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Indobufen versus aspirin in patients with acute ischaemic stroke in China (INSURE): a randomised, double-blind, double-dummy, active control, non-inferiority trial

2023; Elsevier BV; Volume: 22; Issue: 6 Linguagem: Inglês

10.1016/s1474-4422(23)00113-8

1474-4465

Yuesong Pan, Xia Meng, Baoshi Yuan, S. Claiborne Johnston, Hao Li, Philip M. Bath, Qiang Dong, Chunxue Wang, Jing Jing, Jinxi Lin, Yong Jiang, Xuewei Xie, Aoming Jin, Yue Suo, Hongqin Yang, Yefang Feng, Yanhua Zhou, Qing Liu, Xueli Li, Bin Liu, Hui Zhu, Jinguo Zhao, Xuerong Huang, Haitao Li, Yunyun Xiong, Zixiao Li, Yilong Wang, Xingquan Zhao, Liping Liu, Yongjun Wang, Yongjun Wang, Yanxia Wang, Cunrui Wang, Yazhou Han, Ming Yu, Hongqin Yang, Guoping Zou, Aisheng Wu, Guiru Zhang, Ping Zhang, Mingzong Yan, Jia Zhang, Jingyan Zhao, Huitian Zhang, Qin‐De Qi, Jianling Zhang, Zhishan Zhu, Jinguo Zhao, Wenfeng Fan, Xueli Li, Liguo Chang, Lan Tan, Liang Zhao, Yanzhong Xue, Peiru Liu, Xiaohua Ju, Zuowen Zhang, Linwen Li, Wei Feng, Lixia Yang, Xuemei Li, Zhixiong Zheng, Hui Liang, Wei Yan, Ming Zhang, Ting Wang, Jianbo Yang, Qing Liu, Panbing Huang, Guojun Tan, Yongming Chen, Jin Zhou, Zhongping An, Chunlei Li, Guohua Chen, Runxiu Zhu, Xin Sun, Liu Y, Mei Zhang, Yanguang Zhuo, Fanwen Meng, Hui Zhu, Kebo Li, Wei Zhang, Xiangting Chai, Ke Deng, Jianhua Li, Zhiyou Cai, Hailian Jin, Bo Li, Xiaomei Zhang, Beihai Ge, Wei Hu, Zhen Jiao, Lianmei Zhong, Lijie Ren, Xinyi Li, Songdi Wu, Yinguo Wan, Jinghua Zhang, Xiaoyan Ma, Jizheng Hu, Ge Zhang, Chunling Zheng, Jun Xu, Yuan Zou, Xuerong Huang, Zhihui Duan, Changxin Li, Qingxiu Zhang, Xiaoming Song, Zhengchang Jia, Chun Wang, Peining Shao, Jijun Teng, Hua Bao, Yang‐Kun Chen, Yunfei Wei, Xu Zhang, Xisi Meng, Guangning Li, Yefang Feng, Pengke Pan, Aixia Zhuang, Qiang Dong, Xiaofei Chen, Yanhua Zhou, Jun Tang, Hongwei An, Shihao You, Wei Zhang, Yanyan Tang, Guilian Zhang, Hongyan Li, Miao Guo, Chunlei Yu, Ying Li, Haichao Liu, Pengfei Liang, G. Kang, Huijie Sun, Yu Che, Juan Tang, Dandan Li, Xiaopeng Feng, Yu Geng, Bin Liu, Huibing Wang, Ping Shen, Zhu Huaiping, Farong Li, Lifang Zhang, Minghua Cao, Yong You, Guiyun Cui, Jun Gu, Haitao Li, Xiangfeng Zhang, Xiaojun Liu, Houqin Chen, Yuehua Zhang, Hongnian Zhao, Ke Liang, Rui Zhi, Ling Ma, Yuanhua Wu, Yalan Geng, Ping Sun, Bing Zhong, Dongxue Li, Jingya Jiao, Yanlei Hao, Guozhong Li, Shao-Hua Su, Weiping Ju, Lianqiu Min, Liyan Guo, Yafei Shangguan, Yingdong Tai, Ying Xing, Hongshan Chang, Wenya Chen, Hongtao Tang, Shuchun Huang, Jingxian Fang, Donghui Yu, Hailong Zhao, Lei Xu, Aimei Wu, Hebin Wan, Hongliang Wang, Zhihui Shen, Qing Zhang, Qian Wang,

Atrial Fibrillation Management and Outcomes

Background Aspirin is recommended for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke but can lead to gastrointestinal intolerance and bleeding. Indobufen is used as an alternative antiplatelet agent in some countries, despite an absence of large-scale clinical trials for this indication. We tested the hypothesis that indobufen is non-inferior to aspirin in reducing the risk of new stroke at 90 days in patients with moderate-to-severe ischaemic stroke. Methods We conducted a randomised, double-blind, double-dummy, active control, non-inferiority trial at 163 tertiary and district general hospitals in China. Eligible participants were aged 18–80 years with acute moderate-to-severe ischaemic stroke (National Institutes of Health Stroke Scale score 4–18). We randomly assigned (1:1) participants within 72 h of the onset of symptoms to receive either indobufen (100 mg tablet twice per day) or aspirin (100 mg tablet once per day) for 90 days. The randomisation sequence was computer generated centrally and stratified by local participating centres. Masked local investigators assigned the random code to patients in ascending order and provided a treatment kit corresponding to the random code. The primary efficacy outcome was new stroke and the primary safety outcome was severe or moderate bleeding, both within 90 days. This primary efficacy outcome was assessed in all randomly assigned and consenting patients and in a per-protocol group (ie, all patients finishing the treatment without major violation of the trial protocol). Safety analyses were done in the safety-analysis population (ie, all patients who received at least one dose of the study drug and had a safety assessment available). We assessed the non-inferiority of indobufen versus aspirin using the one-sided upper limit of the 95% CI of the hazard ratio (HR) with a prespecified non-inferiority margin of 1·25. This trial is registered with ClinicalTrials.gov (NCT03871517). Findings This trial took place between June 2, 2019, and Nov 28, 2021. Of 84 093 patients screened, 5438 patients were randomly assigned to receive either indobufen (n=2715) or aspirin (n=2723), all of whom were included in the primary analyses. Median age was 64·2 years (IQR 56·1–70·6); 1921 (35·3%) were women and 3517 (64·7%) were men. Stroke occurred within 90 days in 213 (7·9%) patients in the indobufen group versus 175 (6·4%) in the aspirin group (HR 1·23, 95% CI 1·01–1·50; pnon-inferiority=0·44). Moderate or severe bleeding occurred in 18 (0·7%) patients in the indobufen group and in 28 (1·0%) in the aspirin group (0·63, 95% CI 0·35 to 1·15; p=0·13). Adverse events within 90 days occurred in 666 (24·5%) patients in the indobufen group and 679 (24·9%) patients in the aspirin group (p=0·73). Interpretation In patients with acute moderate-to-severe ischaemic stroke, indobufen was not non-inferior to aspirin because the upper limit of the 95% CI was greater than 1·25. Furthermore, indobufen seemed to be inferior to aspirin in reducing the risk of recurrent stroke at 90 days because the lower limit of the 95% CI was greater than 1·00. Although moderate or severe bleeding did not differ between groups, these findings do not support the use of indobufen for secondary stroke prevention in patients with moderate-to-severe ischaemic stroke. Funding Hangzhou Zhongmei Huadong Pharmaceutical and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. Translation For the Chinese translation of the abstract see Supplementary Materials section.