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


The results of Hokusai-VTE Cancer and SELECT-D show that edoxaban and rivaroxaban are equally or more effective relative to dalteparin for prevention of VTE recurrence but confer higher risk for major bleeding in patients with cancer, especially gastrointestinal cancer.[45] The association between gastrointestinal cancer and upper gastrointestinal bleeding in patients taking edoxaban might be due to high concentrations of edoxaban in the gastrointestinal lumen exacerbating bleeding directly from the tumor or from gastrointestinal mucosa damaged by chemotherapy targeting gastrointestinal tumors.[54] In light of these data, the ISTH SSC 2018 guidance suggests edoxaban or rivaroxaban for cancer patients with an acute diagnosis of VTE, low risk of bleeding, and no drug–drug interactions with current systemic therapy, after shared decision-making with patients to balance potential reduction in VTE recurrence versus higher bleeding rates.[67] The 2018 National Comprehensive Cancer Network guidance prefers LMWH monotherapy, but suggests DOAC use in patients for whom long-term LMWH therapy is not an option; they note that further investigation in cancer patients is needed for apixaban and dabigatran.[68]

The commonalities between the results of Hokusai-VTE Cancer and SELECT-D trial results predicted similar trends for apixaban, but bleeding rates in ADAM VTE were similar between patients treated with apixaban versus dalteparin.[51] However, although the dalteparin treatment protocol was identical, the rate of major bleeding in dalteparin-treated patients was lower in ADAM VTE relative to Hokusai-VTE Cancer and SELECT-D,[46,47,51] suggesting inter-study differences in patient selection or management. This is especially important because availability of results from Hokusai-VTE, SELECT-D, and ADAM VTE may caution CARAVAGGIO investigators not to include patients with certain cancers—such as colorectal cancer, associated with excess gastrointestinal bleeding during edoxaban and rivaroxaban versus dalteparin treatment—in the ongoing apixaban trial. Such potential patient selection bias needs to be considered when CARAVAGGIO results become available, and careful evaluation of the patient populations will be necessary for any comparison among these trials of DOACs for treatment of cancer-associated VTE. Detailed analyses will be required to differentiate the safety profiles of apixaban, edoxaban, and rivaroxaban in patients with cancer.

An often-understated benefit of DOAC therapy relative to LMWH is the effect of longer treatment duration due to better patient persistence. In a recent large observational study including patients with cancer-associated VTE treated with LMWH or rivaroxaban, median duration of therapy was significantly shorter for LMWH versus rivaroxaban (1 versus 3 months).[36] Although the rates of VTE recurrence were initially similar, they began to diverge in favor of rivaroxaban versus LMWH treatment after ~6 weeks; this divergence might reflect LMWH treatment discontinuation.[36] Even in the randomized clinical trial setting, Hokusai-VTE recorded numerically longer drug exposure, higher rate of study treatment completion, and lower rate of patients discontinuing treatment due to dosing inconvenience for edoxaban versus dalteparin.[46] These differences in treatment duration could contribute to the numerically lower VTE recurrence rate in patients receiving edoxaban versus dalteparin.[46] Better treatment persistence with DOACs versus LMWH is likely to be a strong consideration in anticoagulant selection for VTE treatment in patients with cancer.

Even with publication of new and ongoing studies, the evidence for DOAC treatment of cancer-associated VTE has limitations that should prompt further research. First, patient selection for clinical trials may not reflect the entire patient population; results from observational studies should be helpful in this regard. Second, there remains little evidence on optimal duration of anticoagulation or choice of anticoagulant for VTE treatment longer than 6–12 months in patients with cancer.[69,70] Finally, the new studies give an overview of DOAC treatment of patients with cancer-associated VTE but provide little guidance on which patients are most likely to benefit from DOAC therapy. Additional studies in patients with well-defined risk profiles are necessary to determine which patients are most likely to benefit from prevention of VTE recurrence or suffer from bleeding events during DOAC treatment.

Prevention of cancer-associated VTE is another potential use for DOACs. Thromboprophylaxis is recommended for hospitalized patients with active cancer and patients undergoing major cancer surgery, and suggested for outpatients with specific cancer types with a very high risk of VTE—such as advanced pancreatic cancer—with LMWH as the preferred agent.[12,17,71] Two recent randomized, double-blind, placebo-controlled studies provide data on DOAC use in ambulatory cancer patients. In the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) study, objectively documented major VTE—defined as proximal DVT or pulmonary embolism—occurred in significantly fewer apixaban-treated patients [12/288 (4.2%)] versus placebo-treated patients [28/275 (10.2%); P < 0.001] with a Khorana score ≥2 initiating a new course of chemotherapy for cancer treatment.[72] However, major bleeding occurred significantly more frequently in patients treated with apixaban versus placebo [10/288 (3.5%) versus 5/275 (1.8%); P = 0.046].[72] Similarly, ambulatory patients with a solid tumor or lymphoma and Khorana score ≥2 treated with rivaroxaban compared with placebo in the CASSINI trial had a numerically lower rate of a composite of VTE events [25/420 (6.0%) versus 37/421 (8.8%); P = 0.10] and numerically higher rate of major bleeding [8/405 (2.0%) versus 4/404 (1.0%)].[73] The AVERT and CASSINI trials showed that thromboprophylaxis with a DOAC was effective and associated with a low bleeding rate in ambulatory patients with cancer considered to have intermediate-to-high risk of VTE. However, the clinical benefit of DOACs for primary thromboprophylaxis still needs to be established.

Based on the evidence presented, DOACs appear to be reasonable and often preferable alternatives to LMWH for management of VTE in patients with cancer without potential drug–drug interactions with chemotherapy or high risk for bleeding, especially when patient preference or practical considerations threaten persistence with LMWH therapy. Figure 1 shows a potential treatment approach based on current treatment guidelines and the new randomized controlled clinical trial evidence summarized here. In patients with VTE and gastrointestinal cancer, DOAC use should be considered on a case-by-case basis and with an understanding of the RR and benefits. Ongoing research is still needed to provide additional insight into any potential class effects of factor Xa inhibitors in patients with cancer, on the relative efficacy of thromboprophylaxis with DOACs, and on management of drug–drug interactions between DOACs and anticancer agents.

Figure 1.

Potential treatment approach for cancer-associated VTE based on current treatment guidelines and new randomized controlled trial evidence. aReduced dose or full dose following transfusion. bIncludes patients with gastrointestinal cancer as well as risk factors unrelated to cancer. cOn a case-by-case basis with an understanding of the relative risks and benefits. DDI, drug–drug interactions; DOAC, direct oral anticoagulant; LMWH, low-molecular-weight heparin; VTE, venous thromboembolism.