Gary E. Raskob, PhD
Patients with cancer who have venous thromboembolism (VTE) had similar rates of recurrent VTE or bleeding with the oral factor Xa inhibitor edoxaban (Savaysa) or the low-molecular weight heparin (LMWH) dalteparin (Fragmin), according to results of an international randomized trial presented at the 2017 ASH Annual Meeting.
The 12-month rate of the composite endpoint was 12.8% in the edoxaban group and 13.5% in the dalteparin group. The similarity between treatment groups met statistical criteria for demonstrating noninferiority for edoxaban (P
Analysis of results at 6 months—the typical guideline-recommended duration for VTE prophylaxis—showed rates of 10.5% with edoxaban and 10.7% with dalteparin. This difference also achieved statistical significance for noninferiority, as specified in the trial design (P
= .018). Additionally, an analysis of the separate components of the composite endpoint showed a higher rate of major bleeding with edoxaban.
“The lower rate of recurrent VTE observed with edoxaban was offset by a similar increase in the risk of major bleeding,” said Gary E. Raskob, PhD, dean of the College of Public Health at the University of Oklahoma Health Sciences Center. “There was more upper-gastrointestinal (GI) bleeding with edoxaban, mainly in patients who had GI cancer at entry.”
“Major bleeding was less severe with edoxaban, and the rates of severe major bleeding were similar between the groups,” Raskob added. “Survival free of recurrent VTE or major bleeding—probably the endpoint of most interest to clinicians—also was similar.”
The findings came from the Hokusai-VTE Cancer Study, which involved 1046 patients with cancer and acute symptomatic or incidental VTE. The trial had several objectives: examine the effects of extending VTE prophylaxis from the usual 6 months to 12 months, evaluate the safety and efficacy of a direct oral anticoagulant (DOAC) in a hypercoagulable population of patients with cancer, and compare a DOAC directly with a LMWH.
All patients began treatment with dalteparin and either continued with the LMWH or switched to edoxaban after a 5-day run-in period with dalteparin. In addition to the primary endpoint, secondary endpoints included separate analyses of VTE recurrence and bleeding and an analysis of freedom from VTE recurrence or major bleeding.
Statistically powered to demonstrate noninferiority of edoxaban to dalteparin, the trial design specified 1.5 as the upper limit of the 95% confidence intervals for noninferiority. The primary analysis yielded a hazard ratio of 0.97, associated with confidence intervals of 0.76 and 1.36.
A prespecified analysis of the composite endpoint after 6 months of follow-up also met statistical standards for noninferiority with a hazard ratio of 1.01 and an upper confidence limit of 1.46. An analysis of patients treated in accordance with the trial protocol also demonstrated noninferiority (HR 0.69-1.46; P
Separate examination of recurrent VTE and major bleeding yielded mixed results. Raskob reported that 34 patients in the edoxaban arm had recurrent VTE (6.5%) compared with 54 patients (10.3%) in the dalteparin arm, which led to a statistically significant difference (-3.8%; 95% CI, -7.1% to -0.4%).
Major bleeding, on the other hand, occurred more often with edoxaban (6.3% vs 3.2%). An analysis of types and sites of bleeding showed 2 fatal hemorrhages and 4 intracranial hemorrhages in the dalteparin arm versus 0 and 2, respectively, with edoxaban. Raskob said 20 major bleeding episodes in the edoxaban arm occurred in patients with GI cancers at enrollment as compared with 6 in the dalteparin group. Enrollment of patients with GI cancers stopped after the disparity was noted.
To gain insight into differences in bleeding incidence, investigators analyzed the severity of major bleeding in the 2 treatment groups. They found that the difference in total incidence of major bleeding resulted from an excess of less severe bleeds in the edoxaban arm. A total of 12 grade 3/4 major bleeding episodes occurred in each group (2.3% overall incidence). In the edoxaban arm, an additional 21 grade 2 bleeding episodes occurred versus 5 in the dalteparin group.
The 12-month event-free survival was almost identical in the 2 groups. The cumulative rate of freedom from recurrent VTE, major bleeding, or death was 55.0% with edoxaban and 56.5% with dalteparin.
During a study discussion during a press conference at the 2017 ASH Annual Meeting, moderator Robert Brodsky, MD, director of hematology at Johns Hopkins Medicine, said the findings could “usher in a new standard of care.”
"It is a common question that oncologists face, and a lot of patients can't inject themselves — it's not an easy thing to do,” said Brodsky.
Raskob GE, Van Es N, Verhamme P, et al. A randomized, open-label, blinded outcome assessment trial evaluating the efficacy and safety of LMWH/edoxaban versus dalteparin for venous thromboembolism associated with cancer: Hokusai VTE-cancer study. In: Proceedings from the 2017 ASH Annual Meeting; December 9-12, 2017; Atlanta, Georgia. Abstract LBA-6.