Low-molecular-weight heparin is the standard, guideline-recommended anticoagulation therapy for patients with cancer and venous thromboembolism (VTE), but the daily subcutaneous injections can be burdensome. Newer direct oral anticoagulants could offer an easier-to-use alternative for these patients, without compromising efficacy, according to results from a non-inferiority trial published in the New England Journal of Medicine. Lead author Gary E. Raskob, PhD, of the University of Oklahoma Health Sciences Center in Oklahoma City, also presented these findings as a late-breaking abstract at the 2017 American Society of Hematology Annual Meeting.
“For the vast majority of patients with cancer-associated VTE, treatment with oral edoxaban can replace the injectable dalteparin,” he said during his presentation. “Preventing VTE recurrence and major bleeding can allow the oncologist to really focus on the patient’s cancer treatment.”
The randomized, open-label Hokusai VTE Cancer trial included 1,046 adult patients with active cancer and acute symptomatic or incidentally detected deep vein thrombosis, acute symptomatic pulmonary embolism (PE), or incidentally detected PE involving segmental or more proximal pulmonary arteries.
Patients were excluded if they received more than 72 hours of pretreatment with anticoagulants prior to randomization, had active bleeding or contraindication to either study agent, or had a platelet count less than 50,000/mL.
Participants were randomized 1:1 to receive edoxaban 60 mg once-daily (n=522; mean age = 64.3 years; standard deviation [SD] = 11.0 years) or dalteparin 200 IU/kg once-daily for 30 days, followed by dalteparin 150 IU/kg once-daily (n=524; mean age = 53.7 years; SD=11.7 years).
In the edoxaban cohort, 465 patients (89.1%) had solid tumors and 56 (10.7%) had hematologic malignancies. In the dalteparin cohort, 467 patients (89.1%) had solid tumors and 55 (10.5%) had hematologic malignancies. The most common tumor types in each cohort were colorectal (n=83 [15.9%] vs. n=79 [15.1%]), lung (n=77 [14.8%] vs. n=75 [14.3%]), and genitourinary (n=65 [12.5%] vs. n=71 [13.5%]).
The median treatment duration was 211 days (interquartile range [IQR] = 76-357 days) in the edoxaban group and 184 days (IQR=85-341 days) in the dalteparin group (p=0.01). Counts of pills and syringes indicated that 447 (85.6%) and 465 patients (88.7%), respectively, received at least 80 percent of the prescribed treatment prior to discontinuation.
After a minimum of nine months of follow-up, edoxaban was deemed non-inferior in preventing the composite outcome of recurrent VTE or major bleeding (primary endpoint). In the edoxaban group, 67 patients (12.8%) experienced a recurrent VTE or major bleeding, compared with 71 patients (13.5%) in the dalteparin group (hazard ratio = 0.97; 95% CI 0.70-1.36; p=0.006).
As seen in the TABLE, secondary outcomes, including incidence of major bleeding and recurrent VTE also were non-inferior between the two treatment groups. “There was a lower rate of recurrent VTE observed with edoxaban, but that was offset by a similar increase in risk of major bleeding,” Dr. Raskob said, adding that “major bleeding was less severe with edoxaban, but rates of severe bleeding were similar.”
The researchers reported no statistically significant impact between subgroups and treatment, except for those with gastrointestinal cancer, who were more likely to have an increase in the risk of bleeding while receiving edoxaban, compared with dalteparin (p=0.02).
Adverse events (AEs) occurred in 308 edoxaban-treated patients (59.0%) and 286 dalteparin-treated patients (54.6%), while serious AEs occurred in 217 (41.6%) and 195 (37.2%) patients, respectively (p values not reported). The most common AEs occurring in each cohort were:
- malignant neoplasm progression (n=68 [13.0%] for edoxaban vs. n=67 [12.8%] for dalteparin)
- neoplasm progression (n=23 [4.4%] vs. n=21 [4.0%])
- pneumonia (n=16 [3.1%] vs. n=14 [2.7%])
- dyspnea (n=9 [1.7%] vs. n=6 [1.1%])
- lung neoplasm malignancy (n=8 [1.5%] vs. n=6 [1.1%])
AEs led to treatment discontinuation in 101 edoxaban-treated patients (19.3%) and 109 dalteparin-treated patients (20.8%); AEs led to death in 116 (22.2%) and 126 (24.0%) patients, respectively.
The study is limited by its open-label design, although “long-term administration of placebo injections was not considered to be appropriate,” the authors noted. In addition, the median duration of the assigned treatment was shorter with dalteparin, which may have influenced relative efficacy.
Daiichi Sankyo provided funding for the study and was responsible for the trial design, protocol, and oversight.
The corresponding authors report financial support from Daiichi Sankyo, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen, Johnson and Johnson, Pfizer, Portola, Merck, Medscape, LEO Pharma, Sanofi, and Medtronic.
Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med. 2017 December 12. [Epub ahead of print]