A Multicenter, Single-Blind, Randomized, Warfarin-Controlled Trial of Edoxaban in Patients With Chronic Thromboembolic Pulmonary Hypertension: KABUKI Trial

In patients with chronic thromboembolic pulmonary hypertension (CTEPH), lifelong anticoagulation with vitamin K antagonists is recommended by experts to prevent recurrent pulmonary embolism and worsening of CTEPH.¹ Data from randomized controlled trials on direct oral anticoagulants for CTEPH are lacking.

The KABUKI trial (Clinical Trial to Investigate Safety and Efficacy of Edoxaban in Patients With CTEPH) was a phase 3, investigator-initiated, multicenter, single-blind, randomized, warfarin-controlled, noninferiority trial to evaluate the efficacy and safety of edoxaban, a Factor Xa inhibitor, in subjects with CTEPH. The study design and protocol have been reported.² Eleven Japanese institutions participated in this study. Eligible patients had CTEPH with World Health Organization functional class I to III and had been on warfarin for at least 3 months before enrollment. Patients who had undergone reperfusion therapy (including pulmonary endarterectomy and balloon pulmonary angioplasty) and were being treated with pulmonary vasodilators were also eligible. The target international normalized ratio for warfarin dose adjustment adopted in this trial was 1.5 to 2.5, considering Japanese guidelines.³ The daily dose of edoxaban (60 mg for body weight ≥60 kg, 30 mg for body weight <60 kg) was the same as that used for preventing venous thromboembolism. The study was approved by the institutional review board and subjects provided informed consent. The primary outcome was the ratio of pulmonary vascular resistance (PVR, Wood Units) at week 48 to PVR at baseline. Secondary outcomes were clinical worsening of CTEPH (death, CTEPH-related hospitalization, rescue reperfusion treatment, initiation or dose escalation of pulmonary vasodilator, and ≥15% reduction in 6-minute walk distance with worsening World Health Organization functional class), World Health Organization functional class, 6-minute walk distance, and N-terminal pro–B-type natriuretic peptide level. Incidence of symptomatic venous thromboembolism and d-dimer level were prespecified exploratory outcomes. Safety outcome was clinically relevant bleeding, including major bleeding.⁴ Clinical worsening of CTEPH and bleeding events were judged by an independent clinical trial adjudication committee. The week 48 to baseline ratio of PVR for hypothetical CTEPH subjects without anticoagulation was estimated to be 1.54, and the ratio in the warfarin group was 1.09 on the basis of our database.⁵ Thus, the noninferiority margin was calculated to be 1.188. The data that support the findings of this study are available from the corresponding author on reasonable request.

Eighty patients with CTEPH were screened for eligibility. Seventy-four patients (mean age 63.6±12.3 years, 62.2% women) underwent randomization; 37 were assigned to edoxaban and 37 to warfarin, and they constituted the safety analysis population. The per protocol population, which was the primary analysis set, consisted of 72 patients (36 in the edoxaban group and 36 in the warfarin group). No patients in the edoxaban group discontinued edoxaban, whereas 2 (5.8%) patients in the warfarin group discontinued warfarin due to adverse event and consent withdrawal. All 36 (100%) subjects had received reperfusion treatments before enrollment, had mild disease, and were generally stable. In the warfarin group, time in therapeutic range during the trial was 79.7±17.9% for international normalized ratio 1.5 to 2.5 and 58.5±30.2% for international normalized ratio 2.0 to 3.0. In the per protocol analysis of the primary outcome, the ratio of geometric means for the edoxaban group compared with the warfarin group (treatment effect) was 0.920 (95% CI, 0.820–1.032; P<0.001 for noninferiority; Figure A). All prespecified secondary end points and exploratory outcomes showed minimal changes in the 2 groups, with no significant intergroup differences (Figure B–F). No clinical worsening events and no symptomatic venous thromboembolism occurred in either group. In the safety analysis, clinically relevant nonmajor bleeding was reported in 1 patient (2.7%) in the edoxaban group and 1 patient (2.7%) in the warfarin group. Major bleeding was reported in 1 patient (2.7%) in the warfarin group. Serious adverse events occurred in 1 patient (2.7%) in the edoxaban group and 3 patients (8.1%) in the warfarin group. No patients died during the trial.

Figure.

Summary of primary findings in the KABUKI trial. A, Primary end point: week 48 to baseline ratio of pulmonary vascular resistance (PVR). Geometric mean ratio of PVR (week 48 to baseline) was 0.93 (95% CI, 0.86–1.01) in the edoxaban group and 1.01 (95% CI, 0.93–1.10) in the warfarin group, resulting in a treatment effect (ratio of geometric means for edoxaban compared with warfarin of 0.920 [95% CI, 0.820–1.032]; P<0.0001 for noninferiority). B, Exploratory outcome: change in PVR at week 48 from baseline. The least squares (LS) mean difference between the edoxaban group and warfarin group (treatment effect) of change in PVR at week 48 from baseline was −0.155 Wood Units (95% CI, −0.416 to 0.107; P=0.242). C, Secondary end point: changes in 6-minute walk distance at week 48 from baseline. The LS mean difference between the edoxaban group and warfarin group (treatment effect) of change in 6-minute walk distance at week 48 was 5.6 m (95% CI, –16.4 to 27.6; P=0.612). D, Secondary end point: changes in NT-proBNP level at prespecified visits from baseline. The LS mean difference between the edoxaban group and warfarin group (treatment effect) of change in NT-proBNP level at week 48 from baseline was 0.834 pg/mL (95% CI, 0.672–1.036; P=0.099). E, Exploratory outcome: changes in mean pulmonary artery pressure at week 48 from baseline. The LS mean difference between the edoxaban group and the warfarin group (treatment effect) of change in pulmonary artery pressure at week 48 from baseline was 0.2 mm Hg (95% CI, –2.0 to 2.3; P=0.888). F, Exploratory outcome: changes in d-dimer level at prespecified visits from baseline. The LS mean difference between the edoxaban group and the warfarin group (treatment effect) of change in d-dimer level at week 48 from baseline was 0.07 µg/mL (95% CI, –0.07 to 0.21; P=0.337). NT-proBNP indicates N-terminal pro–B-type natriuretic peptide.

In the KABUKI trial, 48-week treatment with edoxaban was noninferior to warfarin with respect to preventing worsening PVR in patients with CTEPH. The incidence of clinically relevant bleeding was similar with no significant between-group difference.

This trial has some limitations. First, the trial was not designed or powered to identify the effects of edoxaban on clinical outcomes, but rather to provide evidence of noninferiority of edoxaban to warfarin with respect to pulmonary hemodynamics. Second, all participants in this trial had previously received reperfusion therapy, because the study did not allow for elective reperfusion therapy or dose adjustment of pulmonary vasodilators during the trial. Third, the sample size was small for a noninferiority study, although this was unavoidable for a rare disease studied in a single country. A large-scale, multinational, longer-term study is needed to robustly establish the safety and efficacy of edoxaban for anticoagulation in patients with CTEPH.

In conclusion, in patients with CTEPH who had undergone reperfusion treatment and were on stable warfarin therapy, edoxaban was noninferior to warfarin for preventing the worsening of pulmonary hemodynamics during the 48-week treatment, and symptomatic venous thromboembolism and clinically relevant bleeding events were as low as warfarin.

ARTICLE INFORMATION

Acknowledgments

This study was funded by a grant from Japan Medical and Research Development (JP22lk0201125), and a research grant from Daiichi-Sankyo Co., Ltd. The authors thank members of the Independent Data and Safety Monitoring Committee (H. Ogino [Tokyo Medical University, Tokyo, Japan] and N. Tanabe [Chibaken Saiseikai Narashino Hospital, Narashino, Japan]), and members of the Clinical Event Committee (Koichiro Sugimura [International University of Health and Welfare, Narita, Japan], K. Kubota [Kagoshima University, Kagoshima, Japan], and H. Shimokawahara [Okayama Medical Center, Okayama, Japan]), and all patients, investigators, and health care professionals involved in the study.

Sources of Funding

This study was funded by Japan Agency for Medical Research and Development (Grant Number: JP22lk0201125) and Daiichi-Sankyo Co., Ltd. on the basis of a contract.

Disclosures

Dr Hosokawa reports personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, and Pfizer, outside the submitted work. Dr Taniguchi reports grants from Janssen Pharmaceutical and Nippon Shinyaku; and personal fees from Janssen Pharmaceutical and Nippon Shinyaku, outside the submitted work. Dr Ikeda reports personal fees from Daiichi-Sankyo, Bayer Yakuhin, and Bristol-Myers Squibb, outside the submitted work. Dr Inami reports personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside the submitted work. Dr Murohara reports a grant and personal fees from Daiichi Sankyo, outside the submitted work. Dr Hatano reports a grant from Japan Agency for Medical Research and Development and personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside the submitted work. Dr Tamura reports grants from Bayer Yakuhin, Nippon Shinyaku, and Mochida Pharmaceutical; and personal fees from Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Janssen Pharmaceutical, outside the submitted work. Dr Yamashita reports a grant from Abbott Vascular Japan; and personal fees from Kaneka Medix, Boston Scientific Japan, Nihon Kohden, Philips Japan, Janssen Pharmaceutical, and Bayer Yakuhin, outside the submitted work. Dr Tsujino reports personal fees from Janssen Pharmaceutical and Nippon Shinyaku; and affiliation with the division supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, and Mochida Pharmaceutical, outside the submitted work. Dr Yaoita reports personal fees from Bayer Yakuhin and Konica Minolta, outside the submitted work. Dr Minatsuki reports a grant from Fukuda Foundation for Medical Technology, outside the submitted work. Dr Todaka reports a grant from Mochida Pharmaceutical; and personal fee from Bayer Yakuhin, outside the submitted work. Dr Fukuda reports grants from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical; and personal fees from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical, outside the submitted work. Dr Tsutsui reports grants from Mitsubishi Tanabe Pharma, IQVIA Services Japan, MEDINET, Medical Innovation Kyushu, Kowa, Daiichi Sankyo, Johnson & Johnson, NEC, and Nippon Boehringer Ingelheim; personal fees from Novartis Pharma, Ono Pharmaceutical, Nippon Boehringer Ingelheim, Bayer Yakuhin, Kowa, Teijin Pharma, Mitsubishi Tanabe Pharma, Pfizer Japan, Daiichi Sankyo, Novartis Pharma, Janssen Pharmaceutical, Pfizer Japan, Bayer Yakuhin, Otsuka Pharmaceutical, AstraZeneca, and Nippon Rinsho; and is Chairman of Japan Heart Failure Society, outside the submitted work. Dr Abe reports a grant from Konica Minolta and Daiichi Sankyo, outside the submitted work. Drs Watanabe, Yasuda, Kobayakawa, Adachi, and Tatsumi report no conflicts of interest.