An investigator-initiated, multicenter, randomized, placebo-controlled, double-blind trial to determine the efficacy and safety of intravenous tenecteplase thrombolysis in acute ischemic stroke (AIS) patients with recent direct oral anticoagulants (DOACs) intake in improving the 90-day functional outcome.
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Inclusion Criteria:
1. Age 18 years or older.
2. Clinically diagnosed with acute ischemic stroke.
3. DOACs intake within 48 hours prior to enrollment, or on an ongoing DOACs therapy but the exact time of last intake is unknown.
* To ensure a representative study population, the investigators will limit the number of patients who took DOACs within 24-48 hours before enrollment or those with unknown last intake time to 50% of the planned sample size. If this number is reached, the inclusion criterion 3 will be modified:
DOACs intake within 24 hours prior to enrollment.
4. Study intervention (IVT or placebo) can be started
1. within 4.5 hours of last known well (LKW). OR
2. within 4.5 to 24 hours of LKW (including wake-up stroke) AND evidence of target mismatch profile on CT perfusion or MR perfusion (ischemic core volume \< 50mL, hypoperfused volume to ischemic core volume ratio \> 1.6, mismatch volume ≥10ml).
* Hypoperfused tissue is defined as Tmax \>6s on CT perfusion or MR perfusion. Ischemic core is defined as rCBF \<30% on CT perfusion or ADC\<620μm\^2/s on diffusion MRI.
5. Baseline National Institutes of Health Stroke Scale (NIHSS) 4-25. OR Disabling stroke with baseline NIHSS of 0-3, including complete hemianopia, aphasia, measurable deficit on motor power, or other disabling neurological deficit judged by the investigator.
6. Written informed consent signed by patients or their legally authorized representatives.
Exclusion Criteria:
1. Intracranial or subarachnoid hemorrhage confirmed by cranial computed tomography (CT) or magnetic resonance imaging (MRI), or any intracranial hemorrhage history.
2. Allergic to tenecteplase.
3. Pre-stroke mRS≥2
4. Planned endovascular treatment.
5. Currently on dual antiplatelet therapy in addition to DOAC therapy.
6. Planned DOAC reversal treatment (including Idarucizumab, Andexanet and tranexamic acid).
7. Hypodensity on non-contrast CT estimates to be ≥ 1/3 MCA territory.
8. Severe head trauma or other severe trauma in the last 3 months.
9. Intracranial tumor, arteriovenous malformation and large-size aneurysm (≥10 mm) found before enrollment.
10. Intracranial surgery, intraspinal surgery or other major surgeries within 3 months before enrollment (based on the assessment of the investigators)
11. Gastrointestinal or urinary system hemorrhage within the past 3 weeks.
12. Active visceral bleeding.
13. Aortic arch dissection confirmed by examination or medical history.
14. Infective endocarditis confirmed by examination or medical history.
15. Platelet count less than 100 × 10\^9 /L.
16. Patients received heparin or low-molecular-weighted heparin treatment within 24h before enrollment.
17. Pregnant or lactating women.
18. Blood glucose \<50 mg/dl (2.78mmol/L) or \>400 mg/dl (22.2mmol/L) during screening.
19. Uncontrolled hypertension with persistent systolic blood pressure \>185 mmHg or diastolic blood pressure \>110 mmHg, refractory to medical management.
20. Life expectancy less than 6 months due to malignancy, severe cardiopulmonary disease, or other terminal illness.
21. Participating in other trials.
22. Other conditions deemed unsuitable for the study by the investigator, such as inability to comprehend or comply with study procedures or follow-up due to mental illness, cognitive or emotional disorder.