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

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 center dot 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 center dot 2 years (IQR 56 center dot 1-70 center dot 6); 1921 (35 center dot 3%) were women and 3517 (64 center dot 7%) were men. Stroke occurred within 90 days in 213 (7 center dot 9%) patients in the indobufen group versus 175 (6 center dot 4%) in the aspirin group (HR 1 center dot 23, 95% CI 1 center dot 01-1 center dot 50; p non-inferiority=0 center dot 44). Moderate or severe bleeding occurred in 18 (0 center dot 7%) patients in the indobufen group and in 28 (1 center dot 0%) in the aspirin group (0 center dot 63, 95% CI 0 center dot 35 to 1 center dot 15; p=0 center dot 13). Adverse events within 90 days occurred in 666 (24 center dot 5%) patients in the indobufen group and 679 (24 center dot 9%) patients in the aspirin group (p=0 center dot 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 center dot 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 center dot 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. Copyright (c) 2023 Elsevier Ltd. All rights reserved.