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

Special Considerations for use of DOACs in the Treatment of Cancer-associated VTE

Practical Considerations

Although DOAC treatment is associated with lower rates of VTE recurrence and comparable rates of major bleeding relative to LMWH in patients with cancer, particularly nongastrointestinal cancer, practical considerations may limit DOAC use. Unlike parenteral LMWH, oral anticoagulants including DOACs are subject to interference from chemotherapy-induced nausea and vomiting; therefore, LMWH may be preferable in patients with frequent vomiting.[12] The DOACs require careful dosing in patients with renal impairment, and drug labeling provides little support for use of DOACs to treat VTE in patients with severe renal impairment.[55–58] Similar concerns apply to LMWH use in patients with severe renal impairment, and unfractionated heparin or VKAs are preferred in this population.[12,19,59] Caution is also required in patients with thrombocytopenia; current clinical guideline recommendations and practice guidance suggestions include standard-dose LMWH treatment in patients with platelet counts >50 000/μl and no evidence of bleeding, and case-by-case decisions based on individual risk/benefit considerations for patients with platelet counts <50 000/μl.[12,60] The 2018 ISTH guidance suggests withholding anticoagulation in patients with platelet counts <25 000/μl who are at lower risk for recurrent VTE and considering platelet transfusion to maintain platelet counts above 40 000–50 000/μl in patients with thrombocytopenia and high risk for VTE recurrence.[60]

Another concern in DOAC use in patients with cancer is drug–drug interactions with anticancer agents.[12] Apixaban, rivaroxaban, and edoxaban are substrates of cytochrome 450 3A4 (CYP3A4) to varying degrees—edoxaban is minimally metabolized by CYP3A4—and of P-glycoprotein (P-gp), and the prodrug dabigatran etexilate is also a P-gp substrate.[61,62] Strong CYP3A4 and P-gp inhibitors significantly increase DOAC plasma levels, while strong CYP3A4 and P-gp inducers significantly decrease plasma DOAC levels.[61,62] The importance of potential interactions of anticancer agents with DOACs via CYP3A4 or P-gp have been comprehensively reviewed elsewhere.[61–63] In brief, anticancer drug classes with potential class-wide interactions with DOACs include antimitotic microtubule inhibitors, most tyrosine kinase inhibitors, and most immune-modulating agents including glucocorticoids;[62] cyclosporine is known to increase plasma edoxaban exposure.[64] There are also potential interactions between DOACs and individual drugs among the topoisomerase inhibitors, anthracyclines, alkylating agents, and hormonal agents.[62] However, antimetabolites, platinum-based agents, intercalating agents, and monoclonal antibodies have minimal potential for drug–drug interactions with DOACs.[62]

Although SELECT-D and CARAVAGGIO exclude patients taking any strong inducer or inhibitor of CYP3A4 or P-gp, Hokusai-VTE Cancer excludes only patients using certain potent P-gp–inhibiting drugs, with dose adjustment to edoxaban 30 mg once daily for patients taking other strong P-gp inhibitors.[46–48] Patients in Hokusai-VTE Cancer continued treatment with several anticancer medications with potential interactions with edoxaban, including taxanes (7.7% of edoxaban-treated patients), topoisomerase inhibitors (5.7%), kinase inhibitors (3.4%), vinca alkaloids (3.1%), and immunomodulating agents (3.1%).[46] The comparable safety and efficacy of edoxaban versus dalteparin in Hokusai-VTE Cancer patients with nongastrointestinal cancers suggests that drug–drug interactions between DOACs and anticancer agents are clinically manageable. Ongoing studies evaluating interactions of apixaban with anticancer agents (NCT03083782 and NCT02749617)[65,66] should provide additional data to guide dose adjustments.

Special Populations

Certain populations of patients with cancer have increased risk of VTE recurrence and/or bleeding and require special consideration during anticoagulant treatment of cancer-associated VTE. Patients with brain tumors are at high risk for recurrent VTE and anticoagulant-associated intracranial hemorrhage (ICH), although the bleeding risk is not considered a contraindication to anticoagulation.[59] Patients with brain tumors were included in both Hokusai-VTE Cancer (reported as 'other') and SELECT-D (n = 3), but not in sufficient numbers to assess the RR of ICH during treatment with DOACs versus LMWH.[46,47] Patients with multiple myeloma have high rates of VTE due to disease- and treatment-specific risk factors,[18] but neither Hokusai-VTE Cancer nor SELECT-D enrolled large numbers of such patients.[46,47] Finally, patients with gastrointestinal cancer experienced higher rates of gastrointestinal bleeding during treatment with edoxaban or rivaroxaban relative to LMWH.[46,47] Based on available evidence and as reflected in the ISTH Scientific and Standardization Committee (SSC) 2018 guidance on the role of DOACs in treatment of cancer-associated VTE, patients with gastrointestinal cancer and VTE should not receive DOACs when other anticoagulant options are available.[67] Limited data are available on treatment of cancer-associated VTE in patients with additional noncancer risk factors for anticoagulant-associated bleeding, such as elderly patients and patients with renal impairment, but extrapolation from studies in patients without cancer suggests additional monitoring may be appropriate during use of any anticoagulant agent.[59]