Oral rivaroxaban for Japanese patients with symptomatic venous thromboembolism - the J-EINSTEIN DVT and PE program

Norikazu Yamada, Atsushi Hirayama, Hideaki Maeda, Satoru Sakagami, Hiroo Shikata, Martin H Prins, Anthonie Wa Lensing, Masaharu Kato, Junichi Onuma, Yuki Miyamoto, Kazuma Iekushi, Mariko Kajikawa, Norikazu Yamada, Atsushi Hirayama, Hideaki Maeda, Satoru Sakagami, Hiroo Shikata, Martin H Prins, Anthonie Wa Lensing, Masaharu Kato, Junichi Onuma, Yuki Miyamoto, Kazuma Iekushi, Mariko Kajikawa

Abstract

Background: The global EINSTEIN DVT and PE studies compared rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) with enoxaparin/vitamin K antagonist therapy and demonstrated non-inferiority for efficacy and superiority for major bleeding. Owing to differences in targeted anticoagulant intensities in Japan, Japanese patients were not enrolled into the global studies. Instead, a separate study of deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in Japanese patients was conducted, which compared the Japanese standard of care with a reduced dose of rivaroxaban.

Methods: We conducted an open-label, randomized trial that compared 3, 6, or 12 months of oral rivaroxaban alone (10 mg twice daily or 15 mg twice daily for 3 weeks followed by 15 mg once daily) with activated partial thromboplastin time-adjusted intravenous unfractionated heparin (UFH) followed by warfarin (target international normalized ratio 2.0; range 1.5-2.5) in patients with acute, objectively confirmed symptomatic DVT and/or PE. Patients were assessed for the occurrence of symptomatic recurrent venous thromboembolic events or asymptomatic deterioration and bleeding.

Results: Eighty-one patients were assigned to rivaroxaban and 19 patients to UFH/warfarin. Three patients were excluded because of serious non-compliance issues. The composite of symptomatic venous thromboembolic events or asymptomatic deterioration occurred in 1 (1.4%) rivaroxaban patient and in 1 (5.3%) UFH/warfarin patient (absolute risk difference, 3.9% [95% confidence interval, -3.4-23.8]). No major bleeding occurred during study treatment. Clinically relevant non-major bleeding occurred in 6 (7.8%) patients in the rivaroxaban group and 1 (5.3%) patient in the UFH/warfarin group.

Conclusions: The findings of this study in Japanese patients with acute DVT and/or PE suggest a similar efficacy and safety profile with rivaroxaban and control treatment, consistent with that of the worldwide EINSTEIN DVT and PE program.

Trial registration: Clinicaltrials.gov: NCT01516840 and NCT01516814.

Keywords: Deep vein thrombosis; Japan; Pulmonary embolism; Randomized trial; Rivaroxaban; Unfractionated heparin; Venous thromboembolism; Warfarin.

Figures

Figure 1
Figure 1
Patient flow diagram. bid, twice daily; ITT, intention-to-treat; od, once daily; UFH, unfractionated heparin.

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