The ESCAPIST trial was an open-label, multicenter, and randomized trial performed between March 27, 2020 and March 27, 2021 at seven-stroke centers in China. All the enrolled patients provided a written informed consent prior to inclusion. This study was in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice Guidelines and the CONSORT statement. The trial protocol was approved by the ethics committee of the Affiliated Hospital of Qingdao University and all participating centers. The ESCAPIST trial was registered on the Chinese Clinical Trial Registry (http://www.chictr.org.cn; ChiCTR2000031297).

Inclusion criteria included aged 18 years or older, mild-to-moderate stroke [National Institutes of Health Stroke Scale (NIHSS) score, 4–15], within 12 h after stroke onset, and patient or his legal representative signing informed consent. The main exclusion criteria were undergoing rt-PA or EVT treatment, the premorbid modified Rankin Scale (mRS) score of ≥ 2 [mRS; range, 0 (no symptoms) to 6 (death)], intracranial hemorrhage within 3 months, disturbance of blood coagulation, aberrant thrombocytopenia or neutropenia, severe cardiac, hepatic or renal insufficiency, a life expectancy of <3 months, pregnancy, and atrial fibrillation. Considering a relatively high risk of hemorrhagic transformation, we excluded patients with stroke due to cardiogenic embolism defined according to a published study (18).

Eligible patients were randomly assigned (1:1) to receive tirofiban with regular treatment or to receive regular treatment alone (control). Randomization was conducted using the computer and stratified by a clinical center. Investigators and patients were aware of the treatment allocation. However, independent trained outcome assessors and statisticians were masked to the treatment assignment. Randomization and treatments were monitored by the ethics committee of each participating center. In the control group, regular treatment was aspirin at a dose of 100 mg per day for 90 days. In the tirofiban group, patients received tirofiban (Lunan Better Pharmaceutical Corporation, LTD, Linyi, China) infusion, a loading dose of 0.4 μg/kg/min over 30 min followed by a maintenance dose of 0.1 μg/kg/min up to 48 h. Subsequently, regular treatment was initiated 4 h before the completion of tirofiban infusion. Other strategies of treatment included statins, management of blood glucose, blood pressure, or combinations of these treatments, which follow the current guidelines for the early management of patients with AIS from the American Heart Association/American Stroke Association (5).

The primary efficacy outcome was the proportion of favorable functional outcome (mRS score, 0–2) at 90 days. The secondary efficacy outcomes included a shift in the distribution of 90-day mRS scores and the NIHSS score (range, 0–42) at 24 h and 7 days. The higher NIHSS score represents the more severe stroke. In addition, we conducted a subgroup analysis of favorable functional outcomes according to age (≤ 80 years or > 80 years), time to randomization (0–4.5 h or 4.5–12 h; 0–8 h or 8–12 h), the Trial of Org 10172 in Acute Stroke Treatment classification [large-artery atherosclerosis (LAA) group or small-vessel occlusion (SVO) group] (19) and diabetes mellitus (Yes or No).

The primary safety outcome was sICH as reflected by neuroimaging evidence (CT or MRI) and aggravated neurological symptoms (a change in NIHSS by ≥4 points) within 7 days. The sICH was defined according to the Heidelberg Bleeding Classification (20). Other safety outcomes included all-cause mortality and bleeding from any other organ within 90 days after treatment. An independent central adjudication committee, masked to the treatment assignment, confirmed the efficacy and safety outcomes collected.

For the primary efficacy outcome, the proportion of 90-day favorable functional outcome was assumed to increase by 15% with tirofiban plus regular treatment compared to that with regular treatment alone. Assuming a dropout rate of 10% and 1:1 randomization, a sample of 400 patients (200 patients in each group) was estimated and provided a power of 86% with a two-sided type I error of 0.05 to detect the difference between the two groups.

All data were analyzed using Statistical Analysis System (SAS) software (version 9.4). For categorical variables, data were presented as numbers and percentages. For continuous variables, data were presented using median with interquartile range (IQR). The chi-squared test, the Mann–Whitney U-test, or the Fisher's exact test was used to compare differences for categorical variables and continuous variables between two groups, as appropriate. The shift in the direction of a better outcome on the mRS scores was estimated with multivariable ordinal logistic regression as an adjusted common odds ratio (OR) with 95% CIs between the two groups. All the analyses were two sides. P < 0.05 were considered to indicate statistical significance.

From March 27, 2020 to March 27, 2021, 415 patients were assessed and 35 of 415 patients decided to withdraw from this trial before randomization. Finally, 380 eligible patients were enrolled from seven-stroke units in China and randomly assigned to tirofiban plus regular treatment (n = 190) or regular treatment alone (n = 190) (Figure 1). After randomization, 18 patients (8 of 190 patients in the tirofiban group and 10 of 190 patients in the control group) decided to withdraw their informed consent immediately without treatment. Five patients refused to receive tirofiban treatment. No patients were lost during the 90-day follow-up.

At baseline, the median age was 67 (IQR, 59–75), and 126 (70.0%) patients were men in the control group, while the numbers were 67 (IQR, 59–74) and 115 (65.0%), respectively, in the tirofiban group (Table 1). The proportion of stroke subtype [LAA: 86 (47.8%) vs. 72 (40.7%); p = 0.18] was generally similar (Table 1). The median NIHSS score at baseline was 5 (IQR, 4–8) in the control group and 6 (IQR, 4-8) in the tirofiban group (p = 0.78). Overall, the baseline demographic and clinical characteristics of the two groups were well-balanced. In this study, 49 patients within 4.5 h after stroke onset were enrolled in the control group and 50 patients within 4.5 h after stroke onset were enrolled in the tirofiban group. Considering hemorrhagic transformation, 33 of 49 patients refused rt-PA treatment in the control group and 38 of 50 patients refused rt-PA treatment in the tirofiban group. In addition, 16 patients in the control group and 10 patients in the tirofiban group did not receive rt-PA treatment due to contraindications with a history of ischemic stroke within 3 months. Two patients in the tirofiban group were given up treatment due to the high cost of rt-PA (Supplementary Table 1).

The primary outcome defined as the 90-day mRS score of 0–2 was evaluated and analyzed. The proportion of patients with a favorable functional outcome was 79.1% (140 of 177) in the tirofiban group vs. 67.8% (122 of 180) in the control group (OR, 1.80; 95% CI, 1.12 to 2.90; p = 0.0155), which was in favor of the tirofiban intervention (Table 2). A shift in the distribution of the mRS scores toward better outcome was associated with tirofiban treatment (adjusted common OR, 2.31; 95% CI, 1.58 to 3.39; p < 0.0001) (Figure 2). The median mRS score was 1 (IQR, 0–2) in the tirofiban group and 2 (IQR, 1–3) in the control group (Table 2) at 90 days. The median NIHSS score at 24 h was 6 (IQR, 4–9) in the control group, and 3 (IQR, 2–6) in the tirofiban group, indicating an improved neurological deficit (p < 0.0001). At 7 days, the median NIHSS score was also lower in the tirofiban group [3 (IQR, 1–5)] than that in the control group [5 (IQR, 2–8)] (p < 0.0001) (Table 2). All the secondary clinical outcomes favored tirofiban intervention.

There was no difference in the occurrence of serious adverse events between the two groups (Table 2). The rate of sICH was 0.6% in both groups (p = 0.99). The proportion of patients with gastrointestinal, urological, gingival, or mucocutaneous bleeding, was 4.0 vs. 3.3% (OR, 1.19; 95% CI, 0.39–3.63; p = 0.75). However, the mortality rate at 90 days was decreased after tirofiban treatment (0.6 vs. 3.9%; OR, 0.14; 95% CI, 0.02–1.15; p = 0.0339) (Table 2).

The favorable functional outcome at 90 days (mRS, 0–2) was further analyzed (Figure 3). In patients with age <80 years, tirofiban treatment effects (132 of 164 [80.5%] patients with mRS ≤ 2) were stronger than control [107 of 160 (66.9%) patients with mRS ≤ 2] (OR, 2.04; 95% CI, 1.23–3.39; p = 0.0054). The time to receive tirofiban on the influence of functional outcome was also assessed. We observed a higher proportion of patients with a favorable outcome (79.4%, 108 of 136) in the tirofiban group than that (67.9%, 89 of 131) in the control group within 8 h after stroke onset (OR, 1.82; 95% CI, 1.05–3.17; p = 0.0331) (Figure 3). In addition, we further performed analysis on patients eligible or ineligible for rt-PA treatment. The data indicated that a more favorable outcome was achieved in the tirofiban group. For patients who were eligible for rt-PA treatment, the proportion of favorable outcomes was 87.5% (35 of 40) in the tirofiban group, and the proportion was 66.7% (22 of 33) in the control group (p = 0.04). For patients who were ineligible for rt-PA treatment, the proportion of favorable outcomes was 78.7% (100 of 127) in the tirofiban group, and the proportion was 64.1% (84 of 131) in the control group (p = 0.01) (Figure 3). We also assessed the patients eligible or ineligible for rt-PA treatment in the tirofiban group. However, there was no significant difference for the proportion of favorable outcomes in patients eligible for rt-PA compared to that in patients ineligible for rt-PA (87.5 vs. 78.7%; p = 0.26). Additionally, the difference was not significant between patients who were qualified for EVT and patients who were not qualified for EVT (76 vs. 60%; p = 0.07). Although there was no statistical significance between the two groups, there was an upward trend for the proportion of favorable outcomes in patients who were treated with tirofiban at an early stage. These data further reflect that IVT and EVT are more effective treatments for AIS.

The treatment effects among different etiology of stroke also varied greatly between the two groups. The patients with AIS due to LAA were more likely to have a favorable functional outcome in the tirofiban group than the control group (OR, 2.67; 95% CI, 1.38–5.17; p = 0.0033) (Figure 3). In the LAA subtype, the NIHSS score decreased at 24 h and 7 days in the tirofiban group compared with the control group (p < 0.0001) (Supplementary Table 2). However, the treatment effects did not differ in patients with AIS due to SVO between the two groups (OR, 1.05; 95% CI, 0.48–2.31; p = 0.90) (Figure 3). Although the NIHSS score decreased at 24 h after stroke onset in the tirofiban group that belongs to the SVO subtype (p = 0.0017), there was no difference at 7 days between the two groups (p = 0.0551) (Supplementary Table 2). Similarly, we observed that tirofiban was only effective in patients with AIS due to LAA within 8 h (OR, 2.44; 95% CI, 1.16–5.14; p = 0.0182). However, no difference in tirofiban treatment effects existed between the two groups in other situations (Supplementary Table 3). In addition, it seemed that tirofiban exerts a better effect in patients without diabetes mellitus, although there was no statistically significant difference between the two groups (Figure 3).