In today’s session, Dr. Agnes Lee from the University of British Columbia and the BC Cancer Agency discussed the treatment of cancer associated thrombosis (CAT). Dr. Lee started by saying that “Venous thromboembolism (VTE) contributes to significant morbidity in patients with cancer; it is the second leading cause of death in patients with cancer, interferes with cancer treatment, increases health care utilization, and imposes emotional and economic burden in this important patient population.”
The standard of care for treatment of CAT changed to low molecular weight heparin nearly 20 years ago following the publication of the CLOT study that reported the efficacy of the low molecular weight heparin (LMWH), dalteparin, in reducing the risk of recurrent thrombosis, as compared to warfarin in this patient cohort.
The first study comparing a direct oral anticoagulant (DOAC) with LMWH in cancer patients was the Hokusai VTE Cancer study, published in the NEJM in 2018. It explored the use of edoxaban and compared it to the use of LMWH administered in a similar fashion described in the CLOT study. Results showed that edoxaban was non-inferior to dalteparin (HR 0.97 p=0.006 for non-inferiority) for the combined outcome of recurrent thrombosis and major bleeding. Although there was no significant difference in recurrent thrombosis, major bleeding was significantly increased in patients taking edoxaban as compared to dalteparin (6.9% vs 4.0%; p=0.04). This increase was primarily driven by major bleeding events in patients with gastrointestinal (GI) cancers.
A second publication in 2018 reported the results of the SELECT-D trial. This pilot trial compared another DOAC, rivaroxaban, to dalteparin in patients with CAT. Results of this trial found that rivaroxaban was associated with a lower risk of recurrent VTE (4.0% vs 9.0%; HR 0.43; 95% CI 0.19-0.99) The 6-month cumulative rate of major bleeding was 4% for dalteparin and 6% for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). However, a higher rate of clinically relevant non-major bleeding was observed with rivaroxaban. Notably, individuals with esophageal and gastroesophageal cancer were excluded half way during the conduct of this study due to a very high rate of major bleeding in patients treated with rivaroxaban.
Based on these important trials, international recommendations have been updated by the ISTH SSC subcommittee on Haemostasis and Malignancy who suggest the use of edoxaban or rivaroxaban over LMWH in patients with CAT. The exception to this recommendation includes patients with a higher risk of bleeding such as those with upper GI, genitourinary tumors or individuals with GI mucosal abnormalities. The National Comprehensive Cancer Network (NCCN) provides a category 1 recommendation for dalteparin monotherapy and also for LMWH for one week followed by edoxaban. These guidelines provide a category 2A recommendation for rivaroxaban monotherapy. Canadian consensus statements recommend LMWH in cancer patients who have a high risk of bleeding, GI or urothelial cancer, and in patients with drug/drug interactions to a DOAC. These guidelines recommend edoxaban or rivaroxaban in all other cancer patients treated for CAT.
Dr. Lee summarized her recommendations as follows: LMWH is her first choice based on her experience and is preferred in GI malignancies or patients with a high risk of bleeding. She prefers a DOAC in patients who do not have GI malignancies, and she adds that she restricts the use of warfarin to those who are unable to use LMWH or DOACs in these patient populations.