Direct Oral Anticoagulants: New Standard of Care for VTE in Patients with Cancer?
Direct oral anticoagulants (DOACs) may soon replace low-molecular-weight heparin (LMWH) as the standard of care for the management of venous thromboembolism (VTE) in patients with cancer, judging by the results of 2 randomized trials presented at ASH 2017. The caveat is that DOACs are associated with more bleeding events, especially in patients with gastrointestinal (GI) cancer who should continue receiving LMWH.
These trials were the first to compare newer DOAC agents and LMWH in patients with cancer, who are known to be at increased risk for VTE. Until now, oncologists had no good data to recommend a DOAC over LMWH.
Edoxaban versus Dalteparin
The DOAC edoxaban (Lixiana) was noninferior to the LMWH dalteparin (Fragmin) in the HOKUSAI-VTE clinical trial. At 12 months, a first recurrent VTE or major bleeding event occurred in 12.8% of patients who received edoxaban versus 13.5% in those receiving dalteparin. During the first 6 months, recurrent VTE or a major bleeding event was observed in 10.5% of patients in the edoxaban arm versus 10.7% in the dalteparin arm, but major bleeding events were more frequent with edoxaban.
“Evidence-based guidelines recommend LMWH 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,” said Gary E. Raskob, PhD, Dean and Regents Professor, College of Public Health, University of Oklahoma, Oklahoma City.
“HOKUSAI-VTE, the largest trial of DOAC versus LMWH in patients with cancer, showed that treatment with oral edoxaban was noninferior to subcutaneous injections of dalteparin, a LMWH. The lower rate of recurrent VTE observed with edoxaban is offset by a similar increase in risk of major bleeding,” Dr Raskob said. “There were more upper gastrointestinal bleeds, mainly in patients with gastrointestinal cancer, suggesting that use of DOAC should be limited in these patients.”
The HOKUSAI-VTE study was conducted at 114 sites in Australia, New Zealand, North America, and Europe and included 1046 patients with various types of cancer and acute or symptomatic VTE. Patients were randomly assigned to receive LMWH for 5 days, followed by edoxaban 60 mg daily or dalteparin for a minimum of 6 months and up to 12 months.
Although major bleeding events were more frequent with edoxaban (6.3% vs 3.2%), no fatal bleeding occurred in either group. Major bleeding events were reported in 17 patients who received edoxaban, most of whom had gastric cancer and GI bleeding, versus 3 patients in the dalteparin group.
Major bleeding was less severe, however, in the edoxaban arm, Dr Raskob said. The event-free survival (with no recurrent VTE or bleeding) rate at 1 year was about 55% in both treatment arms.
Rivaroxaban versus Dalteparin
The SELECT-D clinical trial randomly assigned 406 cancer patients with associated incidental or symptomatic VTE to receive 6 months of dalteparin or rivaroxaban (Xarelto), a DOAC.
Annie Young, PhD, Professor of Nursing, University of Warwick, Coventry, England, who presented the results, said that patients with GI cancer were excluded from the SELECT-D trial, because these patients are at an increased risk for bleeding compared with other types of cancer.
The 6-month rate of recurrent VTE was 4% for the rivaroxaban group versus 11% for the dalteparin group. The 6-month overall survival rate was 75% for the rivaroxaban group and 70% for the dalteparin group.
Major bleeding events were reported in 5% of the rivaroxaban group and 3% of the dalteparin group. The rate of clinically relevant nonmajor bleeding was 12% with rivaroxaban versus 3% with dalteparin. One fatal bleeding event occurred in each treatment arm. Most major bleeding events were GI-related; no bleeding events in the central nervous system were reported.
“Clinicians are already adopting DOACs into practice for these patients. Now they have data from this study to indicate that DOACs are potentially safe in patients with cancer. We conclude that in terms of therapeutic decision-making, a careful discussion between the patient and physician should focus on risk of recurrence and the risk of bleeding,” Dr Young stated.
“I think these studies will usher in a new standard of care for VTE, a common situation that oncologists face,” said ASH Secretary Robert Brodsky, MD, Director, Division of Hematology, Johns Hopkins Medicine, Baltimore, MD, who moderated a press conference on this topic at ASH 2017.