Use of Direct Oral Anticoagulants in Preventing VTE in Patients With Cancer


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THE FIRST TWO randomized trials to directly compare direct oral anticoagulants vs low–molecular-weight heparin for management of venous thromboembolism (VTE) in patients with cancer suggest that direct oral anticoagulants may become the new standard of care.1,2 Direct oral anticoagulants appear to reduce the rate of recurrent VTE vs low–molecular-weight heparin in patients with cancer, albeit with an increased rate of bleeding. The findings of these studies were presented at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition. 

The larger Hokusai VTE–Cancer trial1 showed the direct oral anticoagulant edoxaban was noninferior to the low–molecular-weight heparin (dalteparin [Fragmin]) for the composite endpoint of first recurrent VTE or major bleeding event at 12 months: 12.8% vs 13. 5%, respectively. These results were similar during the first 6 months of treatment, but major bleeding was more frequent with edoxaban. 

The “select-d” pilot trial2 showed that at 6 months, rivaroxaban had a lower cumulative VTE recurrence rate than dalteparin (4% vs 11%, respectively). The 6-month cumulative rate of major bleeding was 6% for rivaroxaban and 4% for dalteparin. Clinically relevant nonmajor bleeding was more frequently observed with rivaroxaban: 13% vs 4%, respectively. 

Gary Raskob, PhD

Gary Raskob, PhD

“Cancer patients are at increased risk of VTE, and treatment can be challenging, causing morbidity and mortality and interfering with definitive cancer therapy. New oral direct oral anticoagulants had not been tested in cancer patients before this. Evidence-based guidelines recommend low–molecular-weight heparin for the prevention and treatment of VTE in cancer patients. These drugs are given subcutaneously for 6 months or longer, and burdensome injections limit their adoption,” explained lead investigator of the Hokusai VTE–Cancer trial, Gary Raskob, PhD, of the University of Oklahoma Health Sciences Center College of Public Health, Oklahoma City. 

Hokusai VTE–Cancer Trial 

“OUR STUDY, the largest trial of direct oral anticoagulants vs low–molecular-weight heparin in cancer patients, showed that treatment with oral edoxaban was noninferior to subcutaneous injections of dalteparin. The lower rate of recurrent VTE observed with edoxaban is offset by a similar increase in the risk of major bleeding,” Dr. Raskob said. 

“There were more upper gastrointestinal bleeds, mainly in patients with gastrointestinal cancer,” he added. “This risk of bleeding should be considered relative to the risk of recurrent thrombosis, and patient preference also should be taken into account for each patient.” 

“Treatment with oral edoxaban was noninferior to subcutaneous injections of dalteparin. The lower rate of recurrent VTE observed with edoxaban is offset by a similar increase in the risk of major bleeding.”
— Gary Raskob, PhD

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The Hokusai VTE–Cancer trial was conducted at 114 sites in Australia, New Zealand, North America, and Europe and included 1,046 patients with various types of cancer and acute or symptomatic VTE. Patients were randomized to receive low–molecular-weight heparin for 5 days followed by edoxaban at 60 mg/d vs dalteparin and treated for at least 6 months for up to 12 months. The presence of VTE was confirmed by imaging. 

For the primary outcome (first recurrent VTE or major bleeding event), edoxaban was noninferior (P = .006). The rate for the primary outcome over the first 6 months was 10.5% for edoxaban vs 10.7% for dalteparin, and the rate per protocol was identical in the two arms (10.4%). 

A separate analysis of the two components of the composite primary endpoint was conducted. For recurrent VTE, edoxaban had a –3.8% advantage over dalteparin: 6.5% vs 10.3%. Although major bleeding occurred more often with edoxaban (6.3% vs 3.2%), no episode of fatal bleeding occurred in either group. 

“We found the major bleeds were less severe on direct oral anticoagulants,” Dr. Raskob said. The main difference in major bleeding was due to a higher number of grade 2 bleeding episodes, which accounted for 64% of the major bleeding episodes in the edoxaban arm vs 29% of those in the dalteparin group. At 1 year, event-free survival (with no recurrent VTE or bleeding) was about 55% in both arms. 

Select-d Trial 


“Clinicians are already adopting direct oral anticoagulants into practice for selected patients with cancer. Now they have data from this study to indicate they are potentially safe in cancer patients.”
— Annie Young, PhD

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THE SELECT-d TRIAL enrolled 406 patients with cancer and associated VTE and randomized them to receive treatment with dalteparin or rivaroxaban (Xarelto) for 6 months. At baseline, 58% had metastatic cancer; the qualifying event was an incidental VTE in 52% of patients and a symptomatic VTE in 48% of patients. At the time the qualifying VTE occurred, 69% were on anticancer therapy. Lead investigator Annie Young, PhD, of the University of Warwick, UK, noted that as the study came to a close, patients with esophageal cancer were excluded as a precautionary measure because of higher bleeding risks compared with other types of cancer. 

The 6-month rate of recurrent VTE rate was 4% for rivaroxaban vs 11% for dalteparin. The 6-month overall survival rate was 75% with rivaroxaban and 70% with dalteparin. The cumulative major bleeding rate was 6% in the rivaroxaban group and 4% in the dalteparin group. The rate of clinically relevant nonmajor bleeding was 13% vs 4%, respectively. 

“Clinicians are already adopting direct oral anticoagulants into practice for selected patients with cancer. Now they have data from this study to indicate they are potentially safe in cancer patients. We conclude that in terms of therapeutic decision-making, a careful discussion between the patient and physician should focus on the balance between the risk of recurrence and the risk of bleeding,” Dr. Young stated. ■

DISCLOSURE: Dr. Raskob has served as a consultant to BMS, Eli Lilly, Janssen, Johnson & Johnson, Pfizer, Portola, Boehringer-Ingelheim, Bayer Healthcare, and Daiichi Sankyo; as well as received honoraria from BMS, Pfizer, Medscape, and Daiichi Sankyo. Dr. Young has received honoraria from Leo Pharma, Bayer, and Helsinn as well as received research funding from Bayer. The select-d trial was sponsored by the University of Warwick, UK, and funded by an educational grant from Bayer AG. 

REFERENCES 

1. Raskob GE, et al: 2017 ASH Annual Meeting. Abstract LBA-6. Presented December 12, 2017. 

2. Young A, et al: 2017 ASH Annual Meeting. Abstract 625. Presented December 11, 2017.

 


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