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: Easton J. Donald , Aunes Maria , Albers Gregory W. , Amarenco Pierre , Bokelund-Singh Sara , Denison Hans , Evans Scott R. , Held Peter , Jahreskog Marianne , Jonasson Jenny , Minematsu Kazuo , Molina Carlos A. , Wang Yongjun , Wong K.S. Lawrence , Johnston S. Claiborne , Ameriso Sebastiá F. , Donnan Geoffrey , Lemmens Robin , Massaro Ayrton , Titianova Ekaterina , Hill Michael D. , Lavados Pablo , Skoloudik David , Röther Joachim , Norbert Szegedi , Agnelli Giancarlo , Bornstein Natan , Tanahashi Norio , Góngora Angel Arauz , Pretell Edwin , San Jose Maria Cristina Z. , Czlonkowska Anna , Bajenaru Ovidiu , Stakhovskaya Ludmila , Brozman Miroslav , Kim Jong-Sung , Wahlgren Nils , Michel Patrik , Lee Tsong Hai , Suwanwela Nijasri Charnnarong , Kutluk Kursad , Moskovko Sergii , Kasner Scott , Laskowitz Daniel , Clark Wayne , Nguyen Huy Thang , Ameriso Sebastian , Lepera Sandra , Romano Marina , Paulon David , Ioli Pablo , Zurru Cristina , Bruera Guadalupe , Jure Lorena , Klein Francisco , Povedano Guillermo , Levi Christopher , Phan Thanh , Markus Romesh , Anderson Craig , Sabet Arman , Davis Stephen , Lee Andrew , Kleinig Timothy , Wong Andrew , Krause Martin , Jannes Jim , Wijeratne Tissa , Lemmens Robin , Hemelsoet Dimitri , Peeters André , Tack Philippe , Vanacker Peter , Laloux Patrice , Van Landegem William , Vanhooren Geert , Desfontaines Philippe , Van Orshoven Marc , Oliveira Fabio , Friedrich Mauricio , Brondani Rosane , Gagliardi Rubens , Fabio Soraia , Dracoulakis Marianna , Bazan Rodrigo , Marrone Luiz , Pontes Neto Octavio , Silva Gisele , Kowacs Pedro , Titianova Ekaterina , Stamenova Paraskeva , Daskalov Marin , Staikov Ivan , Baldaranov Dimo , Maslarov Dimitar , Lilovski Hristo , Petkov Plamen , Petrova Neli , Mavrov Radoslav , Markova Veska , Petrova Valeria , Beleva Tanya , Kralev Borislav , Sotirov Nikolay , Lekova Veska , Hristov Dimcho , Ermenkova Vera , Mateev Lyudmil , Mitkova Rumeliya , Haralanov Liybomir , Ikonomov Rosen , Mihailova Margarita , Georgiev Ivan , Shuaib Ashfaq , Hachinski Vladimir , Boulanger Jean-Martin , Mann Sharan , Hassan Ayman , Mackey Ariane , Menon Bijoy , Minuk Jeffrey , Siddiqui Muzaffar , Eustace Marsha , Vieira Lucia , Selchen Daniel , Beaudry Michel , Stotts Grant , Lavados Pablo , Castro Angel , Gasic Kristo , Rivas Rodrigo , Sanchez Pablo , Roldan Andres , Grossmann Ingrid , Figueroa Christian , Li Jimei , Xu Xiaolin , Chen Huisheng , Li Xiaohong , Yang Yi , Zhang Chunsheng , Wang Baojun , Li Guanglai , Wang Dong , Lin Hong , Tang Yamei , Xu Anding , Wang Yanjiang , Hong Wenke , Song Zhi , Zhang Xu , Jin Xiaoping , Xu Yun , Yan Fuling , Zheng Weihong , Wang Xiaoping , Dong Qiang , Zhao Zhongxin , Zhang Baorong , Zhong Wangtao , Wen Guoqiang , Xu Jun , Li Guozhong , Dong Xueshuang , Tian Xiangyang , Zhang Zhaohui , Xu En , Liu Kaixiang , Chen Jun , Skoda Ondrej , Skoloudik David , Ehler Edvard , Vaclavik Daniel , Sanak Daniel , Klimosova Sylva , Vitkova Eva , Fiksa Jan , Mikulik Robert , Neumann Jiri , Plny Richard , Leys Didier , Sibon Igor , Mas Jean-Louis , Alamowitch Sonia , Pico Fernando , Hosseini Hassan , Mahagne Marie-Hélène , Touze Emmanuel , Vadot Wilfried , Vannier Stéphane , Nighoghossian Norbert , Samson Yves , Garnier Pierre , Ellie Emmanuel , Guillon Benoît , Timsit Serge , Giroud Maurice , Philippeau Frédéric , Bagan-Triquenot Aude , Wolff Valérie , Raposo Nicolas , Obadia Michel , Debiais Severine , Grimaud Jérôme , Illouz Stéphane , Smadja Didier , Urbanczyk Cédric , Röther Joachim , Berrouschot Jörg , Weimar Christian , Gahn Georg , Soda Hassan , Klimpe Sven , Nabavi Darius , Glahn Jörg , Köhrmann Martin , Krause Lars , Terborg Christoph , Urban Peter , Steiner Thorsten , Ferbert Andreas , Dziewas Rainer , Seidel Günter , Thomalla Götz , Li Richard , Fong Wing Chi , Cheung Raymond , Szegedi Norbert , Pozsegovits Krisztián , Valikovics Attila , Pánczél Gyula , Rózsa Csilla , Németh László , Diószeghy Péter , Óváry Csaba , Csányi Attila , Kerényi Levente , Nagy Valéria , Komoly Sámuel , Bereczki Dániel , Molnár Sándor , Kondákor István , Tanne David , Raphaeli Guy , Telman Gregory , Bornstein Natan , Leker Ronen , Lampl Yair , Agnelli Giancarlo , Corea Francesco , Ricci Stefano , Guidetti Donata , Malferrari Giovanni , Marcheselli Simona , Micieli Giuseppe , Zini Andrea , Di Lazzaro Vincenzo , Gandolfo Carlo , Salmaggi Andrea , Tassi Rossana , Rasura Maurizia , Orlandi Giovanni , Comi Giancarlo , Ricci Stefano , Mancuso Michelangelo , Delodovici Marialuisa , Bovi Paolo , Consoli Domenico , Utsugisawa Kimiaki , Fujita Tsuneo , Kurihara Hideyuki , Maruki Chikashi , Hayashi Takeshi , Ogiichi Tsuneaki , Kumagai Morio , Takenaka Katsunobu , Toyoda Kazunori , Takamatsu Kazuhiro , Ogami Ryo , Kin Shigenari , Aoki Takeshi , Takizawa Katsumi , Omori Shigehiro , Umezawa Takehiko , Toba Yasuyuki , Nonoyama Yutaka , Nakagawa Hidemitsu , Naka Takashi , Morimoto Masanori , Matsumoto Shuichi , Hitotsumatsu Tsutomu , Shingaki Tatsuya , Okuda Satoshi , Ota Mamoru , Sakai Nobuyuki , Yamada Takeshi , Niwa Jun , Fujita Hitoshi , Moriki Akihito , Yoshino Kimihiro , Fukushima Yoshihisa , Mori Takahisa , Sato Atsushi , Kusano Yoshikazu , Kubo Michiya , Yamazaki Masashi , Ooasa Takao , Nishizaki Takafumi , Kitagawa Naoki , Yasaka Masahiro , Manabe Yasuhiro , Yoshioka Akira , Ishihara Masayuki , Kagawa Takato , Ichihashi Toshikazu , Matsuoka Hideki , Ito Yasuhiro , Yamasaki Masahiro , Takaba Hitonori , Saito Hisatoshi , Sato Masahiro , Fukuda Kazumasa , Endo Sumio , Kidooka Minoru , Umemura Toshitaka , Kikkawa Yuriko , Toru Shuta , Yamada Kentaro , Sakai Hideki , Asari Jun , Ezura Masayuki , Nitta Hisashi , Nagano Keiko , Ochiai Jun , Sakai Keiichi , Kobayashi Yasutaka , Yoshii Yasuhiro , Miake Hirotomo , Takita Tomohiro , Taniguchi Hidekazu , Kuroki Kazuhiko , Mizota Takamitsu , Yamamoto Kenichi , Nakane Hiroshi , Iwanaga Takeshi , Chiba Kei , Yoshimoto Tetsuyuki , Torii Tsuyoshi , Kitagawa Takeo , Takashima Hiroshi , Shirasaki Naoki , Dehara Makoto , Wada Naomichi , Hamada Kensuke , Kato Noriyuki , Go Yoshinori , Izumi Ichiro , Ninomiya Hirotomo , Kumai Junichiro , Nakajima Yoshikazu , Kaku Yasuhiko , Isayama Yukihiro , Kawanishi Masahiro , Noda Shinya , Yamamoto Kazuhide , Hazama Takanori , Takahashi Hiroshi , Tanaka Yohei , Hata Takashi , Kazekawa Kiyoshi , Furui Eisuke , Hondo Hideki , Sato Nobuyuki , Kusunoki Katsusuke , Nanri Kazunori , Abe Satoshi , Sasaoka Noboru , Kuroyanagi Takayuki , Suzuki Hisahiko , Fukuyama Kouzou , Nakahara Kimihiro , Gongora Fernando , Góngora Angel Arauz , Cantú Brito Carlos , Villarreal Careaga Jorge , Vazquez Alfaro Rosalia , Aguayo Leytte Geronimo , Berrospi Percy , Chavez Carlos , Pretell Edwin , Rodriguez Liliana , Custodio Nilton , Castañeda Cesar , Perez Julio , San Jose Maria Cristina , Baroque Alejandro , Collantes Epifania , Aquino Abdias , Díaz Alejandro , Roxas Artemio , Lokin Johnny , Advincula Joel , Calderon Emerito , Navarro Jose , Hiyadan John , Surdilla Arturo , Czlonkowska Anna , Ryglewicz Danuta , Krychowiak Grzegorz , Fryze Waldemar , Sobolewski Piotr , Nowak Ryszard , Fiszer Urszula , Papierowska Beata , Zielińska-Turek Justyna , Lasek-Bal Anetta , Kołodziejska Ewa , Kamińska Anna , Adamkiewicz Bożena , Tutaj Andrzej , Szkopek Dorota , Musiatowicz Krzysztof , Bąk Zbigniew , Brzozowski Sławomir , Brola Waldemar , Ferens Antoni , Zalisz Marek , Rejdak Konrad , Rudzińska Monika , Bajenaru Ovidiu , Panea Cristina , Simu Mihaela , Balasa Rodica , Cuciureanu Iulian , Popescu Bogdan , Sabau Monica , Roman-Filip Corina , Pimenov Leonid , Gekht Alla , Milto Anna , Shchukin Ivan , Parfenov Vladimir , Stakhovskaya Liudmila , Arkhipov Mikhail , Sokolova Nadezhda , Bogdanov Enver , Esin Radiy , Khasanova Dina , Golikov Konstantin , Melnikova Elena , Zaslavskiy Leonid , Voznyuk Igor , Nazarov Alexander , Akhmadeeva Leila , Iakupova Aida , Shamalov Nikolay , Belskaya Galina , Chuprina Svetlana , Denisova Olga , Drozdova Ekaterina , Karakulova Yuliya , Sholomov Ilya , Spirin Nikolay , Vostrikova Elena , Mordvintseva Elena , Grigoryeva Vera , Zateyshchikov Dmitry , Gorbachev Vladimir , Chefranova Zhanna , Dudarev Mikhail , Nilk Rostislav , Rozhdestvenskiy Alexey , Gurcik Ladislav , Dvorak Miloslav , Krastev Georgi , Kurca Egon , Vyletelka Juraj , Brozman Miroslav , Kim Jong Sung , Bae Hee-Joon , Kim Yong-Won , Kim Joon-Tae , Cha Jae-Kwan , Nam Hyo Suk , Chang Dae-Il , Lee Yong-Seok , Oh Kyungmi , Yu Sung-Wook , Sohn Sung-Il , Lee Jun , Cho Han Jin , Kim Eung-Gyu , Rha Joung-Ho , Kim Seo Hyun , Molina Cateriano Carlos , Serena Leal Joaquín , Vivancos Mora José , Rodríguez Yañez Manuel , Roquer González Jaume , Purroy García Francisco , Gomis Cortina Meritxell , Masjuan Vallejo Jaime , Arenillas Lara Juan , Segura Martín Tomás , Herrero José Antonio Egido , Tembl Ferrairó Jose Ignacio , Gállego Culleré Jaime , Moniche Álvarez Francisco , Steinberg Anna , Callander Margarita , Laska Ann Charlotte , Bokemark Lena , Mooe Thomas , Käll Tor-Björn , Welin Lennart , Sjöblom Lars , Hambraeus Joakim , Teichert Jörg , Wannberg Hans , Sanner Johan , Ramströmer Bo , Ziedén Bo , Hau Stefan Olsson , Gustafsson Claes , Michel Patrik , Kahles Timo , Lyrer Philippe , Arnold Marcel , Liesch Martin , Medlin Friedrich , Cereda Carlo , Kägi Georg , Luft Andreas , Carrera Emmanuel , Lee Tsong-Hai , Po Helen L. , Chern Chang-Ming , Lien Li-Ming , Chan Lung , Liu Chung-Hsiang , Wu Shey-Lin , Lee Jiann-Der , Chen Chih-Hung , Lin Huey-Juan , Lin Ruey-Tay , Chen Wei-Hsi , Sun Yu , Suwanwela Nijasri Charnnarong , Tantirittisak Tasanee , Muengtaweepongsa Sombat , Nilanont Yongchai , Tiamkao Somsak , Udommongkol Chesda , Watcharasaksilp Kanokwan , Jantararotai Witoon , Kutluk Kursad , Sirin Hadiye , Ince Birsen , Asil Talip , Arsava Murat , Incesu Tulay Kurt , Tireli Hulya , Kucukoglu Hayriye , Ak Fikri , Unal Ali , Ozturk Serefnur , Uzuner Nevzat , Chmyr Galyna , Lebedynets Volodymyr , Nikonov Vadym , Shulga Lyudmyla , Smolanka Volodymyr , Moskovko Sergii , Khavunka Marta , Yavorska Valentyna , Tomakh Nataliya , Kozyolkin Olexandr , Litovaltseva Galyna , Lansberg Maarten , Bernstein Richard , Brown David , Clark Wayne , Dissin Jonathan , Graffagnino Carmelo , Harris Jonathan , Hicks William , Kasner Scott , Katzan Irene , Kramer Jeffrey , Willey Joshua , Silliman Scott , Starkman Sidney , Thaler David , Tremwel Margaret , Concha Mauricio , Rajamani Kumar , Dandapani Bhuvaneswari , Silver Brian , Deal Nathan , Chang Ira , Hassan Ameer , Rudolph Steven , Fischer Kenneth , Kirshner Howard , Logan William , Mallenbaum Sidney , Hefzy Hebah , Latorre Julius , Levine Steven , Ciabarra Anthony , Dafer Rima , Anyanwu Benjamin , Cherian Laurel , Panezai Spozhmy , Khanna Anna , Dodds Jodi , Torbey Michel , Gebel James , Woo Henry , Chiu David , Androulakis Xiao , Burgin William , Pineda Maria , Yilmaz Engin , Altafullah Irfan , Boutwell Christine , Cruz-Flores Salvador , Sapkota Biggya , Fayad Pierre , Jacoby Michael , Rafiq Shahid , Salgado Efrain , Lafranchise Eugene , Felton Warren , Madhavan Ramesh , Zaidat Osama , Pieper Connie , Riviello Ralph , Burnett Aaron , Fischer Michelle , Gentile Nina , Calder Christopher , Dietrich Dennis , Cross Jonathan , Blankenship Larry , Dafer Rima , Montoya Liliana , Grogan Wendell , Young Mark , Khan Farrukh , Campbell Duane , Daboul Nizar , Espinoza Andrey , Cullis Paul , Concepcion Gilberto , Wulff John , Afzal Haider , Jaffrani Naseem , Reiter William , Arshad Tamjeed , Lukovits Timothy , Welker James , Chang Fen Lei , Badruddin Aamir , Babikian Viken , Menon Ravi , Sander James , Springer Mellanie , Nanda Ashish , Mas Luis , Rajan Raj , Silverman Bruce , Hefzy Hebah , Huang David , Carpenter David , Clark Joni , Ching Marilou , Santhakumar Sunitha , Gould Jeffrey , Bansal Vibhav , Vidal Gabriel , Mikesell Timothy , Brick John , French William , Shah Qaisar , Holmstedt Christine , Ishag-Osman Nadir , Kostis John , Shehadeh Abbas , Sethi Pramodkumak , Imam Asher , Mccomas Carl , Tran Duc , Gebreyohanns Mehari , Wiseman Brian , Malik Maheen , Schwarcz Aron , Altschul Dorothea , Castaldo John , Alshekhlee Amer , Gancher Stephen , Krish Nagesh , Nguyen-Huynh Mai , Tremwell Margaret , Sharma Jitendra , Lee Lance , Neil William , Siddiqui Fazeel , Malek Ali , Romero Charles , Huy Thang Nguyen , Hoang Hoa , Nguyen Thang , Nguyen Anh , Nguyen Hung 
Published: June 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.