The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study

Naohisa Hosomi; Yoji Nagai; Tatsuo Kohriyama; Toshiho Ohtsuki; Shiro Aoki; Tomohisa Nezu; Hirofumi Maruyama; Norio Sunami; Chiaki Yokota; Kazuo Kitagawa; Yasuo Terayama; Makoto Takagi; Setsuro Ibayashi; Masakazu Nakamura; Hideki Origasa; Masanori Fukushima; Etsuro Mori; Kazuo Minematsu; Shinichiro Uchiyama; Yukito Shinohara; Takenori Yamaguchi; Masayasu Matsumoto; J-STARS Collaborators

doi:10.1016/j.ebiom.2015.08.006

The Japan Statin Treatment Against Recurrent Stroke (J-STARS): A Multicenter, Randomized, Open-label, Parallel-group Study

EBioMedicine. 2015 Aug 6;2(9):1071-8. doi: 10.1016/j.ebiom.2015.08.006. eCollection 2015 Sep.

Authors

Naohisa Hosomi¹, Yoji Nagai², Tatsuo Kohriyama³, Toshiho Ohtsuki⁴, Shiro Aoki¹, Tomohisa Nezu¹, Hirofumi Maruyama¹, Norio Sunami⁵, Chiaki Yokota⁶, Kazuo Kitagawa⁷, Yasuo Terayama⁸, Makoto Takagi⁹, Setsuro Ibayashi¹⁰, Masakazu Nakamura⁶, Hideki Origasa¹¹, Masanori Fukushima², Etsuro Mori¹², Kazuo Minematsu⁶, Shinichiro Uchiyama¹³, Yukito Shinohara¹⁴, Takenori Yamaguchi⁶, Masayasu Matsumoto¹; J-STARS Collaborators

Collaborators

J-STARS Collaborators:
Takenori Abe, Hitoshi Zizawa, Keiji Chida, Minoru Endo, Masashi Goto, Keiji Hara, Hiroko Ishikawa, Kenji Kamiyama, Taketo Kataoka, Takayuki Katayama, Takamasa Kayama, Yasuaki Kokubo, Shu Konno, Satoshi Koyama, Naohiko Kubo, Tetsuya Maeda, Yoshihiro Makita, Junichi Maruyama, Kazuo Mizoi, Ken Nagata, Jyoji Nakagawara, Taizen Nakase, Hideki Ohyama, Toshiaki Osato, Tsukasa Saito, Kazuhiro Sasaki, Kenichi Sato, Shinya Sato, Tomohiko Sato, Jun Sawada, Yoshinobu Seo, Akifumi Suzuki, Hidekazu Takada, Yasuo Terayama, Hideo Tohgi, Toshiichi Watanabe, Toshiharu Yanagisawa, Hisashi Yonezawa, Kazunori Akaji, Hisanao Akiyama, Takekazu Akiyama, Takenori Akiyama, Shimon Amemiya, Nobuo Araki, Kazumasa Arii, Yasuhisa Daimon, Hiromi Eguma, Takaaki Fukuchi, Daisuke Furuya, Jun Gotoh, Makoto Hamamoto, Yasuhiro Hasegawa, Yukihiro Hasegawa, Akiko Hatano, Kenji Hiraga, Koichi Hirata, Tomo Horikoshi, Haruhiko Hoshino, Hisato Ikeda, Tatsuya Ishikawa, Toshihiko Iwamoto, Taro Kadowaki, Yutaka Kametsu, Nobuo Kamiya, Tadashige Kano, Takao Kanzawa, Yasuo Katayama, Toshiya Katsumata, Mitsuru Kawamura, Hiroaki Kimura, Kazuo Kitagawa, Yasuhisa Kitagawa, Akihiro Kiuchi, Yuichi Komaba, Shunichi Koyoma, Akihiko Kuroiwa, Futaba Maki, Hiroshi Matsuda, Ban Mihara, Masahiro Mishina, Kazuko Mitani, Nobaukazu Miyamoto, Kazuhide Miyazaki, Tohru Mizutani, Saori Moriya, Hidetomo Murakami, Kazuhiro Muramatsu, Takehiko Nagao, Takahide Nagashimna, Tomomi Nakamura, Jiro Nakano, Kazunori Nari, Minoru Nishiyama, Tomohide Ohnuki, Yuko Ohnuki, Sari Okamoto, Seiji Okubo, Manabu Otomo, Satoru Otomo, Takiashi Otomo, Makoto Sakurazawa, Naoshi Sasaki, Akira Sato, Tomokazu Shimazu, Takahiro Shimizu, Kikuko Shiobarta, Makoto Shiraishi, Hiroshi Sugihara, Ryuji Suzuki, Kentaro Suzuki, Makoto Takagi, Youichi Takahashi, Masaki Takao, Masaru Takasaki, Hidetaka Takeda, Hidehiro Takekawa, Shunya Takizawa, Hideki Takubo, Norio Tanahashi, Ryota Tanaka, Yasutaka Tanaka, Yoshio Tanizaki, Sono Toi, Kentaro Tokuoka, Yutaka Tomita, Yukiko Tsutsumi, Shinichiro Uchiyama, Masayuki Ueda, Yuji Ueno, Takahiko Umahara, Takao Urabe, Hirofumi Watanabe, Koji Yamada, Hiroshi Yamaguchi, Kazuo Yamashiro, Kouhei Yamashita, Takashi Yasuda, Massayuki Yokochi, Yasuhiro Yoshii, Naoki Yuasa, Tetsuo Ando, Kenju Aoki, Shunro Endo, Akihiro Fujii, Youshi Fujita, Yuichiro Gondo, Hideo Hamada, Kensuke Hamada, Rina Hashimoto, Eri Hayakawa, Yumiko Hayashi, Mikio Hirayama, Genjirou Hirose, Kentaro Horibe, Masamichi Ikawa, Akira Inukai, Tomohiko Ishihara, Shinji Ito, Muichi Kaito, Takashi Kameyama, Kazuya Kawabata, Toshikazu Kawada, Keiko Kinomoto, Yasutaka Kobayashi, Ayuka Kubo, Masaru Kuriyama, Chiyuki Mabuchi, Tomoo Mano, Makoto Matsui, Masaru Matsui, Eiichirou Mukai, Kenya Murata, Shigemi Nagayama, Hiroto Nakagawa, Yoko Nakano, Tomoko Noda, Kazuya Nokura, Jun Ochiai, Hisashi Okada, Kenji Okita, Satoshi Okuda, Takafumi Sagisaka, Toshimasa Sakakibara, Keishiro Sato, Mamiko Sato, Tatsuya Sato, Masaki Suenaga, Noriaki Suga, Shutaro Takashima, Shigeo Takeuchi, Takuya Tamura, Kortaro Tanaka, Shinichi Terao, Asako Ueno, Kimiko Umemura, Toshitaka Umemura, Hidetaka Watanabe, Kentaro Yamada, Hiroko Yamamoto, Osamu Yamamura, Keizo Yasui, Makoto Yoneda, Hideo Aihara, Tsutomu Azuma, Hideki Etani, Jun Fujinami, Atsushi Fujita, Ryuzo Fukunaga, Hidenao Fukuyama, Naohiro Fumoto, Masahiro Funauchi, Shigetaka Furukado, Yutaka Furukawa, Masashi Hamanaka, Yoshiki Hase, Hiroshi Hasegawa, Kazuo Hashikawa, Masamichi Hayashi, Tachio Hikita, Shuichi Hirose, Hisanori Horiuchi, Taku Hoshi, Hidetaka Hougaku, Masafumi Ihara, Tadashi Ino, Haruhisa Inoue, Takashi Kasai, Tomonobu Kato, Hiromichi Kawai, Michi Kawamoto, Takeshi Kimura, Toru Kimura, Tomoharu Kinoshita, Toru Kita, Kazuo Kitagawa, Masataka Kitaguchi, Akihiro Kitamura, Junya Kobayashi, Mitsuo Kodama, Nobuo Kohara, Eiji Kohmnura, Mika Komori, Kimito Kondo, Tomoyuki Kono, Eiji Kumura, Masato Kuroda, Kengo Maeda, Mari Matsumoto, Kazuo Minematsu, Toshiki Mizuno, Hidehiko Nabatame, Yoshinari Nagakane, Keiko Nagano, Kazuyuki Nagatsuka, Masanori Nakagawa, Shigenobu Nakamura, Yoshifumi Nakaya, Takehiro Nitta, Tomoyuki Ohara, Ryo Ohtani, Shinichiro Okamato, Masaya Okamoto, Kenichi Oku, Emi Omura-Matsuoka, Koh Ono, Kyoko Ozawa, Naoki Saji, Manabu Sakaguchi, Tsutomu Sasaki, Hirotaka Shimizu, Shun Shimohana, Toshiyuki Shiogai, Tetsuo Shioi, Rieko Suzuki, Masayasu Tabuchi, Masafumi Tagaya, Daisuke Takahashi, Makio Takahashi, Tsutomu Takahashi, Mikio Takaya, Tomohiro Tanaka, Haruhiko Terakawa, Hideo Terasawa, Kenichi Todo, Kazuki Tokumoto, Yasuhiro Tomii, Hidekazu Tomimoto, Kazunori Toyoda, Tetsuya Tsukahara, Hirokazu Ueda, Toshiyuki Uehara, Kiyohide Usami, Manabu Watanabe, Yoshiki Yagita, Hiroshi Yamagami, Tatsuhito Yamagami, Hodaka Yamakado, Shiro Yamamoto, Yasumasa Yamamoto, Hiroshi Yamauchi, Hitoshi Yasuda, Chiaki Yokota, Kenji Yoshikawa, Koji Abe, Yoshiaki Adachi, Tatsuo Akimura, Shiro Aoki, Atsuo Aoyama, Masamori Arai, Mutsuko Araki, Hirokazu Bokura, Kentaro Deguchi, Hiroki Fujii, Shunichiro Fujimoto, Toshihiro Fukusako, Akira Handa, Akira Hara, Naoki Hayashi, Seiichiro Hibino, Jitsuo Higaki, Emi Hongo, Kie Honjo, Naohisa Hosomi, Shin-ichirou Ichihara, Keiji Igase, Yasuyuki Iguchi, Kenichi Iijima, Fusao Ikawa, Junko Ikeda, Naomi Ikuta, Eiji Imamura, Isao Inoue, Ken Inoue, Takeshi Inoue, Kayoko Ishihara, Kenichi Ishikawa, Hijiri Ito, Yuko Iwata, Yuishin Izumi, Ryuji Kaji, Tatsushi Kamiya, Yuhei Kanaya, Junichi Kanazawa, Takashi Kanda, Kenichi Kashihara, Satoshi Kataoka, Shinji Katayama, Shoichi Kato, Motoharu Kawai, Kazumi Kimura, Juri Kitmura, Takeshi Kitamura, Katsuzo Kiya, Masuki Kobayashi, Shotai Kobayashi, Masakazu Kohno, Tatsuo Kohriyama, Hiroshi Kondo, Keita Kondo, Hisanori Kowa, Satoshi Kubo, Takashi Kurashige, Katsumi Kurokawa, Noboru Kusaka, Satomi Kushitani, Yasuhiro Manabe, Shinji Manabe, Hirofumi Maruyama, Ichiro Matsubara, Naoki Matsuoka, Hayato Matsushima, Nobuhisa Matsushita, Daisuke Matsuura, Chie Mihara, Yasuyo Mimori, Shingo Mitaki, Takafumi Miyachi, Michie Miyoshi, Ryo Mizuhara, Tomoko Muguruma, Tomoya Mukai, Yoshiki Murakami, Shinji Nagahiro, Masahiro Nagai, Yoshito Nagano, Hiroyuki Naito, Hiromitsu Naka, Minoru Nakagawa, Masahiro Nakamori, Takeshi Nakamura, Shunya Nakane, Kenji Nakashima, Hiroyuki Nakayasu, Takanori Nanba, Hisashi Narai, Takayuki Naya, Kiyoshi Negoro, Tomohisa Nezu, Kyoko Nishi, Shunjiro Nishide, Koichi Noda, Masahiro Nomoto, Eiichi Nomura, Kazuhide Ochi, Jun-ichi Ogasawara, Hiroaki Oguro, Takanori Ohnishi, Manabu Ohno, Tomohiko Ohshita, Toshiho Ohtsuki, Hideo Ohyama, Kazunori Okada, Kensho Okamoto, Bungo Okuda, Takafumi Okura, Nobuhiko Omori, Eiichi Onuki, Kunihiko Osaka, Naohiro Osaka, Sumio Ota, Yoko Ota, Hirokazu Sadahiro, Jun Saito, Hideki Sato, Kensaku Shibazaki, Takesehi Shima, Takeo Shishido, Yoshimasa Sueda, Tomohito Sugiura, Yoshihide Sunada, Norio Sunami, Yutaka Suto, Michiyasu Suzuki, Yoshiteru Tada, Kazue Tajima, Kazuo Takahashi, Tetsuya Takahashi, Kazuhiro Takamatsu, Kensaku Takase, Ikuko Takeda, Nobuo Tamesa, Tetsuya Tamura, Hideo Terasawa, Yuka Terasawa, Hiromasa Toji, Hiroshi Tokinobu, Tsuyoshi Torii, Nobuyuki Umegae, Masaaki Uno, Hideaki Watanabe, Masao Watanabe, Atsuo Yamada, Shingo Yamagata, Shinya Yamaguchi, Shuhei Yamaguchi, Takuya Yamaguchi, Kanji Yamane, Hiroshi Yamashita, Takemori Yamawaki, Noboru Yokoyama, Takakazu Yokoyama, Hiroshi Yoneda, Ushio Yonezawa, Takeo Yoshimura, Kimihiro Yoshino, Junji Yoshioka, Testsuro Ago, Naoki Akamatsu, Shuji Arakawa, Masamichi Atsuchi, Kenichiro Fujii, Shigeru Fujimoto, Kenji Fukuda, Yoshihisa Fukushima, Haruyuki Goda, Makoto Goda, Toshiomi Goto, Yasuyuki Hara, Yoshiya Hashiguchi, Tomoyo Hashimoto, Yoichiro Hashimoto, Shigeaki Hayashi, Saho Higashi, Teruyuki Hirano, Setsuro Ibayashi, Tsuyoshi Imamura, Yoshitomo Ishii, Eiichi Ishikawa, Hiromi Ishikawa, Takao Ishitsuka, Yasuyuki Ito, Juro Jinnouchi, Masahiro Kamouchi, Yuka Kanazawa, Junji Kasuya, Kazuhiro Kishikawa, Jiro Kitayama, Takanari Kitazono, Masatoshi Koga, Yasuhiro Kumai, Masaya Kumamoto, Yoshikazu Maruyama, Ryu Matsuo, Hideki Matsuoka, Mayumi Mori, Kota Mori, Hiroyuki Murai, Makoto Nakajima, Hiroshi Nakane, Toshihisa Nakano, Toshiyasu Ogata, Yasushi Okada, Tsuyoshi Omae, Hiroaki Ooboshi, Masato Osaki, Yoshisuke Saku, Tomohiko Sato, Junichi Takada, Kotaro Takamatsu, Kei-ichiro Takase, Nobuyoshi Takashima, Yuko Tanaka, Atsushi Tashima, Takahisa Tateishi, Tadashi Terasaki, Sadatoshi Tsuji, Akihiko Ueda, Takeshi Uwatoko, Kuniyasu Wada, Masayuki Wakita, Yoko Wakugawa, Yoshiyuki Wakugawa, Masaki Watanabe, Takeshi Yamada, Fumio Yamamoto, Masahiro Yasaka, Kiminobu Yonemura, Sohei Yoshimura

Affiliations

¹ Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
² Foundation for Biomedical Research and Innovation Translational Research Informatics Center, Kobe, Japan.
³ Hiroshima City Rehabilitation Hospital, Hiroshima, Japan.
⁴ Stroke Center, Kinki University, Osakasayama, Japan.
⁵ Department of Neurological Surgery, Matsuyama Shimin Hospital, Matsuyama, Japan.
⁶ National Cerebral and Cardiovascular Center, Suita, Japan.
⁷ Department of Neurology, Tokyo Women's Medical University School of Medicine, Tokyo, Japan.
⁸ Department of Neurology, Iwate Medical University, Morioka, Japan.
⁹ Department of Neurology, Tokyo Saiseikai Central Hospital, Tokyo, Japan.
¹⁰ Seiai Rehabilitation Hospital, Fukuoka, Japan.
¹¹ Division of Biostatistics and Clinical Epidemiology, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences, Toyama, Japan.
¹² Department of Behavioral Neurology and Cognitive Neuroscience, Tohoku University Graduate School of Medicine, Sendai, Japan.
¹³ Clinical Research Center, International University of Health and Welfare, Center for Brain and Cerebral Vessels, Sanno Hospital and Sanno Medical Center, Tokyo, Japan.
¹⁴ Federation of National Public Service Personnel Mutual Aid Associations Tachikawa Hospital, Tokyo, Japan.

Abstract

Background: Although statin therapy is beneficial for the prevention of initial stroke, the benefit for recurrent stroke and its subtypes remains to be determined in Asian, in whom stroke profiles are different from Caucasian. This study examined whether treatment with low-dose pravastatin prevents stroke recurrence in ischemic stroke patients.

Methods: This is a multicenter, randomized, open-label, blinded-endpoint, parallel-group study of patients who experienced non-cardioembolic ischemic stroke. All patients had a total cholesterol level between 4.65 and 6.21 mmol/L at enrollment, without the use of statins. The pravastatin group patients received 10 mg of pravastatin/day; the control group patients received no statins. The primary endpoint was the occurrence of stroke and transient ischemic attack (TIA), with the onset of each stroke subtype set to be one of the secondary endpoints.

Finding: Although 3000 patients were targeted, 1578 patients (491 female, age 66.2 years) were recruited and randomly assigned to pravastatin group or control group. During the follow-up of 4.9 ± 1.4 years, although total stroke and TIA similarly occurred in both groups (2.56 vs. 2.65%/year), onset of atherothrombotic infarction was less frequent in pravastatin group (0.21 vs. 0.64%/year, p = 0.0047, adjusted hazard ratio 0.33 [95%CI 0.15 to 0.74]). No significant intergroup difference was found for the onset of other stroke subtypes, and for the occurrence of adverse events.

Interpretation: Although whether low-dose pravastatin prevents recurrence of total stroke or TIA still needs to be examined in Asian, this study has generated a hypothesis that it may reduce occurrence of stroke due to larger artery atherosclerosis.

Funding: This study was initially supported by a grant from the Ministry of Health, Labour and Welfare, Japan. After the governmental support expired, it was conducted in collaboration between Hiroshima University and the Foundation for Biomedical Research and Innovation.

Keywords: Atherothrombotic infarction; Cholesterol; Hemorrhagic stroke; Ischemic stroke; Statin.

Publication types

Multicenter Study
Randomized Controlled Trial

MeSH terms

Aged
Asian People*
Brain Ischemia / complications
Female
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
Japan
Kaplan-Meier Estimate
Male
Middle Aged
Outcome Assessment, Health Care / methods
Outcome Assessment, Health Care / statistics & numerical data
Pravastatin / therapeutic use*
Proportional Hazards Models
Recurrence
Stroke / drug therapy*
Stroke / ethnology*
Stroke / etiology

Substances

Hydroxymethylglutaryl-CoA Reductase Inhibitors
Pravastatin