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Abstract

Introduction:

The degree of culprit artery stenosis affects the risk of early neurological deterioration (END) after acute ischemic stroke (AIS). The TREND trial demonstrated the efficacy of tirofiban in preventing END in patients with AIS. We aimed to investigate whether the degree of intracranial artery stenosis affects the efficacy of tirofiban in preventing END in patients with AIS.

Patients and Methods:

We conducted a post hoc analysis of the TREND trial, which enrolled patients within 24 h of onset and randomly allocated to receive intravenous tirofiban or oral aspirin. We stratified the stenosis degrees into three subgroups: no stenosis, mild-to-moderate stenosis (stenosis <70%), and severe stenosis or occlusion (stenosis ⩾70%). The primary endpoint is END₄ defined as an increase of the NIHSS ⩾4 within 72 h after randomization. Secondary outcomes include END₂ (defined as an increase of NIHSS ⩾2) within 72 h after randomization, the proportion of mRS 0–1 and 0–2 at 90 days.

Results:

A total of 296 patients were analyzed. In patients with severe stenosis or occlusion, tirofiban significantly reduced the incidence of END₄ (5.7% vs 30.8%, adjusted OR 0.156, 95% CI 0.028–0.873, adjusted p = 0.034), whereas its effects in preventing END₄ were similar to those of aspirin in patients with no stenosis (2.4% vs 4.6%, adjusted OR 0.193, 95% CI 0.018–2.083, adjusted p = 0.175) or mild-to-moderate stenosis (2.9% vs 10.0%, adjusted OR 0.171, 95% CI 0.015–1.943, adjusted p = 0.155). The p value for interaction between stenosis subgroups and treatment was 0.513. Furthermore, tirofiban significantly reduced the incidence of END₂ in patients with mild-to-moderate stenosis (5.9% vs 22.5%, OR 0.146, 95% CI 0.022–0.951, adjusted p = 0.044) and severe stenosis or occlusion (11.4% vs 43.6%, adjusted OR 0.140, 95% CI 0.036–0.540, adjusted p = 0.004). A significant improvement in favorable outcomes with a 90-day mRS of 0–1 was observed only in patients with mild-to-moderate stenosis (85.3% vs 70.0%, adjusted OR 4.617, 95% CI 1.077–19.798, adjusted p = 0.039).

Discussion and conclusion:

Tirofiban may significantly reduce the incidence of END in patients with severe arterial stenosis or occlusion. Further studies are required to confirm the effects of intracranial artery stenosis on the benefits of intravenous tirofiban.

Trial registration:

ClinicalTrials.gov; identifier: NCT04491695.

Graphical Abstract

This is a visual representation of the abstract.

Keywords

Tirofiban intracranial artery stenosis ischemic stroke neurological deterioration

Introduction

Up to 40% of patients experience neurological deterioration in the early stages of acute ischemic stroke (AIS), which is strongly associated with unfavorable outcomes.¹ Notably, ischemic progression plays a pivotal role in this early neurological deterioration (END), accounting for almost over 70% of all the worsening causes.^2,3 Previous studies demonstrated that patients with severe stenosis or occlusion have a heightened risk of 46%–65% of developing END compared to 8.5%–10% in those with normal arterial findings.^4–6 Individuals with artery stenosis or occlusion are especially susceptible to the influences of in-situ thrombus extension and hemodynamic decline, ultimately leading to expansion infarction growth and neurological deterioration.^7–9

To date, many studies have investigated the effects of aggressive antithrombotic therapy in preventing END after ischemic stroke.^10–13 Tirofiban, a non-peptide selective inhibitor of the glycoprotein IIb/IIIa (GP IIb/IIIa) receptor on platelets, inhibits the final common pathway of platelet aggregation, impedes thrombus formation,¹⁴ and it has been widely investigated in patients with AIS. Recently, the TREND trial demonstrated that intravenous tirofiban administered within 24 h of stroke onset could effectively prevent END compared to oral aspirin in patients with acute non-cardioembolic ischemic stroke with good safety profiles.¹⁵ However, whether the culprit intracranial artery stenosis has any impact on the effects of tirofiban in preventing END remains unclear. As different degrees of stenosis are strongly associated with the risk of END and its characteristics, we hypothesized that the degree of intracranial artery stenosis influences the efficacy of tirofiban in preventing END. In this post hoc analysis of the TREND trial, we aimed to assess the influence of intracranial artery stenosis on the effectiveness of tirofiban in preventing END in patients with AIS.

Methods

Study design and patients

This study is a post hoc analysis of the TREND trial, an investigator-initiated, multicenter, prospective, randomized controlled, open-label trial with a blinded endpoint assessment that evaluated the safety and efficacy of intravenous tirofiban administered within 24 h of stroke onset in preventing END in patients with acute non-cardioembolic stroke, in comparison to oral aspirin. Between September 2020 and March 2023, the TREND study enrolled 425 patients from 10 comprehensive stroke centers across China. The participants were randomly assigned to either the tirofiban group or the aspirin group. Details of the trial design, study protocol, and statistical analysis plan have been published.^15,16 Patients were included in this study if vessel imaging data were available that definitely demonstrated the degree of stenosis of the culprit artery. In addition, patients with uncertain infarction lesions, cardioembolic stroke, a baseline NIHSS score of less than 4 points, or those who underwent intravenous thrombolysis, anticoagulation therapy, or endovascular treatment within 72 h of randomization were excluded from the study.

This post hoc analysis was designed to investigate the influence of intracranial artery stenosis on the effects of tirofiban in preventing END in patients with AIS. This study was approved by the ethics committees of all the participating centers. The study is a post hoc analysis of an randomized controlled trial, and informed consent was obtained at the time the study was conducted. The data supporting the findings of this study are available from the corresponding author upon request.

Collected variables and stenosis classification

We examined the baseline variables gathered from the TREND study, including age; sex; medical histories such as hypertension, diabetes, dyslipidemia, ischemic stroke, and intracerebral hemorrhage; smoking status; previous antiplatelet therapy; baseline NIHSS score; blood pressure at admission; glucose levels at admission; time from stroke onset to randomization; infarct location; and stroke etiology. The stroke etiology was determined based on the criteria established by the Trial of Org 10172 in Acute Stroke Treatment (TOAST).¹⁷ Vessel imaging examinations, including computed tomography angiography (CTA) and magnetic resonance angiography (MRA), were performed either prior to enrollment or during patients’ hospitalization.

The culprit vessel was determined by two independent physicians who were blinded to the patient’s baseline characteristics and treatment outcomes based on vascular imaging examinations combined with the infarct lesion and clinical features. In cases of any dispute, a third physician was consulted to make the final decision. The degree of intracranial vessel stenosis was measured using the Warfarin-Aspirin Symptomatic Intracranial Disease Study (WASID) method.¹⁸ Patients were categorized into three groups: no stenosis, mild-to-moderate stenosis (<70%), and severe stenosis or occlusion (⩾70%).

Outcome assessment

The primary efficacy endpoint was END₄, defined as an increase in the NIHSS score by 4 or more points at any time within 72 h of randomization compared to the score immediately before randomization.

The secondary efficacy endpoints included: END₂ (defined as an NIHSS score increase of ⩾2 points within 72 h of randomization), early improvement (defined as an NIHSS score decrease of ⩾4 points within 72 h of randomization), and excellent functional outcome (mRS score of 0–1) and functional independence (mRS score of 0–2) at 90 days.

Safety endpoints included the incidence of symptomatic intracerebral hemorrhage (ICH) and any ICH within 72 h after randomization (according to the European Cooperative Acute Stroke Study III criteria¹⁹), systemic bleeding within 72 h after randomization, and death from any cause within 90-day follow-up.

Statistical analysis

Baseline patient characteristics and clinical outcomes were compared between the tirofiban and aspirin treatment arms within each of three subgroups: patients with no stenosis, mild-to-moderate stenosis, and severe stenosis or occlusion. The baseline characteristics were summarized using descriptive statistics. Continuous data were presented with mean±SD or medians (IQR), and differences between groups were tested using two-sided t-tests or Mann–Whitney U Tests, as appropriate. Categorical data are summarized as frequency (%), with χ² tests for comparisons. For unadjusted analysis, we used univariate binary logistic regression to compare the outcomes between the groups. In the adjusted analysis, multivariate analysis was performed to detect the impact of treatment on efficacy and safety outcomes after accounting for factors such as age, sex, infarction location, baseline NIHSS score, and pre-stroke antiplatelet therapy. We assessed interactions between treatment assignment and stenosis stratification by including the terms for treatment, subgroup, and treatment-by-subgroup interaction in the model with p < 0.05 for a statistically significant interaction effect. Furthermore, Kaplan-Meier failure curves were used to illustrate the cumulative risk of primary endpoint events within 7 days of randomization across different stratifications. Statistical analyses were conducted using R 4.2.3 for Kaplan-Meier failure curves, and SPSS version 26.0.

Results

Among the 425 patients randomized in the TREND study, 129 were excluded from the post hoc analysis, including 29 lacking vessel imaging examinations and 62 without a clear acute infarction lesion. A total of 296 patients were included in this post hoc analysis, with 152 in the tirofiban group and 144 in the aspirin group. There were 148 (50%) patients without stenosis (83 receiving tirofiban and 65 receiving aspirin), 74 (25%) with mild-to-moderate stenosis (34 receiving tirofiban and 40 receiving aspirin), and 74 (25%) with severe stenosis or occlusion (35 receiving tirofiban and 39 receiving aspirin). In this study, intracranial artery stenosis was primarily attributed to atherosclerosis, but one patient was suspected to have an immune-mediated cause of vascular occlusion. A patient flowchart of this study is shown in Figure 1. The baseline characteristics of patients with different stenosis degrees and treatment allocations are presented in Table 1.

Figure 1.

Patient flow chart.

Table 1.

Baseline characteristics of patients with different stenosis stratifications.

Characteristics	No stenosis				Mild to moderate stenosis				Severe stenosis or occlusion
	Total (n = 148)	Tirofiban (n = 83)	Aspirin (n = 65)	P value	Total (n = 74)	Tirofiban (n = 34)	Aspirin (n = 40)	P value	Total (n = 74)	Tirofiban (n = 35)	Aspirin (n = 39)	P value
Age, mean (SD), y	62.48 (9.71)	62.52 (9.62)	62.43 (9.89)	0.957	63.01 (9.74)	63.00 (9.88)	63.02 (9.74)	0.991	64.39 (10.37)	64.51 (10.48)	64.28 (10.41)	0.924
Sex, n (%)				0.430				1.000				1.000
Male	104 (70.3)	61 (73.5)	43 (66.2)		45 (60.8)	21 (61.8)	24 (60.0)		53 (71.6)	25 (71.4)	28 (71.8)
Female	44 (29.7)	22 (26.5)	22 (33.8)		29 (39.2)	13 (38.2)	16 (40.0)		21 (28.4)	10 (28.6)	11 (28.2)
Medical history, n (%)
Hypertension	94 (63.5)	52 (62.7)	42 (64.6)	0.941	49 (66.2)	19 (55.9)	30 (75.0)	0.137	53 (71.6)	28 (80.0)	25 (64.1)	0.209
Diabetes	43 (29.1)	19 (22.9)	24 (36.9)	0.092	27 (36.5)	12 (35.3)	15 (37.5)	1.000	23 (31.1)	13 (37.1)	10 (25.6)	0.415
Dyslipidemia	8 (5.4)	5 (6.0)	3 (4.6)	0.992	6 (8.1)	2 (5.9)	4 (10.0)	0.826	16 (21.6)	8 (22.9)	8 (20.5)	1.000
Ischemic stroke	40 (27.0)	20 (24.1)	20 (30.8)	0.471	23 (31.1)	12 (35.3)	11 (27.5)	0.638	26 (35.1)	13 (37.1)	13 (33.3)	0.921
Intracerebral hemorrhage	5 (3.4)	1 (1.2)	4 (6.2)	0.232	1 (1.4)	1 (2.9)	0 (0.0)	0.935	2 (2.7)	1 (2.9)	1 (2.6)	1.000
Coronary heart disease	13 (8.8)	5 (6.0)	8 (12.3)	0.295	4 (5.4)	1 (2.9)	3 (7.5)	0.727	9 (12.2)	6 (17.1)	3 (7.7)	0.376
Previous antiplatelet therapy^a, n (%)				0.273				0.400				0.407
Single	41 (27.7)	19 (22.9)	22 (33.8)		20 (27.0)	10 (29.4)	10 (25.0)		26 (35.1)	15 (42.9)	11 (28.2)
Dual	7 (4.7)	5 (6.0)	2 (3.1)		2 (2.7)	0 (0.0)	2 (5.0)		2 (2.7)	1 (2.9)	1 (2.6)
Clinical characteristics
Baseline NIHSS score, median [IQR]	5.00 [4.00–6.25]	5.00 [4.00–6.50]	5.00 [4.00–6.00]	0.717	5.00 [4.00–6.00]	5.00 [4.00–6.00]	4.50 [4.00–5.25]	0.159	7.00 [5.00–10.00]	6.00 [5.00–8.50]	7.00 [5.00–11.00]	0.292
Location of cerebral infarction, n (%)				0.218				0.651				0.561
Anterior circulation	100 (67.6)	61 (73.5)	39 (60.0)		52 (70.3)	25 (73.5)	27 (67.5)		44 (59.5)	22 (62.9)	22 (56.4)
Posterior circulation	41 (27.7)	19 (22.9)	22 (33.8)		18 (24.3)	8 (23.5)	10 (25.0)		23 (31.1)	11 (31.4)	12 (30.8)
Anterior and posterior circulation	7 (4.7)	3 (3.6)	4 (6.2)		4 (5.4)	1 (2.9)	3 (7.5)		7 (9.5)	2 (5.7)	5 (12.8)
Blood pressure at randomization, median (SD), mmHg
Systolic	154.61 (19.87)	154.19 (18.58)	155.15 (21.53)	0.771	155.59 (20.38)	154.53 (20.88)	156.50 (20.17)	0.681	155.11 (20.15)	155.26 (19.61)	154.97 (20.89)	0.953
Diastolic	90.44 (14.42)	90.18 (14.33)	90.77 (14.64)	0.806	90.03 (12.17)	89.47 (11.66)	90.50 (12.72)	0.72	87.25 (16.89)	86.09 (14.90)	88.32 (18.67)	0.577
Glucose at admission, median [IQR], mmol/L	6.39 [5.39–8.34]	6.17 [5.28–7.67]	6.61 [5.68–9.78]	0.099	6.36 [5.44–9.99]	6.36 [5.63–11.57]	6.38 [5.36–8.82]	0.504	6.41 [5.38–10.40]	6.29 [5.43–10.80]	6.46 [5.14–8.49]	0.507
Stroke etiology,^b n (%)				0.651				0.591				0.509
Large-artery atherosclerosis	0 (0.0)	0 (0.0)	0 (0.0)		23 (31.1)	9 (26.5)	14 (35.0)		70 (94.6)	33 (94.3)	37 (94.9)
Cardioembolism	0 (0.0)	0 (0.0)	0 (0.0)		0 (0.0)	0 (0.0)	0 (0.0)		0 (0.0)	0 (0.0)	0 (0.0)
Small-vessel occlusion	111 (75.0)	65 (78.3)	46 (70.8)		0 (0.0)	0 (0.0)	0 (0.0)		0 (0.0)	0 (0.0)	0 (0.0)
Other determined cause	0 (0.0)	0 (0.0)	0 (0.0)		0 (0.0)	0 (0.0)	0 (0.0)		1 (1.4)	0 (0.0)	1 (2.6)
Undetermined cause	37 (25.0)	18 (21.7)	19 (29.2)		51 (68.9)	25 (73.5)	26 (65.0)		3 (4.1)	2 (5.7)	1 (2.6)
Culprit artery^c								0.250				0.780
Anterior cerebral artery					3 (4.2)	3 (9.4)	0 (0.0)		2 (2.7)	1 (2.9)	1 (2.6)
Middle cerebral artery					38 (53.5)	15 (46.9)	23 (59.0)		29 (39.2)	12 (34.3)	17 (43.6)
Internal carotid artery					9 (12.7)	5 (15.6)	4 (10.3)		16 (21.6)	9 (25.7)	7 (17.9)
Posterior cerebral artery					6 (8.5)	2 (6.3)	4 (10.3)		6 (8.1)	3 (8.6)	3 (7.7)
Vertebral artery					8 (11.3)	5 (15.6)	3 (7.7)		14 (18.9)	8 (22.9)	6 (15.4)
Basilar artery					7 (9.9)	2 (6.3)	5 (12.8)		7 (9.5)	2 (5.7)	5 (12.8)
Time from symptom onset to randomization				0.609				0.613				0.480
<6 h	25 (16.9)	13 (15.7)	12 (18.5)		12 (16.2)	4 (11.8)	8 (20.0)		13 (17.6)	8 (22.9)	2 (12.8)
6–12 h	57 (38.5)	30 (36.1)	27 (41.5)		30 (40.5)	15 (44.1)	15 (37.5)		29 (39.2)	12 (34.3)	17 (43.6)
>12 h	66 (44.6)	40 (48.2)	26 (40.0)		32 (43.2)	15 (44.1)	17 (42.5)		32 (43.2)	15 (42.9)	17 (43.6)

IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation.

Taking antiplatelet drugs within 1 week before the present symptom onset.

Based on the TOAST classification.

Three patients with mild stenosis were diagnosed by TCD, their data were not calculated into the culprit artery distribution due to concerns about the examination’s reliability. One patient presented with severe stenosis of middle cerebral artery and combined severe vertebral artery stenosis, both of which were associated with the infarction site.

Primary efficacy outcome

A total of 24 patients experienced an END₄. Among the patients with no stenosis, 2 of 83 (2.4%) in the tirofiban group and 3 of 65 (4.6%) in the aspirin group experienced END₄. Among the patients with mild-to-moderate stenosis, 1 of 34 (2.9%) in the tirofiban group and 4 of 40 (10.0%) in the aspirin group experienced END₄. Among patients with severe stenosis or occlusion, two of 35 (5.7%) receiving tirofiban and 12 of 39 (30.8%) receiving aspirin experienced END₄.

In the adjusted analysis, tirofiban significantly reduced the incidence of END₄ in patients with severe stenosis or occlusion (adjusted OR 0.156; 95% CI 0.028–0.873; adjusted p = 0.034; Figure 2). This effect was less pronounced in those with mild-to-moderate stenosis (adjusted OR 0.171; 95% CI 0.015–1.943; adjusted p = 0.155; Figure 2) and those without stenosis (adjusted OR 0.193; 95% CI 0.018–2.083; adjusted p = 0.175; Figure 2). The subgroup×treatment arm interaction was not significant (p for interaction = 0.513; Figure 2).

Figure 2.

Association of treatment with clinical outcomes stratified by stenosis degrees. Adjusted for age, sex, infarction location, baseline NIHSS score, and pre-stroke antiplatelet therapy.

The cumulative risk of END₄ among the different stenosis subgroups in the two treatment assignments is illustrated in Figure 3. There was variation in the cumulative risk of END₄ within 7 days among patients belonging to the different stenosis severity subgroups (p = 0.00035, Figure 3(a)). Specifically, among patients with severe stenosis or occlusion, patients treated with tirofiban exhibited a significantly lower cumulative risk of END₄ development within 7 days than those receiving aspirin therapy (p = 0.006, Figure 3(d)).

Figure 3.

Cumulative risk of early neurological deterioration in patients with different stenosis: (a) total cohort, (b) no stenosis, (c) mild-to-moderate stenosis, and (d) severe stenosis/occlusion

Secondary efficacy outcomes

If END was defined as an increase in the NIHSS score of no less than 2 points within 72 h of onset, supportive evidence for tirofiban treatment was observed in patients with severe stenosis or occlusion (11.4% vs 43.6%, adjusted OR 0.140; 95% CI 0.036–0.540; adjusted p = 0.004; Figure 2) and mild-to-moderate stenosis (5.9% vs 22.5%, adjusted OR 0.146; 95% CI 0.022–0.951; adjusted p = 0.044; Figure 2). Among patients with mild-to-moderate stenosis, 29 of 34 patients (85.3%) in the tirofiban group and 28 of 40 patients (70.0%) in the aspirin group achieved an mRS score of 0–1 at 90 days (adjusted OR 4.617; 95% CI 1.077–10.798; adjusted p = 0.039; Figures 2 and 4). Regarding the outcomes of early improvement and the proportion of mRS 0–2 at 90 days, intravenous tirofiban and oral aspirin had similar effects in patients of all subgroups (p > 0.05, Figures 2 and 4).

Figure 4.

Distribution of mRS score at 90 days. Score range from 0 to 6, with 0 indicating no symptoms, 1, no clinically significant disability, 2, slight disability, 3, moderate disability, 4, moderately severe disability, 5, severe disability, and 6, death.

Safety outcomes

None of the patients in either treatment group experienced ICH. Patients with different degrees of stenosis in the tirofiban group and aspirin group had similar rates of systemic bleeding (1.2% vs 1.5% in patients with no stenosis, adjusted p = 0.802; 8.8% vs 2.5% in patients with mild-to-moderate stenosis, adjusted p = 0.350; and 8.6% vs 15.4% in patients with severe stenosis or occlusion, respectively; adjusted p = 0.244, Figure 2). One patient with mild stenosis who received tirofiban treatment and four patients with occluded arteries (one in the tirofiban group and three in the aspirin group) died during the 90-day follow-up period. Mortality did not differ significantly between the treatment groups for any of the stenosis subtypes.

Discussion

In this post hoc analysis of the TREND trial, we found that intravenous tirofiban significantly reduces the risk of END among AIS patients with culprit artery severe stenosis or occlusion, with no significant benefit of tirofiban in other stenosis stratification were observed. In addition, among patients with culprit artery stenosis of less than 70%, intravenous tirofiban can also lower the risk of END (if defined as ⩾2-point NIHSS score increase) and improve the proportion of favorable outcomes. However, there is no statistically significant difference in treatment effects across subgroups with different degrees of stenosis.

While the point estimates are similar across subgroups, the significant p value observed in the severe stenosis or occlusion subgroup provides indicative evidence of a treatment benefit specifically within this population, which could hold clinical significance.²⁰ The possible explanations are as follows: On the one hand, stroke etiology may be one of the driving factors behind these differences in treatment efficacy, particularly in the group of patients without arterial stenosis, where the majority had small vessel disease as the cause of their stroke. Within this group, artery-to-artery embolism and distal small vessel pathology may be the primary stroke mechanisms, and antiplatelet therapy may not work. On the other hand, in patients with AIS secondary to intracranial artery stenosis, rupture of atherosclerotic plaques and release of tissue factor from the endothelial surface trigger platelet adhesion and aggregation, ultimately leading to the formation of in-situ thrombosis that extends beyond the existing stenosis and intensifies luminal narrowing to a critical level.²¹ This thrombosis can either obstruct the stenosed artery or detach completely or partially, causing distal embolism.²² Furthermore, in cases of severe vascular stenosis, progressive narrowing diminishes antegrade blood flow, resulting in hypoperfusion, which is exacerbated in cases of hypovolemia or hypotension.^23–26 Consequently, this scenario leads to a heightened incidence of neurological deterioration and stroke recurrence, which may benefit more from aggressive antiplatelet therapy.^27,28

The clinical benefit findings of this study were consistent with those of the ESCAPITST trial, which investigated intravenous tirofiban for 48 h or oral aspirin 100 mg/day in non-cardioembolic moderate-to-severe stroke patients within 12 h of symptom onset who did not receive revascularization therapy and found that tirofiban significantly increased the proportion of patients with favorable outcomes among those with severe stenosis or occlusion (59.7% vs 34.3%, p = 0.002), but had no significant effect on patients with mild stenosis.^29,30 In our study, this proportion of patients with mRS scores of 0 and 1 was higher in the tirofiban group than in the aspirin group (62.9% vs 46.2%), although the difference was not statistically significant. Furthermore, among patients with culprit artery stenosis of less than 70%, the proportion of favorable outcomes significantly improved.

This study had several limitations. First, this study enrolled patients with baseline NIHSS scores of 4–20, and the benefit of intravenous tirofiban was only detected in patients with severe stenosis or occlusion; therefore, the benefits of intravenous tirofiban cannot be extrapolated to the entire patient population. Second, the study design did not mandate a repeat brain CT scan during or after the intervention unless neurological deterioration was observed, potentially underestimating the actual risk of intracranial hemorrhage. In addition, the relatively small sample size and low incidence of primary endpoint events across the subgroups resulted in extremely wide 95% CIs for some of our key findings, which reflect the uncertainty associated with our estimates. Furthermore, it is noteworthy that even though there was no statistically significant difference in the effectiveness of tirofiban among non-severe stenosis subgroups, the OR values approached those of the severe stenosis or occlusion patients after adjustment. This necessitates consideration of both the rarity of the endpoint events and the selection bias inherent in post hoc subgroup analyses, which may have diluted the differences in efficacy among different subgroups. Therefore, our findings should be considered exploratory and hypothesis-generating rather than definitive. Larger studies to improve the accuracy of statistical estimates in the future and further validate and expand our findings are needed.

Conclusion

In patients with acute non-cardioembolic ischemic stroke, intravenous tirofiban within 24 h of onset is significantly associated with a reduced incidence of END in those with severe artery stenosis or occlusion. Further studies are required to confirm the effects of intracranial artery stenosis on the efficacy of intravenous tirofiban.

Supplemental Material

sj-docx-1-eso-10.1177_23969873251319151 – Supplemental material for Effects of tirofiban in preventing neurological deterioration in acute ischemic stroke with intracranial artery stenosis: A post hoc analysis of the TREND Trial

Supplemental material, sj-docx-1-eso-10.1177_23969873251319151 for Effects of tirofiban in preventing neurological deterioration in acute ischemic stroke with intracranial artery stenosis: A post hoc analysis of the TREND Trial by Jing Wang, Yue Qiao, Sijie Li, Chuanhui Li, Chuanjie Wu, Pingping Wang, Ting Yang, Xunming Ji, Qingfeng Ma and Wenbo Zhao in European Stroke Journal

Footnotes

Acknowledgements

We thank all study participants and their relatives, and all the investigators of the TREND trial.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Beijing Natural Science Fund for Outstanding Young Scholars (JQ22020), the National Natural Science Fund of China (82422024), and Beijing Nova Program (Z201100006820143).

Ethical approval and informed consent

This study was approved by the ethics committees of Xuanwu Hospital, Capital Medical University, and all the participating centers. The study is a post hoc analysis of an Randomized Controlled Trial, and informed consent was obtained at the time the study was conducted.

Guarantor

Wenbo Zhao

Contributorship

Drs Wenbo Zhao, Xunming Ji, and Qingfeng Ma contributed to the conception, study design, and critical review of the manuscript. Drs Jing Wang, Yue Qiao contributed to data acquisition and analysis, drafted the manuscript and revision of the manuscript, and contributed equally to this work. Drs Jing Wang, Sijie Li, Chuanhui Li, Chuanjie Wu, Pingping Wang, and Ting Yang contributed to drafting a significant portion of the article or figures. Drs Wenbo Zhao and Qingfeng Ma contributed with critical comments during the article revision. All authors approved the submitted article.

ORCID iDs

Jing Wang

Xunming Ji

Data availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Supplemental material

Supplemental material for this article is available online.

References

Seners

Turc

Oppenheim

, et al. Incidence, causes and predictors of neurological deterioration occurring within 24 h following acute ischaemic stroke: a systematic review with pathophysiological implications. J Neurol Neurosurg Psychiatry 2015; 86: 87–94.

Seners

Baron

JC.

Revisiting 'progressive stroke': incidence, predictors, pathophysiology, and management of unexplained early neurological deterioration following acute ischemic stroke. J Neurol 2018; 265: 216–225.

Zhang

, et al. Early neurological deterioration after recanalization treatment in patients with acute ischemic stroke: a retrospective tudy. Chin Med J 2018; 131: 137–143.

Ois

Martinez-Rodriguez

Munteis

, et al. Steno-occlusive arterial disease and early neurological deterioration in acute ischemic stroke. Cerebrovasc Dis 2008; 25: 151–156.

Zhu

Gong

Zhu

, et al. FLAIR vascular hyperintensity: an unfavorable marker of early neurological deterioration and short-term prognosis in acute ischemic stroke patients. Ann Palliat Med 2020; 9: 3144–3151.

Xue

Yun

Peng

, et al. Where are we heading in post-China angioplasty and stenting for symptomatic intracranial severe stenosis era? Brain Circ 2023; 9: 3–5.

Seners

Hurford

Tisserand

, et al. Is unexplained early neurological deterioration after intravenous thrombolysis associated with thrombus extension? Stroke 2017; 48: 348–352.

Derdeyn

CP.

Mechanisms of ischemic stroke secondary to large artery atherosclerotic disease. Neuroimaging Clin N Am 2007; 17: 303–311.

Alawneh

Moustafa

Baron

JC.

Hemodynamic factors and perfusion abnormalities in early neurological deterioration. Stroke 2009; 40: e443–e450.

10.

Chen

Cui

Wang

, et al. Clopidogrel plus aspirin vs aspirin alone in patients with acute mild to moderate stroke: the ATAMIS randomized clinical trial. JAMA Neurol 2024; 81: 450–460.

11.

Wang

Zhao

, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369: 11–19.

12.

Johnston

Easton

Farrant

, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med 2018; 379: 215–225.

13.

Whiteley

Adams

Jr Bath

, et al. Targeted use of heparin, heparinoids, or low-molecular-weight heparin to improve outcome after acute ischaemic stroke: an individual patient data meta-analysis of randomised controlled trials. Lancet Neurol 2013; 12: 539–545.

14.

Yang

Huo

Miao

, et al. Platelet glycoprotein IIb/IIIa receptor inhibitor tirofiban in acute ischemic stroke. Drugs 2019; 79: 515–529.

15.

Zhao

, et al. Effects of tirofiban on neurological deterioration in patients with acute ischemic stroke: a randomized clinical trial. JAMA Neurol 2024; 81: 594–602.

16.

Wang

, et al. Safety and efficacy of tirofiban in preventing neurological deterioration in acute ischemic stroke (TREND): protocol for an investigator-initiated, multicenter, prospective, randomized, open-label, masked endpoint trial. Brain Circ 2024; 10: 168–173.

17.

Adams

Bendixen

Kappelle

, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Toast. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24: 35–41.

18.

Chimowitz

Kokkinos

Strong

, et al. The warfarin-aspirin symptomatic intracranial disease study. Neurology 1995; 45: 1488–1493.

19.

Hacke

Kaste

Bluhmki

, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008; 359: 1317–1329.

20.

Goel

Shangari

Mittal

, et al. Endogenous defense mechanism-based neuroprotection in large-vessel acute ischemic stroke: a hope for future. Brain Circ 2024; 10: 51–59.

21.

Bentzon

Otsuka

Virmani

, et al. Mechanisms of plaque formation and rupture. Circ Res 2014; 114: 1852–1866.

22.

Woo

Kim

Lee

, et al. Wall shear stress associated with stroke occurrence and mechanisms in middle cerebral artery atherosclerosis. Stroke 2023; 25: 132–140.

23.

Zhao

, et al. Association of culprit plaque enhancement ratio, hypoperfusion and HbA1c with recurrent ischemic stroke in patients with atherosclerotic stenosis of the middle cerebral artery. Eur J Radiol 2023; 168: 111107.

24.

Lyu

Tian

, et al. Perfusion and plaque evaluation to predict recurrent stroke in symptomatic middle cerebral artery stenosis. Stroke Vasc Neurol 2019; 4: 129–134.

25.

Yang

Wang

, et al. Enhancing the clinical value of single-phase computed tomography angiography in the assessment of collateral circulation in acute ischemic stroke: a narrative review. Brain Circ 2024; 10: 35–41.

26.

Ran

Wang

Chen

, et al. Compromised dynamic cerebral autoregulation is a hemodynamic marker for predicting poor prognosis even with good recanalization after endovascular thrombectomy. Brain Circ 2024; 10: 77–84.

27.

Eaton

Duru

Powers

CJ.

Direct transfer for thrombectomy in patients with large vessel occlusions on computed tomography angiography results in safe revascularization. Brain Circ 2023; 9: 25–29.

28.

Toudou-Daouda

Yatwa-Zaniwe

Aminou-Tassiou

, et al. Intravenous thrombolysis plus tirofiban versus tirofiban alone in Caucasian patients with acute anterior choroidal or paramedian pontine infarction. Brain Circ 2024; 10: 250–256.

29.

Han

Man

Ding

, et al. Subtyping treatment response of tirofiban in acute ischemic stroke based on neuroimaging features. Clin Transl Sci 2024; 17: e13686.

30.

Han

Liu

, et al. Efficacy and safety of tirofiban in clinical patients with acute ischemic stroke. Front Neurol 2021; 12: 785836.

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