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)

Abstract

Purpose Venous thromboembolism (VTE) is common in patients with cancer. Long-term daily subcutaneous low molecular weight heparin has been standard treatment for such patients. The purpose of this study was to assess if an oral factor Xa inhibitor, rivaroxaban, would offer an alternative treatment for VTE in patients with cancer. Patient and Methods In this multicenter, randomized, open-label, pilot trial in the United Kingdom, patients with active cancer who had symptomatic pulmonary embolism (PE), incidental PE, or symptomatic lower-extremity proximal deep vein thrombosis (DVT) were recruited. Allocation was to dalteparin (200 IU/kg daily during month 1, then 150 IU/kg daily for months 2-6) or rivaroxaban (15 mg twice daily for 3 weeks, then 20 mg once daily for a total of 6 months). The primary outcome was VTE recurrence over 6 months. Safety was assessed by major bleeding and clinically relevant nonmajor bleeding (CRNMB). A sample size of 400 patients would provide estimates of VTE recurrence to within ± 4.5%, assuming a VTE recurrence rate at 6 months of 10%. Results A total of 203 patients were randomly assigned to each group, 58% of whom had metastases. Twenty-six patients experienced recurrent VTE (dalteparin, n = 18; rivaroxaban, n = 8). The 6-month cumulative VTE recurrence rate was 11% (95% CI, 7% to 16%) with dalteparin and 4% (95% CI, 2% to 9%) with rivaroxaban (hazard ratio [HR], 0.43; 95% CI, 0.19 to 0.99). The 6-month cumulative rate of major bleeding was 4% (95% CI, 2% to 8%) for dalteparin and 6% (95% CI, 3% to 11%) for rivaroxaban (HR, 1.83; 95% CI, 0.68 to 4.96). Corresponding rates of CRNMB were 4% (95% CI, 2% to 9%) and 13% (95% CI, 9% to 19%), respectively (HR, 3.76; 95% CI, 1.63 to 8.69). Conclusion Rivaroxaban was associated with relatively low VTE recurrence but higher CRNMB compared with dalteparin.

Comparative risk of major bleeding with rivaroxaban and warfarin: Population‐based cohort study of unprovoked venous thromboembolism

“…The hypothesis that direct‐acting anticoagulants may predispose patients with underlying gastrointestinal pathologies to gastrointestinal bleeds to a greater extent than other anticoagulants is supported by data from two recent VTE in cancer trials . In the HOKUSAI VTE Cancer trial, a randomized, open‐label, non‐inferiority trial evaluating edoxaban vs dalteparin in patients with cancer‐associated thrombosis (CAT), more patients treated with edoxaban experienced major bleeds (6.9% in the edoxaban group and 4.0% in the dalteparin group; HR, 1.77; 95% CI = 1.03‐3.04), and this difference was appeared to be driven by increased gastrointestinal bleeding in patients with gastrointestinal cancer (13.2% in the edoxaban group and 2.4%, in the dalteparin group; P = 0.0169) .…”

“…In the HOKUSAI VTE Cancer trial, a randomized, open‐label, non‐inferiority trial evaluating edoxaban vs dalteparin in patients with cancer‐associated thrombosis (CAT), more patients treated with edoxaban experienced major bleeds (6.9% in the edoxaban group and 4.0% in the dalteparin group; HR, 1.77; 95% CI = 1.03‐3.04), and this difference was appeared to be driven by increased gastrointestinal bleeding in patients with gastrointestinal cancer (13.2% in the edoxaban group and 2.4%, in the dalteparin group; P = 0.0169) . Though absolute numbers were low, an increase in major gastrointestinal bleeding was also observed with rivaroxaban vs dalteparin treatment of cancer‐associated VTE in the randomized SELECT‐D trial (eight vs four events, respectively) . The mechanism behind the observed increased in gastrointestinal bleeding observed with oral direct factor Xa inhibitors vs other anticoagulants (in CAT and NVAF) has not been well elucidated.…”

Treatment of cancer‐associated venous thromboembolism: 12‐month outcomes of the placebo versus rivaroxaban randomization of the SELECT‐D Trial (SELECT‐D: 12m)

“…A total of 214 patients (53%) were males, the median age was 67 years (range, 22‐87 years), 234 (58%) had metastatic disease, and 211 (52%) patients had an incidental PE (Table ). The primary analyses of recurrent VTE and bleeding at 6 months have been published …”

“…The excess of major bleeding with edoxaban was confined to patients with gastrointestinal cancer . In the SELECT‐D trial, patients received rivaroxaban or dalteparin for 6 months . Using rivaroxaban reduced the 6‐month VTE recurrence rate compared with dalteparin (hazard ratio [HR] = 0.43; 95% confidence interval [CI], 0.19‐0.99).…”

Biosimilars of low molecular weight heparins: Relevant background information for your drug formulary

“…The LMWHs however still have an established and important role in the prevention and treatment of acute thromboembolic complications. In cancer patients with venous thromboembolism and prophylaxis during pregnancy, LMWHs remains the drugs of choice …”