XARELTO® in Cancer Patients Associated with Fewer Episodes of VTE Compared with FRAGMIN® but Increase in Nonmajor Bleeding

SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke.

Approximately 20% of cancer patients develop VTE and there is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer. The current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations for at least 6 months or probably longer, as long as the cancer is active. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Direct Oral AntiCoagulants (DOACs) have been proven to be noninferior to COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of acute VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. However, the efficacy and safety of DOACs for the treatment of cancer-associated VTE have not been established. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® , the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. In the EINSTEIN trial which compared XARELTO® with LMWH followed by COUMADIN® in patients with acute symptomatic DVT or PE, only 5.5% of patients had active cancer at baseline.

This study was conducted to assess VTE recurrence rates in patients with active cancer, treated with either XARELTO® or FRAGMIN® (Dalteparin) and whether XARELTO® would offer an alternative treatment for cancer patients with VTE. SELECT-D (Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism) is a randomized, open-label, multicenter pilot trial in which patients with active cancer, who had symptomatic Pulmonary Embolism (PE), incidental PE, or symptomatic lower-extremity proximal Deep Vein Thrombosis (DVT) were enrolled to receive either XARELTO® or FRAGMIN®. Active cancer was defined as a diagnosis of cancer (other than Basal-cell or Squamous-cell skin carcinoma) in the previous 6 months, any treatment for cancer within the previous 6 months, recurrent or metastatic cancer, or cancer not in Complete Remission (hematologic malignancy). In this study, 58% of the patients had metastatic disease, approximately 25% of patients had Colorectal cancer and 83% were receiving chemotherapy at the time of their VTE. A total of 406 patients were randomly assigned in a 1:1 ratio to receive either FRAGMIN® 200 IU/kg SC once daily for the first 30 days and then 150 IU/kg SC daily for an additional 5 months or XARELTO® 15 mg orally twice daily for 3 weeks, then 20 mg once daily for a total of 6 months. Patients were assessed at 3-month intervals until month 12 and then at 6-month intervals until month 24. The primary outcome was VTE recurrence over 6 months, using compression ultrasound (CUS). Secondary outcomes were major bleeding and Clinically Relevant NonMajor Bleeding (CRNMB).

The cumulative VTE recurrence rate at 6 months was 11% for patients receiving FRAGMIN® and 4% for patients receiving XARELTO® (HR=0.43). The 6-month cumulative rate of major bleeding was 4% for FRAGMIN® and 6% for XARELTO® (HR= 1.83). Corresponding cumulative rate of CRNMB at 6 months was 4% and 13% respectively. Most major bleeding events were GI, and there were no CNS bleeds. Patients with esophageal or gastroesophageal cancer experienced more major bleeds with XARELTO® than with FRAGMIN® (36% versus 11%). Overall Survival at 6 months was 70% with FRAGMIN® and 75% with XARELTO®.

It was concluded that XARELTO® was associated with relatively low VTE recurrencein patients with cancer but with higher Clinically Relevant NonMajor Bleeding, compared with LMWH, FRAGMIN®. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). Young AM, Marshall A, Thirlwall J, et al. Journal of Clinical Oncology 2018;36:2017-2023