ATLANTA — Low-molecular-weight heparin (LMWH) is the standard therapy for cancer-related venous thromboembolism (VTE), but oral anticoagulant agents may be a viable alternative, suggest new findings.
A large randomized study found oral edoxaban (Savaysa, Daiichi Sankyo) to be noninferior to subcutaneous injection with dalteparin (Fragmin, Pfizer), in terms of recurrent VTE or major bleeding.
A primary event (defined as first recurrent VTE or major bleeding event) occurred in 67 of 522 patients (12.8%) in the edoxaban group compared with 71 of 524 patients (13.5%) in the dalteparin group (hazard ratio with edoxaban, 0.97; P = .0056 for noninferiority). This extrapolated to a risk difference (edoxaban minus dalteparin) of –0.7%.
The findings were presented here at the at the American Society of Hematology (ASH) 2017 Annual Meeting and Exposition and were published simultaneously in the New England Journal of Medicine to coincide with the meeting.
“There was a lower rate of recurrent VTE observed with edoxaban, but that was offset by a similar increase in risk of major bleeding,” said lead author, Gary E. Raskob, PhD, dean of the College of Public Health at University of Oklahoma Health Sciences Center, Oklahoma City.
Dr Gary E. Raskob
However, he noted that significantly more major bleeding events occurred with edoxaban, many of which were upper gastrointestinal bleeding, seen primarily in patients with gastrointestinal cancers at study entry. “But the major bleeding was less severe with edoxaban,” said Dr Raskob, “and the rates of for severe major bleeding were similar between groups.”
Patient survival free of recurrent VTE or major bleeding was also similar in both cohorts.
A New Standard of Care
“I think this is going to usher in a new standard of care,” commented Robert A. Brodsky, MD, professor of medicine and oncology and the director of the Division of Hematology at Johns Hopkins School of Medicine in Baltimore, Maryland. “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.”
Dr Robert A. Brodsky
Some patients are also older, may not have the resources to get assistance, and don’t have anyone who can inject it for them, he told Medscape Medical News. “And it’s painful, so this is a big issue.”
He noted that the issues around bleeding and gastrointestinal cancer will have to be addressed.
Cost is another concern. Hospitals or healthcare systems around the world may balk at the higher price of the oral agents, but that remains to be seen. “But going forward, I think this is going to become a new standard,” he said.
Patients With Cancer at Higher Risk for VTE
The risk for recurrent VTE and bleeding is higher in patients with cancer than in the general population. Both recurrent VTE and bleeding contribute to mortality and morbidity and can also interfere with cancer therapy. But cancer-associated VTE is challenging to treat because patients are at high risk for recurrence and major bleeding.
Guidelines from major organizations, such as the American Society of Clinical Oncology, recommend LMWH for initial and long-term therapy. However, many patients find subcutaneous self-injection burdensome, and that may limit adherence to therapy, Dr Raskob pointed out.
Direct oral anticoagulant agents have efficacy similar to that of vitamin K antagonists for the treatment. They have been associated with less frequent and less severe bleeding and are widely used to treat VTE in individuals without cancer. However, until now their role in cancer- associated VTE has been unclear.
Endpoints Similar
Dr Raskob and his colleagues conducted the Hokusai VTE Cancer trial to compare the oral factor Xa inhibitor edoxaban with subcutaneous dalteparin in patients with cancer-associated VTE. Their goal was to compare the regimens for at least 6 months and up to 12 months; the primary endpoint was the composite outcome of recurrent VTE or major bleeding.
Secondary outcomes included a separate analysis of recurrent VTE and major bleeding and survival that was free of recurrent VTE or major bleeding
The efficacy and safety data were collected during the entire 12-month study period, Dr Raskob explained, and there was independent blind adjudication of all suspected outcomes.
A total of 1050 patients (1046 in the final intention-to-treat group) were enrolled at 114 centers in 13 countries. Of this group, 525 were randomly assigned to edoxaban at 60 mg once daily (or 30 mg once daily in patients with a creatinine clearance of 30 to 50 mL/min or a body weight < 60 kg) and 525 to subcutaneous dalteparin at 200 IU/kg once daily for 1 month, followed by 150 IU/kg for the duration of treatment.
At baseline, 657 patients (63%) had a pulmonary embolism with or without deep-vein thrombosis, and the rest of the cohort had isolated deep-vein thrombosis. Overall, 706 (67%) had symptomatic VTE, while the remainder were incidental. Almost all patients had active (97%) cancer, and 53% had metastatic disease.
Recurrent VTE occurred in 34 patients (6.5%) in the edoxaban group vs 54 (10.3%) in the dalteparin group, for a risk difference of –3.8 percentage points (95% confidence interval [CI], –7.1 to –0.4 percentage points). No patients died, and deep-vein thrombosis occurred in 13 vs 30 patients, respectively; 22 and 40 patients, respectively, were symptomatic.
Major bleeding events occurred at nearly double the rate in the edoxaban group: 33 (6.3%) vs 17 (3.2%), for a risk difference of 3.1 percentage points (95% CI, 0.5 – 5.7 percentage points). In the edoxaban group, most bleeding was observed in the upper gastrointestinal region (17 vs 3), while there were slightly more intracranial bleeding episodes with dalteparin (2 vs 4).
However, despite a higher frequency of severe major bleeding events with edoxaban, categories 3 and 4 were similar for both agents (12 patients in each group, respectively).
Twelve-month survival free of recurrent VTE and major bleeding was also similar for edoxaban and dalteparin (55.0% and 56.5%, respectively).
“Oral edoxaban for up to 12 months is noninferior to subcutaneous dalteparin for the treatment of cancer-associated VTE,” Dr Raskob concluded.
The study was funded by Daiichi Sankyo. Dr Raskob made the following disclosures: BMS: consultancy, honoraria; Eli Lilly: consultancy; Janssen: consultancy; Johnson & Johnson: consultancy; Pfizer: consultancy, honoraria; Portola: consultancy; Boehringer-Ingelheim: consultancy; Medscape: honoraria; Bayer Healthcare: consultancy; Daiichi Sankyo: consultancy, honoraria. Coauthor Dr van Es revealed the following: Daiichi Sankyo: honoraria; Pfizer: honoraria. Several coauthors also reported relationships with industry, as noted in the paper.
American Society of Hematology (ASH) 2017 Annual Meeting. Abstract LBA6, presented December 12, 2017.
N Engl J Med. Published online December 12, 2017. Abstract
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