A multicenter randomized phase II open label study to compare the safety and efficacy of direct oral anticoagulants versus subcutaneous dalteparin for cancer-associated venous thromboembolism in patients with advanced upper gastrointestinal, hepatobiliary and pancreatic cancer

Abstract

Background The anticoagulation therapy in Cancer-associated venous thromboembolism (CA-VTE) is challenging especially in balancing the risks of recurrence of CA-VTE and bleeding during anticoagulation as cancer itself is a risk for both. Recently, direct oral anticoagulants (DOAC) has been recommended as treatment options equivalent to subcutaneous dalteparin. However, the issues about the bleeding risk of DOAC therapy have been continuously raised. This study evaluated the safety and efficacy of DOAC vs. subcutaneous dalteparin for CA-VTE in patients with advanced upper gastrointestinal (GI) tract, hepatobiliary, or pancreatic cancer.

Methods This was a multicenter, randomized, open-label, phase II trial in five centers. Patients were randomly assigned to receive rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily) /apixaban (10 mg twice daily for the first 7 days, then 5mg twice daily) or dalteparin (200 IU/kg once daily for the first month, then 150 IU/kg once daily). Randomization was stratified by the Eastern Cooperative Oncology Group Performance Status, primary cancer type, active chemotherapy, and participating centers. The primary endpoint was the rates of clinically relevant bleeding (CRB) in full-analysis-set (FAS).

Results A total of 90 patients were randomly assigned to the DOAC (n=44) and dalteparin group (n=46) in FAS. The rates of CRB and major bleeding (MB) were 34.1% and 13.0% (P=0.018), and 18.2% and 4.3% (P=0.047) between DOAC and dalteparin groups. The cumulative incidence of CRB and MB were higher in DOAC group than in dalteparin group (hazard ratio [HR] 2.83; P=0.031 and HR 4.32; P=0.064). Cancer involvement at GI mucosa was also a significant risk factor for CRB in univariate analysis. Recurrent CA-VTE occurred in 2.3% with DOAC and 2.2% with dalteparin (P=1.000).

Conclusions The DOAC therapy further increased the risk of bleeding compared with dalteparin in patients with active advanced upper GI tract, hepatobiliary, or pancreatic cancer, requiring extra-caution when selecting anticoagulants for CA-VTE.

Clinical trial identification NCT03139487.

Legal entity responsible for the study S.R. Park.

Funding The research has been supported by Korean Society of Medical Oncology and by a grant (2017-0327) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Republic of Korea.

Disclosure All authors have declared no conflicts of interest.