on mortality (death rate) or the risk of blood clots. However, it increased the risk of major bleeding in 107 more people per 1000 population and minor bleeding in 167 more people per 1000 population. Apixaban had no effect on mortality, recurrence of blood clots in blood vessels, major bleeding or minor bleeding; however, these findings were based on only one study.

Certainty of the evidence 
When comparing warfarin to no warfarin, we judged the certainty of the evidence (how sure and confident we are of the findings) to be moderate for mortality at one year and major and minor bleeding, low for symptomatic deep vein thrombosis (blood clot within a deep vein, most commonly the legs) and very low for pulmonary embolism (blood clot in the blood vessels of the lungs).

When comparing apixaban to no apixaban, we judged the certainty of evidence to be low for mortality at three months, major and minor bleeding, pulmonary embolism and symptomatic deep vein thrombosis.

Editorial note: this is a living systematic review. Living systematic reviews offer a new approach to review updating in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.

Author(s)

Lara A Kahale, Maram B Hakoum, Ibrahim G Tsolakian, 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

This systematic review does not provide evidence for a mortality benefit from oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation. In fact, current evidence suggests that there is no mortality benefit from oral anticoagulation therapy. The intervention may be associated with a reduction in venous thromboembolism but also with an increased risk of minor and major bleeding and by the burden of vitamin K antagonist treatment (e.g. periodically checking international normalized ratio levels).

Implications for research

Future research should investigate the effects of oral anticoagulation in people with different cancer subtypes (e.g. small cell lung cancer, non‐small cell lung cancer) and different cancer stages. While the last clinical trial on this topic was published in 2014, there are still ongoing studies discussing oral anticoagulation in people with cancer. There is also a need to investigate the effects of other anticoagulants (e.g. low‐molecular‐weight heparins, fondaparinux) in people with different types and stages of cancer (Akl 2014a).