Intravenous thrombolysis versus antiplatelet therapy in minor stroke patients with large vessel occlusion

Abstract Aim Our study aimed to explore the effectiveness and safety of intravenous t‐PA compared with dual antiplatelet therapy (DAPT) and aspirin alone for minor stroke with National Institutes of Health Stroke Scale (NIHSS) score ≤5 and large vessel occlusion (LVO). Methods Patients with minor stroke harboring LVO within 4.5‐h time window were included from the Third China National Stroke Registry (CNSR‐III) between August 2015 and March 2018 in China. Clinical outcomes including modified Rankin scale (mRS) score, recurrent stroke, and all‐cause mortality at 90 days and 36‐h symptomatic intracerebral hemorrhage (sICH) were collected. Multivariable logistic regression models and propensity score matching analyses were used to determine the association between treatment groups and clinical outcomes. Results A total of 1401 minor stroke patients with LVO were included. Overall 251 patients (17.9%) received intravenous t‐PA, 722 patients (51.5%) received DAPT, and 428 patients (30.5%) received aspirin alone. The intravenous t‐PA was associated with greater proportions of mRS 0–1 (aspirin versus t‐PA: adjusted odds ratio [aOR], 0.50; 95% confidence interval [CI], 0.32 to 0.80; p = 0.004; DAPT versus t‐PA: aOR, 0.76; 95% CI, 0.49 to 1.19; p = 0.23). Using propensity score matching analyses, the results were similar. There was no difference in 90‐day recurrent stroke among the groups. The rates of all‐cause mortality in intravenous t‐PA, DAPT, and aspirin groups were 0%, 0.55%, 2.34%, respectively. No patient developed sICH within 36 h of intravenous t‐PA. Conclusion In patients with minor stroke harboring LVO within 4.5‐h time window, intravenous t‐PA was associated with higher odds for the excellent functional outcome, as compared with the aspirin alone. Further randomized controlled trials are warranted.


| INTRODUC TI ON
About 30% of patients with minor stroke have a 90-day functional disability. 1 Even though the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) 2

and the
Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) 3 trials have shown early clopidogrel plus aspirin could reduce the risk of 90-day recurrent stoke for minor stroke with NIHSS ≤3 and high-risk TIA with ABCD2 ≥ 4 by 32% and 27%, respectively, minor stroke are still at high risk of short-and long-term poor functional outcomes and recurrent stroke. 4,5 Patients with acute ischemic stroke and large vessel occlusion (LVO) might present with low NIHSS scores, partly due to good collateral status. 6 However, these patients might be at high risk of deterioration. 7,8 The CT And MRI in the Triage of TIA and minor cerebrovascular events to identify High-risk patients (CATCH) study 9 showed that the presence of symptomatic intracranial or extracranial vessel occlusion or stenosis ≥50% was the main predictor for deterioration and once aggravated, even if given a secondary reperfusion therapy (intravenous thrombolysis and/or endovascular treatment), the 90-day functional outcome of these patients was not better than primary reperfusion therapy. 10,11 Up to now, there is limited evidence of thrombolysis for acute minor stroke with LVO. The Potential of rt-PA for Ischemic Strokes with Mild Symptoms (PRISMS) trial was a phase 3, randomized, double-blinded trial which compared intravenous t-PA to aspirin in non-disabling minor ischemic stroke. 12 Nevertheless, the trial was terminated prematurely due to slow enrollment and did not include LVO. The 2019 updated guidelines for the early management of acute ischemic stroke from the American Heart Association/ American Stroke Association 13 and the 2021 European guidelines for intravenous thrombolysis in acute ischemic stroke 14 could not provide evidence-based recommendations. We aimed to compare the clinical effectiveness and safety of minor ischemic stroke with LVO receiving intravenous t-PA, dual antiplatelet treatment (DAPT), and aspirin alone. We hypothesized that intravenous t-PA might be associated with better 90-day functional outcomes than DAPT or aspirin alone in minor ischemic stroke with LVO.

| ME THODS
The CNSR-III, designed to establish the etiology, imaging, and biology markers for clarifying the pathogenesis and prognostic factors of ischemic stroke, was a nationwide prospective registry for patients presented to hospitals with acute ischemic stroke (AIS) and transient ischemic attack (TIA) between August 2015 and March 2018 in China. All patients with age older than 18 years fulfilling the criteria of diagnosis of AIS or TIA within 7 days were consecutively enrolled. Trained research coordinators utilized an electronic data capture system to collect data and paper-based case report forms were recorded if an electronic data capture system was not available. Independent contract research organization monitored the data independently throughout the study. All data were deidentified before data analysis. The detailed design, rationale, and basic description of the CNSR-III have been published previously. 15 The study was approved by the Institutional Review Board and informed consent from patient or legally authorized representative was required. Aspirin (a dose of 100 mg per day) was given within 24 h after symptom onset. DAPT was defined as aspirin plus clopidogrel (aspirin at a dose of 100 mg per day, plus clopidogrel at an initial dose of 75 mg or 300 mg, followed by 75 mg per day) within 24 h after symptom onset.

| Study population
Intravenous t-PA (0.9 mg/kg to a maximum dose of 90 mg, with 10% as initial bolus and the remainder over 1 h intravenous infusion) was administered within 4.5-h time window. The exclusion criteria were (1) admission diagnosis of TIA and (2) endovascular therapy including arterial thrombolysis and mechanical thrombectomy. We classified the included patients into disabling and non-disabling stroke group in the further subgroup analysis. Disabling stroke was defined as complete hemianopsia (≥2 on the NIHSS Question #3), or severe aphasia (≥2 on NIHSS Question #9), or visual or sensory extinction (≥1 on NIHSS Question #11), or any weakness limiting sustained effort against gravity (≥2 on NIHSS Question #6 or #7) or any consciousness disorder (≥1 on NIHSS Question #1a). 16

| Data collection and definitions
Patients were divided into intravenous t-PA, DAPT, and aspirin alone groups based on their firstly initiated treatment. We extracted the following variables: demographics (including age, sex, and weight), medical history (including current smoking, hypertension, diabetes mellitus, dyslipidemia, coronary heart disease/myocardial infarction, atrial fibrillation, prior TIA, prior stroke), prior mRS (range, 0 to 6, with lower scores indicating better functional status), medication history (including antiplatelet, anticoagulant, and lipid-lowering agents), baseline random blood glucose, baseline systolic blood pressure, baseline diastolic blood pressure, stroke severity (measured by NIHSS, range, 0 to 42, with higher scores indicating severe stroke, including the score of subitems), onset to treatment time, etc. Etiology classification of ischemic stroke was based on an expanded version of the TOAST (Trial of Org 10,172 in Acute Stroke Treatment) classification. 17

| Assessments
The primary outcome was an excellent functional outcome which was defined as mRS score of 0-1 at 90 days. The secondary outcomes included favorable functional outcome (defined as mRS score of 0-2 at 90 days), recurrent stroke at 90 days, recurrent ischemic stroke at 90 days, and all-cause mortality at 90 days. The safety outcomes included rates of (1) symptomatic intracerebral hemorrhage

| Statistical analyses
The data were tested for normal distribution using the Kolmogorov-Smirnov test. Continuous variables were summarized as mean ± standard deviation (SD) if the distribution was normal or as median with interquartile range (IQR) otherwise, and differences were assessed using the ANOVA test whether normally distributed or non-parametric test. Categorical variables were presented as frequencies with percentages, and the 2 test was used to compare the distributions between groups. Clinical outcomes (mRS 0-1, mRS 0-2, recurrent stroke, recurrent ischemic stroke and all-cause mortality) were compared using a multivariable logistic regression after adjusting for confounding factors that were significant at the p < 0.1 level in the univariate analysis. To test the robustness of our results, subgroup analyses in disabling or not, NIHSS 0-2 and NIHSS 3-5 were further performed using the same statistical methods. Additional propensity score matching (PSM) analyses were performed to balance the baseline characteristics in the whole cohort, and symptomatic LVO, separately. And 1:1 matching was performed based on the nearest-neighbor matching algorithm with a caliper width of 0.25. Two-sided p < 0.05 was considered statistically significant. All analyses were performed using the SAS, version 9.4, software (SAS Institute, Cary, NC, USA).

| Patient flowchart
A total of 1401 patients with minor stroke (NIHSS ≤5) and LVO within 4.5-h time window were included for subsequent analysis and in Figure 1

| Baseline characteristics
The baseline characteristics of the 1401 patients are described in Table 1. The medium onset to needle time was 2.9 h (interquar-

| Functional outcome
Our analysis showed that the proportion of excellent functional outcome was significantly higher in intravenous t-PA group (86.80%  Table 2). The results were consistent with those using PSM analysis (Tables S1-S4).

| Recurrent stroke
There was no statistical difference in 90-day recurrent stroke among three groups (

| All-cause mortality
There were 4 patients (0.55%) died at 90 days in the DAPT group, 10 (2.34%) in the aspirin group, and none in the intravenous t-PA group (Table 2).

| Hemorrhagic events
The hemorrhagic safety outcomes are shown in

| Subgroup analysis of disabling versus nondisabling stroke
In non-disabling subgroup, patients treated with intravenous t-PA were associated with higher odds for excellent and favorable functional outcomes compared with patients with aspirin alone (aspirin versus intravenous t-PA; aOR, 0.44; 95% CI, 0.25 to 0.77; p = 0.004; aOR, 0.35; 95% CI, 0.14 to 0.87; p = 0.02, respectively) (Table 3, Figure 2). The recurrent stroke and recurrent ischemic stroke were not significantly different among the three groups ( Figure 2). In disabling subgroup, the excellent functional outcome, favorable functional outcome, recurrent stroke, and recurrent ischemic stroke were not significantly different among the three groups ( Figure 2).

| Subgroup analysis of baseline NIHSS of 0-2 versus NIHSS of 3-5
In baseline NIHSS score of 3 to 5 subgroups, patients treated with intravenous t-PA were associated with higher odds for excellent functional outcome compared with patients with aspirin alone (aspirin versus intravenous t-PA; 70.56% vs. 83.33%; aOR, 0.53; 95%     CI, 0.29 to 0.96; p = 0.04) ( Table 3, Figure 2). The favorable functional outcome, recurrent stroke, and recurrent ischemic stroke were not significantly different among the three groups ( Figure 2).
In baseline NIHSS score of 0 to 2 subgroups, although both the rates  Figure 2). The recurrent stroke and recurrent ischemic stroke were not significantly different among the three groups ( Figure 2).

| Symptomatic LVO
In the subgroup of symptomatic LVO, the proportions of 90-day mRS score of 0 to 1 in intravenous t-PA, DAPT, and aspirin groups  (Tables S6 and S7). Using PSM analysis, the results were similar (Tables S8-S11).

| Asymptomatic LVO
In the subgroup of asymptomatic LVO, the rates of 90-day mRS score of 0 to 1 in intravenous t-PA, DAPT, and aspirin groups were

| DISCUSS ION
Our study found that intravenous t-PA with minor stroke and LVO was better than aspirin, but similar to DAPT for achieving 90-day ex- outcomes. 22 Up to now, head-to-head comparisons between thrombolytic drugs and antiplatelet agents are also lacking. Some ongoing trials such as Antiplatelet vs R-tPA for Acute Mild Ischemic Stroke (ARAMIS) (NCT03661411) and TEMPO-2 (NCT02398656) will provide more evidence.
In the present analysis, there was no 36-h sICH and severe systemic bleeding in the intravenous t-PA group. Although the safety outcomes among the three groups were incomparable, the risk of hemorrhagic events in our patients who received intravenous t-PA was consistent with previous studies (0% to 5%). 12,[22][23][24] In subgroup analysis, the effect of intravenous t-PA was statistically more pronounced in the non-disabling than in disabling subgroup. This is in contrast to the PRISMS trial which indicated that alteplase was not superior to the aspirin in improving functional outcomes in non-disabling minor stroke. 12  It showed that patients with such characteristics could benefit from intravenous alteplase. In the study, minor non-disabling stroke was defined as patients with baseline NIHSS score ≤5 and a score of 0 or 1 on each baseline NIHSS score item (items 1a to 1c being 0). 25 However, these findings need to be verified in future randomized trials. We did not find a significant association between intravenous t-PA and excellent outcome in disabling subgroup. One possible explanation for this result is the small sample size in disabling subgroup.
According to the current rates of excellent outcome in disabling sub- bleeding in the DAPT and aspirin group were missing in our registry, making it difficult to compare the key safety outcome of these strategies. Fourth, imaging evaluation was not standardized in our study, LVO was detected by either MRA, CTA, or DSA, and the imaging to onset time was about 1 day, which means some patients with t-PA may have LVO imaging screening after t-PA usage, so we may miss those recanalized patients after t-PA. Therefore, our study only included patients with t-PA and LVO may underestimate the effectiveness of t-PA. However, it will not change our findings that t-PA is better than aspirin. Whether t-PA is superior to DAPT is still waiting for further investigations. In addition, due to inadequate drug compliance, there was a certain rate in patients with discontinuation of antiplatelet therapy during follow-up. Our study is only exploratory analysis based on the registry cohort, and the results need to be verified in other multicenter prospective cohorts, preferably randomized controlled trials.

| CON CLUS ION
Minor stroke harboring LVO receiving intravenous t-PA, as compared with aspirin monotherapy, is associated with higher odds for 90-day excellent functional outcome. Further randomized controlled trials are needed.

ACK N OWLED G M ENTS
We thank all the participating centers in the CNSR-III program for their hard work on data collection.