Director of the Vanderbilt Hemophilia/ Hemostasis Treatment Clinic,

Vanderbilt University Medical Center, Nashville, Tennessee

In the treatment of acute venous thromboembolism (VTE) associated with an underlying malignancy, direct oral anticoagulants (DOACs) are now considered acceptable for some patient populations. National Comprehensive Cancer Network Guidelines indicate that low molecular weight heparin (LMWH) is an appropriate anticoagulant for the first 6 months in patients with proximal deep vein thrombosis or pulmonary embolism.

1 LMWH is also recommended for the prevention of recurrent VTE in patients with advanced metastatic cancer.

 However, the guidelines also stipulate that for patients who prefer to avoid injections or have other limitations in the use of LMWH, apixaban (Eliquis), a DOAC, is an acceptable alternative. That means clinicians must distinguish which patients might be appropriate candidates for DOACs instead of continued use of LMWH. This is particularly challenging in the setting of an active gastrointestinal (GI) malignancy, where DOACs have shown higher rates of GI bleeding.

In recent years, several randomized controlled trials compared factor Xa inhibitor DOACs with the LMWH dalteparin (Fragmin) for preventing recurrent VTE in patients with cancer.

 In 2 of these studies, investigators concluded that rivaroxaban (Xarelto) and edoxaban (Savaysa) slightly lowered rates of recurrent VTE compared with LMWH but at the expense of higher rates of clinically relevant nonmajor bleeding, particularly GI bleeding.

The Hokusai VTE Cancer study randomized 1050 patients to LMWH followed by oral edoxaban versus subcutaneous dalteparin. This trial proved noninferiority of oral edoxaban to dalteparin with respect to the composite outcome of recurrent VTE or major bleeding at 12 months post randomization, with a 7.9% VTE recurrence rate in the edoxaban group compared with 11.3% in the dalteparin group. However, there was a significant increase in major bleeding with edoxaban (6.9%) compared with dalteparin (4%).

Analysis of the tumor types included hepatocellular, hepatobiliary, cholangiocarcinoma, and biliary cancers, all of which were associated with bleeding. This is important because the GI bleeding was not limited to patients with gastric or colorectal malignancies.

 Because the bleeding occurred in a diverse group of GI tumors, this relevant subset information should be considered when making clinical decisions for this patient population. Analysis of the Hokusai patients with VTE indicated that there were no fatal bleeding events with the use of edoxaban; however, 2 fatal bleeding events occurred among patients treated with dalteparin.

The SELECT-D study of 406 patients showed lower rates of recurrent VTE with rivaroxaban (4%) compared with dalteparin (11%) but higher rates of major bleeding (6% vs 4%, respectively) at 6 months.

 Although the rate of major bleeding was relatively low for both trial arms, there was a 3-fold increase in clinically relevant nonmajor bleeding with rivaroxaban (13%) compared with dalteparin (4%).4 Bleeding events in the Hokusai VTE Cancer study and SELECT-D trial primarily occurred in the GI tract and were higher in patients with GI cancers. In addition, the risk of bleeding is amplified in patients with preexisting GI lesions, including cancer, ulcers, and diverticulitis.

Data from the ADAM VTE trial, presented at the American Society of Hematology Annual Meeting in December 2018, also reinforced the use of apixaban in VTE associated with an underlying malignancy. The investigators concluded that a comparable number of patients in the apixaban and dalteparin arms had major bleeding as the primary endpoint (0% vs 2.1%; 

 The findings also showed improved rates of recurrent VTE with the use of apixaban compared with dalteparin (3.4% vs 14.1%, respectively; 

 Further analysis of the subset of patients with GI malignancies who were included in this trial could yield additional relevant information.

Despite the increased GI bleeding with the use of factor Xa inhibitors in patients with GI cancers, the use of DOACs is not excluded in this population. An individualized patient approach in the evaluation of hemorrhagic risk factors is recommended in these complex decisions. Medication counseling, education, and informed consent are paramount.

Consideration of relevant factors includes evaluation for concomitant use of ulcerogenic medications, impaired renal or hepatic function, and prior history of GI bleeding. This information may inform clinical decisions regarding the initiation of DOAC in patients with GI malignancies. In addition, coadministration of a proton pump inhibitor or histamine H2 receptor antagonist can significantly reduce the risk of upper GI bleeding.

More studies are needed to define how best to stratify the risks of hemorrhage among the diverse patients living with GI malignancies. Consideration of factors such as initial tumor burden, prior surgery, and the effects of systemic therapy on bleeding rates will be of interest for future study. In the absence of further data, the optimal anticoagulant takes into consideration a variety of components, including patient preference, the indication for anticoagulation, comorbidities, reversibility, and other factors relevant to the clinical scenario.

NCCN Practice Guidelines in Oncology. Cancer-Associated Venous Thromboembolic Disease, version 1.2019. National Comprehensive Cancer Network website. org/professionals/physician_gls/pdf/vte.pdf. Published February 28, 2019. Accessed December 16, 2018.

Raskob GE, van Es N, Verhamme P, et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. 

. 2018;378(7):615-624. doi: 10.1056/NEJMoa1711948.

Kaaijpoel N, Di Nisio M, Mulder FI, et al. Clinical impact of bleeding in cancer-associated venous thromboembolism: results from the Hokusai VTE Cancer study. 

. 2018;118(8):1439-1449. doi: 10.1055/s-0038-1667001.

Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). 

. 2018;36(20):2017-2023. doi: 10.1200/JCO.2018.78.8034.

Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. 

. 2014;383(9921):955-962. doi: 10.1016/S0140-6736(13)62343-0.

Cheung KS, Leung WK. Gastrointestinal bleeding in patients on novel oral anticoagulants: risk, prevention and management. 

 2017;23(11):1954-1963. doi: 10.3748/wjg.v23.i11.1954.

McBane R, Wysokinski W, Le-Rademacher J, et al. Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial. Presented at: 2018 American Society of Hematology Annual Meeting and Exposition; December 1-4, 2018; San Diego, CA. Abstract 421.

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The optimal anticoagulant takes into consideration a variety of components, including patient preference, the indication for anticoagulation, comorbidities, reversibility, and other factors relevant to the clinical scenario.

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