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Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent StrokeA Randomized Clinical Trial and Meta-analysis

Educational Objective
To determine the optimum blood pressure target in secondary stroke prevention.
1 Credit CME
Key Points

Question  What is the optimum blood pressure target in secondary stroke prevention?

Findings  In this randomized clinical trial that included 1263 patients with a history of stroke, intensive blood pressure control to less than 120/80 mm Hg tended to reduce stroke recurrence compared with standard blood pressure control (<140/90 mm Hg). When this finding was pooled with the results of prior trials of intensive blood pressure control for secondary stroke prevention in an updated meta-analysis, intensive blood pressure treatment significantly reduced stroke recurrence by 22%.

Meaning  Intensive blood pressure control to less than 130/80 mm Hg is recommended for secondary stroke prevention.

Abstract

Importance  The Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that a systolic blood pressure (BP) target less than 120 mm Hg was superior to less than 140 mm Hg for preventing vascular events. This trial excluded patients with prior stroke; therefore, the ideal BP target for secondary stroke prevention remains unknown.

Objective  To assess whether intensive BP control would achieve fewer recurrent strokes vs standard BP control.

Design, Setting, and Participants  Randomized clinical trial (RCT) of standard vs intensive BP control in an intent-to-treat population of patients who had a history of stroke. Patients were enrolled between October 20, 2010, and December 7, 2016. For an updated meta-analysis, PubMed and the Cochrane Central Library database were searched through September 30, 2018, using the Medical Subject Headings and relevant search terms for cerebrovascular disease and for intensive BP lowering. This was a multicenter trial that included 140 hospitals in Japan; 1514 patients who had a history of stroke within the previous 3 years were approached, but 234 refused to give informed consent.

Interventions  In total, 1280 patients were randomized 1:1 to BP control to less than 140/90 mm Hg (standard treatment) (n = 640) or to less than 120/80 mm Hg (intensive treatment) (n = 640). However, 17 patients never received intervention; therefore, 1263 patients assigned to standard treatment (n = 630) or intensive treatment (n = 633) were analyzed.

Main Outcomes and Measures  The primary outcome was stroke recurrence.

Results  The trial was stopped early. Among 1263 analyzed patients (mean [SD] age, 67.2 [8.8] years; 69.4% male), 1257 of 1263 (99.5%) completed a mean (SD) of 3.9 (1.5) years of follow-up. The mean BP at baseline was 145.4/83.6 mm Hg. Throughout the overall follow-up period, the mean BP was 133.2/77.7 (95% CI, 132.5-133.8/77.1-78.4) mm Hg in the standard group and 126.7/77.4 (95% CI, 125.9-127.2/73.8-75.0) mm Hg in the intensive group. Ninety-one first recurrent strokes occurred. Nonsignificant rate reductions were seen for recurrent stroke in the intensive group compared with the standard group (hazard ratio [HR], 0.73; 95% CI, 0.49-1.11; P = .15). When this finding was pooled in 3 previous relevant RCTs in a meta-analysis, the risk ratio favored intensive BP control (relative risk, 0.78; 95% CI, 0.64-0.96; P = .02; absolute risk difference, −1.5%; 95% CI, −2.6% to −0.4%; number needed to treat, 67; 95% CI, 39-250).

Conclusions and Relevance  Intensive BP lowering tended to reduce stroke recurrence. The updated meta-analysis supports a target BP less than 130/80 mm Hg in secondary stroke prevention.

Trial Registration  ClinicalTrials.gov identifier: NCT01198496

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Article Information

Accepted for Publication: April 25, 2019.

Corresponding Author: Kazuo Kitagawa, MD, PhD, Department of Neurology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan (kitagawa.kazuo@twmu.ac.jp).

Published Online: July 29, 2019. doi:10.1001/jamaneurol.2019.2167

Author Contributions: Dr Shimada had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Shimada was the principal investigator.

Concept and design: Kitagawa, Yamamoto, Sunami, Ueda, Rakugi, Ohya, Okada, Higaki, Tanahashi, Kimura, Umemura, Matsumoto, Shimamoto, Ito, Saruta, Shimada.

Acquisition, analysis, or interpretation of data: Kitagawa, Yamamoto, Arima, Maeda, Kanzawa, Eguchi, Kamiyama, Minematsu, Ueda, Ohya, Kohro, Yonemoto, Tanahashi, Umemura, Matsumoto.

Drafting of the manuscript: Kitagawa, Arima, Maeda, Sunami, Ueda, Rakugi, Ohya, Yonemoto, Higaki, Kimura, Umemura, Matsumoto, Shimamoto, Saruta.

Critical revision of the manuscript for important intellectual content: Kitagawa, Yamamoto, Kanzawa, Eguchi, Kamiyama, Minematsu, Ueda, Ohya, Kohro, Yonemoto, Okada, Tanahashi, Umemura, Matsumoto, Shimamoto, Ito, Saruta, Shimada.

Statistical analysis: Arima, Maeda, Kamiyama, Kohro, Yonemoto, Matsumoto.

Obtained funding: Ueda, Ohya, Matsumoto, Ito, Shimada.

Administrative, technical, or material support: Kitagawa, Kanzawa, Eguchi, Minematsu, Rakugi, Ohya, Higaki, Umemura, Matsumoto, Shimamoto.

Supervision: Kitagawa, Yamamoto, Kanzawa, Minematsu, Higaki, Tanahashi, Matsumoto, Shimamoto, Ito, Saruta, Shimada.

Conflict of Interest Disclosures: Dr Kitagawa reported receiving grants and personal fees from Daiichi Sankyo, Bayer Inc, Takeda Pharmaceutical, Nippon Boehringer Ingelheim, Kyowa Hakko Kirin, Sumitomo Dainippon Pharma, Astellas Pharma, and Sanofi. Dr Arima reported receiving personal fees from Bayer, Daiichi Sankyo, Fukuda Denshi, Kyowa Kirin, and Takeda. Dr Minematsu reported receiving personal fees from Bayer Yakuhin, Otsuka Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Pfizer, Mitsubishi Tanabe Pharma Cooperation, Japan Stryker, Kowa, Nihon Medi-Physics Co, BMS, Sawai Pharmaceutical Co, Sumitomo Dainippon Pharma Co Ltd, Daiichi Sankyo, Asteras Pharma, and Nippon Chemiphar and reported receiving other financial support from AstraZeneca, CSL Behring, Medico’s Hirata, and Bayer Yakuhin. Dr Ueda reported receiving grants from Kowa Soyaku, Bayer, Bristol-Myers Squibb, Pfizer, Daiichi Sankyo, and Takeda Yakuhin and reported receiving personal fees from Ezai, Novartis, MSD, and Boelinger Ingelheim. Dr Rakugi reported receiving grants and/or personal fees from MSD, Astellas Pharma, Daiichi Sankyo, Dainippon Sumitomo Pharma, Bayer Yakuhin, Kyowa Hakko Kirin, Mochida Pharmaceutical, Nippon Boehringer Ingelheim, Takeda Pharmaceutical, Mitsubishi Tanabe Pharma, Novartis Pharma, Otsuka Pharmaceutical, Pfizer Japan, Shionogi & Co, and Teijin Pharma. Dr Ohya reported receiving grants and/or personal fees from Takeda Pharma, Daiichi Sankyo, Novartis Pharma, Asterasu, Dainippon Sumitomo, MSD, Bayer, Pfizer, and Boehringer Ingelheim. Dr Umemura reported receiving grants from Dainippon Sumitomo, Asteras, Pfizer, Nippon Boehringer Ingelheim, Daiichi Sankyo, and Takeda and reported receiving personal fees from Nippon Boehringer Ingelheim and Takeda. Dr Matsumoto reported receiving personal fees from Kowa Pharmaceutical Co Ltd, Takeda Pharmaceutical Co Ltd, Bayer Yakuhin, Ltd, Sanofi KK, Daiichi Sankyo, Otsuka Pharmaceutical Co Ltd, Astellas Pharma Inc, AstraZeneca KK, Mochida Pharmaceutical Co, Ltd, Sumitomo Dainippon Pharma Co Ltd, Amgen Astellas BioPharma KK, Esai Co, Ltd, and Pfizer Japan Inc. Dr Shimamoto reported receiving personal fees from Takeda, Sumitomo Dainippon Pharma Co Ltd, MSD, Astellas Pharma, Boehringer Ingelheim, and Bayer Yakuhin. Dr Ito reported receiving grants and/or personal fees from MSD, Daiichi Sankyo, Takeda, Astellas, and Boehringer Ingelheim. Dr Shimada reported receiving personal fees from Dainippon Sumitomo Ltd, and Daiichi Sankyo. No other disclosures were reported.

Funding/Support: The Recurrent Stroke Prevention Clinical Outcome (RESPECT) Study was funded by Merck and Co Inc, Bristol-Myers Squibb, Towa Pharmaceutical Co, Ltd, and Omron Corporation.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The members of the Recurrent Stroke Prevention Clinical Outcome (RESPECT) Study Group are listed below.

Chief Investigator: Kazuyuki Shimada, MD, Shin-Oyama City Hospital, Oyama, Tochigi, Japan.

Writing Committee: Kazuyuki Shimada (chair), MD, Shin-Oyama City Hospital, Oyama, Tochigi, Japan; Kazuo Kitagawa, MD, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan; Yasumasa Yamamoto, MD, Kyoto Katsura Hospital, Nishikyo, Kyoto, Japan; Hisatomi Arima, MD, Fukuoka University Faculty of Medicine, Jyonan, Fukuoka, Japan; Shinichiro Ueda, MD, University of the Ryukyus School of Medicine, Nakagamigun, Okinawa, Japan; Takahide Kohro, MD, Jichi Medical School, Shimotsuke, Tochigi, Japan; Koji Yonemoto, PhD, University of the Ryukyus Faculty of Medicine, Nakagamigun, Okinawa, Japan.

Steering Committee: Kazuyuki Shimada (chair), MD, Shin-Oyama City Hospital, Oyama, Tochigi, Japan; Satoshi Umemura, MD, Yokohama Rosai Hospital, Yokohama, Kanagawa, Japan; Yasushi Okada, MD, National Hospital Organization Kyushu Medical Center, Chuo, Fukuoka, Japan; Genjiro Kimura, MD, Cardio-renal and Health Research Institute, Nagoya, Aichi, Japan; Kazuaki Shimamoto, MD, Japan Health Care College, Sapporo, Hokkaido, Japan; Norio Tanahashi, MD, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan; Jitsuo Higaki, MD, Minami-Matsuyama Hospital, Matsuyama, Ehime, Japan; Masayasu Matsumoto, MD, Sakai City Medical Center, Sakai, Osaka, Japan.

Protocol Committee: Masayasu Matsumoto (chair), MD, Sakai City Medical Center, Sakai, Osaka, Japan; Sadayoshi Ito, MD, Tohoku University School of Medicine, Sendai, Miyagi, Japan; Shinichiro Ueda, MD, University of the Ryukyus School of Medicine, Nakagamigun, Okinawa, Japan; Yusuke Ohya, MD, University of the Ryukyus Graduate School of Medicine, Nakagamigun, Okinawa, Japan; Kazuo Kitagawa, MD, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan; Yasumasa Yamamoto, MD, Kyoto Katsura Hospital, Nishikyo, Kyoto, Japan; Hiromi Rakugi, MD, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

End Point Committee: Kazuo Minematsu (chair), MD, General of the Hospital, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan; Kazuomi Kario, MD, Jichi Medical School, Shimotsuke, Tochigi, Japan; Yoshihiko Saito, MD, Nara Medical University, Kashihara, Nara, Japan; Yasuo Terayama, MD, Iwate Medical University, Morioka, Iwate, Japan; Kazunori Toyoda, MD, General of the Hospital, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan; Takafumi Okura, MD, Ehime University Graduate School of Medicine, Toon, Ehime, Japan; Haruhiko Hoshino, MD, Tokyo Saiseikai Central Hospital, Minato, Tokyo, Japan; Hirofumi Makino, MD, Okayama University Graduate School of Medicine, Okayama, Japan; Kazuo Eguchi, MD, Hanyu General Hospital, Hanyu, Saitama, Japan; Haruhito Uchida, MD, Okayama University Graduate School of Medicine, Okayama, Japan.

Statistical Analysis Team: Hisatomi Arima (chair), MD, Fukuoka University Faculty of Medicine, Jyonan, Fukuoka, Japan; Takahide Khoro, MD, Jichi Medical School, Shimotsuke, Tochigi, Japan; Koji Yonemoto, PhD, University of the Ryukyus Faculty of Medicine, Nakagamigun, Okinawa, Japan.

Independent Data and Safety Monitoring Committee: Shinichiro Uchiyama (chair), MD, International University of Health and Welfare, Minato, Tokyo, Japan; Hideki Etani, MD, OBP Clinic, Chuou, Osaka, Japan; Tatsuo Kohriyama, MD, Brain Attack Center, Ota Memorial Hospital, Fukuyama, Hiroshima, Japan; Hidekazu Tomimoto, MD, Mie University Graduate School of Medicine, Tsu, Mie, Japan; Taku Yoshio, MD, Jichi Medical University Hospital, Shimotsuke, Tochigi, Japan; Takao Saruta, MD, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Shotai Kobayashi, MD, Shimane University, Izumo, Shimane, Japan.

Data Management Center: Hiroko Usami, PhD, Nonprofit Organization RESPECT Study Group, Hachioji, Tokyo, Japan.

RESPECT Study Investigators: The investigators are listed below by location in Japan and by institution.

Hokkaido: Satoshi Iihoshi, MD, Takeshi Mikami, MD, Nobuhiro Mikuni, MD, Kei Miyata, MD, and Tomohiro Murakami, MD, Sapporo Medical University, Sapporo, Hokkaido, Japan; Hideki Endo, MD, Takahito Fukui, MD, Kentaro Fumoto, MD, Keiji Hara, MD, Kaori Honjo, MD, Kenji Kamiyama, MD, Yusuke Kinoshita, MD, Masana Maeda, MD, Masaaki Mikamoto, MD, Daisuke Mori, MD, Takeo Murahashi, MD, Ryota Nomura, MD, Shusaku Noro, MD, Tatsuya Ogino, MD, Masahiro Okuma, MD, Yasuhumi Otake, MD, Koichiro Shindo, MD, Hironori Sugio, MD, Hidekazu Takada, MD, Kazuki Takahira, MD, Akiko Takeuchi, MD, Toshiichi Watanabe, MD, and Yohei Yamaguchi, MD, Nakamura Memorial Hospital, Sapporo, Hokkaido, Japan; Takeo Abumiya, MD, and Kiyohiro Houkin, MD, Hokkaido University, Sapporo, Hokkaido, Japan; Shigeki Matsumura, MD, and Tomohiro Murakami, MD, Sapporo Miyanosawa Neurosurgical Hospital, Sapporo, Hokkaido, Japan; Rikiya Shinohe, MD, Ebetsu City Hospital, Ebetsu, Hokkaido, Japan; Kiyomi Kuroshima, MD, Katsumi Takizawa, MD, and Kazuto Yoshida, MD, Japanese Red Cross Asahikawa Hospital, Asahikawa, Hokkaido, Japan; Hideo Morimoto, MD, Fukagawa Municipal Hospital, Fukagawa, Hokkaido, Japan; Naoyuki Hasebe, MD, Asahikawa Medical University, Asahikawa, Hokkaido, Japan; Satoshi Koyama, MD, and Junichi Maruyama, MD, Asahikawa Rehabilitation Hospital, Asahikawa, Hokkaido, Japan; Shinsuke Irie, MD, Kushiro Neurosurgical Clinic, Kushiro, Hokkaido, Japan.

Aomori Prefecture: Takahiro Nakano, MD, Yukari Ogasawara, MD, and Hiroki Ohkuma, MD, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan; Kazuo Shibanai, MD, Hachinohe JRC Hospital, Hachinohe, Aomori, Japan.

Akita Prefecture: Kentaro Hikichi, MD, Shinya Kobayashi, MD, Junta Moroi, MD, Taizen Nakase, MD, Takeshi Okada, MD, Daiki Takano, MD, Shunsuke Takenaka, MD, and Shotaro Yoshioka, MD, Research Institute for Brain and Blood Vessels–Akita, Akita, Japan; Toshiharu Yanagisawa, MD, Akita University Graduate School of Medicine, Akita, Japan; Yutaka Hirata, MD, Kita-Akita Municipal Hospital, Kita-Akita, Akita, Japan.

Iwate Prefecture: Shu Konno, MD, Matuzono Second Hospital, Morioka, Iwate, Japan; Tomohiko Sato, MD, National Hospital Organization, Iwate Hospital, Ichinoseki, Iwate, Japan.

Yamagata Prefecture: Miiko Ito, MD, Rei Kondo, MD, Wataru Mori, MD, and Shinjiro Saito, MD, Yamagata City Hospital SAISEIKAN, Yamagata, Japan; Yasuaki Kokubo, MD, Yamagata University Faculty of Medicine, Yamagata, Japan.

Miyagi Prefecture: Hideaki Kato, MD, and Hideki Oyama, MD, Senseki Hospital, Higashi-Matsushima, Miyagi, Japan; Kaneyuki Matsuo, MD, Matsuo Kenko Clinic, Sendai, Miyagi, Japan; Masahiro Matsumoto, MD, and Mari Nakamura, MD, Tohoku Rosai Hospital, Sendai, Miyagi, Japan.

Fukushima Prefecture: Takayuki Koizumi, MD, and Hiroyuki Sato, MD, Takeda General Hospital, Aizuwakamatsu, Fukushima, Japan.

Ibaraki Prefecture: Yasushi Shibata, MD, Mito Kyodo General Hospital, Mito, Ibaraki, Japan.

Tochigi Prefecture: Kazuo Eguchi, MD, and Kazuomi Kario, MD, Jichi Medical University, Shimotsuke, Tochigi, Japan; Masaaki Hashimoto, MD, Kazuo Eguchi, MD, Hideharu Kurita, MD, and Eiji Matsumoto, MD, IUHW Hospital, Shiobara, Tochigi, Japan.

Gunma Prefecture: Koji Ishiguro, MD, Takasaki General Medical Center, Takasaki, Gunma, Japan; Ken Asakura, MD, Hiroya Fujimaki, MD, and Kazuki Wakabayashi, MD, Maebashi Red Cross Hospital, Maebashi, Gunma, Japan; Kazunori Akaji, MD, Tomo Horikoshi, MD, Tadashige Kano, MD, Takao Kanzawa, MD, Takehiro Katano, MD, Hiroaki Kimura, MD, Ban Mihara, MD, Kentaro Suzuki, MD, and Yohei Takayama, MD, Institute of Brain and Blood Vessel Mihara Memorial Hospital, Isesaki, Gunma, Japan.

Saitama Prefecture: Akira Ishii, MD, Sin-ichi Momomura, MD, Hitoshi Sugawara, MD, and Takeshi Yamashita, MD, Saitama Medical Center, Jichi Medical University, Saitama, Japan; Uichi Kaneko, MD, and Toshie Takahashi, MD, Saitama Red Cross Hospital, Saitama, Japan; Toshinari Arai, MD, Soka Municipal Hospital, Soka, Saitama, Japan; Yoshihiro Tanaka, MD, Dokkyo Medical University Saitama Medical Center, Koshigaya, Saitama, Japan; Shigehisa Inokuma, MD, Inokuma Clinic, Kawagoe, Saitama, Japan; Yuji Kato, MD, and Norio Tanahashi, MD, Saitama Medical University International Medical Center, Hidaka, Saitama, Japan.

Chiba Prefecture: Naoki Ishige, MD, National Hospital Organization Chiba Medical Center, Chiba, Japan; Kazuhiro Muramatsu, MD, Shigeru Nogawa, MD, and Takahito Yoshizaki, MD, Tokyo Dental College Ichikawa General Hospital, Ichikawa, Chiba, Japan; Takashi Ohashi, MD, Tokyo Women’s Medical University Yachiyo Medical Center, Yachiyo, Chiba, Japan; Sumio Suda, MD, Kimitsu Chuo Hospital, Kisarazu, Chiba, Japan.

Tokyo: Yasuyuki Iguchi, MD, and Hidetaka Mitsumura, MD, The Jikei University School of Medicine, Minato, Tokyo, Japan; Tomohide Adachi, MD, Haruhiko Hoshino, MD, Fumie Konoeda, MD, and Koichi Oki, MD, Tokyo Saiseikai Central Hospital, Minato, Tokyo, Japan; Ryota Tanaka, MD, Takao Urabe, MD, and Kazuo Yamashiro, MD, Juntendo University Hospital, Bunkyo, Tokyo, Japan; Akihiro Ito, MD, Hirofumi Nakatomi, MD, and Masaaki Shojima, MD, The University of Tokyo, Bunkyo, Tokyo, Japan; Kuniaki Otsuka, MD, and Koichi Shibata, MD, Tokyo Women’s Medical University Medical Center East, Arakawa, Tokyo, Japan; Takato Abe, MD, Yoshiaki Itoh, MD, Koichi Oki, MD, and Norihiro Suzuki, MD, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Kazuo Kitagawa, MD, and Sono Toi, MD, Tokyo Women’s Medical University, Shinjuku, Tokyo, Japan; Tamio Teramoto, MD, Teikyo University, Itabashi, Tokyo, Japan; Atsushi Fukunaga, MD, Yuki Kujuro, MD, Kouichi Ohta, MD, Takashi Osada, MD, and Katuyoshi Shimizu, MD, Tachikawa Hospital, Tachikawa, Tokyo, Japan; Yasuhisa Kitagawa, MD, and Kentaro Tokuoka, MD, Tokai University Hachioji Hospital, Hachioji, Tokyo, Japan.

Kanagawa Prefecture: Masao Omura, MD, Yokohama Rosai Hospital, Yokohama, Kanagawa, Japan; Hideyuki Kikyo, MD, Yokohama Public Medical Center for Stroke and Neurology, Yokohama, Kanagawa, Japan; Tomoya Kamide, MD, Yoshihisa Kitamura, MD, Katsuyoshi Miyashita, MD, Kentaro Mori, MD, Hiroshi Shima, MD, and Akira Tamase, MD, Yokohama Sakae Kyosai Hospital, Yokohama, Kanagawa, Japan; Tsugio Akutsu, MD, and Kazutoshi Nishiyama, MD, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan; Shunya Takizawa, MD, and Tsuyoshi Uesugi, MD, Tokai University School of Medicine, Isehara, Kanagawa, Japan.

Nagano Prefecture: Uichi Ikeda, MD, Megumi Koshikawa, MD, and Saeko Yamasaki, MD, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; Atsushi Inoue, MD, Nagano Prefectural Kiso Hospital, Kisofukushima, Nagano, Japan.

Ishikawa Prefecture: Yasuko Matsumoto, MD, and Kazuyoshi Yamaguchi, MD, Ishikawa Prefectural Central Hospital, Kanazawa, Ishikawa, Japan; Genjirou Hirose, MD, and Satoshi Kontani, MD, Asanogawa General Hospital, Kanazawa, Ishikawa, Japan; Kazuya Takasawa, MD, Public Central Hospital of Matto Ishikawa, Hakusan, Ishikawa, Japan.

Niigata Prefecture: Katsumi Hirahara, MD, Hirahara Naika Clinic, Jouetsu, Niigata, Japan; Makoto Kodama, MD, and Nobue Yagihara, MD, Niigata University School of Medicine, Niigata, Japan.

Shizuoka Prefecture: Takashi Hata, MD, and Makoto Hori, MD, Shizuoka City Shimizu Hospital, Shimizu, Shizuoka, Japan.

Aichi Prefecture: Rokuhei Oda, MD, Nishio Municipal Hospital, Nishio, Aichi, Japan; Ayuka Kubo, MD, and Satoshi Okuda, MD, National Hospital Organization Nagoya Medical Center, Nagoya, Aichi, Japan; Kentaro Yamada, MD, Nagoya City East Medical Center, Nagoya, Aichi, Japan; Hiroki Takeuchi, MD, Higashi Nagoya National Hospital, Nagoya, Aichi, Japan; Yoshio Araki, MD, Mizuki Ito, MD, Joe Senda, MD, and Toshihiko Wakabayashi, MD, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; Shinji Ito, MD, and Tatsuro Mutoh, MD, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

Gifu Prefecture: Yukinori Kawase, MD, Hashimoto Clinic, Gifu, Japan; Fumio Ando, MD, Ando Clinic, Kani, Gifu, Japan.

Mie Prefecture: Shinya Okamoto, MD, Iwasaki Hospital, Tsu, Mie, Japan; Takuya Shimada, MD, and Akihiro Shindo, MD, Sakakibara Onsen Hospital, Tsu, Mie, Japan; Masakatsu Nishikawa, MD, Atsushi Niwa, MD, Ryogen Sasaki, MD, Akihiro Shindo, MD, and Hidekazu Tomimoto, MD, Mie University Graduate School of Medicine, Tsu, Mie, Japan; Hiroto Murata, MD, Saiseikai Matsusaka General Hospital, Matsusaka, Mie, Japan; Kenichiro Yata, MD, Suzuka Kaisei Hospital, Suzuka, Mie, Japan.

Shiga Prefecture: Koushun Matsuo, MD, Omihachiman Community Medical Center, Omihachiman, Shiga, Japan.

Kyoto: Hideo Yagi, MD, Koseikai Takeda Hospital, Shimogyo, Kyoto, Japan; Toshiyuki Shiogai, MD, Kyoto Takeda Hospital, Shimogyo, Kyoto, Japan; Yoshinari Nagakane, MD, and Yasumasa Yamamoto, MD, Kyoto Second Red Cross Hospital, Kamigyo, Kyoto, Japan; Jun Fujinami, MD, Masanori Nakagawa, MD, Ryo Ohara, MD, and Yasuhiro Tomii, MD, Kyoto Prefectural University of Medicine, Kamigyo, Kyoto, Japan; Yoshiki Arakawa, MD, Takeshi Funaki, MD, Masafumi Ihara, MD, Akihiro Kitamura, MD, Takakuni Maki, MD, Susumu Miyamoto, MD, Yoshifumi Nakaya, MD, Ryosuke Takahashi, MD, Yohei Takenobu, MD, and Kazumichi Yoshida, MD, Kyoto University Graduate School of Medicine, Sakyo, Kyoto, Japan; Tadashi Ino, MD, Rakuwakai Otowa Hospital, Yamashina, Kyoto, Japan; Nagako Murase, MD, and Ryo Ohotani, MD, National Hospital Organization Kyoto Medical Center, Fushimi, Kyoto, Japan; Yasuhiro Tomii, MD, and Yasumasa Yamamoto, MD, Kyoto Katsura Hospital, Nishikyo, Kyoto, Japan; Atsushi Kawashima, MD, and Akiko Watanabe, MD, Fukuchiyama City Hospital, Fukuchiyama, Kyoto, Japan; Yuko Hayashi, MD, Takuma Ohmichi, MD, Rei Yasuda, MD, Akira Yoshioka, MD, and Natsuko Yuki, MD, National Hospital Organization Maizuru Medical Center, Maizuru, Kyoto, Japan; Masahiro Makino, MD, Yasuhiro Tomii, MD, and Tatsuyuki Yamaguchi, MD, Kyoto Chubu Medical Center, Nantan, Kyoto, Japan.

Osaka: Jyo Matsuzaki, MD, Hitoshi Niki, MD, Shoichi Shiraishi, MD, and Takehiko Yanagihara, MD, Tane General Hospital, Nishi, Osaka, Japan; Keiichi Yamada, MD, Kansai Electric Power Hospital, Fukushima, Osaka, Japan; Jun Hatate, MD, Kaori Miwa, MD, and Shuhei Okazaki, MD, Osaka University Graduate School of Medicine, Suita, Osaka, Japan; Shoji Arihiro, MD, Ryosuke Doijiri, MD, Kyoko Higashida, MD, Katsufumi Kajimoto, MD, Kotaro Miyashita, MD, Kazuyuki Nagatsuka, MD, Kozue Saito, MD, Yuri Sugiura, MD, Hotake Takizawa, MD, Takako Torii, MD, Kazunori Toyoda, MD, and Chiaki Yokota, MD, General of the Hospital, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan; Yoshinaga Kajimoto, MD, and Toshihiko Kuroiwa, MD, Osaka Medical College, Takatsuki, Osaka, Japan; Ryuzo Fukunaga, MD, and Tsutomu Takahashi, MD, JCHO Hoshigaoka Medical Center, Hirakata, Osaka, Japan; Kazutami Nakao, MD, Kawachi General Hospital, Higashiosaka, Osaka, Japan; Yuta Kajiyama, MD, Yasuyoshi Kimura, MD, Takashi Naka, MD, Hironori Otomune, MD, Takao Tanahashi, MD, and Takuya Uehara, MD, Higashiosaka City Medical Center, Higashiosaka, Osaka, Japan; Hiroyuki Hashimoto, MD, and Toshihiko Uematsu, MD, Osaka Rosai Hospital, Sakai, Osaka, Japan.

Nara Prefecture: Kazuo Kataoka, MD, Kinki University Nara Hospital, Ikoma, Nara, Japan; Satoshi Okayama, MD, and Satoshi Somekawa, MD, Nara Medical University, Kashihara, Nara, Japan; Shuichi Yamada, MD, Oyodo Town Hospital, Ikoma, Nara, Japan; Rie Sasaki, MD, and Shigeru Yamano, MD, Nara Prefecture General Rehabilitation Center, Shikigun, Nara, Japan.

Wakayama Prefecture: Naoyuki Nakao, MD, and Shinji Obayashi, MD, Wakayama Medical University, Kimiidera, Wakayama, Japan.

Hyogo Prefecture: Hirotoshi Hamaguchi, MD, Tatsushi Toda, MD, and Kazuo Washida, MD, Kobe University Graduate School of Medicine, Kobe, Hyogo, Japan; Taku Hoshi, MD, Tomoyuki Kono, MD, Hiroaki Sekiya, MD, Norifumi Sugo, MD, Kenichi Todo, MD, Masaya Togo, MD, Hiroshi Yamagami, MD, and Shiro Yamamoto, MD, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan; Yoshihiko Shiro, MD, and Norifumi Sugo, MD, Kobe City Medical Center West Hospital, Kobe, Hyogo, Japan; Hirotoshi Hamaguchi, MD, Kita-Harima Medical Center, Ono, Hyogo, Japan; Toshio Takaoka, MD, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.

Shimane Prefecture: Satoshi Abe, MD, Chizuko Hamada, MD, Masaki Ishihara, MD, Katuhiko Kadota, MD, Tomonori Nakagawa, MD, Hiroaki Oguro, MD, Hiroyuki Takayoshi, MD, Takuya Yamaguchi, MD, and Shuuhei Yamaguchi, MD, Shimane University Faculty of Medicine, Izumo, Shimane, Japan; Ryo Mizuhara, MD, Kazunori Okada, MD, and Shingo Yamagata, MD, Ohda Municipal Hospital, Ohda, Shimane, Japan; Kazunori Okada, MD, Ohda Silver Clinic, Ohda, Shimane, Japan; Akira Sasaki, MD, JCHO Tamatsukuri Hospital, Matsue, Shimane, Japan.

Okayama Prefecture: Koji Abe, MD, Kentaro Deguchi, MD, Shoko Deguchi, MD, and Yumiko Nakano, MD, Okayama University Graduate School of Medicine, Okayama, Japan; Satoshi Hirai, MD, Masaaki Uno, MD, and Kimihiko Yokosuka, MD, Kawasaki Medical School, Kurashiki, Okayama, Japan; Yasuhiro Manabe, MD, National Hospital Organization Okayama Medical Center, Kita, Okayama, Japan.

Hiroshima Prefecture: Hijiri Ito, MD, Vihara Hananosato Hospital, Miyoshi, Hiroshima, Japan; Shiro Aoki, MD, Naohisa Hosomi, MD, Yasuki Kihara, MD, Tomohiko Kisaka, MD, Hirofumi Maruyama, MD, and Masayasu Matsumoto, MD, Hiroshima University Graduate School of Medicine, Hiroshima, Japan; Hayato Araki, MD, and Ryo Ogami, MD, Mazda Hospital, Akigun, Hiroshima, Japan; Tsuyoshi Torii, MD, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Hiroshima, Japan; Noboru Yokoyama, MD, and Takakazu Yokoyama, MD, Yokoyama Hospital, Kure, Hiroshima, Japan; Satoshi Kataoka, MD, and Takeshi Kitamura, MD, Chugoku Rosai Hospital, Kure, Hiroshima, Japan.

Yamaguchi Prefecture: Takashi Kanda, MD, Toshihiko Maeda, MD, and Fumitaka Shimizu, MD, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan; Kozaburo Seki, MD, Yamaguchi Rosai Hospital, Sanyoonoda, Yamaguchi, Japan.

Kagawa Prefecture: Yuko Bando, MD, and Masaki Ohara, MD, Ayagawa National Health Insurance SUE Hospital, Ayautagun, Kagawa, Japan.

Kochi Prefecture: Masahiro Yamasaki, MD, Chikamori Hospital, Okawasuji, Kochi, Japan; Noritaka Masahira, MD, Tetsuya Ueba, MD, and Yusuke Ueba, MD, Kochi Medical School, Nankoku, Kochi, Japan.

Ehime Prefecture: Norio Sunami, MD, Matsuyama Shimin Hospital, Matsuyama, Ehime, Japan; Yuichi Fujimoto, MD, Keiko Haro, MD, Hidenori Ogata, MD, and Norihiko Shida, MD, Matsuyama Red Cross Hospital, Matsuyama, Ehime, Japan; Takeshi Matsumoto, MD, and Kensho Okamoto, MD, Ehime Prefectural Central Hospital, Matsuyama, Ehime, Japan; Jitsuo Higaki, MD, and Takafumi Okura, MD, Ehime University Graduate School of Medicine, Toon, Ehime, Japan; Ryuichi Kawamoto, MD, Seiyo Municipal Nomura Hospital, Seiyo, Ehime, Japan.

Fukuoka Prefecture: Shuji Arakawa, MD, and Shoji Arihiro, MD, Kyushu Rosai Hospital, Kitakyushu, Fukuoka, Japan; Hirofumi Shii, MD, and Hidetoshi Kanai, MD, Kokura Kinen Hospital, Kitakyushu, Fukuoka, Japan; Shigeru Fujimoto, MD, Juro Jinnouchi, MD, Takayuki Matsuki, MD, and Masato Osaki, MD, Steel Memorial Yawata Hospital, Kitakyushu, Fukuoka, Japan; Kimika Arakawa, MD, Ai Ibaraki, MD, Kanako Kiyohara, MD, Yuko Ohta, MD, Hideyuki Oniki, MD, Minako Sakaki, MD, Mitsuhiro Tominaga, MD, and Takuya Tsuchihashi, MD, National Hospital Organization Kyushu Medical Center, Chuo, Fukuoka, Japan; Saho Higashi, MD, Hiromi Ishikawa, MD, Koji Ishitsuka, MD, Jiro Kitayama, MD, and Hiroshi Nakane, MD, National Hospital Organization Fukuoka Higashi Medical Center, Koga, Fukuoka, Japan; Takeo Yoshimura, MD, Fukuoka City Hospital, Hakata, Fukuoka, Japan; Shunsuke Kakino, MD, and Yoshirou Kaneko, MD, Fukuoka Tokushukai Medical Center, Kasuga, Fukuoka, Japan.

Kumamoto Prefecture: Junnosuke Inoue, MD, Kumamoto Jikei Hospital, Kumamoto, Japan.

Kagoshima Prefecture: Yoshikazu Maruyama, MD, Imakiire General Hospital, Shimotatuo, Kagoshima, Japan.

Okinawa Prefecture: Katsunori Isa, MD, Yusuke Ohya, MD, and Hirokuni Sakima, MD, University of the Ryukyus Graduate School of Medicine, Nakagamigun, Okinawa, Japan; Seigo Nakada, MD, Chibana Clinic, Chibana, Okinawa, Japan.

Data Sharing Statement: See Supplement 3.

Additional Contributions: Hiroko Usami, PhD, chief secretary of the Recurrent Stroke Prevention Clinical Outcome (RESPECT) Study Group, performed data management and protocol and manuscript preparation. Yasuko Ohtsuki, BA, clinical research coordinator, International University of Health and Welfare Hospital, contributed to patient recruitment and acquisition of informed consent. They were not compensated for their contributions. We appreciate the contributions of all the investigators and other clinical and research staff involved in the trial.

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