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Fondaparinux prevents venous thromboembolism after joint replacement surgery in Japanese patients

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Abstract

Venous thromboembolism (VTE) is an important complication of major orthopaedic surgery of the lower limbs. Fondaparinux, a synthetic pentasaccharide and highly selective inhibitor of activated Factor Xa, is the first in a new class of antithrombotic agents. To determine the optimal dose in Japanese patients, double-blind, placebo-controlled, dose-ranging studies of fondaparinux were conducted in patients undergoing total knee replacement (TKR) or total hip replacement (THR) surgery. Patients were randomly assigned to receive a once-daily subcutaneous injection of fondaparinux (0.75, 1.5, 2.5, or 3.0 mg) or placebo in Study 1 (TKR) and Study 2 (THR). In Study 1, the incidence of VTE was 65.3% in the placebo group and was 34.2%, 21.3%, 16.2%, and 9.5% in the groups receiving 0.75, 1.5, 2.5, and 3.0 mg fondaparinux respectively. In Study 2, the incidence of VTE was 33.8% in the placebo group and was 24.2%, 4.6%, 7.4%, and 14.4% in the 0.75, 1.5, 2.5, and 3.0 mg fondaparinux groups respectively. Dose–response effects were observed in both studies; however, no statistically significant differences in major bleeding events were found among any groups. Fondaparinux proved to be a potent anticoagulant with a favourable benefit-to-risk ratio in the prevention of VTE in these study patients.

Résumé

Les complications thromboemboliques sont nombreuses dans la plupart des interventions de chirurgie orthopédique au niveau des membres inférieurs. Le fondaparinux (pentas saccharide synthétique) est un élément important parmi tous les agents anti-thrombotiques. De façon à déterminer la dose optimale de ce produit, une étude en double aveugle avec placebo a été conduite chez des patients devant bénéficier d’une prothèse totale du genou ou d’une prothèse totale de hanche. Les patients ont été randomisés de façon à recevoir une fois par jour une injection sous cutanée de fondaparinux (0.75, 1.5, 2.5, ou 3 mg) ou de placebo. L’incidence de la thrombose veineuse a été de 65.3% dans le groupe placebo et de 34.2%, 21.3%, 16.2% et 9.5% dans les groupes recevant respectivement 0.75, 1.5, 2.5 et 3 mg de fondaparinux, pour le groupe prothèse du genou. Pour le groupe prothèse de hanche l’incidence des complications thromboemboliques a été de 33.8% dans le groupe placebo et a été respectivement de 24.2%, 4.6%, 7.4% et 14.4% dans les groupes ayant reçu 0.75, 1.5, 2.5 et 3 mg de fondaparinux. Il n’y a pas de différence significatives en terme de saignement, dans chaque groupe. le fondaparinux est un anti-coagulant actif avec un bénéfice/risque important dans la prévention des thromboses veineuses et des accidents thromboemboliques dans cette étude de patients.

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Acknowledgements

These studies were supported by a grant from GlaxoSmithKline, Sanofi-synthelabo and NV Organon.

Members of Steering Committee

Takahiro Ochi (Chairman), National Sagamihara Hospital, Sagamihara

Takeo Matsuno, Orthopedic Surgery, Asahikawa Medical College, Asahikawa

Kozo Nakamura, Orthopedic Surgery, Tokyo University, School of Medicine, Tokyo

Tomihisa Koshino, International University of Health and Welfare, Tokyo

Hisashi Iwata, Center for Rheumatic Diseases and Artificial Joint, Nagoya Kyoritsu Hospital, Nagoya

Hideki Yoshikawa, Orthopedic Surgery, Osaka University, School of Medicine, Osaka

Takeshi Fuji, Orthopedic Surgery, Osaka Koseinenkin Hospital, Osaka

Toru Sato, Orthopedic Surgery, Okayama University, School of Medicine, Okayama

Sumiki Yamamoto, Centre for Rheumatic Diseases, Matsuyama Red Cross Hospital, Matsuyama

Takehiko Torisu, Orthopedic Surgery, Ohita Medical University, School of Medicine, Ohita

The members of the Central Independent Adjudication Committee for Efficacy (CIACE) of Study 1 & 2:

Satoru Fujita, Orthopaedic Surgery, Dai-ichi Hospital Medical Corporation of Showakai, Takarazuka

Hironobu Nakamura, Osaka University, Graduate School of Medicine Faculty of Medicine, Course of Advanced Medicine; Medical Robotics and Image Science, Osaka

Saki Nakata, Osaka University, Graduate School of Medicine Faculty of Medicine, Course of Advanced Medicine; Medical Robotics and Image Science, Osaka

Kenji Nakamura, Department of Radiology, Osaka City University Medical School, Osaka

The members of the central independent adjudication committee for safety (CIACS) of Study 1 & 2:

Hisaichi Fujii, Department of Transfusion and Cell Processing, Tokyo Women’s Medical University, School of Medicine, Tokyo

Ikuro Maruyama, Department of Laboratory Medicine; Faculty of Medicine, Kagoshima University, Kagoshima

Mitsuyoshi Nakashima, Hamamatsu University School of Medicine, Hamamatsu

Taisuke Tomatsu, Department of Rheumatology; Tokyo Women’s Medical University, School of Medicine, Tokyo

The principal investigators for Study 1 (TKR):

Yukiyoshi Oishi, Toyohashi Municipal Hospital, Toyohashi

Tatsunori Maeda, Asahikawa Medical College Hospital, Asahikawa

Hiroshi Tanaka, Yamaguchi University Hospital, Ube

Fujio Higuchi, Kurume University Medical Center, Kurume

Toshihisa Kanamono, Nagano Red Cross Hospital, Nagano

Takaharu Nabeshima, Toneyama National Hospital, Toyonaka

Masaaki Kakiuchi, Osaka Police Hospital, Osaka

Takeshi Fuji, Osaka Koseinenkin Hospital, Osaka

Yoshiaki Yanase, Kitano Hospital, Osaka

Takashi Soejima and Takahiro Ohkawa, Kurume University Hospital, Kurume

Hideto Machida, Kanto Rosai Hospital, Kawasaki

Hideji Kura, Sapporo Medical University Hospital, Sapporo

Hiromi Oda, The University of Tokyo Hospital, Tokyo

Masafumi Ishizuki, Tsuchiura Kyodo General Hospital, Tsuchiura

Makoto Kawakubo, Tokyo Dental College Ichikawa General Hospital, Ichikawa

Shoji Kumaki, Hokushin General Hospital, Nakano

Naoki Kodama, Gifu Prefectural Gero-Onsen Hospital, Gero

Masashi Kataoka, Oita Medical University Hospital, Hasama

Toshihiko Hara, Kyushu-Rosai Hospital, Kitakyushu

Shin-ichi Katsuo, Fukui General Hospital, Fukui

Naoto Mitsuki and Renzo Okamoto, Yokohama City University Medical Center, Yokohama

Tomoyuki Saito, Yokohama City University Hospital, Yokohama

Shigeru Harada, Tsukuba Rokujinkai Foundation Tsukuba Gakuen Hospital, Tsukuba

Masanori Shimode, Kanto Medical Center NTT EC, Tokyo

Yoshiki Okuda, Shakaihoken Kobe Central Hospital, Kobe

Hirofumi Kuroki, International Medical Center of Japan, Tokyo

Makoto Takasu, Aizu Chuo Hospital, Aizuwakamatsu

Tadashi Tanaka, Kimitsu Chuo Hospital, Kisarazu

Takahisa Yasoda and Naoto Mitsuki, Fujisawa Municipal Hospital, Fujisawa

Yukio Yoshida, Higashi Municipal Hospital of Nagoya, Nagoya

Kazuhiro Yamaguchi and Shinichiro Hara, Nagasaki Rosai Hospital, Sasebo

Toshihito Mori, National Sagamihara Hospital, Sagamihara

Kazuo Kaneko, Juntendo University Juntendo Izunagaoka Hospital, Izunagaoka

Sampei Nakata and Sumiki Yamamoto, Matsuyama Red Cross Hospital, Matsuyama

Toshikazu Tanaka, Tsukuba Memorial Hospital, Tsukuba

Taiki Kanno, Eniwa Hospital, Eniwa

Katsumi Chiba, Medical Corporation Fukushima Kouseikai Fukushima Daiichi Hospital, Fukushima

Shoichi Kushitani, Rinku General Medical Center, Izumisano

Masayoshi Ohga, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima

Toshiyuki Tsurumoto, Nagasaki University Hospital, Nagasaki

Etsuo Chosa, Miyazaki Medical College Hospital, Kiyotake

Chiaki Tanaka, Kyoto Municipal Hospital, Kyoto

Sen-eki Kobayashi, Shinshu University Hospital, Matsumoto

Shigeo Sano, Sanraku Hospital, Tokyo

Takashi Ohya, Obihiro Kosei Hospital, Obihiro

Kazunori Ohno, Teine Keijinkai Hospital, Sapporo

Katsuhiro Shimada, National Murayama Hospital, Musashi-murayama

Yoji Mikami, Japan Labour Health and Welfare Organization Yokohama Rosai Hospital, Yokohama

Akira Arakaki, Tomishiro Chuo Hospital, Tomigusuku

Yoshimitsu Hoshikawa, St Luke’s International Hospital, Tokyo

Shuji Okinaga, Tokyo Teishin Hospital, Tokyo

Syojiro Kato and Makoto Kurimura, Jinseisha Edogawa Hospital, Tokyo

Koji Suzuki, Hokkaido Orthopedic Memorial Hospital, Sapporo

Osamu Sugawara, Kitami Red Cross Hospital, Kitam

Kazuyoshi Hirose, Nagoya Kyoritsu Hospital, Nagoya-shi

Keiju Fujiwara, Osaka Prefectural General Hospital, Osaka

Takehiro Takebayashi, Sapporo Insurance General Hospital, Sapporo

Kazumasa Terada, National Kyushu Medical Center, Fukuoka

Hideya Kawamura, Kyushu Kousei Nenkin Hospital, Kitakyushu

The principal investigators for Study 2 (THR):

Yukiyoshi Oishi, Toyohashi Municipal Hospital, Toyohashi

Toru Sato, Okayama University Hospital, Okayama

Tadashi Teranishi, Asahikawa Medical College Hospital, Asahikawa

Hiroshi Tanaka, Yamaguchi University Hospital, Ube

Fujio Higuchi, Kurume University Medical Center, Kurume

Toshihisa Kanamono, Nagano Red Cross Hospital, Nagano

Takaharu Nabeshima, Toneyama National Hospital, Toyonaka

Masaaki Kakiuchi, Osaka Police Hospital, Osaka

Takeshi Fuji, Osaka Koseinenkin Hospital, Osaka

Yoshiaki Yanase, Kitano Hospital, Osaka

Takahiro Ohkawa and Masaru Kumagai, Kurume University Hospital, Kurume

Hideto Machida, Japan Labour Health and Welfare Organization Kanto Rosai Hospital, Kawasaki

Satoshi Nagoya, Sapporo Medical University Hospital, Sapporo

Masafumi Ishizuki, Tsuchiura Kyodo General Hospital, Tsuchiura

Masaaki Matsubara and Tetsuya Jinno, Tokyo Medical and Dental University Medical Hospital, Tokyo

Shoji Kumaki, Hokushin General Hospital, Nagano

Naoki Kodama, Gifu Prefectural Gero-Onsen Hospital, Gero

Toshihiko Hara, Kyushu-Rosai Hospital, Kitakyusyu

Shin-ichi Katsuo, Fukui General Hospital, Fukui

Kazuhiro Mizutani, Toho University Ohashi Hospital, Tokyo

Renzo Okamoto and Naoto Mitsuki, Yokohama City University Medical Center, Yokohama

Tomoyuki Saito, Yokohama City University Hospital, Yokohama

Shigeru Harada, Tsukuba Rokujinkai Foundation, Tsukuba Gakuen Hospital, Tsukuba

Masanori Shimode, Kanto Medical Center NTT EC, Tokyo

Yoshiki Okuda, Shakaihoken Kobe Central Hospital, Kobe

Hirofumi Kuroki, International Medical Center of Japan, Tokyo

Makoto Takasu, Aizu Chuo Hospital, Aizuwakamatsu

Tadashi Tanaka, Kimitsu Chuo Hospital, Kisarazu

Haruo Ito, Tokyo Koseinenkin Hospital, Tokyo

Naoto Mitsuki and Takahisa Yasoda, Fujisawa Municipal Hospital, Fujisawa

Yukio Yoshida, Higashi Municipal Hospital of Nagoya, Nagoya

Shinichiro Hara and Kazuhiro Yamaguchi, Nagasaki Rosai Hospital, Sasebo

Toshihito Mori, National Sagamihara Hospital, Fujisawa

Kazuo Kaneko, Juntendo University Juntendo Izunagaoka Hospital, Izunagaoka

Sumiki Yamamoto and Sampei Nakata, Matsuyama Red Cross Hospital, Matsuyama

Toshikazu Tanaka, Tsukuba Memorial Hospital, Tsukuba

Motoyuki Shundo, Eniwa Hospital, Eniwa

Katsumi Chiba, Medical Corporation Fukushima Kouseikai Fukushima Daiichi Hospital, Fukushima

Shoichi Kushitani, Rinku General Medical Center, Izumisano

Masayoshi Ohga, Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima

Hirosi Enomoto, Nagasaki University Hospital, Nagasaki

Hiroshi Usui, National Tokyo Medical Center, Tokyo

Etsuo Chosa, Miyazaki Medical College Hospital, Kiyotake

Chiaki Tanaka, Kyoto Municipal Hospital, Kyoto

Sen-eki Kobayashi, Shinshu University Hospital, Matsumoto

Shigeo Sano, Sanraku Hospital, Tokyo

Takashi Ohya, Obihiro Kosei Hospital, Obihiro

Katsuhiro Shimada, National Murayama Hospital, Musashi-murayama

Yoshimitsu Hoshikawa, St Luke’s International Hospital, Tokyo

Shuji Okinaga, Tokyo Teishin Hospital, Tokyo

Naoyuki Katayama, Hokkaido Orthopedic Memorial Hospital, Sapporo

Osamu Sugawara, Kitami Red Cross Hospital, Kitami

Kazuyoshi Hirose, Nagoya Kyoritsu Hospital, Nagoya

Keiju Fujiwara, Osaka Prefectural General Hospital, Osaka

Takehiro Takebayashi, Sapporo Insurance General Hospital, Sapporo

Hisaaki Miyahara, National Kyushu Medical Center, Fukuoka

Masanobu Saito, Osaka Minami National Hospital, Kawachinagano

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Correspondence to Takeshi Fuji.

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For the Steering Committee of the Japan Fondaparinux Study in Arthroplasty.

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Fuji, T., Fujita, S. & Ochi, T. Fondaparinux prevents venous thromboembolism after joint replacement surgery in Japanese patients. International Orthopaedics (SICO 32, 443–451 (2008). https://doi.org/10.1007/s00264-007-0360-7

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  • DOI: https://doi.org/10.1007/s00264-007-0360-7

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