Oral anticoagulation in people with cancer who have no therapeutic or prophylactic indication for anticoagulation New search for studies and content updated (conclusions changed)

Abstract

Abstract 

Background 

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

Objectives 

To evaluate the efficacy and safety of oral anticoagulants in ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), with no standard therapeutic or prophylactic indication for anticoagulation.

Search methods 

We conducted comprehensive searches on 14 June 2021, following the original electronic searches performed in February 2016 (last major search). We electronically searched the following databases: CENTRAL, MEDLINE, Embase. In addition, we handsearched conference proceedings, checked references of included studies, and searched for ongoing studies. As part of the living systematic review approach, we are running continual searches and will incorporate new evidence rapidly after it is identified.

Selection criteria 

We included randomised controlled trials (RCTs) assessing the benefits and harms of vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs) in ambulatory people with cancer (i.e., not hospital inpatients during the time of their participation in trials) These people are typically undergoing systemic anticancer therapy, possibly including chemotherapy, targeted therapy, immunotherapy, or radiotherapy, but otherwise have no standard therapeutic or prophylactic indication for anticoagulation.

Data collection and analysis 

Using a standardised form, two review authors independently extracted data on study design, participants, intervention outcomes of interest, and risk of bias. Outcomes of interest included all‐cause mortality, pulmonary embolism, symptomatic deep vein thrombosis (DVT), major bleeding, minor bleeding and health‐related quality of life. We assessed the certainty of evidence for each outcome using the GRADE approach.

Main results 

Of 12,620 identified citations, 10 RCTs fulfilled the inclusion criteria. The oral anticoagulant was a vitamin K antagonist (VKA) in six of these RCTs, and a direct oral anticoagulant (DOAC) in the remaining four RCTs (three studies used apixaban; one used rivaroxaban). The comparator was either placebo or no prophylaxis.

Compared to no prophylaxis, vitamin K antagonists (VKAs) probably reduce mortality at six months slightly (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.77 to 1.13; risk difference (RD) 22 fewer per 1000, 95% CI 72 fewer to 41 more; moderate‐certainty evidence), and probably reduce mortality at 12 months slightly (RR 0.95, 95% CI 0.87 to 1.03; RD 29 fewer per 1000, 95% CI 75 fewer to 17 more; moderate‐certainty evidence). One study assessed the effect of a VKA compared to no prophylaxis on thrombosis; the evidence was very uncertain about the effect of VKA compared to no VKA on pulmonary embolism and symptomatic DVT (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; RR 0.08, 95% CI 0.01 to 1.42; RD 35 fewer per 1000, 95% CI 37 fewer to 16 more; very low‐certainty evidence, respectively). Also, VKAs probably increase major and minor bleeding at 12 months (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 for major bleeding, and 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 for minor bleeding).

Compared to no prophylaxis, at three to six months, direct oral anticoagulants (DOACs) probably reduce mortality slightly (RR 0.94, 95% CI 0.64 to 1.38, RD 11 fewer per 1000, 95% CI 67 fewer to 70 more; moderate‐certainty evidence), probably reduce the risk of pulmonary embolism slightly compared to no prophylaxis (RR 0.48, 95% CI 0.24 to 0.98; RD 24 fewer per 1000, 95% CI 35 fewer to 1 fewer; moderate‐certainty evidence), probably reduce symptomatic DVT slightly (RR 0.58, 95% CI 0.30 to 1.15; RD 21 fewer per 1000, 95% CI 35 fewer to 8 more; moderate‐certainty evidence), probably do not increase major bleeding (RR 1.65, 95% CI 0.72 to 3.80; RD 9 more per 1000, 95% CI 4 fewer to 40 more; moderate‐certainty evidence), and may increase minor bleeding (RR 3.58, 95% CI 0.55 to 23.44; RD 55 more per 1000, 95% CI 10 fewer to 482 more; low‐certainty evidence).

Authors' conclusions 

In ambulatory people with cancer undergoing chemotherapy, targeted therapy, immunotherapy, or radiotherapy (either alone or in combination), the current evidence on VKA thromboprophylaxis suggests that the harm of major bleeding might outweigh the benefit of reduction in venous thromboembolism. With DOACs, the benefit of reduction in venous thromboembolic events outweighs the risk of major 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 'What's new' section in the  Cochrane Database of Systematic Reviews for the current status of this review.

Author(s)

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

Abstract

Plain language summary 

Are oral blood thinners safe and effective for people being treated for cancer? 

Key messages 

‐ It is reasonable to give direct oral anticoagulants (a type of blood thinning medicine) to people being treated for cancer, especially if they have an increased risk of blood clots, because the benefit of reduction in blood clots appears to outweigh the risk of major bleeding.

‐ For a different type of blood thinner, vitamin K antagonists (warfarin), the risk of major bleeding might outweigh the benefit of a reduction in formation of blood clots in the legs and lungs.

‐ More research is needed on the effects of blood thinners in people with different types and stages of cancers.

What are blood thinners 

Blood thinners are medicines that help prevent blood from clotting. People at a high risk of getting blood clots can take blood thinners to reduce their chances of developing serious conditions such as heart attacks and strokes.

Why might blood‐thinning treatment be helpful for people with cancer?

People with cancer undergoing systemic treatment (any medication that travels through your body in the bloodstream to find, damage or destroy cancer cells, including chemotherapy, radiotherapy, immunotherapy and target therapy) are at increased risk of blood clots. While blood thinners can decrease the risk of getting blood clots, they can also increase the risk of serious and fatal bleeding. Therefore, it is important to understand the benefits and harms of using blood thinners in these people to allow them and their doctors to make informed decisions.

What did we want to find out? 

We wanted to find out if giving preventative, oral (by mouth) blood thinners was better than no preventative treatment for people being treated for cancer. We focused on people with cancer who were not admitted to hospital for their cancer treatment.

We were interested in the effects of blood thinners on:

‐ death;

‐ formation of blood clots in veins (venous thromboembolism). Venous thromboembolism includes deep vein thrombosis (DVT) where a clot lodges in the lower leg, thigh or pelvis, and pulmonary embolism where a clot lodges in the lungs;

‐ major and minor bleeding.

What did we do? 

We searched for studies that examined the benefits and harms of blood thinners for people being treated for cancer who otherwise had no signs, symptoms or conditions that suggested blood thinning was definitely needed.

We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find? 

We found 10 studies that involved 2934 people with cancer. The biggest study had 841 people and the smallest had 24 people. The studies used two types of blood thinner:

‐ the vitamin K antagonist, warfarin; or

‐ direct [ER1] oral anticoagulants (specifically, apixaban and rivaroxaban).

Main results 

Compared to no preventative treatment, warfarin, the vitamin K antagonist medicine:

‐ probably reduces death at 6 months and at 12 months slightly (22 and 29 fewer deaths, respectively, per 1000 people);

‐ may have little to no effect on formation of blood clots, but we are very uncertain about the results;

‐ probably increases major bleeding and minor bleeding at 12 months (107 more major bleeds and 167 more minor bleeds per 1000 people).

Compared to no preventative treatment, direct oral anticoagulant medicines:

‐ probably reduce death at 3 to 6 months slightly (11 fewer deaths per 1000 people);

‐ probably reduce blood clots in the lungs and legs slightly (24 fewer in the lungs and 19 fewer in the legs per 1000 people);

‐ probably do not increase major bleeding (9 more major bleeds per 1000 people);

‐ may increase minor bleeding (55 more minor bleeds per 1000 people).

This suggests that :

with a vitamin K antagonist, the risk of major bleeding might outweigh the benefit of any reduction in the risk of blood clots in the legs and lungs;

with direct oral anticoagulants, the benefit of reduction in the risk of blood clots in the legs and lungs outweighs the risk of major bleeding.

What are the limitations of the evidence? 

We are moderately confident in the evidence for death, major bleeding and minor bleeding. In eight of the studies, the methods used may have affected the results.

We are not confident in the evidence for blood clots in people who were given vitamin K antagonist medicine because the evidence came from one study only. This study gave the medicine in a fixed rather than variable dose, which is not current best practice.

How up to date is this evidence? 

This review updates our previous review. The evidence is up to date to June 2021.

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 'What's new' section on the Cochrane Database of Systematic Reviews for the current status of this review.

Author(s)

Lara A Kahale, Charbel F Matar, Ibrahim Tsolakian, Maram B Hakoum, 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 shows that the current evidence suggests that, with vitamin K antagonists (VKAs), the harm of major bleeding might outweigh the benefit of reduction in venous thromboembolism (VTE). With direct oral anticoagulants (DOACs), the benefit of reduction in VTE events outweighs the risk of major bleeding. Based on this, it would be reasonable to start an individual on oral thromboprophylaxis, particularly if they are judged to be at increased risk of developing VTE. Direct oral anticoagulants appear to have a safer profile and do not require the unnecessary need for periodic checking of international normalized ratio levels. Several other important factors should be considered before starting people on oral thromboprophylaxis. Some of these factors include cost, drug interactions with concomitant pharmacotherapy, and lack of readily accessible reversal agents in case of major bleeding. Ideally, a person’s risk of bleeding with the addition of a VKA or DOAC needs to be individualised prior to initiation of anticoagulation, by considering other factors of their clinical picture (i.e. drug interactions, inherent clotting disorders) (Pelletier 2021).

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. There is also a need to investigate the effects of oral anticoagulants compared to parenteral anticoagulants in people with different types and stages of cancer and various medical and surgical histories.

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