Efficacy and Safety of Ticagrelor and Aspirin in Patients With Moderate Ischemic Stroke
Authors: Yongjun Wang, Yuesong Pan, Hao Li, Pierre Amarenco, Hans Denison, Scott R. Evans, Anders Himmelmann, Stefan James, Filip Birve, Per Ladenvall, Carlos A. Molina, S. Claiborne Johnston, Sebastian Ameriso, Leonardo Gonzalez, Pablo Ioli, Lorena Jure, Guillermo Povedano, Guadalupe Bruera, Gustavo Herrera, Juan J Martin Artesi, Virginia A. Pujol Lereis, Conrado J Estol, Maia Gomez Schneider, Santiago Pigretti, Fernando Lipovestky, María C Zurru, Stephen Davis, Andrew Wong, Tissa Wijeratne, Arman Sabet, Andrew Lee, Vincent Thijs, Robin Lemmens, Laetitia Yperzeele, Geert Vanhooren, Peter Vanacker, Iris Vansteenkiste, Vicky Maqueda, André Peeters, Marie-Christine Hasenbroekx, Wendy Van Daele, Adinda De Pauw, Regilio Oedit, Wouter De Vooght, Philippe Desfontaines, Yves Vandermeeren, Marianna DA Dracoulakis, Rodrigo Bazan, Octavio M Pontes Neto, Daniel DC Bezerra, Luiz C Marrone, Pedro A Kowacs, Carla HC Moro, Paulo CO Macelino, Marco TA Pedatella, Ekaterina Titianova, Ivan Staikov, Dimitar Maslarov, Plamen Petkov, Tanya Beleva, Borislav Kralev, Nikolay Sotirov, Dimcho Hristov, Rumeliya M Ivanova, Margarita V Mihailova, Ashfaq M Shuaib, Andrew Demchuk, Michel Beaudry, Anthony R Winder, Sumiti Nayar, Huaguang Zheng, Shuya Li, Xingquan Zhao, Guoqiang Wen, Xueshuang Dong, Guozhong Li, Zhaohui Zhang, Huisheng Chen, Dong Wang, Xiaohong Li, Yuncheng Wu, Xu Zhang, Baorong Zhang, Wenke Hong, Xiaogang Li, Lijuan Wang, Li Liu, Xiaolin Xu, Peifu Wang, Weihong Zheng, Jinsheng Zeng, Yukai Wang, Yan Jia, Yongqiu Li, Bo Hu, Wei Shen, Zhi Song, Zhiping Hu, Yunhai Liu, Kaifu Ke, Deqin Geng, Shigang Zhao, Runxiu Zhu, Qiumin Qu, Xiuli Zhao, Qi Wan, Yunhua Yue, Huishan Du, Meiyun Zhang, Yan Wang, Dongfang Li, Dongyu Wang, Yongqiang Li, Xufang Xie, Tingmin Yu, Qi Liu, Mingxiu Yang, Xiaoping Pan, Lijun Xu, Deen Xu, Gang Li, Anding Xu, Martin Roubec, Petr Geier, Daniel Vaclavik, Jiri Neumann, Jana Bednarova, Robert Mikulik, David Hlinovsky, Pierre Amarenco, Charlotte Cordonnier, Igor Sibon, Caroline Arquizan, Sonia Alamowitch, Bertrand Lapergue, Jean-Marc Olivot, Nicolas Raposo, Marie-Hélène Mahagne, Emmanuel Touze, Gilles Rodier, Stéphane Vannier, Yves Samson, Michael Obadia, Emmanuel Ellie, Benoît Guillon, Serge Timsit, Yannick Bejot, Valérie Wolff, Didier Smadja, Aude Bagan-Triquenot, Pierre Garnier, Xavier Ducrocq, Peggy Reiner, Thierry Moulin, Frédéric Philippeau, Fernando Pico, Sébastien Richard, Joachim Röther, Jörg Berrouschot, Hassan Soda, Carsten Pohlmann, Christoph Terborg, Darius G Nabavi, Rainer Dziewas, Martin Köhrmann, Jörg Glahn, Lars Marquardt, Bernd Kallmünzer, Karin Weißenborn, Lawrence KS Wong, Yannie O-Y Soo, Richard Li, Wing C Fong, Siu H Li, Raymond Cheung, Kin K Yip, Joshua WM Fok, Michael YP Fu, Norbert Szegedi, Krisztián Pozsegovits, Attila Valikovics, Gyula Pánczél, Csilla Rózsa, Péter Diószeghy, Attila Csányi, Levente Kerényi, Valéria Nagy, László Szapáry, Dániel Bereczki, Sándor Molnár, Gyula Timár, András G Folyovich, Mária Sátori, Ildikó Vastagh, Praveen K S, Rajnish Kumar, Atul Prasad, Vikram Sharma, Alok Verma, Indraneel Basu, Abu Z Ansari, Vijaya Pamidimukkala, B.S. Raghavendra, Vivek D Junewar, Sumit Singh, Advait P Kulkarni, Padma MV Srivastava, K Pramod, Sanjay G Ramteke, Jaideep Bansal, Kewal Krishan, Hrishikesh Kumar, Priyanka V Kashyap, Ramakrishnan Tcr, Gopal R Adrasetty, Amit Yeole, Rahul B Baviskar, Giancarlo Agnelli, Danilo Toni, Stefano Ricci, Rossana Tassi, Giuseppe Micieli, Michelangelo Mancuso, Giovanni Orlandi, Alberto Chiti, Marialuisa Delodovici, Federico Carimati, Alessandro De Vito, Francesco Perini, Cinzia Finocchi, Tiziana Tassinari, Massimo Del Sette, Luisa Roveri, Andrea Zini, Guido Bigliardi, Francesca R Pezzella, Letizia Cupini, Alessandro Adami, Giampaolo Tomelleri, Carla Zanferrari, Angel A Arauz Góngora, Minerva López Ruíz, Angelica Ruíz Franco, José OJ Chacon Romero, Fernando Cruz Castillo, Jose L Ruiz-Sandoval, Jesús  D López Tapia, Edgar A Castillo Vargas, Juan F Gongora Rivera, Guillermo Rivera Martinez, Jorge Villarreal Careaga, Nilton Custodio, Oscar G. Pamo Reyna, Cesar A Castañeda, Edwin J Pretell, Nestor Najar, Julio C Perez, Luisa Cardoza, Carlos Chavez, Maria Reyes, Anna Członkowska, Waldemar Fryze, Piotr Sobolewski, Ryszard Nowak, Dorota Szkopek, Zbigniew Bąk, Sławomir Brzozowski, Waldemar Brola, Marek Zalisz, Konrad Rejdak, Marta Bilik, Małgorzata Fudala, Andrzej Tutaj, Anetta Lasek-Bal, Jan Kochanowicz, Bartosz Karaszewski, Tomasz Berkowicz, Beata Zwiernik, Dorota Różański, Jan P Mejnartowicz, Szymon Jurga, Jacek Rożniecki, Maciej Świat, Ovidiu A Bajenaru, Cristina A Panea, Mihaela A Simu, Rodica Balasa, Dan L Cuciureanu, Bogdan O Popescu, Monica Sabau, Corina Roman-Filip, Liudmila Odnopozova, Oleg Artyukov, Anna Milto, Liudmila V Stakhovskaya, Sergei Aksentiev, Svetlana E Chuprina, Elena B Kuznetsova, Ilya I Sholomov, Alexander Malygin, Elena Mordvintseva, Rostislav Y Nilk, Inna Ershova, Dina Khasanova, Leila Akhmadeeva, Aida Iakupova, Ekaterina A Drozdova, Marine Tanashyan, Evgenij Pudov, Lybov A Shpagina, Svetlana Berns, Liudmila G Lenskaya, Konstantin Golikov, Andrey V Kovalenko, Elena Vasilieva, Elena Reznik, Mikhail Zykov, Evgeniy Kovalchuk, Dmitry Popov, Andrey Belkin, Olga Androfagina, Tatyana Lokshtanova, Elena V Melnikova, Fahmi Al-Senani, Nouf Almansour, Fawaz Alhussein, Ali Alkhathaami, Saeed Alghamdi, Miroslav Brozman, Marta Mikloskova, Georgi Krastev, Vlastimil Serdahely, Michal Kovacik, Ladislav Gurcik, Miloslav Dvorak, Egon Kurca, Andrea Cimprichova, Marian Kycina, Erika Zacharova, Richard Risnovsky, Hee-Joon Bae, Kyung B Lee, Yong-Jin Cho, Jong-Moo Park, Joon-Tae Kim, Jun Lee, Jae-Kwan Cha, Sung-Il Sohn, Dong-Ick Shin, Soo J Lee, Byung-Chul Lee, Jay C Choi, Moo S Park, Dae-Il Chang, Joung-Ho Rha, Sang M Sung, Yangha Hwang, Carlos Molina Cateriano, Jaume Roquer González, Jaime Masjuan Vallejo, Meritxell Gomis Cortina, Francisco Moniche Álvarez, Miguel Á Gamero García, Soledad Pérez Sánchez, Francisco Purroy García, Santiago Trillo Senín, Tomás Segura Martín, Joaquín Serena Leal, Juan Arenillas Lara, Joan Martí-Fàbregas, Aida Lago Martín, Carlos Tejero Juste, Javier Marta Moreno, Nicolás López Hernández, Lars Sjöblom, Ann C Laska, Margarita Callander, Thomas Mooe, Jan-Erik Karlsson, Mihaela O Romanitan, Arne Lindgren, Niaz Ahmed, Björn Cederin, Christine Kremer, Tsong-Hai Lee, Jiann-Shing Jeng, Chih-Hung Chen, Helen L. Po, Chia-Wei Liou, Huey-Juan Lin, Ruey-Tay Lin, Hsiu-Fen Lin, Li-Ming Lien, Lung Chan, Wei-Shih Huang, Wen-Yi Huang, Ta-Cheng Chen, Chin-I Chen, Po-Lin Chen, Chun-Pai Yang, Yu Sun, Nijasri Charnnarong Suwanwela, Aurauma Chutinet, Tasanee Tantirittisak, Sombat Muengtaweepongsa, Yongchai Nilanont, Somsak Tiamkao, Chesda Udommongkol, Witoon Jantararotai, Tabtim Chongsuvivatwong, Suwat Srisuwananukorn, Wasutha Khaykhaew, Supachai Paiboonpol, Makorn Limudomporn, Saengduan Mayotarn, Kanoksri Samintharapanya, Arkhom Arayawichanon, Thanoot Thamangraksat, Duangpol Srimanee, Galyna Chmyr, Nataliya Tomakh, Alla Cherkez, Sergii Moskovko, Vadym Nikonov, Svitlana Shkrobot, Lyudmyla Shulga, Hanna Hrebeniuk, Valentyna Yavorska, Nataliia Lytvynenko, Marta Khavunka, Iryna Kobets, Nataliia Chemer, Ivanna Tashchuk, Olha Myronova, Thang H Nguyen, Tan V Vo, Thanh T Tran, Nga TP Nguyen, Anh D Nguyen, Binh T Nguyen, Thang B Nguyen, Ngoc H Nguyen, Quang D Nguyen, Nhan D Le, Dai D Pham
Journal: JAMA Neurology (2021)

Prior trials of dual antiplatelet therapy excluded patients with moderate ischemic stroke. These patients were included in the Acute Stroke or Transient Ischaemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death (THALES) trial, but results have not been reported separately, raising concerns about safety and efficacy in this subgroup.To evaluate the efficacy and safety of ticagrelor plus aspirin in patients with moderate ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 4 to 5).The THALES trial was a randomized trial conducted at 414 hospitals in 28 countries in January 2018 and December 2019. This exploratory analysis compared patients with moderate stroke (baseline NIHSS score of 4 to 5) with patients with less severe stroke (NIHSS score of 0 to 3). A total of 9983 patients with stroke were included in the present analysis, after excluding 2 patients with NIHSS scores greater than 5 and 1031 patients with transient ischemic attack. Data were analyzed from March to April 2021.Ticagrelor (180-mg loading dose on day 1 followed by 90 mg twice daily on days 2 to 30) or placebo within 24 hours after symptom onset. All patients received aspirin, 300 to 325 mg, on day 1 followed by aspirin, 75 to 100 mg, daily on days 2 to 30. Patients were observed for 30 additional days.The primary outcome was time to stroke or death within 30 days. The primary safety outcome was time to severe bleeding.In total, 3312 patients presented with moderate stroke and 6671 presented with less severe stroke. Of those in the moderate stroke group, 1293 (39.0%) were female, and the mean (SD) age was 64.5 (10.8) years; of those in the less severe stroke group, 2518 (37.7%) were female, and the mean (SD) age was 64.8 (11.2) years. The observed primary outcome event rate in patients with moderate stroke was 7.6% (129 of 1671) for those in the ticagrelor group and 9.1% (150 of 1641) for those in the placebo group (hazard ratio, 0.84; 95% CI, 0.66-1.06); the primary outcome event rate in patients with less severe stroke was 4.7% (158 of 3359) for those in the ticagrelor group and 5.7% (190 of 3312) for those in the placebo group (hazard ratio, 0.82; 95% CI, 0.66-1.01) (P for interaction = .88). Severe bleeding occurred in 8 patients (0.5%) in the ticagrelor group and in 4 patients (0.2%) in the placebo group in those with moderate stroke compared with 16 patients (0.5%) and 3 patients (0.1%), respectively, with less severe stroke (P for interaction = .26).In this study, patients with a moderate ischemic stroke had consistent benefit from ticagrelor plus aspirin vs aspirin alone compared with patients with less severe ischemic stroke, with no further increase in the risk of intracranial bleeding or other severe bleeding events.ClinicalTrials.gov Identifier: NCT03354429.