Hokusai-VTE Study: Once-Daily Edoxaban Matches Warfarin for Averting Recurrent DVT, PE

September 01, 2013

(Updated) AMSTERDAM, THE NETHERLANDS — Another oral factor Xa inhibitor, this time the once-daily edoxaban (Lixiana, Daiichi-Sankyo), has shown it may be at least as effective as warfarin for preventing recurrences in patients with acute venous thromboembolism (VTE), while cutting the risk of some types of bleeding [1].

In the Hokusai-VTE Study, >8200 patients were randomized to either edoxaban or warfarin, each after at least five days of open-label enoxaparin or unfractionated heparin. At one year, edoxaban-treated patient outcomes were noninferior vs the other group for efficacy and superior for fatal and intracranial bleeding. A difference for major bleeding didn't attain significance.

"We succeeded in enrolling patients across a broad spectrum of venous thromboembolic manifestations, ranging from limited proximal deep-vein thrombosis [DVT] to severe pulmonary embolism [PE], and the relative efficacy was observed throughout," write the authors, officially the Hokusai-VTE investigators. Dr Harry R Büller (Academic Medical Center, Amsterdam, the Netherlands) is the steering committee chair.

Notably in the study, patients were treated for at least three months but were evaluated at 12 months whether or not they remained on randomized therapy. "The relative efficacy of edoxaban was not limited to patients receiving medication, but it was evident even among those who stopped treatment before 12 months," the group writes.

Hokusai-VTE is published online today in the New England Journal of Medicine to coincide with its presentation here at the European Society of Cardiology (ESC) 2013 Congress.

Its results largely parallel those of AMPLIFY for apixaban (Eliquis, Pfizer/Bristol-Myers Squibb), EINSTEIN-DVT and EINSTEIN-PE for rivaroxaban (Xarelto, Bayer), both factor Xa inhibitors, and RECOVER for the direct thrombin inhibitor dabigatran (Pradaxa, Boehringer Ingelheim). Although sometimes major methodological differences make it tough to compare the trials, in all the new oral agent was noninferior for efficacy and, to different degrees, superior for some bleeding events compared with usual care involving warfarin.

The 4921 patients with DVT and 3319 with a PE in Hokusai-VTE initially received open-label enoxaparin or unfractionated heparin for at least five days, followed by double-blinded edoxaban or warfarin. Edoxaban was given at 60 mg orally once daily or 30 mg/day in patients with a creatinine clearance of 30-50 mL/min or a body weight of 60 kg or less. The warfarin group stayed within the therapeutic range 63.5% of the time, higher than the 40% to 50% in clinical-practice registries, according to the authors. Randomized treatment continued for at least three months but up to 12 months at the physician's discretion.

Hazard Ratio (95% CI) for Primary and Secondary Outcomes, Edoxaban (N=4118) vs Warfarin (N=4122)

End points HR (95% CI) p
Primary efficacy outcome a   Noninferiority
12-months study period 0.89 (0.70–1.13) <0.001
While on treatment b 0.82 (0.60–1.14) <0.001
Safety outcomes (on treatment)   Superiority
Primaryc 0.81 (0.71–0.94) 0.004
Major bleeding 0.84 (0.59–1.21) 0.35
Clinically relevant nonmajor bleeding 0.80 (0.68–0.93) 0.004
Any bleeding 0.82 (0.75–0.90) <0.001

a. First symptomatic recurrent VTE (DVT or fatal or nonfatal PE) or VTE-related death

b. While taking or within three days of stopping or interrupting drug

c. First major or clinically relevant nonmajor bleeding

Among the 938 patients with PE who also had right ventricular dysfunction, as defined by natriuretic peptide levels, the rate of recurrence was 3.3% for edoxaban and 6.2% for warfarin HR 0.52 (95% CI 0.28–0.98)

Results were similar in the subgroup of patients who met the criteria for the 30-mg/day edoxaban dose: 0.73 (95% CI 0.42–1.26) for recurrent VTE, 0.62 (95% CI 0.44-0.86) for clinically relevant bleeding and 0.50 (95% CI 0.24–1.03) for major bleeding.

In a morning press conference, Büller discussed the heparin lead-in used in this trial--something that sets it apart from other recent trials of new oral anticoagulants (that used single-drug strategies) and could be construed as a limitation of the study.

On the contrary, said Büller, the fact that patients were randomized in Hokusai VTE after at least five days of open-label enoxaparin or unfractionated heparin meant that the trial investigators actually enrolled very high-risk patients.

"One of the concerns that has been raised with some of the other studies is that physicians and investigators were a little reluctant to not use low-molecular-weight heparin and therefore not happy to include [patients with] large clots," he said. "In this study, if you go by the definition of [N-terminal probrain natriuretic factor] NT-proBNP, 35% of PE in this study are large clots, and that's exactly the group where I think the novel observation is."

Press conference moderator Dr Keith Fox (University of Edinburgh, Scotland) made the point that warfarin patients, but not edoxaban patients, actually had a period of overlap wherein they were receiving both heparin and warfarin for several days, something that might have had an impact on the higher bleeding rates in this group.

In response, Büller pointed to the much faster activation time of edoxaban, saying that due to the kinetics of warfarin overlap time is unavoidable and necessary.

Turning to the types of bleeding that were most notably reduced with edoxaban in this study, namely intracranial and retroperitoneal bleeding, Büller said that this is in keeping with other studies of the new oral anticoagulants as a class.

"What we are starting to realize in AF and VTE is that the type of bleeds with these new oral anticoagulants are really different."

The study was funded by Daiichi-Sankyo. Büller discloses consulting for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Isis Pharmaceuticals, and ThromboGenetics and receiving grant support from Bayer and Pfizer. Disclosures for the coauthors are listed in the paper.

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