Katherine C. Rappazzo, MD
Resident, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Jennifer R. Green, MD
Assistant Professor of Medicine,
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.1
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.2,3
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%).2
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.3
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.3
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.4
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.5,6