Intravenous thrombolysis versus standard medical therapy in minor stroke patients with large vessel severe stenosis or occlusion: a systematic review and meta-analysis

Abstract

Background

Patients with mild stroke (National Institutes of Health Stroke Scale [NIHSS] ≤ 5) and severe intracranial stenosis or occlusion represent a high-risk subgroup for early neurological deterioration (END) and are strong predictors of poor 3-month functional outcomes. The effectiveness of intravenous thrombolysis (IVT) in patients with minor stroke and large vessel severe stenosis or occlusion (LVSSO) remains uncertain. This study aims to assess the comparative efficacy and safety of IVT versus standard medical therapy (SMT) through a systematic review and meta-analysis of both randomized and observational studies.

Methods

A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was conducted to identify studies evaluating IVT in minor stroke with LVSSO from database inception through March 13, 2025. The primary outcome was defined as an excellent functional outcome (modified Rankin Scale [mRS] 0–1) at 90 days. Pooled analyses were performed using odds ratios (ORs) with 95% confidence intervals (CIs) for the overall population and prespecified subgroups. The study protocol was prospectively registered in the PROSPERO international registry (CRD42025637459).

Results

A total of five studies were included, comprising 1090 patients with mild ischemic stroke and LVSSO treated with IVT and 3501 patients treated with SMT. Compared with SMT, IVT significantly improved the 90-day excellent functional outcome (mRS 0–1) (OR, 1.58 [95% CI, 1.16–2.15]). In the large vessel occlusion subgroup, IVT was also significantly associated with an excellent 90-day functional outcome (OR, 1.52 [95% CI, 1.03–2.23]). No significant differences were observed between groups in 90-day favorable functional outcome (mRS 0–2), symptomatic intracranial hemorrhage (sICH), 90-day mortality, or 90-day stroke recurrence.

Conclusions

These findings suggest that IVT may be associated with improved 90-day excellent functional outcomes in patients with mild acute ischemic stroke (AIS) and LVSSO, without increasing the risk of sICH.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12916-026-04777-0.

Background

Over 50% of patients presenting with acute ischemic stroke (AIS) exhibit mild neurological deficits at initial clinical assessment [1], typically defined by a National Institutes of Health Stroke Scale (NIHSS) score of 0 to 5 [2]. One-third of these patients who do not receive intravenous thrombolysis (IVT) experience stroke progression or recurrence within 90 days, which is associated with a significantly increased risk of severe functional disability [3]. IVT plays a critical role in cerebral reperfusion by salvaging the ischemic penumbra and reducing neurological deterioration when administered within the therapeutic window [4]. Accordingly, international guidelines [2, 5] recommend IVT with alteplase within 4.5 h for patients with mild disabling stroke, and the Expert Consensus Statement of the European Stroke Organisation [5] recommends IVT for patients with mild non-disabling stroke in the presence of large vessel occlusion (LVO). However, the safety and efficacy of IVT in patients with mild non-disabling stroke and LVO remain uncertain due to concerns about its risk–benefit profile. Identifying subtypes of mild stroke that are likely to benefit from IVT is essential. The presence of symptomatic intracranial or extracranial severe arterial stenosis or occlusion is a known predictor of recurrent stroke in patients with minor stroke [6]. Additionally, patients with mild stroke and intracranial vascular occlusion represent a high-risk subgroup for early neurological deterioration (END) and poor 3-month prognosis [6, 7]. In patients with mild stroke and LVO, studies have shown that thrombus length ≥ 9 mm and proximal occlusion are significant predictors of worsening after thrombolysis [8]. Despite these findings, previous meta-analyses have focused on patients with mild stroke, and no meta-analysis has specifically addressed patients with mild stroke and large vessel severe stenosis or occlusion (LVSSO). This study aims to compare the efficacy of IVT with standard medical therapy (SMT) in patients with mild ischemic stroke and LVSSO, focusing on 90-day excellent functional outcomes (modified Rankin Scale [mRS] 0–1) and the occurrence of symptomatic intracranial hemorrhage.

Methods

Approval and registration of standard protocols

This systematic review was conducted following the Meta-analysis of Observational Studies in Epidemiology (MOOSE) [9] guidelines and in alignment with the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 (PRISMA 2020) [10] statement. The protocol was prospectively registered with the International Prospective Register of Systematic Reviews (PROSPERO) (https://www.crd.york.ac.uk/PROSPERO/view/CRD42025637459).

Eligibility criteria

Inclusion criteria were defined as follows:

1. Population: Adults (≥ 18 years) with minor ischemic stroke (NIHSS score 0–5) eligible for IVT within 4.5 h of symptom onset

2. Vascular lesion: Radiologically confirmed large vessel severe stenosis or occlusion (LVSSO), defined as ≥ 70% stenosis of intracranial or extracranial vessels, based on the North American Symptomatic Carotid Endarterectomy Trial (NASCET) [11] criteria

3. Intervention: IVT with alteplase

4. Comparison: SMT according to international guidelines, including antiplatelet or anticoagulant therapy, statins, and risk factor management (e.g., hypertension, hyperglycemia), excluding thrombolysis

5. Outcomes: Functional outcomes and safety outcomes

6. Study design: Randomized controlled trials (RCTs) or observational studies with comparison groups

Exclusion criteria included the following:

1. Studies without a parallel control group

2. Patients who received endovascular thrombectomy or bridging therapy

3. Non-original research articles, including case reports, guidelines, systematic reviews, and conference abstracts

4. Studies that did not follow prespecified definitions for minor stroke or outcome measures

5. Studies with serious methodological flaws, including observational studies with a Newcastle–Ottawa scale score (NOS) [12] < 7 and RCTs with a high risk of bias assessed using the Cochrane risk of bias 2 (RoB2) tool [13].

Data source and search strategy

A systematic literature search was conducted in PubMed, Embase, the Cochrane Library, and Web of Science from inception through March 13, 2025. Only studies published in English were included. The search strategy combined controlled vocabulary (e.g., MeSH/Emtree terms) and free-text terms such as “mild stroke,” “thrombolytic therapy,” “tissue plasminogen activator,” “tenecteplase,” “urokinase-type plasminogen activator,” “large vessel occlusion,” and “large vessel severe stenosis.” Complete search strategies are provided in Additional file 1: Search strategies.

Study selection and data extraction

Retrieved references were imported into EndNote, where automatic duplicate removal was followed by manual verification. Titles and abstracts were screened for initial eligibility, and full-text articles were subsequently reviewed according to the predefined inclusion and exclusion criteria. Screening was conducted independently and blindly by three reviewers (L. X.1, R. L., and L. X.2) using predefined eligibility criteria; any discrepancies were resolved through discussion, with a senior reviewer (Z. L.) acting as arbiter when needed. In cases of overlapping study populations, the study with the larger sample size was included. Two reviewers (M. D. and H. Y.) independently extracted data using standardized Microsoft Excel spreadsheets. Extracted data included the first author’s name, year of publication, country, study type, time from onset to treatment, sample size, thrombolytic drug, and other relevant variables (Additional file 1: Table S1). All extracted data were cross-verified against the original publications.

Assessment of bias and quality of evidence

The quality of cohort and case–control studies was assessed using the NOS [12]. Observational studies with a score of ≥ 7 were considered to be of good quality and were included in the meta-analysis. The Cochrane RoB2 tool [13] was used to evaluate the quality and risk of bias in RCTs. Two researchers (T. Z. and L. T.) independently assessed the overall quality of the included studies. Any discrepancies were initially resolved by discussion; if consensus could not be reached, a third senior author (Z. L.) acted as arbiter.

Measures of effect

The primary outcome was defined as an excellent functional outcome at 90 days, corresponding to a mRS score of 0–1. Secondary outcomes included 90-day mortality and 90-day stroke recurrence. The safety outcome was defined as symptomatic intracranial hemorrhage (sICH). sICH was defined according to the European Cooperative Acute Stroke Study (ECASS) III [14], ECASS II [15], the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) [16] criteria, and any intracranial hemorrhage on imaging with an NIHSS increase of ≥ 4 points from baseline [17] (Additional file 1: Table S2).

Statistical analysis

Statistical analyses were performed using Stata software (version 18.0). Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated for all dichotomous outcomes. Post hoc exploratory subgroup analyses for the primary outcome were performed for patients with mild non-disabling stroke, patients receiving dual antiplatelet therapy (DAPT), those with LVO, and those from observational studies. Heterogeneity among studies was evaluated using the Cochrane Q test and the Higgins I² statistic. An I² value ≥ 50% or a Q test result of P < 0.10 was considered indicative of significant heterogeneity. A random effects model was used when heterogeneity was present; otherwise, a fixed effects model was applied [18]. Publication bias was assessed using funnel plots and Egger’s linear regression test. Sensitivity analysis was conducted using the leave-one-out method, removing each study in turn.

Results

Results of the conducted search

The database search retrieved 1593 articles. After removing 580 duplicates, 1013 articles remained for screening. Following title and abstract review, 16 articles were selected for full-text screening. Of these, 11 were excluded based on the inclusion and exclusion criteria (Additional file 1: Table S3). Finally, one RCT and four observational studies were included in the meta-analysis (Fig. 1).

Fig. 1.

Flowchart of literature search and selection. EVT, endovascular thrombectomy; RCT, randomized controlled trial; LVSSO, large vessel severe stenosis or occlusion

Study characteristics and quality evaluation

The basic characteristics of the studies included in this meta-analysis are summarized in Additional file 1: Table S1. A total of 5 studies comprising 4591 patients were included, of whom 1090 received IVT and 3501 received SMT. All studies were conducted in China and published between 2011 and 2024.

One randomized controlled trial was assessed as having a low risk of bias. Four observational studies were evaluated using the NOS, with scores ranging from 8 to 9 points. All included studies met the predefined inclusion criteria (Additional file 1: Tables S4 and S5).

Outcome

Primary outcome: excellent functional outcome of mRS score of 0 to 1

Four studies [17, 19–21] reported data on 90-day excellent functional outcomes, defined as a mRS score of 0–1 (Fig. 2). IVT was significantly associated with a higher rate of excellent functional outcome compared to BMT (395/470, 84.04% versus 1056/1317, 80.18%, P = 0.004; Table). Pooled analysis showed a significant difference between the IVT and SMT groups, with moderate heterogeneity (OR, 1.58 [95% CI, 1.16–2.15]; I² = 42.5%, P = 0.157). In contrast, the analysis of the single RCT included showed no significant difference between IVT and SMT in terms of excellent functional outcome (OR, 0.56 [95% CI, 0.05–5.96]).

Fig. 2.

Forest plot for minor stroke (National Institutes of Health Stroke Scale [NIHSS] ≤ 5) with large vessel severe stenosis or occlusion (LVSSO) between intravenous thrombolysis (IVT) and standard medical therapy (SMT) with modified Rankin Scale (mRS) score 0 to 1

Subgroup analyses for the 90-day excellent functional outcome were performed across three subgroups (Fig. 3). In the subgroup analysis of three observational studies, no significant difference in excellent outcome was found between the IVT and SMT groups (OR, 1.60 [95% CI, 0.92–2.80]). Among patients with mild non-disabling stroke, the difference between IVT and SMT was also not significant (OR, 1.97 [95% CI, 0.38–10.23]). Similarly, there was no significant difference between the IVT and DAPT groups (OR, 1.26 [95% CI, 0.89–1.77]). However, in the LVO subgroup, IVT was significantly associated with better 90-day excellent functional outcomes compared to SMT, with low heterogeneity (OR, 1.52 [95% CI, 1.03–2.23]).

Fig. 3.

Subgroup analyses on modified Rankin Scale (mRS) score 0 to 1. IVT, intravenous thrombolysis; SMT, standard medical therapy; DAPT, dual antiplatelet therapy; LVO, large vessel occlusion

Favorable functional outcome of mRS score of 0 to 2

Two studies [17, 20] reported data on 90-day functional outcomes defined as mRS scores of 0 to 2 (Additional file 1: Fig. S1). Rates of favorable functional outcome in the IVT group compared with the SMT group revealed no significant difference (258/273, 94.51% versus 1057/1149, 91.99%, P = 0.142; Table 1). No significant difference was observed between the IVT and SMT groups, with low heterogeneity (OR, 1.54 [95% CI, 0.87–2.75]; I² = 0%, P = 0.650).

Table 1.

Outcomes in the IVT and SMT groups

Outcomes	IVT (%)	SMT (%)	p-values
mRS score 0–1	395/470	1056/1317	0.004
mRS score 0–2	258/273	1057/1149	0.142
Mortality	3/370	17/1283	0.192
Recurrent stroke	28/370	87/1283	0.512
sICH	14/738	48/2303	0.708

IVT Intravenous thrombolysis, SMT Indicates standard medical therapy, mRS modified Rankin Scale, and sICH symptomatic intracranial hemorrhage

Mortality

Two studies [19, 20] reported data on 90-day mortality (Fig. 4). Rates of mortality in the IVT and SMT group were not different (3/370, 0.81% versus 17/1283, 1.33%, P = 0.192; Table 1). No significant difference was observed between the IVT and SMT groups, with substantial heterogeneity (OR, 0.40 [95% CI, 0.10–1.59]; I² = 49.8%, P = 0.158).

Fig. 4.

Forest plots for minor stroke (National Institutes of Health Stroke Scale [NIHSS] ≤ 5) between intravenous thrombolysis (IVT) and standard medical therapy (SMT) with symptomatic intracranial hemorrhage (sICH), mortality at 90 days, and recurrent stroke

Recurrent stroke

Two studies [19, 20] provided data on recurrent stroke (Fig. 4), with no significant difference between the IVT and SMT groups and no heterogeneity (OR, 1.17 [95% CI, 0.74–1.85]; I² = 0%, P = 0.612). The rate of recurrent stroke is not significantly different between the IVT and BMT groups (28/370, 7.57% vs. 87/1283, 6.78%; P = 0.512; Table 1).

Symptomatic intracranial hemorrhage

Two studies [19, 22] reported the incidence of sICH (Fig. 4), showing no significant difference between the IVT and SMT groups and no heterogeneity (OR, 0.89 [95% CI, 0.49–1.62]; I² = 48.4%, P = 0.164). There was no statistically significant difference in the rate of sICH between the IVT and SMT groups (14/738, 1.90% versus 48/2303, 2.08%; P = 0.708; Table 1).

Risk of bias

Publication bias was assessed using funnel plots (Additional file 1: Figs. S2, S3, S4, S5, S6), which illustrated outcomes for excellent functional prognosis, favorable functional prognosis, mortality, recurrent ischemic stroke, and sICH. The Egger test for excellent functional prognosis showed no evidence of publication bias (Egger test: P = 0.908) (Additional file 1: Fig. S7). However, given the limited number of included studies, the reliability of both funnel plots and Egger’s test is reduced, and the results should be interpreted with caution.

Sensitivity analysis

A leave-one-out sensitivity analysis was conducted for the 90-day excellent functional outcome (mRS 0–1). The study by Duan et al. [20] was identified as the primary source of heterogeneity. When this study was excluded, the difference between the IVT and SMT groups was no longer statistically significant (OR, 1.60 [95% CI, 0.97–2.64]) (Additional file 1: Fig. S8). The heterogeneity was attributed to the high weight assigned to the Duan et al. study.

Discussion

The effectiveness of IVT in patients with mild stroke and LVSSO remains uncertain. This meta-analysis showed that IVT significantly increased the proportion of patients achieving excellent 90-day functional outcomes (mRS 0–1) compared with SMT. Subgroup analysis confirmed that this benefit remained significant in the LVO subgroup. However, there was no significant difference between the IVT and SMT groups in terms of 90-day favorable functional outcomes (mRS 0–2), sICH, stroke recurrence, or mortality. The moderate heterogeneity (I² = 42.5%) in the primary outcome analysis suggests that the treatment effect may vary depending on factors such as study design, antiplatelet regimens, baseline characteristics, and other variables. In the sensitivity analysis, after excluding the study by Duan et al., the statistical significance for excellent functional outcome was lost, and the confidence interval widened. These findings underscore the need for further studies to validate the effectiveness of IVT in this specific patient population.

The observational study by Luo et al. [22] was excluded from the primary outcome analysis due to the absence of 90-day excellent functional outcome data. Based on the proportion of patients achieving a discharge mRS score of 0–1, the study concluded that IVT was safe and effective in patients with mild stroke and LVO. To some extent, this conclusion is associated with the findings of our analysis. Notably, there was no statistically significant difference in functional outcomes between IVT and SMT in the subgroup of patients with mild non-disabling stroke. This underscores the limitation of using NIHSS alone to define stroke severity, as it may not accurately capture the extent of functional impairment. These subgroup analyses were post hoc exploratory and may be subject to potential biases due to the limited number of studies included. We emphasize that these subgroup findings should be interpreted with caution and require validation in larger, more rigorously designed randomized controlled trials.

However, the evidence regarding the effect of IVT on END remains limited. Among the included studies, only Cui et al. [17] provided data on END. Their findings indicated no significant difference between the IVT and SMT groups in preventing END (adjusted risk difference = 2.3 [95% CI –17.6 to 22.3], P = 0.82). However, the study’s limited sample size (n = 36 with mild stroke and LVO) and the exploratory nature of the post hoc analysis suggest a high risk of type II error, potentially underestimating true differences. Future large-scale prospective RCTs are needed to validate these findings.

Patients with mild stroke and LVO represent a high-risk subgroup for END and are independent predictors of poor 3-month outcomes. Our subgroup analysis for LVO suggests that IVT significantly improves 90-day excellent functional outcomes in this patient subgroup. However, subgroup analyses in the TEMPO-2 [23] and ARAMIS [17] studies did not demonstrate a benefit of IVT for patients with mild stroke and LVO. This discrepancy may be attributed to the limited statistical power resulting from small sample sizes. Larger, well-designed RCTs are needed to further validate the efficacy of IVT in this patient population. Currently, the evidence does not support the routine use of endovascular therapy (EVT) in patients with mild stroke and LVO. A meta-analysis [24] reported that EVT did not significantly improve 90-day functional outcomes compared with SMT in patients with mild stroke and anterior circulation LVO, while it was associated with an increased risk of intracranial hemorrhage. Further large RCTs are needed to explore whether patients with acute mild stroke and LVO benefit from EVT.

Importantly, patients with mild stroke and LVSSO often exhibit robust collateral circulation [25]. A meta-analysis of 28 studies [26] showed that patients with good baseline collateral circulation who received IVT had a significantly lower risk of sICH compared to those with poor collaterals (RR = 0.38, 95% CI 0.16–0.90, P = 0.03). These patients also had significantly higher rates of favorable functional outcomes (mRS 0–2 or 0–1 at 3–6 months) (RR = 2.45, 95% CI 1.94–3.09, P < 0.001). These findings may support the hypothesis that good collateral circulation enhances the clinical benefit of intravenous thrombolysis by maintaining perfusion in the ischemic penumbra and delaying progression of the infarct core.

This systematic review and meta-analysis is the first to assess the efficacy of IVT in patients with mild stroke and LVSSO. Several limitations must be considered. First, the inclusion of observational studies introduces potential selection bias due to non-randomized treatment allocation between IVT and SMT. Second, limited statistical power increases the risk of type II error. Third, although conceptually similar, the differences in sICH definitions across studies contribute to clinical heterogeneity. Fourth, all included patients were from Chinese populations. Given the significantly higher prevalence of intracranial atherosclerotic stenosis in East Asian compared to Caucasian populations [27], the generalizability of these findings requires confirmation in broader populations. To minimize confounding, we excluded patients who received EVT following IVT. All included studies used alteplase as the thrombolytic agent; therefore, the results may not be applicable to patients receiving newer thrombolytic therapies.

Conclusions

This systematic review and meta-analysis provides the first evaluation of IVT versus SMT in patients with acute mild ischemic stroke and LVSSO. This study suggests that IVT may be associated with improved 90-day excellent functional outcomes in patients with mild AIS and LVSSO, without an increased risk of sICH. However, the evidence is limited by small sample sizes and low statistical power. Large multicenter RCTs using advanced perfusion imaging are urgently needed to clarify the efficacy of IVT in this high-risk population.

Abbreviations

AIS

Acute ischemic stroke

NIHSS

National Institutes of Health Stroke Scale

LVO

Large vessel occlusion

IVT

Intravenous thrombolysis

SMT

Standard medical therapy

END

Early neurological deterioration

LVSSO

Large vessel severe stenosis or occlusion

mRS

Modified Rankin Scale

sICH

Symptomatic intracranial hemorrhage

ECASS

European Cooperative Acute Stroke Study

RoB2

Risk of bias 2

NOS

Newcastle-Ottawa scale

OR

Odds ratio

CI

Confidence interval

RCT

Randomized controlled trial

DAPT

Dual antiplatelet therapy

TEMPO-2

Tenecteplase versus standard of care for minor ischemic stroke with proven occlusion

ARAMIS

Antiplatelet vs rt-PA for acute mild ischemic stroke

EVT

Endovascular therapy

PRISMA

Systematic reviews and meta-analyses

PROSPERO

Prospective register of systematic reviews

Authors’ contributions

ZL and TZ conceived and designed the study. LX1, RL, and LX2 carried out the literature search and screening of articles for the revised manuscript. MD and HY extracted data. TZ, LX1, and LJ performed the updated data analysis. TZ and LT performed the quality assessment. TZ wrote the first draft of the manuscript. ZL and LT revised the manuscript. All authors read and approved the final manuscript.

Funding

This study was partially supported by grants from the Yantai Science and Technology Plan Project (grant number 2021YD033) and Medical and Health Science and Technology Project of Shandong Province (grant number 202303070650).

Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This systematic review and meta-analysis is based on previously published data. No new data were gathered from human subjects or animals; therefore, ethical approval and informed consent were not required. The review followed the PRISMA guidelines and is registered with PROSPERO (registration number: CRD42025637459).

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.