Dalteparin (Fragmin), a low molecular weight heparin, is the standard of care for the extended treatment and prevention of acute VTE recurrence in patients with cancer. Rivaroxaban, a direct oral anticoagulant (DOAC), is a highly selective direct Factor Xa inhibitor with oral bioavailability, and may be another treatment option for this patient population.
“Clinicians are already adopting DOACs into practice for these patients,” Annie Young, PhD, Warwick Medical School, University of Warwick, Coventry in the United Kingdom, said in an ASH press release. However, comparisons between the two regimens are limited.
Young and colleagues conducted the prospective, randomized, open label, multicenter pilot trial, designed to compare dalteparin, administered subcutaneously, with rivaroxaban for the treatment of VTE in 406 patients with cancer, including those with symptomatic or incidental pulmonary embolism (iPE) or symptomatic lower extremity proximal deep vein thrombosis (DVT).
In month 1, patients in the dalteparin arm received 200 IU/kg daily followed by 150 IU/kg in months 2 through 6. Patients in the rivaroxaban arm were administered 15 mg twice daily for 3 weeks followed by 20 mg once daily for 6 months in total. After 6 months of trial treatment, DVT patients who were residual vein thrombosis (RVT)-positive and patients with PE at presentation, could be randomized to placebo or rivaroxaban for an additional 6 months.
The initial randomization included 530 patients, of which 150 patients remained in each arm of the second randomization to assess the duration of anticoagulation. The trial sample size was reduced when the second randomization closed due to a high attrition rate.
A revised sample size of 203 patients in each arm comprised the evaluation for the trial’s primary endpointVTE recurrence. Secondary endpoints included major bleeds and clinically relevant non-major bleeds—including overt bleeds resulting in unscheduled contact with a physician or interruption or discontinuation of study drug—acceptability, survival, and health economics.
Patients were a median age of 67 years, of which more than half were males (53%) and majority were white (95%). They presented with either early or locally advanced disease (n = 156; 38%), metastatic disease (n = 240; 59%); or hematologic malignancies (n = 10; 3%). Patients also presented with iPE (n = 214; 53%), or had symptomatic PE or DVT (n = 192; 47%). Of the 280 patients who were receiving anticancer treatment at the time of the VTE, most were receiving chemotherapy (n = 232; 83%) or targeted therapy (n = 41; 15%).
The rivaroxaban arm (4%; 95% CI, 2-9) induced lower rates of VTE recurrence compared with the dalteparin arm (11%; 95% CI, 7-17). Major bleeds appeared similar between arms, with 6 bleeds from 6 patients who received dalteparin (3%; 95% CI, 1-6) and 9 bleeds from 8 patients who received rivaroxaban (4%; 95% CI, 2-8).
However, more CRNMBs occurred in the rivaroxaban arm, totaling 28 bleeds from 27 patients (13%; 95% CI, 9-19) compared with 5 bleeds in 5 patients who received dalteparin (2%; 95% CI, 1-6). Overall, 11 patients (5%; 95% CI, 3-9) in the dalteparin arm had bleeds categorized as either major bleeds or CRNMBs compared with 34 patients (17%; 95% CI, 12-22) in the rivaroxaban arm.
The researchers are conducting further analyses to try to understand factors that may have contributed to this difference, according to an ASH press release.
“Now [clinicians] have data from this study to indicate that DOACs are potentially safe in cancer patients,” Young said in the press release. “We need to be looking at different groups of people and different types of bleeds in more detail, so that we can choose the best treatment for each patient.”
In addition, a total of 208 patients completed 6 months of treatment, including 100 patients who received dalteparin (52%) and 108 patients who were on rivaroxaban (55%). At 6 months, the rivaroxaban arm (74%; 95% CI, 68-80) demonstrated superior overall survival compared with the dalteparin arm (70%; 95% CI, 63-76).
In the second randomization, only 92 patients of the required 300 were recruited, including 82 PEs and 10 DVTs. Patients did not continue to the second randomization as a result of death or withdrawal (50%); being RVT-negative (12%); failing the other eligibility criteria (24%); or declining to participate in randomization (14%).