Introduction

Current guidelines recommend intravenous alteplase is the standard of care for the treatment of acute ischemic stroke (AIS) within 4.5 h of symptom onset1,2,3. Approximately 50% of AIS cases are classified as minor stroke, defined by a National Institutes of Health Stroke Scale (NIHSS) score of ≤ 54,5. However, recent study have demonstrated that dual antiplatelet therapy (DAPT) may be noninferior to intravenous alteplase in terms of excellent functional outcome at 90 days for patients with minor stroke, but early neurological deterioration and bleeding incident occurred in the alteplase group were high than DAPT6.

Tenecteplase is a genetically modified version of alteplase with higher fibrin specificity, greater resistance to inactivation of fibrinogen activator inhibitor-1, and longer half-life that permits quick bolus delivery. Currently, It has already become the standard intravenous thrombolysis for eligible patients with ST-elevation myocardial infarction and has shown promising results in AIS7,8,9. Authors of several cohort studies have showed a higher incidence of reperfusion at 24 h and better clinical outcomes with tenecteplase than with alteplase in AIS patients10,11. Therefore, American Heart Association/American Stroke Association, the European Stroke Organization, and the Australian and New Zealand Living Stroke Guidelines have endorsed tenecteplase as an alternative to alteplase for AIS2,8,12. Furthermore, a large-scale prospective observational study also found that tenecteplase was associated with a lower risk of systemic bleeding complications compared to alteplase8.

In this study, we aim to assess the risk of systemic bleeding complications associated with tenecteplase compared to DAPT for patients with minor nondisabling AIS. We hypothesized that Tenecteplase will be associated with lower risk of systemic bleeding complications than DAPT in this patient population.

Methods

Patient and study design

The data were obtained from the prospective registry of our stroke database. All consecutive patients with minor nondisabling AIS who treated by DAPT or tenecteplase between January 2020 and June 2023 were enrolled if meeting these inclusion criteria: (1) age ≥ 18 years; (2) National Institutes of Health Stroke Scale (NIHSS)( range, 0 to 42; higher scores indicate greater stroke severity) score ≤ 5, with less than or equal to 1 point on single-item scores, such as vision, language, neglect, or single limb weakness, and a score of 0 in the consciousness item; (3) computed tomography(CT) or magnetic resonance imaging (MRI) was performed on admission to identify ischemic stroke; and (4) receiving study treatment within 4.5 h of stroke symptoms. Exclusion criteria included: (1) pre- stroke disability (modified Rankin Scale [mRS] score (range, 0 [no symptoms] to 6 [death]), ) ≥ 2; (2) history of intracerebral hemorrhage; (3) definite indication for anticoagulation.

The following data were also collected: patient’s demographics, comorbidities, risk factors of stroke, symptom onset of stroke, NIHSS, mRS, treated with intravenous thrombolysis (IVT) or DAPT, time from onset-to-needle (OTN), time from door-to-needle (DTN), clinical outcomes such as mRS after 90 days, symptomatic intracerebral hemorrhage (sICH), and any bleeding events.

The study adhered to the ethical guidelines of the Declaration of Helsinki and received approval from the Ethics Committee of Zhejiang Provincial People’s Hospital (Approval No. KY2017019). Due to the study’s retrospective nature, the Ethics Committee of Zhejiang Provincial People’s Hospital waived the requirement to obtain informed consent.

Outcomes

The primary outcome was an excellent functional outcome, defined as a modified Rankin Scale (mRS) score of 0 to 1 at 90 days. Secondary outcomes were included a favorable functional outcome (mRS score of 0 to 2) at 90 days and length of hospital stay. Safety outcomes included symptomatic intracerebral hemorrhage (sICH) and any bleeding events during the study period. sICH was defined as the presence of hemorrhage on a head CT scan, accompanied by neurological deterioration (≥ 4-point increase in NIHSS). Major bleeding was defined as the need for a transfusion of two or more units of blood or a decrease in hemoglobin of ≥ 2 g/dL and without life-threatening. Other cases of bleeding were classified as minor, such as gingival bleeding, etc13.

Statistical analysis

Baseline characteristics and clinical outcomes were compared hierarchically based on ‘Tenecteplase’ or ‘DAPT’ thrombus surface phenotype. The results were presented as frequency, mean ± standard deviation (SD), or median (interquartile range, IQR). The overall sample used Pearson’s χ2-test or Fisher’s exact test for categorical variables. In contrast, the Student’s t-test or Mann Whitney U test (for non-Gaussian distributions) is used for continuous variables comparison. P < 0.05 was considered statistically significant. All statistical analyses were conducted using SPSS Statistics (Version 25), and graphical presentations were created using GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA).

Results

Demographics and clinical characteristics

Between January 2020 and June 2023, a total of 156 patients were screened, and 62 patients were enrolled into this study. Patient selection process is shown in Fig. 1. Baseline characteristics of patients were shown in Table 1. We categorized the patients into DAPT group and tenecteplase group. The median (IQR) age was 66 years (IQR 58–76), and 21 patients (34%) were female. Thirty-one patients (50%) received tenecteplase, and 31 (50%) were treated with DAPT. Compared to the DAPT group, patients treated with tenecteplase were lower rates of hypertension (19/31 [61.3%] vs. 26/31 [83.9%], P = 0.04), had lower INR at treatment (median [IQR], 0.97 [0.92–1.00] vs. 1.01 [0.98–1.07]; P = 0.01), had lower systolic blood pressure at treatment (median [IQR], 159 [128–189] vs. 167 [144–193]; P = 0.03), had higher NIHSS score at treatment (median [IQR], 4 [2–5] vs. 1 [1–2]; P = 0.01).

Fig. 1
figure 1

Flow chart of patient selection.

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Table 1 Characteristics of study participants.
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Primary and secondary outcomes

For the primary outcome, the proportion of patients with mRS scores of 0 or 1 at 90d was 74.2% (23/31) in the DAPT group and 71.0% (22/31) in the tenecteplase group. There were no differences in the rate of mRS score 0–1 at 90d between DAPT group and tenecteplase group (P = 0.78). No significant differences were observed between the groups for the secondary outcomes, including mRS scores of 0–2 at 90 days (96.8% [30/31] vs. 90.3% [28/31], P = 0.31) and length of hospital stay (median [IQR], 7 [6–10] vs. 8 [6–12], P = 0.7) (Table 2; Fig. 2).

Table 2 Clinic outcomes of included patients.
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Fig. 2
figure 2

Distribution of Modified Rankin Scale Scores at 90 days.

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Safety outcomes

In the tenecteplase group, one patient experienced sICH, and eight experienced other bleeding events, while none in the DAPT group had sICH, and only one patient experienced a minor bleeding event. Neither group of patients had major bleeding events. There were differences in the rate of the minor bleeding events between DAPT group and tenecteplase group (3.2% [1/31] vs. 25.8% [8/31], P = 0.01) (Table 2; Fig. 3).

Fig. 3
figure 3

Rates of symptomatic intracerebral hemorrhage and any bleeding events.

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Discussion

In this study, we found that among patients with minor nondisabling acute ischemic stroke (AIS) treated within 4.5 h of symptom onset, intravenous tenecteplase was comparable to dual antiplatelet therapy (DAPT) in achieving excellent functional outcomes (modified Rankin Scale [mRS] 0–1) at 90 days. Secondary outcomes, including favorable functional outcomes (mRS 0–2) and hospital length of stay, also showed no statistically significant differences between the two treatment groups. However, patients receiving tenecteplase experienced a higher incidence of bleeding events compared to those on DAPT.

Tenecteplase is a genetically modified alteplase. Three variants of the alteplase molecule enhance its specificity to fibronectin 15-fold, resistance to fibrinogen activator inhibitors 80-fold, and prolonged its half-life9. Authors of several cohort studies have reported that tenecteplase, as an intravenous thrombolytic agent, at a dose of 0.25 mg/kg was similar to alteplase in all patients with AIS within 4.5 h of symptom onset14,15. Additionally, Bala et al. showed that in patients presenting with LVO who were candidates for endovascular therapy (EVT), tenecteplase also showed similar safety and efficacy compared to alteplase16. The CERTAIN trial further highlighted that tenecteplase was associated with a lower risk of sICH than alteplase8.

Our findings align with but also differ from previous clinical trials that explored the role of intravenous thrombolysis in minor stroke. The PRISMS trial, which compared alteplase with single antiplatelet therapy in patients with acute minor ischemic stroke, concluded that alteplase did not provide additional benefit over antiplatelet therapy and raised concerns about bleeding risks17. But IST-3 randomized trial showed that the superiority of intravenous alteplase compared with standard medical therapy for patients with minor ischemic stroke18. Therefore, it may be challenging for stroke physicians to decide whether to treat intravenous alteplase in patients with minor nondisabling stroke within 4.5 h of symptom onset. For addressing this challenge, the ARAMIS study was designed with a strategy that differed from that of the PRISMS study. Aspirin plus clopidogrel (300 mg loading dose) was administered for 12 ± 2 days, followed by guideline-based antiplatelet treatment until 90 days in ARAMIS study. The strategy of DAPT was based on the CHANCE and POINT studies, which found the superiority of DAPT to aspirin alone in minor acute stroke19,20. But there was more early neurological deterioration (9.1%), more risk of sICH and bleeding events in the alteplase group compared with DAPT6.

This trail was the first study to attempt to address how to choose DAPT and tenecteplase for patients with acute minor nondisabling AIS within 4.5 h of symptom onset. While the proportion of patients achieving excellent functional outcome (78.2% vs. 71.0%) was lower than that achieved in the ARAMIS study (91.5% vs. 93.7%), which might partially be attributed to differing comorbidities, or vascular risk factor profile. However, the percentage of patients with good functional outcome (96.8% vs. 90.3%) was similar to ARAMIS study (95.9% vs. 95.4%).

In terms of safety, our results indicate a higher risk of sICH and a significantly greater number of bleeding events in the tenecteplase group compared to DAPT. These findings emphasize the importance of weighing the benefits of thrombolysis with tenecteplase against the potential bleeding risks, particularly in patients with minor nondisabling AIS.

Limitations

This study had several limitations. (1) The retrospective nature of the study and the relatively small number of patients is one of the most important aspects limiting the clinical significance of the current results. Therefore, the results should be interpreted with caution. (2) Our study was performed at a single Asian institution, and the population-specific experience may not be generalizable globally. (3) Only patients treated within 4.5 h from stroke symptom onset were included, so our results may not be generalizable to patients treated outside this window.

Conclusions

In summary, the findings in this study showed that patients presenting with minor nondisabling AIS within 4.5 h of symptom onset, dual antiplatelet treatment was similar to intravenous tenecteplase with regard to excellent functional outcome at 90 days. However, more proportion of patients with bleeding events treated with tenecteplase.