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

Results From Hokusai-VTE Cancer and SELECT-D

Hokusai-VTE Cancer enrolled 1050 patients, of whom 11% had hematological malignancies and 89% had solid tumors.[46] The most frequent tumor types were colorectal (15.9% versus 15.1%), lung (14.8% versus 14.3%), genitourinary (12.5% versus 13.5%), and breast (12.3% versus 11.5%) in patients receiving edoxaban versus dalteparin; 6.3% of edoxaban-treated patients versus 4.0% of dalteparin-treated patients had upper gastrointestinal cancer.[46] Median treatment duration was numerically longer for edoxaban (211 days) versus dalteparin (184 days), and 38.3% of patients receiving edoxaban versus 29.4% receiving dalteparin completed study treatment.[46] Patients taking edoxaban versus dalteparin had relatively similar rates of treatment discontinuation due to death (16.5% versus 19.1%) and clinical outcome or adverse event (15.1% versus 11.8%).[46] However, the rate of treatment discontinuation due to patient dissatisfaction with dosing inconvenience was numerically higher for dalteparin (14.9%) relative to edoxaban (4.0%).[46] Edoxaban was statistically noninferior to dalteparin; the composite primary outcome of recurrent VTE or major bleeding occurred in 12.8% of patients receiving edoxaban versus 13.5% of patients receiving dalteparin.[46] Edoxaban was associated with a numerical 3.4% lower absolute rate of recurrent VTE (7.9% versus 11.3%) and a significant 2.9% higher absolute rate of major bleeding (6.9% versus 4.0%) compared with dalteparin.[46] Death related to VTE or bleeding occurred in six patients in each treatment group.[46] Event-free survival and death from any cause were similar between edoxaban and dalteparin (55.0% versus 56.5% and 39.5% versus 36.6%, respectively).[46] In subgroup analyses, only patients with gastrointestinal cancer were at a significantly increased risk of bleeding with edoxaban treatment relative to dalteparin.[46]

A secondary analysis of Hokusai-VTE Cancer focused on the sites, clinical presentation, clinical course and outcome, and the tumor types associated with bleeding events in more detail.[54] This analysis confirmed that there were no fatal bleeds with edoxaban treatment, and two fatal bleeds with dalteparin (one patient with metastatic breast cancer had fatal subdural hematoma after a fall; one patient with metastatic skin melanoma had fatal lower gastrointestinal bleeding).[54] Overall, severe bleeding (bleeding events that presented as medical emergencies or were almost immediately fatal) was reported in 1.9% of edoxaban patients and 2.1% of dalteparin patients.[54] Among patients with gastrointestinal cancer, the clinical presentation of bleeding was severe in 3.0% versus 2.1% with edoxaban and dalteparin treatment, respectively.[54] Furthermore, in patients with gastrointestinal cancers, the clinical presentation was upper gastrointestinal bleeding in the majority (71.4%) of major bleeding events in the edoxaban group.[54]

SELECT-D was a smaller study than Hokusai-VTE Cancer, with 406 patients enrolled.[47] The most common primary cancer types were colorectal (27% versus 23%), lung (11% versus 12%), and breast (10% each) in patients receiving rivaroxaban versus dalteparin; hematologic cancers and genitourinary cancers were reported as individual tumor types rather than categories.[47] An interim safety review of the first 220 patients found a difference in major bleeding between patients with esophageal or gastroesophageal cancer receiving rivaroxaban versus dalteparin, and such patients were subsequently excluded from enrollment; in the final analysis, 5% of rivaroxaban-treated patients and 9% of dalteparin-treated patients had esophageal or gastroesophageal tumors.[47] Median treatment duration was similar between rivaroxaban and dalteparin (5.9 versus 5.8 months).[47] Patients receiving rivaroxaban versus dalteparin most often discontinued study treatment because of death (rivaroxaban, 28/203; dalteparin, 33/203), outcome or adverse event (rivaroxaban, 35/203; dalteparin, 22/203), and patient decision (rivaroxaban, 7/203; dalteparin, 10/203); the most common reason for study withdrawal was patient choice (rivaroxaban, 11/203; dalteparin, 19/203).[47] Patients receiving rivaroxaban had a numerically lower rate of VTE recurrence (4% versus 11%), comparable rate of major bleeding (6% versus 4%), and numerically higher rate of CRNM bleeding (13% versus 4%) relative to patients receiving dalteparin.[47] Most major bleeding events were gastrointestinal, and patients with esophageal or gastroesophageal cancer experienced major bleeding numerically more frequently when treated with rivaroxaban relative to dalteparin (36% versus 11%).[47] Most CRNM bleeding events were gastrointestinal or urologic.[47]

Meta-analysis of 6-month outcomes in Hokusai-VTE Cancer and SELECT-D reported lower incidence of recurrent VTE [relative risk (RR): 0.65; 95% confidence interval (CI): 0.42–1.01], higher incidence of major bleeding (RR: 1.74; 95% CI: 1.05–2.88), and CRNM bleeding (RR: 2.31; 95% CI: 0.85–6.28), and no difference in mortality (RR: 1.03; 95% CI: 0.85–1.26) in patients treated with edoxaban or rivaroxaban versus dalteparin.[45] Mortality was also similar between patients with cancer and VTE treated with DOACs versus LMWH in the individual studies. Hokusai-VTE Cancer reported death rates of 15.3% versus 13.5% after 3 months, 26.8% versus 24.2% after 6 months, and 39.5% versus 36.6% after 12 months in patients treated with edoxaban versus dalteparin, respectively; 181/206 deaths in patients taking edoxaban and 172/192 deaths in patients receiving dalteparin were considered cancer related.[46] Overall 6-month survival rates in SELECT-D were comparable between patients taking rivaroxaban (75%) versus dalteparin (70%); causes of death were not reported.[47]

Preliminary results from ADAM VTE were presented at the 2018 American Society of Hematology meeting. Patients treated with apixaban (n = 145) had similar, very low rates of major bleeding, a significantly lower rate of VTE recurrence, and similar rates of major + CRNM bleeding and mortality relative to dalteparin-treated patients (n = 142).[51] Notably, ADAM VTE was a smaller study relative to Hokusai-VTE Cancer or SELECT-D, outcome event rates differed between the published abstract and the oral presentation, and certain important tumor types (colorectal, lung, and genitourinary) were unevenly distributed between treatment arms. Consequently, the role of apixaban in treatment of cancer-associated VTE will remain uncertain until further trials report apixaban results in this setting.