Risk for Major Bleeding in Patients Receiving Ticagrelor Compared With Aspirin After Transient Ischemic Attack or Acute Ischemic Stroke in the SOCRATES Study (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes)
Authors: J. Donald Easton, Maria Aunes, Gregory Albers, Pierre Amarenco, Sara Bokelund-Singh, Hans Denison, Scott Evans, Peter Held, Maria Jahreskog, Jenny Jonasson, Kazuo Minematsu, Yongjun Wang, K.S. Lawrence Wong, S. Claiborne Johnston, Sebastiá Ameriso, Geoffrey Donnan, Ayrton Massaro, Michael Hill, Norio Tanahashi, Ludmila Stakhovskaya, Jong-Sung Kim, Nils Wahlgren, Tsong Hai Lee, Kursad Kutluk, Sergii Moskovko, Scott Kasner, Daniel Laskowitz, Wayne Clark, Huy Thang Nguyen, Sebastian Ameriso, Sandra Lepera, Marina Romano, David Paulon, Pablo Ioli, Cristina Zurru, Guadalupe Bruera, Lorena Jure, Francisco Klein, Guillermo Povedano, Christopher Levi, Thanh Viet Phan, Romesh Markus, Craig Anderson, Arman Sabet, Stephen Davis, Andrew Lee, Timothy Klein, Andrew Wong, Martin Krause, Jim Jannes, Tissa Wijeratne, Robin Lemmens, Dimitri Hemelsoet, André Peeters, Philippe Tack, Peter Vanacker, Patrice Laloux, William van Landegem, Geert Vanhooren, Philippe Desfontaines, Marc van Orshoven, Fábio Oliveira, Mauricio Friedrich, Rosane Brondani, Rubens Gagliardi, Fabio Fabio, Maria Dracoulakis, Rodrigo Bazan, Luiz Marrone, Octavio Pontes Neto, Gisele Silva, Pedro Kowacs, Ekaterina Titianova, Paraskeva Stamenova, Marin Daskalov, Ivan Staikov, Dimo Baldaranov, Dimitar Maslarov, Hristo Lilovski, Plamen Petkov, Neli Petrova, Radoslav Mavrov, Veska Markova, Valeria Petrova, Tanya Beleva, Borislav Kralev, Nikolay Sotirov, Veska Lekova, Hristo Hristov, Vera Ermenkova, Lyudmil Mateev, Rumeliya Mitkova, Liybomir Haralanov, Rosen Ikonomov, Margarita Mihailova, Ivan Georgiev, Ashfaq Shuaib, Vladimir Hachinski, Martin Boulanger, Sharan Mann, Ayman Hassan, Ariane Mackey, Bijoy Menon, Jeffrey Minuk, Muzaffar Siddiqui, Marsha Eustace, Lucia Vieira, Daniel Selchen, Grant Stotts, Pablo Lavados, Angel Castro, Kristo Gasic, Rodrigo Rivas, Pablo Sánchez, Andres Roldan, Ingrid Grossmann, Christian Figueroa, Jim Li, Xiaolin Xu, Huisheng Chen, Xiaohong Li, Yi Yang, Chunsheng Zhang, Baojun Wang, Guanglai Li, Dong Wang, Hong Li, Yamei Tang, Anding Xu, Yanjiang Wang, Hong Hong, Zhi Song, Xiaoping Jin, Fuling Yan, Weihong Zheng, Xiaoping Wang, Dong Dong, Zhongxin Zhao, Baorong Zhang, Wangtao Wang, Guoqiang Wen, Guozhong Li, Dong Xu, Xiangyang Tian, Zhaohui Zhang, Xu Xu, Kaixiang Li, Jun Chen, Ondrej Skoda, David Skoloudik, Edvard Ehler, Daniel Vaclavik, Daniel Sanak, Sylva Klimosova, Eva Vitkova, Jan Fiksa, Robert Mikulik, Jiri Neumann, Richard Plny, Didier Leys, Igor Sibon, Jean-Louis Mas, Sonia Alamowitch, Fernando Pico, Marie-Hélène Mahagne, Emmanuel Touzé, Wilfried Vadot, Stephane Vannier, Norbert Norbert, Yves Samson, Pierre Garnier, Emmanuel Ellie, Benoit Guillon, Serge Timsit, Maurice Giroud, Philippe Philippeau, Aude Bagan-Triquenot, Valérie Wolff, Nicolas Raposo, Severine Debiais, Jérôme Grimaud, Stéphane Illouz, Didier Smadja, Cédric Urbanczyk, Joachim Röther, Jörg Berrouschot, Christian Weimar, Georg Gahn, Hassan Hassan, Sven Klimpe, Darius Nabavi, Jörg Glahn, Martin Köhrmann, Lars Krause, Christoph Terborg, Peter Urban, Thorsten Steiner, Andreas Ferbert, Rainer Dziewas, Günter Seidel, Götz Thomalla, Richard Li, Wing Chi Fong, Raymond Cheung, Szegedi Norbert, Krisztián Pozsegovits, Attila Valikovics, Gyula Pánczél, Csilla Rózsa, László Németh, Péter Diószeghy, Csaba Óváry, Attila Csányi, Levente Kerényi, Valéria Nagy, Sámuel Komoly, Dániel Bereczki, Sándor Molnár, István Kondákor, David Tanné, Guy Raphaeli, Gregory Telman, Natan Bornstein, Ronen Leker, Yair Lampl, Giancarlo Agnelli, Francesco Corea, Donata Guidetti, Giovanni Malferrari, Marc Marcheselli, Giuseppe Micieli, Andrea Zini, Vincenzo Di Lazzaro, Carlo Gandolfo, Andrea Salmaggi, Rossana Tassi, Maurizia Rasura, Giovanni Orlandi, Giancarlo Comi, Stefano Ricci, Michel Michel, Maria Delodovici, Paolo Bovi, Domenico Consoli, Kimiaki Kim, Tsuneo Fujita, Hideyuki Kurihara, Chikashi Maruki, Takeshi Hayashi, Tsuneaki Ogiichi, Morio Kumagai, Katsunobu Takenaka, Kazunori Toyoda, Kazuhiro Takamatsu, Ryo Ogami, Shigenari Kin, Takeshi Aoki, Katsumi Takizawa, Shigehiro Omori, Takehiko Umezawa, Yasuyuki Toba, Yutaka Nonoyama, Hidemitsu Nakagawa, Takashi Naka, Masanori Mas, Shuichi Matsumoto, Tsutomu Hitotsumatsu, Tatsuya Shingaki, Satoshi Okuda, Mamoru Ota, Nobuyuki Sakai, Takeshi Yamada, Jun Niwa, Hitoshi Fujita, Akihito Moriki, Yoshihisa Fukushima, Takahisa Mori, Atsushi Sato, Yoshikazu Kusano, Michiya Kubo, Masashi Mas, Takao Ooasa, Takafumi Nishizaki, Naoki Kitagawa, Yasuhiro Manabe, Akira Yoshioka, Takato Kagawa, Toshikazu Ichihashi, Hideki Matsuoka, Yasuhiro Ito, Hitonori Takaba, Hisatoshi Saito, Kazumasa Fukuda, En Endo, Minoru Kidooka, Toshitaka Umemura, Yuriko Kikkawa, Shuta Toru, Kentaro Yamada, Hideki Sakai, Jun Asari, Masayuki Mas, Hisashi Nitta, Keiko Nagano, Jun Ochiai, Keiichi Sakai, Yasutaka Kobayashi, Yasuhiro Yoshii, Hirotomo Miake, Tomohiro Takita, Hidekazu Taniguchi, Kazuhiko Kuroki, Takamitsu Mizota, Kenichi Yamamoto, Hiroshi Naka, Takeshi Iwanaga, Kei Chiba, Tetsuyuki Yoshimoto, Tsuyoshi Torii, Takeo Kitagawa, Takashi Takashima, Naoki Shirasaki, Makoto Dehara, Naomichi Wada, Kensuke Hamada, Noriyuki Kato, Yoshinori Yoshino, Ichiro Izumi, Hirotomo Ninomiya, Jun Kumai, Yoshikazu Naka, Yasuhiko Kaku, Yukihiro Isayama, Masahiro Mas, Shinya Noda, Kazuhide Yamamoto, Takanori Hazama, Hiroshi Takahashi, Yohei Tanaka, Takashi Hata, Kiyoshi Kazekawa, Eisuke Furui, Hideki Hondo, Nobuyuki Sato, Katsusuke Kusunoki, Kazunori Nanri, Satoshi Sato, Noboru Sasaoka, Takayuki Kuroyanagi, Hisahiko Suzuki, Kouzou Fukuyama, Kimihiro Kim, Fernando Go, Angel Arauz Góngora, Carlos Cantú Brito, Jorge Villarreal Careaga, Rosalia Vazquez Alfaro, Geronimo Aguayo Leytte, Percy Berrospi, Carlos Chavez, Edwin Pretell, Liliana Li, Nilton Custodio, Cesar Castañeda, Julio Pérez, Maria San Jose, Alejandro Baroque, Epifania Collantes, Abdias Aquino, Alejandro Díaz, Artemio Roxas, Johnny Lokin, Joel Advincula, Emerito Calderon, Jose Navarro, John Hiyadan, Arturo Surdilla, Anna Czlonkowska, Danuta Ryglewicz, Grzegorz Krychowiak, Waldemar Fryze, Piotr Sobolewski, Ryszard Nowak, Urszula Fiszer, Beata Papierowska, Justyna Zielińska-Turek, Anetta Lasek-Bal, Ewa Kołodziejska, Anna Kamińska, Bożena Adamkiewicz, Andrzej Tutaj, Dorota Szkopek, Krzysztof Musiatowicz, Zbigniew Bąk, Sławomir Brzozowski, Waldemar Brola, Antoni Ferens, Marek Zalisz, Konrad Rejdak, Monika Rudzińska, Ovidiu Bajenaru, Cristina Panea, Mihaela Simu, Rodica Balasa, Iulian Cuciureanu, Bogdan Popescu, Monica Sabau, Corina Roman-Filip, Leonid Pimenov, Alla Gekht, Anna Milto, Ivan Shchukin, Vladimir Parfenov, Liudmila Stakhovskaya, Mikhail Arkhipov, Nadezhda Sokolova, En Bogdanov, Radiy Esin, Dina Khasanova, Konstantin Go, Elena Melnikova, Leonid Zaslavskiy, Igor Voznyuk, Alexander Nazarov, Leila Akhmadeeva, Aida Iakupova, Nikolay Shamalov, Galina Belskaya, Svetlana Chuprina, Olga Denisova, Ekaterina Drozdova, Yuliya Karakulova, Ilya Sholomov, Nikolay Spirin, Elena Vostrikova, Elena Mordvintseva, Vera Grigoryeva, Dmitry Zateyshchikov, Vladimir Go, Zhanna Chefranova, Mikhail Dudarev, Rostislav Nilk, Alexey Rozhdestvenskiy, Ladislav Gurcik, Miloslav Dvorak, Georg Krastev, Egon Kurca, Juraj Vyletelka, Miroslav Brozman, Jong Sung Kim, Hee-Joon Bae, Yong-Won Kim, Joon-Tae Kim, Jae-Kwan Cha, Hyo Suk Nam, Dae-Il Cha, Yong-Seok Lee, Kyungmi Oh, Sung-Wook Yu, Sung-Il Sohn, Jun Lee, Han Jin Jin, Eung-Gyu Kim, Joung-Ho Rha, Seo Hyun Kim, Carlos Molina, Joaquín Serena Leal, José Vivancos Mora, Manuel Rodríguez Yañez, Jaume Go, Francisco Purroy García, Meritxell Go, Jaime Mas, Juan Arenillas Lara, Tomás Segura Martín, Antoni Herrero, Jose Tembl Ferrairó, Jaime Gállego Culleré, Francisco Moniche Álvarez, Anna Steinberg, Margarita Callander, Ann Charlotte Cha, Lena Bokemark, Thomas Mooe, Tor-Björn Käll, Lennart Welin, Lars Sjöblom, Joakim Hambraeus, Jörg Teichert, Hans Wannberg, Johan Sanner, Bo Ramströmer, Bo Ziedén, Stefan Olsson Hau, Claes Gustafsson, Patrik Michel, Timo Kahles, Philippe Lyrer, Marc Arnold, Martin Li, Friedrich Friedrich, Carlo Cereda, Georg Kägi, Andreas Luft, Emmanuel Carrera, Tsong-Hai Lee, Helen Po, Chang-Ming Cha, Li-Ming Li, Lung Cha, Chung-Hsiang Li, Shey-Lin Li, Jiann-Der Lee, Chih-Hung Chen, Juan Li, Ruey-Tay Li, Wei-Hsi Chen, Yu Yu, Nijasri Charnnarong Suwanwela, J Donald Easton
Journal: Circulation (2017)

Background: Patients with minor acute ischemic stroke or transient ischemic attack are at high risk for subsequent stroke, and more potent antiplatelet therapy in the acute setting is needed. However, the potential benefit of more intense antiplatelet therapy must be assessed in relation to the risk for major bleeding. The SOCRATES trial (Acute Stroke or Transient Ischemic Attack Treated With Aspirin or Ticagrelor and Patient Outcomes) was the first trial with ticagrelor in patients with acute ischemic stroke or transient ischemic attack in which the efficacy and safety of ticagrelor were compared with those of aspirin. The main safety objective was assessment of PLATO (Platelet Inhibition and Patient Outcomes)–defined major bleeds on treatment, with special focus on intracranial hemorrhage (ICrH). Methods: An independent adjudication committee blinded to study treatment classified bleeds according to the PLATO, TIMI (Thrombolysis in Myocardial Infarction), and GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) definitions. The definitions of ICrH and major bleeding excluded cerebral microbleeds and asymptomatic hemorrhagic transformations of cerebral infarctions so that the definitions better discriminated important events in the acute stroke population. Results: A total of 13 130 of 13 199 randomized patients received at least 1 dose of study drug and were included in the safety analysis set. PLATO major bleeds occurred in 31 patients (0.5%) on ticagrelor and 38 patients (0.6%) on aspirin (hazard ratio, 0.83; 95% confidence interval, 0.52–1.34). The most common locations of major bleeds were intracranial and gastrointestinal. ICrH was reported in 12 patients (0.2%) on ticagrelor and 18 patients (0.3%) on aspirin. Thirteen of all 30 ICrHs (4 on ticagrelor and 9 on aspirin) were hemorrhagic strokes, and 4 (2 in each group) were symptomatic hemorrhagic transformations of brain infarctions. The ICrHs were spontaneous in 6 and 13, traumatic in 3 and 3, and procedural in 3 and 2 patients on ticagrelor and aspirin, respectively. In total, 9 fatal bleeds occurred on ticagrelor and 4 on aspirin. The composite of ICrH or fatal bleeding included 15 patients on ticagrelor and 18 on aspirin. Independently of bleeding classification, PLATO, TIMI, or GUSTO, the relative difference between treatments for major/severe bleeds was similar. Nonmajor bleeds were more common on ticagrelor. Conclusions: Antiplatelet therapy with ticagrelor in patients with acute ischemic stroke or transient ischemic attack showed a bleeding profile similar to that of aspirin for major bleeds. There were few ICrHs. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01994720.