Abstract
Background
Tirofiban has emerged as a potential treatment for acute ischemic stroke. We aimed to evaluate the efficacy and safety of tirofiban in patients with minor stroke within 4.5 hours of symptom onset.
Methods
We emulated a target trial using observational data. Patients with minor stroke (National Institutes of Health Stroke Scale score ≤5) who received tirofiban or alteplase within 4.5 hours were included. The primary outcome was excellent functional outcome (modified Rankin Scale score 0–1) at 90 days. Secondary outcomes included modified Rankin Scale score of 0 to 2 at 90 days, 24‐hour National Institutes of Health Stroke Scale changes, ordinal shift in modified Rankin Scale, and early neurological deterioration or improvement. Safety outcomes included symptomatic intracranial hemorrhage, intracranial hemorrhage, any bleeding, and 90‐day all‐cause death.
Results
Of 677 eligible patients, 369 received tirofiban and 308 received alteplase. There was no significant difference in 90‐day modified Rankin Scale score of 0 to 1 between groups (risk ratio, 1.06 [95% CI, 0.97–1.16]; P=0.20). Tirofiban was associated with lower risks of neurological deterioration at 24 hours (risk ratio, 0.31 [95% CI, 0.16–0.59]; P<0.001), intracranial hemorrhage (risk ratio, 0.06 [95% CI, 0.01–0.46]; P=0.007), and any bleeding (risk ratio, 0.13 [95% CI, 0.06–0.30]; P<0.001). No symptomatic intracranial hemorrhage occurred in the tirofiban group. Ninety‐day all‐cause death did not differ significantly.
Conclusions
In minor acute ischemic stroke treated within 4.5 hours, intravenous tirofiban showed no significant difference in 90‐day functional outcomes relative to alteplase and was associated with lower risks of early neurological deterioration and bleeding, suggesting it could be considered a potential treatment option pending further randomized trials.
Registration
URL: https://www.chictr.org.cn; Unique Identifier: ChiCTR2500106107.
Keywords: alteplase, functional outcome, intravenous thrombolysis, minor stroke, target trial emulation, tirofiban
Subject Categories: Cerebrovascular Disease/Stroke, Ischemic Stroke
Nonstandard Abbreviations and Acronyms
- AIS
acute ischemic stroke
- ARAMIS
Antiplatelet Versus R‐tPA for Acute Mild Ischemic Stroke
- ECASS III
European Cooperative Acute Stroke Study III
- END
early neurological deterioration
- ICH
intracranial hemorrhage
- mRS
modified Rankin Scale
- NIHSS
National Institutes of Health Stroke Scale
- PP
per‐protocol
- PRISMS
Potential of rtPA for Ischemic Strokes With Mild Symptoms
- PUMICE
Prourokinase in Mild Ischemic Stroke
- RESCUE BT2
Efficacy and Safety of Tirofiban Compared With Aspirin in the Treatment of Acute Ischemic Stroke
- sICH
symptomatic intracranial hemorrhage
- TOAST
Trial of ORG 10172 in Acute Stroke Treatment
- TREND
Tirofiban for the Prevention of Neurological Deterioration in Acute Ischemic Stroke
Clinical Perspective.
What Is New?
In patients with minor acute ischemic stroke treated within 4.5 hours of symptom onset, tirofiban showed no significant difference in 90‐day functional outcomes compared with alteplase and was associated with lower risks of early neurological deterioration and bleeding.
What Are the Clinical Implications?
These findings suggest that tirofiban may be a treatment option for patients with minor acute ischemic stroke when administered within 4.5 hours of symptom onset.
Acute ischemic stroke (AIS) is a leading cause of disability and death worldwide. 1 Minor AIS, typically defined as a National Institutes of Health Stroke Scale (NIHSS) score ≤5, accounts for more than half of all AIS cases. 2 Despite mild symptoms at presentation, approximately one third of patients with minor AIS still have poor functional outcomes at 90 days. 3 , 4 Current guidelines recommend intravenous thrombolysis for disabling minor AIS. 5 , 6 , 7 For nondisabling minor AIS, the PRISMS (Potential of rtPA for Ischemic Strokes With Mild Symptoms) study showed no significant difference in 90‐day functional outcomes between intravenous alteplase and oral aspirin. 8 The ARAMIS (Antiplatelet Versus R‐tPA for Acute Mild Ischemic Stroke) trial demonstrated that oral dual antiplatelet therapy was noninferior to intravenous alteplase. 9 A recent meta‐analysis of 4 randomized controlled trials indicated that, compared with standard care, intravenous thrombolysis did not improve functional outcomes in disabling or nondisabling minor AIS and was associated with an increased risk of symptomatic intracranial hemorrhage (sICH) and death. 10
Tirofiban, a fast‐acting, highly selective nonpeptide glycoprotein IIb/IIIa receptor inhibitor, effectively reduces platelet aggregation and prevents thrombus formation. 11 Due to its short half‐life, the antiplatelet effect of tirofiban is rapidly reversible after discontinuation. 12 The RESCUE BT2 (Efficacy and Safety of Tirofiban Compared With Aspirin in the Treatment of Acute Ischemic Stroke) trial showed that intravenous tirofiban significantly improved the proportion of excellent functional outcomes in patients with AIS without large‐ or medium‐vessel occlusion. 13 The TREND (Tirofiban for the Prevention of Neurological Deterioration in Acute Ischemic Stroke) study found that intravenous tirofiban reduced the incidence of early neurological deterioration (END) in patients with AIS. 14 However, these trials initiated tirofiban within 24 hours of symptom onset and excluded patients with minor AIS. Therefore, the efficacy and safety of tirofiban in minor AIS within 4.5 hours of onset have not been fully evaluated.
Using a target trial emulation framework, this study aimed to compare intravenous tirofiban and alteplase in patients with minor AIS treated within 4.5 hours of symptom onset, including patients with both disabling and nondisabling stroke in terms of functional outcomes, NIHSS score changes, bleeding events, and all‐cause death.
METHODS
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Data Source
We consecutively enrolled patients with minor AIS admitted to the Department of Neurology at the China–Japan Union Hospital of Jilin University between January 2022 and February 2025. The China–Japan Union Hospital of Jilin University is an advanced stroke center in China, performing >300 intravenous thrombolysis procedures annually. The hospital maintains an internal stroke database, recording clinical information and 90‐day follow‐up outcomes (obtained via telephone) for hospitalized patients with stroke. The study was conducted in accordance with the principles of the Declaration of Helsinki, and the study report adheres to the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. The study protocol was approved by the Ethics Committee of China–Japan Union Hospital of Jilin University (2025062302) and registered with the Chinese Clinical Trial Registry (ChiCTR2500106107). Written informed consent was waived due to the retrospective nature of the study.
Baseline demographic and clinical data, including age, sex, hypertension, diabetes, prior stroke history, coronary heart disease, atrial fibrillation, hyperlipidemia, current smoking, systolic and diastolic blood pressure at admission, prestroke modified Rankin Scale (mRS) score (range, 0–6), time from symptom onset to treatment, baseline NIHSS score, 24‐hour NIHSS score, fasting blood glucose, imaging, and early evolution of symptoms, were extracted from the hospital stroke database for all eligible patients. Stroke onset was defined as the last time the patient was seen in a normal state. Minor stroke was defined by an NIHSS total score of ≤5. According to the 2019 American Heart Association/American Stroke Association guidance on indications for intravenous thrombolysis, disabling stroke was defined as complete hemianopia (NIHSS item 3, score ≥2), severe aphasia (NIHSS item 9, score ≥2), neglect (NIHSS item 11, score ≥1), any limb weakness unable to resist gravity (NIHSS item 6 or 7, score ≥2), or any functional deficit resulting in an NIHSS total score >5. Cases not meeting these criteria were classified as instances of nondisabling minor stroke. 5 Stroke subtypes were classified according to the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) system as large‐artery atherosclerosis, small‐vessel occlusion, cardioembolism, undetermined pathogenesis, or other determined pathogenesis. 15 Stroke location was classified on the basis of clinical symptoms and imaging data as anterior circulation stroke (anterior cerebral artery, middle cerebral artery, or internal carotid artery) or posterior circulation stroke (posterior cerebral artery, vertebral artery, or basilar artery).
Target Trial Emulation Protocol
Inclusion and Exclusion Criteria
Inclusion criteria were as follows: (1) patients aged ≥18 years; (2) patients diagnosed with AIS, with an NIHSS total score of ≤5; and (3) patients who received treatment within 4.5 hours of symptom onset. Separately, patients who met the following criteria were excluded: (1) prestroke mRS score ≥2; (2) patients with a history of cerebral hemorrhage and other guideline‐based contraindications to intravenous thrombolysis 7 ; (3) patients enrolled in a randomized controlled trial with uncertainty about receiving placebo; and (4) patients who planned to receive mechanical thrombectomy at admission. The study allowed rescue mechanical thrombectomy or intravenous tirofiban following END.
Treatment Strategies
Treatment choice was physician dependent according to our national guidelines. 7 The tirofiban group received an intravenous bolus of 0.4 μg/kg per minute of tirofiban for the first 30 minutes, followed by a continuous infusion of 0.1 μg/kg per minute for 24 to 72 hours. The duration of tirofiban infusion was determined by the treating physician on the basis of the patient's clinical condition. Antiplatelet or other antithrombotic therapy was bridged 4 hours before the end of tirofiban infusion according to guidelines. Separately, the alteplase group received a total dose of 0.9 mg/kg (maximum 90 mg), with 10% given as a bolus and 90% infused over 1 hour. Antiplatelet or other antithrombotic therapy was initiated 24 hours after thrombolysis according to guidelines.
Assignment Procedure
Time 0 was defined as the time when patients completed the necessary imaging and laboratory examinations, which was the earliest reliably recorded time point closest to eligibility confirmation in this retrospective study. Patients were classified according to the observed treatment strategy within 4.5 hours of symptom onset. Each eligible patient was cloned and assigned to each treatment group at time 0 to emulate randomization. Patients who did not adhere to their assigned treatments were censored, and inverse probability of censoring weighting was applied to account for artificial censoring. Separately, inverse probability of treatment weighting was applied to adjust for baseline covariates to ensure comparability between treatment groups.
Follow‐Up
Patients were evaluated at baseline, 24 hours, and 7 days or at discharge (if earlier) and 90 days after time 0.
Outcome Measures
The primary outcome was excellent functional outcome at 90 days (mRS score 0–1). The secondary outcomes were favorable functional outcome at 90 days (mRS score 0–2), neurological improvement at 24 hours (defined by an NIHSS score decrease of ≥2 from baseline), neurological deterioration at 24 hours (defined by an NIHSS score increase of ≥2 from baseline, not due to cerebral hemorrhage), 24‐hour NIHSS score change, and ordinal shift in mRS score at 90 days.
The safety outcomes were sICH, any ICH, any bleeding events within 7 days or at discharge (if earlier), and all‐cause death at 90 days. sICH was defined per ECASS III (European Cooperative Acute Stroke Study III) criteria as cerebral or intracranial hemorrhage identified as the primary cause of neurological deterioration, with an NIHSS score increase of ≥4 or leading to death. 16
Causal Contrast and Analysis Plan
The primary effect analysis was based on modified intention‐to‐treat (ITT) analysis and per‐protocol (PP) analysis.
Sample Size Calculation
Previous studies reported 90‐day mRS score 0 to 1 rates of 88.5% in the intravenous thrombolysis group and 75% in the tirofiban group. 14 , 17 Given the lower baseline NIHSS scores in our study population, we assumed a 90‐day mRS score 0 to 1 rate of 80% in the tirofiban group. With a 2‐sided α of 0.05 and 80% power, the estimated sample size was 288 cases per group. Assuming a 10% rate of loss to follow‐up, the total sample size was 634 cases.
Statistical Analysis
The Shapiro–Wilk test was used to assess the normality of continuous variables. Group differences were compared using Student's t test or the Mann–Whitney U test on the basis of normality, reported using mean±SD values or median (interquartile range [IQR]) values. Categorical variables were compared using the χ2 test or Fisher's exact test and reported as frequencies (percentages).
A logistic regression model was used to construct a propensity score model, incorporating baseline covariates, including age, sex, hypertension, diabetes, prior stroke history, coronary heart disease, hyperlipidemia, atrial fibrillation, current smoking, systolic and diastolic blood pressure at admission, time from symptom onset to treatment, baseline NIHSS score, fasting blood glucose, disabling status, and early evolution of symptoms. In the modified ITT analysis, each eligible patient was cloned and assigned to each treatment group at time 0. Each patient was followed until treatment initiation. Clones were censored if the patient did not receive the assigned treatments. In the PP analysis, additional informative censoring was applied at the time patients received rescue therapy, showed failure to adhere to the treatments, or were lost to follow‐up. To reduce selection bias introduced by artificial censoring, stabilized inverse probability of censoring weights was applied, which adjusted the weights of the remaining patients according to the probability of not being censored. Separately, stabilized inverse probability of treatment weights was applied to address imbalance in covariates and confounders. The product of stabilized inverse probability of censoring weighting and stabilized inverse probability of treatment weighting was used to estimate the treatment effect in the modified ITT analysis and the PP analysis. Extreme weights were truncated at the first and 99th percentiles. Standardized mean differences were calculated for each covariate after weighting, with standardized mean difference <0.1 indicating good balance between groups.
In the weighted data set, modified Poisson regression models with robust standard errors were used to estimate risk ratios (RRs) and 95% CIs for the primary and other binary outcomes. Linear regression models were used to analyze group differences in NIHSS score changes, reported as mean differences with SD and 95% CI. Ordinal logistic regression was used for shift analysis to assess the effect of treatment strategies on the 90‐day mRS distribution, with the Brant test performed to evaluate the proportional odds assumption, reported as odds ratios with 95% CIs. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs for all‐cause death. Missing data were handled using multiple imputation, generating 20 complete data sets. The same weighting and statistical models were applied to each imputed data set, and estimates were combined using Rubin's rules to obtain overall effect estimates and 95% CIs. 18
Subgroup analyses for the primary outcome were conducted by age (<65 or ≥65 years), sex (male or female), diabetes history (yes or no), baseline NIHSS score (0–3 or 4–5), time from onset to treatment (<3 or 3–4.5 hours), disabling status (yes or no), stroke subtype (large‐artery atherosclerosis, small‐vessel occlusion, cardioembolism, other determined cause, undetermined cause), and stroke location (anterior circulation, posterior circulation, anterior and posterior circulation), with interaction P values reported.
Sensitivity analyses were performed using complete case analysis to assess the robustness of the results. In addition, patients were censored at the time of early evolution of symptoms to evaluate the impact of early evolution of symptoms on the treatment effect. Next, a landmark analysis was performed including only patients who initiated treatment within 60 minutes after admission to further mitigate potential immortal time bias and reduce bias arising from delayed treatment initiation. Statistical significance was set at a 2‐sided P≤0.05. Statistical analyses were conducted using R 4.5.1 software (R Development Core Team; http://www.r‐project.org).
RESULTS
Between January 2022 and February 2025, 766 patients diagnosed with minor AIS within 4.5 hours of onset were assessed for eligibility. After screening, 677 patients were included in the modified ITT analysis, including 369 in the tirofiban group and 308 in the alteplase group. The median age was 65 years (IQR, 58–72), and 202 (29.8%) were women. Twenty‐five (tirofiban group, n=12; alteplase group, n=13) patients were lost to follow‐up within 90 days. The tirofiban group had a longer mean time from onset to treatment, lower baseline NIHSS scores, reduced proportions of disabling stroke and hyperlipidemia, older mean age, and lower systolic and diastolic blood pressures at admission. Two patients in the tirofiban group underwent mechanical thrombectomy, while 8 in the alteplase group underwent mechanical thrombectomy, and 18 received tirofiban due to END. Ultimately, 624 patients were included in the PP analysis (Figure 1).
Figure 1. Patient inclusion and exclusion flowchart.
END indicates early neurological deterioration; and mRS, modified Rankin Scale.
After weighting, a weighted population was obtained, including 367.0 patients in the tirofiban group and 298.7 in the alteplase group, with more balanced baseline characteristics (standardized mean differences <0.1 for all covariates). The median baseline NIHSS score was 2 (IQR, 1–4) in the tirofiban group and 2 (IQR, 1–3) in the alteplase group, with a mean time from stroke onset to treatment of 180 minutes (IQR, 120–240) and 180 minutes (IQR, 120–210), respectively. Details of baseline characteristics before and after weighting are shown in Table 1.
Table 1.
Baseline Characteristics (ITT Population)
| Baseline characteristics | Before IPTW | After IPTW | |||
|---|---|---|---|---|---|
| Tirofiban (n=369) | Alteplase (n=308) | Tirofiban (n=367.0) | Alteplase (n=298.7) | SMD | |
| Age, y, median (IQR) | 66 (58–73) | 64 (57–70) | 65 (57–71) | 65 (58–70) | 0.024 |
| Sex, n (%) | |||||
| Male | 257 (69.7) | 218 (70.8) | 255.3 (69.6) | 206.3 (69.1) | 0.011 |
| Female | 112 (30.3) | 90 (29.2) | 111.8 (30.5) | 92.4 (30.9) | |
| Hypertension, n (%) | 228 (61.8) | 181 (58.8) | 226.2 (61.6) | 182.0 (60.9) | 0.015 |
| Diabetes, n (%) | 118 (32.0) | 82 (26.6) | 108.4 (29.5) | 84.9 (28.4) | 0.025 |
| History of stroke, n (%) | 107 (29.0) | 75 (24.4) | 99.2 (27.0) | 80.8 (27.0) | 0.001 |
| Coronary heart disease, n (%) | 44 (11.9) | 42 (13.6) | 45.1 (12.3) | 35.9 (12.0) | 0.008 |
| Atrial fibrillation, n (%) | 30 (8.1) | 14 (4.6) | 23.7 (6.5) | 18.5 (6.2) | 0.012 |
| Smoking, n (%) | 136 (36.9) | 128 (41.6) | 142.8 (38.9) | 117.6 (39.4) | 0.009 |
| Systolic blood pressure, mm Hg, median (IQR) | 143 (132–161) | 150 (140–165) | 145 (133–164) | 150 (139–163) | 0.026 |
| Diastolic blood pressure, mm Hg, median (IQR) | 83 (76–91) | 86 (79–94) | 84 (78–93) | 85 (79–93) | 0.038 |
| Glucose, mg/dL, median (IQR) | 5.9 (5.2–7.3) | 5.8 (5.1–7.1) | 5.8 (5.2–7.2) | 5.7 (5.0–6.9) | 0.029 |
| Hyperlipidemia, n (%) | 189 (51.2) | 182 (59.1) | 202.7 (55.2) | 172.1 (57.6) | 0.048 |
| Time from onset to treatment, min, median (IQR) | 180.0 (120.0–240.0) | 150.0 (120.0–180.0) | 180.0 (120.0–240.0) | 180.0 (120.0–210.0) | 0.055 |
| Baseline NIHSS score, median (IQR) | 2 (1–3) | 3 (2–4) | 2 (1–4) | 2 (1–3) | 0.058 |
| Disabling stroke, n (%) | |||||
| Yes | 47 (12.7) | 66 (21.4) | 57.8 (15.8) | 48.2 (16.1) | 0.010 |
| No | 322 (87.3) | 242 (78.6) | 309.2 (84.3) | 250.6 (83.9) | |
| Early evolution of symptoms, n (%) | |||||
| Worsening | 2 (0.54) | 5 (1.62) | 1.8 (0.49) | 2.7 (0.91) | 0.050 |
| Improvement | 8 (2.17) | 7 (2.27) | 8.0 (2.19) | 6.4 (2.16) | |
The sample sizes in the table represent the effective sample sizes after weighting, and all analyses used exact weight values.
IPTW, inverse probability of treatment weighting; IQR, interquartile range; ITT, intention‐to‐treat; NIHSS, National Institutes of Health Stroke Scale; and SMD, standardized mean differences.
Primary Outcome
In the modified ITT analysis, after weighting, the proportion of patients with an mRS score of 0 to 1 at 90 days was 80.3% in the tirofiban group and 75.7% in the alteplase group, with no statistically significant difference (RR, 1.06 [95% CI, 0.97–1.16]; P=0.20; Table 2). In the PP analysis, the corresponding proportions were 80.6% in the tirofiban group and 79.6% in the alteplase group, also showing no statistically significant difference (RR, 1.01 [95% CI, 0.93–1.10]; P=0.78; Table 3). Similar group differences were observed in the sensitivity analysis (Tables S1). Subgroup analyses demonstrated interactions between treatment effect and time from onset to treatment, sex, and stroke location (P for interaction<0.05). Among patients treated within 3 hours of onset, the tirofiban group appeared to have a trend toward better functional outcomes. No heterogeneity in treatment effects was observed in other subgroups (Figure 2).
Table 2.
Efficacy and Safety Outcomes in the ITT Population
| Outcomes | No. with event (%) | |||
|---|---|---|---|---|
| Tirofiban (n=367.0) | Alteplase (n=298.7) | Effect estimate (95% CI) | P value | |
| Primary outcome | ||||
| mRS score 0–1 at 90 d | 294.7 (80.3) | 226.1 (75.7) | 1.06 (0.97 to 1.16) | 0.20 |
| Secondary outcomes | ||||
| mRS score 0–2 at 90 d | 331.4 (90.3) | 258.4 (86.5) | 1.04 (0.98 to 1.11) | 0.17 |
| Early neurological improvement at 24 h | 24.2 (6.6) | 63.0 (21.1) | 0.31 (0.18 to 0.53) | <0.001 |
| Early neurological deterioration at 24 h | 15.4 (4.2) | 40.6 (13.6) | 0.31 (0.16 to 0.59) | <0.001 |
| NIHSS score change at 24 h from baseline, mean±SD | −0.04±1.11 | 0.26±3.77 | −0.31 (−0.72 to 0.10) | 0.14 |
| mRS score distribution at 90 d | 0.77 (0.57–1.03) | 0.08 | ||
| Safety outcomes | ||||
| sICH at 7 d or discharge | 0 (0) | 4.2 (1.4) | NE | NE |
| ICH at 7 d or discharge | 0.7 (0.2) | 10.8 (3.6) | 0.06 (0.01–0.46) | 0.007 |
| Any bleeding at 7 d or discharge | 5.1 (1.4) | 32.0 (10.7) | 0.13 (0.06–0.30) | <0.001 |
| All‐cause death at 90 d | 1.5 (0.4) | 6.3 (2.1) | 0.21 (0.04–1.06) | 0.06 |
The sample sizes in the table represent the effective sample sizes after weighting, and all analyses used exact weight values.
ICH indicates intracranial hemorrhage; ITT, intention‐to‐treat; mRS, modified Rankin Scale; NE, not estimated; NIHSS, National Institutes of Health Stroke Scale; and sICH, symptomatic intracranial hemorrhage.
Table 3.
Efficacy and Safety Outcomes in the PP Population
| Outcomes | No. with event (%) | |||
|---|---|---|---|---|
| Tirofiban (n=352.7) | Alteplase (n=262.2) | Effect estimate (95% CI) | P value | |
| Primary outcome | ||||
| mRS score 0–1 at 90 d | 284.3 (80.6) | 208.7 (79.6) | 1.01 (0.93 to 1.10) | 0.78 |
| Secondary outcomes | ||||
| mRS score 0–2 at 90 d | 319.2 (90.5) | 234.1 (89.3) | 1.01 (0.96 to 1.07) | 0.65 |
| Early neurological improvement at 24 h | 22.2 (6.3) | 61.1 (23.3) | 0.27 (0.16 to 0.47) | <0.001 |
| Early neurological deterioration at 24 h | 14.8 (4.2) | 35.7 (13.6) | 0.31 (0.16 to 0.59) | <0.001 |
| NIHSS score change at 24 h from baseline, mean±SD | −0.03±1.13 | −0.10±3.43 | 0.07 (−0.35 to 0.5) | 0.74 |
| mRS score distribution at 90 d | 0.88 (0.65 to 1.19) | 0.41 | ||
| Safety outcomes | ||||
| sICH at 7 d or discharge | 0 (0) | 3.9 (1.5) | NE | NE |
| ICH at 7 d or discharge | 0 (0) | 8.7 (3.3) | NE | NE |
| Any bleeding at 7 d or discharge | 2.8 (0.8) | 26.7 (10.2) | 0.08 (0.03 to 0.24) | <0.001 |
| All‐cause death at 90 d | 1.4 (0.4) | 3.7 (1.4) | 0.30 (0.05 to 1.81) | 0.19 |
The sample sizes in the table represent the effective sample sizes after weighting, and all analyses used exact weight values.
ICH indicates intracranial hemorrhage; mRS, modified Rankin Scale; NE, not estimated; NIHSS, National Institutes of Health Stroke Scale; PP, per‐protocol; and sICH, symptomatic intracranial hemorrhage.
Figure 2. Subgroup analysis of the primary outcome in the intention‐to‐treat population.
The sample sizes in the figure are the rounded values after weighting, and all analyses used exact weight values. NIHSS indicates National Institutes of Health Stroke Scale; and RR, risk ratio.
Secondary Outcomes
In the modified ITT analysis, after weighting, the tirofiban group had a lower rate of END at 24 hours compared with the alteplase group (RR, 0.31 [95% CI, 0.16–0.59]; P<0.001), while the alteplase group had more frequent neurological improvement at 24 hours (RR, 0.31 [95% CI, 0.18–0.53]; P<0.001). No statistically significant differences were observed between groups in 90‐day mRS score of 0 to 2 (RR, 1.04 [95% CI, 0.98–1.11]; P=0.17), 24‐hour NIHSS score change (mean difference, −0.31 [95% CI, −0.72 to 0.10], P=0.14), or 90‐day mRS score distribution (odds ratio, 0.77 [95% CI, 0.57–1.04], P=0.08; Figure 3). Similar results were obtained in the PP analysis (Table 3).
Figure 3. Distribution of modified Rankin Scale Scores at 90 days in the intention‐to‐treat population.
Safety Outcomes
In the modified ITT analysis, after weighting, no patients in the tirofiban group experienced sICH, while 1.4% of patients in the alteplase group did. The incidence of ICH was 0.2% in the tirofiban group and 3.6% in the alteplase group (RR, 0.06 [95% CI, 0.01–0.46]; P=0.007). Any bleeding events occurred in 1.4% of the tirofiban group and 10.7% of the alteplase group (RR, 0.13 [95% CI, 0.06–0.30]; P<0.001). No statistically significant difference was observed in 90‐day all‐cause death between groups (HR, 0.21 [95% CI, 0.04–1.06]; P=0.06). Similar results were obtained in the PP analysis (Table 3).
DISCUSSION
This target trial emulation study showed that, in patients with minor AIS within 4.5 hours of onset, the proportion of patients achieving an excellent functional outcome (mRS score 0–1) at 90 days was similar between those receiving intravenous tirofiban and those receiving intravenous alteplase. However, the tirofiban group had significantly lower rates of END at 24 hours, sICH, any ICH, and any bleeding events. Intravenous tirofiban did not increase the risk of 90‐day all‐cause death. Subgroup analysis suggested that tirofiban might be associated with greater benefit in patients treated within 3 hours of symptom onset.
In the unweighted data, some baseline characteristics were imbalanced between the tirofiban and alteplase groups. However, after inverse probability weighting, all baseline characteristics were balanced, and the weighted baseline characteristics were similar to those in 2 randomized controlled trials, the ARAMIS and PUMICE (Prourokinase in Mild Ischemic Stroke) trials, conducted in Chinese populations with minor AIS. 9 , 17 However, the rate of excellent functional outcome at 90 days in our study was slightly lower than that reported in these 2 randomized controlled trials. This difference may be partly explained by the strict exclusion of disabling stroke in the ARAMIS trial and the lower proportion of disabling stroke in the PUMICE trial (11.2% versus 16.7% in our study). Moreover, unlike these randomized trials, our study was based on real‐world observational data, in which treatment selection may have been influenced by clinical severity and imaging findings. To reduce the resulting selection bias, we applied stabilized inverse probability of treatment weighting including key covariates. After weighting, all standardized mean differences were <0.1, indicating acceptable baseline balance. In subgroup analyses, a trend toward better functional outcomes with tirofiban was observed among patients treated within 3 hours of onset. However, given the exploratory nature of subgroup analyses, these findings should be interpreted cautiously and considered hypothesis generating.
Regarding secondary outcomes, the tirofiban group had a significantly lower rate of END (4.2% versus 13.6%), consistent with a randomized controlled trial in China on early intravenous tirofiban for preventing END in AIS (4.2%). 14 One possible explanation is that tirofiban has a rapid onset of action and potent antiplatelet effects, which may help prevent further thrombus propagation or reocclusion. However, the alteplase group showed greater early neurological improvement (21.1% versus 6.6%), consistent with the ARAMIS and PUMICE trials. 9 , 17 This early improvement did not translate into significant differences in 90‐day functional outcomes, possibly due to the higher risk of END and sICH in the alteplase group, which may offset the potential benefits of early improvement. In addition, our results demonstrated no significant difference in mean 24‐hour NIHSS change between groups. However, the alteplase group exhibited higher rates of both early neurological improvement and END. The increased END may offset the benefits of early neurological improvement, potentially explaining the absence of a statistically significant difference in overall NIHSS change.
For safety outcomes, the tirofiban group had a lower ICH incidence (0.2%), with no cases of sICH, consistent with the TREND trial's ICH incidence of 0.5%. 14 The alteplase group had an sICH incidence of 1.4%, similar to the ARAMIS (0.9%) and PUMICE (0.7%) trials. 9 , 17
The strengths of this study lie in its use of a target trial emulation framework, which simulates a target trial by clearly defining inclusion/exclusion criteria, treatment strategies, assignment procedures, and causal contrasts, thereby reducing confounding and selection biases common in observational studies. 19 Stabilized inverse probability weighting effectively balanced baseline covariates, and multiple imputation addressed missing data. The consistency between ITT and PP analyses and the sensitivity analysis further validated the findings' reliability. The study's real‐world data included both disabling and nondisabling minor AIS, which enhances the clinical applicability and generalizability of the results. These strengths collectively fortify the evidence base for tirofiban as a potential alternative treatment for minor AIS.
However, this study also has some limitations. First, as an observational study, despite using a target trial emulation framework to simulate randomization and adjust for baseline confounders, residual confounding or unmeasured confounding may remain. This is particularly relevant for imaging findings (large‐vessel occlusion screening, perfusion–diffusion mismatch, and early ischemic changes), which were not routinely obtained for all patients and therefore not included in the propensity score model (Table S4). Residual confounding from these unmeasured imaging factors cannot be excluded and may have influenced treatment selection and observed outcomes. Another confounder is the posttreatment antiplatelet therapy. Patients receiving alteplase cannot receive antiplatelets for 24 hours while patients receiving tirofiban may have had more intensive antithrombotic therapy early. In addition, residual bias cannot be fully excluded because the exact time of treatment decision could not be directly determined in this retrospective study. Second, the study's single‐center design and enrollment of patients primarily from China and a high proportion of men, may limit the generalizability of the results to other races or regions. Third, the sample size may be insufficient. The absolute difference in treatment effect actually observed in this study was 4.6%, which is less than the preset absolute difference in treatment effect (8.5%). The discrepancy between the expected and the observed effect may result in an insufficient sample size calculation, which may explain the absence of statistical significance in the primary outcome. Nevertheless, the results of this study may provide a reference for the sample size in future studies of patients with minor AIS receiving tirofiban therapy within 4.5 hours of onset.
CONCLUSIONS
In minor AIS treated within 4.5 hours, intravenous tirofiban showed no significant difference in 90‐day excellent functional outcomes relative to alteplase and was associated with lower risks of early neurological deterioration and bleeding, suggesting it could be considered a potential treatment option pending further randomized trials.
Sources of Funding
This study was supported by the Jilin Provincial Special Project for Health Scientific Research Talents (2025SCZ41), the Jilin Provincial Science and Technology Innovation Platform Construction Project (YDZJ202602CXJD064), and the Clinical Research Project of China–Japan Union Hospital of Jilin University (ZBK2025037).
Disclosures
None.
Supporting information
Tables S1–S4
STROBE Checklist
This manuscript was sent to Fadar Oliver Otite, MD, SM, Associate Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.125.047187
For Sources of Funding and Disclosures, see page 10.
Contributor Information
Jing Mang, Email: mangjing@jlu.edu.cn.
Zhongxin Xu, Email: xuzhongxin@jlu.edu.cn.
References
- 1. GBD 2021 Nervous System Disorders Collaborators . Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the global burden of disease study 2021. Lancet Neurol. 2024;23:344–381. doi: 10.1016/S1474-4422(24)00038-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Xiong Y, Gu H, Zhao XQ, Yang X, Wang C, Wang YL, Liu LP, Zhou Q, Fisher M, Li Z, et al. Clinical characteristics and in‐hospital outcomes of varying definitions of minor stroke: from a large‐scale nation‐wide longitudinal registry. Stroke. 2021;52:1253–1258. doi: 10.1161/STROKEAHA.120.031329 [DOI] [PubMed] [Google Scholar]
- 3. Saber H, Khatibi K, Szeder V, Tateshima S, Colby GP, Nour M, Jahan R, Duckwiler G, Liebeskind DS, Saver JL. Reperfusion therapy frequency and outcomes in mild ischemic stroke in the United States. Stroke. 2020;51:3241–3249. doi: 10.1161/STROKEAHA.120.030898 [DOI] [PubMed] [Google Scholar]
- 4. Romano JG, Smith EE, Liang L, Gardener H, Campo‐Bustillo I, Khatri P, Bhatt DL, Fonarow GC, Sacco RL, Schwamm LH. Distinct short‐term outcomes in patients with mild versus rapidly improving stroke not treated with thrombolytics. Stroke. 2016;47:1278–1285. doi: 10.1161/STROKEAHA.115.011528 [DOI] [PubMed] [Google Scholar]
- 5. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, Biller J, Brown M, Demaerschalk BM, Hoh B, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2019;50:e344–e418. doi: 10.1161/STR.0000000000000211 [DOI] [PubMed] [Google Scholar]
- 6. Berge E, Whiteley W, Audebert H, De Marchis GM, Fonseca AC, Padiglioni C, de la Ossa NP, Strbian D, Tsivgoulis G, Turc G. European Stroke Organisation (ESO) guidelines on intravenous thrombolysis for acute ischaemic stroke. Eur Stroke J. 2021;6:I–LXII. doi: 10.1177/2396987321989865 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Liu L, Chen W, Zhou H, Duan W, Li S, Huo X, Xu W, Huang L, Zheng H, Liu J, et al. Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of ischaemic cerebrovascular diseases. Stroke Vasc Neurol. 2020;5:159–176. doi: 10.1136/svn-2020-000378 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Khatri P, Kleindorfer DO, Devlin T, Sawyer RN Jr, Starr M, Mejilla J, Broderick J, Chatterjee A, Jauch EC, Levine SR, et al. Effect of alteplase vs aspirin on functional outcome for patients with acute ischemic stroke and minor nondisabling neurologic deficits: the PRISMS randomized clinical trial. JAMA. 2018;320:156–166. doi: 10.1001/jama.2018.8496 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Chen HS, Cui Y, Zhou ZH, Zhang H, Wang LX, Wang WZ, Shen LY, Guo LY, Wang EQ, Wang RX, et al. Dual antiplatelet therapy vs alteplase for patients with minor nondisabling acute ischemic stroke: the ARAMIS randomized clinical trial. JAMA. 2023;329:2135–2144. doi: 10.1001/jama.2023.7827 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Doheim MF, Nguyen TN, Xiong Y, Chen HS, Bhatt NR, Wang Y, Nogueira RG. Meta‐analysis of randomized controlled trials on IV thrombolysis in patients with minor acute ischemic stroke. Neurology. 2025;105:e213863. doi: 10.1212/WNL.0000000000213863 [DOI] [PubMed] [Google Scholar]
- 11. Yang M, Huo X, Miao Z, Wang Y. Platelet glycoprotein IIb/IIIa receptor inhibitor tirofiban in acute ischemic stroke. Drugs. 2019;79:515–529. doi: 10.1007/s40265-019-01078-0 [DOI] [PubMed] [Google Scholar]
- 12. RESCUE BT Trial Investigators , Qiu Z, Li F, Sang H, Luo W, Liu S, Liu W, Guo Z, Li H, Sun D, et al. Effect of intravenous tirofiban vs placebo before endovascular thrombectomy on functional outcomes in large vessel occlusion stroke: the RESCUE BT randomized clinical trial. JAMA. 2022;328:543–553. doi: 10.1001/jama.2022.12584 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Zi W, Song J, Kong W, Huang J, Guo C, He W, Yu Y, Zhang B, Geng W, Tan X, et al. Tirofiban for stroke without large or medium‐sized vessel occlusion. N Engl J Med. 2023;388:2025–2036. doi: 10.1056/NEJMoa2214299 [DOI] [PubMed] [Google Scholar]
- 14. Zhao W, Li S, Li C, Wu C, Wang J, Xing L, Wan Y, Qin J, Xu Y, Wang R, et al. Effects of tirofiban on neurological deterioration in patients with acute ischemic stroke: a randomized clinical trial. JAMA Neurol. 2024;81:594–602. doi: 10.1001/jamaneurol.2024.0868 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators . Low molecular weight heparinoid, Org 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA. 1998;279(16):1265–1272. doi: 10.1001/jama.279.16.1265 [DOI] [PubMed] [Google Scholar]
- 16. Neuberger U, Möhlenbruch MA, Herweh C, Ulfert C, Bendszus M, Pfaff J. Classification of bleeding events: comparison of ECASS III (European Cooperative Acute Stroke Study) and the new Heidelberg bleeding classification. Stroke. 2017;48:1983–1985. doi: 10.1161/STROKEAHA.117.016735 [DOI] [PubMed] [Google Scholar]
- 17. Xiong Y, Meng X, Jin A, Campbell BCV, Xu A, Dong Q, Xu Y, Pan Y, Jiang Y, Niu S, et al. Prourokinase vs standard care for patients with mild ischemic stroke: the PUMICE randomized clinical trial. JAMA Neurol. 2025;82:258–266. doi: 10.1001/jamaneurol.2024.4688 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Sterne JA, White IR, Carlin JB, Spratt M, Royston P, Kenward MG, Wood AM, Carpenter JR. Multiple imputation for missing data in epidemiological and clinical research: potential and pitfalls. BMJ. 2009;338:b2393. doi: 10.1136/bmj.b2393 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am J Epidemiol. 2016;183:758–764. doi: 10.1093/aje/kwv254 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Tables S1–S4
STROBE Checklist