
==== Front
Hypertens Res
Hypertens Res
Hypertension Research
0916-9636
1348-4214
Springer Nature Singapore Singapore

38977876
1742
10.1038/s41440-024-01742-3
Article
Blood pressure during long-term cilostazol-based dual antiplatelet therapy after stroke: a post hoc analysis of the CSPS.com trial
Toyoda Kazunori toyoda@ncvc.go.jp

1
Koga Masatoshi 1
Tanaka Kenta 2
Uchiyama Shinichiro 3
Sunami Hisato 4
Omae Katsuhiro 24
Kimura Kazumi 5
Hoshino Haruhiko 6
Fukuda-Doi Mayumi 12
Miwa Kaori 1
Koge Junpei 1
Okada Yasushi 7
Sakai Nobuyuki 8
Minematsu Kazuo 9
Yamaguchi Takenori 1
for the CSPS.com Trial InvestigatorsYamaguchi Takenori 10
for the Study sponsor
Yamaguchi Takenori 11
for the Principal Investigator
Toyoda Kazunori 11
Uchiyama Shinichiro 12
Hoshino Haruhiko 13
Kimura Kazumi 14
Okada Yasushi 15
Sakai Nobuyuki 16
Tanaka Kotaro 17
for the Steering Committee
Toyoda Kazunori 11
for the Protocol Authoring Committee
Naritomi Hiroaki 18
Goto Shinya 19
Isomura Tatsuya 20
for the Independent Data Monitoring Committee
Minematsu Kazuo 21
Houkin Kiyohiro 22
Matsumoto Masayasu 23
Terayama Yasuo 24
Tomimoto Hidekazu 25
Tominaga Teiji 26
Yasuda Satoshi 11
for the Event Evaluation Committee
Orikasa Hideki 17
Kumagai Naoko 17
for the Statistical Analysis Committee
for the Publication Committee
Miyasaki Akihiro 27
Isobe Masanori 28
Suda Yoshitaka 29
Kitagawa Kazuo 30
Nagatsuka Kazuyuki 11
Toru Shuta 31
Katsuno Makoto 32
Murao Kenichi 33
Ikeda Norio 34
Nakashima Kazuya 35
Okabe Shinichi 36
Kurimoto Masanori 37
Ihara Ikuo 38
Matsuoka Hideki 39
Mabuchi Shoji 40
Hara Hideo 41
Yoshimoto Teruyuki 42
Matsuoka Takeshi 43
Arai Yoshikazu 44
Iwasaki Yasuyuki 45
Hattori Manabu 46
Takahashi Kazuya 47
Fukushima Yoshihisa 48
Ezura Masayuki 49
Takeda Yasuaki 50
Nakahara Kimihiro 51
Okada Masahiro 52
Mitaki Shingo 53
Yoshida Kosuke 54
Kamiyama Kenji 55
Kuwashiro Takahiro 56
Iwanaga Takeshi 57
Takahashi Akira 58
Maruyama Junichi 59
Yamamoto Teiji 60
Maruyama Michiyuki 61
Taguchi Yoshiharu 62
Hashidume Kazuhiro 63
Takizawa Katsumi 64
Iguchi Yasuyuki 65
Kitajima Kazuhito 66
Yoshimura Shinichi 67
Arakawa Syuji 68
Inoue Takeshi 69
Yamaguchi Hiroyuki 70
Suzuki Susumu 71
Watanabe Youichi 72
Yasutomi Daisuke 73
Tanaka Ryota 74
Yamamoto Takuji 75
Ando Tetsuo 76
Ito Yasuhiro 77
Hattori Naoki 78
Yamamoto Nobutaka 79
Takahashi Tsutomu 80
Arihiro Syoji 81
Kanda Naoaki 82
Hamaguchi Hirotoshi 83
Kasuya Junji 84
Honda Masaru 85
Oyama Hiroshi 86
Yoshida Hidefumi 87
Okuda Satoshi 88
Matsuura Keita 89
Ieda Toshiaki 90
Kanzawa Takao 91
Takahashi Makio 92
Sadahiro Hirokazu 93
Miyahara Takahiro 94
Yamada Masahiko 95
Aoki Takeshi 96
Nakase Taizen 97
Hayashi Katsuhiko 98
Umemura Toshitaka 99
Tsugu Yasukuni 100
Miya Fumitaka 101
Otani Ryo 102
Yamada Keiichi 103
Kajimoto Yoshinaga 104
Nakane Hiroshi 105
Shinno Kiyohito 106
Hara Akio 107
Saito Ryoichi 108
Araki Yuzo 109
Otsuki Toshiho 110
Abe Koji 111
Kin Shigenari 112
Tsuji Takehisa 113
Sakai Shota 114
Tsuboi Yoshio 115
Kawamorita Atsushi 116
Shimizu Hiroaki 117
Araki Nobuo 118
Hata Takashi 119
Ryu Hiroshi 120
Yamatani Kazumasa 121
Minami Shinji 122
Maruta Takahiro 123
Eto Masaki 124
Takayama Katsutoshi 125
Hashikawa Kazuo 126
Mabuchi Eiichiro 127
Sakagami Yoshio 128
Tsuchimoto Syoji 129
Kitayama Jiro 130
Shirakawa Kiyoshi 131
Takahashi Haruki 132
Uchinokura Syunro 133
Osaka Naohiro 134
Imafuku Ichiro 135
Otsuka Toshiro 136
Itabashi Ryo 137
Kujiraoka Yuji 138
Miura Naohisa 139
Nomura Koichi 140
Kobari Masahiro 141
Yasui Keizo 142
Kashino Susumu 143
Murata Hiroto 144
Nozaki Kazuhiko 145
Yamashita Kosuke 92
Matsumoto Katsumi 146
Shibata Yuji 147
Aoyama Atsuo 148
Watanabe Yoshimasa 149
Eto Toru 150
Mekaru Susumu 151
Honda Tsuneo 152
Seike Masato 153
Kurisaka Masahiro 154
Imaizumi Toshio 155
Wada Kojiro 156
Suzuki Norihiro 157
Yoshino Atsuo 158
Hara Yukiko 159
Takizawa Shunya 160
Kamimoto Kaoru 161
Iizuka Hiroshi 162
Toma Yasuo 163
Komuro Taro 164
Sueyoshi Atsushi 165
Nakajima Yoshikazu 23
Sakaki Takayuki 166
Miyake Hiroji 167
Idei Masaru 168
Hitotsumatsu Tsutomu 169
Nakahara Shigehiro 170
Kawanishi Masahiko 171
Kitaoka Takuji 172
Isobe Naoyuki 173
Hokama Masanobu 174
Shibata Toshihide 175
Tsuruta Kazuhito 176
Moriki Akihito 177
Makino Masahiro 178
Otaki Masafumi 179
Ajiki Minoru 180
Yamazaki Takaaki 181
Houkin Kiyohiro 182
Yasui Nobuyuki 183
Hirata Koichi 184
Kato Hiroyuki 185
Suzuki Ichiro 186
Kawamata Takakazu 30
Uesaka Yoshikazu 187
Yamashita Kohei 188
Enomoto Yukiko 189
Onodera Osamu 190
Ikeda Masato 191
Miyamoto Susumu 192
Sakaguchi Manabu 193
Nakase Hiroyuki 194
Yagita Yoshiki 195
Kitahara Tetsuhiro 196
Irie Katsumi 197
Kusuhara Tomohiko 198
Kawazoe Kazumasa 199
Nagahiro Shinji 200
Kawada Norikazu 201
Adachi Akiko 202
Fukusako Toshihiro 203
Tsuruta Wataro 204
Fujimura Naoko 205
Koizumi Takayuki 206
Tomimitsu Hiroyuki 207
Fujimoto Shigeru 208
Tsuchiya Tsukasa 209
Aizawa Hitoshi 210
Ishizu Nobutaka 211
Nogawa Shigeru 212
Furumoto Hideharu 213
Ueda Toshihiro 214
Imae Syogo 215
Nakayama Teiji 216
Namba Hiroki 217
Ochiai Jun 218
Yamana Tomoko 219
Mase Mitsuhito 220
Matsukawa Noriyuki 220
Niwa Hisayoshi 221
Muramatsu Masatoshi 222
Nakashima Yoshio 223
Iwamoto Fuminori 224
Yoneda Syunichi 225
Hashimoto Kenji 226
Matsushita Tatsuo 227
Kunieda Takenobu 228
Masuo Osamu 229
Yamamoto Hirotaka 230
Hosomi Naohisa 231
Ogami Ryo 232
Kuramoto Koichi 233
Matsumoto Takahiro 234
Shinozaki Hirotsugu 235
Sugimori Hiroshi 236
Hashimoto Yoichiro 237
Suzuki Hidenori 25
Waza Masahiro 238
Kujyuro Yuki 239
Kamei Eiichi 240
Uchida Yasufumi 241
Nagayama Masao 242
Hiroki Masahiko 243
Sakura Hiroshi 244
Noujo Tatsuru 245
Tajima Yasutaka 246
Wada Hajime 247
Hodozuka Akira 248
Ide Wataru 249
Shibata Yasushi 250
Yamamoto Shinji 251
Ishihara Masayuki 252
Miyata Satsuki 253
Matsuoka Yoshiyuki 254
Sakurai Yasuhisa 255
Miura Yoshiharu 256
Yokota Takanori 257
Iwabuchi Satoshi 258
Tsuruta Wataro 187
Arimoto Hirohiko 259
Suda Sumio 260
Ohashi Takashi 261
Kuroda Katsuhiro 262
Matsuhisa Takashi 263
Yokoyama Kazutoshi 264
Katada Eiichi 265
Fujishiro Kenichiro 266
Inukai Akira 267
Kobayashi Yasushi 268
Sakai Hideki 269
Yamamoto Kenichi 270
Asakura Ken 271
Yoshimoto Yuhei 272
Kusano Yoshikazu 273
Takahashi Ryoichi 274
Higashi Sotaro 275
Park Cheho 276
Nakada Mitsutoshi 277
Matsui Makoto 278
Nagakane Yoshinari 279
Yoshioka Akira 280
Makino Masahiro 281
Yamaguchi Kazuyoshi 282
Hagihara Yasushi 283
Yamada Tomonori 284
Hashimoto Kenji 285
Fujita Toshiaki 286
Kumagai Tetsuya 287
Sumida Masayuki 288
Morioka Motohiro 289
Oboshi Hiroaki 290
Kitazono Takanari 291
Ando Yukio 292
Minato Seiichiro 293
Agawa Masahito 294
Kono Takeshi 295
Izumidani Tomohiko 295
Ueba Tetsuya 296
Takeuchi Hiroaki 297
Monden Syuji 298
Shiraishi Syoji 299
Syoji Hidehiko 300
Nakamura Tatsuya 300
Ikawa Naoki 301
Sugihara Hiroshi 302
Toyonaga Shinichi 303
Kon Hiroyuki 304
Kanamori Yuji 305
Tanaka Hiroaki 306
for the Clinical Sites and Site Investigators, by Enrolment

1 https://ror.org/01v55qb38 grid.410796.d 0000 0004 0378 8307 Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Japan
2 https://ror.org/01v55qb38 grid.410796.d 0000 0004 0378 8307 Department of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan
3 grid.511745.3 0000 0004 4655 7437 Clinical Research Center for Medicine, International University of Health and Welfare, Center for Brain and Cerebral Vessels, Sanno Medical Center, Tokyo, Japan
4 https://ror.org/01v55qb38 grid.410796.d 0000 0004 0378 8307 Department of Biostatistics, National Cerebral and Cardiovascular Center, Suita, Japan
5 https://ror.org/00krab219 grid.410821.e 0000 0001 2173 8328 Department of Neurological Science, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan
6 https://ror.org/0346ycw92 grid.270560.6 0000 0000 9225 8957 Department of Neurology, Tokyo Saiseikai Central Hospital, Tokyo, Japan
7 https://ror.org/022296476 grid.415613.4 Clinical Research Institute and Department of Cerebrovascular Medicine and Neurology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan
8 https://ror.org/04j4nak57 grid.410843.a 0000 0004 0466 8016 Department of Neurosurgery, Kobe City Medical Center General Hospital, Kobe, Japan
9 grid.519457.b 0000 0004 1782 9798 Headquarters of the Iseikai Medical Corporation, Osaka, Japan
10 https://ror.org/00cs79398 Japan Cardiovascular Research Foundation, Suita, Japan
11 https://ror.org/01v55qb38 grid.410796.d 0000 0004 0378 8307 National Cerebral and Cardiovascular Center, Suita, Japan
12 https://ror.org/055mpn097 grid.511745.3 0000 0004 4655 7437 Sanno Hospital and Sanno Medical Center, Suita, Japan
13 https://ror.org/0346ycw92 grid.270560.6 0000 0000 9225 8957 Tokyo Saiseikai Central Hospital, Tokyo, Japan
14 https://ror.org/00krab219 grid.410821.e 0000 0001 2173 8328 Nippon Medical School, Tokyo, Japan
15 https://ror.org/022296476 grid.415613.4 Kyushu Medical Center, Fukuoka, Japan
16 https://ror.org/04j4nak57 grid.410843.a 0000 0004 0466 8016 Kobe City Medical Center General Hospital, Kobe, Japan
17 https://ror.org/0445phv87 grid.267346.2 0000 0001 2171 836X University of Toyama, Toyama, Japan
18 Senri Chuo Hospital, Toyonaka, Japan
19 https://ror.org/01p7qe739 grid.265061.6 0000 0001 1516 6626 Tokai University School of Medicine, Isehara, Japan
20 grid.519416.e Clinical Study Support, Inc., Nagoya, Japan
21 https://ror.org/05p6jx952 grid.505796.8 0000 0004 7475 2205 Medical Corporation Iseikai, Osaka, Japan
22 https://ror.org/02e16g702 grid.39158.36 0000 0001 2173 7691 Hokkaido University, Sapporo, Japan
23 https://ror.org/014nm9q97 grid.416707.3 0000 0001 0368 1380 Sakai City Medical Center, Sakai, Japan
24 https://ror.org/04cybtr86 grid.411790.a 0000 0000 9613 6383 Iwate Medical University, Morioka, Japan
25 https://ror.org/01529vy56 grid.260026.0 0000 0004 0372 555X Mie University, Tsushima, Japan
26 https://ror.org/01dq60k83 grid.69566.3a 0000 0001 2248 6943 Tohoku University, Sendai, Japan
27 Ichinomiya Nishi Hospital, Ichinomiya, Japan
28 https://ror.org/01s9rzk09 grid.415582.f 0000 0004 1772 323X Kushiro Rosai Hospital, Kushiro, Japan
29 Yuri Kumiai General Hospital, Yuri-Honjo, Japan
30 https://ror.org/014knbk35 grid.488555.1 0000 0004 1771 2637 Tokyo Women’s Medical University Hospital, Tokyo, Japan
31 grid.416457.5 0000 0004 1775 4175 Nitobe Memorial Nakano General Hospital, Tokyo, Japan
32 Doutou neurosurgery, Kitami, Japan
33 Shiroyama Hospital, Habikino, Japan
34 Ube Kohsan Central Hospital, Ube, Japan
35 Kobe Ekisaikai Hospital, Kobe, Japan
36 grid.417547.4 0000 0004 1763 9564 Seirei Memorial Hospital, Hitachi, Japan
37 Kurobe City Hospital, Kurobe, Japan
38 Sakurakai Hospital, Osakasayama, Japan
39 https://ror.org/03nd0nz77 grid.416799.4 NHO Kagoshima Medical Center, Kagoshima, Japan
40 Otaru General Hospital, Otaru, Japan
41 https://ror.org/04f4wg107 grid.412339.e 0000 0001 1172 4459 Saga University Hospital, Saga, Japan
42 Kashiwaba Neurosurgical Hospital, Sapporo, Japan
43 Date Red Cross Hospital, Date, Japan
44 https://ror.org/00m8adh64 grid.440149.c Municipal Tsuruga Hospital, Tsuruga, Japan
45 https://ror.org/00qf0yp70 grid.452874.8 0000 0004 1771 2506 Toho University Omori Medical Center, Tokyo, Japan
46 Daido Hospital, Nagoya, Japan
47 Japanese Red Cross Society Himeji Hospital, Himeji, Japan
48 grid.416532.7 0000 0004 0569 9156 St.Mary’s Hospital, Kurume, Japan
49 https://ror.org/02cq51909 grid.415495.8 Sendai Medical Center, Sendai, Japan
50 grid.416089.2 JCHO Tokyo Yamate Medical Center, Tokyo, Japan
51 Takagi Hospital, Oume, Japan
52 Sumoto Itsuki Hospital, Sumoto, Japan
53 https://ror.org/03nvpm562 grid.412567.3 Shimane University Hospital, Izumo, Japan
54 NHO Asahikawa Meidical Center, Asahikawa, Japan
55 https://ror.org/02gxymm77 grid.416445.6 0000 0004 0616 1702 Nakamura Memorial Hospital, Sapporo, Japan
56 https://ror.org/022296476 grid.415613.4 NHO Kyushu Medical Center, Fukuoka, Japan
57 Japan Red Cross Okayama Hospital, Okayama, Japan
58 https://ror.org/03tpq9v45 0000 0004 4663 7111 Sapporo Shiroishi Memorial Hospital, Sapporo, Japan
59 Asahikawa Rehabilitation Hospital, Asahikawa, Japan
60 https://ror.org/00q1p9b30 grid.508290.6 Southern TOHOKU General Hospital, Koriyama, Japan
61 Saiseikai Yokohamashi Tobu Hospital, Yokohama, Japan
62 https://ror.org/04a2npp96 grid.452851.f Toyama University Hospital, Toyama, Japan
63 Fujieda Heisei Memorial Hospital, Fujieda, Japan
64 https://ror.org/037m3rm63 grid.413965.c 0000 0004 1764 8479 Japanese Red Cross Asahikawa Hospital, Asahikawa, Japan
65 grid.411898.d 0000 0001 0661 2073 Jikei University, Tokyo, Japan
66 Yokohamashintoshi Neurosurgical Hospital, Yokohama, Japan
67 https://ror.org/001yc7927 grid.272264.7 0000 0000 9142 153X Hyogo College of Medicine Hospital, Nishinomiya, Japan
68 https://ror.org/04tprjr04 grid.416320.2 0000 0004 1772 1760 Steel Memorial Yawata Hospital, Kitakyushu, Japan
69 https://ror.org/03cfz7739 grid.415097.e 0000 0004 0642 2597 Kawasaki Hospital, Kurashiki, Japan
70 https://ror.org/00xzbkw82 grid.416798.5 0000 0004 5936 5274 Ohkawara Neurosurgical Hospital, Muroran, Japan
71 Rumoi Central Clinic, Rumoi, Japan
72 https://ror.org/022mjvt30 grid.415148.d Japanese Red Cross Fukushima Hospital, Fukushima, Japan
73 https://ror.org/005xkwy83 grid.416239.b Tokyo Medical Center, Tokyo, Japan
74 https://ror.org/04g0m2d49 grid.411966.d Juntendo University Hospital, Tokyo, Japan
75 https://ror.org/035svbv36 grid.482667.9 Juntendo University Shizuoka Hospital, Shizuoka, Japan
76 https://ror.org/05c06ww48 grid.413779.f 0000 0004 0377 5215 Anjo Kosei Hospital, Anjo, Japan
77 https://ror.org/00hcz6468 grid.417248.c 0000 0004 1764 0768 TOYOTA Memorial Hospital, Toyota, Japan
78 https://ror.org/04fc5qm41 grid.452852.c 0000 0004 0568 8449 Toyota Kosei Hospital, Toyota, Japan
79 Kanazawa Neurosurgical Hospital, Kanazawa, Japan
80 https://ror.org/00qdkc036 grid.414342.4 0000 0004 0377 3391 JCHO Hoshigaoka Medical Center, Hirakata, Japan
81 grid.415645.7 0000 0004 0378 8112 JOHAS Kyushu Rosai Hospital, Kitakyushu, Japan
82 grid.513082.d Imamura General Hospital, Kagoshima, Japan
83 Kita-Harima Medical Center, Ono, Japan
84 Atsuchi Neurosurgical Hospital, Kagoshima, Japan
85 Shunan Memorial Hospital, Kudamatsu, Japan
86 Muroran City General Hospital, Muroran, Japan
87 https://ror.org/0457h8c53 grid.415804.c 0000 0004 1763 9927 Shizuoka General Hospital, Shizuoka, Japan
88 https://ror.org/04ftw3n55 grid.410840.9 0000 0004 0378 7902 Nagoya Medical Center, Nagoya, Japan
89 Suzuka Kaisei Hospital, Suzuka, Japan
90 https://ror.org/03k36hk88 grid.417360.7 0000 0004 1772 4873 Yokkaichi Municipal Hospital, Yokkaichi, Japan
91 https://ror.org/00rxj0v78 grid.471636.1 Mihara Memorial Hospital, Isezaki, Japan
92 grid.410775.0 0000 0004 1762 2623 Japanese Red Cross Osaka Hospital, Osaka, Japan
93 grid.413010.7 0000 0004 5933 3205 Yamaguchi University Hospital, Ube, Japan
94 Yame General Hospital, Yame, Japan
95 https://ror.org/02r946p38 grid.410788.2 0000 0004 1774 4188 Kagoshima City Hospital, Kagoshima, Japan
96 grid.412167.7 0000 0004 0378 6088 Hokkaido Neurosurgical Memorial Hospital, Sapporo, Japan
97 https://ror.org/003z23p70 grid.419094.1 0000 0001 0485 0828 Research Institute for Brain and Blood Vessels-Akita, Akita, Japan
98 Ogaki Tokushukai Hospital, Ogaki, Japan
99 grid.410815.9 0000 0004 0377 3746 JOHAS Chubu Rosai Hospital, Nagoya, Japan
100 https://ror.org/00rsqd019 grid.417244.0 0000 0004 0642 0874 Toyokawa City Hospital, Toyokawa, Japan
101 Japanese Red Cross Ise Hospital, Ise, Japan
102 https://ror.org/045kb1d14 grid.410835.b NHO Kyoto Medical Center, Kyoto, Japan
103 https://ror.org/02srt1z47 grid.414973.c Kansai Electric Power Hospital, Osaka, Japan
104 grid.412398.5 0000 0004 0403 4283 Osaka Medical College Hospital, Takatsuki, Japan
105 https://ror.org/03hsr7383 grid.505833.8 NHO Fukuoka-higashi Medical Center, Koga, Japan
106 https://ror.org/01bk7pz18 grid.417070.5 Tokushima Prefectural Central Hospital, Tokushima, Japan
107 Yamaga Chuo Hospital, Yamaga, Japan
108 NHO Kanagawa Hospital, Kanagawa, Japan
109 Inuyama Chuo General Hospital, Inuyama, Japan
110 https://ror.org/00qmnd673 grid.413111.7 0000 0004 0466 7515 Kindai University Hospital, Osakasayama, Japan
111 https://ror.org/019tepx80 grid.412342.2 0000 0004 0631 9477 Okayama University Hospital, Okayama, Japan
112 Fukuoka Shin Mizumaki Hospital, Mizumaki, Japan
113 Tobata Kyoritsu Hospital, Kitakyushu, Japan
114 Kokura Kinen Hospital, Kitakyushu, Japan
115 https://ror.org/00d3mr981 grid.411556.2 0000 0004 0594 9821 Fukuoka University Hospital, Fukuoka, Japan
116 Iwate Prefectural Iwai Hospital, Ichinoseki, Japan
117 https://ror.org/02szmmq82 grid.411403.3 0000 0004 0631 7850 Akita University Hospital, Akita, Japan
118 https://ror.org/02tyjnv32 grid.430047.4 0000 0004 0640 5017 Saitama Medical University Hospital, Moroyama, Japan
119 https://ror.org/00hswnf74 grid.415801.9 0000 0004 1772 3416 Shizuoka City Shimizu Hospital, Shizuoka, Japan
120 Aoyama General Hospital, Toyokawa, Japan
121 Toyama Red Cross Hospital, Toyama, Japan
122 Nanto Municipal Hospital, Nanto, Japan
123 Kanazawa Nishi Hospital, Kanazawa, Japan
124 Higashiosaka City Medical Center, Higashiosaka, Japan
125 Ishinkai Yao General Hospital, Yao, Japan
126 https://ror.org/00b6s9f18 grid.416803.8 0000 0004 0377 7966 NHO Osaka National Hospital, Osaka, Japan
127 https://ror.org/04w3f9b42 grid.416860.d 0000 0004 0590 7891 Takarazuka City Hospital, Takarazuka, Japan
128 https://ror.org/00w1fsg08 grid.413713.3 0000 0004 0378 7726 Hyogo Prefectural Awaji Medical Center, Sumoto, Japan
129 Onomichi Municipal Hospital, Onomichi, Japan
130 https://ror.org/022mjvt30 grid.415148.d Japanese Red Cross Fukuoka Hospital, Fukuoka, Japan
131 https://ror.org/00hx9k210 grid.415288.2 0000 0004 0377 6808 Sasebo City General Hospital, Sasebo, Japan
132 Obase Hospital, Kanda, Japan
133 Miyakonojo Medical Assocciation Hospital, Miyakonojo, Japan
134 https://ror.org/05450xf19 grid.440184.d Osaka Neurosurgical Hospital, Totonaka, Japan
135 grid.410819.5 0000 0004 0621 5838 JOHAS Yokohama Rosai Hospital, Yokohama, Japan
136 Ogachi Central Hospital, Yuzawa, Japan
137 https://ror.org/03fgbah51 grid.415430.7 0000 0004 1764 884X Kohnan Hospital, Sendai, Japan
138 https://ror.org/03q7y2p06 grid.414493.f 0000 0004 0377 4271 Ibaraki Prefectural Central Hospital, Kasama, Japan
139 grid.518368.1 0000 0004 1776 3514 Itabashi Chuo Medical Center, Tokyo, Japan
140 Shioda Hospital, Katsuura, Japan
141 https://ror.org/03j7khn53 grid.410790.b 0000 0004 0604 5883 Japanese Red Cross Shizuoka Hospital, Shizuoka, Japan
142 https://ror.org/043pqsk20 grid.413410.3 0000 0004 0378 3485 Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan
143 Asuke Hospital, Toyota, Japan
144 Saiseikai Matsusaka General Hospital, Matsusaka, Japan
145 https://ror.org/00xwg5y60 grid.472014.4 0000 0004 5934 2208 Shiga University of Medical Science Hospital, Otsu, Japan
146 Iseikai Hospital, Osaka, Japan
147 Nishiwaki Municipal Hospital, Nishiwaki, Japan
148 https://ror.org/03rq2h425 grid.415748.b 0000 0004 1772 6596 Shimane Prefectural Central Hospital, Izumo, Japan
149 Seiai Rehabilitation Hospital, Fukuioka, Japan
150 https://ror.org/05pet2p92 grid.416298.0 0000 0004 0642 6969 Nishida Hospital, Saiki, Japan
151 https://ror.org/03rvjk961 0000 0004 0642 5624 Urazoe General Hospital, Urazoe, Japan
152 Shirakawa Hospital, Shirakawa, Japan
153 Izumino Hospital, Bouchikai, Kochi, Japan
154 Health Care System JINSEI-KAI Hosogi Hospital, Kochi, Japan
155 https://ror.org/05mhswc23 grid.415580.d 0000 0004 1772 6211 Kushiro City General Hospital, Kushiro, Japan
156 https://ror.org/02e4qbj88 grid.416614.0 0000 0004 0374 0880 National Defense Medical College, Tokorozawa, Japan
157 https://ror.org/01k8ej563 grid.412096.8 0000 0001 0633 2119 Keio University Hospital, Tokyo, Japan
158 https://ror.org/05jk51a88 grid.260969.2 0000 0001 2149 8846 Nihon University School of Medicine, Tokyo, Japan
159 https://ror.org/055m51988 grid.417107.4 0000 0004 1775 2364 Ohkubo Hospital, Tokyo, Japan
160 https://ror.org/01p7qe739 grid.265061.6 0000 0001 1516 6626 Tokai University, Isehara, Japan
161 Nagoya City East Medical Center, Nagoya, Japan
162 https://ror.org/04eht1y76 grid.415442.2 0000 0004 1763 8254 Komaki City Hospital, Komaki, Japan
163 https://ror.org/006qqk144 grid.415124.7 0000 0001 0115 304X Fukui Prefectural Hospital, Fukui, Japan
164 https://ror.org/05n5d3f06 grid.416372.5 0000 0004 1772 6481 Nagahama City Hospital, Nagahama, Japan
165 Uji-Tokushukai Medical Center, Uji, Japan
166 https://ror.org/04xhnr923 grid.413719.9 Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan
167 https://ror.org/03zzjb946 grid.416310.1 0000 0004 1765 2670 Nishinomiya Kyouritsu Neurosurgical Hospital, Nishinomiya, Japan
168 grid.517562.2 0000 0004 1771 9281 Kitakyushu General Hospital, Kitakyushu, Japan
169 grid.415758.a Shin Koga Hospital, Kurume, Japan
170 Sato Daiichi Hospital, Usa, Japan
171 https://ror.org/033sspj46 grid.471800.a Kagawa University Hospital, Miki, Japan
172 Noichi Chuo Hospital, Konan, Japan
173 https://ror.org/05nr3de46 grid.416874.8 0000 0004 0604 7643 JA Onomichi General Hospital, Onomichi, Japan
174 https://ror.org/05m4bwg25 grid.415777.7 0000 0004 1774 7223 Shinonoi General Hospital, Nagano, Japan
175 Iwate Prefectural Kuji Hospital, Kuji, Japan
176 Junwakai Memorial Hospital, Miyazaki, Japan
177 Mominoki Hospital, Kochi, Japan
178 Kyoto Okamoto Memorial Hospital, Kumiyama, Japan
179 https://ror.org/027fjzp74 grid.416691.d 0000 0004 0471 5871 Obihiro-Kosei General Hospital, Obihiro, Japan
180 NHO Hokkaido Medical Center, Sapporo, Japan
181 Hakodate Neurosurgical Hospital, Hakodate, Japan
182 https://ror.org/02e16g702 grid.39158.36 0000 0001 2173 7691 Hokkaido University Graduate School of Medicine, Sapporo, Japan
183 Sendai East Neurosurgical Hospital, Sendai, Japan
184 https://ror.org/05k27ay38 grid.255137.7 0000 0001 0702 8004 Dokkyo Medical University, Mibu, Japan
185 https://ror.org/04ds03q08 grid.415958.4 0000 0004 1771 6769 International Univesity of Healthcare and Welfare Hospital, Nasushiobara, Japan
186 https://ror.org/01gezbc84 grid.414929.3 0000 0004 1763 7921 Japanese Red Cross Medical Center, Tokyo, Japan
187 https://ror.org/05rkz5e28 grid.410813.f 0000 0004 1764 6940 Toranomon Hospital, Tokyo, Japan
188 Kitakurihama Neurosurgery, Yokosuka, Japan
189 https://ror.org/01kqdxr19 grid.411704.7 Gifu University Hospital, Gifu, Japan
190 https://ror.org/03b0x6j22 grid.412181.f 0000 0004 0639 8670 Niigata University Medical & Dental Hospital, Niigata, Japan
191 Kanazawa Municipal Hospital, Kanazawa, Japan
192 https://ror.org/04k6gr834 grid.411217.0 0000 0004 0531 2775 Kyoto University Hospital, Kyoto, Japan
193 https://ror.org/05rnn8t74 grid.412398.5 0000 0004 0403 4283 Osaka University Hospital, Suita, Japan
194 https://ror.org/045ysha14 grid.410814.8 0000 0004 0372 782X Nara Medical University, Kashiwara, Japan
195 https://ror.org/059z11218 grid.415086.e 0000 0001 1014 2000 Kawasaki Medical School, Kurashiki, Japan
196 Saiseikai Yamaguchi Hospital, Yamaguchi, Japan
197 Hakujuji Hospital, Sasebo, Japan
198 Kida Hospital for Neurology, Pulmonology and Internal medicine, Shimabara, Japan
199 https://ror.org/02hg8ry82 grid.459719.7 Japanese Red Cross Kagoshima Hospital, Kagoshima, Japan
200 grid.412772.5 0000 0004 0378 2191 Tokushima University Hospital, Tokushima, Japan
201 Matsusaka Chuo General Hospital, Matsusaka, Japan
202 Hakuai Hospital, Yonago, Japan
203 Yamaguchi Prefectural Grand Medical Center, Hofu, Japan
204 https://ror.org/028fz3b89 grid.412814.a 0000 0004 0619 0044 University of Tsukuba Hospital, Tsukuba, Japan
205 Saiseikai Futsukaichi Hospital, Chikushino, Japan
206 https://ror.org/04hjbmv12 grid.419841.1 0000 0001 0673 6017 Takeda General Hospital, Takeda, Japan
207 https://ror.org/0299dqs22 grid.410854.c 0000 0004 1772 0936 JA Toride Medical Center, Toride, Japan
208 https://ror.org/04at0zw32 grid.415016.7 0000 0000 8869 7826 Jichi Medical University Hospital, Shimotsuke, Japan
209 https://ror.org/04vqzd428 grid.416093.9 Saitama Medical Center, Saitama, Japan
210 https://ror.org/012e6rh19 grid.412781.9 0000 0004 1775 2495 Tokyo Medical University Hospital, Tokyo, Japan
211 https://ror.org/05asn5035 grid.417136.6 0000 0000 9133 7274 NHO Tokyo National Hospital, Tokyo, Japan
212 https://ror.org/00gr1q288 grid.412762.4 0000 0004 1774 0400 Tokai University Hachioji Hospital, Hachioji, Japan
213 NHO Chiba Medical Center, Chiba, Japan
214 https://ror.org/043axf581 grid.412764.2 0000 0004 0372 3116 St. Marianna University School of Medicine Toyoko, Kawasaki, Japan
215 Fujiyoshida Municipal Medical Center, Fujiyoshida, Japan
216 https://ror.org/05vrdt216 grid.413553.5 0000 0004 1772 534X Hamamatsu Medical Center, Hamamatsu, Japan
217 https://ror.org/00z8pd398 grid.471533.7 0000 0004 1773 3964 Hamamatsu University Hospital, Hamamatsu, Japan
218 https://ror.org/01nhcyg40 grid.416417.1 0000 0004 0569 6780 Nagoya Ekisaikai Hospital, Nagoya, Japan
219 Tsushima City Hospital, Tsushima, Japan
220 https://ror.org/02adg5v98 grid.411885.1 0000 0004 0469 6607 Nagoya City University Hospital, Nagoya, Japan
221 https://ror.org/00vzw9736 grid.415024.6 0000 0004 0642 0647 Kariya Toyota General Hospital, Kariya, Japan
222 Kuwana City Medical Center, Kuwana, Japan
223 https://ror.org/04a5eyp42 grid.417236.5 0000 0004 1775 0801 Toyama Rosai Hospital, Toyama, Japan
224 grid.460257.2 0000 0004 1773 9901 JCHO Osaka Hospital, Osaka, Japan
225 NIPPONBASHI Hospital, Osaka, Japan
226 https://ror.org/01jhgy173 grid.415381.a 0000 0004 1771 8844 Kishiwada City Hospital, Kishiwada, Japan
227 https://ror.org/059t16j93 grid.416862.f Takatsuki General Hospital, Takatsuki, Japan
228 https://ror.org/001xjdh50 grid.410783.9 0000 0001 2172 5041 Kansai Medical University Hospital, Hirakata, Japan
229 https://ror.org/005qv5373 grid.412857.d 0000 0004 1763 1087 Wakayama Medical University, Wakayama, Japan
230 Itami Kousei Neurosurgical Hospital, Itami, Japan
231 https://ror.org/038dg9e86 grid.470097.d 0000 0004 0618 7953 Hiroshima University Hospital, Hiroshima, Japan
232 Mazda Hospital, Huchu, Japan
233 Omuta City Hospital, Omuta, Japan
234 JCHO Fukuoka Yutaka Central Hospital, Nogata, Japan
235 Social Insurance Inatsuki Hospital, Kama, Japan
236 https://ror.org/01emnh554 grid.416533.6 Saga-ken Medical Center Koseikan, Saga, Japan
237 https://ror.org/007ge8322 grid.415532.4 0000 0004 0466 8091 Kumamoto City Hospital, Kumamoto, Japan
238 Seidoukai Kakamigahara Rehabilitation Hospital, Kakamigahara, Japan
239 https://ror.org/03q7hxz75 grid.416823.a KKR Tachikawa Hospital, Tachikawa, Japan
240 Saiseikai Hiroshima Hospital, Hiroshima, Japan
241 Uchida Neurosurgery Hospital, Kochi, Japan
242 https://ror.org/04gr92547 grid.488467.1 0000 0004 0569 4072 IUHW Atami Hospital, Atami, Japan
243 https://ror.org/03tjj1227 grid.417324.7 0000 0004 1764 0856 Tsukuba Medical Center Hospital, Tsukuba, Japan
244 https://ror.org/03kjjhe36 grid.410818.4 0000 0001 0720 6587 Tokyo Women’s Medical University Medical Center East, Tokyo, Japan
245 Tomakomai City Hospital, Tomakomai, Japan
246 https://ror.org/0498kr054 grid.415261.5 0000 0004 0377 292X Sapporo City General Hospital, Sapporo, Japan
247 https://ror.org/025h9kw94 grid.252427.4 0000 0000 8638 2724 Asahikawa Medical University, Asahikawa, Japan
248 Kyoujinkai Taisetsu Hospital, Asahikawa, Japan
249 https://ror.org/05r7vy677 grid.452447.4 0000 0004 0595 9093 Hokuto Hospital, Obihiro, Japan
250 Mito Kyodo General Hospital, Mito, Japan
251 https://ror.org/004t34t94 grid.410824.b 0000 0004 1764 0813 Tsuchiura Kyodo General Hospital, Tsuchiura, Japan
252 https://ror.org/057hbdz28 grid.417054.3 Tochigi Medical Center, Tochigi, Japan
253 https://ror.org/0406qcr55 grid.459660.8 Haga Red Cross Hospital, Haga, Japan
254 Saiyu Soka Hospital, Soka, Japan
255 https://ror.org/02qa5hr50 grid.415980.1 0000 0004 1764 753X Mitsui Memorial Hospital, Tokyo, Japan
256 https://ror.org/04eqd2f30 grid.415479.a 0000 0001 0561 8609 Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hosptal, Tokyo, Japan
257 https://ror.org/051k3eh31 grid.265073.5 0000 0001 1014 9130 Tokyo Medical and Dental University Medical Hospital, Tokyo, Japan
258 https://ror.org/00mre2126 grid.470115.6 Toho University Ohashi Medical Center, Tokyo, Japan
259 Mishuku Hospital, Tokyo, Japan
260 Kimitsu Chuo Hospital, Kimitsu, Japan
261 https://ror.org/038s3xg41 Tokyo Women’s Medical University Yachiyo Medical Center Yachiyo, Yachiyo, Japan
262 https://ror.org/03xrts777 grid.415810.9 0000 0004 0466 9158 Shizuoka Medical Center, Shizuoka, Japan
263 https://ror.org/051mfb226 grid.460103.0 0000 0004 1771 7518 Tokai Central Hospital, Kakamigahara, Japan
264 Kizawa Memorial Hospital, Minokamo, Japan
265 grid.518268.0 0000 0004 0568 8545 Nagoya City West Medical Center, Nagoya, Japan
266 grid.414470.2 0000 0004 0377 9435 JCHO Chukyo Hospital, Nagoya, Japan
267 NHO Higashinagoya National Hospital, Nagoya, Japan
268 https://ror.org/01z9vrt66 grid.413724.7 Okazaki City Hospital, Okazak, Japan
269 Toyohashi Medical Center, Toyohashi, Japan
270 Midori Municipal Hospital, Nagoya, Japan
271 Japanese Red Cross Maebashi Hospital, Maebashi, Japan
272 https://ror.org/05kq1z994 grid.411887.3 0000 0004 0595 7039 Gunma University Hospital, Maebashi, Japan
273 https://ror.org/02mssnc42 grid.416378.f 0000 0004 0377 6592 Nagano Municipal Hospital, Nagano, Japan
274 https://ror.org/004cah429 grid.417235.6 0000 0001 0498 6004 Toyama Prefectural Central Hospital, Toyama, Japan
275 https://ror.org/03t7c1217 grid.440095.c 0000 0004 0640 9245 Keiju Medical Center, Nanao, Japan
276 https://ror.org/021f4qx93 grid.416605.0 0000 0004 0595 3863 Noto General Hospital, Nanao, Japan
277 https://ror.org/00xsdn005 grid.412002.5 0000 0004 0615 9100 Kanazawa University Hospital, Kanazawa, Japan
278 https://ror.org/03q129k63 grid.510345.6 0000 0004 6004 9914 Kanazawa Medical University Hospital, Uchinada, Japan
279 https://ror.org/0460s9920 grid.415604.2 0000 0004 1763 8262 Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan
280 Maizuru Medical Center, Maizuru, Japan
281 Kyoto Chubu Medical Center, Nantan, Japan
282 https://ror.org/02cv4ah81 grid.414830.a 0000 0000 9573 4170 Ishikawa Prefectural Central Hospital, Kanazawa, Japan
283 Rinku General Hospital Medical Center, Izumisano, Japan
284 https://ror.org/02k3rdd90 grid.471868.4 0000 0004 0595 994X Osaka Minami Medical Center, Kawachinagano, Japan
285 https://ror.org/03ycmew18 grid.416591.e 0000 0004 0595 7741 Matsushita Memorial Hospital, Moriguchi, Japan
286 https://ror.org/03zsbd109 grid.413665.3 0000 0004 0380 2762 Hanwa Memorial Hospital, Osaka, Japan
287 https://ror.org/024ran220 grid.414976.9 0000 0004 0546 3696 Kansai Rosai Hospital, Amagasaki, Japan
288 https://ror.org/01h48bs12 grid.414175.2 0000 0004 1774 3177 Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan
289 https://ror.org/00vjxjf30 grid.470127.7 0000 0004 1760 3449 Kurume University Hospital, Kurume, Japan
290 https://ror.org/04zkc6t29 grid.418046.f 0000 0000 9611 5902 Fukuoka Dental College Medical & Dental Hospital, Fukuoka, Japan
291 https://ror.org/00ex2fc97 grid.411248.a 0000 0004 0404 8415 Kyushu University Hospital, Fukuoka, Japan
292 https://ror.org/02vgs9327 grid.411152.2 0000 0004 0407 1295 Kumamoto University Hospital, Kumamoto, Japan
293 Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Japan
294 https://ror.org/0273vqz67 grid.413882.4 Tokushima Prefecture Naruto Hospital, Naruto, Japan
295 https://ror.org/02hg8ry82 grid.459719.7 Japanese Red Cross Kochi Hospital, Kochi, Japan
296 grid.415887.7 0000 0004 1769 1768 Kochi Medical School, Kochi, Japan
297 Tannan Regional Medical Center, Sabae, Japan
298 grid.413724.7 0000 0004 0378 6598 Sera Central Hospital, Sera, Japan
299 https://ror.org/057g1dn72 grid.415530.6 0000 0004 0407 1623 Kumamoto Central Hospital, Kumamoto, Japan
300 Nishitokyo Central General Hospital, Nishitokyo, Japan
301 https://ror.org/04rzagz55 grid.415841.d Tano Hospital, Tano, Japan
302 https://ror.org/03w4vm615 grid.440096.f Kitakasiwa Rehabilitation General Hospital, Kashiwa, Japan
303 Tosa Municipal Hospital, Tosa, Japan
304 grid.513200.5 Seirei Hamamatsu City Rehabilitation Hospital Hamamatsu, Hamamatsu, Japan
305 Fukuoka Rehabilitation Hospital, Fukuoka, Japan
306 Yokohama City Minato Red Cross Hospital, Yokohama, Japan
9 7 2024
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© The Author(s) 2024
2024
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We determined the associations of follow-up blood pressure (BP) after stroke as a time-dependent covariate with the risk of subsequent ischemic stroke, as well as those of BP levels with the difference in the impact of long-term clopidogrel or aspirin monotherapy versus additional cilostazol medication on secondary stroke prevention. In a sub-analysis of a randomized controlled trial (CSPS.com), patients between 8 and 180 days after stroke onset were randomly assigned to receive aspirin or clopidogrel alone, or a combination of cilostazol with aspirin or clopidogrel. The percent changes, differences, and raw values of follow-up BP were examined. The primary efficacy outcome was the first recurrence of ischemic stroke. In a total of 1657 patients (69.5 ± 9.3 years, female 29.1%) with median 1.5-year follow-up, ischemic stroke recurred in 74 patients. The adjusted hazard ratio for ischemic stroke of a 10% systolic BP (SBP) increase from baseline was 1.19 (95% CI 1.03–1.36), that of a 10 mmHg SBP increase was 1.14 (1.03–1.28), and that of SBP as the raw value with the baseline SBP as a fixed (time-independent) covariate was 1.14 (1.00–1.31). Such significant associations were not observed in diastolic BP-derived variables. The estimated adjusted hazard ratio curves for the outcome showed the benefit of dual therapy over a wide SBP range between ≈120 and ≈165 mmHg uniformly. Lower long-term SBP levels after ischemic stroke were associated with a lower risk of subsequent ischemic events. The efficacy of dual antiplatelet therapy including cilostazol for secondary stroke prevention was evident over a wide SBP range.

Keywords

Cerebral infarction
Hypertension
Stroke prevention
Cilostazol
Antiplatelet therapy
issue-copyright-statement© The Japanese Society of Hypertension 2024
==== Body
pmcIntroduction

Long-term treatment with cilostazol, a phosphodiesterase 3 inhibitor, coupled with aspirin or clopidogrel was shown to halve the risk of recurrent ischemic stroke and have a similar risk of severe or life-threatening bleeding compared to aspirin or clopidogrel alone in patients at high risk for recurrent noncardioembolic ischemic stroke in a randomized, controlled trial, the Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com) [1]. Cilostazol is known to have a lower risk of bleeding than the other antiplatelet agents [2, 3], and the result of the safety outcome was within the expectations of the trial investigators. In contrast, the strong efficacy of the dual antiplatelet therapy (DAPT) with half the risk of recurrent ischemic stroke exceeded our assumptions to some extent. The possible clinical conditions causing such clear efficacy need clarification.

The post-stroke blood pressure (BP) level is predictive of recurrent stroke risk [4–7]. Several guidelines recommend intensive BP lowering for chronic stroke to prevent recurrent stroke [8–10]. Appropriate risk-factor modification would strengthen the preventive power of antithrombotic pharmacotherapy. Thus, BP control might have affected the main results of CSPS.com.

The primary research objective of the present sub-study was to determine the associations of long-term BP after stroke as a time-dependent covariate with the risk of subsequent ischemic events, including recurrent ischemic stroke, in the CSPS.com cohort. The secondary objective was to clarify the associations of follow-up BP level with the therapeutic superiority of cilostazol-based DAPT to monotherapy

Point of view Clinical relevance

Lower long-term systolic blood pressure levels during single antiplatelet therapy or cilostazol-based dual antiplatelet therapy in noncardioembolic ischemic stroke patients were associated with a lower risk of subsequent ischemic events. Cilostazol-based dual antiplatelet therapy was superior to single antiplatelet therapy in secondary stroke prevention over a wide systolic blood pressure range.

Future direction

The positive results of promising trial treatments would be more clearly identified when the vascular risk factors of the participants, including hypertension, are appropriately controlled.

Consideration for the Asian population

Secondary stroke prevention using cilostazol, that is popular in Asia, can be more effective by optimal blood pressure control.

Methods

Study design and setting

CSPS.com was a multicenter, randomized, open-label, parallel-group trial, involving participants from 292 sites across Japan registered from December 2013 through March 2017. The trial protocol, statistical analysis plan, design, and main and major post hoc results of CSPS.com have been reported previously [1, 11–15]. CSPS.com was registered in ClinicalTrials.gov NCT01995370 and the University Hospital Medical Information Network clinical trial registry in Japan UMIN 000012180 and approved by the ethics committee at each participating site. All patients gave written, informed consent before randomization. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.

Participants

Eligible patients were between 20 and 85 years of age who had a non-cardioembolic ischemic stroke identified on magnetic resonance imaging between 8 and 180 days before the start of the protocol treatment and were taking either aspirin or clopidogrel alone as antiplatelet therapy when providing informed consent. The patients were required to meet at least one of the following three criteria indicating a high risk for stroke recurrence: (a) ≥ 50% stenosis of a major intracranial artery; (b) ≥ 50% stenosis of an extracranial artery; and (c) two or more of the following risk factors (age ≥ 65 years, hypertension, diabetes mellitus, chronic kidney disease, peripheral arterial disease, history of ischemic stroke other than the qualifying one for this trial, history of ischemic heart disease, and current smoking). Additional information regarding the inclusion and exclusion criteria is provided elsewhere [1, 11]. For example, patients with emboligenic heart disease were excluded from the study. In this sub-study, patients with consistent BP data at baseline and at least once during the follow-up period were included.

Patients were randomly assigned in a 1:1 ratio to receive either monotherapy with aspirin (81 or 100 mg) or clopidogrel (50 or 75 mg) once daily or dual therapy with cilostazol (100 mg, twice daily, the recommended dose for stroke prevention in Japan) and either aspirin (81 or 100 mg) or clopidogrel (50 or 75 mg), once daily. Trial medication was continued for half a year or longer, for a maximum of 3.5 years. Changes in these three antiplatelet medications were not permitted after informed consent was obtained. Systolic and diastolic BPs (SBP, DBP) were measured in a sitting position at follow-up visits 1, 3, and 6 months later and every 6 months thereafter.

Outcomes

The primary efficacy outcome was the first recurrence of ischemic stroke. The secondary efficacy outcome was the first occurrence of a composite of stroke, myocardial infarction, and vascular death. The safety outcome was the first occurrence of severe or life-threatening bleeding as defined in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries classification [16]. These events have been defined elsewhere [1, 11].

Statistical analysis

Continuous data are reported as medians (interquartile range) or means ± standard deviation, and categorical data are presented as numbers (%). In principle, all BP data were treated as time-dependent covariates. The variables “percent change” and “difference” were derived as the ratio of BP values to baseline BP value and the difference from baseline at each time point, respectively. Note that these variables are still time-dependent covariates.

For example, consider a patient with a baseline BP value of 140 mmHg and follow-up BP values of 150, 140, and 130 mmHg. In the “raw value” analysis, the follow-up values of 150, 140, and 130 mmHg are directly used, with the baseline value of 140 mmHg serving as a fixed (time-independent) adjustment variable. In the “difference” analysis, the changes from the baseline are calculated as 10, 0, and −10 mmHg, respectively. For the “percent change” analysis, the converted values are computed as follows: (150/140)*100, (140/140)*100 and (130/140)*100, yielding percentages of 107%, 100%, and 93% respectively.

A Cox proportional hazards model was used to calculate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of the percent changes, differences, and raw values of BP. For the analysis of raw values, follow-up BP values were treated as time-dependent covariates, while baseline BP value was included as time-independent covariate. HRs are represented as per 10% for percent change and per 10 mmHg for difference and raw value. Multivariable adjustment was performed using sex, age, and variables that were proven to affect the outcomes of CSPS.com, including assigned treatment, antiplatelet agents at randomization, intracranial artery stenosis, and the timing of starting trial treatment [11–14]. The preventive effect of dual therapy relative to monotherapy on outcomes considering its interaction with BP levels was visualized using a generalized additive model. In brief, the hazard function was estimated through a generalized additive model of Poisson regression, which allows for flexible modeling of complex nonlinear relationships, and calculated aHR and 95% CI values were plotted against BP. All statistical analyses were performed using R version 4.2.0 (R Core Team 2022). Fitting the generalized additive model was done with pammtools and mgcv R packages.

Results

Of the total 1879 randomized patients, 222 were excluded from the present study due to lack of sufficient and consistent data on BP (or unclear description between the timing of events onset and that of follow-up BP measurement), and 1657 were finally studied; 790 were assigned to dual therapy and 867 to monotherapy (Fig. 1). Table 1 shows the patients’ baseline characteristics. Overall, average BP was 139.0 ± 19.7/79.0 ± 13.4 mmHg at baseline and 136.1 ± 12.6/77.0 ± 9.2 mmHg at mean follow-up. The median duration of follow-up was 1.5 years overall (interquartile range 1.0–2.3 years), resulting in 2700.9 person-years of follow-up. Ischemic stroke occurred in 74 patients, the composite of stroke, myocardial infarction, and vascular death occurred in 92 patients, and severe or life-threatening bleeding occurred in 18 patients. All severe or life-threatening bleeding events were symptomatic intracranial hemorrhages. Figure 2 shows BP levels at each visit. The median number of BP measurements per patient was 5 (interquartile range: 4–7).Fig. 1 Trial profile

Table 1 Patients’ baseline characteristics and blood pressure levels

	Total	Monotherapy	Dual therapy	
N	1,657	867	790	
Age, y	69.5 ± 9.3	69.6 ± 9.2	69.5 ± 9.3	
Female sex	482 (29.1)	237 (29.3)	245 (31.0)	
Asian a	1,657 (100)	867 (100)	790 (100)	
Body mass index, kg/m2	23.8 ± 3.5	23.7 ± 3.4	23.9 ± 3.6	
Medical history	
 Hypertension	1,419 (85.6)	740 (85.4)	679 (85.9)	
 Dyslipidemia	935 (56.4)	501 (57.8)	434 (54.9)	
 Diabetes mellitus	632 (38.1)	331 (38.2)	301 (38.1)	
 Chronic kidney disease	100 (6.0)	46 (5.3)	54 (6.8)	
 Peripheral arterial disease	46 (2.8)	21 (2.4)	25 (3.2)	
 History of ischemic strokeb	246 (14.8)	136 (15.7)	110 (13.9)	
 History of ischemic heart disease	87 (5.3)	44 (5.1)	43 (5.4)	
Current smoking	476 (28.7)	254 (29.3)	222 (28.1)	
Intracranial artery stenosis	493 (29.8)	256 (29.5)	237 (30.0)	
Extracranial artery stenosis	236 (14.2)	131 (15.1)	105 (13.3)	
Antihypertensive medication	
 Calcium channel blockers	817 (49.3)	427 (49.3)	390 (49.4)	
 Angiotensin-converting enzyme inhibitors/angiotensinb receptor blockers	815 (49.2)	425 (49.0)	390 (49.4)	
 β-blockers, α/β-blockers	93 (5.6)	43 (5.0)	50 (6.3)	
 Diuretics	79 (4.8)	46 (5.3)	33 (4.2)	
 Others	37 (2.2)	21 (2.4)	16 (2.0)	
Clopidogrel at randomization	973 (58.7)	518 (59.7)	455 (57.6)	
Stroke subtype	
 Lacunar	825 (49.8)	427 (49.3)	398 (50.4)	
 Atherothrombotic	717 (43.3)	375 (43.3)	342 (43.3)	
Infarct location	
 Supratentorial (purely)	1,243 (75.0)	649 (74.9)	594 (75.2)	
 Infratentorial (purely)	394 (23.8)	204 (23.5)	190 (24.1)	
 Both	20 (1.2)	14 (1.6)	6 (0.8)	
Time to randomization after index event, days	27 [14–63]	26 [14-62.5]	27 [14–63]	
Blood pressure levels, mmHg	
 Baseline, systolic	139.0 ± 19.7	139.9 ± 20.6	138.1 ± 18.7	
 Baseline, diastolic	79.0 ± 13.4	79.5 ± 13.4	78.5 ± 13.2	
 Mean follow-up, systolic	136.1 ± 12.6	137.1 ± 12.6	135.1 ± 12.6	
 Mean follow-up, diastolic	77.0 ± 9.2	77.5 ± 9.2	76.5 ± 9.3	
Data are numbers (%), medians [interquartile range], or means ± SD

aSelf-reported

bExcept the qualifying one for this trial

Fig. 2 Blood pressure at each visit

Primary outcome of ischemic stroke

Table 2 shows the associations of BP-derived variables with recurrent ischemic stroke. When BP was treated as a time-dependent covariate, the aHR of a 10% SBP increase from baseline was 1.19 (95% CI: 1.03–1.36), and that of a 10 mmHg SBP increase from baseline was 1.14 (1.03–1.28). With the baseline SBP as a fixed (time-independent) covariate, the aHR of SBP was 1.14 (1.00–1.31) per 10 mmHg. On the other hand, no DBP-derived variables showed significant associations with the outcome.Table 2 Associations of variables derived from blood pressure with outcomes

	Crude	Adjusted	
Hazard ratio (95% confidence interval)	P	Hazard ratio (95% confidence interval)	P	
Ischemic stroke	
Systolic	Percent change	1.21 (1.05–1.39)	< 0.01	1.19 (1.03–1.36)	0.02	
	Difference	1.16 (1.04–1.29)	< 0.01	1.14 (1.03–1.28)	0.01	
	Raw value	1.17 (1.02–1.35)	0.02	1.14 (1.00–1.31)	0.06	
Diastolic	Percent change	1.07 (0.95–1.21)	0.26	1.07 (0.94–1.21)	0.31	
	Difference	1.11 (0.94–1.32)	0.21	1.10 (0.93–1.30)	0.26	
	Raw value	1.06 (0.86–1.31)	0.57	1.08 (0.87–1.33)	0.50	
Composite events	
Systolic	Percent change	1.20 (1.06–1.36)	< 0.01	1.18 (1.04–1.34)	< 0.01	
	Difference	1.16 (1.05–1.28)	< 0.005	1.15 (1.04–1.26)	< 0.01	
	Raw value	1.17 (1.03–1.33)	0.01	1.15 (1.01–1.30)	0.03	
Diastolic	Percent change	1.09 (0.98–1.22)	0.12	1.09 (0.98–1.22)	0.13	
	Difference	1.14 (0.98 – 1.32)	0.10	1.13 (0.97–1.32)	0.11	
	Raw value	1.14 (0.94–1.37)	0.19	1.14 (0.95–1.38)	0.17	
Intracranial hemorrhage	
Systolic	Percent change	1.11 (0.82 –1.50)	0.51	-	-	
	Difference	1.09 (0.87–1.37)	0.44	-	-	
	Raw value	1.10 (0.82–1.46)	0.53	-	-	
Diastolic	Percent change	0.91 (0.68–1.20)	0.50	-	-	
	Difference	0.91 (0.64–1.28)	0.58	-	-	
	Raw value	1.01 (0.66–1.57)	0.95	-	-	
Cox proportional hazards model

Per 10% for “percent change” and per 10 mmHg for “difference” and “raw value”

Baseline blood pressure value was included as time-independent covariate for the analysis of “raw value”.

Adjusted by sex, age, assigned treatment, antiplatelet agents at randomization, intracranial artery stenosis, the time of starting trial treatment

Variables of diastolic blood pressure are analyzed using 1655 patients due to the lack of baseline diastolic blood pressure values for 2 patients

Adjusted analysis of intracranial hemorrhage was not performed due to the small event number

Table 3 shows the associations of SBP-derived variables with recurrent ischemic stroke in subgroups by assigned antiplatelet therapy and those by the antiplatelet agent at randomization. Similar numerical data with those in the overall patients were obtained in all subgroups, with significant associations of the percent change and the difference in SBP in the monotherapy subgroup and the clopidogrel subgroup. Note that the event rate was somewhat higher in patients taking clopidogrel (50/973) than those taking aspirin (24/684). The difference was probably because the physicians preferred clopidogrel to aspirin for patients with history of ischemic stroke and those with intra-/extracranial artery stenosis, that showed clearly higher risk of recurrent ischemic stroke [1, 12].Table 3 Associations of variables derived from systolic blood pressure with ischemic stroke

	Crude	Adjusted	
Hazard ratio (95% confidence interval)	P	Hazard ratio (95% confidence interval)	P	
Assigned to receive monotherapy (867 patients, 54 events of ischemic stroke)	
Percent change	1.20 (1.02–1.42)	0.03	1.19 (1.00–1.40)	0.04	
Difference	1.15 (1.02–1.31)	0.03	1.14 (1.00–1.30)	0.04	
Raw value	1.17 (0.99–1.38)	0.06	1.16 (0.98–1.36)	0.08	
Assigned to receive dual therapy (790 patients, 20 events)	
Percent change	1.21 (0.92–1.59)	0.16	1.19 (0.92–1.54)	0.19	
Difference	1.17 (0.94–1.44)	0.16	1.16 (0.94–1.42)	0.16	
Raw value	1.13 (0.87–1.48)	0.35	1.11 (0.85–1.45)	0.46	
Clopidogrel at randomization (973 patients, 50 events)	
Percent change	1.24 (1.05 –1.46)	0.01	1.22 (1.03–1.44)	0.02	
Difference	1.18 (1.04–1.35)	0.01	1.17 (1.02–1.34)	0.02	
Raw value	1.19 (1.00 – 1.41)	0.05	1.16 (0.98–1.38)	0.09	
Aspirin at randomization (684 patients, 24 events)	
Percent change	1.13 (0.87–1.46)	0.35	1.13 (0.88–1.46)	0.34	
Difference	1.10 (0.91–1.33)	0.33	1.10 (0.91–1.33)	0.31	
Raw value	1.13 (0.90–1.43)	0.29	1.10 (0.87–1.38)	0.42	
Cox proportional hazards model

Per 10% for “percent change” and per 10 mmHg for “difference” and “raw value”

Baseline blood pressure value was included as time-independent covariate for the analysis of “raw value”

Adjusted by sex, age, assigned treatment, antiplatelet agents at randomization, intracranial artery stenosis, the time of starting trial treatment

Fig. 3A shows the aHR of dual therapy relative to monotherapy plotted against SBP. The estimated aHR curve for the outcome showed the benefit of dual therapy over a wide SBP range from ≈120 mmHg to ≈165 mmHg uniformly, with the greatest risk reduction when SBP was ≈150 mmHg.Fig. 3 Hazard ratio curve of the dual therapy group versus the monotherapy group. A Ischemic stroke, B a composite of stroke, myocardial infarction, and vascular death. Adjusted by sex, age, assigned treatment, antiplatelet agents at randomization, intracranial artery stenosis, and the time of starting trial treatment

Other outcomes

The aHR for the secondary outcome of composite events of a 10% and a 10 mmHg SBP increase from baseline was 1.18 (1.04–1.34) and 1.15 (1.04–1.26), respectively (Table 2). With the baseline SBP as a fixed covariate, the aHR of SBP was 1.15 (1.01–1.30). No DBP-derived variables showed significant associations with the outcome. The estimated aHR curve for the outcome showed the benefit of dual therapy relative to monotherapy over a wide SBP range from ≈120 mmHg to ≈160 mmHg uniformly (Fig. 3B).

No SBP-derived or DBP-derived variables showed significant associations with the safety outcome of severe or life-threatening bleeding (Table 2).

Discussion

This was a sub-analysis of the randomized CSPS.com trial to determine the effects of follow-up BP parameters as a time-dependent covariate on recurrent stroke risk. The first major finding of this study was that both ischemic stroke and composite cardiovascular events increased significantly as the variables derived from SBP increased, but not as the DBP-derived variables increased. The second major finding was that the benefit of dual therapy was uniformly observed over a wide SBP range, with the greatest risk reduction when SBP was ≈150 mmHg.

Cilostazol inhibits phosphodiesterase activity and suppresses cyclic adenosine monophosphate (cAMP) degradation, increases intracellular cAMP concentrations, activates the cAMP-dependent protein kinase A, and inhibits platelet aggregation [2, 3, 17]. Both cilostazol monotherapy and cilostazol-based long-term DAPT were recommended as the first-line antiplatelet agents for secondary stroke prevention in Japan [10] and several Asian countries based on the results of CSPS2 and CSPS.com [1, 18]. Cilostazol monotherapy was weakly recommended for stroke or transient ischemic attack attributable to moderate to severe intracranial artery stenosis in the United States of America [19]. Cilostazol has pleiotropic effects other than inhibiting platelet aggregation, such as a vasodilatory effect on smooth muscle cells via the increase in intracellular cAMP concentrations [20]. The vasodilation may cause mild BP lowering; a 2 to 4 mmHg lower SBP level was observed during cilostazol-based DAPT than during monotherapy throughout the follow-up period in the overall CSPS.com cohort [1].

Lower percent changes, differences, and raw values of SBP were associated with lower risks of ischemic stroke. This “the lower, the better” phenomenon in stroke survivors was common to the results of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) [4, 7], but different from those of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study, where the risk was higher for patients with SBP < 120 mmHg [21]. Since patients within 120 days after stroke were enrolled in PRoFESS and those within 5 years were enrolled in PROGRESS, failure of cerebral autoregulation during subacute stroke might have affected the results more in PRoFESS. In addition, the Secondary Prevention of Small Subcortical Strokes (SPS3) and Recurrent Stroke Prevention Clinical Outcome (RESPECT) trials showed a significant risk reduction of intracerebral hemorrhage in patients with a target SBP < 130 mm Hg or < 120 mmHg compared with a higher target but did not show the significant reduction of ischemic stroke [22–24]. A reason for the differences in results between these trials and ours is that in our study, SBP was treated as a time-dependent covariate, and our findings were not confined to a specific SBP range, such as around 130 mmHg. Additionally, the discrepancies may be due to the fact that patients’ SBP data were treated consecutively in our study, without grouping patients based on a specific SBP value. Another possible explanation was the higher percentage of patients assigned to dual therapy in the lower mean SBP population, since dual therapy excessively lowered SBP by 2 to 4 mmHg.

In contrast, the DBP-derived variables were not associated with the outcome. The J-shaped relationship between DBP and adverse cardiovascular outcomes including stroke with DBP nadir around 70–80 mmHg has been repeatedly reported [25–30]. The J-shaped curve might be due to the positive association of low DBP and evident or subclinical myocardial damage [31] and due to the high frequency of isolated systolic hypertension with an increased pulse pressure in the low DBP cohort [30, 32]. However, the presence of a J-shaped relationship between DBP and the risk of stroke alone was somewhat unclear [25, 26, 31], presumably partly due to differences in mechanisms between cerebral and coronary autoregulation [33].

The benefit of dual therapy was observed over a wide SBP range. This suggests a simple message: the positive results of promising trial treatments can be more clearly identified when the vascular risk factors of the participants are appropriately controlled. Patients with good BP management might also be mindful of their general health condition and modify risk factors other than hypertension, and thus the impact of dual therapy might be clearer in such patients.

Visit-to-visit SBP variability was reported to be firmly associated with stroke outcomes and subsequent events [34–36]. Since the number of visits in the present patients was small (median 5), the association between BP variability and outcomes was not examined.

The strength of this study was that BP was treated as a time-dependent covariate and evaluated over time. For example, summarizing a patient’s BP values into a single statistic, e.g., mean BP, and treating it as a time-independent covariate would be equivalent to assuming that the patient’s BP is constant at the mean BP level throughout the follow-up period. However, this may miss the more detailed relationship between BP and events. The present method takes into account the fact that a patient’s BP is not constant and can change during the follow-up period, allowing for a more detailed and relevant assessment.

The limitations of the present study include the post hoc nature of the analysis, meaning that the associations identified might not necessarily imply causality. Severe stroke could cause both subsequent events and higher BP values. Second, visits for BP measurement were not frequent for patients developing events early after enrollment. Third, the present sample size seemed to be small for appropriate subgroup analyses, although numerical results indicated a tendency for a positive association between SBP and subsequent ischemic stroke regardless of assigned antiplatelet therapy and the antiplatelet agent at randomization. Fourth, the number of severe or life-threatening bleeding events (intracranial hemorrhage) was too small to perform meaningful statistical analysis. Hemorrhagic stroke generally shows a stronger association with follow-up BP than ischemic stroke [7, 37, 38].

Perspective of Asia

In Asia, cilostazol is widely used for secondary stroke prevention. DAPT including cilostazol decreased the risk of recurrent ischemic stroke compared to aspirin or clopidogrel monotherapy in patients with lacunar stroke and those with intracranial arterial stenosis [15, 39]; both of these pathologies are common to Asian population. BP lowering after stroke is an optimal strategy to strengthen the power of cilostazol-based DAPT in Asian stroke patients.

Conclusion

The present sub-study renewed our understanding of the importance of intensive BP lowering for secondary stroke prevention and also suggested the necessity of appropriate BP control for success in stroke clinical trials.

Supplementary information

Supplementary Materials

Supplementary information

Supplementary information

The online version contains supplementary material available at 10.1038/s41440-024-01742-3.

for the CSPS.com Trial Investigators

Study sponsor Takenori Yamaguchi10

Principal Investigator Takenori Yamaguchi11

Steering Committee Kazunori Toyoda11, Shinichiro Uchiyama12, Haruhiko Hoshino13, Kazumi Kimura14, Yasushi Okada15, Nobuyuki Sakai16, Kotaro Tanaka17

Protocol Authoring Committee Kazunori Toyoda11, Haruhiko Hoshino13, Kazumi Kimura14

Independent Data Monitoring Committee Hiroaki Naritomi18, Shinya Goto19, Tatsuya Isomura20

Event Evaluation Committee Kazuo Minematsu21, Kiyohiro Houkin22, Masayasu Matsumoto23, Yasuo Terayama24, Hidekazu Tomimoto25, Teiji Tominaga26, Satoshi Yasuda11

Statistical Analysis Committee Hideki Orikasa17, Naoko Kumagai17

Publication Committee Takenori Yamaguchi11, Haruhiko Hoshino13, Kazumi Kimura14, Hideki Orikasa17, Kazunori Toyoda11, Shinichiro Uchiyama12

Clinical Sites and Site Investigators, by Enrolment Akihiro Miyasaki27, Masanori Isobe28, Yoshitaka Suda29, Kazuo Kitagawa30, Kazuyuki Nagatsuka11, Shuta Toru31, Makoto Katsuno32, Nobuyuki Sakai16, Kenichi Murao33, Norio Ikeda34, Kazuya Nakashima35, Shinichi Okabe36, Masanori Kurimoto37, Ikuo Ihara38, Hideki Matsuoka39, Shoji Mabuchi40, Hideo Hara41, Teruyuki Yoshimoto42, Takeshi Matsuoka43, Yoshikazu Arai44, Yasuyuki Iwasaki45, Manabu Hattori46, Kazuya Takahashi47, Yoshihisa Fukushima48, Masayuki Ezura49, Yasuaki Takeda50, Kimihiro Nakahara51, Masahiro Okada52, Shingo Mitaki53, Kosuke Yoshida54, Kenji Kamiyama55, Takahiro Kuwashiro56, Takeshi Iwanaga57, Akira Takahashi58, Junichi Maruyama59, Teiji Yamamoto60, Michiyuki Maruyama61, Yoshiharu Taguchi62, Kazuhiro Hashidume63, Katsumi Takizawa64, Yasuyuki Iguchi65, Kazuhito Kitajima66, Shinichi Yoshimura67, Syuji Arakawa68, Takeshi Inoue69, Hiroyuki Yamaguchi70, Susumu Suzuki71, Yasuo Terayama24, Youichi Watanabe72, Daisuke Yasutomi73, Ryota Tanaka74, Takuji Yamamoto75, Tetsuo Ando76, Yasuhiro Ito77, Naoki Hattori78, Nobutaka Yamamoto79, Tsutomu Takahashi80, Syoji Arihiro81, Naoaki Kanda82, Hirotoshi Hamaguchi83, Junji Kasuya84, Masaru Honda85, Hiroshi Oyama86, Hidefumi Yoshida87, Satoshi Okuda88, Keita Matsuura89, Toshiaki Ieda90, Takao Kanzawa91, Makio Takahashi92, Hirokazu Sadahiro93, Takahiro Miyahara94, Masahiko Yamada95, Takeshi Aoki96, Taizen Nakase97, Katsuhiko Hayashi98, Toshitaka Umemura99, Yasukuni Tsugu100, Fumitaka Miya101, Ryo Otani102, Keiichi Yamada103, Yoshinaga Kajimoto104, Hiroshi Nakane105, Kiyohito Shinno106, Akio Hara107, Ryoichi Saito108, Yuzo Araki109, Toshiho Otsuki110, Koji Abe111, Shigenari Kin112, Takehisa Tsuji113, Shota Sakai114, Yoshio Tsuboi115, Atsushi Kawamorita116, Hiroaki Shimizu117, Nobuo Araki118, Takashi Hata119, Hiroshi Ryu120, Kazumasa Yamatani121, Shinji Minami122, Takahiro Maruta123, Masaki Eto124, Katsutoshi Takayama125, Kazuo Hashikawa126, Eiichiro Mabuchi127, Yoshio Sakagami128, Syoji Tsuchimoto129, Jiro Kitayama130, Kiyoshi Shirakawa131, Haruki Takahashi132, Syunro Uchinokura133, Naohiro Osaka134, Ichiro Imafuku135, Toshiro Otsuka136, Ryo Itabashi137, Yuji Kujiraoka138, Naohisa Miura139, Koichi Nomura140, Masahiro Kobari141, Keizo Yasui142, Susumu Kashino143, Hiroto Murata144, Kazuhiko Nozaki145, Kosuke Yamashita92, Katsumi Matsumoto146, Yuji Shibata147, Atsuo Aoyama148, Yoshimasa Watanabe149, Toru Eto150, Susumu Mekaru151, Tsuneo Honda152, Masato Seike153, Masahiro Kurisaka154, Toshio Imaizumi155, Kojiro Wada156, Norihiro Suzuki157, Atsuo Yoshino158, Yukiko Hara159, Shunya Takizawa160, Kaoru Kamimoto161, Hiroshi Iizuka162, Yasuo Toma163, Taro Komuro164, Atsushi Sueyoshi165, Yoshikazu Nakajima23, Takayuki Sakaki166, Hiroji Miyake167, Masaru Idei168, Tsutomu Hitotsumatsu169, Shigehiro Nakahara170, Masahiko Kawanishi171, Takuji Kitaoka172, Naoyuki Isobe173, Masanobu Hokama174, Toshihide Shibata175, Kazuhito Tsuruta176, Akihito Moriki177, Masahiro Makino178, Masafumi Otaki179, Minoru Ajiki180, Takaaki Yamazaki181, Kiyohiro Houkin182, Nobuyuki Yasui183, Koichi Hirata184, Hiroyuki Kato185, Ichiro Suzuki186, Takakazu Kawamata30, Yoshikazu Uesaka187, Kohei Yamashita188, Yukiko Enomoto189, Osamu Onodera190, Masato Ikeda191, Susumu Miyamoto192, Manabu Sakaguchi193, Hiroyuki Nakase194, Yoshiki Yagita195, Tetsuhiro Kitahara196, Katsumi Irie197, Tomohiko Kusuhara198, Kazumasa Kawazoe199, Shinji Nagahiro200, Norikazu Kawada201, Akiko Adachi202, Toshihiro Fukusako203, Wataro Tsuruta204, Naoko Fujimura205, Takayuki Koizumi206, Hiroyuki Tomimitsu207, Shigeru Fujimoto208, Tsukasa Tsuchiya209, Hitoshi Aizawa210, Nobutaka Ishizu211, Shigeru Nogawa212, Hideharu Furumoto213, Toshihiro Ueda214, Syogo Imae215, Teiji Nakayama216, Hiroki Namba217, Jun Ochiai218, Tomoko Yamana219, Mitsuhito Mase220, Noriyuki Matsukawa220, Hisayoshi Niwa221, Masatoshi Muramatsu222, Yoshio Nakashima223, Fuminori Iwamoto224, Syunichi Yoneda225, Kenji Hashimoto226, Tatsuo Matsushita227, Takenobu Kunieda228, Osamu Masuo229, Hirotaka Yamamoto230, Naohisa Hosomi231, Ryo Ogami232, Koichi Kuramoto233, Takahiro Matsumoto234, Hirotsugu Shinozaki235, Hiroshi Sugimori236, Yoichiro Hashimoto237, Hidenori Suzuki25, Masahiro Waza238, Yuki Kujyuro239, Eiichi Kamei240, Yasufumi Uchida241, Masao Nagayama242, Masahiko Hiroki243, Hiroshi Sakura244, Tatsuru Noujo245, Yasutaka Tajima246, Hajime Wada247, Akira Hodozuka248, Wataru Ide249, Yasushi Shibata250, Shinji Yamamoto251, Masayuki Ishihara252, Satsuki Miyata253, Yoshiyuki Matsuoka254, Yasuhisa Sakurai255, Yoshiharu Miura256, Takanori Yokota257, Haruhiko Hoshino13, Satoshi Iwabuchi258, Wataro Tsuruta187, Hirohiko Arimoto259, Sumio Suda260, Takashi Ohashi261, Katsuhiro Kuroda262, Takashi Matsuhisa263, Kazutoshi Yokoyama264, Eiichi Katada265, Kenichiro Fujishiro266, Akira Inukai267, Yasushi Kobayashi268, Hideki Sakai269, Hidekazu Tomimoto25, Kenichi Yamamoto270, Ken Asakura271, Yuhei Yoshimoto272, Yoshikazu Kusano273, Ryoichi Takahashi274, Sotaro Higashi275, Cheho Park276, Mitsutoshi Nakada277, Makoto Matsui278, Yoshinari Nagakane279, Akira Yoshioka280, Masahiro Makino281, Kazuyoshi Yamaguchi282, Yasushi Hagihara283, Tomonori Yamada284, Kenji Hashimoto285, Toshiaki Fujita286, Tetsuya Kumagai287, Masayuki Sumida288, Motohiro Morioka289, Hiroaki Oboshi290, Takanari Kitazono291, Yukio Ando292, Seiichiro Minato293, Masahito Agawa294, Takeshi Kono295, Tomohiko Izumidani295, Tetsuya Ueba296, Hiroaki Takeuchi297, Syuji Monden298, Syoji Shiraishi299, Hidehiko Syoji300, Tatsuya Nakamura300, Naoki Ikawa301, Hiroshi Sugihara302, Shinichi Toyonaga303, Hiroyuki Kon304, Yuji Kanamori305, Hiroaki Tanaka306

Funding

Grants covering the research: Supported by the Japan Agency for Medical Research and Development (AMED: JP24lk0221186, JP24lk0221171) and JSPS KAKENHI (JP23H02831). CSPS.com was conducted under a trial contract between the consignee, Japan Cardiovascular Research Foundation, and the consignor, Otsuka Pharmaceutical Co., Ltd. The Japan Cardiovascular Research Foundation received funding for trial implementation and management from Otsuka. Otsuka did not directly contribute to trial design, data management, or statistical analysis of CSPS.com and did not contribute to any components in this sub-study.

Compliance with ethical standards

Conflict of interest

All of the following are outside the submitted work. Toyoda reports honoraria from Otsuka Pharmaceutical, Daiichi-Sankyo, Bristol-Myers-Squibb, Bayer Yakuhin, and Janssen. Koga reports honoraria from Bayer Yakuhin, Daiichi-Sankyo, Mitsubishi Tanabe Pharma Corporation, and research support from, Daiichi-Sankyo, Nippon Boehringer Ingelheim. Hoshino reports honoraria from Otsuka Pharmaceutical, Bristol-Myers-Squibb and Pfizer. Okada reports honoraria from Daiichi-Sankyo and Pfizer. Sakai reports a research grant from Biomedical Solutions, Medtronic, Terumo and TG Medical; lecturer’s fees from Asahi-Intec, Biomedical Solutions, Daiichi Sankyo, Kaneka, Medtronic, Stryker and Terumo; and membership on the advisory boards for Johnson & Johnson, Medtronic and Terumo. Minematsu reports honoraria from Bayer Yakuhin and Pfizer. None of the other authors have any conflicts of interest to declare.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

A list of authors and their affiliations appear above the funding section.
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