Risk of Recurrent Venous Thromboembolism and Bleeding in Cancer Patients Treated with Direct Oral Anticoagulants Versus Low Molecular Weight Heparin

Reduces recurrent VTE with a possible increased risk of major bleeding.

Benefits in NNT

1 in 41 were helped (recurrent VTE prevented)
2.44% were helped (lower risk of recurrent VTE)

Harms in NNT

No one was harmed (no significant difference in risk of major bleeding compared to LMWH)
No one was harmed
View As:

Efficacy Endpoints

Recurrent VTE

Harm Endpoints

Major bleeding


Venous thromboembolism (VTE) occurs in up to 30% of patients with cancer.1, 2 Prior guidelines have recommended low molecular weight heparin (LMWH) for 3-6 months as first-line therapy in cancer patients with newly-diagnosed VTE.3, 4, 5 Unfortunately, LMWH is associated with poor compliance due to the need for subcutaneous injection.6, 7 Direct oral anticoagulants (DOACs) have been increasingly used for the treatment of VTE, are administered orally with no requirement for regular laboratory monitoring, and may have fewer drug-drug interactions as compared with warfarin, despite DOACs possessing a greater cost compared to other therapies. Several more recent guidelines, including the National Comprehensive Cancer Network (NCCN) and International Society on Thrombosis and Haemostasis (ISTH), recommend DOACs, based on limited data.8, 9 However, other guidelines including the American Society of Clinical Oncology still preferentially recommend LMWH,10 and DOAC efficacy and safety remain controversial in patients with cancer and acute VTE when compared to LMWH.

This systematic review and meta-analysis included studies comparing DOACs with LMWH for the treatment of VTE in patients with cancer.11 The primary outcomes were VTE recurrence and major bleeding in patients with cancer receiving DOACs or LMWH. Major bleeding was defined as clinically overt bleeding associated with a decrease in hemoglobin of 2 g/dL or more, requiring transfusion of two or more units of blood, occurring in a critical site (e.g. intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, pericardial or intramuscular with compartment syndrome), or fatal bleeding as per ISTH criteria. Authors conducted subgroup analyses based on study design, specific medication, and duration of follow-up.

The authors identified 11 relevant studies (n=4509), with 2 randomized controlled trials (RCTs) (1 trial each evaluating edoxaban and rivaroxaban) and 9 observational cohort studies (6 studies evaluating rivaroxaban and 3 studies other DOACs). The follow-up period was ≥ 1 month in all studies. DOACs reduced VTE recurrence from 11.45% to 9.01% (absolute risk reduction [ARR] 2.44%), with a relative risk (RR) of 0.72 (95% confidence interval [CI] 0.60-0.85) and number needed to treat (NNT) of 41 compared to LMWH. Subgroup analyses of RCTs and observational studies demonstrated a consistent reduction in VTE recurrence with DOACs. Overall, there was no statistically significant difference in major bleeding, including intracerebral, retroperitoneal, and intraspinal. Subgroup analyses of only observational studies, length of follow-up (6 and 12 months), and rivaroxaban also revealed no increased risk of bleeding. However, subgroup analysis of only RCTs did find increased risk of major bleeding with DOACs (RR 1.78, 95% CI 1.11-2.87).


This meta-analysis possesses several limitations. The 2 RCTs demonstrating increased rates of major bleeding with DOACs primarily involved the gastrointestinal (GI) tract.12, 13 However, both studies included a large number of patients with GI malignancies, and these studies were industry sponsored. It is unclear whether DOACs may be safer in patients without GI tract malignancies, and further data are needed. The definition of active cancer was not consistent in the included studies, and not all studies classified the cancer types or stages. Many studies also did not specify the type or the chronicity of VTE. Included studies evaluated different DOACs and LMWH comparators. This meta-analysis included predominately observational studies, which can introduce confounders and selection bias. While these studies demonstrated incidences of recurrent VTE similar to RCTs, differences in the baseline characteristics of patients and potential unidentified confounders can introduce bias. Follow-up and duration of therapy varied in the included studies, producing a potential source of heterogeneity.

This meta-analysis suggests cancer patients who receive DOACs have significantly reduced risk of VTE when compared to LMWH, with the best evidence found with rivaroxaban. The risk of major bleeding is less clear, as data across all studies fail to show a difference, but RCT data suggest increased harm. In the context of this study, DOACs remain a viable option to reduce risk of VTE in cancer patients, particularly among patients at low risk of bleeding. Their oral administration and lack of required monitoring is patient-centric and likely improves compliance.14 We have assigned a color recommendation of Yellow (Unclear if Benefits) based upon the benefit for reduction of VTE, but potential increased risk of major bleeding reported in RCTs. Larger, high-quality RCTs are needed to establish with more certainty the promising benefits suggested by these data, as well as further study of the effects of cancer type and specific DOAC medication.

The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.


Brit Long, MD; Alex Koyfman, MD; Michael Gottlieb, MD, RDMS
Supervising Editor: James McCormack, MD; Gary Green, MD


October 1, 2019