Treatment of Cancer-Associated Venous Thromboembolism in the Age of Direct Oral Anticoagulants

C. Ay; J. Beyer-Westendorf; I. Pabinger


Ann Oncol. 2019;30(6):897-907. 

In This Article

Abstract and Introduction


Anticoagulation for cancer-associated venous thromboembolism (VTE) can be challenging due to complications—including bleeding and potential drug–drug interactions with chemotherapy—associated with vitamin K antagonists and inconvenience of low-molecular-weight heparin (LMWH). Direct oral anticoagulants (DOACs) could partially overcome these issues, but until recently there were no large clinical trials assessing their efficacy and safety in cancer patients. This review summarizes clinical treatment guidelines, prior clinical and real-world evidence for anticoagulant choice, recent clinical trials assessing DOACs for cancer-associated VTE (i.e. Hokusai-VTE Cancer, SELECT-D, CARAVAGGIO, and ADAM VTE), and special considerations for DOAC use. Based on established data, clinical guidelines recommend patients with cancer-associated VTE receive LMWH treatment of at least 3–6 months. Nevertheless, LMWH is underused and associated with poor compliance and persistence in these patients relative to oral anticoagulants. Clinical data supporting DOAC use in cancer patients are becoming available. In Hokusai-VTE Cancer, edoxaban was noninferior to dalteparin for the composite of recurrent VTE and major bleeding (12.8% versus 13.5%), with numerically lower recurrent VTE (7.9% versus 11.3%) and significantly higher major bleeding (6.9% versus 4.0%); only patients with gastrointestinal cancer had significantly higher risk of bleeding with edoxaban. In SELECT-D, rivaroxaban had numerically lower VTE recurrence (4% versus 11%), comparable major bleeding (6% versus 4%), and numerically higher clinically relevant nonmajor bleeding (13% versus 4%) versus dalteparin. Most bleeding events were gastrointestinal or urologic; patients with esophageal/gastroesophageal cancer had higher rates of major bleeding with rivaroxaban (36% versus 11%). For comparison of apixaban versus dalteparin, CARAVAGGIO is ongoing, and preliminary results from ADAM VTE are favorable. This review concludes that DOACs appear to be reasonable alternatives to LMWH for treatment of cancer-associated VTE. In patients with gastrointestinal cancer, DOAC use should be considered on a case-by-case basis with consideration of the relative risks and benefits.


Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is a significant concern for patients with cancer. For example, the occurrence of cancer-associated VTE is a significant predictor of death within 1 year of cancer diagnosis.[1] In addition, VTE is one of the leading causes of death in cancer patients receiving outpatient chemotherapy,[2] and a VTE diagnosis can delay or interrupt initiation of adjuvant chemotherapy.[3]

The risk for cancer-associated VTE depends on cancer type and is generally higher in patients with metastatic disease; an international meta-analysis of VTE in patients with cancer found an annual incidence between 0.5% and 20% depending on cancer type and other risk factors.[4] Several validated risk scoring models exist for cancer-associated VTE, which include factors based on clinical characteristics (e.g. tumor type and body mass index), laboratory parameters (e.g. hemoglobin levels and thrombocyte counts), and biomarkers (e.g. soluble P-selectin and D-dimer).[5–8]

Treatment of VTE in patients with cancer can be challenging due to complications including increased risk of bleeding and potential drug–drug interactions with chemotherapy. Vitamin K antagonists (VKAs) after initial heparin treatment were a recommended option for long-term oral treatment of VTE in patients without cancer.[9] However, VKAs are not recommended for cancer-associated VTE. Relative to patients without cancer, patients with cancer are at threefold to fourfold higher risk for VTE recurrence even with VKA treatment and are up to a sixfold higher risk for anticoagulant-associated bleeding.[10,11] Furthermore, potential complications of cancer treatment such as chemotherapy-induced vomiting and drug–drug interactions between VKAs and anticancer medications can interfere with oral anticoagulants.[12,13] Low-molecular-weight heparin (LMWH) treatment is associated with similar or lower rates of VTE recurrence and bleeding relative to VKAs in patients with cancer-associated VTE, does not rely on gastrointestinal absorption, and interacts minimally with chemotherapy agents.[12,14,15] Therefore, LMWH is recommended by clinical guidelines and other practice guidance as first-line treatment of short- and long-term management of cancer-associated VTE.[12,13,16–19]

Direct oral anticoagulants (DOACs), including direct thrombin inhibitors (dabigatran) and direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban, and betrixaban), have advantages relative to VKAs including fixed dose regimen, predictable pharmacology and anticoagulation, and no need for regular laboratory monitoring. In addition, unlike LMWH, DOACs are orally dosed and do not require long-term subcutaneous injections, which can act as a barrier to regular LMWH treatment.[20] As a class, DOACs have similar efficacy as VKAs for treatment of acute VTE, but are associated with less major bleeding.[21] Until recently, there was limited clinical data from randomized clinical trials on efficacy and safety of DOACs versus LMWH for treatment of cancer-associated VTE. However, newly available evidence suggests a role for DOACs for VTE treatment in many patients with cancer. This review will discuss the current standard of treatment and the existing evidence, newly published and ongoing studies, and possible issues regarding DOACs for treatment of VTE in patients with cancer.