This randomized clinical trial analyzes data for patients with acute noncardioembolic stroke who were given intravenous tirofiban within 24 hours of stroke onset to gauge its effect on early neurological deterioration compared with oral aspirin.
Key Points
Question
Does intravenous tirofiban reduce early neurological deterioration in patients with acute noncardioembolic stroke?
Findings
In this randomized clinical trial including 425 patients, the proportion of patients who experienced neurological deterioration within 72 hours was significantly lower in the tirofiban group compared with the aspirin group. The safety profiles of tirofan and aspirin were similar.
Meaning
Given the safety and efficacy profiles of intravenous tirofiban in patients with acute noncardioembolic stroke, tirofiban could be used as a first-line antiplatelet drug to prevent early neurological deterioration.
Abstract
Importance
Evidence supports using antiplatelet therapy in patients with acute ischemic stroke. However, neurological deterioration remains common under the currently recommended antiplatelet regimen, leading to poor clinical outcomes.
Objective
To determine whether intravenous tirofiban administered within 24 hours of stroke onset prevents early neurological deterioration in patients with acute noncardioembolic stroke compared with oral aspirin.
Design, Setting, and Participants
This investigator-initiated, multicenter, open-label, randomized clinical trial with blinded end-point assessment was conducted at 10 comprehensive stroke centers in China between September 2020 and March 2023. Eligible patients were aged 18 to 80 years with acute noncardioembolic stroke within 24 hours of onset and had a National Institutes of Health Stroke Scale (NIHSS) score of 4 to 20.
Intervention
Patients were assigned randomly (1:1) to receive intravenous tirofiban or oral aspirin for 72 hours using a central, web-based, computer-generated randomization schedule; all patients then received oral aspirin.
Main Outcome
The primary efficacy outcome was early neurological deterioration (increase in NIHSS score ≥4 points) within 72 hours after randomization. The primary safety outcome was symptomatic intracerebral hemorrhage within 72 hours after randomization.
Results
A total of 425 patients were included in the intravenous tirofiban (n = 213) or oral aspirin (n = 212) groups. Median (IQR) age was 64.0 years (56.0-71.0); 124 patients (29.2%) were female, and 301 (70.8%) were male. Early neurological deterioration occurred in 9 patients (4.2%) in the tirofiban group and 28 patients (13.2%) in the aspirin group (adjusted relative risk, 0.32; 95% CI, 0.16-0.65; P = .002). No patients in the tirofiban group experienced intracerebral hemorrhage. At 90-day follow-up, 3 patients (1.3%) in the tirofiban group and 3 (1.5%) in the aspirin group died (adjusted RR, 1.15; 95% CI, 0.27-8.54; P = .63), and the median (IQR) modified Rankin scale scores were 1.0 (0-1.25) and 1.0 (0-2), respectively (adjusted odds ratio, 1.28; 95% CI, 0.90-1.83; P = .17).
Conclusions and Relevance
In patients with noncardioembolic stroke who were seen within 24 hours of symptom onset, tirofiban decreased the risk of early neurological deterioration but did not increase the risk of symptomatic intracerebral hemorrhage or systematic bleeding.
Trial Registration
ClinicalTrials.gov Identifier: NCT04491695
Introduction
Acute ischemic stroke (AIS) is characterized by a sudden onset and quick peak of neurological deficits that often result in disability; however, from 5% to 40% of patients experience neurological deterioration (ND) after symptom onset, leading to worse outcomes and increased morbidity.1,2,3 Ischemic stroke progression is the main cause of ND, especially during the first few days after stroke onset.4,5 Antiplatelet therapy has been investigated to prevent early ND in patients with AIS. Two randomized clinical trials have found that in patients with AIS, intensive antiplatelet therapy with clopidogrel and aspirin could prevent early ND and improve functional outcomes. However, because of drug resistance and because the neurological deficit of dysphagia can lead to difficulty in administering drugs promptly, the incidence of early ND remains high in patients with AIS.6,7
Tirofiban, a rapid-onset and nonpeptide selective inhibitor of the platelet glycoprotein IIb/IIIa receptor, prevents thrombus formation by inhibiting the common pathway for platelet aggregation.8 Tirofiban is widely used in patients with acute coronary artery disease, reducing the risk of vascular complications and the need for revascularization if used early.9,10,11 Several clinical studies have suggested that tirofiban may be effective in patients with AIS, whether or not they were treated with intravenous thrombolysis or endovascular therapy.12,13,14,15 More recently, a large clinical trial found that intravenous tirofiban was associated with greater likelihood of an excellent outcome in patients with recent-onset stroke or progression of stroke symptoms and nonoccluded large- and medium-sized cerebral vessels.16 Whether tirofiban can prevent early ND in patients with AIS and a National Institutes of Health Stroke Scale (NIHSS) score of 4 or more remains unclear.
The Safety and Efficacy of Tirofiban for the Prevention of Neurological Deterioration in Acute Ischemic Stroke (TREND) trial was conducted to test the hypothesis that intravenous tirofiban could prevent early ND without increasing the risk of symptomatic intracerebral hemorrhage (ICH) in patients with acute noncardioembolic stroke and an NIHSS score of 4 to 20 if initiated within 24 hours of onset and used for 72 hours.
Methods
Trial Design
This study was an investigator-initiated, multicenter, prospective, randomized, open-label, blinded end-point trial. The trial protocol was approved by the ethics committees of Xuanwu Hospital, Capital Medical University, and all participating centers. The trial protocol and statistical analysis plan are in Supplement 1 and Supplement 2, respectively. All participating centers conducted the TREND trial according to the same protocol. All recruited patients or their legal representatives provided written informed consent before enrolment.
An independent data and safety monitoring board monitored the study’s adverse events, progress, and overall integrity. An independent clinical event committee adjudicated the efficacy and safety outcomes, procedure-related complications, and serious adverse events. This trial was conducted in accordance with the ethical principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The overall flow of patients and treatments in this trial is described in the Study Design and Treatment Allocation section of the eMethods of Supplement 3.
Participants
The study participants were adults aged 18 to 80 years who presented with AIS within 24 hours of symptom onset or time last known well, with a NIHSS score of 4 to 20 points. In addition, to alleviate the ceiling effect of the NIHSS score, the Medical Research Council score for paralyzed limbs was required to be 2 or higher. The detailed selection criteria are provided in the eMethods of Supplement 3.
Randomization and Masking
Patients meeting all the inclusion criteria and none of the exclusion criteria were allocated randomly to the intravenous tirofiban or oral aspirin groups in a 1:1 ratio. The local principal investigator or treating physician enrolled patients in the trial. Randomization was performed via a real-time, dynamic, internet-based procedure and stratified by age, infarction location, and prestroke treatment with antiplatelet drugs. A block size of 4 was used for stratified block randomization. The patients and treating physicians were aware of the study medications; the trial steering committee and investigators who performed the follow-up neurological function evaluations and examinations were blinded to the treatment allocation assignment and were not involved in the care of patients.
Study Procedures
All patients in the TREND trial were treated according to international and Chinese guidelines.17,18,19 The allocated treatments were initiated within 10 minutes after randomization. In the tirofiban group, intravenous tirofiban (tirofiban hydrochloride and sodium chloride injection, Grand Pharmaceutical) was administered at 0.4 μg/kg of body weight per minute for 30 minutes, followed by a continuous infusion of 0.1 μg/kg/min for up to 71.5 hours. Subsequently, patients received oral aspirin (Bayer Health Care Manufacturing). A 4-hour overlap was required when transitioning from tirofiban to oral medication. The patients in the oral aspirin group received oral aspirin directly. For all enrolled patients, aspirin was administered at 150 to 300 mg/d during the first 2 weeks after symptom onset and 100 to 300 mg/d after that for secondary prevention.
Clinical assessments were performed face to face at baseline; at 24, 48, and 72 hours after randomization; and on day 7 (or at discharge, whichever came earlier). Medical examinations were performed during screening, including blood tests, cranial computed tomography, and 12-lead electrocardiography. Treatment information, stroke cause classification, and imaging and blood examination results during hospitalization were recorded at discharge. Follow-up assessments were performed at 30 and 90 days; the outcome data were collected using centralized standardized telephone interviews.
End Points
The primary efficacy end point was early ND within 72 hours of randomization in the modified intention-to-treat population. Early ND was defined as an increase in NIHSS score of 4 or more points at any time within 72 hours of randomization compared with the score immediately before randomization. The baseline and follow-up NIHSS scores were assessed by the same 2 independent investigators blinded to the study allocation; any disagreement was resolved by consensus. If no consensus could be reached, another investigator blinded to the treatment assignment made the final decision. All the investigators involved in evaluating the NIHSS scores were trained and qualified for the assessment of NIHSS score.
Secondary efficacy end points were as follows: early ND within 72 hours of randomization (defined as an NIHSS score increase of ≥2 points compared with baseline), early improvement within 72 hours of randomization (defined as an NIHSS score decrease of ≥4 points), level of disability at 90 days as assessed by the shift across all 7 levels of the modified Rankin scale (mRS), an excellent functional outcome at 90 days (mRS score of 0-1), functional independence at 90 days (mRS score of 0-2), and change in NIHSS score from baseline to 24 hours, 72 hours, and 7 days.
The primary safety end point was symptomatic ICH within 72 hours after randomization. Symptomatic ICH was assessed using the European Cooperative Acute Stroke Study III criteria20 and defined as any ICH identified as the predominant cause of clinical deterioration with an NIHSS score increase of 4 points or more or leading to death. The other safety end points included death from any cause within 90 days, the incidence of ICH within 72 hours after randomization, systematic bleeding graded according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries criteria21 within 72 hours after randomization, and any adverse or serious adverse events within 90 days. The local principal investigators were responsible for reporting adverse events during hospitalization; the clinical events committee verified all adverse and severe adverse events.
Statistical Analysis
The sample size estimations were based on previous trials.22,23,24,25 The incidence of early ND was assumed to be 20.0% in the oral aspirin group; an absolute difference of 10 percentage points between the intravenous tirofiban and oral aspirin groups was expected. To demonstrate the expected treatment effect of an absolute difference of 10 percentage points (50% decrease in relative terms) with a type I error α of .05 (2-sided) and a power (1 − β) of 80%, a sample size of 400 patients (200 in each group) was required if they were allocated in a 1:1 ratio. A total sample size of 420 patients (210 per treatment group) was required, assuming a 5% attrition rate.
For the primary efficacy analysis, data were analyzed according to a modified intention-to-treat principle, which included patients who underwent randomization with the exception of 1 patient from the tirofiban group who was lost to follow-up within 72 hours. The χ2 test was used in the unadjusted analysis. In the adjusted analysis, Poisson regression with robust error was used and adjusted for age, sex, location of infarction, baseline NIHSS score, prestroke antiplatelet therapy, and stroke-cause subtype. The relative risk (RR) was calculated with a corresponding 95% CI. Subgroup analyses were prespecified for the primary outcome according to age, sex, infarction location determined by magnetic resonance imaging, NIHSS score, onset to randomization time, prestroke antiplatelet therapy, and stroke-cause subtype.
Data were analyzed according to the modified intention-to-treat principle for the secondary efficacy analysis. Early ND, early improvement, and the proportions of mRS scores in the ranges 0 to 1, 0 to 2, and 0 to 3 were similar to those of the primary efficacy outcome analysis. The t test or Wilcoxon rank sum test was used to analyze differences in neurological impairment and quality of life, as appropriate. Linear regression was used for NIHSS score changes in the adjusted analysis. The proportional odds model was used for the 90-day mRS scores in the shift analysis; the proportional odds assumption was evaluated using a Brant test. The adjusted analysis used the same variable as the primary efficacy outcome analysis.
Safety analysis was performed on the safety set population, defined as patients who received tirofiban within 72 hours of randomization. The χ2 test or Fisher exact test was used for the unadjusted analysis, as appropriate; Poisson regression with robust error was used for the adjusted analysis.
Prespecified sensitivity analyses of the efficacy outcomes were performed for the full analysis set (FAS), defined as patients who did not meet the inclusion criteria or satisfied the exclusion criteria, and the per-protocol population, defined as those excluded from the FAS because of study protocol violations.
No interim analyses were performed. No adjustments were made for multiplicity in the analysis of secondary outcomes. All statistical analyses were conducted with R version 4.3.1 (R Foundation for Statistical Computing). A 2-sided P ≤ .05 was considered significant. The TREND trial was registered at ClinicalTrials.gov (NCT04491695).
Results
Baseline Characteristics
Between September 12, 2020, and March 31, 2023, 682 patients were screened at 10 comprehensive stroke centers in China (Figure 1). The study included 425 patients (62.3%), with 213 in the tirofiban group and 212 in the aspirin group. Ten patients in the tirofiban group and 17 in the aspirin group did not meet the inclusion criteria or satisfy the exclusion criteria; these 27 patients were excluded from the FAS population. In addition, 7 patients in the tirofiban group and 7 in the aspirin group were excluded from the FAS population because of study protocol violations. Ultimately, 398 patients (203 in the tirofiban group and 195 in the aspirin group) were included in the FAS (eTable 1 in Supplement 3); 384 patients (196 in the tirofiban group and 188 in the aspirin group) were included in the per-protocol population (eTable 3 in Supplement 3).
Figure 1. Trial Profile.
CAS indicates carotid artery stent procedure; FAS, full analysis set; IVT, intravenous thrombolysis; mITT, modified intention-to-treat; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; PP, per-protocol.
The baseline characteristics were similar between the 2 groups of patients (Table 1). The median (IQR) age of 425 patients was 64.0 years (56.0-71.0 years); 124 patients (29.2%) were female, and 301 patients (70.8%) were male. The median (IQR) NIHSS score at admission was 5.0 (4.0-7.0) in the tirofiban group and 5.0 (4.0-8.0) in the aspirin group. The median (IQR) time from stroke onset to randomization was 12.5 hours (7.8-19.2 hours) in the tirofiban group and 10.5 hours (6.6-21.0 hours) in the aspirin group. The location of infarction for 238 patients (56.0%) was the anterior circulation, the cause for 114 patients (26.8%) was large-artery atherosclerosis, and 124 patients (29.2%) had small-vessel occlusion.
Table 1. Demographic and Baseline Characteristics.
| Characteristic | No. (%) | |
|---|---|---|
| Tirofiban group (n = 213) | Aspirin group (n = 212) | |
| Age, median (IQR), y | 64 (56-70) | 64 (56-71) |
| Sex | ||
| Male | 154 (72.3) | 147 (69.3) |
| Female | 59 (27.7) | 65 (30.7) |
| Medical history | ||
| Hypertension | 132 (62.0) | 134 (63.2) |
| Diabetes | 68 (31.9) | 67 (31.6) |
| Dyslipidaemia | 24 (11.3) | 25 (11.8) |
| Coronary heart disease | 27 (12.7) | 28 (13.2) |
| Cerebral infarction | 57 (26.7) | 59 (27.8) |
| Intracerebral hemorrhage | 5 (2.3) | 7 (3.3) |
| Smoking) | ||
| Previous smoking | 97 (45.5) | 103 (48.6) |
| Current smoking | 82 (38.5) | 87 (41) |
| Previous antiplatelet therapya | ||
| Single | 62 (29.1) | 65 (30.7) |
| Dual | 10 (4.7) | 6 (2.8) |
| Baseline NIHSS score, median (IQR) | 5 (4-7) | 5 (4-8) |
| Distribution | ||
| <10 | 188 (88.3) | 176 (83) |
| ≥10 | 25 (11.7) | 36 (17) |
| Location of cerebral infarction | ||
| Anterior circulation | 126 (59.2) | 112 (52.8) |
| Posterior circulation | 47 (22.1) | 53 (25) |
| Anterior and posterior circulation | 8 (3.8) | 17 (8) |
| Undefinedb | 32 (15.0) | 30 (14.2) |
| BP at randomization, median (IQR), mm Hg | ||
| Systolic | 155 (140-168) | 153 (138.5-168) |
| Diastolic | 88 (79-97) | 88 (78.5-99) |
| Glucose at admission, median (IQR), mmol/L | 6.4 (5.4-9.2) | 6.4 (5.4-9.0) |
| Stroke causec | ||
| Large-artery atherosclerosis | 49 (23.0) | 65 (30.7) |
| Cardioembolism | 4 (1.9) | 5 (2.4) |
| Small-vessel occlusion | 72 (33.8) | 52 (24.5) |
| Other determined cause | 0 | 3 (1.4) |
| Undetermined cause | 88 (41.3) | 87 (41) |
| Time from symptom onset to randomization, median interval (IQR), h | 12.5 (7.8-19.2) | 10.5 (6.6-21) |
| ≤12 h | 114 (53.5) | 126 (59.4) |
| >12 h | 99 (46.5) | 86 (40.6) |
| Degree of culprit vessel stenosisd | ||
| No stenosis | 93/169 (55) | 75/166 (45.2) |
| Mild (<50%) | 27/169 (16) | 27/166 (16.3) |
| Moderate stenosis (50%-69%) | 11/169 (6.5) | 19/166 (11.4) |
| Severe stenosis (70%-99%) | 22/169 (13) | 19/166 (11.4) |
| Occlusion (100%) | 15/169 (8.9) | 26/166 (15.7) |
Abbreviations: BP, blood pressure; NIHSS, National Institutes of Health Stroke Scale.
Taking antiplatelet drugs within 1 week before the present symptom onset.
Twelve patients (6 in the tirofiban group and 6 in the aspirin group) showed no cerebral infarction accounting for the neurological deficits, and 50 patients (26 in the tirofiban group and 24 in the aspirin group) lacked magnetic resonance imaging that prevented the localization of cerebral detection.
Based on the TOAST classification.
Culprit vessel occlusion or stenosis was defined based on vessel examinations and the diagnosis according to the clinician’s interpretation of clinical features and investigators’ results at discharge from the hospital. In the tirofiban group, 32 patients experienced acute ischemic stroke with undefined cerebral infarction, and 13 patients did not undergo computed tomographic, magnetic resonance, or digital subtraction angiography. In the aspirin group, 30 patients experienced neurological deficits with undefined cerebral infarction, and 16 patients did not undergo computed tomographic, magnetic resonance, or digital subtraction angiography.
Efficacy
Treatment with intravenous tirofiban was associated with decreased early ND (defined as an NIHSS score increase of ≥4 points), with 9 of 213 patients (4.2%) in the tirofiban group and 28 of 212 patients (13.2%) in the aspirin group (adjusted RR, 0.32; 95% CI, 0.16-0.65; P = .002) experiencing early ND within 72 hours of randomization (Table 2). The subgroup analyses of the primary outcomes are shown in Figure 2; the point estimates of all the subgroup analyses favored tirofiban even though some were not statistically significant because of a lack of statistical power. Tirofiban appeared to be more effective in the following subgroups: patients older than 60 years, those who had no antiplatelet therapy before the stroke, those with anterior circulation stroke, patients with an NIHSS score less than 10 points, those whose onset to randomization was longer than 12 hours, and those whose stroke subtype was large-artery atherosclerosis (Figure 2).
Table 2. Efficacy Outcomes for the Modified Intention-to-Treat Population.
| Endpoint | Tirofiban group (n = 213) | Aspirin group (n = 212) | Measure of effect | Unadjusted (95% CI) | Unadjusted P value | Adjusted (95% CI)a | Adjusted P valuea |
|---|---|---|---|---|---|---|---|
| Primary efficacy end point | |||||||
| Early ND within 72 h after randomization, No./total No. (%) | 9/213 (4.2) | 28/212 (13.2) | RR | 0.32 (0.15 to 0.66) | .001 | 0.32 (0.16 to 0.65) | .002 |
| Secondary efficacy end points | |||||||
| Early ND (NIHSS score increase ≥2 within 72 h after randomization), No./total No. (%) | 25/213 (11.7) | 50/212 (23.6) | RR | 0.50 (0.32 to 0.77) | .001 | 0.49 (0.32 to 0.75) | .001 |
| mRS score at 90 db | |||||||
| Median (IQR) | 1 (0 to 1.25) | 1 (0 to 2) | cOR | 1.30 (0.92 to 1.84) | .14 | 1.28 (0.90 to 1.83) | .17 |
| 0 or 1, No. (%) | 159/212 (75) | 145/212 (68.4) | RR | 1.10 (0.97 to 1.24) | .10 | 1.08 (0.97 to 1.21) | .16 |
| 0 to 2, No. (%) | 189/212 (89.2) | 182/212 (85.8) | RR | 1.04 (0.97 to 1.12) | .24 | 1.03 (0.96 to 1.10) | .47 |
| 0 to 3, No. (%) | 199/212 (93.9) | 197/212 (92.9) | RR | 1.01 (0.96 to 1.06) | .51 | 1.00 (0.96 to 1.05) | .88 |
| NIHSS score change from baseline | |||||||
| At 24 h after randomization | |||||||
| Median (IQR) | 0 (0 to 0) | 0 (0 to 0) | Median of differencec | 0 (0 to 0) | .51 | NA | NA |
| Mean (SD) | −0.33 (1.88) | −0.01 (3.26) | MD | −0.32 (−0.83 to 0.18) | .21 | −0.32 (−0.81 to 0.18) | .21 |
| At 72 h after randomization | |||||||
| Median (IQR) | −1 (−2 to 0) | −1 (−2 to 0) | Median of differencec | 0 (−1 to 0) | .38 | NA | NA |
| Mean (SD) | −0.97 (2.95) | −0.58 (3.77) | MD | −0.39 (−1.03 to 0.26) | .24 | −0.39 (−1.01 to 0.24) | .22 |
| At 7 d after randomization or at early discharge | |||||||
| Median (IQR) | −2 (−4 to −1) | −2 (−3 to 0) | Median of differencec | 0 (−1 to 0) | .32 | NA | NA |
| Mean (SD) | −2.03 (3.07) | −1.74 (3.01) | MD | −0.29 (−0.96 to 0.38) | .39 | −0.29 (−0.90 to 0.36) | .40 |
| Early improvement (NIHSS score decrease ≥4), No./total No. (%) | 28/213 (13.1) | 28/212 (13.2) | RR | 1.00 (0.61 to 1.62) | 1.00 | 1.13 (0.70 to 1.18) | .62 |
Abbreviations: cOR, crude odds ratio; MD, mean difference; mRS, modified Rankin scale; NA, not applicable; ND, neurological deterioration; NIHSS, National Institutes of Health Stroke Scale; RR, relative risk.
Adjusted for age, sex, location of infarction, baseline NIHSS score, prestroke antiplatelet therapy, and etiological stroke subtype.
One patient in the tirofiban group was lost to follow-up at 90 days.
Median of difference was calculated using Wilcoxon rank sum test with continuity correction.
Figure 2. Neurological Deterioration According to the Prespecified Subgroups.
MRI indicates magnetic resonance imaging; NIHSS, National Institutes of Health Stroke Scale.
The prespecified secondary outcomes are summarized in Table 2. If early ND was defined as an NIHSS score increase of 2 or more, treatment with intravenous tirofiban was associated with reduced early ND with 25 of 213 patients (11.7%) in the tirofiban group, and 50 patients (23.6%) in the aspirin group experienced early ND (adjusted RR, 0.49; 95% CI, 0.32-0.75; P = .001).
Patients in the tirofiban group had better functional outcomes at 90 days, even though no statistical between-group differences were detected (median mRS score = 1; IQR, 0-1.25, in the tirofiban group; mRS score = 1; IQR, 0-2, in the aspirin group; adjusted odds ratio 1.28; 95% CI, 0.90-1.83; P = .17) (Table 2 and Figure 3 and eFigures 1 and 3 in Supplement 3). Results of the excellent outcome, functional independence, early improvement within 72 hours of randomization, and changes in NIHSS score from baseline to 24 hours, 72 hours, and 7 days after randomization also favored tirofiban treatment, but no significant difference was detected (Table 2 and eTable 7 in Supplement 3).
Figure 3. Distributions of the Modified Rankin Scale Score at 90 Days.
One patient in the tirofiban group was lost to follow-up at 90 days.
Unadjusted analyses for primary and secondary outcomes were similar to the prespecified multivariable-adjusted analyses (Table 2). Results were similar for the modified intention-to-treat analysis and sensitivity analyses based on the FAS (eTable 2 and eFigure 2 in Supplement 3) and per-protocol populations (eTable 4 and eFigure 4 in Supplement 3).
Safety
The safety outcomes are presented in eTable 5 in Supplement 3. No patients in either treatment group experienced symptomatic ICH. Three of 226 patients (1.3%) treated with tirofiban and 3 of 198 (1.5%) treated with aspirin died by 90 days follow-up; the mortality did not significantly differ between treatment groups (adjusted RR, 1.15; 95% CI, 0.27-8.54; P = .63). None of the patients treated with tirofiban experienced ICH; 2 of 198 patients (1.0%) treated with aspirin experienced ICH. Serious adverse events occurred in 5 of 226 patients (2.2%) receiving tirofiban and 4 of 198 (2.0%) receiving aspirin (adjusted RR, 1.31; 95% CI, 0.35-4.88; P = .69) (eTable 6 in Supplement 3). Bleeding events were not significantly different between groups.
Discussion
This randomized clinical trial showed that, compared with oral aspirin, 72-hour treatment with intravenous tirofiban lowered the risk of early ND in patients with AIS with NIHSS scores of 4 to 20 who were assigned within 24 hours after symptom onset; it did not increase the risk of ICH or systematic bleeding. The reduction in the percentage of the tirofiban group demonstrating 4-point worsening in NIHSS score within 72 hours was not reflected in the 90-day mRS outcomes, where a nonsignificant favorable trend was observed.
Similar to a previous study that recruited patients within the first 24 hours after stroke onset, which showed the incidence of ND was 16.3% in the first 72 hours,24 the results of this study showed a 13.2% incidence of ND in the oral aspirin group. Consistent with 2 randomized clinical trials conducted in China, RESCUE BT-2 and ESCAPIST,16,26 this study screened and enrolled patients with potentially atherosclerotic AIS while excluding patients with suspected or definite cardioembolic stroke, assuming that tirofiban may be more effective in preventing early ND in patients with AIS due to large-artery atherosclerosis. Furthermore, the results of the subgroup analysis did show that tirofiban was effective in the large-artery atherosclerosis subgroup. Approximately 70% of patients were male in this study, which is similar to previous studies, and the findings of this trial applied to both sexes; the results of the subgroup analysis showed that tirofiban could reduce the incidence of ND in both male and female patients.
The incidence of ICH was 0.5% in this study, and no patients experienced symptomatic ICH. This finding may be attributable to most enrolled patients having had a mild stroke (the median NIHSS score was 5.0 at baseline); a lower risk of ICH was expected in patients with mild baseline symptoms and a small baseline infarct core.27 The TREND trial did not include patients with presumed cardioembolic stroke because this population often has a large infarction core and a high risk of hemorrhagic transformation, which could contribute to the low incidence of ICH. In addition, follow-up imaging was not mandatory in this trial, which may lead to the underreporting of asymptomatic ICH and contribute to the low incidence of ICH.
In this trial, the incidence of early ND between the 2 treatment groups showed a significant difference, which appeared inconsistent with the median change in NIHSS score between baseline and 72 hours. These discrepancies may be attributable to the fact that the data of change in NIHSS score at 72 hours from baseline were described with median and IQR, which appeared to be identical (ie, median: −1; IQR, −2 to 0) between the 2 groups. However, if the data of change in NIHSS score at 72 hours were described with mean (SD), there were changes of −0.97 (2.95) in the tirofiban group and −0.58 (3.77) in the aspirin group, respectively, which was in favor of the treatment of tirofiban and consistent with the beneficial effects of the primary outcome even though no statistical difference was detected.
Limitations
The TREND study had several limitations. This trial excluded patients who had a severe stroke (NIHSS score >20), minor stroke (NIHSS score <4), or cardioembolic stroke, and those who underwent intravenous thrombolysis or endovascular thrombectomy, possibly limiting the generalizability of the results. Second, although the results of this trial showed that intravenous tirofiban could reduce the incidence of ND, the mechanisms of ND (stroke progression, recurrent stroke, or others) were not distinguished, and follow-up imaging was not mandatory in this trial, which means asymptomatic ICH might have gone undetected and its incidence underestimated. In addition, due to the imperfect interrater and intrarater reliability of the NIHSS score, some patients may have been misclassified. Furthermore, this trial was conducted among Chinese patients with AIS, who have a high proportion of intracranial artery stenosis. Therefore, the results may not be generalizable to other populations. Finally, despite observing nonsignificant favorable trends across secondary efficacy outcomes, the benefit of tirofiban on early ND did not translate into a statistically significant change in NIHSS score at 24 or 72 hours from baseline, as well as in the 90-day mRS outcomes. Therefore, further studies are needed to determine the clinical benefit of tirofiban in this patient population.
Conclusions
In this randomized clinical trial among patients with acute noncardiacembolic ischemic stroke who presented within 24 hours of symptom onset, intravenous tirofiban resulted in a lower likelihood of early ND than oral aspirin. In addition, it was not associated with an increased risk of ICH or systematic bleeding. Further randomized clinical trials are needed to determine the efficacy of tirofiban for functional outcomes.
Trial protocol
Statistical analysis plan
eMethods
eTable 1. Demographic and Baseline Characteristics of the Full-Analysis-Set
eTable 2. Efficacy Outcomes of the Full-analysis-set
eTable 3. Demographic and Baseline Characteristics of the Per-protocol Population
eTable 4. Efficacy Outcomes of the Per-protocol Population
eTable 5. Safety Outcomes of the Intention-to-treat Population
eTable 6. Number of Patients with Adverse Events (by System Organ Class) Up to 90-day Visit
eTable 7. Efficacy Outcomes of the Intention-to-treat Population with an Additional Post-hoc Adjustment of the Culprit Vessel Occlusion
eFigure 1. Distributions of the mRS Scores at 90 Days in the Full-analysis-set
eFigure 2. The Relative Risk for Neurological Deterioration According to the Prespecified Subgroups in the Full-analysis-set
eFigure 3. Distributions of the mRS Scores at 90 Days in the Per-protocol Population
eFigure 4. The Relative Risk for Neurological Deterioration According to the Prespecified Subgroups in the per-protocol population
Nonauthor collaborators
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol
Statistical analysis plan
eMethods
eTable 1. Demographic and Baseline Characteristics of the Full-Analysis-Set
eTable 2. Efficacy Outcomes of the Full-analysis-set
eTable 3. Demographic and Baseline Characteristics of the Per-protocol Population
eTable 4. Efficacy Outcomes of the Per-protocol Population
eTable 5. Safety Outcomes of the Intention-to-treat Population
eTable 6. Number of Patients with Adverse Events (by System Organ Class) Up to 90-day Visit
eTable 7. Efficacy Outcomes of the Intention-to-treat Population with an Additional Post-hoc Adjustment of the Culprit Vessel Occlusion
eFigure 1. Distributions of the mRS Scores at 90 Days in the Full-analysis-set
eFigure 2. The Relative Risk for Neurological Deterioration According to the Prespecified Subgroups in the Full-analysis-set
eFigure 3. Distributions of the mRS Scores at 90 Days in the Per-protocol Population
eFigure 4. The Relative Risk for Neurological Deterioration According to the Prespecified Subgroups in the per-protocol population
Nonauthor collaborators
Data sharing statement