Daiichi Sankyo’s once-daily oral factor Xa inhibitor edoxaban is as effective as warfarin with a better safety profile when used for preventing recurrence of acute venous thromboembolism, according to results from the Phase III Hokusai-VTE trial presented at the European Society of Cardiology congress in Amsterdam.
Presenting the results, which were also published online in the New England Journal of Medicine, lead investigator Harry Büller of the Academic Medical Center in Amsterdam predicted that the findings will “shake things up a bit” in the new oral anticoagulant market. He stated that the results showed edoxaban to be an “attractive regimen for the full spectrum of VTE patients”.
Dr Büller said that “what makes this study unique is new insight that there are subgroups in which we might need to revisit what we currently think about the treatment of VTE”. The Hokusai-VTE trial included a broader spectrum of VTE patients compared to those included in other recent oral anticoagulant trials, including a large subgroup (30%) of patients with pulmonary embolism (PE) and right ventricular dysfunction, and another subgroup (20%) at high risk for bleeding due to renal impairment and low body weight.
In the Daiichi Sankyo-supported study, 4,921 patients with deep-vein thrombosis and 3,319 with PE received initial subcutaneous LMWH therapy and were then randomised to either 60mg of edoxaban daily or standard warfarin for three to 12 months. For the primary efficacy endpoint of recurrent symptomatic VTE, edoxaban proved non-inferior to warfarin (recurrent VTE in 3.2% vs 3.5% respectively) but in the subgroup of patients with PE and right ventricular dysfunction, efficacy was superior with edoxaban halving recurrence (3.3% vs 6.2%).
For the principal safety outcome of clinically relevant bleeding, edoxaban was superior with a rate of 8.5% compared to 10.3% in the warfarin group. Among the sub-group of patients at high risk for bleeding, by halving the daily dose of edoxaban to 30mg, efficacy was maintained with significantly less bleeding than observed in the warfarin group, said Dr Büller.
In this high-risk subgroup, clinically relevant bleeding occurred in 7.9% of those treated with edoxaban, compared to 12.8% of those treated with warfarin, while superior efficacy was maintained in the edoxaban arm (3.0% vs 4.2%). Previous trials of oral anticoagulants have not identified these specific sub-groups, he added.
‘Nice and surprising finding’
“It was a nice and surprising finding that the combination of LMWH and edoxaban in the PE group resulted in a highly significant and clinically relevant reduction of about 50% in recurrent disease,” said Dr Büller. Claiming that “our findings are likely to be generalisable”, he added that “we included patients with both provoked and unprovoked VTE and treatment durations varied from three to 12 months at the discretion of the treating physician.”
The results are good news and may simplify treatment of VTE, said Dr Büller. “The problem with warfarin is that food, alcohol and many medications interfere with the level and so you’re obliged to do frequent laboratory testing to measure the international normalised ratio and adjust the dose,” he said. “The great advantage of the new oral anticoagulants is they have very predictable kinetics and dynamics and therefore can be given in a fixed dose and do not need monitoring.”
Along with enthusiasm for oral anticoagulants, there is also growing hope that injectable heparin might be safely eliminated, thus switching two inconvenient therapies for one pill, Dr Büller concluded.
Alexander Cohen of King’s College, London and a Hokusai-VTE investigator, said that current European Union guidelines on the use of new oral anticoagulants are currently being revised and predicted that within five years, very few VTE patients will be treated with warfarin and heparin. “It will be a sea-change,” he said.
Edoxaban is currently approved only in Japan, where it is marketed as Lixiana, but filings should be submitted to regulators in the USA and Europe by the first quarter of 2014. Edoxaban will go up against two other already-approved factor Xa inhibitors – Bayer/Johnson & Johnson’s Xarelto (rivaroxaban) and Pfizer/Bristol-Myers Squibb’s Eliquis (apixaban).
