Ticagrelor Added to Aspirin in Acute Nonsevere Ischemic Stroke or Transient Ischemic Attack of Atherosclerotic Origin
Authors: Amarenco Pierre , Denison Hans , Evans Scott R. , Himmelmann Anders , James Stefan , Knutsson Mikael , Ladenvall Per , Molina Carlos A. , Wang Yongjun , Johnston S. Claiborne , Butcher Kenneth , Li Shuya , Zheng Huaguang , Skoloudik David , Wong Lawrence , Meshkova Ketevana , Suwanwela Nijasri C. , Ameriso Sebastian , Gonzalez Leonardo , Ioli Pablo , Jure Lorena , Povedano Guillermo , Bruera Guadalupe , Herrera Gustavo , Martin Artesi Juan Jose , Pujol Lereis Virginia A. , Estol Conrado J. , Gomez Schneider Maia , Pigretti Santiago , Lipovestky Fernando , Zurru María Cristina , Davis Stephen , Wong Andrew , Wijeratne Tissa , Sabet Arman , Lee Andrew , Thijs Vincent , Lemmens Robin , Yperzeele Laetitia , Vanhooren Geert , Vanacker Peter , Vansteenkiste Iris , Maqueda Vicky , Peeters André , Hasenbroekx, Van Daele Marie-Christine , Hasenbroekx Wendy , De Pauw Adinda , Oedit Regilio , De Vooght Wouter , Desfontaines Philippe , Vandermeeren Yves , De Pauw Adinda , Dracoulakis Marianna D.A. , Bazan Rodrigo , Pontes Neto Octavio M. , Bezerra Daniel D.C. , Marrone Luiz C. , Kowacs Pedro A. , Moro Carla H.C. , Macelino Paulo C.O. , Pedatella Marco Tulio A. , Titianova Ekaterina , Staikov Ivan , Maslarov Dimitar , Petkov Plamen , Beleva Tanya , Kralev Borislav , Sotirov Nikolay , Hristov Dimcho , Ivanova Rumeliya M. , Mihailova Margarita V. , Shuaib Ashfaq M. , Demchuk Andrew , Beaudry Michel , Winder Anthony R. , Nayar Sumiti , Zhao Xingquan , Wen Guoqiang , Dong Xueshuang , Li Guozhong , Zhang Zhaohui , Chen Huisheng , Wang Dong , Li Xiaohong , Wu Yuncheng , Zhang Xu , Zhang Baorong , Hong Wenke , Li Xiaogang , Wang Lijuan , Liu Li , Xu Xiaolin , Wang Peifu , Zheng Weihong , Zeng Jinsheng , Wang Yukai , Jia Yan , Li Yongqiu , Hu Bo , Shen Wei , Song Zhi , Hu Zhiping , Liu Yunhai , Ke Kaifu , Geng Deqin , Zhao Shigang , Zhu Runxiu , Qu Qiumin , Zhao Xiuli , Wan Qi , Yue Yunhua , Du Huishan , Zhang Meiyun , Wang Yan , Li Dongfang , Wang Dongyu , Li Yongqiang , Xie Xufang , Yu Tingmin , Liu Qi , Yang Mingxiu , Pan Xiaoping , Xu Lijun , Xu Deen , Li Gang , Xu Anding , Roubec Martin , Geier Petr , Vaclavik Daniel , Neumann Jiri , Bednarova Jana , Mikulik Robert , Hlinovsky David , Cordonnier Charlotte , Sibon Igor , Arquizan Caroline , Alamowitch Sonia , Lapergue Bertrand , Olivot Jean-Marc , Raposo Nicolas , Mahagne Marie-Hélène , Touze Emmanuel , Rodier Gilles , Vannier Stéphane , Samson Yves , Obadia Michael , Ellie Emmanuel , Guillon Benoît , Timsit Serge , Bejot Yannick , Wolff Valérie , Smadja Didier , Bagan-Triquenot Aude , Garnier Pierre , Ducrocq Xavier , Reiner Peggy , Moulin Thierry , Philippeau Frédéric , Pico Fernando , Richard Sébastien , Röther Joachim , Berrouschot Jörg , Soda Hassan , Pohlmann Carsten , Terborg Christoph , Nabavi Darius G. , Dziewas Rainer , Köhrmann Martin , Glahn Jörg , Marquardt Lars , Kallmünzer Bernd , Weißenborn Karin , Soo Yannie Oi-Yan , Li Richard , Fong Wing Chi , Li Siu Hung , Cheung Raymond , Yip Kin Keung , Fok Joshua Wai Ming , Fu Michael Y.P. , Szegedi Norbert , Pozsegovits Krisztián , Valikovics Attila , Pánczél Gyula , Rózsa Csilla , Diószeghy Péter , Csányi Attila , Kerényi Levente , Nagy Valéria , Szapáry László , Bereczki Dániel , Molnár Sándor , Timár Gyula , Folyovich András G. , Sátori Mária , Vastagh Ildikó , Kumar Praveen S. , Kumar Rajnish , Prasad Atul , Sharma Vikram , Verma Alok , Basu Indraneel , Ansari Abu Z. , Pamidimukkala Vijaya , B Raghavendra , S  , Junewar ., Vivek D. , Singh Sumit , Kulkarni Advait Prakash , Srivastava Padma M.V. , Pramod K. , Ramteke Sanjay G. , Bansal Jaideep , Krishan Kewal , Kumar Hrishikesh , Kashyap Priyanka V. , Ramakrishnan T.C.R. , Adrasetty Gopal R. , Yeole Amit , Baviskar Rahul B. , Agnelli Giancarlo , Toni Danilo , Ricci Stefano , Tassi Rossana , Micieli Giuseppe , Mancuso Michelangelo , Orlandi Giovanni , Chiti Alberto , Delodovici Marialuisa , Carimati Federico , De Vito Alessandro , Perini Francesco , Finocchi Cinzia , Tassinari Tiziana , Del Sette Massimo , Roveri Luisa , Zini Andrea , Bigliardi Guido , Pezzella Francesca R. , Cupini Letizia , Adami Alessandro , Tomelleri Giampaolo , Zanferrari Carla , Arauz Góngora Angel A. , López Ruíz Minerva , Ruíz Franco Angelica , Chacon Romero José O.J. , Cruz Castillo Fernando , Ruiz-Sandoval Jose L. , López Tapia Jesús D. , Castillo Vargas Edgar A. , Gongora Rivera Juan F. , Rivera Martinez Guillermo , Villarreal Careaga Jorge , Custodio Nilton , Pamo Reyna Oscar G. , Castañeda Cesar A. , Pretell Edwin J. , Najar Nestor , Perez Julio C. , Cardoza Luisa , Chavez Carlos , Reyes Maria , Członkowska Anna , Fryze Waldemar , Sobolewski Piotr , Nowak Ryszard , Szkopek Dorota , Bąk Zbigniew , Brzozowski Sławomir , Brola Waldemar , Zalisz Marek , Rejdak Konrad , Bilik Marta , Fudala Małgorzata , Tutaj Andrzej , Lasek-Bal Anetta , Kochanowicz Jan , Karaszewski Bartosz , Berkowicz Tomasz , Zwiernik Beata , Różański Dorota , Mejnartowicz Jan P. , Jurga Szymon , Rożniecki Jacek , Świat Maciej , Bajenaru Ovidiu A. , Panea Cristina A. , Simu Mihaela A. , Balasa Rodica , Cuciureanu Dan I. , Popescu Bogdan O. , Sabau Monica , Roman-Filip Corina , Odnopozova Liudmila , Artyukov Oleg , Milto Anna , Stakhovskaya Liudmila V. , Aksentiev Sergei , Chuprina Svetlana E. , Kuznetsova Elena B. , Sholomov Ilya I. , Malygin Alexander , Mordvintseva Elena , Nilk Rostislav Y. , Ershova Inna , Khasanova Dina , Akhmadeeva Leila , Iakupova Aida , Drozdova Ekaterina A. , Tanashyan Marine , Pudov Evgenij , Shpagina Lybov A. , Berns Svetlana , Lenskaya Liudmila G. , Golikov Konstantin , Kovalenko Andrey V. , Vasilieva Elena , Reznik Elena , Zykov Mikhail , Kovalchuk Evgeniy , Popov Dmitry , Belkin Andrey , Androfagina Olga , Lokshtanova Tatyana , Melnikova Elena V. , Al-Senani Fahmi , Almansour Nouf , Alhussein Fawaz , Alkhathaami Ali , Alghamdi Saeed , Brozman Miroslav , Mikloskova Marta , Krastev Georgi , Serdahely Vlastimil , Kovacik Michal , Gurcik Ladislav , Dvorak Miloslav , Kurca Egon , Cimprichova Andrea , Kycina Marian , Zacharova Erika , Risnovsky Richard , Bae Hee-Joon , Lee Kyung Bok , Cho Yong-Jin , Park Jong-Moo , Kim Joon-Tae , Lee Jun , Cha Jae-Kwan , Sohn Sung-Il , Shin Dong-Ick , Lee Soo Joo , Lee Byung-Chul , Choi Jay Chol , Park Moo Seok , Chang Dae-Il , Rha Joung-Ho , Sung Sang Min , Hwang Yangha , Roquer González Jaume , Masjuan Vallejo Jaime , Gomis Cortina Meritxell , Moniche Álvarez Francisco , Gamero García Miguel Ángel , Pérez Sánchez Soledad , Purroy García Francisco , Trillo Senín Santiago , Segura Martín Tomás , Serena Leal Joaquín , Arenillas Lara Juan , Martí-Fàbregas Joan , Lago Martín Aida , Tejero Juste Carlos , Marta Moreno Javier , López Hernández Nicolás , Sjöblom Lars , Laska Ann Charlotte , Callander Margarita , Mooe Thomas , Karlsson Jan-Erik , Romanitan Mihaela Oana , Lindgren Arne , Ahmed Niaz , Cederin Björn , Kremer Christine , Lee Tsong-Hai , Jeng Jiann-Shing , Chen Chih-Hung , Po Helen L. , Liou Chia-Wei , Lin Huey-Juan , Lin Ruey-Tay , Lin Hsiu-Fen , Lien Li-Ming , Chan Lung , Huang Wei-Shih , Huang Wen-Yi , Chen Ta-Cheng , Chen Chin-I , Chen Po-Lin , Yang Chun-Pai , Sun Yu , Chutinet Aurauma , Tantirittisak Tasanee , Muengtaweepongsa Sombat , Nilanont Yongchai , Tiamkao Somsak , Udommongkol Chesda , Jantararotai Witoon , Chongsuvivatwong Tabtim , Srisuwananukorn Suwat , Khaykhaew Wasutha , Paiboonpol Supachai , Limudomporn Makorn , Mayotarn Saengduan , Samintharapanya Kanoksri , Arayawichanon Arkhom , Thamangraksat Thanoot , Srimanee Duangpol , Chmyr Galyna , Tomakh Nataliya , Cherkez Alla , Moskovko Sergii , Nikonov Vadym , Shkrobot Svitlana , Shulga Lyudmyla , Hrebeniuk Hanna , Yavorska Valentyna , Lytvynenko Nataliia , Khavunka Marta , Kobets Iryna , Chemer Nataliia , Tashchuk Ivanna , Myronova Olha , Nguyen Thang H. , Vo Tan V. , Tran Thanh T. , Nguyen Nga T.P. , Nguyen Anh D. , Nguyen Binh T. , Nguyen Thang B. , Nguyen Ngoc H. , Nguyen Quang D. , Le Nhan D. , Pham. Dai D. 
Published: November 2020

Background and Purpose:
Among patients with a transient ischemic attack or minor ischemic strokes, those with ipsilateral atherosclerotic stenosis of cervicocranial vasculature have the highest risk of recurrent vascular events.

Methods:
In the double-blind THALES (The Acute Stroke or Transient Ischemic Attack Treated With Ticagrelor and ASA for Prevention of Stroke and Death) trial, we randomized patients with a noncardioembolic, nonsevere ischemic stroke, or high-risk transient ischemic attack to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–30) or placebo added to aspirin (300–325 mg on day 1 followed by 75–100 mg daily for days 2–30) within 24 hours of symptom onset. The present paper reports a prespecified analysis in patients with and without ipsilateral, potentially causal atherosclerotic stenosis ≥30% of cervicocranial vasculature. The primary end point was time to the occurrence of stroke or death within 30 days.

Results:

Of 11 016 randomized patients, 2351 (21.3%) patients had an ipsilateral atherosclerotic stenosis. After 30 days, a primary end point occurred in 92/1136 (8.1%) patients with ipsilateral stenosis randomized to ticagrelor and in 132/1215 (10.9%) randomized to placebo (hazard ratio 0.73 [95% CI, 0.56–0.96],
P
=0.023) resulting in a number needed to treat of 34 (95% CI, 19–171). In patients without ipsilateral stenosis, the corresponding event rate was 211/4387 (4.8%) and 230/4278 (5.4%), respectively (hazard ratio, 0.89 [95% CI, 0.74–1.08];
P
=0.23,
P
interaction
=0.245). Severe bleeding occurred in 4 (0.4%) and 3 (0.2%) patients with ipsilateral atherosclerotic stenosis on ticagrelor and on placebo, respectively (
P
=NS), and in 24 (0.5%) and 4 (0.1%), respectively, in 8665 patients without ipsilateral stenosis (hazard ratio=5.87 [95% CI, 2.04–16.9],
P
=0.001).

Conclusions:
In this exploratory analysis comparing ticagrelor added to aspirin to aspirin alone, we found no treatment by ipsilateral atherosclerosis stenosis subgroup interaction but did identify a higher absolute risk and a greater absolute risk reduction of stroke or death at 30 days in patients with ipsilateral atherosclerosis stenosis than in those without. In this easily identified population, ticagrelor added to aspirin provided a clinically meaningful benefit with a number needed to treat of 34 (95% CI, 19–171).

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT03354429.