ATLANTA-In patients with a variety of cancers, oral therapy with edoxaban-a direct oral anticoagulant (DOAC)-was just as effective and safe in terms of the risks of recurrent venous thromboembolism (VTE) and bleeding as injections with the low molecular weight heparin (LMWH) dalteparin in the multinational randomized Hokusai VTE-Cancer Study reported at the 2017 American Society of Hematology Annual Meeting (Abstract LBA-6).
The Hokusai study randomized 1,050 patients with acute symptomatic or incidental VTE who had a range of cancers (mostly solid tumors) being treated with several interventions at 114 centers in 13 countries.
Half received the oral factor Xa inhibitor edoxaban at a dose of 60 mg once daily (or 30 mg once daily in patients with a creatinine clearance of 30-50 mL per minute or a body weight below 60 kg) after initially receiving LMWH for a minimum of 5 days.
The remaining patients were treated with subcutaneous injections of dalteparin 200 units per kg once daily for 1 month followed by 150 units per kg thereafter. Patients were treated for up to 12 months and all were followed up for at least 9 months.
Key Findings
Edoxaban was found to be non-inferior to dalteparin with respect to the primary composite endpoint of recurrent thromboembolism and bleeding, which occurred in 12.8 percent of those receiving edoxaban and 13.5 percent of those treated with dalteparin.
Raskob said that when they looked at the individual components of the composite endpoint they noted that the oral anticoagulant "prevented a little more thrombosis." Although it had an increase in major bleeding rate this was balanced by a slightly lower rate of recurrent VTE.
Analyses of secondary outcomes and subgroups revealed that the two drugs were identical in the rates of the most severe category of major bleeding, that bleeding was most common in the upper gastrointestinal (GI) tract, and that, overall, the treatments in the two arms of the study were equivalent.
"When we look at the major bleeding, it's mainly in patients with GI cancer. But an important new finding from our trial is confirmation of what was learned from earlier studies-that bleeding with the oral anticoagulants is less severe," he said. "The risk of a life-threatening bleed on the two treatments was essentially the same."
Avoid Injections
Investigators concluded that the DOAC was a suitable and effective oral alternative for treating symptomatic or incidentally detected VTE in most adult patients with cancer and that it had the potential to benefit outcomes by improving compliance in comparison with LMWH, which has to be injected.
"[The] findings show that edoxaban treatment is non-inferior to the low molecular weight heparin therapy," said lead author Gary E. Raskob, PhD, Dean of the College of Public Health and Professor of Medicine and Epidemiology at the University of Oklahoma in Oklahoma City.
"The goal was to see if we could apply direct oral anticoagulants-which have been shown effective and safer in the broad population of patients with venous thromboembolism-to cancer patients, meeting an unmet need of finding a replacement for injectable anticoagulants that many patients discontinue well before the recommended duration because they don't want to continue to inject themselves," he said.
The investigators noted that treatment of cancer-associated VTE had been especially challenging since, although these patients were at increased risk of both recurrent VTE and major bleeding, it wasn't easy for them to administer standard daily subcutaneous injections of LMWH treatment themselves.
"The clear advantage is that you replace the need to inject. And that's an improvement in the patient's quality of life and their therapy. It means that it's likely that the patient will be able to stay on treatment longer because it's more tolerable to have a pill once a day than to inject yourself for 6, 8, 9, and 12 months. So by maintaining patients on therapy longer, I think we will prevent many recurrent thrombosis events-which is a big contributor to mortality in cancer patients who are surviving."
Practice Implications
Raskob concluded that treatment with the oral DOAC edoxaban was non-inferior to standard guideline treatment with dalteparin for the two most important complications in these patients. Although he advised using the DOAC with caution in patients with GI cancer-in whom the bleeding risk "may be a little bit higher"-he affirmed that there could now be a change of standard. "In the majority of patients, we can probably now transition to using oral medication," he emphasized.
When asked if the findings translated to other DOACs, Raskob said that the results did not yet confirm this and this was not surprising since other DOACs acted through a variety of mechanisms and were metabolized differently from edoxaban. He suggested clinicians use DOAC therapy that's supported by an evidence base-which now included edoxaban. Raskob concluded that there was a need to look at optimal regimens for patients with gastrointestinal cancers and investigate which DOACs worked best in the context of different chemotherapy regimens.
Peter M. Goodwin is a contributing writer.