Long-term outcome of chronic thromboembolic pulmonary hypertension using direct oral anticoagulants and warfarin: a Japanese prospective cohort study.

Background: Chronic thromboembolic pulmonary hypertension (CTEPH) requires lifelong anticoagulation. Long-term outcomes of CTEPH under current anticoagulants are unclear.
Objectives: The CTEPH AC registry is a prospective, nationwide cohort study comparing the safety and effectiveness of direct oral anticoagulants (DOACs) and warfarin for CTEPH.
Patients/methods: Patients with CTEPH, both tre atment-naïve and on treatment, were eligible for the registry. Inclusion criteria were patients aged ≥20 years and those who were diagnosed with CTEPH according to standard guidelines. Exclusion criteria were not specified. The primary efficacy outcome was a composite morbidity, and mortality outcome comprised all-cause death, rescue reperfusion therapy, initiation of parenteral pulmonary vasodilators, and worsened 6-minute walk distance and WHO functional class. The safety outcome was clinically relevant bleeding, including major bleeding.
Results: Nine hundred twenty-seven patients on oral anticoagulants at baseline were analyzed: 481 (52%) used DOACs and 446 (48%) used warfarin. The 1-, 2-, and 3-year rates of composite morbidity and mortality outcome were comparable between the DOAC and warfarin groups (2.6%, 3.1%, and 4.2% vs 3.0%, 4.8%, and 5.9%, respectively; P = .52). The 1-, 2-, and 3-year rates of clinically relevant bleeding were significantly lower in DOACs than in the warfarin group (0.8%, 2.4%, and 2.4% vs 2.5%, 4.8%, and 6.4%, respectively; P = 0.036). Multivariable Cox proportional-hazards regression models revealed lower risk of clinically relevant bleeding in the DOAC group than the warfarin group (hazard ratio: 0.35; 95% CI: 0.13-0.91; P = .032).
Conclusion: This registry demonstrated that under current standard of care, morbidity and mortality events were effectively prevented regardless of anticoagulants, while the clinically relevant bleeding rate was lower when using DOACs compared with warfarin.
Competing Interests: Declaration of competing interests K.H. received personal fees from Janssen Pharmaceuticals, Bayer Yakuhin, Nippon Shinyaku, and Pfizer, outside of the submitted work. K.A. received a grant from Konica Minolta and Daiichi Sankyo, outside of the submitted work. Y. Tamura received grants from Bayer Yakuhin, Nippon Shinyaku, and Mochida Pharmaceutical and personal fees from Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Janssen Pharmaceutical, outside of the submitted work. N.N. is member of the board of directors of the Japan Association for Medical Informatics. K. Todaka reports receiving a grant from Mochida Pharmaceutical and received a personal fee from Bayer Yakuhin, outside of the submitted work. Y. Taniguchi received grants from Janssen Pharmaceutical and Nippon Shinyak and received personal fees from Janssen Pharmaceutical and Nippon Shinyaku, outside of the submitted work. T.I. received personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside of the submitted work. I.T. received personal fees from Janssen Pharmaceutical and Nippon Shinyak and is affiliated with the division supported by endowments from Nippon Shinyaku, Nippon Boehringer Ingelheim, and Mochida Pharmaceutical, outside of the submitted work. J.Y. received a grant from Abbott Vascular Japan and received personal fees from Kaneka Medix, Boston Scientific Japan, Nihon Kohden, Philips Japan, Janssen Pharmaceutical, and Bayer Yakuhin, outside of the submitted work. N.I. received personal fees from Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, and Bristol-Myers Squibb, outside of the submitted work. H.S. received a grant from Bayer Yakuhin and received personal fees from Actelion Pharmaceuticals Japan, Bayer Yakuhin, and Nippon Shinyaku, outside of the submitted work. T.K. reports receiving personal fees from Kaneka Medix, Abbott Medical Japan, and ACIST Japan, outside of the submitted work. M.H. received personal fees from Janssen Pharmaceutical and Bayer Yakuhin, outside of the submitted work. H.O. received grants from Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer Japan, Eisai, GlaxoSmithKline, Mochida Pharmaceutical, Janssen Pharmaceutical, and Nippon Shinyaku, and received consulting fees from Terumo, Japan Lifeline, and Century Medical and personal fees from Bayer Yakuhin, Daiichi Sankyo, Pfizer Japan, and Nippon Shinyaku, outside of the submitted work. Y.F. received grants from Actelion Pharmaceuticals Japan, Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, Pfizer Japa, and personal fees from Actelion Pharmaceuticals Japan, Janssen Pharmaceutical, Bayer Yakuhin, Nippon Shinyaku, Daiichi Sankyo, Pfizer Japan, and Bristol-Myers Squibb, outside of the submitted work. N.T. received personal fees from Janssen Pharmaceutical, Bayer Yakuhin, and Nippon Shinyaku, outside of the submitted work. H.M. received grants from Bayer and Nippon Shinyaku; received personal fees from Bayer Yakuhin, Nippon Shinyaku, Mochida Pharmaceutical, Kaneka Medix, and Janssen Pharmaceutical, , outside of the submitted work; is a member of the board of directors or advisory committees for the International CTEPH Association and Japanese Pulmonary Circulation and Pulmonary Hypertension Society; and is a member of the data safety monitoring boards for Janssen Pharmaceutical, United Therapeutics, and Bayer. K. Fukuda received grants from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical, and received personal fees from Bayer Yakuhin, Daiichi Sankyo, Nippon Boehringer Ingelheim, Pfizer, Eisai, Janssen Pharmaceutical, Nippon Shinyaku, GlaxoSmithKline, and Mochida Pharmaceutical, outside of the submitted work. H.T. received grants from Mitsubishi Tanabe Pharma, IQVIA Services Japan, Medinet, Medical Innovation Kyushu, Kowa, Daiichi Sankyo, Johnson & Johnson, NEC, and Nippon Boehringer Ingelheim; received 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, outside the submitted work; and is the chairman of the Japan Heart Failure Society. Soiken Corp accessed and verified the data. The remaining authors K. Funakoshi, S.A., S.M., K. Tatsumi, and T.O. have no competing interests to disclose.
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